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Academic literature on the topic 'D1 MSNs'
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Journal articles on the topic "D1 MSNs"
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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.
Dissertations / Theses on the topic "D1 MSNs"
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Bertran-Gonzalez, Jesus. "Study of segregated signaling responses of striatonigral and striatopallidal neurons in BAC transgenic mice." Paris 6, 2009. http://www.theses.fr/2009PA066348.
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Le striatum reçoit et intègre des informations arrivant de régions corticales et thalamiques et de neurones dopaminergiques du mésencéphale, formant ainsi la station d'entrée principale au circuit des ganglions de la base (GB). Il est principalement composé de deux sous-types de neurones GABAergiques épineux de taille moyenne (MSNs), qui projettent vers différents noyaux. La voie directe est constituée par les neurones striatonigraux, qui projettent directement vers la substance noire pars reticulé (SNr), la station de sortie des GB. La voie indirecte lie le striatum et la SNr par des relais intermédiaires, dont les premières projections sont ceux des neurones striatopallidaux. Etant donné leurs influences opposées au niveau de la SNr, les informations transmises par les neurones striatonigraux et striatopallidaux à travers des circuits thalamocorticaux sont cruciales pour la sortie finale des GB. La dopamine (DA) module les informations corticostriatales et thalamostriatales au travers des différents types de récepteurs de la DA exprimés dans les MSNs. Les récepteurs de type D1 (D1R) sont connus pour activer des programmes importants de la signalisation moléculaire tels que les modules cAMP/PKA/DARPP-32 et MAPK/ERK, tous deux usant de réponses cytoplasmiques et nucléaires essentielles. D'autre part, les récepteurs de type D2 (D2R) sont négativement associés à la formation de l’AMPc, et sont fonctionnellement couplés aux récepteurs d'adénosine A2A (A2AR) dans un jeu opposé qui régule des réactions intracellulaires et au niveau de la membrane. À la lumière de la controverse existant encore sur la distribution ségrégée vs superposée des sous-types de récepteurs de la DA dans les neurones striatonigraux et striatopallidaux, nous avons entrepris une série d'études neuro-anatomiques et histologiques pour la caractérisation des souris transgéniques BAC drd1a-EGFP et drd2-EGFP, qui marquent les cellules exprimant D1R et D2R, respectivement. Nous avons constaté que les D1R et D2R sont respectivement distribués dans les neurones striatonigraux et striatopallidaux de manière très ségrégée, et nous avons estimé les proportions de neurones exprimant D1R, D2R ou les deux dans différentes régions du striatum. Nos résultats appuient l'organisation des GB dans les voies directe et indirecte, mais nous avons détecté la présence de certains terminaux des D1R-MSNs au niveau du globus pallidus latéral. Surtout, nous avons clairement démontré que, après des traitements de cocaïne aigus et chroniques, à la fois des réponses cytoplasmiques -révélées par l'activation de ERK- et réponses nucléaires -révélées par l'activation de MSK1 et la phosphorylation de l'histone H3- se produisent exclusivement dans les neurones striatonigraux, une distribution qui est largement suivie plus tard par l'induction des gènes immédiats précoces c-fos et zif268. Nous démontrons également que l’antipsychotique typique halopéridol, ainsi que des inhibiteurs spécifiques des D2R, activent toutes ces réponses de signalisation sélectivement dans les neurones striatopallidaux, par un mécanisme de dérépression des A2AR. En parallèle, nous révélons des régulations moléculaires exclusives des réponses nucléosomales dans ces cellules. Dans l'ensemble, les résultats présentés dans cette thèse mettent en évidence une forte ségrégation histologique et fonctionnelle des neurones du striatum, ce qui est essentiel pour la compréhension de la modulation des GB exercée par la DA dans le striatum.
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Rubakovic, Anastasia. "Dendritic topology of D1 and D2 medium spiny neurons in the Q-175 mouse model of Huntington's disease." Thesis, 2017. https://hdl.handle.net/2144/23855.
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Direct (D1) and indirect (D2) pathway medium spiny neurons (MSNs) in the striatum are severely affected in Huntington’s disease. The aim of this study was to compare the dendritic topology and electrophysiological properties of wild type (WT) D1 and D2 MSNs with those in the Q-175 mouse model of Huntington’s disease. By scanning biocytin-filled MSNs using high-resolution confocal imaging, we quantified the dendritic lengths and complexity of WT and Q-175+/- D1 and D2 MSNs. We correlated these dendritic topological parameters with various electrophysiological properties. Q175+/- D1 MSNs had significantly larger total dendritic lengths, more complex dendritic arbors, and a larger mean number of primary dendrites than their WT counterparts. Q175+/- D2 MSNs had similar total dendritic lengths, dendritic complexities, and mean number of primary branches as the WT D2 MSNs. WT D1 and D2 MSNs were similar in terms of their total dendritic length, total number of intersections, and mean number of primary dendrites suggesting a degree of homogeneity in these cell populations. We found no correlations between membrane resistance, rheobase, EPSC frequency, or EPSC amplitude, and total dendritic length or dendritic complexity of MSNs when observed separately (WT and Q175+/-) or combined, with one exception, a positive correlation between rheobase and total intersections. These findings add to the understanding of the morphology of D1 and D2 MSNs in general, as well as how they are differentially affected by the presence of a CAG expansion in the Q-175+/- mouse model of Huntington’s disease.