Dissertations / Theses: 'In vivo Electrophysiology'

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Kodandaramaiah, Suhasa Bangalore. "Robotics for in vivo whole cell patch clamping." Diss., Georgia Institute of Technology, 2012. http://hdl.handle.net/1853/51932.

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Whole-cell patch clamp electrophysiology of neurons in vivo enables the recording of electrical events in cells with great precision, and supports a wide diversity of morphological and molecular analysis experiments important for the understanding of single-cell and network functions in the intact brain. However, high levels of skill are required in order to perform in vivo patching, and the process is time-consuming and painstaking. Robotic systems for in vivo patching would not only empower a great number of neuroscientists to perform such experiments, but would also open up fundamentally new kinds of experiment enabled by the resultant high throughput and scalability. We discovered that in vivo blind whole cell patch clamp electrophysiology could be implemented as a straightforward algorithm and developed an automated robotic system that was capable of performing this algorithm. We validated the performance of the robot in both the cortex and hippocampus of anesthetized mice. The robot achieves yields, cell recording qualities, and operational speeds that are comparable to, or exceed, those of experienced human investigators. Building upon this framework, we developed a multichannel version of “autopatcher” robot capable establishing whole cell patch clamp recordings from pairs and triplets of neurons in the cortex simultaneously. These algorithms can be generalized to control arbitrarily large number of electrodes and the high yield, throughput and automation of complex set of tasks results in a practical solution for conducting patch clamp recordings in potentially dozens of interconnected neurons in vivo.

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Suk, Ho-Jun. "Automated cell-targeted electrophysiology in vivo and non-invasive gamma frequency entrainment." Thesis, Massachusetts Institute of Technology, 2019. https://hdl.handle.net/1721.1/122429.

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Thesis: Ph. D., Harvard-MIT Program in Health Sciences and Technology, 2019
Cataloged from student-submitted PDF version of thesis.
Includes bibliographical references (pages 105-110).
Targeted patch clamp recording is a powerful method for characterizing visually identified cells in intact neural circuits, but it requires skill to perform. We found that a closed-loop real-time imaging strategy, which continuously compensates for cell movement while approaching the cell with a pipette tip, allows for the development of an algorithm amenable to automation. We built a robotic system that can implement this algorithm and validated that our system can automatically patch fluorophore-expressing neurons of multiple types in the living mouse cortex, with yields comparable to skilled human experimenters. By facilitating targeted patch clamp recordings in vivo, our robot may enable scalable characterization of identified cell types in intact neural circuits. Activities of individual neurons in neural circuits give rise to network oscillations, whose frequencies are closely related to specific brain states.
For example, network oscillations in the 30 - 90 Hz range, observed using electroencephalogram (EEG), are called gamma oscillations and increase during attention, memory formation, and recall. In Alzheimer's disease (AD), gamma oscillations are disrupted compared to healthy individuals. Recently, noninvasive visual and auditory stimulations at 40 Hz, called Gamma ENtrainment Using Sensory stimulus ("GENUS"), have been shown to positively impact pathology and improve memory in AD mouse models, with concurrent visual and auditory GENUS leading to a more widespread effect in the AD mouse brain compared to visual or auditory stimulation alone. However, it is unclear what effect such sensory stimulations would have on the human brain. To test for the safety and feasibility of GENUS in humans, we developed a device that can deliver 40 Hz light and sound stimulations at intensity levels tolerable to humans.
We found that our device can safely lead to steady 40 Hz entrainment in cognitively normal young (20 - 33 years old) and older (55 - 75 years old) subjects, with concurrent visual and auditory stimulation leading to stronger and more widespread entrainment than visual or auditory stimulation alone. These findings suggest that GENUS can be a safe and effective method for widespread 40 Hz entrainment, which may have therapeutic effects in people suffering from AD.
by Ho-Jun Suk.
Ph. D.
Ph.D. Harvard-MIT Program in Health Sciences and Technology

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Crnic, Agnes. "Effects of Acute and Sustained Administration of Vilazodone (EMD68843) on Monoaminergic Systems: An In Vivo Electrophysiological Study." Thesis, Université d'Ottawa / University of Ottawa, 2014. http://hdl.handle.net/10393/31498.

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Vilazodone is a partial 5-HT1A receptor agonist and a selective serotonin reuptake inhibitor (SSRI). Acute administration caused a dose-dependent decrease in dorsal raphe (DR) serotonin (5-HT) neuron firing rates. Vilazodone significantly decreased DR 5-HT neuronal firing following 2-day administration, which was shown to recover completely after 14-day administration. The 2-day administration of vilazodone significantly decreased firing in ventral tegmental area dopamine neurons; this effect persisted after 14-day treatment. The firing rate of norepinephrine neurons in the locus coeruleus was not significantly altered following 2-day treatment but did decrease following 14-day treatment. In the hippocampus, 14-day treatment with vilazodone significantly enhanced tonic activation, while having no effect on 5-HT reuptake. Vilazodone produced effects similar to conventional SSRIs while also inducing alterations in monoaminergic neurons that may be associated with its 5-HT1A properties and may have a role in the field of treatment resistant depression.

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Parent, Katherine L., and Katherine L. Parent. "Probing Neural Communication by Expanding In Vivo Electrochemical and Electrophysiological Measurements." Diss., The University of Arizona, 2017. http://hdl.handle.net/10150/626155.

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Neural communication is imperative for physical and mental health. Dysfunction in either ionic signaling or chemical neurotransmission can cause debilitating disorders. Thus, study of neurotransmission is critical not only to answer important fundamental questions regarding learning, decision making, and behavior but also to gain information that can provide insight into the neurochemistry of neurological disorders and lead to improved treatments. The work presented herein describes the development of techniques and instrumentation to enable advancements in neuroscientific inquiry. The effect of different temporal patterns and durations of simulation of the prefrontal cortex on dopamine release in the nucleus accumbens was examined and revealed a complex interaction that can help improve deep brain stimulation therapies. A measurement platform that combines electrophysiological and electrochemical techniques is described. The instrumentation is capable of concurrent monitoring of neural activity and dopamine release in vivo and in freely moving rodents. Analysis techniques to allow absolute quantification of tonic dopamine concentrations in vivo are detailed and the temporal resolution of the technique was vastly improved from ten minutes to forty seconds. An instrument that can simultaneously probe both dopamine and serotonin dynamics in either of their two temporal modes of signaling (tonic and phasic) using either fast-scan cyclic voltammetry or fast-scan controlled-adsorption voltammetry at two individually addressable microelectrodes is described. Together these new tools represent a significant step forward in the field of neuroanalytical chemistry by enable multiple brain regions, signaling modes (ionic flux in addition to both tonic and phasic neurotransmission), neurochemicals, and to be measured together.

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Pitcher, Toni Leigh, and n/a. "In vivo electrophysiology of striatal spiny projection neurons in the spontaneously hypertensive rat (SHR)." University of Otago. Department of Anatomy & Structural Biology, 2007. http://adt.otago.ac.nz./public/adt-NZDU20070321.114819.

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The aim of this thesis was to investigate neuronal cellular mechanisms that may underlie the behavioural characteristics of the spontaneously hypertensive rat strain (SHR). The SHR was developed by selective breeding for elevated blood pressure and is also described as having increased levels of locomotor behaviour compared to its normotensive control strain, the Wistar-Kyoto. This hyperactivity and other behaviours, including altered sensitivity to reinforcement, have been used to model aspects of behaviour displayed in attention deficit hyperactivity disorder. In vivo intracellular recording of striatal spiny projection neuron activity in urethaneanaesthetised animals from three genetically related strains: the SHR, Wistar-Kyoto and standard Wistar, was employed to measure basic cellular properties and cellular mechanisms of reward-related learning. This population of neurons was chosen because alterations in their activity can influence behaviour and they are known to show cellular changes (synaptic plasticity) that are associated with learning. Cellular properties were measured in 71 neurons. Comparison between strains revealed a significant difference in action potential amplitude and duration between the SHR and Wistar-Kyoto strains. Interestingly, when measured at a later time, in a different sample of rats, the SUR action potential amplitude and duration were significantly different from the earlier sample. A change in the membrane potential repolarisation rate following action potential firing also occurred over this time. Twenty-nine of these neurons were also used in a study investigating the neuronal responses to a low dose of amphetamine (0.5 mg/kg). Changes were observed in some cellular properties following intraperitoneal administration of amphetamine. Synaptic plasticity at the corticostriatal synapses is sensitive to the timing of dopamine release in relation to cortical input. In anaesthetised preparations the spiny projection neuron membrane potential fluctuates between hyperpolarised (DOWN) and depolarised (UP) states, which reflect the level of cortical input. During the present study the responses of nine neurons to the induction of cortical spreading depression were observed to investigate the suitability of this method for use during synaptic plasticity experiments. Spiny projection neurons showed unpredictable responses to cortical spreading depression, therefore this method was not used further. Corticostriatal synaptic plasticity was induced in sixteen spiny projection neurons from two strains: SHR and Wistar. High frequency stimulation of the dopamine neurons in the substantia nigra, during the DOWN-state, did not induce any significant changes in corticostriatal synaptic efficacy. This was also true when high frequency stimulation of dopamine neurons was applied during the UP-state in neurons from the SHR strain. This thesis represents the first in vivo intracellular study of neuronal physiology in the SHR and Wistar-Kyoto rat strains. Results revealed action potential differences between these two behaviourally distinct rat strains. Synaptic mechanisms thought to underlie reward-related learning were not different between the SHR and Wistar strains, although the observed levels of plasticity were inconsistent with previous literature.

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Malezieux, Meryl. "Dynamique intracellulaire des cellules pyramidales de CA3 dans l'hippocampe pendant les états de veille." Thesis, Bordeaux, 2018. http://www.theses.fr/2018BORD0317/document.

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Les états de veille sont composés d’états cérébraux distincts, corrélés avec différents comportements et caractérisés par des oscillations spécifiques observables dans le potentiel de champ local (Local Field Potential, LFP). Bien que les différents états cérébraux et leur signature dans le LFP aient été caractérisés, les mécanismes cellulaires sous-jacents restent à ce jour peu connus. Des changements des propriétés de neurones uniques seraient corrélés avec, et pourraient participer à la génération de ces changements d’états cérébraux. L’activité coordonnée et synchronisée de neurones facilite certains processus cognitifs tels que la mémoire. L’hippocampe joue un rôle essentiel dans les mémoires spatiale et épisodique, et dans l’hippocampe, CA3 est important pour la formation d’associations facilitant l’encodage rapide de la mémoire. De plus, les informations provenant du cortex entorhinal, du gyrus denté, et de CA3 même sont comparées et intégrées dans CA3 avant d’être transmises à CA1. Lors de périodes de repos, le LFP hippocampique présente une activité large et irrégulière (Large Irregular Activity, LIA), ponctuée par des oscillations plus rapides, les sharp-wave ripples, jouant un rôle dans la consolidation de la mémoire. Lors de périodes exploratoires, le LFP hippocampique oscille aux fréquences theta (6-12 Hz) et gamma (30-100 Hz). Les cellules pyramidales (CP) de CA3 jouent un rôle important dans chacun de ces états ; elles sont nécessaires pour les sharp wave lors de périodes de repos, et les oscillations gamma lors de comportements exploratoires. Dans le but d’étudier les modulations intracellulaires des CP de CA3, nous avons réalisé des enregistrements de patch-clamp en configuration cellule entière chez l’animal éveillé. Nous avons associé ces enregistrements avec des mesures du diamètre pupillaire et de la vitesse de locomotion de l’animal, ainsi qu’avec l’enregistrement de l’activité oscillatoire du LFP dans l’hippocampe. Nos résultats montrent que certaines CP de CA3 sont sensibles à la modulation intracellulaire lors de différents rythmes hippocampiques, et ont tendance à diminuer leur potentiel de membrane moyen, leur excitabilité, leur variance et leur décharge de potentiel d’action lors des oscillations theta par rapport aux périodes de LIA. De futures études permettront de déterminer si ces changements sont dus à des changements d’entrées synaptiques et/ou de neuromodulateurs. Ces modulations pourraient jouer un rôle dans l’émergence des rythmes oscillatoires du LFP, et permettre à CA3 de réaliser différentes fonctions mnésiques à différents moments
Wakefulness is comprised of distinct brain states, correlated with different behaviors and characterized by specific oscillatory patterns in the local field potential (LFP). While much work has characterized different brain states and their LFP signatures, the underlying cellular mechanisms are less known. Changes in single cell properties are thought to correlate with and possibly result in these changes in brain state. Synchronized and coordinated activity among distributed neurons supports cognitive processes such as memory. The hippocampus is essential for spatial and episodic memory, and within the hippocampus, area CA3 is important for rapid encoding of one-trial memory. Additionally, CA3 is the site where information from the entorhinal cortex, dentate gyrus, and CA3 itself is compared and integrated before output to CA1. During quiet wakefulness, the hippocampal LFP displays large irregular activity (LIA) punctuated by sharp-wave ripples, which play a role in memory consolidation. During exploratory behaviors, hippocampal LFP oscillates at both theta and gamma frequencies. CA3 pyramidal cells (PCs) play an important role in each of these brain states; they are necessary for both sharp waves during quiet wakefulness and for gamma oscillations during exploratory behavior. We explored the changes that occur in the intracellular dynamics of CA3 PCs during changes in brain state, by using whole-cell patch-clamp recordings from CA3 PCs in awake head-fixed mice. We combined those recordings with measurements of pupil diameter, treadmill running speed and LFP recordings of oscillatory activity. Our findings show that some CA3 PCs are prone to intracellular modulation during brain rhythms, and tend to decrease their average membrane potential, excitability, variance and output firing during theta as compared to LIA. Future studies will demonstrate whether these effects are due to changes in synaptic and/or neuromodulatory inputs. This modulation at the single-cell level in CA3 could play a role in the emergence of oscillations, and underlie the ability of CA3 to perform different memory functions during different brain states

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Pollnow, Stefan [Verfasser], and Olaf [Akademischer Betreuer] Dössel. "Characterizing Cardiac Electrophysiology during Radiofrequency Ablation : An Integrative Ex vivo, In silico, and In vivo Approach / Stefan Pollnow ; Betreuer: Olaf Dössel." Karlsruhe : KIT Scientific Publishing, 2019. http://d-nb.info/1186145404/34.

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Shim, Stacey. "Alterations of the Monoaminergic Systems in the Rat Brain by Sustained Administration of Carisbamate and Lamotrigine." Thèse, Université d'Ottawa / University of Ottawa, 2012. http://hdl.handle.net/10393/23478.

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Carisbamate (CRS) and lamotrigine (LTG) are anticonvulsants which act mainly on neuronal voltage-gated sodium channels, that have been shown to have antidepressant-like effects in animal models of depression. In vivo electrophysiological recordings were carried out following 2 and 14 days of CRS or LTG administration. Overall firing activity in the dorsal raphe, locus coeruleus and ventral tegmental area were decreased with CRS. Similarly, a decrease in the dorsal raphe was also observed with LTG. Despite these presynaptic decreases in firing activity, both anticonvulsants exhibited significant enhancement of serotonergic transmission in the hippocampus as demonstrated by increased tonic activation of postsynaptic 5-HT1A receptors. This may be attributed to the observed desensitization of the terminal 5-HT1B autoreceptors. This study suggests that the enhanced serotonergic effect may be associated with an antiglutamatergic effect, and may contribute to the antidepressant-like effect of CRS in the forced swim test and the antidepressant properties of LTG.

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Klimas, Aleksandra. "High-Throughput All-Optical Cardiac Electrophysiology| Design, Validation, and Applications in vitro and in vivo." Thesis, The George Washington University, 2018. http://pqdtopen.proquest.com/#viewpdf?dispub=10621781.

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Biological systems are inherently dynamic, requiring active interrogation and recording to provide a full understanding of their underlying mechanics. In order to fully characterize such a system, both readily quantifiable signals as well as a means of dynamic control are necessary. In the heart, the propagation of electrical waves driving contraction are mediated by the flow of ions through various ion channels working in concert to drive de- and re-polarization of the cell membrane. Typically, the culprit of electrical dysfunction in the heart is due to some disruption of normal function of one or more of these ion channels. In order to study these complex electrical disturbances, known as arrhythmias, high spatiotemporal resolution imaging and interrogation are necessary.

Traditional methods of interrogation have relied on the use of electrodes and patch clamp methods, which are inherently low throughput and have limited spatial resolution. Additionally, these approaches do not lend well for in vivo use. While studies of cardiac tissue have also employed optical mapping techniques where voltage- or calcium-sensitive fluorescent reporters provide detailed information about cell activation, repolarization, and wave propagation maps, stimulation has remained primarily limited to electrical means. However, recently developed optogenetic tools provide a means of high-spatiotemporal resolution (and potentially tissue-type specific) means of interrogation. By combining both of these methods, high-spatiotemporal dynamic characterization of cardiac electrophysiology can be achieved.

Here we present how all-optical approaches can be achieved via employing optogenetics in order to explore cardiac electrophysiology at the in vitro as well as in vivo scale. The main optical design is first implemented for in vitro use, where we demonstrate how OptoDyCE, our all-optical dynamic cardiac electrophysiology platform, can be used to screen drug effects in both isolated primary myocytes and human induced pluripotent stem-cell derived cardiomyocytes (hiPSC-CMs) grown in monolayers and 3D tissue constructs. We then characterize an upgraded version of OptoDyCE, capable of simultaneous imaging of membrane voltage and intracellular calcium signals. The system is used for screening of 12 blinded compounds to demonstrate how the platform can used for pro-arrhythmia prediction at the high-throughput (HT) scale. All compounds were properly identified as ‘safe’ or ‘unsafe’ using the multi-parameter endpoints, made possible with high-spatiotemporal resolution recordings under spontaneous and paced conditions. To further demonstrate how all-optical approaches improve proarrhythmia prediction, we tested vanoxerine, a compound that failed Phase III clinical trials, and demonstrate OptoDyCE’s ability to easily identify the compound as pro-arrhythmic, unlike techniques employing patch clamp and in silico modeling that deemed the compound safe for use in humans. As hiPSC-CMs provide a novel testbed for drug testing and disease modeling, we then use OptoDyCE to characterize these cells, both in terms of their potential immaturity (a common criticism) and their ability to recapitulate genetic diseases for use in disease modeling. Finally, the requirements for translating OptoDyCE for in vivo use are considered, and successful demonstration in vivo expression of ChR2 in the rat heart by employing systemic viral delivery, providing a model for development and testing of an optical system in intact tissue and for long-term use in behaving animals. Ultimately, we demonstrate the OptoDyCE platform has capacity to revolutionize pre-clinical drug testing, reduce cost, reduce animal use, and make clinically implemented personalized medicine an obtainable goal.

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Squirrell, Daniel. "An in vivo electrophysiological and computational analysis of hippocampal synaptic changes in the Alzheimer's disease mouse." Thesis, University of Manchester, 2015. https://www.research.manchester.ac.uk/portal/en/theses/an-in-vivo-electrophysiological-and-computational-analysis-of-hippocampal-synaptic-changes-in-the-alzheimers-disease-mouse(de740023-7d91-418a-8c88-1141b3cd81f3).html.

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Alzheimer’s disease (AD) is a neurodegenerative disorder resulting in the decline of cognitive function, memory formation and retrieval, and abrupt changes in personality. Damage to brain networks occur during prodromal stages of AD, prior to the development of clinical symptoms of dementia. Further characterising this state and identifying reliable biomarkers for early detection are priorities in AD research. I characterised neuronal changes within the dorsal CA1 and subiculum regions of the hippocampal formation (HF) in the well-characterised 3xTgAD mouse model of AD. These regions are well-established sites for early neurodegeneration in both AD patients and AD animal models. We inserted multi-electrode recording arrays into CA1 and subiculum of urethane anaesthetised 3xTgAD mice and recorded spontaneous local field potential activity. Using traditional and novel information theoretic approaches, I determined the information carrying capacity of the CA1- subiculum network during different network rhythms, and how this altered with age and AD-like pathology. A bipolar stimulating electrode was inserted into CA1, allowing the assessment of synaptic integrity between CA1 and subiculum. Results showed that synaptic and network changes occur in CA1 and subiculum during the early stages of AD-like pathology and correlates with the development of intracellular beta-amyloid. There is a progressive breakdown in synaptic facilitation as early as 3 months in the 3xTgAD mouse. These data support an advanced ageing-like phenotype in AD model mice, with an enhanced age/pathology-dependent breakdown in neuronal communication compared to age-matched controls. In agreement with other studies, 3xTgAD mice demonstrate evidence of pathology-related changes in the network rhythms of the HF. 3xTgAD mice show an increase in the power of alpha and beta rhythms, and a concurrent reduction in the power of delta oscillations. Application of novel information theoretic techniques results in a breakdown in the information carrying capacity of the hippocampal system. This deficit manifests as a reduction in information flow during delta-dominant periods of EEG rhythms, with a specific reduction during slow-wave ripple activity. This change in neuronal communication correlates with the onset of memory-retention/consolidation deficits. These network changes are complex, with alterations in the information carrying capacity of the system during theta rhythms at 6 months, and during slow-wave components by 9 months in the 3xTgAD mouse. This study provides the first evidence of an early and progressive decline in neuronal connectivity and communication that correlates with changes in cognition in the 3xTgAD mouse. Application of novel analytical techniques to multi-site EEG recording revealed early and measureable changes in information processing during the onset of AD-like pathology. These are important new biomarkers for early AD characterisation.

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Annecchino, Luca. "Development and validation of a robotic two-photon targeted whole-cell recording system for in vivo electrophysiology." Thesis, Imperial College London, 2016. http://hdl.handle.net/10044/1/56991.

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Understanding the functional principles of the mammalian cortical circuit is a major challenge in neuroscience. To make progress towards this understanding, one needs to be able to assess the behavioural dynamics of individual neuronal elements of this circuit. Manual whole-cell recording (WCR) in vivo is recognised as the “gold standard” method for electrophysiological interrogation of individual neurons. It allows subthreshold and suprathreshold signals to be recorded, perturbations to be applied through current injection, and DNA vectors to be directly delivered into the patched cells as part of the pipette internal solution. Unfortunately, the WCR technique for in vivo application is a “blind” procedure and has a low-throughput. In addition, the genetic and morphological identity of the recorded neuron often cannot be accounted for. The inherent cell-type non selectivity of this technique can be overcome by combining WCR with two-photon laser scanning microscopy, and targeting recordings to specifically labelled individual cells or cell classes. Targeted electrophysiological interrogation allows one to examine the properties of both single cells and neuronal assemblies and, additionally, the role of cell type-specific proteins in orchestrating neuronal responses. Targeted recordings in vivo may enable to test a wide range of hypotheses related to information processing in the cortical circuits. However, probing and studying the properties of individual cells in live animal preparations remains a challenge in neuroscience. In particular, precise vision-guided control of patch pipette motion and viewpoint generation of microscope objective for targeted single-cell electrophysiological interrogation is problematic. It requires specialised skills acquired through extensive practice and training by individual operators. Although automatic patch clamp technology has been in use for some years exclusively for cell culture-based paradigms, only recently has Kodandaramaiah et al. demonstrated a “blind” automated patch clamp system for in vivo recordings. However, a fully automatic method for in vivo WCR targeting specific cells or cell-types has not been implemented in any robotic system so far. In this study an automated two-photon targeted whole-cell patch clamping algorithm is demonstrated as a workable solution. The aim of this work was to develop a robotic integrated targeted autopatcher that minimised labour intensive procedures and increased the throughput both in blind and two-photon targeted WCR in live animals. The system automatically controls a micromanipulator, a microelectrode signal amplifier a two-photon microscope and a custom made regulator for controlling the internal pressure of the pipette. The two-photon microscope acquires images of fluorescently labelled cells, and cell-targets for patch clamp are selected via a point-and-click graphical user interface. Optical coordinates are initially converted to the micromanipulator coordinate system and a suitable path calculated to guide the patch pipette towards the target. This platform allows to compensate for brain tissue deformation and subsequent neuronal target movement caused by pipette insertion. As proof-of-concept, the system was tested in both “blind” and two-photon targeted paradigms and achieved performances comparable to human operators, in terms of yield, recording quality and operational speed. Hit rate for “blind” WCR was 51.4% (n=18, 35 attempts across 5 mice). RITA was also calibrated and tested for targeting specific cell types in the cortex of intact mouse brain labelled via fluorescent dye loading (e.g. Oregon Green BAPTA-1 and/or Sulforhodamine 101). Pipettes were automatically guided to the target cells and recordings obtained from visually identified neurons as well as astrocytes. These results prove the feasibility of robotic targeted WCR patch clamp in vivo and establish this system as a powerful tool for automated electrophysiological experiments in the brain.

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Velmurugan, Sathya. "Actions of appetite regulating peptides on supraoptic nucleus (SON) oxytocin neurones." Thesis, University of Edinburgh, 2009. http://hdl.handle.net/1842/3938.

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Oxytocin has established roles in parturition and lactation, but can also be released in response to non-reproductive stimuli, such as hyperosmolarity and stress. As a majority of appetite regulating peptides activate the hypothalamo-pituitary-adrenal stress axis, and oxytocin is also a stress hormone in the rat, it was hypothesized that the oxytocin system in the neurohypophysial axis could be a target for appetite-regulating peptides of central and peripheral origin. The effects of central administration of neuropeptide Y (NPY; a central orexigenic peptide and a central and peripheral neurotransmitter co-released with noradrenaline; n=5 rats) and systemic administration of secretin (a peripheral gut peptide belonging to the family of brain-gut peptides; n=26) and leptin (a peripheral anorexigenic peptide from adipose tissue; n=23) on the electrical activity of SON oxytocin neurones in vivo were studied in urethane-anaesthetized female rats with extracellular recording. Effects were compared with the excitatory responses to cholecystokinin (CCK; a peripheral anorexigenic gut peptide; n=45). Influences of fasting and pregnancy and effects of these peptides on the activity of SON vasopressin neurones were also studied. Results: (1) All the central and peripheral appetite peptides tested increased the electrical activity of SON oxytocin neurones. (a) NPY: Basal firing rate of 3.5 ± 1.05 (mean ± s.e.m) spikes/s was increased by 1 ± 0.45 spikes/s 1min after NPY (basal vs 0-10min post-NPY: P=0.03, paired t-test; n=5). (b) Secretin: Basal rate of 4.1 ± 0.4 spikes/s was increased by 1.7 ± 0.2 spikes/s 2.5min after secretin (basal vs 0-10min post-secretin: P<0.001, paired t-test; n=26). (c) Leptin: Basal rate of 3.4 ± 0.4 spikes/s was increased by 0.4 ± 0.08 spikes/s 1.5min after leptin (basal vs 0-10min post-leptin: P=0.01, paired t-test; n=23). (d) CCK: Basal rate of 3.6 ± 0.3 spikes/s was increased by 1.1 ± 0.15 spikes/s 1min after CCK (basal vs 0-10min post- CCK: P<0.001, Wilcoxon signed rank test; n=45). (2) Secretin induced excitatory responses were greater than to other peptides (P<0.001, Kruskal-Wallis one-way ANOVA on ranks). (3) Secretin dose-dependently increased SON oxytocin neurone electrical activity and peripheral oxytocin release in anaesthetized rats. (4) Intracerebroventricular infusion and microdialysis studies with benoxathian (α1 adrenergic antagonist) revealed that secretininduced excitation of SON oxytocin and vasopressin neurones involves central excitatory noradrenergic pathways. (5) Fasting for 18h did not alter the excitation of SON oxytocin neurones induced by secretin, CCK and leptin. (6) The pathway leading to excitation of oxytocin neurones by CCK was not influenced by prior leptin administration. (7) SON oxytocin neurones were responsive to leptin during late pregnancy. (8) NPY-induced excitation of oxytocin neurones was intact in anaesthetised late pregnant rats, contrasting with attenuated oxytocin secretory responses observed previously in conscious rats. (9) Systemic NPY excited SON oxytocin neurones. (10) Systemic CCK administration either inhibited (77%) or did not affect (23%) SON vasopressin neurones, while leptin had no significant effect, and responses to secretin were predominantly excitatory (67%). Systemic NPY inhibited vasopressin neurones, but central NPY was ineffective. Conclusion: Appetite peptides target SON oxytocin neurones. Postprandially released secretin and leptin might, like CCK, induce peripheral oxytocin release, so as to regulate water and electrolyte homeostasis, which is inevitably disturbed during feeding. Any central release of oxytocin induced by these peptides, might regulate feeding behaviour and satiety. Oxytocin neurone excitation induced by NPY may be relevant during stress responses.

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Lau, Petrina Yau Pok. "Long-term plasticity of excitatory inputs onto identified hippocampal neurons in the anaesthetized rat." Thesis, University of Oxford, 2015. http://ora.ox.ac.uk/objects/uuid:172e0d36-0d67-4932-962e-9ee08dcc366c.

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Use-dependent long-term plasticity in synaptic connections represents the cellular substrate for learning and memory. The hippocampus is the most thoroughly investigated brain area for long-term synaptic plasticity, long-term potentiation (LTP) and long-term depression (LTD) are both well characterized in glutamatergic excitatory connections between hippocampal principal cells in vitro and in vivo. An increasing number of studies based on acute brain slice preparations report LTP and LTD in excitatory synapses onto postsynaptic hippocampal GABAergic inhibitory interneurons. However, a systematic study of activity-induced long-term plasticity in excitatory synaptic connections to inhibitory GABAergic interneurons in vivo is missing. To determine whether LTP and LTD occur in excitatory synaptic connections to the hippocampal CA1 area GABAergic interneurons types in intact brain, I have used juxtacellular recording to measure synaptically evoked short-delay postsynaptic action potential probability in identified CA1 neurons in the urethane-anaesthetized rats. Plasticity in excitatory synaptic connections to CA1 cell types was measured as a change of afferent pathway stimulation-evoked postsynaptic spike probability and delay. In the study only experiments with monosynaptic-like short-delay (range 3-12 ms) postsynaptic spikes phase-locked to afferent stimulation were used. Afferent fibres were stimulated from the CA1 area of the hippocampus at the contralateral (left) side to avoid simultaneous monosynaptic activation of GABAergic fibres and to exclude antidromic spikes in recorded CA1 cells (in right hemisphere). Plasticity in pathways was tested using theta-burst high-frequency stimulation (TBS, 100 pulses), which is one of the most common synaptic plasticity induction protocols in acute brain slice studies. I discovered that TBS elicited permanent potentiation in single shock-evoked postsynaptic spike probability with shortening or no change in evoked spike latency in various postsynaptic neuron types including three identified pyramidal cells and parvalbumin-expressing (PV+) interneurons. Most fast-spiking PV+ cells showed LTP including an axo-axonic cell and one bistratified cell, whereas two identified basket cells exhibited LTD in similar experimental conditions. In addition, I discovered diverse plasticity in non-fast spiking interneurons, reporting LTP in an ivy cell, and LTD in three incompletely identified regular-spiking CA1 interneurons. I report that the underlying brain state, defined as theta oscillation (3-6 Hz) or non-theta in local field potential, failed to explain whether LTP, LTD or no plasticity was generated in interneurons. The results show that activity-induced potentiation and depression similar to LTP and LTD also occur in excitatory synaptic pathways to various CA1 interneurons types in vivo. I propose that long-term plasticity in excitatory connections to inhibitory interneurons may be take place in learning and memory processes in the hippocampus.

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Schweigmann, Michael [Verfasser]. "Versatile LCP surface microelectrodes for combining electrophysiology and in vivo two-photon imaging in the murine CNS / Michael Schweigmann." Saarbrücken : Saarländische Universitäts- und Landesbibliothek, 2020. http://d-nb.info/1232240095/34.

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15

Jiang, Jojo L. "Alterations of the Monoaminergic Systems by Sustained Triple Reuptake Inhibition." Thèse, Université d'Ottawa / University of Ottawa, 2012. http://hdl.handle.net/10393/23171.

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Recent approaches in depression therapeutics include triple reuptake inhibitors, drugs that target three monoamine systems. Using in vivo electrophysiological and microdialysis techniques, the effects of 2- and 14-day treatments of escitalopram, nomifensine and the co-administration of these two drugs (TRI) were examined in male Sprague-Dawley rats. Short- and long-term TRI administration decreased NE firing and had no effect on DA neurons. Normal 5-HT firing rates were maintained after 2-day TRI administration compared to the robust inhibitory action of selective serotonin reuptake inhibitors (SSRIs). Escitalopram treatment enhanced the tonic activation of the 5-HT1A receptors given the increase in firing observed following WAY100635 administration. Nomifensine treatment enhanced tonic activation of the α2–adrenoceptors following idazoxan administration. TRI treatment caused a robust increase in extracellular DA levels that was in part mediated by a serotonergic contribution. Therapeutic effects of the drugs examined in this study may be due to the enhancement of 5-HT, NE and/or DA neurotransmission.

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Iro, Chidiebere Michael. "Investigation of the Mechanisms of Action of Ketamine on the Monoamine Systems: Electrophysiological Studies on the Rat Brain." Thesis, Université d'Ottawa / University of Ottawa, 2019. http://hdl.handle.net/10393/39910.

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Background: A single infusion of ketamine has rapid antidepressant properties, although the drawback is a lack of sustained effect. A previous study showed a rapid enhancement (within 2 hours) in ventral tegmental area (VTA) dopamine (DA) neuron population and locus coeruleus (LC) norepinephrine (NE) firing and bursting activity following a single ketamine administration. The current study investigated whether these changes are present 24 hours after a single administration and if they are maintained with repeated administration. Additionally, we examined dorsal raphe nucleus (DRN) serotonin (5-HT) neurons to assess the effects of single and repeated ketamine administration on these neurons. Methods: Ketamine (10 mg/kg, i.p.) was administered to male Sprague Dawley rats once or repeatedly (3 times/week) for 2 weeks. After single and repeated administration of ketamine, electrophysiological recordings were done in the VTA, LC and DRN in anesthetized rats, 24 hrs, 3 or 7 days post-administration. Spike frequency, bursting, and for VTA neurons, spontaneously active neurons/trajectory were assessed. Results: In the VTA, LC and DRN, 24 hrs after ketamine was injected acutely there was no significant difference between controls and treated animals in all parameters assessed. However, after repeated administration, there was an increase in bursting and number of spontaneously discharging neurons per tract of VTA DA neurons as well as an increase in frequency of discharge of LC NE neurons. While the increased number of spontaneously discharging neurons per tract had dissipated after 3 days, the enhanced bursting was still present but dissipated after 7 days. As for LC NE neurons, the increased frequency of discharge was no longer present after 3 days. No significant differences in the firing of DRN 5-HT neurons were observed between controls and treated animals even after ketamine was administered repeatedly. Conclusion: These results indicate that repeated but not acute administration of ketamine maintained the increase in population activity of DA neurons and firing activity of NE neurons.

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Hanini-Daoud, Maroua. "Traitement des informations thalamiques au travers des ganglions de la base : approche électrophysiologique et optogénétique in vivo." Thesis, Aix-Marseille, 2016. http://www.theses.fr/2016AIXM4109.

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Le centre médian/parafasciculaire (CM/Pf) du thalamus a récemment émergé comme un élément d'intérêt dans le contexte de la maladie de Parkinson. Ainsi le fonctionnement normal et pathologique des GB ne peut pas être pleinement élucidé sans qu'il ne soit pris en considération. Dans ce contexte, nous avons analysé le transfert des informations thalamiques dans les GB en enregistrant, in vivo, les réponses évoquées au niveau de la structure de sortie des GB, la substantce noire pars reticulata (SNr) soit par la stimulation électrique ou optogénétique du CM/Pf. Ensuite, nous avons étudié les composantes des GB impliquées dans ces réponses en analysant les réponses évoquées par l'activation optogenetique spécifique des voies thalamo-striée, thalamo-subthalamique ou thalamo-nigrale. À la fois l'activation électrique et optogenetique du CM/Pf évoquent des réponses complexes dans la SNr qui sont composées d'une inhibition qui peut être précédée et/ou suivie d'excitations. L'inhibition et l'excitation tardive dépendent de l'activation des voies trans-striatales, alors que les premières excitations mettent en jeu les voies thalamo-subthalamique et thalamo-nigrale. Nous avons également étudié l'impact des interneurones cholinergiques du striatum ainsi que les afférences dopaminergiques sur le transfert des informations thalamiques dans les GB. Pour ce faire, nous avons enregistré les réponses évoquées au niveau des neurones de projection du striatum suite à la stimulation électrique du CM/Pf avec ou sans l'inhibition optogénétique des CINs. Nous serons alors en mesure de déterminer comment les CINs sont impliqués dans le transfert des informations thalamiques au sein des GB
The centre median/parafascicular (CM/Pf) of the thalamus has recently emerged as a component of interest in the context of Parkinson’s disease. Thus normal and pathological dynamics of BG cannot be fully understood unless it is taken into account. Here, we analyzed the transfer of CM/Pf information through BG by recording, in vivo, the evoked responses of BG output neurons in the substantia nigra pars reticulata (SNr) to either electrical or optogenetic CM/Pf stimulations. Then, we investigated the BG components involved in these responses by analyzing the responses evoked by specific optogenetic activation of the thalamo-striatal, thalamo-subthalamic or thalamo-nigral pathways. Both electrical and optogenetic activation of CM/Pf evoke complex responses in SNr that are composed of an inhibition that can be preceded and/or followed by excitations. The inhibition and the late excitation rely on the activation of the trans-striatal pathways, whereas the early excitations involve thalamo-subthalamic and thalamo-nigral projections. We are currently analyzing whether and how the striatal cholinergic interneurons (CINs) and the dopaminergic afferent system modulate the transfer of thalamic information within the BG. For the second part of my project, we analyzed the treatment of thalamic information from CM/Pf at the level of the striatum. To do this, we recorded the evoked responses of striatal projection neurons by the electrical stimulation of the CM/Pf with or without the inhibition of the CINs by optogenetics. We will then be able to determine how CINs are involved in the transfer of thalamic information at the level of the striatum

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Davis, Katherine. "Hippocampal dysfunction in the 3xTgAD mouse model of Alzheimer's disease." Thesis, University of Manchester, 2012. https://www.research.manchester.ac.uk/portal/en/theses/hippocampal-dysfunction-in-the-3xtgad-mouse-model-of-alzheimers-disease(ba2d4704-9e22-4213-8bc7-a1c55a0e0ccd).html.

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Alzheimer’s disease (AD) is a neurodegenerative disorder, characterised by severe memory loss and the accumulation of amyloid-beta (Aβ) and tau pathology within neocortex and medial temporal lobe (MTL) structures. Episodic memory impairment is a defining feature of early AD. The hippocampal formation (HF), a major network involved in both memory formation and retrieval is one of the first areas affected by AD pathology. However, the aetiology of AD is unknown; specifically how Aβ and tau pathologies cause memory impairment and how the physiological function of HF is affected. In this thesis, the 3xTgAD mouse was used as a high fidelity model of human AD pathological progression to study the function of HF during early (intracellular Aβ) and more progressive (extracellular plaque and hyperphosphorylated tau pathology) AD stages, referred to as ‘young’ and ‘old’ respectively. Specifically we: i) applied the hippocampal-dependent What-Where-Which (WWWhich) task to study the onset and progression of episodic-like memory decline (previously uncharacterised in the 3xTgAD mouse); ii) examined allocentric spatial memory in radial arm water maze (RAWM) and spontaneous alternation (SA) behaviour in T-Maze to discern whether cognitive differences exist between spontaneous and negatively reinforced tasks (the latter could be influenced by an exaggerated stress response); and iii) performed electrophysiological recordings in vivo from the HF of urethane-anaesthetised 3xTgAD and control mice to study basic synaptic connectivity, short-term synaptic plasticity and neuronal reverberation across the CA1-DG axis using a multi-site electrode. Our results showed an early and specific deficit for WWWhich episodic-like memory in the 3xTgAD model, with a decline in performance witnessed in mice as young as 3 months. In contrast, 3xTgAD component memory comprising single or dual associations of ‘What’, ‘Where’, ‘Which’ and ‘When’ remained intact suggesting the episodic impairment was due to dysfunction during the association of three component information streams within hippocampus (Chapters 3 and 4). 3xTgAD mice were equally impaired for allocentric spatial memory in RAWM and in their SA behaviour, suggesting no inherent advantage of examining cognition in paradigms which elicit behavioural distress (Chapter 5). We witnessed the development of subtle synaptic abnormalities in young 3xTgAD mice in the form of enhanced short-term paired pulse facilitation in CA1 and DG, however, a paucity of response facilitation in CA1 in response to train stimulation. In contrast, we saw intact basic synaptic function (fibre integrity and synaptic connectivity) in 3xTgAD mice of both young and old ages, suggesting gross hippocampal circuitry remained in place (Chapter 6). Finally, we saw an effect of normal ageing on cognition in the WWWhich and spatial tasks (Chapters 4 and 5), and a decline in neuronal reverberation with age in control and 3xTgAD mice. Dysfunction in these two parameters (behavioural and electrophysiological) coincided with the onset of intracellular Aβ accumulation within HF in 3xTgAD mice. This suggests a role of intracellular Aβ in impairing the physiological function of HF in AD which translates as cognitive decline in hippocampal-dependent forms of memory. Episodic memory was found to be especially sensitive to AD-related pathology and impairment, thus the WWWhich task may be applied to faithfully study the onset of cognitive decline in other AD mouse models. Further examination of the relative contribution of Aβ to hippocampal dysfunction in the 3xTgAD model is required.

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Villet, Maxime. "Dynamique cortico-striatale dans l'automatisation de la mémoire." Electronic Thesis or Diss., Université Côte d'Azur, 2024. http://www.theses.fr/2024COAZ6022.

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La mémoire est une fonction essentielle pour tout organisme afin d'apprendre, de consolider et de récupérer des informations traitées par notre cerveau. La mémoire de travail (MT) se définit par la représentation temporaire d'information, subissant un traitement qui permet l'élaboration du comportement. Le comportement peut résulter soit de la concaténation de différentes actions en vue d'un objectif (A-O), soit d'une réponse plus automatique à la présentation d'un stimulus (Hb).De nombreuses études structuro-fonctionnelles ont déterminé que le cortex médio-préfrontal (mCPF) joue un rôle essentiel dans la MT. Cette structure traite les informations de la MT, permettant la genèse d'un comportement adapté. En particulier, le mCPF joue un rôle essentiel dans l'acquisition du comportement A-O et dans l'Hb. Au même titre, le striatum présente une dichotomie structurelle lui conférant à la fois un rôle dans le comportement A-O pour sa partie dorsomédial (SDM) et dans le comportement Hb pour sa partie dorsolatérale (SDL). Contrairement au mCPF, le striatum dorsal a été impliqué dans des conditionnements ou des apprentissages spontanés, plus prône à l'automatisation.De manière étonnante, les études se sont concentrées sur le lien entre la MT et l'A-O, négligeant ainsi son rôle au cours de l'Hb. Notre première étude s'est donc intéressée à l'évolution du comportement Hb dans le cadre de la MT. Pour ce faire, nous avons réalisé l'inhibition du mCPF (DREADD). En évaluant cette mémoire lors d'une tâche d'alternance, nos résultats suggèrent que le mCPF joue un rôle crucial dans l'apprentissage initial de la tâche, mais qu'il n'est plus indispensable lorsque la tâche, surentraînée, devient plus automatique. Nous avons également exploré la possibilité d'un relais par le SDL dans cette automatisation. Ainsi le SDL semble être impliqué dans l'étape finale de l'apprentissage de la MT, une fois que le comportement est devenu Hb. De plus, nous avons observé qu'une perturbation du SDL pendant cette phase induit une nouvelle adaptation de la stratégie d'apprentissage, A-O. Ce résultat met en évidence l'existence d'une trace dormante dans le mCPF, qui coexiste malgré l'établissement d'un comportement Hb.Notre seconde étude s'est intéressée à la dynamique fonctionnelle neuronale entre le SDL et le SDM dans une tâche d'alternance spatiale continue chez le rat. Nos résultats montrent et quantifient le fait que les neurones du SDM et SDL sont tous deux engagés dans le processus d'apprentissage, de sa mise en place à sa phase de stabilisation. Nous avons ensuite déterminé le pouvoir codant des neurones pour des évènements. Quel que soit le stade d'apprentissage, nous avons plus de neurones codants dans le SDM comparé au SDL, suggérant une plus grande implication du SDM dans l'apprentissage. En revanche le nombre de neurones codants décroit dans le SDM alors qu'il croit dans le SDL au cours des stages d'apprentissage. Cette diminution n'influence pas le pouvoir codant du SDM. Ceci suggère que le réseau doit probablement se réorganiser pour être tout aussi efficace en termes de décodage mais avec moins de neurones. En revanche le nombre de neurones dans le SDL est linéairement relié au pouvoir codant. Ainsi ces résultats montrent une réorganisation graduelle du réseau, qui diffère entre le SDM et le SDL et un engagement des deux structures de la phase initiale d'apprentissage au maintien, en contraste avec les théories de transfert graduel du SDM et SDL au cours des stades d'apprentissage.Ces deux études montrent l'implication réciproque du mCPF et du SDL dans une tâche de MT et du SDM et SDL dans une tâche d'alternance spontanée. Elles révèlent aussi qu'un processus d'automatisation peut se mettre en place quelle que soit la tâche et que la trace mnésique ne migre pas réellement d'une structure à l'autre. Il y aurait une réorganisation des réseaux leur permettant d'être tout aussi efficace avec moins de neurones ou dans un état dormant
Memory is an essential function for any organism, enabling the processing, consolidation and retrieval of information by neuronal networks in the brain. Working memory (WM) is defined as the temporary representation of information that is undergoing processing to allow the development of behaviour. Behaviour may be the result of the concatenation of different actions with the intention of achieving an objective (A-O), or it may be the consequence of a more automatic response to the presentation of a stimulus (Hb).A substantial body of evidence from structural-functional studies has demonstrated that the medio-prefrontal cortex (mPFC) is a crucial component in the WM process. This structure is responsible for processing WM information, thereby enabling the generation of adapted behaviour. In particular, the mCPF plays a pivotal role in the acquisition of A-O behaviour and in the formation of Hb. Similarly, the striatum displays a structural dichotomy, whereby its dorsomedial part (DMS) is associated with A-O behaviour and its dorsolateral part (DLS) is linked to Hb behaviour. In contrast to the mCPF, the dorsal striatum has been associated with conditioning or spontaneous learning, exhibiting a greater propensity for automation than the WM.It is noteworthy that studies have focused on the relationship between WM and A-O, with minimal attention devoted to its involvement in Hb. Our first study was conducted to elucidate the evolutionary trajectory of Hb behaviour within the context of WM. For this, the mCPF was inhibited (DREADD). The results of our study indicate that the mCPF plays a pivotal role in the initial learning of the task, but that it is no longer a prerequisite when the task has been overtrained and has become automatic. Furthermore, the potential role of the DLS in this automation process was investigated. The findings of our study indicate that the DLS is implicated in the final stage of learning, including WM, once the behaviour has become habitual. Furthermore, it was observed that a disruption to the DLS during this phase resulted in a novel adaptation of the learning strategy, A-O. This result indicates the presence of a dormant trace within the mCPF, which persists despite the establishment of Hb behaviour.Our second study proceeded to investigate the neuronal functional dynamics between the DLS and DMS in a continuous spatial alternation task in rats. Our results demonstrate and quantify that both DMS and DLS neurons are engaged in the learning process, from its initial stages to its stabilization phase. Subsequently, the capacity of the neurons to code for events was determined. Regardless of the learning phase, we observed a greater number of coding neurons in the DMS compared to the DLS, indicating a heightened involvement of the DMS in the learning process. Conversely, the number of coding neurons decreases in the DMS whereas it increases in the DLS during the learning stages. This decrease does not influence the coding power of the DMS. This suggests that the network probably needs to be reorganized to be just as efficient in terms of decoding but with fewer neurons. On the other hand, the number of neurons in the DLS is linearly related to the coding power. These results thus show a gradual reorganization of the network, which differs between the DMS and the DLS, and a commitment of the two structures from the initial learning phase to maintenance, in contrast with theories of gradual transfer of the DMS and DLS during the learning stages.The two studies demonstrate the reciprocal involvement of the mCPF and DLS in a working memory task and of the DMS and DLS in a spontaneous alternation task. They illustrate that an automation process can be established regardless of the task, but that the memory trace does not truly migrate from one structure to another. The networks undergo reorganization so that they can either be equally effective with fewer neurons or remain in a dormant state

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Dubanet, Olivier. "Dynamique des interactions entre excitation et inhibition périsomatique dans le circuit hippocampique normal et épileptique in vivo." Thesis, Bordeaux, 2019. http://www.theses.fr/2019BORD0259.

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L'hippocampe est une structure essentielle pour les processus d’apprentissage et la mémoire. Le fonctionnement de ce circuit neuronal repose sur des interactions complexes entre cellules pyramidales glutamatergiques excitatrices et divers types d'interneurones GABAergiques inhibiteurs, dont on connait mal les rôles exacts car il est très difficile d'étudier in vivo la fonction inhibitrice issue d'interneurones spécifiques. L'altération des interactions synaptiques entre cellules pyramidales et interneurones de l'hippocampe est de plus à la base de pathologies neurologiques telle que l'épilepsie, neurodéveloppementales telle que l'autisme, ou neurodégénératives telle que la maladie d'Alzheimer. Parmi les différents types d'interneurones, ceux qui expriment la parvalbumine (PV) et dont l'axone projette sur les corps cellulaires (inhibition périsomatique) des cellules pyramidales ont une organisation anatomique qui les rend particulièrement efficaces pour bloquer la décharge de potentiels d'action chez leurs cellules cibles. C'est la raison pour laquelle on considère qu'ils jouent un rôle particulièrement important non seulement dans le codage de l'information (en contrôlant quelle cellule est en mesure ou non de décharger) mais aussi dans l'équilibre du circuit, pour éviter que l'excitation réciproque entre cellules pyramidales ne dégénère en crise d'épilepsie. L'efficacité de cette inhibition dite périsomatique dépend largement du gradient électrochimique des ions chlorure (Cl-), c'est à dire la combinaison entre le potentiel membranaire et la répartition des ions Cl- entre l'intérieur et l'extérieur du neurone cible. Or, ces paramètres ne cessent de changer au fil de l'activité neuronale, et il a même été démontré que le gradient Cl- pouvait s'inverser, générant un effet paradoxalement excitateur de la transmission GABAergique. Ce phénomène, qui participerait à la mise en place physiologique des circuits neuronaux immatures, est aujourd'hui également considéré comme une source majeure de dérèglement des circuits neuronaux dans diverses pathologies comme l'épilepsie, l'autisme ou la schizophrénie. Il s'agit donc d'un champs de recherche aux implications cliniques directes, et la recherche de drogues permettant de restaurer un gradient Cl- physiologique représente un espoir thérapeutique majeur, mais les données contradictoires de la littérature appellent à la recherche d'une évaluation directe, qui n'a pas été réalisée jusque-là faute de disposer d'une approche technique adéquate. Pendant ma thèse, par des techniques d'électrophysiologie, d’opto- et de pharmaco-génétique, j'ai contribué à la mise au point d'une nouvelle approche méthodologique sophistiquée d'évaluation de la transmission GABAergique périsomatique dans l'hippocampe, à même de respecter la complexité des dynamiques de l'activité neuronale spontanée in vivo. Mon travail de thèse a consisté à étudier le rôle fonctionnel des interneurones parvalbumine (PV) de l'inhibition périsomatique dans le circuit hipocampique adulte, dans les conditions physiologiques et dans deux modèles d'épilepsie chez la souris. J'ai ainsi pu détecter in vivo l'expression d'un GABA excitateur mais qui ne semble pas participer à la génération des crises aigues car exprimé dans la période de silence post-ictale, ni à l'épileptogénèse car exprimé seulement de façon anecdotique une semaine post-status epilepticus, un stade auquel j'ai également observé que la majorité des neurones pyramidaux de CA3 n'étaient plus sous contrôle inhibiteur périsomatique. En plus de contribuer à mieux comprendre l'épileptogénèse, ces travaux pourraient servir de modèle pour l'évaluation de la contribution d'un GABA excitateur à diverses conditions pathologiques, et de l'efficacité réelle de diverses approches visant à moduler le gradient chlore pour restaurer une fonction inhibitrice in vivo
The hippocampus is a key structure for learning and memory. The function of this neuronal circuit is based on complex interactions between excitatory glutamatergic pyramidal cells and various types of inhibitory GABAergic interneurons. The precise roles fullfiled by interneuron subtypes is still unclear because it is challenging to study in vivo the inhibitory function of specific interneurons. Alterations of the synaptic interactions between pyramidal cells and interneurons in the hippocampus also underlie neurological pathologies such as epilepsy, neurodevelopmental diseases such as autism, or neurodegenerative diseases such as Alzheimer's disease. Among the different types of interneurons, those that express parvalbumin (PV) and project to pyramidal cell bodies (perisomatic inhibition) are particularly efficient in blocking action potential generation in their target cells. PV interneurons therefore play a central role in neuronal coding (by controlling which cell can fire or not) but also in the balance between global excitation and inhibition within the circuit, prevention runaway excitation between interconnected pyramidal cells and the generation of epileptic seizure. Functional perisomatic inhibition directly depends on Cl- electrochemical gradient, or the interaction between membrane potential and Cl- distribution across the membrane of the target neuron. However, these parameters change continuously during neuronal activity, and it has been shown that the Cl- gradient can be reversed, resulting in paradoxically excitatory GABAergic transmission. This phenomenon, which contributes to the physiological maturation of neuronal circuits during early development, is also considered as a major source of neuronal circuit dysfunction in various pathologies such as epilepsy, autism or schizophrenia. This field of research is therefore clinically relevant, and the research for drugs restoring a physiological Cl- gradient is very active. However, a direct assessment of the excitatory GABA hypothesis has been hindered by the technical difficulty of probing endogenous GABAergic synaptic function in vivo, and contradictory data in the literature call for a direct evaluation. During my PhD, using electrophysiological, opto- and pharmaco-genetic techniques, I have contributed to develop a new and sophisticated methodological approach to evaluate the perisomatic GABAergic transmission in the hippocampus, respecting the complexity of spontaneous neuronal activity dynamics in vivo. I have studied the functional role of perisomatic inhibition from PV interneurons in the adult hippocampal circuit, in physiological conditions and in two models of epileptic mice in which I was able to detect an excitatory GABAergic transmission in vivo. However, excitatory GABA was unlikely to participate in epileptogenesis because it was expressed only during the period of post-ictal silence after acute seizures, or in a potentially negligible minority of pyramidal cells one week post-status epilepticus during the latent period that precedes the emergence of chronic epilepsy, a stage during which I also demonstrated that the majority of CA3 pyramidal neurons were no longer under perisomatic inhibitory control. In addition to contribute to a better understanding of epileptogenesis, this approach constitutes an invaluable tool to quantify the actual in vivo efficacy of drugs designed to modulate Cl- homeostasis and restore physiological GABAergic inhibition, thereby meeting high clinical and therapeutical expectations

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Cabanas, Magali. "Modification des activités de réseaux in vivo chez un modèle murin de la maladie de Huntington." Thesis, Bordeaux, 2016. http://www.theses.fr/2016BORD0345/document.

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La maladie de Huntington est une pathologie héréditaire qui se caractérise par une dégénérescence sélective des neurones striataux de la voie indirecte des ganglions de la base. Chez les patients ainsi que chez les souris modèles de la pathologie, en plus des symptômes moteurs, cognitifs et psychiatriques, des troubles du sommeil peuvent aussi apparaitre dès la phase pré-symptomatique. L’étude électrophysiologique in vivo des souris transgéniques R6/1a, en outre, révélé en début de phase symptomatique l’apparition du rythme pathologique β observé principalement durant le sommeil. Ces travaux de thèses ont donc eut pour but d’étudier le lien entre les modifications d’activités de réseaux cérébraux, les troubles du sommeil et l’émergence du rythme β ainsi que l’implication de ces anomalies dans les perturbations comportementales observées chez les souris R6/1. Notre étude de l’imagerie c-Fos a montré une hyperactivation de la voie frontostriatale chez ces souris, et ceci uniquement au stade pré-symptomatique sans aucune modification d’activation de la voie indirecte. Notre étude pharmacogénétique a démontré que la modification d’activité de ces neurones de projection striataux pouvait modifier l’alternance veille/sommeil mais ne pouvaient générer le rythme β. Enfin, notre étude pharmacologique a établit le lien entre le dysfonctionnement du système orexinergique et l’émergence du rythme β chez les souris R6/1. Ces travaux ont permis de mieux décrire des modifications d’activités de réseaux associées aux différents stades de la pathologie, en particulier au stade présymptomatique, et leurs contributions aux troubles du sommeil et l’émergence du rythme β
Huntington’s disease (HD) is an inherited pathology that causes selective degeneration ofindirect striatal pathway neurons of the basal ganglia. In addition to the classic motor,cognitive and psychiatric symptoms, patients and mouse models of HD develop sleepdisorders, which can appear at as early as pre-symptomatic stage. Furthermore, in vivoelectrophysiological study of R6/1 transgenic mice revealed a unique and pathological βrhythm that appear at early symptomatic stage and which is mainly observed during sleep.The aim of this thesis work was to examine the link between changes in cerebral networkactivities, sleep disturbances and β rhythm, and to determine the contribution of theseabnormalities to the behavioral disturbances observed in R6/1 mice. Our neuroimaging study of the marker of neuronal activity c-Fos showed a hyperactivation of frontostriatal pathway at pre-symptomatic stage without any activity changes of the vulnerable indirect pathway neurons. Our pharmacogenetic study demonstrated that changes of striatal projection neuronal activity can modify sleep/wake behaviors, without inducing the pathological β rhythm. Finally, our pharmacological study established a link between orexinergic system dysfunction and β rhythm emergence in R6/1 mice. Our data, therefore, described further the natures of altered neural circuit activity associated with different disease stages, in particular pre-motor symptomatic period, and the importance of these alterations for sleep disturbances as well as β rhythm appearance in transgenic HD mice

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Ridler, Thomas. "Entorhinal cortex dysfunction in rodent models of dementia." Thesis, University of Exeter, 2017. http://hdl.handle.net/10871/30575.

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As both the major input and output of the hippocampal formation, the entorhinal cortex (EC) occupies a pivotal position in the medial temporal lobe. The discovery of grid cells in the medial entorhinal cortex (mEC) has led to this region being widely implicated in spatial information processing. Importantly, the EC is also the first area affected by dementia pathology, with neurons appearing particularly susceptible to degeneration. Despite this, little is known about how pathology affects the functional output of mEC neurons, either in their ability to coordinate firing to produce network oscillations, or to represent information regarding the external environment. This thesis will use electrophysiological techniques to examine how dementia pathology contributes to the breakdown of mEC neuronal networks using the rTg4510 mouse model of tauopathy. The first 2 results chapters will show how the anatomical organisation along the dorso-ventral axis of the mEC has profound influence on the network activity that can be observed both in brain slices and awake-behaving mice. It will further show how deficits in network activity in rTg4510 mice occur differentially across this axis, with dorsal mEC appearing more vulnerable to changes in oscillatory function than ventral. The third results chapter will begin to explore the relationship between global network activity and the external environment, showing that rTg4510 mice display clear deficits in the relationship between oscillation properties and locomotor activity. Finally, the underlying basis for these changes will be examined, through the recording of single-unit activity in these mice. It will show a decreased tendency for mEC neurons to display firing rates modulated by running speed, as well as an almost complete breakdown of grid cell periodicity after periods of tau overexpression. Understanding how dementia pathology produces changes to neuronal function and ultimately cognition is key for understanding and treating the disease. This thesis will therefore provide novel insights into the dysfunction of the EC during dementia pathology.

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Danysz, Wojciech, Gunnar Flik, Andrew McCreary, Carsten Tober, Wilfried Dimpfel, Jean C. Bizot, Richard Kostrzewa, et al. "Effects of Sarizotan in Animal Models of ADHD: Challenging Pharmacokinetic–Pharmacodynamic Relationships." Digital Commons @ East Tennessee State University, 2015. https://dc.etsu.edu/etsu-works/948.

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Sarizotan 1-[(2R)-3,4-dihydro-2H-chromen-2-yl]-N-[[5-(4-fluorophenyl) pyridin-3-yl]methyl] methenamine, showed an in vivo pharmaco-EEG profile resembling that of methylphenidate which is used in attention deficit/hyperactivity disorder (ADHD). In turn, we tested sarizotan against impulsivity in juvenile rats measuring the choice for large delayed vs. a small immediate reward in a T-maze and obtained encouraging results starting at 0.03 mg/kg (plasma levels of ~11 nM). Results from rats treated neonatally with 6-hydroxydopamine (6-OHDA), also supported anti-ADHD activity although starting at 0.3 mg/kg. However, microdialysis studies revealed that free brain concentration of sarizotan at active doses were below its affinity for 5-HT1A receptors, the assumed primary target. In contrast, electrophysiological experiments in mid-brain Raphé serotonergic cells paralleled by plasma sampling showed that there was ~60 % inhibition of firing rate—indicating significant activation of 5-HT1A receptors—at a plasma concentration of 76 nM. In line with this, we observed that sarizotan concentrations in brain homogenates were similar to total blood levels but over 500 fold higher than free extracellular fluid (ECF) concentrations as measured using brain microdialysis. These data suggest that sarizotan may have potential anti-ADHD effects at low doses free of the previously reported side-effects. Moreover, in this case a classical pharmacokinetic–pharmacodynamic relationship based on free brain concentrations seems to be less appropriate than target engagement pharmacodynamic readouts.

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Ng, Kheng-Seong. "The human rectum: innervation in health and impact of surgery on function." Thesis, The University of Sydney, 2016. http://hdl.handle.net/2123/16431.

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Much current understanding of the function and (neuro)physiology of the human colon and rectum is based on studies of small animals, with a relative paucity of literature using human tissue. Furthermore, the impact of surgery on hindgut function, most commonly encountered through anterior resection of the rectum, remains inconsistently described. This thesis looks to better understand and characterise hindgut afferent and intrinsic innervation using human tissue, and to clinically and physiologically assess bowel dysfunction following anterior resection. In Part I, ‘ex vivo’ studies of the intrinsic and extrinsic innervation of the colon and rectum were performed to determine whether differences exist that might explain the rectum’s unique ability to provide sophisticated sensory information to the brain in its function in the storage and elimination of faeces. Electrophysiological studies were successful in recording extracellular nerve activity in hindgut afferents and demonstrated that rectal tissue was more mechano- and chemo-sensitive than colonic tissue. Wholemount immunostains of human hindgut myenteric plexuses were prepared, and this allowed the quantitative assessment and neurochemical profiling of myenteric ganglia. Despite differences in their extrinsic afferent innervation, there was no regional variation in intrinsic innervation between colon and rectum. In Part II, clinical assessment of bowel function following anterior resection confirmed that objective symptoms of bowel dysfunction are ubiquitous following surgery. Phenotypes of ‘anterior resection syndrome’ (ARS) were identifiable based on types of symptoms reported. Data from control groups, both in the community and those following surgery on other abdomino-pelvic organs (right hemicolectomy and cystectomy), confirmed that the symptom constellation comprising ‘ARS’ is unique to patients following anterior resection. There is marked clinical heterogeneity in patients following anterior resection. Future studies are required to establish a pathophysiological taxonomy for patients with ‘ARS’ now that symptom phenotypes have been identified. Whether identification of these subgroups influences outcomes of treatments for post-operative bowel dysfunction remains to be determined.

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Vitrac, Clément. "Contrôle dopaminergique de la motricité au niveau cortical et striatal." Thesis, Poitiers, 2014. http://www.theses.fr/2014POIT2282/document.

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Le cortex moteur primaire et le striatum permettent la planification et la sélection de mouvements. La dopamine régule l'activité des neurones dans ces deux structures. La perte des neurones à dopamine projetant de la substance noire compacte vers le striatum est à l'origine de troubles moteurs observés dans la maladie de Parkinson. Nous avons caractérisé le contrôle par la dopamine des neurones du cortex moteur primaire chez la souris et avons démontré que les fibres dopaminergiques innervent préférentiellement la représentation des membres antérieurs dans les couches corticales profondes. Nous avons montré que la dopamine module localement l’activité électrophysiologique des neurones cortico-striataux via les récepteurs D2. Ces résultats montrent que la dopamine peut exercer un contrôle direct sur la motricité au niveau des neurones du cortex moteur primaire. Nous avons par la suite déterminé le potentiel des thérapies cellulaires dans un modèle animal de la maladie de Parkinson. Les approches actuelles privilégient la greffe ectopique de neurones à dopamine dans la région cible, le striatum. Nous avons choisi une approche alternative consistant à pratiquer la greffe au niveau de la région lésée, la substance noire compacte. Nous avons montré chez la souris que la lésion des neurones dopaminergiques altère les propriétés électrophysiologiques des neurones du striatum et que la greffe homotopique de neurones entraîne une meilleure récupération de ces caractéristiques électrophysiologiques que la greffe ectopique dans le striatum.Ces résultats ouvrent des perspectives d'étude des effets de la greffe homotopique sur l'activité des autres structures contrôlant la motricité
Primary motor cortex and striatum are involved in movement planification and selection. Dopamine regulates the neuronal activity of these two structures. The motor impairments observed in Parkinson's disease originates from the loss of dopamine neurons projecting from the substantia nigra pars compacta to the striatum.We characterized the dopaminergic control of the neurons of primary motor cortex in mice and we demonstrated that dopaminergic fibers preferentially innervate the forelimb representation map in the deep cortical layers. Furthermore, we demonstrated that dopamine locally modulates the electrophysiological activity of the cortico-striatal neurons through D2 receptors. These results show that dopamine can directly control motor function by influencing neuronal activity in primary motor cortex.Thereafter, we determined the potential of cell replacement therapies in an animal model of Parkinson's disease. In most studies, the transplanted dopamine neurons have been placed within the striatum. We have chosen an alternative approach by grafting neurons into the lesioned nucleus, substantia nigra. We showed in mice that the lesion of dopaminergic neurons impaired the electrophysiological properties of the striatal neurons. Whereas these properties are not fully restored with an intra-striatal transplant, all the electrophysiological characteristics are recovered with an intra-nigral graft. This result opens new perspectives to study the homotopic graft effects on the activity of the other structures controlling motor function

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26

Thomazeau, Aurore. "Dysfonctions synaptiques glutamatergiques dans le cortex préfrontal de modèles murins de trisomie 21 surexprimant le gène Dyrk1a et stratégies thérapeutiques." Thesis, Bordeaux 2, 2012. http://www.theses.fr/2012BOR21921/document.

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La trisomie 21 est la première cause de retard mental, phénotype majeur de la maladie. Elle est due à la présence d’un chromosome 21 supplémentaire. De nombreux gènes sont présents sur ce chromosome mais quelques-uns ont été proposés comme candidats pour les phénotypes neurocognitifs associés à la maladie, notamment le gène Dyrk1a. Il code pour une sérine-thréonine kinase, DYRK1A, à rôle majeur dans le développement cérébral et l’activité synaptique. Le cortex préfrontal sous-tend un ensemble de fonctions cognitives supérieures dont les fonctions exécutives et est impliqué dans la régulation du comportement émotionnel et de l’humeur, composantes largement affectées dans la trisomie 21. Ce travail de thèse a permis de caractériser des défauts majeurs de la transmission et la plasticité synaptique glutamatergique au sein du cortex préfrontal de deux modèles murins différents de trisomie 21: le modèle mBACtgDyrk1a surexprimant le gène murin Dyrk1a et le modèle Ts65Dn surexprimant 130 gènes de l’analogue murin du chromosome 21 dont Dyrk1a. Un autre versant de l’étude a concerné l’utilisation d’un composé inhibiteur de l’activité DYRK1A ou d’autres cibles cellulaires pour corriger les altérations préfrontales observées, constituant ainsi de nouvelles pistes thérapeutiques pour les phénotypes neurocognitifs associés à la trisomie 21
Down syndrome is the major cause of mental retardation, the main phenotype of the pathology. It is due to an extra chromosome 21. Many genes have been proposed as candidates for the neurocognitive phenotypes of Down syndrome, notably Dyrk1a. It encodes the serine-threonine kinase DYRK1A which is involved in brain development and synaptic functions. The prefrontal cortex mediates higher cognitive functions, such as executive functions and emotional regulation. This study highlighted major deficits in prefrontal cortex glutamatergic transmission and plasticity of two mouse models for Down syndrome: the overexpressing Dyrk1a mBACtgDyrk1a model and the Ts65Dn model, overexpressing around 130 murine orthologous genes of HSAS21 chromosome. Another aspect of this study was the development of new effective therapeutic strategy for Down syndrome neurocognitive phenotypes based on DYRK1A or other cellular targets activity inhibition

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Bienvenu, Thomas Claude Michel. "Functional specialisation of GABAergic cells in the basolateral amygdala." Thesis, University of Oxford, 2011. http://ora.ox.ac.uk/objects/uuid:d52fb5ad-19cc-41b8-a1e2-2f25ef82dddf.

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The amygdala, in particular its basolateral part (BLA), plays a critical role in binding affective qualities to otherwise neutral stimuli, and in eliciting emotional behaviors. Plasticity of inputs to BLA projection neurons involved in emotional memory has been extensively studied. However, how BLA neurons collectively process sensory information to encode and stabilize emotional memories is unknown. Precise coordination of BLA network activities seems critical. Specifically, timed integration of salient stimuli, and synchrony with hippocampal theta oscillations appear to be important. Recent reports suggest that GABAergic neurons may be instrumental in shaping ensemble activity in the BLA. Studies of neocortex and hippocampus showed that diverse GABAergic interneuron types play highly specific roles in coordinating network operations. The presence of similar interneuron populations in the BLA suggests comparable mechanism may govern its activities. However, GABAergic cell types and their functions have not been characterized.

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Gao, Xiaojie. "Regulation and functions of burst firing: the role of KCNQ3 potassium channels in vivo." Doctoral thesis, Humboldt-Universität zu Berlin, 2020. http://dx.doi.org/10.18452/22144.

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Ionenkanäle leiten Ionenströme über neuronale Membranen, wodurch Aktionspotentiale erzeugt und weitergeleitet werden. Sie spielen eine zentrale Rolle bei der Regulierung der Erregbarkeit und des Aktivierungsverhaltens von Neuronen. KCNQs sind eine wichtige Familie von spannungsgesteuerten Kaliumkanälen; ihre Dysfunktion kann zu verschiedenen neurologischen Krankheiten führen, einschließlich Erkrankung an Epilepsie und Taubheit. Es wurde gezeigt, dass KCNQ2 und KCNQ3 den M-Strom verantwortlich sind. Letzterer ist für die Regulierung des repetitiven Feuerns von Pyramidenzellen entscheidend. Im Gegensatz zu KCNQ2, ist die funktionelle Bedeutung von KCNQ3 noch nicht aufgeklärt. In dieser Arbeit zeigen wir mittels extrazellulärer Elektrophysiologie in vivo, dass bei konstitutiven Kcnq3 Knockoutmäusen die hippokampalen Pyramidenzellen vermehrt burstartig feuern. Außerdem weisen diese Tiere eine verminderte Spike-Frequenz-Anpassung auf und die Wahrscheinlichkeit des Burst-Feuerns während zwei verschiedener Oszillationen – Theta gegen Nicht-Theta – kann nicht mehr unterscheiden werden. Des Weiteren zeigen Kcnq3-Knockout- Pyramidenzellen während der Theta-Oszillation weder eine dominante Phasenpräferenz, noch eine Koordination ihrer Burst-Feuerung. Die Thetawellen Phasenpräzision tritt weiterhin bei dem vorübergehend verstärkten Feuern auf. Das räumliche selektive Feuern von mutmaßlichen Ortszellen blieb auch bei den Knockout-Mäusen erhalten, aber es ist hauptsächlich vom Burst- Feuern abhängig. Diese Studie zeigt, dass der KCNQ3-Ionenkanal eine wichtige Rolle bei der Regulierung der neuronalen Erregbarkeit und der Informationsverarbeitung spielt, und gibt damit Einblicke in die Bedeutsamkeit der KCNQ3-Ionenkanäle bezüglich der neurologischen Störungen.
Ion channels conduct ion flows across neuronal membrane whereby action potential is generated and propagated. They play a central role in regulating the excitability and firing behavior of a neuron. Among them, the KCNQs present a prominent family of voltage-gated potassium channels. Dysfunction of KCNQ2–5 channels can lead to varied neurological diseases including early onset epilepsy and deafness. In cortex and hippocampus, KCNQ2 and KCNQ3 have been demonstrated to underlie the non-inactivating M-current critical for controlling the repetitive firing of pyramidal cells. However, the functional significance of KCNQ3, unlike that of KCNQ2, remains elusive. Here, by applying in vivo extracellular electrophysiology in Kcnq3 constitutive knockout mice and the wild-type littermates, we find that hippocampal pyramidal cells lacking KCNQ3 exhibit increased burst firing. Moreover, the spike frequency adaptation of their bursts is diminished, and the burst propensity during two different field oscillations – theta versus non-theta – becomes indistinguishable. During theta oscillations, Kcnq3 knockout pyramidal cells no longer display unimodal phase preference and do not coordinate their burst firing. But phase advancement along successive theta cycles continues to occur at times of transiently intensified firing. The selective firing of place cells is largely preserved in the knockout while mainly relying on bursts. These results suggest that KCNQ3 channels indeed play a significant and specific role in regulating the neurons’ excitability and information processing, thus providing crucial mechanistic insights into the relevance of the KCNQ3 channels in neurological disorders.

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Carus-Cadavieco, Marta. "Coordination of innate behaviors by GABAergic cells in lateral hypothalamus." Doctoral thesis, Humboldt-Universität zu Berlin, 2018. http://dx.doi.org/10.18452/19135.

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Der laterale Hypothalamus (LH) reguliert angeborene Verhaltensweisen. Ob und wie die Koordination von hypothalamischen Neuronengruppen Verhaltensübergänge reguliert, blieb jedoch unbekannt. In dieser Arbeit wurde Optogenetik mit neuronalen Ableitungen in verhaltenden Mäusen kombiniert. LHVgat Neurone erhöhten ihre Aktivitätsrate während Übergängen vom NREM-Schlaf zum Wachzustand. LHVgat Zellen projizieren zum Nucleus reticularis des Thalamus (RTN). Optogenetische Aktivierung von Vgat Ausgängen im RTN führte eine starke, frequenzabhängige Inhibierung von RTN Zellen herbei und replizierte Verhaltenszustands-abhängige Aktivitätsraten in RTN Neuronen. Ableitungen von LH Neuronen während Umgebungserkundung ergaben, dass 65% der LH Neurone ihre Aktivitätsrate erhöhten, wenn das Tier began sich fortzubewegen. 'Top-down’ Vorderhirn Innervation des LH erfolgt größtenteils durch Signale ausgehend vom lateralen Septums (LS). Während spontaner Umgebungserkundung und freiem Zugang zu Futter wiesen der LH und das LS Gamma-Oszillationen (30-90 Hz) auf, welche neuronale Aktivität innerhalb und zwischen diesen beiden Gehirnregionen synchronisierten. Optogenetische Stimulation von Somatostatin-positiven GABAergen Projektionen zum LH mit Gamma-Frequenz förderte die Nahrungssuche und erhöhte die Wahrscheinlichkeit des Betretens der Nahrungszone. Inhibitorische Signale des LS bewirkten eine Unterteilung der LH Neurone: entsprechend ihrer Aktivität im Bezug zur Nahrungsstelle wurden sie während bestimmter Phasen der Gamma-Oszillation aktiviert. Dabei führte optogenetische Stimulation von LS-LH Neuronen mit Gamma-Frequenz keine Veränderung bei der Nahrungsaufnahme selbst herbei. Insgesamt liefert diese Arbeit neue Einsichten über die Funktion der neuronalen Netzwerke des LH, welche durch Signalgebung mit unterschiedlichen Zeitskalen über die Koordination mit vor- und nachgeschalteten neuronalen Netzwerken Übergange zwischen verschiedenen angeborenen Verhaltensweisen regeln.
Lateral hypothalamus (LH) is crucial for regulation of innate behaviors. However, it remained unknown whether and how temporal coordination of hypothalamic neuronal populations regulates behavioral transitions. This work combined optogenetics with neuronal recordings in behaving mice. LHVgat cells were optogenetically identified. LHVgat neurons increased firing rates upon transitions from non-REM (NREM) sleep to wakefulness, and their optogenetic stimulation during NREM sleep induced a fast transition to wakefulness. LHVgat cells project to the reticular thalamic nucleus (RTN). Optogenetic activation of LHVgat terminals in the RTN exerted a strong frequency-dependent inhibition of RTN cells and replicated state-dependent changes in RTN neurons activity. Recordings of LH neurons during exploration revealed that 65% of LH neurons increased their activity upon the onset of locomotion. Top-down forebrain innervation of LH is provided, to a great extent, by inhibitory inputs from the lateral septum (LS). During spontaneous exploration in a free-feeding model, LS and LH displayed prominent gamma oscillations (30-90 Hz) which entrained neuronal activity within and across the two regions. Optogenetic gamma-frequency stimulation of somatostatin-positive GABAergic projections to LH facilitated food-seeking, and increased the probability of entering the food zone. LS inhibitory input enabled separate signaling by LH neurons according to their feeding-related activity, making them fire at distinct phases of the gamma oscillation. In contrast to increased food intake during optogenetic stimulation of LHVgat cells, food intake during gamma-rhythmic LS-LH stimulation was not changed. Overall this works provides new insight into the function of LH circuitry, that employs signalling at different time scales, which, in coordination with upstream and downstream circuits, regulates transitions between innate behaviors.

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Van, Rheede Joram Jacob. "The emergence of visual responses in the developing retinotectal system in vivo." Thesis, University of Oxford, 2013. http://ora.ox.ac.uk/objects/uuid:57cb9bff-a085-4ac4-b413-c29112eeb78e.

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Patterned neuronal activity driven by the sensory environment plays a key role in the development of precise synaptic connectivity in the brain. It is well established that the action potentials (‘spikes’) generated by individual neurons are crucial to this developmental process. A neuron’s spiking activity is jointly determined by its synaptic inputs and its intrinsic excitability. It is therefore important to ask how a neuron develops these attributes, and whether the emergence of spiking might itself be governed by activity-dependent processes. In this thesis, I address these questions in the retinotectal system of Xenopus laevis. First, I investigate the extent to which visuospatial information is available to the developing retinotectal system. I show that the eyes of developing Xenopus larvae are hyperopic at the onset of vision, but rapidly grow towards correct vision. Despite its imperfect optics, the Xenopus eye is able to generate spatially restricted activity on the retina, which is evident in the spatial structure of the receptive fields (RFs) of tectal neurons. Using a novel method to map the visually driven spiking output and synaptic inputs of the same tectal neuron in vivo, I show that neuronal spiking activity closely follows the spatiotemporal profile of glutamatergic inputs. Next, I characterise a population of neurons in the developing optic tectum that does not fire action potentials, despite receiving visually evoked glutamatergic and γ-aminobutyric acid (GABA)ergic synaptic inputs. A comparison of visually spiking and visually non-spiking neurons reveals that the principal reason these neurons are ‘silent’ is that they lack sufficient glutamatergic synaptic excitation. In the final section of the thesis, I investigate whether visually driven activity can play a role in the ‘unsilencing’ of these silent neurons. I show that non-spiking tectal neurons can be rapidly converted into spiking neurons through a visual conditioning protocol. This conversion is associated with a selective increase in glutamatergic input and implicates a novel, spike-independent form of synaptic potentiation. I provide evidence that this novel plasticity process is mediated by GABAergic inputs that are depolarising during early development, and can act in synergy with N-methyl-D-aspartate receptors (NMDARs) to strengthen immature glutamatergic synapses. Consistent with this, preventing the depolarising effects of GABA or blocking NMDARs abolished the activity-dependent unsilencing of tectal neurons. These results therefore support a model in which GABAergic and glutamatergic transmitter systems function synergistically to enable a neuron to recruit the synaptic excitation it needs to develop sensory-driven spiking activity. This represents a transition with important consequences for both the functional output and the activity-dependent development of a neuron.

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Delestrée, Nicolas. "Excitabilité intrinsèque, couverture synaptique et vacuolisation dendritique des motoneurones spinaux chez la souris SOD1-G93A, modèle de la Sclérose Latérale Amyotrophique." Thesis, Paris 5, 2014. http://www.theses.fr/2014PA05T035/document.

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Les motoneurones tiennent une place remarquable dans l'organisme : ils constituent l'interface entre le système nerveux central et le système musculaire. Leur excitabilité est une caractéristique primordiale dans le comportement moteur puisqu'elle définit la force musculaire développée en réponse à la commande motrice. Chez la souris, la décharge des motoneurones est marquée par la présence d'oscillations de mode mixte (MMOs) entre les potentiels d'action. Ces MMOs permettent la décharge des motoneurones à basse fréquence et sont responsables d'un régime de décharge particulier nommé zone sous-Primaire, pendant lequel la fréquence de décharge est très variable et le gain de la relation courant-Fréquence élevé. Nous avons étudié les mécanismes responsables de l'apparition de ces MMOs à la fois de manière expérimentale, dans une préparation in vivo de souris anesthésié, incluant l'utilisation du Dynamic Clamp, et théorique, au moyen d'un modèle mono-Compartimental de motoneurone. Nos résultats ont montré que ces MMOs étaient causées par les courants sodiques et potassiques responsables des potentiels d'action et qu'elles émergeaient d'un état de faible excitabilité de la membrane, dû à l'inactivation lente des courants sodiques. Nous avons également montré que le courant de post-Hyperpolarisation pouvait paradoxalement augmenter l’excitabilité des motoneurones et réduire les MMOs en dé-Inactivant le courant sodique. La Sclérose Latérale Amyotrophique (SLA) conduit à la dégénérescence spécifique de ces motoneurones qui s'accompagne d'une vacuolisation de leur arborisation dendritique. L'augmentation précoce de l'excitabilité des motoneurones dans la maladie a largement été évoquée pour rendre compte de leur atteinte. Une hyperexcitabilité, aussi bien d'origine intrinsèque qu'extrinsèque pourrait en effet produire une excitotoxicité délétère pour la cellule. Si une telle modification de l'excitabilité est en cause dans la maladie, elle devrait persister jusqu'aux âges auxquels se produisent les premières dénervations des jonctions neuromusculaires. Nous avons enregistré les propriétés électrophysiologiques des motoneurones dans une préparation in vivo de souris adultes SOD1-G93A, modèle de la SLA. Nos résultats ont montré que leur conductance d'entrée était augmentée dans les jours qui précèdent les premières dénervations de leurs jonctions neuromusculaires. Malgré cela, leur excitabilité n'était pas modifiée. Loin d'être intrinsèquement hyperexcitables, une fraction d'entre eux perdaient même leur capacité à décharger de manière répétée. Nous avons finalement étudié la vacuolisation qui prend place dans les dendrites des motoneurones au cours de la maladie et son lien avec la couverture synaptique. Nous avons montré que la vacuolisation dendritique prenait place avant les dénervations et que la taille des vacuoles augmentait avec l'âge des souris SOD1-G93A. De manière intéressante, cette progression semblait plus rapide dans les motoneurones les plus sensibles à la maladie. Bien que la couverture synaptique n'était pas modifiée au cours de la maladie, nous avons mis en évidence une densité de synapses excitatrices et inhibitrices plus importante sur les régions dendritiques qui se vacuolisent. Ces résultats suggèrent un lien entre l'activité synaptique et la formation de vacuoles dans les motoneurones au cours de la SLA. Les motoneurones ne présentant pas d'hyperexcitabilité intrinsèque, une excitotoxicité d'origine synaptique pourrait alors être responsable de leur dégénérescence
Motoneurones hold a remarkable position in the organism: they are the interface between the central nervous system and the muscular system. Their excitability is a crucial characteristic in motor behavior since it determines the muscular force produced in response to motor command. In mice, motoneurone discharge is marked by the presence of sub-Threshold oscillations between action potentials which create a behavior of mixed mode oscillations (MMOs). These MMOs allow the motoneurones to fire at low frequency and are responsible for a sub-Primary range of discharge during which the firing frequency is irregular and the slope of current-Frequency relation is steep. We investigated the mechanisms responsible for these MMOs by in vivo recordings in anesthetized mice, using Dynamic Clamp, and by theoretical modelization in a monocompartimental model of motoneurone. Our results showed that MMOs were caused by sodium and potasium currents responsible for action potentials and that they emerged from a state of low membrane excitability caused by a slow inactivation of the sodium current. Paradoxically, we also showed that the after-Hyperpolarization current was able to increase the membrane excitability and to reduce MMOs by de-Inactivating the sodium current. Amyotrophic Lateral Sclerosis (ALS) leads to the specific degeneration of these motoneurones and is accompanied by a vacuolation of their dendritic trees. An early increase in motoneurons excitability during the disease has been widely proposed to account for their degeneration. Indeed, a motoneuron hyperexcitability of intrinsic or extrinsic origin could produce a deleterious excitotoxicity. If such a change of excitability is involved in the disease, it should last until the ages where the first denervation of neuromuscular junctions occurs. We recorded the electrophysiological properties of motoneurones in an in vivo preparation of adult SOD1-G93A mice, model of ALS. Our results showed that their input conductance was increased before the first denervation of their neuromuscular junctions. Nevertheless, their excitability was not modified. Far from being intrinsically hyperexcitable, a fraction of them even lost their ability to discharge repeatedly. We finally studied the vacuolation that takes place in dendrites of motoneurones during the disease and its relation with synaptic coverage. We have shown that the dendritic vacuolation takes place before the denervation and that the size of these vacuoles increases with age in SOD1-G93A mice. Interestingly, this increase was faster in the most vulnerable motoneurones. Although synaptic coverage was not altered in the disease, we ¬revealed higher densities of excitatory and inhibitory synapses on dendritic regions that vacuolate. These results suggest a link between synaptic activity and vacuoles formation in motoneurones during ALS. Motoneurones were not intrinsically hyperexcitable, instead, an excitotoxicity from a synaptic origin may be responsible for their degeneration

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Chauviere, Laëtitia. "Déficits cognitifs et altération de l'activité de réseau au cours de l'épileptogenèse dans un modèle expérimental d'épilepsie du lobe temporal." Thesis, Aix-Marseille 2, 2010. http://www.theses.fr/2010AIX20662/document.

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L’épilepsie du lobe temporal (ELT) est la forme d’épilepsie partielle la plus fréquente chez l’adulte. Elle se caractérise par une période de latence pendant laquelle l’ELT se met en place. Cette période est appelée épileptogenèse. L’épileptogenèse reste une période inaccessible chez l’Homme. Cependant, les modèles animaux présentent l’avantage de pouvoir l’étudier, dans le but de prévenir l’ELT. Ainsi, mon travail de thèse a consisté à mettre en évidence des marqueurs prédictifs de l’épileptogenèse, sur le plan cognitif et électrophysiologique in vivo, à partir du modèle pilocarpine. Les résultats ont montré que dès le stade précoce de l’épileptogenèse, des déficits de mémoire spatiale corrélaient avec une diminution de la puissance des oscillations thêta chez les animaux pilocarpine, sans modification jusqu’au stade chronique. Au même stade, une diminution de la puissance et de la fréquence des oscillations thêta lors du comportement d’exploration a été observée. L’activité interictale, activité paroxystique présente chez les patients entre leurs crises et caractéristique du stade épileptogène dans les modèles animaux, ne corrèle pas directement avec les déficits cognitifs mais diminue la puissance des oscillations thêta dans l’onde après la pointe au cours de l’épileptogenèse mais plus au stade chronique, ce qui suggère une importante modification du réseau avant le stade chronique. On a également décrit deux types d’activité interictale dont les propriétés (amplitude, nombre) et la dynamique au cours du temps sont modifiées juste avant la première crise spontanée, ce qui pourrait constituer, comme les déficits spatiaux et l’altération du rythme thêta, un marqueur prédictif de l’épileptogenèse. De plus, une augmentation du couplage entre l’hippocampe et le CE est observée au cours de l’épileptogenèse mais plus au stade chronique, alors qu’une modification du flux de l’information entre ces deux structures au stade épileptogène précoce persiste jusqu’au stade chronique, indépendamment de la présence ou non d’activité interictale. Ces résultats mettent en évidence la construction d’un réseau épileptogène, un changement majeur du réseau avant la première crise spontanée, et des marqueurs qui pourraient être prédictifs de l’épileptogenèse. L’ELT, les oscillations et les fonctions cognitives faisant intervenir des propriétés de réseau, tels les processus de synchronisation, l’enregistrement de 15 structures au sein du lobe temporal a montré, à partir du modèle pilocarpine, un réseau doté de caractéristiques plus « small-world » (SW) qui tendrait à se synchroniser plus localement, avec une perte des connexions longue distance. Ces résultats pourraient expliquer les altérations de réseau observées précédemment au cours de l’épileptogenèse. L’analyse SW et de cohérence, à l’échelle de ce réseau de structures, lors de différents états (comportementaux, processus cognitifs), mettent en évidence des changements de la dynamique lors de ces états, en conditions normales et pathologiques. Toutes ces modifications de réseau doivent être sûrement recrutées dans la mise en place d’un cerveau épileptique et des altérations cognitives associées
Temporal lobe epilepsy (TLE) is the most common form of partial epilepsy in adults. TLE is characterized by a latent period during which TLE takes place. This period is called epileptogenesis. In TLE patients, epileptogenesis is unexplored. However, the use of animal models, like pilocarpine model, allows the study of epileptogenic processes, in order to try to prevent TLE. Thus, my PhD work tries to yield some predictive markers of epileptogenesis, in the pilocarpine model. We studied cognitive and electrophysiological in vivo alterations in this model. We showed that there are early and persistent spatial deficits that correlate with a decrease of the power of theta oscillations, i.e. during the early stage of epileptogenesis and the chronic stage. At the same time, there is also a decrease of power and frequency of theta rhythm during exploratory behaviors. Interictal-like activity (ILA) is a pathological activity present during epileptogenesis in experimental models. ILA does not correlate with cognitive deficits, but decreases theta power after the spike, i.e. in its wave, during epileptogenesis but not during the chronic stage anymore. This suggests an important network alteration before the chronic stage. Indeed, we described two types of ILA, whose properties (number, amplitude) and dynamics evolved during epileptogenesis with a major switch just before the first spontaneous seizure. All together, these results may constitute, with spatial deficits and theta rhythm alterations, predictive markers of epileptogenesis. Moreover, we showed an increase in the coupling, ILA-dependent, between the hippocampus and the entorhinal cortex, during epileptogenesis but not during the chronic stage, whereas a reversal of the information flow between these two structures occurs at the early stage of epileptogenesis and persists without any modification till the chronic stage. These results suggest the build-up of an epileptogenic network, a major switch of network properties just before the first spontaneous seizure, and some markers that could be predictive of epileptogenesis. TLE, oscillations and cognition involved processes at the network level, in particular synchronization processes. These processes could be possible via oscillations, which allow information transfer between structures of the network, in order to provide behavioral and cognitive processing. Recordings performed in 15 different structures of the temporal lobe showed, in pilocarpine animals, a network with more “small-world” (SW) features, with a higher local clustering and a loss of long-range connections. These results could explain cognitive and oscillatory alterations observed previously during epileptogenesis. SW and coherence analysis, at the network level, between signals during different brain-states (behaviors and cognitive processes) showed changes in dynamics occurring during these states, in normal and epileptogenic conditions. All these modifications in network activities may be involved in the construction of an epileptic brain and in associated cognitive deficits

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Ziebro, Thomas R. "In vivo PPy(DBS) sensors to quantify excitability of cells via sodium fluctuations in extracellular solution." The Ohio State University, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=osu1492031927557033.

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Gajowa, Marta. "Synaptic and cellular mechanisms underlying functional responses in mouse primary visual cortex." Thesis, Sorbonne Paris Cité, 2018. http://www.theses.fr/2018USPCB125.

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L'élaboration de l'information dans le cerveau est basée sur les propriétés des neurones qui analysent leurs inputs et génèrent les potentiels d'actions, ainsi que sur un réseau synaptique d'une complexité beaucoup plus importante que ce que l'homme peut créer. Mon projet consiste à étudier ces éléments dans le cortex visuel de la souris, pour décrire comment ils permettent aux neurones de répondre à des caractéristiques du scène visuelle. Je développe des outils optogénétiques pour pouvoir stimuler des neurones individuels in vivo, ce qui va ensuite être intégré avec des mesures de leur réponse visuelle pour déterminer le circuit synaptique fonctionnel Je vais ensuite faire des mesures précises des inputs synaptiques évoqués par les stimuli visuels, suivies des réinjections des reconstructions statistiques de ces inputs dans le même neurone, établir des limites biophysiques permettant de déchiffrer le code neuronal dans des conditions normales et pathologiques
Feature selectivity of cortical neurons, one example of functional properties in the brain, is the ability of neurons to respond to particular stimulus attributes - e.g. the receptive field of a neuron in the primary visual cortex (V1) with respect to object movement direction. This thesis contributes to understanding how feature selectivity arises in mouse V1. It is divided into two parts, each based on distinct approaches to elucidate visual processing mechanisms, the first at a population level and the second at the single neuron level. First, on a population level, I have developed tools towards an eventual project that combines 2-photon optogenetics, 2-photon imaging and traditional whole-cell electrophysiology to map functional connectivity in V1. This map will provide a link between cell tuning (i.e. cell function) and network architecture, enabling quantitative and qualitative distinction between two extreme scenarios in which cells in mouse V1 are either randomly connected, or are associated in specialized subnetworks. Here I describe the technical validation of the method, with the main focus on finding the appropriate biological preparation and reagents. Second, based on whole-cell patch recordings of single mouse V1 neurons in vivo, I characterize the neuronal input-output (I/O) transfer function using current and conductance inputs, the latter intended to mimic the biophysical properties of synapses in a functional context. I employ a novel closed-loop in vivo protocol based on a combination of current, voltage and dynamic clamp recording modes. I first measure the basic I/O transfer function of a given neuron with current and conductance steps, under current and dynamic clamp, respectively. I then measure the visually evoked spiking output, under current clamp, and the synaptic conductance input, under voltage clamp, to that neuron. Finally, I reintroduce variations of the visually-evoked conductance input to the same cell under dynamic clamp. In that manner, I describe an I/O transfer function which allows a characterization of the mathematical operations performed by the neuron during functional processing. Furthermore, modifications of the relative scaling and the temporal characteristics of the excitatory and inhibitory components of the reintroduced synaptic input, enables dissection of each component's role in shaping the spiking output, as well as to infer overall differences between various physiological cell types (e.g. regular-adapting, presumably excitatory, versus fast-spiking, presumably inhibitory, neurons). Finally, examination of the transfer functions, in particular their dependence on temporal modifications, provides insights on the relationship between the neuronal code and the biophysical properties of neurons and their network

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Pracucci, Enrico. "Unraveling alterations of excitation/inhibition balance in in vivo models of epilepsy and genetic autism." Doctoral thesis, Scuola Normale Superiore, 2019. http://hdl.handle.net/11384/85883.

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One prominent feature of brain computation is the excitation inhibition balance (E/I balance) that represents one of the main homeostatic functions of the brain. Its aim is to maintain the neural circuits in a narrow and safe range of action. Within this range, the brain network can receive and analyze sensory inputs and produce a modulated output, proportional to the stimuli intensity. Any imbalance in this equilibrium leads to abnormal responses to external stimuli and results in pathological behavior. Indeed, neurological pathologies known for featuring a deep alteration of the E‐I balance are epilepsy and autism, which often occur together in the same patient. Several human genetic syndromes caused by alterations of genes involved in neural development feature signs like autism and epilepsy. Thus, they represent important cases for studying and understanding the role of these single altered genes in the development and regulation of the brain balance. In return, we hope that this knowledge of these genes and more generally of human brain network can be useful in treating the patients affected by these conditions and can help us improve their quality of life. In my work, I studied the regulation of the E/I balance in mouse models of neurological diseases from three different points of view. In the first set of experiments, I studied the E/I balance in a focal model of epileptiform activity. This model is produced by the local application of bicuculline to the mouse cortex. Bicuculline is a competitive GABAA receptor antagonist that, when applied, leads to the development of persistent and periodic interictal spikes at the injection site, while activity appears to be normal in nearby areas that are not reached by bicuculline. In our experiments, we showed that, even in the apparently normal area, there is a disruption of cortical computation. Specifically, the disruption occurs whenever an interictal spike is generated in the epileptic focus. This can have important impact on our understanding of epilepsy and of its treatment since interictal spikes are a common feature not only of epileptic patients, but can also appear in non‐epileptic subject, apparently without any consequence. From our results, we concluded that interictal activity can actually interfere with brain operation not only in the center of the epileptiform activity, but also in the connected areas, where the E/I balance is not directly disrupted. These results provide an example of the fact that apparently non‐symptomatic interictal spikes can affect brain computation. The second experimental model that I studied is a mouse model for a specific human genetic disease: the Phelan‐McDermid syndrome. This is a developmental disease, caused by a genomic deletion at site 22q13. The main suspect for causing the disease is one gene, Shank3, which encodes for a scaffold protein localized in the post‐synaptic density of glutamatergic synapses. In this model, we studied the computation of visual stimuli and we found an alteration of the contrast‐response curve. This is a defining relationship of visual processing: it is the transfer function that converts the visual input into a neural output. This means that to each intensity of visual stimulation corresponds a certain intensity of the neural response, of the visual cortex. We determined that, in Shank3 mutant mice, this curve was altered and showed an increased response to less intense stimuli and showed also a poor modulation of responses to high‐contrast stimulations. An interpretation of this can be that these mice are more sensitive to low‐contrast stimuli, but completely lose the ability of telling apart different high‐contrast stimuli from each other. Therefore, the Phelan McDermid mouse becomes “blinded” by weak stimulations as if they were seeing strong stimulus. Finally, we studied the behavior of the chloride ion in a drug‐induced epileptic seizure model. Chloride ion is of pivotal importance in neurons were the activation of ionotropic GABA and glycine receptors, which increase chloride membrane conductance in response to GABA or glycine release respectively. The intracellular concentration of chloride ions decides what is the effect of GABA release. Traditionally, ionotropic GABA receptors activation was thought to be inhibitory only, but the excitatory or inhibitory nature of these receptors is determined by the intracellular concentration of chloride ions. This concentration in normal adult neurons is thought to be around 5 mM: at this concentration, the effect of the activation of GABA receptors is an inhibition of the postsynaptic element. We investigated if the chloride concentration can be varied under extreme pathologic conditions as during epileptic seizures in a drug induced mouse model. In these animals, the epileptic seizures were produced by local administration of 4‐aminopyridine (4‐AP), a potassium channel antagonist. The effect of 4‐AP is to cause accumulation of chloride ions in neurons and this suggests that, in epileptic crisis, the role of inhibitory neurons can actually favor excitation.

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Chik, William Wai Bun. "In vivo and in vitro high density spatial and temporal resolution, visual and thermal mapping of radiofrequency ablation lesions utilising novel technologies to improve the success and safety of cardiac electrophysiology ablation procedures." Thesis, The University of Sydney, 2014. http://hdl.handle.net/2123/12885.

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Radiofrequency ablation (RFA) has emerged as an important curative therapy for treatment of cardiac arrhythmias. However, significant deficiencies exist in achieving successful RFA outcomes while ensuring patients safety. Therefore, in this thesis we constructed an in vitro novel thermochromic phantom model to accurately assess RFA lesion size with higher spatial and temporal in order to achieve the optimal balance of delivering RF energy without causing overheating. Additionally, we ablated using an in vivo novel direct endocardial visualisation ablation catheter that preserves a clear field of view during delivery of RF energy at the desired target site. We developed a novel and practical electrogram-gated delivery of RFA such that it negated the effects cardiac contractions and respiratory motion related sliding catheter motion for creation of predictably consistent lesion depth irrespective of the degree of catheter motion occurring. Finally, we developed an in vitro novel acoustic hydrophone to detect impending steam pop during RFA such that it can be prevented in time to avoid potentially devastating clinical complications of cardiac perforation, tamponade and death. Ultimately, our goal was to enhance the proceduralist’s ability to achieve a desired balance between creating transmural lesion and preventing tissue overheating with steam pop and/or thrombus formation.

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Rajaraman, Swaminathan. "Micromachined three-dimensional electrode arrays for in-vitro and in-vivo electrogenic cellular networks." Diss., Atlanta, Ga. : Georgia Institute of Technology, 2009. http://hdl.handle.net/1853/28129.

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Thesis (M. S.)--Electrical and Computer Engineering, Georgia Institute of Technology, 2009.
Committee Chair: Mark G. Allen; Committee Member: Elliot L. Chaikof; Committee Member: Ionnis (John) Papapolymerou; Committee Member: Maysam Ghovanloo; Committee Member: Oliver Brand.

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Nguyen, Thanh Hai. "Cibles sérotoninergiques et non sérotoninergiques des ISRS : approches Pharmacologique et Génétique in vivo chez la souris." Phd thesis, Université Paris Sud - Paris XI, 2011. http://tel.archives-ouvertes.fr/tel-00663312.

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Les inhibiteurs sélectifs de recapture de la sérotonine (5-HT) (ISRS) bloquent directement le transporteur de la 5-HT (SERT) et stimulent indirectement de multiples auto- et hétérorécepteurs5-HT par l'augmentation de la concentration extracellulaire de 5-HT dans la fente synaptique. Cependant, le rôle des différents récepteurs ainsi que leur interaction dans les effets thérapeutiques des ISRS restent mal connus. Nous avons tenté de les identifier à l'aide de tests neurochimiques (microdialyse intracérébrale in vivo) et électrophysiologiques en utilisant une approche pharmacologique (utilisation de escitalopram, de ligands des récepteurs 5-HT1A/2A) et génétique (utilisation de souris knock-out [KO] SERT, 5-HT1A ou 5-HT2A). Les études neurochimiques et électrophysiologiques révèlent que les auto-(1A) et hétéro-(2A) récepteursagissent de concert pour maintenir une influence inhibitrice sur le système sérotoninergique, en particulier, en réponse au escitalopram : l'absence d'un récepteur est compensée par une régulation de l'autre. Enfin, les souris KO SERT constituent un nouveau modèle pour tester le mécanisme du escitalopram dans l'augmentation des concentrations de noradrénaline (NA).

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Kaufmann, Anna-Kristin. "Functional properties of the intact and compromised midbrain dopamine system." Thesis, University of Oxford, 2017. https://ora.ox.ac.uk/objects/uuid:8769a453-aa91-4509-b06e-48f25e88f15a.

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The midbrain dopamine system is involved in many aspects of purposeful behaviour and, when compromised, can have devastating effects on movement and cognition as seen in diseases like Parkinson's. In the healthy brain, dopamine neurons are thought to play particularly important roles in learning by signalling errors in reward prediction. The objective of this thesis was to investigate the diversity in the functional properties of the midbrain dopamine system, and how this is altered through genetic variation of relevance to Parkinson's and development of cell phenotype. This objective was addressed with a combination of behavioural experiments, in vivo single-cell recording and labelling (both in anaesthetised as well as awake rodents), immunofluorescence labelling, retrograde tracing and stereology. In a first set of experiments, it was demonstrated that chronic as well as acute genetic challenges can alter the firing patterns of midbrain dopamine neurons. Using a novel bacterial artificial chromosome-transgenic rat model, it was shown that the R1441C mutation in human leucine-rich repeat kinase 2, which is linked to Parkinson's, leads to motor deficits and an age-dependent reduction in the in vivo firing variability and burst firing of substantia nigra pars compacta (SNc) dopamine neurons. These findings help reveal processes of early, pre-degenerative dysfunction in dopamine neurons in Parkinson's. Similar effects on firing variability and burst firing of SNc dopamine neurons were found in a mouse model with conditional knock- out of the transcription factors Forkhead box A1 and A2 (FoxA1/2) in midbrain dopamine neurons. These findings indicate that FoxA1/2 are not only crucial for the early development of dopamine neurons, but also their function in the mature brain. In a second set of experiments in wildtype mice, it was demonstrated that midbrain dopamine neurons (located in SNc and ventral tegmental area) show diverse expression of the molecular markers Calbindin, Calretinin, Aldh1a1, Sox6, Girk2, SatB1 and Otx2. It was found that selective expression of these markers is of use for discriminating between midbrain dopamine neurons that project to dorsal striatum or nucleus accumbens. To elucidate whether the diverse molecular marker expression would map onto dopamine neurons whose firing correlates with distinct behavioural events, midbrain dopamine neurons were recorded and labelled in head-fixed awake mice either exposed to neutral sensory stimuli or performing a classical conditioning paradigm. The population activity of midbrain dopamine neurons was not modulated by neutral sensory stimuli. Interestingly, fewer than 50% of identified dopamine neurons showed phasic firing increases following reward- predicting cue and/or reward delivery, despite the common assumption that most (if not all) midbrain dopamine neurons signal reward prediction errors. Instead, firing was modulated by other explanatory factors, such as licking, or showed no modulation during the task. Response types of midbrain dopamine neurons were not correlated with their anatomical location nor the selective or combinatorial expression of the markers Aldh1a1, Calbindin and Sox6. In conclusion, the first set of experiments identified how different genetic burdens can alter the in vivo firing of midbrain dopamine neurons, and provide new insights into how circuits can change in pathological or compensatory ways at early disease stages in Parkinson's. The second set of experiments revealed striking heterogeneity of midbrain dopamine neurons in the intact system, and established further a functional diversity in the response types of identified midbrain dopamine neurons that is only partially consistent with canonical reward prediction error signalling.

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Delaville, Claire. "Implication des systèmes monoaminergiques dans la physiopathologie de la maladie de Parkinson : étude comportementale et électrophysiologique in vivo." Thesis, Bordeaux 2, 2011. http://www.theses.fr/2011BOR21828/document.

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Depuis les années 60, la maladie de Parkinson est considérée comme une conséquence de la perte des neurones dopaminergiques de la substance noire pars compacta. Cependant, dans les modèles animaux de cette pathologie, la perte dopaminergique seule ne reproduit pas de façon simultanée les symptômes moteurs et non moteurs observés chez les patients. De plus en plus d’études suggèrent l’implication des systèmes noradrénergique et sérotoninergique à la fois dans la manifestation des symptômes mais aussi dans les effets secondaires de la L-Dopa et de la stimulation à haute fréquence (SHF) du noyau sous thalamique (NST). Le travail de cette thèse s’inscrit dans ce champ de recherche visant une meilleure compréhension de la physiopathologie et la thérapie de la maladie de Parkinson.Dans un premier temps, nous nous sommes intéressés au rôle respectif des trois monoamines dans la manifestation des symptômes moteurs et non moteurs ainsi que dans l’activité pathologique de trois structures majeures des ganglions de la base, le NST, la pars reticulata de la substance noire et le globus pallidus. L’ensemble de nos résultats démontre que la perturbation des trois systèmes monoaminergiques joue un rôle important à la fois dans la manifestation des troubles moteurs et non moteurs mais aussi dans l’induction de l’activité électrique pathologique des neurones au sein des ganglions de la base. Dans un second temps, nous avons étudié l’efficacité des traitements antiparkinsoniens sur les troubles moteurs et non-moteurs induits par les différentes déplétions monoaminergiques. Nos résultats montrent que quand la déplétion dopaminergique est associée à la déplétion d’une autre monoamine la SHF du NST présente une efficacité moins importante que celle lors d’une déplétion en dopamine seule. Ceci permet d’expliquer le manque d’efficacité de ce traitement chez certains patients.Enfin, comme peu d’études se sont intéressées au rôle de la noradrénaline dans la modulation de l’activité neuronale au sein des ganglions de la base, nous avons étudié les effets d’agents noradrénergiques injectés localement dans le NST sur le comportement moteur et sur l’activité électrique des neurones du NST. Nos résultats montrent que la modulation noradrénergique au niveau du NST ne dépendait pas de l’innervation dopaminergique au sein des ganglions de la base. De plus, nous avons pu mettre en évidence que les récepteurs alpha1 modulent la fréquence de décharge, tandis que les récepteurs alpha2 jouent un rôle important dans la genèse de l’activité en bouffée des neurones du NST ce qui pourrait être á l’origine des déficits moteurs.Les résultats des travaux de cette thèse ont donc permis d’apporter de nouvelles évidences sur l’implication des trois systèmes monoaminergiques dans la physiopathologie des symptômes moteurs et non moteurs, dans l’activité pathologique des ganglions de la base ainsi que dans l’efficacité des traitements antiparkinsoniens. De plus, nous avons pu montrer que les récepteurs noradrénergiques alpha sont impliqués dans le contrôle de l’activité des neurones du NST et par conséquent dans le contrôle moteur
The loss of dopamine (DA) nigro-striatal neurons has been the pathophysiological focus of the devastating conditions of Parkinson’s disease, but depletion of DA alone in animal models has failed to simultaneously elicit both the motor and non-motor deficits of PD. There is growing evidence that additional loss of locus coeruleus noradrenaline (NA) and dorsal raphe serotonin (5-HT) neurons in PD could be involved in the clinical expression of many of the observed deficits but also on the efficiency and on the side effects of antiparkinsonian treatments, L-Dopa and High Frequency Stimulation (HFS) of the subthalamic nucleus (STN).First, we focused on the respective role of DA, NA and 5-HT systems on motor and non-motor deficits and on the pathological activity of three basal ganglia nuclei, STN, substantia nigra pars reticulata and globus pallidus. Results of the present study bring new insights into the combined roles of the three monoaminergic systems in the motor and non motor symptoms of PD and also into the pathological activity of basal ganglia nuclei.Second, we studied the involvement of DA, NA and 5-HT depletions on the efficiency of L-Dopa and HFS of STN. Our results show that when DA depletion is combined with another monoamine depletion, STN HFS is less efficient compared to the situation when DA is depleted alone. These data provide a clear explanation on the lack of efficacy of this treatment in some operated parkinsonian patients.Finally, as few studies focused on NAergic modulation of basal ganglia, we studied the effects of NAergic agents locally injected into the STN on motor behavior and also on STN neuronal activity. We show that alpha 1 NAergic receptors are implicated in the modulation of firing rate and that alpha 2 receptors play an important role in the emergence of burst activity, which could be at the origin of motor deficits.Results of this thesis provide new evidences on the involvement of the three monoaminergic systems in motor and non motor symptoms and also in the efficiency of antiparkinsonian treatments. Moreover, we show that NAergic alpha receptors are implicated in the control of STN neuronal activity and consequently in the motor control

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Gupta, Sujasha. "Development and Utilization of a Novel Synaptic Transistor to Detect Dynamic Neuronal Processes." The Ohio State University, 2020. http://rave.ohiolink.edu/etdc/view?acc_num=osu1590765716831174.

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Zanona, Querusche Klippel. "Estudo dos efeitos da MT3 na plasticidade sináptica de longa duração e interações com a sinalização gabaérgica em hipocampo dorsal pela eletrofisiologia in vivo em animal anestesiado." reponame:Biblioteca Digital de Teses e Dissertações da UFRGS, 2015. http://hdl.handle.net/10183/132342.

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A sinalização muscarínica exerce função modulatória sobre diferentes aspectos da cognição e emoções. Todos os cinco subtipos de receptores muscarínicos (mAChR), M1 a M5, são expressos no hipocampo de mamíferos e são ativados de forma sobreposta pela maioria dos fármacos, dificultando avanços significativos na compreensão da contribuição de cada componente desse sistema. A toxina muscarínica 3 (MT3) é um antagonista seletivo para o subtipo M4, permitindo a investigação das ações modulatórias deste receptor no aprendizado, memória e plasticidade sináptica. Os M4 são receptores acoplados à proteína G (GPCRs) que atuam via Gi/o desencadeando efeitos inibitórios sobre as células em que estão presentes. Estudos comportamentais anteriores indicam que a administração de MT3 imediatamente após o treino em uma tarefa aversiva produz efeito amnéstico, enquanto que a administração antes da evocação, causa facilitação. Uma explicação para estes resultados é que os circuitos locais envolvidos na consolidação e na evocação da memória diferem em sua natureza. Nesse contexto, sugere-se que o efeito amnéstico da MT3 sobre a consolidação seja consequência da supressão da inibição de interneurônios GABAérgicos; enquanto que na evocação, esse efeito se daria sobre as sinapses glutamatérgicas. Assim, no presente trabalho, com o objetivo de investigar como o receptor M4 modula a plasticidade sináptica de longa duração e interage com uma dessas sinalizações, no caso a GABAérgica, utilizou-se a técnica de eletrofisiologia in vivo de hipocampo de ratos anestesiados. Para tanto, foram realizados registros extracelulares do potencial excitatório pós-sináptico de campo (fEPSP) de CA1 evocados por estimulação contralateral da via Colateral de Schaffer com infusão dos fármacos 15 min antes ou depois da estimulação elétrica de alta ou baixa frequência (HFS: 10 trens 0,5 Hz, 20 pulsos 100 Hz; ou LFS: 600 pulsos 1 Hz, respectivamente). MT3 (4,0 μg/μl), bicuculina (0,06 μg/μl), baclofen (0,2 μg/μl) e veículo, isoladamente ou combinados, não alteraram a amplitude da resposta evocada basal ou a facilitação por pulso pareado (FPP) 15 min após a infusão. MT3 aparentemente atenuou, mas não de forma significativa, a potenciação de longa duração (LTP) em relação ao controle (potenciação 60 min após a HFS de 31,8% e 66,0%, respectivamente). Além disso, não houve diferença significativa entre a amplitude do fEPSP no período basal e 60 min após a HFS sob ação da MT3. Bicuculina, embora não tenha abolido a LTP e nem causado alteração na FPP, produziu uma potenciação de apenas 36,4%. Baclofen promoveu uma potenciação semelhante à dos controles. A administração de baclofen também reduziu significativamente a FPP em relação ao basal. A administração conjunta de MT3 com bicuculina ou baclofen promoveu uma potenciação semelhante ao controle. MT3 não apresentou efeito sobre a manutenção da LTP quando aplicada 15 min após a HFS. Por fim, não foi possível induzir a depressão de longa duração (LTD) com o protocolo de LFS utilizado. Embora não tenha ocorrido diferença estatisticamente significativa entre os grupos devido ao baixo número de animais utilizados, os dados sugerem a possibilidade de uma amplitude reduzida da LTP quando da injeção de bicuculina. Baclofen alterou a FPP em relação ao fEPSP basal, o mesmo não tendo sido observado no grupo controle. Com a administração concomitante de MT3, tais alterações deixam de ser identificadas. Ainda que os achados experimentais sejam inconclusivos e preliminares, este trabalho permitiu a padronização da técnica de eletrofisiologia in vivo em animal anestesiado o que abre portas para futuras investigações.
The cholinergic muscarinic system exerts modulatory function over different aspects of cognition and emotion. All five muscarinic receptors subtypes (mAChR), M1 to M5, are expressed at mammals hippocampus and at least two of them are simultaneously activated by most of the drugs, hindering significant advances on the role of each component of this system. The muscarinic toxin 3 (MT3) is a selective antagonist for the M4 subtype, allowing the investigation of the modulatory actions of this receptor over learning, memory and synaptic plasticity. The M4 are G protein coupled receptors (GPCRs) that act through Gi/o triggering inhibitory effects on which cells they are occur. Previous behavioral studies have shown that administration of MT3 soon after aversive task training exerts amnestic effects over memory, while administration prior to recall, leads to facilitation. A possible explanation to these results could be that the local circuits involved on memory consolidation and recall are different in nature. On this perspective, the amnestic effect of MT3 over memory consolidation should be consequence of GABAergic interneurons inhibition suppression; while the effect on recall, should be over glutamatergic synapses modulation. Thereby, the present work, with the objective to investigate how the M4 receptor modulates long-term synaptic plasticity and interacts with the GABAergic system, in vivo electrophysiological approach of anesthetized rats’ hippocampus was applied. Hence, field excitatory postsynaptic potentials (fEPSP) from CA1 were recorded after stimulation of contralateral Schaffer Collateral pathway with drugs infusion 15 min before or after high or low frequency electric stimulation (HFS: 10 trains 0.5 Hz, 20 pulses 100 Hz; LFS: 600 pulses 1 Hz, respectively). Neither MT3 (4.00 μg/μl), bicuculline (0.06 μg/μl), baclofen (0.20 μg/μl) nor vehicle, isolated or combined, changed the baseline evoked response amplitude 15 min after infusion nor the paired-pulse facilitation ratio (PPF). MT3 apparently attenuated, but not significantly, the long-term potentiation (LTP) compared to control (31.8% and 66.0% potentiation 60 min after HFS, respectively). In addition, there was no significant difference between baseline and 60 min after HFS fEPSP amplitude at MT3 group. Bicuculline, although did not abolish LTP neither changed PPF, it did produce a potentiation of only 36.4%. Baclofen induced a potentiation similar to control group. Baclofen administration also significantly reduced PPF compared to baseline. The simultaneous administration of MT3 and bicuculline or baclofen led to a potentiation similar to the control group. MT3 did not show any effect over LTP maintenance when applied 15 min after HFS. Lastly, it was not possible to induce long-term depression (LTD) with the used LFS protocol. Although there was no statistical significance between groups due to the low animal numbers used, data suggest that bicuculline had reduced LTP amplitude. Baclofen did alter PPF and the same was not observed on control group. When bicuculline or baclofen were injected with MT3, those alterations were not observed. These are inconclusive and preliminary results, notwithstanding this work allowed to set up the in vivo electrophysiology technique in anesthetized animals what will provide new tools for future research.

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Couderc, Yoni. "Dopaminergic modulation of the insular cortex in anxiety-related behaviors and emotional valence." Electronic Thesis or Diss., Bordeaux, 2025. http://www.theses.fr/2025BORD0017.

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L'anxiété est une réponse adaptative des individus exposés à un contexte potentiellement menaçant. Cependant, des niveaux d'anxiété peuvent rester élevés de manière persistante, indépendamment de l'environnement, et devenir pathologiques. Bien que les troubles anxieux soient les affections psychiatriques les plus répandues – caractérisés par des niveaux chroniques élevés d'anxiété et un biais attentionnel envers les stimuli à valence négative – les mécanismes neurobiologiques sous-jacents restent encore mal compris. De nombreuses études, menées chez l'humain et dans des modèles précliniques, ont mis en évidence l'implication de différents neuromodulateurs, notamment la sérotonine, la noradrénaline, mais aussi la dopamine. Des études d'imagerie fonctionnelle ont montré que le cortex insulaire (ou insula), en particulier sa région antérieure, est hyperactivé chez les individus souffrant de troubles anxieux en réponse à des stimuli saillants ou négatifs. Bien que la neurotransmission dopaminergique soit connue pour réguler l'anxiété chez l'humain et dans les modèles animaux, ses effets spécifiques sur l'insula antérieure restent largement inexplorés.Cette thèse vise à explorer le rôle de la transmission dopaminergique dans le cortex insulaire dans la modulation de l'anxiété et de la valence émotionnelle chez la souris. À travers une approche multifactorielle, cette recherche a permis de révéler comment la dopamine module la fonction de l'insula antérieure dans les comportements liés à l’anxiété et à la valence émotionnelle, selon trois niveaux d’analyse clés. (1) Tout d’abord, nous avons cartographié le système dopaminergique insulaire et identifié une forte densité de neurones exprimant les récepteurs dopaminergiques de type 1 (D1), particulièrement marquée dans l’insula antérieure, et sept fois supérieure à celle des neurones exprimant les récepteurs de type 2 (D2). De plus, l’activation pharmacologique des récepteurs D1 dans l’insula antérieure s’est révélée anxiogène, établissant un lien direct entre la signalisation dopaminergique insulaire et les comportements associés à l’anxiété. (2) Par photométrie en fibre, nous avons montré que l’amplitude de la libération de dopamine sur les neurones D1-positifs de l’insula antérieure augmentait lorsque les souris étaient exposées à des espaces anxiogènes ou à des chocs électriques légers. Cette libération de dopamine était positivement corrélée avec le niveau d'anxiété intrinsèque des souris, renforçant l'idée que la dopamine joue un rôle central dans la modulation des réponses anxieuses. (3) Enfin, grâce à l’analyse par intelligence artificielle des dynamiques de population neuronale et des enregistrements de neurones unitaires dans l’insula antérieure, nous avons identifié des propriétés de codage neuronal distinctes pour les environnements anxiogènes et protégés, ainsi que pour les stimuli gustatifs à valence positive ou négative. De façon intéressante, l’activation systémique des récepteurs D1, qui augmente les comportements de type anxieux, perturbe cette dichotomie de codage en rendant le codage des espaces protégés plus variable et celui des espaces anxiogènes plus spécifique. De plus, le codage des espaces anxiogènes était corrélé positivement au niveau d’anxiété intrinsèque des souris. Nous avons également observé une tendance à une corrélation positive entre la spécificité du codage des stimuli gustatifs négatifs et le niveau d'anxiété des souris.En conclusion, ces résultats mettent en lumière un nouveau modèle de codage neuronal dans l’insula antérieure, en lien avec l’anxiété et la valence émotionnelle. Ils dévoilent également des mécanismes de codage dépendant des récepteurs D1 dans l’insula antérieure de la souris, ouvrant ainsi de nouvelles perspectives pour comprendre et traiter les troubles anxieux
Anxiety is an adaptive response of individuals exposed to a potentially threatening context. However, anxiety levels can be persistently high independently of the environment and become pathological. Although anxiety disorders represent the most prevalent psychiatric conditions - characterized by chronic high levels of anxiety and an attentional bias towards negative valence - the underlying neurobiology remains poorly understood. Numerous studies in humans and in preclinical models revealed the implication of different neuromodulators including serotonin, norepinephrine, but also dopamine. Imaging studies have shown that the insular cortex (or insula), particularly its anterior region, is hyperactivated in individuals with anxiety disorders in response to salient or negative stimuli. Although dopamine neurotransmission is known to regulate anxiety in humans and animal models, its specific regulatory effects on the anterior insula have remained largely unexplored.This PhD dissertation aims to investigate the role of dopamine transmission in the insular cortex in shaping anxiety and emotional valence in mice. Through a multifaceted approach, this research uncovered how dopamine modulates anterior insula function in anxiety and valence processing at three key levels of analysis. (1) First, we mapped the dopaminergic system of the insular cortex and revealed a high density of neurons expressing type-1 dopamine receptors (D1) in the insula, particularly important in the anterior insula, and seven times greater than the density of neurons expressing type-2 dopamine receptors (D2). Then, we found that pharmacological activation of D1 in the anterior insula is anxiogenic, suggesting a direct link between insular dopamine signaling and anxiety-related behaviors. (2) Using fiber-photometry, we identified that the amplitude of dopamine release onto D1+ neurons in the anterior insula while mice were in anxiogenic spaces or receiving mild foot shocks was both positively correlated with mice level of trait anxiety. (3) Finally, population dynamics and deep-learning analyses of anterior insula single-unit recordings uncovered distinct coding patterns of anxiety-provoking and safe environments, as well as tastants of positive and negative valence. Remarkably, systemic D1 activation, which heightens anxiety-related behaviors, dampens this coding dichotomy by increasing coding variability for protected spaces while increasing the coding specificity for anxiogenic spaces. Interestingly, the coding reliability of anxiogenic areas was positively correlated with mice level of trait anxiety, and we observed a trend towards a positive correlation between the coding reliability of a negative tastants, and mice level of anxiety.Altogether, our findings provide a new model of neural population coding of anxiety and emotional valence and unravel D1-dependent coding mechanisms in the mouse anterior insula

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Reisiger, Anne-Ruth. "Pathologie du système de récompense : effets à long terme d’une exposition chronique à la nicotine et au sucrose." Thesis, Bordeaux 1, 2013. http://www.theses.fr/2013BOR14870/document.

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La prise volontaire de nicotine augmente l'excitabilité de la voie ILCx-BNST, entraînant une hyperactivité des neurones DA de l’ATV. Dans une première partie, l'objectif était d’étudier les neuroadaptations de la voie ILCx-BNST induites par l'auto-administration intraveineuse (AAIV) de nicotine. Les récepteurs cannabinoides CB1 contrôlent les propriétés renforçantes de la nicotine. Par conséquent, nous avons examiné le rôle des récepteurs CB1 du BNST. Nous montrons que l'acquisition de l’AAIV de nicotine est associée à une facilitation persistante de l'induction d’une potentialisation à long terme (LTP) CB1-dépendantes des synapses ILCx-BNST. La stimulation électrique du ILCx favorise également la persistance du comportement de recherche de nicotine pendant les périodes où la drogue n'est pas disponible. En outre, en utilisant la pharmacologie intra-BNST, nous montrons que la stimulation des récepteurs CB1 du BNST au cours de l’acquisition de lAAIV augmente la sensibilité aux stimuli associés à la nicotine. L’idée qu’il existe un appétit incontrôlable pour les aliments palatables, en dépit des conséquences négatives. Dans une seconde partie, notre projet a porté sur le rôle des neurones dopaminergiques (DA) de l’ATV dans la perception d’un stimulus aversif chez l’animal exposé au sucrose. Nos résultats indiquent que le sucrose augmente l'activité spontanée des neurones DA de la VTA. En outre, si un choc électrique provoque une inhibition presque complète de l'activité de VTA neurones DA chez les rats témoins, le sucrose perturbe la signalisation d'un stimulus aversif, indépendamment de l’état calorique du rat
Learning mechanisms associated with active responding for nicotine enhanced the excitability of the ILCx-BNST pathway. The objective of this project was to better understand the involvement of the ILCx-BNST pathway in nicotine self-administration. Since the endocannabinoid system controls nicotine reinforcement and nicotine-induced synaptic modifications, we examined the role of CB1 receptors in the BNST. We showed that acquisition of nicotine IVSA was associated with a persistent facilitation of LTP induction at ILCx-BNST synapses. Behaviorally, electrical stimulation temporarily increased excessive responding to nicotine when nicotine was not available. Moreover, using intra-BNST pharmacology, we revealed that stimulation of BNST CB1 receptors enhanced sensitivity to nicotine-paired cue. In contrast, after a prolonged history of nicotine intake, it blocked drug-seeking in a reinstatement model of relapse. Drug addiction is partly due to the inability to stop using despite negative consequences. The hypothesis that palatable food induces similar uncontrolled consumption is becoming more widespread. As drug addiction is known to increases activity of VTA DA neurons, we aimed to examine whether exposure to sucrose would induce similar neuronal modifications and impair the capacity to respond to an aversive stimulus. We found that sucrose enhanced spontaneous activity of DA VTA neurons. In addition, while a footshock caused a nearly complete inhibition of activity of VTA DA neurons in control rats, sucrose disrupted signaling of an aversive stimulus. These modifications were independent from the caloric state of the rats

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Monlezun, Laura. "Etudes structurales et fonctionnelles de la pompe d'efflux MexAB-OprM impliquée dans la résistance aux antibiotiques chez Pseudomonas aeruginosa." Phd thesis, Université René Descartes - Paris V, 2012. http://tel.archives-ouvertes.fr/tel-00801703.

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Pseudomonas aeruginosa est un pathogène opportuniste impliqué dans les infections nosocomiales. Sa multi résistance aux antibiotiques s'exerce notamment grâce à l'activation de pompes d'efflux membranaires. Il s'agit de systèmes tripartites composés d'une porine de la famille OMF (Outer Membrane Factor) ancrée dans la membrane externe, d'un transporteur de la famille des RND (Resistance Nodulation Division) localisé dans la membrane interne et d'un adaptateur périplasmique de la famille des MFP (Membrane Fusion Protein) qui consolide l'ensemble. Le travail réalisé au cours de cette thèse apporte une contribution à la compréhension des mécanismes d'assemblage et d'ouverture des pompes d'efflux ainsi qu'à leur régulation grâce au développement de nouveaux outils empruntés à la physique, à la biochimie et à la microbiologie. Une première étude a permis de déterminer la stoechiométrie d'interaction entre MexA et OprM par gel bleu natif (Ferrandez, Monlezun et al. 2012). Une deuxième étude a été consacrée, dans le cadre d'une collaboration avec l'équipe de B. Le Pioufle (ENS Cachan), à la caractérisation par électrophysiologie de l'ouverture de la porine OprM, insérée dans une membrane artificielle reconstituée sur une biopuce (Wang, Monlezun et al. 2012). Puis, afin d'étudier cette fois ci, le mécanisme d'ouverture de la porine OprM in vivo, une étude fonctionnelle par complémentation chez Pseudomonas aeruginosa a été initiée. Enfin, dans le cadre d'une collaboration avec l'équipe de P. Plésiat (Laboratoire de Bactériologie, Besançon), deux analyses de mutants cliniques par modélisation ont été réalisées sur le régulateur MexZ de la pompe MexXY/OprM et de la porine d'influx des carbapénèmes OprD.

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Williams, Mark. "Dynamique de l’excitabilité corticale dans l’épilepsie-absence et intégration sensorielle Integrative properties and transfer function of cortical neurons initiating absence seizures in a rat genetic model Building Up Absence Seizures in the Somatosensory Cortex: From Network to Cellular Epileptogenic Processes." Thesis, Sorbonne université, 2018. http://www.theses.fr/2018SORUS608.

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Une crise d’épilepsie résulte de la survenue soudaine d’une activité neuronale anormalement intense, rythmique et synchrone dans une région plus ou moins étendue du système nerveux central. Les conséquences cliniques sont extrêmement variées, selon les zones cérébrales affectées et la durée des crises, allant de brèves secousses musculaires très focalisées à une perte de conscience complète, éventuellement associée à des convulsions. Dans le cas de l’épilepsie-absence, une épilepsie généralisée d’origine génétique survenant fréquemment chez les enfants, les crises s’expriment essentiellement par une suspension des processus conscients dans toutes leurs dimensions, y compris une interruption des perceptions conscientes. Ces symptômes sont corrélés à des décharges de pointes-ondes (DPO) dans les électroencéphalogrammes (EEG) bilatéraux. Les mécanismes physiopathologiques des altérations de conscience au cours des crises d’épilepsie-absence restent l’objet de débats intenses, opposant des altérations fonctionnelles à grande échelle à un filtrage des informations exogènes par les oscillations épileptiques. Au cours de mes recherches, j’ai exploré l’hypothèse alternative, mais non exclusive, d’un dysfonctionnement dynamique dans les processus d’intégration sensorielle au sein des circuits thalamo-corticaux primaires. Des explorations électrophysiologiques fines n’étant pas réalisables chez les enfants épileptiques, j’ai utilisé un modèle génétique présentant une forte homologie avec la pathologie humaine : le Genetic Absence Epilepsy Rat from Strasbourg (GAERS). En combinant in vivo des enregistrements électrocorticographiques (ECoG) et intracellulaires dans le cortex somatosensoriel primaire (S1), précédemment identifié comme le site de déclenchement des crises, j’ai d’abord analysé les propriétés intégratives et d’excitabilité des neurones pyramidaux du cortex S1, durant et en dehors des crises, et je les ai comparées à celles des neurones homologues chez des rats non épileptiques. J’ai montré que ces neurones présentent lors des périodes inter-ictales une excitabilité accrue, s‘exprimant par une augmentation de la décharge des neurones en réponse à des stimulations excitatrices d’intensité croissante ainsi qu’une tendance exacerbée à se re-polariser suite à une hyperpolarisation de grande amplitude, suggérant un accroissement du courant cationique h. Au cours des crises, les mêmes neurones montraient des changements différentiels dans leur excitabilité membranaire selon la composante pointe ou onde dans l‘ECoG correspondant. La pointe était associée à une augmentation de décharge évoquée par un courant dépolarisant et à une diminution de résistance membranaire. Symétriquement, l’onde était corrélée avec une augmentation de résistance membranaire et une diminution d’excitabilité. Ces changements dynamiques des propriétés intégratives neuronales suggèrent une instabilité des réponses corticales lors du cycle pointe-onde pouvant « brouiller » les signaux sensoriels lors des crises. J’ai testé cette hypothèse en analysant les réponses des neurones corticaux, et des neurones thalamo-corticaux correspondants, à des stimulations appliquées sur les vibrisses controlatérales. Bien que les réponses synaptiques induites dans les neurones du cortex S1 par les stimulations sensorielles n’étaient pas globalement altérées lors des crises, elles étaient plus amples et plus efficaces pour déclencher des potentiels d’action pendant l’onde comparé à la composante pointe. Cet accroissement relatif de la réponse neuronale lors de l’onde ECoG résulte probablement de l’accroissement de résistance membranaire précédemment décrit, d’une augmentation de la force électromotrice des courants synaptiques glutamatergiques et de la forte probabilité de décharge des neurones thalamiques correspondants lors de cette composante
An epileptic seizure results from the sudden occurrence of abnormally intense, rhythmic and synchronous neuronal activity, in a more or less broad region of the central nervous system. The clinical consequences are extremely varied, depending on the affected brain areas and the duration of the seizures, ranging from brief localized muscular twitches to a complete loss of consciousness, potentially associated with convulsions. Absence epilepsy is a generalised epilepsy of genetic origin, mostly affecting children of school age. During absence attacks, children experience a suspension of conscious processes in all their dimensions, including an interruption of conscious perceptions. These symptoms are correlated with bilateral spike-wave discharges (SWD) in the electroencephalograms (EEGs). The pathophysiological mechanisms underlying the alteration of consciousness during absences remain the subject of an intense debate, opposing functional dysfunctions on large scale neural networks to a filtering of sensory information by epileptic oscillations. During my PhD research, I explored the alternative, but not exclusive, hypothesis of a dynamic dysfunction in sensory integration processes within primary thalamo-cortical circuits. Given that multi-scale electrophysiological investigations cannot be conducted in epileptic children, I used a genetic model prsenting a strong homology with the human pathology: the Genetic Absence Epilepsy Rat from Strasbourg (GAERS).By combining in vivo electrocorticographic (ECoG) and intracellular recordings in the primary somatosensory cortex (S1), previously identified as the site of seizure initiation, I first analysed the integrative properties and excitability of S1 pyramidal neurons, during and in between seizures, and compared them to those measured in homologous neurons from non-epileptic rats. I showed that these neurons exhibit a higher excitability during inter-ictal periods, expressed as an increased firing response to excitatory stimuli of increasing intensity, as well as an exacerbated tendency to depolarize following a hyperpolarization of large amplitude, suggesting an augmented cationic current h. During seizures, the same neurons showed specific changes in their membrane excitability, according to the spike or wave component in the corresponding ECoG. The spike component was associated with increased current-evoked firing and a decreased membrane resistance. Conversely, the wave was correlated with an increase in membrane resistance and a decrease in excitability. These dynamic changes in neuronal integrative properties suggest an instability of cortical responses during the spike-wave epileptic cycle that could "scramble" sensory signals during seizures. I tested this hypothesis by analysing the sensory responses of cortical neurons, and corresponding thalamo-cortical neurons, to stimulations applied to contralateral whiskers. Although synaptic responses induced in S1 neurons by sensory stimuli were not globally impaired during seizures, they were larger and more likely to trigger action potentials during wave compared to the spike component. This relative increase in neuronal responsiveness during the ECoG wave probably results from the previously described increase in membrane resistance, an augmented driving force of glutamatergic synaptic currents and a higher probability of action potentials discharge in the corresponding thalamic neurons during this component. My doctoral research indicates that sensory inputs processing persists in the thalamo-cortical circuits during SWDs, but that the alternation of the spike and wave components introduces a strong instability of the neuronal responses during seizures. This new pathophysiological mechanism could contribute to the inability to generate a conscious, stable and effective, perception during generalised epileptic seizures

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47

Pye, Richard Laurence. "Measuring the Acute Physiological Effects of Leptin in the Carotid Body." Wright State University / OhioLINK, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=wright1449583350.

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De, la crompe de la boissiere Brice. "Etude dynamique de la génération des oscillations Beta dans la maladie de Parkinson : approche électrophysiologique et optogénétique." Thesis, Bordeaux, 2016. http://www.theses.fr/2016BORD0325/document.

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Les ganglions de la base (GB) forment une boucle complexe avec le cortex et le thalamus qui est impliquée dans la sélection de l’action et le contrôle du mouvement. Les activités oscillatoires synchronisées dans le réseau des GB ont été proposées comme pouvant jouer un rôle essentiel dans la coordination du flux de l’information au sein de ces circuits neuronaux. Ainsi, leur dérégulation dans le temps et l’espace pourrait devenir pathologique. Dans la maladie de Parkinson (MP), l’expression anormalement élevée d’oscillations neuronales comprises dans les gammes de fréquences beta (β, 10-30 Hz) serait la cause des déficits moteurs (akinétique et bradykinétique) de cette maladie. Cependant, les réseaux neuronaux à l’origine des oscillations β et l’implication physiopathologique de celles-ci restent encore inconnus. Le noyau sous-thalamique (NST) est un carrefour anatomique des GB situé au centre de réseaux potentiellement impliqués dans l’émergence de ces états hyper-synchronisés. L’objectif de cette thèse était de déterminer le rôle causal des principales entrées du NST (i.e. le cortex moteur, le globus pallidus, et le noyau parafasciculaire du thalamus) dans le maintien et la propagation des oscillations β. Pour cela, nous avons développé des approches de manipulation optogénétique combinées à des enregistrements électrophysiologiques in vivo dans un modèle rongeur de la MP. L’ensemble de nos travaux démontre la contribution respective des différents circuits neuronaux interrogés et souligne l’importance du globus pallidus dans le contrôle de la propagation et du maintien des oscillations β dans l’ensemble de la boucle des GB
The basal-ganglia (BG) form a complex loop with the cortex and the thalamus that is involved in action selection and movement control. Synchronized oscillatory activities in basal-ganglia neuronal circuits have been proposed to play a key role in coordinating information flow within this neuronal network. If synchronized oscillatory activities are important for normal motor function, their dysregulation in space and time could be pathological. Indeed, in Parkinson’s disease (PD), many studies have reported an abnormal increase in the expression level of neuronal oscillations contain in the beta (β) frequency range (15-30 Hz). These abnormal β oscillations have been correlated with two mains symptoms of PD: akinesia/bradykinesia. However, which BG neuronal circuits generate those abnormal β oscillations, and whether they play a causal role in PD motor dysfunction is not known. The subthalamic nucleus (STN) is a key nucleus in BG that receives converging inputs from the motor cortex, the parafascicular thalamic nucleus and the globus pallidus. Here, we used a rat model of PD combined with in vivo electrophysiological recordings and optogenetic silencing to investigate how selective manipulation of STN inputs causally influence BG network dynamic. Our data highlight the causal role of the globus pallidus in the generation and propagation mechanisms of abnormal β-oscillations

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Aby, Franck. "Les neurones sérotoninergiques du noyau raphé Magnus dans le contrôle de la transmission nociceptive dans la corne dorsale de la moelle épinière : une étude optogénétique dans différents contextes pathophysiologiques." Thesis, Bordeaux, 2019. http://www.theses.fr/2019BORD0354.

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La douleur est une sensation et une expérience émotionnelle désagréable résultant de stimulations potentiellement nuisibles pour protéger l'intégrité du corps. Un mécanisme endogène impliquant le système PAG-RVM, module la sensation de douleur en filtrant les entrées nociceptives. Un équilibre entre des influences excitatrices et inhibitrices contrôle la transmission nociceptive et une perturbation de cet équilibre conduit à l’installation de douleurs pathologiques. Dans ce travail, nous avons utilisé une approche optogénétique pour cibler spécifiquement les neurones sérotoninergiques (5-HT) du noyau du raphé Magnus (RMg) projetant sur la corne dorsale de la moelle épinière. Nous avons montré que ces neurones exerçaient une action analgésique tonique par une diminution de l'excitabilité des neurones de projection de la corne dorsale de la moelle épinière. Cet effet étant indépendant du sexe. Nous avons également observé que les neurones sérotoninergiques (5-HT) sont indirectement liés aux neurones de projection par l'intermédiaire d'interneurones inhibiteurs locaux. Puis, nous avons montré que les neurones sérotoninergiques (5-HT) du RMg recevaient des projections des neurones à somatostatine du ventro-latérale de la substance grise périaqueducale (vlPAG) exerçant une facilitation descendante de la transmission nociceptive. Fait intéressant, nous montrons que dans un modèle de neuropathie périphérique, l'action inhibitrice des neurones à sérotonine (5-HT) du RMg est transformée en influence excitatrice, aussi bien chez les mâles que les femelles, en raison d'un déplacement de l'équilibre du chlore au sein de la moelle épinière. Ces résultats suggèrent que la même voie descendante peut être à la fois excitatrice et inhibitrice dans des conditions pathologiques, révélant des informations cruciales sur les changements à long terme associés à la douleur chronique
Pain is an unpleasant sensation and emotional experience elicited by potentially harmful stimulations to protect the integrity of the body. An endogenous mechanism involving the PAG-RVM modulatory system control pain sensation by filtering nociceptive inputs. A balance between both excitatory and inhibitory influences control nociceptive transmission and impairment in this balance leads to the development of pathological pain. In the present study, we used an optogenetic approach to specifically target serotoninergic neurons (5-HT) that projected to the dorsal horn of the spinal cord. We showed that these neurons exerted a tonic analgesic action through a decreased excitability of projection neurons of the dorsal horn of the spinal cord. This effect is gender independent. We also observed that 5-HT neurons are indirectly connected to projection neurons through local inhibitory interneurons. Then, we showed that 5-HT neurons of the RMg received descending inputs from the SST neurons of the ventro-lateral part of the periaqueductal gray (vlPAG) that exerted downward facilitation on pain transmission. Interestingly, we show that 5-HT inhibitory action is switched to an excitatory influence in a model of peripheral neuropathy due to a spinal chloride equilibrium shift. These results suggest that the same descending pathway can be both excitatory and inhibitory upon pathological conditions, providing crucial insights about long-term changes associated with chronic pain

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Glangetas, Christelle. "The Bed Nucleus of the Stria Terminalis between Stress and Reward." Thesis, Bordeaux, 2014. http://www.theses.fr/2014BORD0419/document.

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L’objectif principal de mon projet de thèse a été d’identifier les mécanismes neuronaux adaptatifs se mettant en place au niveau des circuits de la récompense et des circuits activés en réponse à un stress aigu. Plus spécifiquement, nous avons étudié le rôle du noyau du lit de la strie terminale (BNST) au sein de ces deux circuits. Mon hypothèse est que le BNST appartient à un circuit de structures interconnectées dans lequel il intègre des informations contextuelles (hippocampe ventral) et des informations émotionnelles (cortex préfrontal médian) afin, d’une part, de réguler les niveaux d’anxiété innés ainsi que les réponses induites par les centres du stress suite à un épisode de stress aigu mais également, d’adapter l’activité des neurones dopaminergiques de l’aire tegmentale ventrale (VTA) en vue de motiver ou d’empêcher la reproduction d’un comportement associé à un stimulus récompensant ou aversif. Afin de tester cette hypothèse, nous avons mis en place et développé différents projets de recherche combinant des approches d’électrophysiologie in vivo, anatomiques et comportementales. Dans un premier temps, nous nous sommes intéressés au BNST en tant que structure clef participant à la régulation des centres de stress. Grâce à l’utilisation d’approches d’électrophysiologie in vivo chez la souris anesthésiée, nous avons montré qu’après l’exposition à un stress aigu, les neurones du BNST adaptent leur réponse suite à la stimulation du cortex préfrontal médian et passent d’une dépression à long terme (LTD) en situation contrôle à une potentialisation à long terme (LTP) après un stress aigu. Nous avons disséqué une partie des mécanismes permettant l’élaboration de ces plasticités grâce à l’utilisation de souris génétiquement modifiés pour le récepteur aux endocannabinoïdes de type 1 (CB1-R). Ainsi, nous avons trouvé que la LTD et la LTP mis en place dans le BNST sont médiées par le système endocannabinoïde via les récepteurs CB1. Ensuite, nous avons étudié le rôle du ventral subiculum (vSUB) dans la régulation des neurones du BNST ainsi que l’impact de l’activation de cette voie vSUB-BNST sur l’autre voie glutamatergique ILCx-BNST. Tout d’abord, nous avons montré par des approches électrophysiologiques et anatomiques, qu’un même neurone du BNST est capable d’intégrer des informations provenant à la fois du ventral subiculum et du cortex infralimbic (ILCx). Nous avons induit in vivo une LTP NMDA dépendante dans la voie vSUB-BNST suite à un protocole de stimulation haute fréquence dans le vSUB alors qu’en parallèle ce même protocole induit une LTD sur ces mêmes neurones dans la voie ILCx–BNST. Deplus, nous avons noté que ces adaptations plastiques se mettant en place dans le BNST suiteà une simple stimulation haute fréquence dans le vSUB permettent à long terme de diminuerles niveaux d’anxiété innés chez le rat. Enfin, nous avons mis en évidence que le BNST est un relai excitateur entre le vSUBet la VTA. Nous avons montré qu’une stimulation à haute fréquence dans le vSUBpotentialise in vivo l’activité des neurones dopaminergiques (DA) de la VTA. Or le vSUBne projette pas de manière directe sur les neurones DA de la VTA. Nous avons observé quece protocole de stimulation haute fréquence dans le vSUB induit dans un premier temps uneLTP NMDA dépendante dans les neurones du BNST projetant à la VTA qui est nécessairepour observer cette potentialisation des neurones DA. En dernier lieu, nous avons montréque cette potentialisation des neurones DA de la VTA augmente la réponse locomotrice à unchallenge avec de la cocaine.Ainsi, l’ensemble de ces projets nous ont permis de confirmer et de préciser lafonction majeure du BNST dans la régulation du stress et de l’anxiété ainsi que dans lecircuit de la motivation
The main goal of my PhD was to identify the adaptive neuronal mechanismsdeveloping in the reward circuit and in the circuit implicated in the regulation of stressresponses. More specifically, we have studied the function of the bed nucleus of the striaterminalis (BNST) in both circuits.My hypothesis was that, the BNST belongs to interconnected circuits in whichintegrates contextual (from ventral hippocampus) and emotional informations (from medialprefrontal cortex). Thus, the BNST diffuses these informations in order to regulate the basalinnate level of anxiety and stress centers responses induced after acute stress exposure, butalso to adapt the activity of dopaminergic neurons of the ventral tegmental area (VTA) thatcan promote or prevent a behavioral task associated with a rewarding or aversive stimulus.To test this hypothesis, we decided to develop several research projects usingelectrophysiological, anatomical and behavioral approaches.Firstly, we focused our interest on the stress circuit in which the BNST is a keystructure which participates in regulating the responses of stress centers after acute stressexposure. By using in vivo electrophysiology approach in anesthetized mice, we haveshown that after acute restraint stress, BNST neurons adapt their plastic responses inducedby the tetanic stimulation of the medial prefrontal cortex: switch from long term depression(LTD) under control condition to long term potentiation (LTP) after acute stress condition.Furthermore, we demonstrated that both LTD and LTP are endocannabinoid dependent byusing genetic modified mice for the type 1 endocannabinoid receptors and localpharmacological approach in the BNST.In a second step, we studied the function of the ventral subiculum (vSUB) in theregulation of BNST neurons and the impact of the vSUB-BNST pathway activation on theother glutamatergic ILCx-BNST pathway. In a first set of experiments, we showed that asame single BNST neuron could integrate informations from both vSUB and the infralimbiccortex. By using high frequency stimulation (HFS) protocols, we induced in vivo NMDAdependentLTP in the vSUB-BNST pathway whereas the same protocol led to LTD in thesame BNST neurons in the ILCx-BNST pathway. Moreover, we noted single application ofHFS protocol in the vSUB induced a long term decrease of the basal innate level of anxietyin rats.Lastly, we presented the BNST as a key excitatory relay between the vSUB and theVTA. Here, we have shown that in vivo HFS protocols in the vSUB potentiate the activity ofdopaminergic (DA) neurons of the VTA. However, the vSUB does not directly project to theVTA. We observed that a HFS protocol in the vSUB first induce NMDA-dependent LTP inBNST neurons that project to the VTA, which is necessary to promote the potentiation of7VTA DA neurons. In the last step, we demonstrated in vivo that the potentiation of VTA DAneurons increases the locomotor response to cocaine challenge.All together, these projects allow us to confirm and detail the major function of theBNST in the regulation of stress and anxiety and also in the motivational circuit

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Dissertations / Theses on the topic 'In vivo Electrophysiology'

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