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Harada, Akina, Nidhi Kaushal, Kazunori Suzuki, et al. "Balanced Activation of Striatal Output Pathways by Faster Off-Rate PDE10A Inhibitors Elicits Not Only Antipsychotic-Like Effects But Also Procognitive Effects in Rodents." International Journal of Neuropsychopharmacology 23, no. 2 (2019): 96–107. http://dx.doi.org/10.1093/ijnp/pyz056.
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Abstract Background Faster off-rate competitive enzyme inhibitors are generally more sensitive than slower off-rate ones to binding inhibition by enzyme substrates. We previously reported that the cyclic adenosine monophosphate concentration in dopamine D1 receptor-expressing medium spiny neurons (D1-MSNs) may be higher than that in D2-MSNs. Consequently, compared with slower off-rate phosphodiesterase 10A inhibitors, faster off-rate ones comparably activated D2-MSNs but partially activated D1-MSNs. We further investigated the pharmacological profiles of phosphodiesterase 10A inhibitors with different off-rates. Methods Phosphodiesterase 10A inhibitors with slower (T-609) and faster (T-773) off-rates were used. D1- and D2-MSN activation was assessed by substance P and enkephalin mRNA induction, respectively, in rodents. Antipsychotic-like effects were evaluated by MK-801- and methamphetamine-induced hyperactivity and prepulse inhibition in rodents. Cognition was assessed by novel object recognition task and radial arm maze in rats. Prefrontal cortex activation was evaluated by c-Fos immunohistochemistry in rats. Gene translations in D1- and D2-MSNs were evaluated by translating ribosome affinity purification and RNA sequencing in mice. Results Compared with T-609, T-773 comparably activated D2-MSNs but partially activated D1-MSNs. Haloperidol (a D2 antagonist) and T-773, but not T-609, produced antipsychotic-like effects in all paradigms. T-773, but not T-609 or haloperidol, activated the prefrontal cortex and improved cognition. Overall gene translation patterns in D2-MSNs by all drugs and those in D1-MSNs by T-773 and T-609 were qualitatively similar. Conclusions Differential pharmacological profiles among those drugs could be attributable to activation balance of D1- and D2-MSNs. The “balanced activation” of MSNs by faster off-rate phosphodiesterase 10A inhibitors may be favorable to treat schizophrenia.
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Damodaran, Sriraman, Rebekah C. Evans, and Kim T. Blackwell. "Synchronized firing of fast-spiking interneurons is critical to maintain balanced firing between direct and indirect pathway neurons of the striatum." Journal of Neurophysiology 111, no. 4 (2014): 836–48. http://dx.doi.org/10.1152/jn.00382.2013.
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The inhibitory circuits of the striatum are known to be critical for motor function, yet their contributions to Parkinsonian motor deficits are not clear. Altered firing in the globus pallidus suggests that striatal medium spiny neurons (MSN) of the direct (D1 MSN) and indirect pathway (D2 MSN) are imbalanced during dopamine depletion. Both MSN classes receive inhibitory input from each other and from inhibitory interneurons within the striatum, specifically the fast-spiking interneurons (FSI). To investigate the role of inhibition in maintaining striatal balance, we developed a biologically-realistic striatal network model consisting of multicompartmental neuron models: 500 D1 MSNs, 500 D2 MSNs and 49 FSIs. The D1 and D2 MSN models are differentiated based on published experiments of individual channel modulations by dopamine, with D2 MSNs being more excitable than D1 MSNs. Despite this difference in response to current injection, in the network D1 and D2 MSNs fire at similar frequencies in response to excitatory synaptic input. Simulations further reveal that inhibition from FSIs connected by gap junctions is critical to produce balanced firing. Although gap junctions produce only a small increase in synchronization between FSIs, removing these connections resulted in significant firing differences between D1 and D2 MSNs, and balanced firing was restored by providing synchronized cortical input to the FSIs. Together these findings suggest that desynchronization of FSI firing is sufficient to alter balanced firing between D1 and D2 MSNs.
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Wei, Wei, Shengyuan Ding, and Fu-Ming Zhou. "Dopaminergic treatment weakens medium spiny neuron collateral inhibition in the parkinsonian striatum." Journal of Neurophysiology 117, no. 3 (2017): 987–99. http://dx.doi.org/10.1152/jn.00683.2016.
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The striatal medium spiny neurons (MSNs) are critical to both motor and cognitive functions. A potential regulator of MSN activity is the GABAergic collateral axonal input from neighboring MSNs. These collateral axon terminals are further under the regulation of presynaptic dopamine (DA) receptors that may become dysfunctional when the intense striatal DA innervation is lost in Parkinson's disease (PD). We show that DA D1 receptor-expressing MSNs (D1-MSNs) and D2 receptor-expressing MSNs (D2-MSNs) each formed high-rate, one-way collateral connections with a homotypic preference in both normal and DA-denervated mouse striatum. Furthermore, whereas the homotypic preference, one-way directionality and the basal inhibitory strength were preserved, DA inhibited GABA release at the D2-MSN→D2-MSN collateral synapse in a supersensitive manner in the DA-denervated striatum. In contrast, for D1-MSN-originated collateral connections, whereas D1 agonism facilitated D1-MSN→D1-MSN collateral inhibition in the normal striatum, this presynaptic D1R facilitation of GABA release was lost in the parkinsonian striatum. These results indicate that in the parkinsonian striatum, dopaminergic treatment can presynaptically weaken the D2-MSN→D2-MSN collateral inhibition and disinhibit the surrounding D2-MSNs, whereas the D1-MSN→D1-MSN collateral inhibition is weakened by the loss of the presynaptic D1 receptor facilitation, disinhibiting the surrounding D1-MSNs. Together, these newly discovered effects can disrupt the MSN circuits in the parkinsonian striatum and may contribute to dopaminergic treatment-induced aberrant motor and nonmotor behaviors in PD. NEW & NOTEWORTHY With the use of a large database, this study establishes that neighboring homotypic striatal spiny projection neurons have a 50% chance to form one-way collateral inhibitory connection, a substantially higher rate than previous estimates. This study also shows that dopamine denervation may alter presynaptic dopamine receptor function such that dopaminergic treatment of Parkinson's disease can weaken the surround inhibition and may reduce the contrast of the striatal outputs, potentially contributing to dopamine's profound motor and nonmotor behavioral effects.
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Soares-Cunha, Carina, Nivaldo A. P. de Vasconcelos, Bárbara Coimbra, et al. "Nucleus accumbens medium spiny neurons subtypes signal both reward and aversion." Molecular Psychiatry 25, no. 12 (2019): 3241–55. http://dx.doi.org/10.1038/s41380-019-0484-3.
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AbstractDeficits in decoding rewarding (and aversive) signals are present in several neuropsychiatric conditions such as depression and addiction, emphasising the importance of studying the underlying neural circuits in detail. One of the key regions of the reward circuit is the nucleus accumbens (NAc). The classical view on the field postulates that NAc dopamine receptor D1-expressing medium spiny neurons (D1-MSNs) convey reward signals, while dopamine receptor D2-expressing MSNs (D2-MSNs) encode aversion. Here, we show that both MSN subpopulations can drive reward and aversion, depending on their neuronal stimulation pattern. Brief D1- or D2-MSN optogenetic stimulation elicited positive reinforcement and enhanced cocaine conditioning. Conversely, prolonged activation induced aversion, and in the case of D2-MSNs, decreased cocaine conditioning. Brief stimulation was associated with increased ventral tegmenta area (VTA) dopaminergic tone either directly (for D1-MSNs) or indirectly via ventral pallidum (VP) (for D1- and D2-MSNs). Importantly, prolonged stimulation of either MSN subpopulation induced remarkably distinct electrophysiological effects in these target regions. We further show that blocking κ-opioid receptors in the VTA (but not in VP) abolishes the behavioral effects induced by D1-MSN prolonged stimulation. In turn, blocking δ-opioid receptors in the VP (but not in VTA) blocks the behavioral effects elicited by D2-MSN prolonged stimulation. Our findings demonstrate that D1- and D2-MSNs can bidirectionally control reward and aversion, explaining the existence of controversial studies in the field, and highlights that the proposed striatal functional opposition needs to be reconsidered.
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Calipari, Erin S., Rosemary C. Bagot, Immanuel Purushothaman, et al. "In vivo imaging identifies temporal signature of D1 and D2 medium spiny neurons in cocaine reward." Proceedings of the National Academy of Sciences 113, no. 10 (2016): 2726–31. http://dx.doi.org/10.1073/pnas.1521238113.
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The reinforcing and rewarding properties of cocaine are attributed to its ability to increase dopaminergic transmission in nucleus accumbens (NAc). This action reinforces drug taking and seeking and leads to potent and long-lasting associations between the rewarding effects of the drug and the cues associated with its availability. The inability to extinguish these associations is a key factor contributing to relapse. Dopamine produces these effects by controlling the activity of two subpopulations of NAc medium spiny neurons (MSNs) that are defined by their predominant expression of either dopamine D1 or D2 receptors. Previous work has demonstrated that optogenetically stimulating D1 MSNs promotes reward, whereas stimulating D2 MSNs produces aversion. However, we still lack a clear understanding of how the endogenous activity of these cell types is affected by cocaine and encodes information that drives drug-associated behaviors. Using fiber photometry calcium imaging we define D1 MSNs as the specific population of cells in NAc that encodes information about drug associations and elucidate the temporal profile with which D1 activity is increased to drive drug seeking in response to contextual cues. Chronic cocaine exposure dysregulates these D1 signals to both prevent extinction and facilitate reinstatement of drug seeking to drive relapse. Directly manipulating these D1 signals using designer receptors exclusively activated by designer drugs prevents contextual associations. Together, these data elucidate the responses of D1- and D2-type MSNs in NAc to acute cocaine and during the formation of context–reward associations and define how prior cocaine exposure selectively dysregulates D1 signaling to drive relapse.
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Arcangeli, Sara, Alessandro Tozzi, Michela Tantucci, et al. "Ischemic-LTP in Striatal Spiny Neurons of both Direct and Indirect Pathway Requires the Activation of D1-Like Receptors and NO/Soluble Guanylate Cyclase/cGMP Transmission." Journal of Cerebral Blood Flow & Metabolism 33, no. 2 (2012): 278–86. http://dx.doi.org/10.1038/jcbfm.2012.167.
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Striatal medium-sized spiny neurons (MSNs) are highly vulnerable to ischemia. A brief ischemic insult, produced by oxygen and glucose deprivation (OGD), can induce ischemic long-term potentiation (i-LTP) of corticostriatal excitatory postsynaptic response. Since nitric oxide (NO) is involved in the pathophysiology of brain ischemia and the dopamine D1/D5-receptors (D1-like-R) are expressed in striatal NOS-positive interneurons, we hypothesized a relation between NOS-positive interneurons and striatal i-LTP, involving D1R activation and NO production. We investigated the mechanisms involved in i-LTP induced by OGD in corticostriatal slices and found that the D1-like-R antagonist SCH-23390 prevented i-LTP in all recorded MSNs. Immunofluorescence analysis confirmed the induction of i-LTP in both substance P-positive, (putative D1R-expressing) and adenosine A2A-receptor-positive (putative D2R-expressing) MSNs. Furthermore, i-LTP was dependent on a NOS/cGMP pathway since pharmacological blockade of NOS, guanylate-cyclase, or PKG prevented i-LTP. However, these compounds failed to prevent i-LTP in the presence of a NO donor or cGMP analog, respectively. Interestingly, the D1-like-R antagonism failed to prevent i-LTP when intracellular cGMP was pharmacologically increased. We propose that NO, produced by striatal NOS-positive interneurons via the stimulation of D1-like-R located on these cells, is critical for i-LTP induction in the entire population of MSNs involving a cGMP-dependent pathway.
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Francis, T. Chase, Hideaki Yano, Tyler G. Demarest, Hui Shen, and Antonello Bonci. "High-Frequency Activation of Nucleus Accumbens D1-MSNs Drives Excitatory Potentiation on D2-MSNs." Neuron 103, no. 3 (2019): 432–44. http://dx.doi.org/10.1016/j.neuron.2019.05.031.
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Oliver, Robert J., Dvijen C. Purohit, Khush M. Kharidia, and Chitra D. Mandyam. "Transient Chemogenetic Inhibition of D1-MSNs in the Dorsal Striatum Enhances Methamphetamine Self-Administration." Brain Sciences 9, no. 11 (2019): 330. http://dx.doi.org/10.3390/brainsci9110330.
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The dorsal striatum is important for the development of drug addiction; however, the role of dopamine D1 receptor (D1R) expressing medium-sized spiny striatonigral (direct pathway) neurons (D1-MSNs) in regulating excessive methamphetamine intake remains elusive. Here we seek to determine if modulating D1-MSNs in the dorsal striatum alters methamphetamine self-administration in animals that have demonstrated escalation of self-administration. A viral vector-mediated approach was used to induce expression of the inhibitory (Gi coupled-hM4D) or stimulatory (Gs coupled-rM3D) designer receptors exclusively activated by designer drugs (DREADDs) engineered to specifically respond to the exogenous ligand clozapine-N-oxide (CNO) selectively in D1-MSNs in the dorsal striatum. CNO in animals expressing hM4D increased responding for methamphetamine compared to vehicle in a within subject treatment paradigm. CNO in animals that did not express DREADDs (DREADD naïve-CNO) or expressed rM3D did not alter responding for methamphetamine, demonstrating specificity for hM4D-CNO interaction in increasing self-administration. Postmortem tissue analysis reveals that hM4D-CNO animals had reduced Fos immunoreactivity in the dorsal striatum compared to rM3D-CNO animals and DREADD naïve-CNO animals. Cellular mechanisms in the dorsal striatum in hM4D-CNO animals reveal enhanced expression of D1R and Ca2+/calmodulin-dependent kinase II (CaMKII). Conversely, rM3D-CNO animals had enhanced activity of extracellular signal-regulated kinase (Erk1/2) and Akt in the dorsal striatum, supporting rM3D-CNO interaction in these animals compared with drug naïve controls, DREADD naïve-CNO and hM4D-CNO animals. Our studies indicate that transient inhibition of D1-MSNs-mediated strengthening of methamphetamine addiction-like behavior is associated with cellular adaptations that support dysfunctional dopamine signaling in the dorsal striatum.
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Ceglia, Ilaria, Ko-Woon Lee, Michael E. Cahill, et al. "WAVE1 in neurons expressing the D1 dopamine receptor regulates cellular and behavioral actions of cocaine." Proceedings of the National Academy of Sciences 114, no. 6 (2017): 1395–400. http://dx.doi.org/10.1073/pnas.1621185114.
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Wiskott-Aldrich syndrome protein (WASP) family verprolin homologous protein 1 (WAVE1) regulates actin-related protein 2/3 (Arp2/3) complex-mediated actin polymerization. Our previous studies have found WAVE1 to be inhibited by Cdk5-mediated phosphorylation in brain and to play a role in the regulation of dendritic spine morphology. Here we report that mice in which WAVE1 was knocked out (KO) in neurons expressing the D1 dopamine receptor (D1-KO), but not mice where WAVE1 was knocked out in neurons expressing the D2 dopamine receptor (D2-KO), exhibited a significant decrease in place preference associated with cocaine. In contrast to wild-type (WT) and WAVE1 D2-KO mice, cocaine-induced sensitized locomotor behavior was not maintained in WAVE1 D1-KO mice. After chronic cocaine administration and following withdrawal, an acute cocaine challenge induced WAVE1 activation in striatum, which was assessed by dephosphorylation. The cocaine-induced WAVE1 dephosphorylation was attenuated by coadministration of either a D1 dopamine receptor or NMDA glutamate receptor antagonist. Upon an acute challenge of cocaine following chronic cocaine exposure and withdrawal, we also observed in WT, but not in WAVE1 D1-KO mice, a decrease in dendritic spine density and a decrease in the frequency of excitatory postsynaptic AMPA receptor currents in medium spiny projection neurons expressing the D1 dopamine receptor (D1-MSNs) in the nucleus accumbens. These results suggest that WAVE1 is involved selectively in D1-MSNs in cocaine-evoked neuronal activity-mediated feedback regulation of glutamatergic synapses.
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Hearing, Matthew C., Jakub Jedynak, Stephanie R. Ebner, et al. "Reversal of morphine-induced cell-type–specific synaptic plasticity in the nucleus accumbens shell blocks reinstatement." Proceedings of the National Academy of Sciences 113, no. 3 (2016): 757–62. http://dx.doi.org/10.1073/pnas.1519248113.
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Drug-evoked plasticity at excitatory synapses on medium spiny neurons (MSNs) of the nucleus accumbens (NAc) drives behavioral adaptations in addiction. MSNs expressing dopamine D1 (D1R-MSN) vs. D2 receptors (D2R-MSN) can exert antagonistic effects in drug-related behaviors, and display distinct alterations in glutamate signaling following repeated exposure to psychostimulants; however, little is known of cell-type–specific plasticity induced by opiates. Here, we find that repeated morphine potentiates excitatory transmission and increases GluA2-lacking AMPA receptor expression in D1R-MSNs, while reducing signaling in D2-MSNs following 10–14 d of forced abstinence. In vivo reversal of this pathophysiology with optogenetic stimulation of infralimbic cortex-accumbens shell (ILC-NAc shell) inputs or treatment with the antibiotic, ceftriaxone, blocked reinstatement of morphine-evoked conditioned place preference. These findings confirm the presence of overlapping and distinct plasticity produced by classes of abused drugs within subpopulations of MSNs that may provide targetable molecular mechanisms for future pharmacotherapies.
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Song, Xiaolei, Haotian Chen, Zicong Shang, et al. "Homeobox Gene Six3 is Required for the Differentiation of D2-Type Medium Spiny Neurons." Neuroscience Bulletin 37, no. 7 (2021): 985–98. http://dx.doi.org/10.1007/s12264-021-00698-5.
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AbstractMedium spiny neurons (MSNs) in the striatum, which can be divided into D1 and D2 MSNs, originate from the lateral ganglionic eminence (LGE). Previously, we reported that Six3 is a downstream target of Sp8/Sp9 in the transcriptional regulatory cascade of D2 MSN development and that conditionally knocking out Six3 leads to a severe loss of D2 MSNs. Here, we showed that Six3 mainly functions in D2 MSN precursor cells and gradually loses its function as D2 MSNs mature. Conditional deletion of Six3 had little effect on cell proliferation but blocked the differentiation of D2 MSN precursor cells. In addition, conditional overexpression of Six3 promoted the differentiation of precursor cells in the LGE. We measured an increase of apoptosis in the postnatal striatum of conditional Six3-knockout mice. This suggests that, in the absence of Six3, abnormally differentiated D2 MSNs are eliminated by programmed cell death. These results further identify Six3 as an important regulatory element during D2 MSN differentiation.
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Kharkwal, Geetika, Daniela Radl, Robert Lewis, and Emiliana Borrelli. "Dopamine D2 receptors in striatal output neurons enable the psychomotor effects of cocaine." Proceedings of the National Academy of Sciences 113, no. 41 (2016): 11609–14. http://dx.doi.org/10.1073/pnas.1608362113.
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The psychomotor effects of cocaine are mediated by dopamine (DA) through stimulation of striatal circuits. Gabaergic striatal medium spiny neurons (MSNs) are the only output of this pivotal structure in the control of movements. The majority of MSNs express either the DA D1 or D2 receptors (D1R, D2R). Studies have shown that the motor effect of cocaine depends on the DA-mediated stimulation of D1R-expressing MSNs (dMSNs), which is mirrored at the cellular level by stimulation of signaling pathways leading to phosphorylation of ERKs and induction of c-fos. Nevertheless, activation of dMSNs by cocaine is necessary but not sufficient, and D2R signaling is required for the behavioral and cellular effects of cocaine. Indeed, cocaine motor effects and activation of signaling in dMSNs are blunted in mice with the constitutive knockout of D2R (D2RKO). Using mouse lines with a cell-specific knockout of D2R either in MSNs (MSN-D2RKO) or in dopaminergic neurons (DA-D2RKO), we show that D2R signaling in MSNs is required and permissive for the motor stimulant effects of cocaine and the activation of signaling in dMSNs. MSN-D2RKO mice show the same phenotype as constitutive D2RKO mice both at the behavioral and cellular levels. Importantly, activation of signaling in dMSNs by cocaine is rescued by intrastriatal injection of the GABA antagonist, bicuculline. These results are in support of intrastriatal connections of D2R+-MSNs (iMSNs) with dMSNs and indicate that D2R signaling in MSNs is critical for the function of intrastriatal circuits.
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Doyle, Trevor B., Brian S. Muntean, Karin F. Ejendal, et al. "Identification of Novel Adenylyl Cyclase 5 (AC5) Signaling Networks in D1 and D2 Medium Spiny Neurons using Bimolecular Fluorescence Complementation Screening." Cells 8, no. 11 (2019): 1468. http://dx.doi.org/10.3390/cells8111468.
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Adenylyl cyclase type 5 (AC5), as the principal isoform expressed in striatal medium spiny neurons (MSNs), is essential for the integration of both stimulatory and inhibitory midbrain signals that initiate from dopaminergic G protein-coupled receptor (GPCR) activation. The spatial and temporal control of cAMP signaling is dependent upon the composition of local regulatory protein networks. However, there is little understanding of how adenylyl cyclase protein interaction networks adapt to the multifarious pressures of integrating acute versus chronic and inhibitory vs. stimulatory receptor signaling in striatal MSNs. Here, we presented the development of a novel bimolecular fluorescence complementation (BiFC)-based protein-protein interaction screening methodology to further identify and characterize elements important for homeostatic control of dopamine-modulated AC5 signaling in a neuronal model cell line and striatal MSNs. We identified two novel AC5 modulators: the protein phosphatase 2A (PP2A) catalytic subunit (PPP2CB) and the intracellular trafficking associated protein—NSF (N-ethylmaleimide-sensitive factor) attachment protein alpha (NAPA). The effects of genetic knockdown (KD) of each gene were evaluated in several cellular models, including D1- and D2-dopamine receptor-expressing MSNs from CAMPER mice. The knockdown of PPP2CB was associated with a reduction in acute and sensitized adenylyl cyclase activity, implicating PP2A is an important and persistent regulator of adenylyl cyclase activity. In contrast, the effects of NAPA knockdown were more nuanced and appeared to involve an activity-dependent protein interaction network. Taken together, these data represent a novel screening method and workflow for the identification and validation of adenylyl cyclase protein-protein interaction networks under diverse cAMP signaling paradigms.
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Filipović, Marko, Maya Ketzef, Ramon Reig, Ad Aertsen, Gilad Silberberg, and Arvind Kumar. "Direct pathway neurons in mouse dorsolateral striatum in vivo receive stronger synaptic input than indirect pathway neurons." Journal of Neurophysiology 122, no. 6 (2019): 2294–303. http://dx.doi.org/10.1152/jn.00481.2019.
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Striatal projection neurons, the medium spiny neurons (MSNs), play a crucial role in various motor and cognitive functions. MSNs express either D1- or D2-type dopamine receptors and initiate the direct-pathway (dMSNs) or indirect pathways (iMSNs) of the basal ganglia, respectively. dMSNs have been shown to receive more inhibition than iMSNs from intrastriatal sources. Based on these findings, computational modeling of the striatal network has predicted that under healthy conditions dMSNs should receive more total input than iMSNs. To test this prediction, we analyzed in vivo whole cell recordings from dMSNs and iMSNs in healthy and dopamine-depleted (6OHDA) anaesthetized mice. By comparing their membrane potential fluctuations, we found that dMSNs exhibited considerably larger membrane potential fluctuations over a wide frequency range. Furthermore, by comparing the spike-triggered average membrane potentials, we found that dMSNs depolarized toward the spike threshold significantly faster than iMSNs did. Together, these findings (in particular the STA analysis) corroborate the theoretical prediction that direct-pathway MSNs receive stronger total input than indirect-pathway neurons. Finally, we found that dopamine-depleted mice exhibited no difference between the membrane potential fluctuations of dMSNs and iMSNs. These data provide new insights into the question of how the lack of dopamine may lead to behavioral deficits associated with Parkinson’s disease. NEW & NOTEWORTHY The direct and indirect pathways of the basal ganglia originate from the D1- and D2-type dopamine receptor expressing medium spiny neurons (dMSNs and iMSNs). Theoretical results have predicted that dMSNs should receive stronger synaptic input than iMSNs. Using in vivo intracellular membrane potential data, we provide evidence that dMSNs indeed receive stronger input than iMSNs, as has been predicted by the computational model.
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Singh, Arun, Li Liang, Yoshiki Kaneoke, Xuebing Cao, and Stella M. Papa. "Dopamine regulates distinctively the activity patterns of striatal output neurons in advanced parkinsonian primates." Journal of Neurophysiology 113, no. 5 (2015): 1533–44. http://dx.doi.org/10.1152/jn.00910.2014.
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Nigrostriatal dopamine denervation plays a major role in basal ganglia circuitry disarray and motor abnormalities of Parkinson's disease (PD). Studies in rodent and primate models have revealed that striatal projection neurons, namely, medium spiny neurons (MSNs), increase the firing frequency. However, their activity pattern changes and the effects of dopaminergic stimulation in such conditions are unknown. Using single-cell recordings in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated primates with advanced parkinsonism, we studied MSN activity patterns in the transition to different motor states following levodopa administration. In the “off” state (baseline parkinsonian disability), a burst-firing pattern accompanied by prolonged silences (pauses) was found in 34% of MSNs, and 80% of these exhibited a levodopa response compatible with dopamine D1 receptor activation (direct pathway MSNs). This pattern was highly responsive to levodopa given that bursting/pausing almost disappeared in the “on” state (reversal of parkinsonism after levodopa injection), although this led to higher firing rates. Nonbursty MSNs fired irregularly with marked pausing that increased in the on state in the MSN subset with a levodopa response compatible with dopamine D2 receptor activation (indirect pathway MSNs), although the pause increase was not sustained in some units during the appearance of dyskinesias. Data indicate that the MSN firing pattern in the advanced parkinsonian monkey is altered by bursting and pausing changes and that dopamine differentially and inefficiently regulates these behaviorally correlated patterns in MSN subpopulations. These findings may contribute to understand the impact of striatal dysfunction in the basal ganglia network and its role in motor symptoms of PD.
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Damez-Werno, Diane M., HaoSheng Sun, Kimberly N. Scobie, et al. "Histone arginine methylation in cocaine action in the nucleus accumbens." Proceedings of the National Academy of Sciences 113, no. 34 (2016): 9623–28. http://dx.doi.org/10.1073/pnas.1605045113.
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Repeated cocaine exposure regulates transcriptional regulation within the nucleus accumbens (NAc), and epigenetic mechanisms—such as histone acetylation and methylation on Lys residues—have been linked to these lasting actions of cocaine. In contrast to Lys methylation, the role of histone Arg (R) methylation remains underexplored in addiction models. Here we show that protein-R-methyltransferase-6 (PRMT6) and its associated histone mark, asymmetric dimethylation of R2 on histone H3 (H3R2me2a), are decreased in the NAc of mice and rats after repeated cocaine exposure, including self-administration, and in the NAc of cocaine-addicted humans. Such PRMT6 down-regulation occurs selectively in NAc medium spiny neurons (MSNs) expressing dopamine D2 receptors (D2-MSNs), with opposite regulation occurring in D1-MSNs, and serves to protect against cocaine-induced addictive-like behavioral abnormalities. Using ChIP-seq, we identified Src kinase signaling inhibitor 1 (Srcin1; also referred to as p140Cap) as a key gene target for reduced H3R2me2a binding, and found that consequent Srcin1 induction in the NAc decreases Src signaling, cocaine reward, and the motivation to self-administer cocaine. Taken together, these findings suggest that suppression of Src signaling in NAc D2-MSNs, via PRMT6 and H3R2me2a down-regulation, functions as a homeostatic brake to restrain cocaine action, and provide novel candidates for the development of treatments for cocaine addiction.
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Goto, Akihiro, Ichiro Nakahara, Takashi Yamaguchi, et al. "Circuit-dependent striatal PKA and ERK signaling underlies rapid behavioral shift in mating reaction of male mice." Proceedings of the National Academy of Sciences 112, no. 21 (2015): 6718–23. http://dx.doi.org/10.1073/pnas.1507121112.
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The selection of reward-seeking and aversive behaviors is controlled by two distinct D1 and D2 receptor-expressing striatal medium spiny neurons, namely the direct pathway MSNs (dMSNs) and the indirect pathway MSNs (iMSNs), but the dynamic modulation of signaling cascades of dMSNs and iMSNs in behaving animals remains largely elusive. We developed an in vivo methodology to monitor Förster resonance energy transfer (FRET) of the activities of PKA and ERK in either dMSNs or iMSNs by microendoscopy in freely moving mice. PKA and ERK were coordinately but oppositely regulated between dMSNs and iMSNs by rewarding cocaine administration and aversive electric shocks. Notably, the activities of PKA and ERK rapidly shifted when male mice became active or indifferent toward female mice during mating behavior. Importantly, manipulation of PKA cascades by the Designer Receptor recapitulated active and indifferent mating behaviors, indicating a causal linkage of a dynamic activity shift of PKA and ERK between dMSNs and iMSNs in action selection.
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Bocchi, Vittoria Dickinson, Paola Conforti, Elena Vezzoli, et al. "The coding and long noncoding single-cell atlas of the developing human fetal striatum." Science 372, no. 6542 (2021): eabf5759. http://dx.doi.org/10.1126/science.abf5759.
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Deciphering how the human striatum develops is necessary for understanding the diseases that affect this region. To decode the transcriptional modules that regulate this structure during development, we compiled a catalog of 1116 long intergenic noncoding RNAs (lincRNAs) identified de novo and then profiled 96,789 single cells from the early human fetal striatum. We found that D1 and D2 medium spiny neurons (D1- and D2-MSNs) arise from a common progenitor and that lineage commitment is established during the postmitotic transition, across a pre-MSN phase that exhibits a continuous spectrum of fate determinants. We then uncovered cell type–specific gene regulatory networks that we validated through in silico perturbation. Finally, we identified human-specific lincRNAs that contribute to the phylogenetic divergence of this structure in humans. This work delineates the cellular hierarchies governing MSN lineage commitment.
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Cui, Qiaoling, Qian Li, Hongyan Geng, et al. "Dopamine receptors mediate strategy abandoning via modulation of a specific prelimbic cortex–nucleus accumbens pathway in mice." Proceedings of the National Academy of Sciences 115, no. 21 (2018): E4890—E4899. http://dx.doi.org/10.1073/pnas.1717106115.
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The ability to abandon old strategies and adopt new ones is essential for survival in a constantly changing environment. While previous studies suggest the importance of the prefrontal cortex and some subcortical areas in the generation of strategy-switching flexibility, the fine neural circuitry and receptor mechanisms involved are not fully understood. In this study, we showed that optogenetic excitation and inhibition of the prelimbic cortex–nucleus accumbens (NAc) pathway in the mouse respectively enhances and suppresses strategy-switching ability in a cross-modal spatial-egocentric task. This ability is dependent on an intact dopaminergic tone in the NAc, as local dopamine denervation impaired the performance of the animal in the switching of tasks. In addition, based on a brain-slice preparation obtained from Drd2-EGFP BAC transgenic mice, we demonstrated direct innervation of D2 receptor-expressing medium spiny neurons (D2-MSNs) in the NAc by prelimbic cortical neurons, which is under the regulation by presynaptic dopamine receptors. While presynaptic D1-type receptor activation enhances the glutamatergic transmission from the prelimbic cortex to D2-MSNs, D2-type receptor activation suppresses this synaptic connection. Furthermore, manipulation of this pathway by optogenetic activation or administration of a D1-type agonist or a D2-type antagonist could restore impaired task-switching flexibility in mice with local NAc dopamine depletion; this restoration is consistent with the effects of knocking down the expression of specific dopamine receptors in the pathway. Our results point to a critical role of a specific prelimbic cortex–NAc subpathway in mediating strategy abandoning, allowing the switching from one strategy to another in problem solving.
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Liang, Jing, Vincent N. Marty, Yatendra Mulpuri, Richard W. Olsen, and Igor Spigelman. "Selective modulation of GABAergic tonic current by dopamine in the nucleus accumbens of alcohol-dependent rats." Journal of Neurophysiology 112, no. 1 (2014): 51–60. http://dx.doi.org/10.1152/jn.00564.2013.
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The nucleus accumbens (NAcc) is a key structure of the mesolimbic dopaminergic reward system and plays an important role in mediating alcohol-seeking behaviors. Alterations in glutamatergic and GABAergic signaling were recently demonstrated in the NAcc of rats after chronic intermittent ethanol (CIE) treatment, a model of alcohol dependence. Here we studied dopamine (DA) modulation of GABAergic signaling and how this modulation might be altered by CIE treatment. We show that the tonic current ( Itonic) mediated by extrasynaptic γ-aminobutyric acid type A receptors (GABAARs) of medium spiny neurons (MSNs) in the NAcc core is differentially modulated by DA at concentrations in the range of those measured in vivo (0.01–1 μM), without affecting the postsynaptic kinetics of miniature inhibitory postsynaptic currents (mIPSCs). Use of selective D1 receptor (D1R) and D2 receptor (D2R) ligands revealed that Itonic potentiation by DA (10 nM) is mediated by D1Rs while Itonic depression by DA (0.03–1 μM) is mediated by D2Rs in the same MSNs. Addition of guanosine 5′- O-(2-thiodiphosphate) (GDPβS) to the recording pipettes eliminated Itonic decrease by the selective D2R agonist quinpirole (5 nM), leaving intact the quinpirole effect on mIPSC frequency. Recordings from CIE and vehicle control (CIV) MSNs during application of D1R agonist (SKF 38393, 100 nM) or D2R agonist (quinpirole, 2 nM) revealed that SKF 38393 potentiated Itonic to the same extent, while quinpirole reduced Itonic to a similar extent, in both groups of rats. Our data suggest that the selective modulatory effects of DA on Itonic are unaltered by CIE treatment and withdrawal.
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Barbour, Aaron J., Sara R. Nass, Yun K. Hahn, Kurt F. Hauser, and Pamela E. Knapp. "Restoration of KCC2 Membrane Localization in Striatal Dopamine D2 Receptor-Expressing Medium Spiny Neurons Rescues Locomotor Deficits in HIV Tat-Transgenic Mice." ASN Neuro 13 (January 2021): 175909142110220. http://dx.doi.org/10.1177/17590914211022089.
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People infected with HIV (PWH) are highly susceptible to striatal and hippocampal damage. Motor and memory impairments are common among these patients, likely as behavioral manifestations of damage to these brain regions. GABAergic dysfunction from HIV infection and viral proteins such as transactivator of transcription (Tat) have been well documented. We recently demonstrated that the neuron specific Cl− extruder, K+ Cl− cotransporter 2 (KCC2), is diminished after exposure to HIV proteins, including Tat, resulting in disrupted GABAAR-mediated hyperpolarization and inhibition. Here, we utilized doxycycline (DOX)-inducible, GFAP-driven HIV-1 Tat transgenic mice to further explore this phenomenon. After two weeks of Tat expression, we found no changes in hippocampal KCC2 levels, but a significant decrease in the striatum that was associated with hyperlocomotion in the open field assay. We were able to restore KCC2 activity and baseline locomotion with the KCC2 enhancer, CLP290. Additionally, we found that CLP290, whose mechanism of action has yet to be described, acts to restore phosphorylation of serine 940 resulting in increased KCC2 membrane localization. We also examined neuronal subpopulation contributions to the noted effects and found significant differences. Dopamine D2 receptor-expressing medium spiny neurons (MSNs) were selectively vulnerable to Tat-induced KCC2 loss, with no changes observed in dopamine D1 receptor-expressing MSNs. These results suggest that disinhibition/diminished hyperpolarization of dopamine D2 receptor-expressing MSNs can manifest as increased locomotion in this context. They further suggest that KCC2 activity might be a therapeutic target to alleviate motor disturbances related to HIV.
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Castro, Liliana. "Transient dopaminergic signaling in health and in Parkinson’s disease: simultaneous cAMP / PKA imaging in D1 and D2 MSNs." Intrinsic Activity 4, Suppl. 2 (2016): A18.37. http://dx.doi.org/10.25006/ia.4.s2-a18.37.
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Mansuri, M. Shahid, Gang Peng, Rashaun S. Wilson, et al. "Differential Protein Expression in Striatal D1- and D2-Dopamine Receptor-Expressing Medium Spiny Neurons." Proteomes 8, no. 4 (2020): 27. http://dx.doi.org/10.3390/proteomes8040027.
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Many neurological disorders and diseases including drug addiction are associated with specific neuronal cell types in the brain. The striatum, a region that plays a critically important role in the development of addictive drug-related behavior, provides a good example of the cellular heterogeneity challenges associated with analyses of specific neuronal cell types. Such studies are needed to identify the adaptive changes in neuroproteomic signaling that occur in response to diseases such as addiction. The striatum contains two major cell types, D1 and D2 type dopaminoceptive medium spiny neurons (MSNs), whose cell bodies and processes are intermingled throughout this region. Since little is known about the proteomes of these two neuronal cell populations, we have begun to address this challenge by using fluorescence-activated nuclear sorting (FANS) to isolate nuclei-containing fractions from striatum from D1 and D2 “Translating Ribosome Affinity Purification” (TRAP) mice. This approach enabled us to devise and implement a robust and reproducible workflow for preparing samples from specific MSN cell types for mass spectrometry analyses. These analyses quantified at least 685 proteins in each of four biological replicates of 50 K sorted nuclei from two D1 mice/replicate and from each of four biological replicates of 50 K sorted nuclei from two D2 mice/replicate. Proteome analyses identified 87 proteins that were differentially expressed in D1 versus D2 MSN nuclei and principal component analysis (PCA) of these proteins separated the 8 biological replicates into specific cell types. Central network analysis of the 87 differentially expressed proteins identified Hnrnpd and Hnmpa2b1 in D1 and Cct2 and Cct7 in D2 as potential central interactors. This workflow can now be used to improve our understanding of many neurological diseases including characterizing the short and long-term impact of drugs of abuse on the proteomes of these two dopaminoceptive neuronal populations.
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Yamaguchi, Takashi, Akihiro Goto, Ichiro Nakahara, et al. "Role of PKA signaling in D2 receptor-expressing neurons in the core of the nucleus accumbens in aversive learning." Proceedings of the National Academy of Sciences 112, no. 36 (2015): 11383–88. http://dx.doi.org/10.1073/pnas.1514731112.
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The nucleus accumbens (NAc) serves as a key neural substrate for aversive learning and consists of two distinct subpopulations of medium-sized spiny neurons (MSNs). The MSNs of the direct pathway (dMSNs) and the indirect pathway (iMSNs) predominantly express dopamine (DA) D1 and D2 receptors, respectively, and are positively and negatively modulated by DA transmitters via Gs- and Gi-coupled cAMP-dependent protein kinase A (PKA) signaling cascades, respectively. In this investigation, we addressed how intracellular PKA signaling is involved in aversive learning in a cell type-specific manner. When the transmission of either dMSNs or iMSNs was unilaterally blocked by pathway-specific expression of transmission-blocking tetanus toxin, infusion of PKA inhibitors into the intact side of the NAc core abolished passive avoidance learning toward an electric shock in the indirect pathway-blocked mice, but not in the direct pathway-blocked mice. We then examined temporal changes in PKA activity in dMSNs and iMSNs in behaving mice by monitoring Förster resonance energy transfer responses of the PKA biosensor with the aid of microendoscopy. PKA activity was increased in iMSNs and decreased in dMSNs in both aversive memory formation and retrieval. Importantly, the increased PKA activity in iMSNs disappeared when aversive memory was prevented by keeping mice in the conditioning apparatus. Furthermore, the increase in PKA activity in iMSNs by aversive stimuli reflected facilitation of aversive memory retention. These results indicate that PKA signaling in iMSNs plays a critical role in both aversive memory formation and retention.
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Nieto Mendoza, Elizabeth, and Elizabeth Hernández Echeagaray. "Dopaminergic Modulation of Striatal Inhibitory Transmission and Long-Term Plasticity." Neural Plasticity 2015 (2015): 1–15. http://dx.doi.org/10.1155/2015/789502.
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Dopamine (DA) modulates glutamatergic synaptic transmission and its plasticity in the striatum; however it is not well known how DA modulates long-term plasticity of striatal GABAergic inhibitory synapses. This work focused on the analysis of both dopaminergic modulation of inhibitory synapses and the synaptic plasticity established between GABAergic afferents to medium spiny neurons (MSNs). Our results showed that low and high DA concentrations mainly reduced the amplitude of inhibitory synaptic response; however detailed analysis of the D1 and D2 participation in this modulation displayed a wide variability in synaptic response. Analyzing DA participation in striatal GABAergic plasticity we observed that high frequency stimulation (HFS) of GABAergic interneurons in the presence of DA at a low concentration (200 nM) favored the expression of inhibitory striatal LTD, whereas higher concentration of DA (20 μM) primarily induced LTP. Interestingly, the plasticity induced in an animal model of striatal degeneration mimicked that induced in the presence of DA at a high concentration, which was not abolished with D2 antagonist but was prevented by PKA blocker.
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Yeh, Su-Peng, Wen-Jyi Lo, and Chang-Fang Chiu. "Bone Marrow-Derived Mesenchymal Stem Cell Homing to Breast Cancer but Not Colon and Renal Cancer and VEGF-C and VEGF-R3 Play the Key Role in Tumor Homing Effect in the Syngeneic Mice (Balb/c) Model,." Blood 118, no. 21 (2011): 3418. http://dx.doi.org/10.1182/blood.v118.21.3418.3418.
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Abstract Abstract 3418 Background Mesenchymal stem cells (MSCs) have the unique ability of homing to tumor tissue. Most of prior studies used xenograft models to demonstrate hMSC homing to human cancer on the immunodeficient mice. This model is far away from clinically relevant condition. It was also unknown whether MSCs target specific or all the tumor types in immunocompotent host as well as the mechanism driving MSCs home to tumor site. Methods Migration assay was done to access the in vitro migration effect of D1 cells (BM-MSCs derived from balb/c mice) in response to 4T1, CT26, and Rag cells (breast cancer, colon cancer, and renal cancer cell line derived from balb/c mice). Firefly luciferase (Luc) stably expressed D1 (D1-Luc) was selected and maintained. 4T1 and CT26 cells were inoculated into 6 weeks balb/c mice. D1-Luc cells were then injected into normal or tumor-bearing balb/c through tail vein at different tumor stage (small tumors and big tumors). Besides, 4T1 and CT26 cells were inoculated into bilateral sides of balb/c mice. After tumor formation, D1-Luc cells were injected locally into one side to see whether the D1-Luc can migrate to the contralateral tumor or not. The in vivo tumor homing was accessed by IVIS (xenogen). Finally, 4T1 and CT26 tumors were excised from the mice to analyze gene expression profile (GEP). Chemokines/cytokines highly expressed on 4T1 but not CT26 were selected for blocking study in vitro and in vivo. Results Both in vitro and in vivo studies showed D1 homing to 4T1 (breast) tumor only but not CT26 (colon) and Rag (renal) tumor. In case of 4T1, D1-Luc homed to all (100%) the tumor-bearing mice though tail vein injection. Besides, D1-Luc cells also home to both big and small 4T1 tumor simultaneously. When D1-Luc injected locally to one side of 4T1-bearing mice, the luciferase activity can be detected at the contralateral 4T1 tumor one hour after injection. In case of CT26, luciferase activity can not be detected on the contralateral CT26 tumor up to 7 days after injection. The GEP study showed VEGF-C, CCL24, CXCL 1/2/7 were highly expressed in 4T1 but not CT26. Blocking the VEGF-C receptor of D1 alone by using neutralizing antibody was sufficient to suppress D1 cells migration toward 4T1 tumor both in vitro and in vivo. The expression of VEGF-C is 100-fold higher in tumor tissue comparing to normal tissues (lung, liver, spleen, and kidney) by using RT-PCR. Conclusions MSCs home to specific tumor only and specific ligand-receptor relationship between MSCs and cancer cells determines the specificity. In this immunocompetent, syngeneic mice model, BM-MSCs homes to breast cancer but not normal tissue via VEGF-C and VEGF-C receptor axis. Our model also provides a good platform to the future development of MSC-based cell therapy. Before starting such a trial in human, it is essential to identify a specific ligand that is highly expressed on tumor (maybe very specific type of tumor) but not normal tissues and the MSCs should have corresponding receptor. This work was supported in part by the research grant from Taiwan National Science Council (NSC-96-3111-B-039-001), and Department of Health, China Medical University Hospital Cancer Research of Excellence (DOH-100-TD-C-111-005). Disclosures: No relevant conflicts of interest to declare.
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Yeh, Su-Peng, Wen-Jyi Lo, Yu-Chien Chang, Wan-Ju Tsai, Chiao-Lin Lin, and Yu-Min Liao. "Tumor Homing Activity of Bone Marrow-Derived Mesenchymal Stem Cell Is Highly Various Among Different Tumors On Syngeneic Mouse Model Using Real-Time in Vivo Imaging Technique." Blood 114, no. 22 (2009): 1453. http://dx.doi.org/10.1182/blood.v114.22.1453.1453.
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Abstract Abstract 1453 Poster Board I-476 Purpose Mesenchymal stem cells (MSCs) have the unique ability of homing to tumor tissue. Most of prior studies using GPF-labeled MSCs in the xenograft models (hMSC-GFP homing to human cancer on the immunodeficient mice) and then counting the GFP(+) cells in the tumor and other tissues to evaluate homing specificity. This model is far away from clinically relevant condition and bios would develop during counting process. More importantly, it remains unknown whether MSCs target specific or all the tumor types in immunocompotent host. Here we use firefly luciferase stably expressed MSCs cell line (D1-Luc) derived from bone marrow of balb/c mice and assess the homing activity on different tumor types (also derived from balb/c mice) by using in vivo imaging system (IVIS). Materials & Methods D1 cells were purchased from ATCC. Firefly luciferase (Luc) stably expressed D1 was selected and maintained after transducing Luc-Neomycin into D1. 4T1, CT26, and Rag cells (breast cancer cell line, colon cancer cell line, and renal cancer cell line derived from balb/c mice) was subcutaneously injected into 6 to 8 weeks balb/c mice and tumor would develop within 1 week. 2 × 106 D1-luc cells were then injected into normal balb/c or tumor-bearing balb/c through tail vein. 1 hour, 1 day, 3 days, 7 days and 14 days after tail vein injection, balb/c mice were anesthetized and luciferase activity in the whole mouse was evaluated by IVIS (xenogen). Results 1 hour after D1-luc tail vein injection, luciferase activity was detected mostly in the lung (normal balb/c and CT26-babl/c) and both lung and tumor (4T1-balb/c and Rag-balb/c). The luciferase activity in lung decreased markedly 1 day after injection and no longer detectable after 3 days in both normal and tumor-bearing mice. However, the luciferase activity accumulated in tumor tissue markedly and progressively increased in 4T1-balb/c and Rag-balb/c since 1 day after tail vein injection and persisted for more than 1 week. The luciferase activity in lung was detectable again 2 weeks after tail vein injection in few 4T1- and Rag-bearing mice. Lung tissue was examined and tumor metastasis in lung was confirmed in these mice. Furthermore, luciferase-positive cells can be detected in the metastatic tumor nests by using immunohistochemical staining. Luciferase activity was not detected at tumor sites of CT26-balb/c at any time point after injection of D1-Luc. Conclusions In this immunocompotent, syngeneic mouse model, BM-MSCs showed a highly various tumor-homing activity. BM-MSCs home to tumor site of breast (4T1) and renal cancer (Rag)-bearing balb/c mice quickly and specifically. By contrary, BM-MSCs homing to tumor site of colon cancer (CT26)-bearing mice was below the detectable limit of IVIS. Our findings suggest MSCs homing to tumor is not a universal conclusion and there must be some mechanism driving MSCs homing to a specific type of tumor rather than all the tumors. However, for a tumor that MSCs specifically targeted, MSCs can home to the primary tumor and also the metastatic site. This information is very important when considering MSCs as a vehicle of cell or gene therapy for cancer. Disclosures No relevant conflicts of interest to declare.
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Abdel Aziz, Mohamed Talaat, Hussien Mostafa Khaled, Ali El Hindawi, et al. "Effect of Mesenchymal Stem Cells and a Novel Curcumin Derivative on Notch1 Signaling in Hepatoma Cell Line." BioMed Research International 2013 (2013): 1–8. http://dx.doi.org/10.1155/2013/129629.
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This study was conducted to evaluate the effect of mesenchymal stem cells (MSCs) and a novel curcumin derivative (NCD) on HepG2 cells (hepatoma cell line) and to investigate their effect on Notch1 signaling pathway target genes. HepG2 cells were divided into HepG2 control group, HepG2 cells treated with MSC conditioned medium (MSCs CM), HepG2 cells treated with a NCD, HepG2 cells treated with MSCs CM and NCD, and HepG2 cells treated with MSCs CM (CM of MSCs pretreated with a NCD). Expression of Notch1, Hes1, VEGF, and cyclin D1 was assessed by real-time, reverse transcription-polymerase chain reaction (RT-PCR) in HepG2 cells. In addition, HepG2 proliferation assay was performed in all groups. Notch1 and its target genes (Hes1 and cyclin D1) were downregulated in all treated groups with more suppressive effect in the groups treated with both MSCs and NCD. Also, treated HepG2 cells showed significant decrease in cell proliferation rate. These data suggest that modulation of Notch1 signaling pathway by MSCs and/or NCD can be considered as a therapeutic target in HCC.
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D’Esposito, Vittoria, Josè Camilla Sammartino, Pietro Formisano, et al. "Effect of Different Titanium Dental Implant Surfaces on Human Adipose Mesenchymal Stem Cell Behavior. An In Vitro Comparative Study." Applied Sciences 11, no. 14 (2021): 6353. http://dx.doi.org/10.3390/app11146353.
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Background: The aim of this research was to evaluate the effects of three different titanium (Ti) implant surfaces on the viability and secretory functions of mesenchymal stem cells isolated from a Bichat fat pad (BFP-MSCs). Methods: Four different Ti disks were used as substrate: (I) D1: smooth Ti, as control; (II) D2: chemically etched, resembling the Kontact S surface; (III) D3: sandblasted, resembling the Kontact surface; (IV) D4: blasted/etched, resembling the Kontact N surface. BFP-MSCs were plated on Ti disks for 72 h. Cell viability, adhesion on disks and release of a panel of cytokines, chemokines and growth factor were evaluated. Results: BFP-MSCs plated in wells with Ti surface showed a viability rate (~90%) and proliferative rate comparable to cells plated without disks and to cells plated on D1 disks. D2 and D4 showed the highest adhesive ability. All the Ti surfaces did not interfere with the release of cytokines, chemokines and growth factors by BFP-MSCs. However, BFP-MSCs cultured on D4 surface released a significantly higher amount of Granulocyte Colony-Stimulating Factor (G-CSF) compared either to cells plated without disks and to cells plated on D1 and D2. Conclusions: The implant surfaces examined do not impair the BFP-MSCs cell viability and preserve their secretion of cytokines and chemokines. Further in vitro and in vivo studies are necessary to define the implant surface parameters able to assure the chemokines’ optimal release for a real improvement of dental implant osseointegration.
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Shao, Pei-Lin, Shun-Cheng Wu, Zih-Yin Lin, Mei-Ling Ho, Chung-Hwan Chen, and Chau-Zen Wang. "Alpha-5 Integrin Mediates Simvastatin-Induced Osteogenesis of Bone Marrow Mesenchymal Stem Cells." International Journal of Molecular Sciences 20, no. 3 (2019): 506. http://dx.doi.org/10.3390/ijms20030506.
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Simvastatin (SVS) promotes the osteogenic differentiation of mesenchymal stem cells (MSCs) and has been studied for MSC-based bone regeneration. However, the mechanism underlying SVS-induced osteogenesis is not well understood. We hypothesize that α5 integrin mediates SVS-induced osteogenic differentiation. Bone marrow MSCs (BMSCs) derived from BALB/C mice, referred to as D1 cells, were used. Alizarin red S (calcium deposition) and alkaline phosphatase (ALP) staining were used to evaluate SVS-induced osteogenesis of D1 cells. The mRNA expression levels of α5 integrin and osteogenic marker genes (bone morphogenetic protein-2 (BMP-2), runt-related transcription factor 2 (Runx2), collagen type I, ALP and osteocalcin (OC)) were detected using quantitative real-time PCR. Surface-expressed α5 integrin was detected using flow cytometry analysis. Protein expression levels of α5 integrin and phosphorylated focal adhesion kinase (p-FAK), which is downstream of α5 integrin, were detected using Western blotting. siRNA was used to deplete the expression of α5 integrin in D1 cells. The results showed that SVS dose-dependently enhanced the gene expression levels of osteogenic marker genes as well as subsequent ALP activity and calcium deposition in D1 cells. Upregulated p-FAK was accompanied by an increased protein expression level of α5 integrin after SVS treatment. Surface-expressed α5 integrin was also upregulated after SVS treatment. Depletion of α5 integrin expression significantly suppressed SVS-induced osteogenic gene expression levels, ALP activity, and calcium deposition in D1 cells. These results identify a critical role of α5 integrin in SVS-induced osteogenic differentiation of BMSCs, which may suggest a therapeutic strategy to modulate α5 integrin/FAK signaling to promote MSC-based bone regeneration.
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Tao, Rong, Chu-Pak Lau, Hung-Fat Tse, and Gui-Rong Li. "Regulation of cell proliferation by intermediate-conductance Ca2+-activated potassium and volume-sensitive chloride channels in mouse mesenchymal stem cells." American Journal of Physiology-Cell Physiology 295, no. 5 (2008): C1409—C1416. http://dx.doi.org/10.1152/ajpcell.00268.2008.
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Bone marrow mesenchymal stem cells (MSCs) are a promising cell source for regenerative medicine; however, their cellular physiology is not fully understood. The present study aimed at exploring the potential roles of the two dominant functional ion channels, intermediate-conductance Ca2+-activated potassium (IKCa) and volume-sensitive chloride ( ICl.vol) channels, in regulating proliferation of mouse MSCs. We found that inhibition of IKCa with clotrimazole and ICl.vol with 5-nitro-1-(3-phenylpropylamino) benzoic acid (NPPB) reduced cell proliferation in a concentration-dependent manner. Knockdown of KCa3.1 or Clcn3 with specific short interference (si)RNAs significantly reduced IKCa or ICl.vol density and channel protein and produced a remarkable suppression of cell proliferation (by 24.4 ± 9.6% and 29.5 ± 7.2%, respectively, P < 0.05 vs. controls). Flow cytometry analysis showed that mouse MSCs retained at G0/G1 phase (control: 51.65 ± 3.43%) by inhibiting IKCa or ICl.vol using clotrimazole (2 μM: 64.45 ± 2.20%, P < 0.05) or NPPB (200 μM: 82.89 ± 2.49%, P < 0.05) or the specific siRNAs, meanwhile distribution of cells in S phase was decreased. Western blot analysis revealed a reduced expression of the cell cycle regulatory proteins cyclin D1 and cyclin E. Collectively, our results have demonstrated that IKCa and ICl.vol channels regulate cell cycle progression and proliferation of mouse MSCs by modulating cyclin D1 and cyclin E expression.
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Benjamin, Courteney L., William M. Adams, Ryan M. Curtis, et al. "Sleeping Patterns of NCAA D1 Collegiate Athletes." Medicine & Science in Sports & Exercise 50, no. 5S (2018): 804–5. http://dx.doi.org/10.1249/01.mss.0000538651.07947.62.
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Hu, Hongyang, Min Chen, Guangzu Dai та ін. "An Inhibitory Role of Osthole in Rat MSCs Osteogenic Differentiation and Proliferation via Wnt/β-Catenin and Erk1/2-MAPK Pathways". Cellular Physiology and Biochemistry 38, № 6 (2016): 2375–88. http://dx.doi.org/10.1159/000445590.
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Background/Aims: Bone marrow-derived mesenchymal stem cells (MSCs) are responsible for new bone formation during adulthood. Accumulating evidences showed that Osthole promotes the osteogenic differentiation in primary osteoblasts. The aim of this study was to investigate whether Osthole exhibits a potential to stimulate the osteogenic differentiation of MSCs and the underlying mechanism. Methods: MSCs were treated with a gradient concentration of Osthole (6.25 µM, 12.5 µM, and 25 µM). Cell proliferation was assessed by western blotting with the proliferating cell nuclear antigen (PCNA) and Cyclin D1 antibodies, fluorescence activated cell sorting (FACS), and cell counting kit 8 (CCK8). MSCs were cultured in osteogenesis-induced medium for one or two weeks. The osteogenic differentiation of MSCs was estimated by Alkaline Phosphatase (ALP) staining, Alizarin red staining, Calcium influx, and quantitative PCR (qPCR). The underlying mechanism of Osthole-induced osteogenesis was further evaluated by western blotting with antibodies in Wnt/β-catenin, PI3K/Akt, BMPs/smad1/5/8, and MAPK signaling pathways. Results: Osthole inhibited proliferation of rat MSCs in a dose-dependent manner. Osthole suppressed osteogenic differentiation of rat MSCs by down-regulating the activities of Wnt/β-catenin and Erk1/2-MAPK signaling. Conclusions: Osthole inhibits the proliferation and osteogenic differentiation of rat MSCs, which might be mediated through blocking the Wnt/β-catenin and Erk1/2-MAPK signaling pathways.
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Xie, Xiaoyan, Miao Liu, and Qiang Meng. "Angelica polysaccharide promotes proliferation and osteoblast differentiation of mesenchymal stem cells by regulation of long non-coding RNA H19." Bone & Joint Research 8, no. 7 (2019): 323–32. http://dx.doi.org/10.1302/2046-3758.87.bjr-2018-0223.r2.
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Objectives Osteoporosis is a systemic bone metabolic disease, which often occurs among the elderly. Angelica polysaccharide (AP) is the main component of angelica sinensis, and is widely used for treating various diseases. However, the effects of AP on osteoporosis have not been investigated. This study aimed to uncover the functions of AP in mesenchymal stem cell (MSC) proliferation and osteoblast differentiation. Methods MSCs were treated with different concentrations of AP, and then cell viability, Cyclin D1 protein level, and the osteogenic markers of runt-related transcription factor 2 (RUNX2), osteocalcin (OCN), alkaline phosphatase (ALP), bone morphogenetic protein 2 (BMP-2) were examined by Cell Counting Kit-8 (CCK-8) and western blot assays, respectively. The effect of AP on the main signalling pathways of phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) and Wnt/β-catenin was determined by western blot. Following this, si-H19#1 and si-H19#2 were transfected into MSCs, and the effects of H19 on cell proliferation and osteoblast differentiation in MSCs were studied. Finally, in vivo experimentation explored bone mineral density, bone mineral content, and the ash weight and dry weight of femoral bone. Results The results revealed that AP significantly promoted cell viability, upregulated cyclin D1 and increased RUNX2, OCN, ALP, and BMP-2 protein levels in MSCs. Moreover, we found that AP notably activated PI3K/AKT and Wnt/β-catenin signalling pathways in MSCs. Additionally, the relative expression level of H19 was upregulated by AP in a dose-dependent manner. The promoting effects of AP on cell proliferation and osteoblast differentiation were reversed by H19 knockdown. Moreover, in vivo experimentation further confirmed the promoting effect of AP on bone formation. Conclusion These data indicate that AP could promote MSC proliferation and osteoblast differentiation by regulating H19. Cite this article: X. Xie, M. Liu, Q. Meng. Angelica polysaccharide promotes proliferation and osteoblast differentiation of mesenchymal stem cells by regulation of long non-coding RNA H19: An animal study. Bone Joint Res 2019;8:323–332. DOI: 10.1302/2046-3758.87.BJR-2018-0223.R2.
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Wang, Dawei, Yonghui Wang, Shihong Xu, et al. "Epigallocatechin-3-gallate Protects against Hydrogen Peroxide-Induced Inhibition of Osteogenic Differentiation of Human Bone Marrow-Derived Mesenchymal Stem Cells." Stem Cells International 2016 (2016): 1–10. http://dx.doi.org/10.1155/2016/7532798.
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Oxidative stress induces bone loss and osteoporosis, and epigallocatechin-3-gallate (EGCG) may be used to combat these diseases due to its antioxidative property. Herein, oxidative stress in human bone marrow-derived mesenchymal stem cells (BM-MSCs) was induced by H2O2, resulting in an adverse effect on their osteogenic differentiation. However, this H2O2-induced adverse effect was nullified when the cells were treated with EGCG. In addition, treatment of BM-MSCs with EGCG alone also resulted in the enhancement of osteogenic differentiation of BM-MSCs. After EGCG treatment, expressions of β-catenin and cyclin D1 were upregulated, suggesting that the Wnt pathway was involved in the effects of EGCG on the osteogenic differentiation of BM-MSCs. This was also confirmed by the fact that the Wnt pathway inhibitor, Dickkopf-1 (DKK-1), can nullify the EGCG-induced enhancement effect on BM-MSC’s osteogenic differentiation. Hence, our results suggested that EGCG can reduce the effects of oxidative stress on Wnt pathway in osteogenic cells, which supported a potentially promising therapy of bone disorders induced by oxidative stress. Considering its positive effects on BM-MSCs, EGCG may also be beneficial for stem cell-based bone repair.
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Dzobo, Kevin, Matjaz Vogelsang, Nicholas E. Thomford, et al. "Wharton’s Jelly-Derived Mesenchymal Stromal Cells and Fibroblast-Derived Extracellular Matrix Synergistically Activate Apoptosis in a p21-Dependent Mechanism in WHCO1 and MDA MB 231 Cancer CellsIn Vitro." Stem Cells International 2016 (2016): 1–17. http://dx.doi.org/10.1155/2016/4842134.
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The tumour microenvironment plays a crucial role in tumour progression and comprises tumour stroma which is made up of different cell types and the extracellular matrix (ECM). Mesenchymal stromal cells (MSCs) are part of the tumour stroma and may have conflicting effects on tumour growth. In this study we investigated the effect of Wharton’s Jelly-derived MSCs (WJ-MSCs) and a fibroblast-derived ECM (fd-ECM) on esophageal (WHCO1) and breast (MDA MB 231) cancer cellsin vitro. Both WJ-MSCs and the fd-ECM, alone or in combination, downregulate PCNA, cyclin D1, Bcl-2, Bcl-xL, and MMPs and upregulate p53 and p21. p21 induction resulted in G2 phase cell cycle arrest and induced apoptosisin vitro. Our data suggest that p21 induction is via p53-dependent and p53-independent mechanisms in WHCO1 and MDA MB 231 cells, respectively. Vascular endothelial growth factor, Akt, and Nodal pathways were downregulated in cancer cells cocultured with WJ-MSCs. We also demonstrate that WJ-MSCs effects on cancer cells appear to be short-lived whilst the fd-ECM effect is long-lived. This study shows the influence of tumour microenvironment on cancer cell behaviour and provides alternative therapeutic targets for potential regulation of tumour cells.
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Shatrova, Alla, Elena Burova, Marianna Kharchenko, et al. "Outcomes of Deferoxamine Action on H2O2-Induced Growth Inhibition and Senescence Progression of Human Endometrial Stem Cells." International Journal of Molecular Sciences 22, no. 11 (2021): 6035. http://dx.doi.org/10.3390/ijms22116035.
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Mesenchymal stem cells (MSCs) are broadly applied in regenerative therapy to replace cells that are lost or impaired during disease. The low survival rate of MSCs after transplantation is one of the major limitations heavily influencing the success of the therapy. Unfavorable microenvironments with inflammation and oxidative stress in the damaged regions contribute to MSCs loss. Most of the strategies developed to overcome this obstacle are aimed to prevent stress-induced apoptosis, with little attention paid to senescence—another common stress reaction of MSCs. Here, we proposed the strategy to prevent oxidative stress-induced senescence of human endometrial stem cells (hMESCs) based on deferoxamine (DFO) application. DFO prevented DNA damage and stress-induced senescence of hMESCs, as evidenced by reduced levels of reactive oxygen species, lipofuscin, cyclin D1, decreased SA-β-Gal activity, and improved mitochondrial function. Additionally, DFO caused accumulation of HIF-1α, which may contribute to the survival of H2O2-treated cells. Importantly, cells that escaped senescence due to DFO preconditioning preserved all the properties of the initial hMESCs. Therefore, once protecting cells from oxidative damage, DFO did not alter further hMESCs functioning. The data obtained may become the important prerequisite for development of a new strategy in regenerative therapy based on MSCs preconditioning using DFO.
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Zamudio-González, Benjamín, Margarita Tadeo-Robledo, Alejandro Espinosa-Calderón, Nelson Martínez-Rodríguez, and Antonio Turrent-Fernández. "Índice de cosecha con macro-nutrimentos en grano de maíz." Revista Mexicana de Ciencias Agrícolas 7, no. 5 (2017): 1077. http://dx.doi.org/10.29312/remexca.v7i5.233.
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 En Valles Altos del Estado de México entre 2 200 a 2 700 msnm se tienen bajos rendimientos de maíz con alto riesgo por clima y siembra de criollos con inadecuadas prácticas de manejo. Los años 2009, 2010 y 2011 (A1, 2, 3) se evaluó la siembra del híbrido H-51 AE en campo con dos densidades (D1= 65 mil y D2= 85 000 plantas ha-1) y tres secuencias anuales de nitrógeno (Ni) al suelo (con N siempre N1= N-N-N, primer año sin nitrógeno N2= 0-N-N y sin N los tres años N3= 0-0-0) y dos dosis de N (N= 300 y N=1 80 kg ha-1). La combinación de factores 2Di*3Ni= 6 tratamientos, donde: T1= D1*N1, T2=D1*N2, T3=D1*N3, T4=D2*N1, T5=D2*N2 y T6=D2*N3. Cada año se adicionó en kg ha-1 de P2O5, K2O, MgO, S y Zn a los tratamientos del T1 al T3 con 0-90-90-44-50-3; y del T4 al T2 con 0-45-45-0-0-0. La prueba se ubicó en las coordenadas 19o 34’23.28” latitud norte y 99o46’25.62” longitud oeste con altitud de 2 628 msnm. Se pesaron la producción de grano, forraje y olote; y los contenidos de macro-nutrimentos para calcular sus índices de cosecha (IC) en grano de maíz por efecto de años, densidades y secuencias de N. Los contenidos totales de cinco macro elementos en kg ha-1 en la biomasa total de maíz en promedio de tres años, fueron: 187.9 de N, 30.6 de P, 69.9 de K, 24.1 de Mg y 11.6 de S. Los índices de cosecha de estos elementos en el grano de maíz fueron: ICN= 0.45, ICP=0.75, ICK= 0.21, ICMg= 0.45 e ICS=0.43. Existió correlación (R2) positiva de producción de grano con biomasa y contenidos [N/ P y Mg]; así como de la biomasa con contenidos [N/P/K y S]. Se justificó aumentar la densidad de siembra pero “alta” fertilización de N al suelo no es rentable en condiciones de mal clima.
 
 
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Rhodes, Thomas J., Michelle Pazienza, and Jodi F. Evans. "ACTH Enhances Lipid Accumulation in Bone-marrow derived Mesenchymal Stem Cells undergoing Adipogenesis." Journal of Student Research 4, no. 1 (2015): 69–73. http://dx.doi.org/10.47611/jsr.v4i1.181.
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ACTH is a major hormone of the stress axis or hypothalamic-pituitary-adrenal (HPA) axis. It is derived from pro-opiomelanocortin (POMC) the precursor to the melanocortin family of peptides. POMC produces the biologically active melanocortin peptides via a series of enzymatic steps in a tissue-specific manner, yielding the melanocyte-stimulating hormones (MSHs), corticotrophin (ACTH) and ?-endorphin. The melanocortin system plays an imperative role in energy expenditure, insulin release and insulin sensitivity. Bone marrow derived mesenchymal stem cells circulate in the blood stream and as progenitor cells have the potential to differentiate into many cell types such as osteoblasts, chondrocytes and adipocytes. Here we examine the effects of ACTH on the mouse D1 bone-marrow derived MSC. ACTH significantly increased lipid accumulation during the adipogenic differentiation of D1 cells in a concentration- dependent manner. ACTH also shifts the temporal pattern of D1 adipogenic differentiation to the left i.e. differentiation occurs earlier with ACTH treatment. No significant differences in protein expression of peroxisome proliferator-activated receptor gamma (PPAR-?2), a regulating transcription factor of adipogenesis were found. Therefore the effects of ACTH are suggested to be mediated by an alternative pathway. Overall the results indicate a connection between increased adipose deposition and the elevated circulating ACTH associated with stress.
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Curtis, Michael Adrian, Natalie Kupperman, Arthur L. Weltman, Jay Hertel, and Joseph Hart. "Workload Characteristics During A Collegiate Ncaa D1 Men’S Basketball Season." Medicine & Science in Sports & Exercise 53, no. 8S (2021): 47. http://dx.doi.org/10.1249/01.mss.0000759628.94069.2b.
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Metzler, Abbie J. "Chronic Intermittent Wrist Pain In A D1 Softball Outfielder." Medicine & Science in Sports & Exercise 53, no. 8S (2021): 436. http://dx.doi.org/10.1249/01.mss.0000764284.75083.fb.
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Paultre, Kristopher J., William Cade, Hannah Ellis, and Thomas M. Best. "Iron and Vitamin D Deficiency in D1 Female Track & Field Athletes." Medicine & Science in Sports & Exercise 51, Supplement (2019): 590. http://dx.doi.org/10.1249/01.mss.0000562273.90964.55.
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Picazo, Anton-Luigi L. "The Correlative Relationship Between Fitness Goals and Wearable Usage: An Observational Double-Blind Study." Medicine & Science in Sports & Exercise 51, Supplement (2019): 836. http://dx.doi.org/10.1249/01.mss.0000562996.51341.d1.
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Myers, Christopher M., Jeong-Su Kim, and John Florian. "Consecutive, Long-Duration Hyperoxic Immersions Effect on Skeletal Muscle Performance in Well Trained, Male Divers." Medicine & Science in Sports & Exercise 51, Supplement (2019): 397. http://dx.doi.org/10.1249/01.mss.0000561691.75602.d1.
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Simmons, Catherine G., Vitor A. Lira, Jenna L. Betters, Quinlyn A. Soltow, and David S. Criswell. "Nitric Oxide Facilitates Calcium-Induced, NFAT-Dependent Transcription in Myotubes." Medicine & Science in Sports & Exercise 39, Supplement (2007): S223. http://dx.doi.org/10.1249/01.mss.0000273843.58870.d1.
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Encheff, Jenna, and Bart Tate. "Rehabilitation of a Patient Status Post Reverse Total Shoulder Replacement." Medicine & Science in Sports & Exercise 39, Supplement (2007): S259. http://dx.doi.org/10.1249/01.mss.0000273992.20890.d1.
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Marquina, Ramón, David González, José Guerrero, Bernhard Hoeger, Antonio Rodríguez-Malaver, and Rafael Reyes. "Aerobic Exercise Effects on Nitric Oxide, Uric Acid, Antioxidant Activity and Oxidative Stress in Saliva of Young- Sedentary Males." Medicine & Science in Sports & Exercise 39, Supplement (2007): S354. http://dx.doi.org/10.1249/01.mss.0000274389.44417.d1.
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Engels, Hermann J., Navdeep S. Lohcham, and Neelege S. Elmore. "Effects of Panax Ginseng on Rest, Exercise and Post-Exercise Recovery Hemodynamics in Healthy College Males." Medicine & Science in Sports & Exercise 39, Supplement (2007): S360. http://dx.doi.org/10.1249/01.mss.0000274414.52933.d1.
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Erceg, David N., Amerigo E. Rossi, Nicole E. Jensky, Christina M. Dieli-Conwright, Scott A. McCauley, and E. Todd Schroeder. "Validation of the Futrex 6100TM and Stayhealthy BC3™ for Estimating Body Composition." Medicine & Science in Sports & Exercise 39, Supplement (2007): S370. http://dx.doi.org/10.1249/01.mss.0000274454.45241.d1.
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Weimar, Wendi, John Garner, Casey Breslin, Loraine Parish, Brian Campbell, and Mary Rudisill. "The Influence Of Ball Weight And Size On Shoulder External Rotation." Medicine & Science in Sports & Exercise 39, Supplement (2007): S477. http://dx.doi.org/10.1249/01.mss.0000274892.02531.d1.
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