Striatal Projection Research Articles

Age-Dependent Degradation of Locomotion Encoding in Huntington's Disease R6/2 Model Mice.

Background:Huntington’s disease (HD) is an inherited fatal neurodegenerative disease, leading to neocortical and striatal atrophy. The commonly studied R6/2 HD transgenic mouse model displays progressive motor and cognitive deficits in parallel to major pathological changes in corticostriatal circuitry.Objective:To study how disease progression influences striatal encoding of movement.Methods:We chronically recorded neuronal activity in the dorsal striatum of R6/2 transgenic (Tg) mice and their age-matched nontransgenic littermate controls (WTs) during novel environment exposure, a paradigm which engages locomotion to explore the novel environment.Results:Exploratory locomotion degraded with age in Tg mice as compared to WTs. We encountered fewer putative medium spiny neurons (MSNs)—striatal projection neurons, and more inhibitory interneurons—putative fast spiking interneurons (FSIs) in Tg mice as compared to WTs. MSNs from Tg mice fired less spikes in bursts without changing their firing rate, while FSIs from these mice had a lower firing rate and more of them were task-responsive as compared to WTs. Additionally, MSNs from Tg mice displayed a reduced ability to encode locomotion across age groups, likely associated with their low prevalence in Tg mice, whereas the encoding of locomotion by FSIs from Tg mice was substantially reduced solely in old Tg mice as compared to WTs.Conclusion:Our findings reveal an age-dependent decay in striatal information processing in transgenic mice. We propose that the ability of FSIs to compensate for the loss of MSNs by processes of recruitment and enhanced task-responsiveness diminishes with disease progression, possibly manifested in the displayed age-dependent degradation of exploratory locomotion.

Cell Type-Specific Membrane Potential Changes in Dorsolateral Striatum Accompanying Reward-Based Sensorimotor Learning.

The striatum integrates sensorimotor and motivational signals, likely playing a key role in reward-based learning of goal-directed behavior. However, cell type-specific mechanisms underlying reinforcement learning remain to be precisely determined. Here, we investigated changes in membrane potential dynamics of dorsolateral striatal neurons comparing naïve mice and expert mice trained to lick a reward spout in response to whisker deflection. We recorded from three distinct cell types: (i) direct pathway striatonigral neurons, which express type 1 dopamine receptors; (ii) indirect pathway striatopallidal neurons, which express type 2 dopamine receptors; and (iii) tonically active, putative cholinergic, striatal neurons. Task learning was accompanied by cell type-specific changes in the membrane potential dynamics evoked by the whisker deflection and licking in successfully-performed trials. Both striatonigral and striatopallidal types of striatal projection neurons showed enhanced task-related depolarization across learning. Striatonigral neurons showed a prominent increase in a short latency sensory-evoked depolarization in expert compared to naïve mice. In contrast, the putative cholinergic striatal neurons developed a hyperpolarizing response across learning, driving a pause in their firing. Our results reveal cell type-specific changes in striatal membrane potential dynamics across the learning of a simple goal-directed sensorimotor transformation, helpful for furthering the understanding of the various potential roles of different basal ganglia circuits.

Rescue of BDNF expression by the thalamic parafascicular nucleus with chronic treatment with the mGluR2/3 agonist LY379268 may contribute to the LY379268 rescue of enkephalinergic striatal projection neurons in R6/2 Huntington’s disease mice

We have found that daily subcutaneous injection with a maximum tolerated dose of the mGluR2/3 agonist LY379268 (20 mg/kg) beginning at 4 weeks of age dramatically improves the motor, neuronal and neurochemical phenotype in R6/2 mice, a rapidly progressing transgenic model of Huntington’s disease (HD). We also previously showed that the benefit of daily LY379268 in R6/2 mice was associated with increases in corticostriatal brain-derived neurotrophic factor (BDNF), and in particular was associated with a reduction in enkephalinergic striatal projection neuron loss. In the present study, we show that daily LY379268 also rescues expression of BDNF by neurons of the thalamic parafascicular nucleus in R6/2 mice, which projects prominently to the striatum, and this increase too is linked to the rescue of enkephalinergic striatal neurons. Thus, LY379268 may protect enkephalinergic striatal projection neurons from loss by boosting BDNF production and delivery via both the corticostriatal and thalamostriatal projection systems. These results suggest that chronic treatment with mGluR2/3 agonists may represent an approach for slowing enkephalinergic neuron loss in HD, and perhaps progression in general.

Inhibition of endoplasmic reticulum stress reverses synaptic plasticity deficits in striatum of DYT1 dystonia mice.

Background and objective: Striatal plasticity alterations caused by endoplasmic reticulum (ER) stress is supposed to be critically involved in the mechanism of DYT1 dystonia. In the current study, we expanded this research field by investigating the critical role of ER stress underlying synaptic plasticity impairment imposed by mutant heterozygous Tor1a+/- in a DYT1 dystonia mouse model.Methods: Heterozygous Tor1a+/- mouse model for DYT1 dystonia was established. Wild-type (Tor1a+/+, N=10) and mutant (Tor1a+/-, N=10) mice from post-natal day P25 to P35 were randomly distributed to experimental and control groups. Patch-clamp and current-clamp recordings of SPNs were conducted with intracellular electrodes for electrophysiological analyses. Striatal changes of the direct and indirect pathways were investigated via immunofluorescence. Golgi-Cox staining was conducted to observe spine morphology of SPNs. To quantify postsynaptic signaling proteins in striatum, RNA-Seq, qRT-PCR and WB were performed in striatal tissues.Results: Long-term depression (LTD) was failed to be induced, while long-term potentiation (LTP) was further strengthened in striatal spiny projection neurons (SPNs) from the Tor1a+/- DYT1 dystonia mice. Spine morphology analyses revealed a significant increase of both number of mushroom type spines and spine width in Tor1a+/- SPNs. In addition, increased AMPA receptor function and the reduction of NMDA/AMPA ratio in the postsynaptic of Tor1a+/- SPNs was observed, along with increased ER stress protein levels in striatum of Tor1a+/- DYT1 dystonia mice. Notably, ER stress inhibitors, tauroursodeoxycholic acid (TUDCA), could rescue LTD as well as AMPA currents.Conclusion: The current study illustrated the role of ER stress in mediating structural and functional plasticity alterations in Tor1a+/- SPNs. Inhibition of the ER stress by TUDCA is beneficial in reversing the deficits at the cellular and molecular levels. Remedy of dystonia associated neurological and motor functional impairment by ER stress inhibitors could be a recommendable therapeutic agent in clinical practice.

Transcranial Magnetic Stimulation Exerts "Rejuvenation" Effects on Corticostriatal Synapses after Partial Dopamine Depletion.

In experimental models of Parkinson's disease (PD), different degrees of degeneration to the nigrostriatal pathway produce distinct profiles of synaptic alterations that depend on progressive changes in N-methyl-D-aspartate receptors (NMDAR)-mediated functions. Repetitive transcranial magnetic stimulation (rTMS) induces modifications in glutamatergic and dopaminergic systems, suggesting that it may have an impact on glutamatergic synapses modulated by dopamine neurotransmission. However, no studies have so far explored the mechanisms of rTMS effects at early stages of PD. We tested the hypothesis that in vivo application of rTMS with intermittent theta-burst stimulation (iTBS) pattern alleviates corticostriatal dysfunctions by modulating NMDAR-dependent plasticity in a rat model of early parkinsonism. Dorsolateral striatal spiny projection neurons (SPNs) activity was studied through ex vivo whole-cell patch-clamp recordings in corticostriatal slices obtained from 6-hydroxydopamine-lesioned rats, subjected to a single session (acute) of iTBS and tested for forelimb akinesia with the stepping test. Immunohistochemical analyses were performed to analyze morphological correlates of plasticity in SPNs. Acute iTBS ameliorated limb akinesia and rescued corticostriatal long-term potentiation (LTP) in SPNs of partially lesioned rats. This effect was abolished by applying a selective inhibitor of GluN2B-subunit-containing NMDAR, suggesting that iTBS treatment could be associated with an enhanced activation of specific NMDAR subunits, which are major regulators of structural plasticity during synapse development. Morphological analyses of SPNs revealed that iTBS treatment reverted dendritic spine loss inducing a prevalence of thin-elongated spines in the biocytin-filled SPNs. Taken together, our data identify that an acute iTBS treatment produces a series of plastic changes underlying striatal compensatory adaptation in the parkinsonian basal ganglia circuit. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Loss of Tsc1 from striatal direct pathway neurons impairs endocannabinoid-LTD and enhances motor routine learning.

SUMMARYTuberous sclerosis complex (TSC) is a neurodevelopmental disorder that often presents with psychiatric conditions, including autism spectrum disorder (ASD). ASD is characterized by restricted, repetitive, and inflexible behaviors, which may result from abnormal activity in striatal circuits that mediate motor learning and action selection. To test whether altered striatal activity contributes to aberrant motor behaviors in the context of TSC, we conditionally deleted Tsc1 from direct or indirect pathway striatal projection neurons (dSPNs or iSPNs, respectively). We find that dSPN-specific loss of Tsc1 impairs endocannabinoid-mediated long-term depression (eCB-LTD) at cortico-dSPN synapses and strongly enhances corticostriatal synaptic drive, which is not observed in iSPNs. dSPN-Tsc1 KO, but not iSPN-Tsc1 KO, mice show enhanced motor learning, a phenotype observed in several mouse models of ASD. These findings demonstrate that dSPNs are particularly sensitive to Tsc1 loss and suggest that enhanced corticostriatal activation may contribute to altered motor behaviors in TSC.

Striatal Control of Movement: A Role for New Neuronal (Sub-) Populations?

The striatum is a very heterogenous brain area, composed of different domains and compartments, albeit lacking visible anatomical demarcations. Two populations of striatal spiny projection neurons (SPNs) build the so-called direct and indirect pathway of the basal ganglia, whose coordinated activity is essential to control locomotion. Dysfunction of striatal SPNs is part of many movement disorders, such as Parkinson’s disease (PD) and L-DOPA-induced dyskinesia. In this mini review article, I will highlight recent studies utilizing single-cell RNA sequencing to investigate the transcriptional profiles of striatal neurons. These studies discover that SPNs carry a transcriptional signature, indicating both their anatomical location and compartmental identity. Furthermore, the transcriptional profiles reveal the existence of additional distinct neuronal populations and previously unknown SPN sub-populations. In a parallel development, studies in rodent models of PD and L-DOPA-induced dyskinesia (LID) report that direct pathway SPNs do not react uniformly to L-DOPA therapy, and that only a subset of these neurons is underlying the development of abnormal movements. Together, these studies demonstrate a new level of cellular complexity for striatal (dys-) function and locomotor control.

Altered corticostriatal synchronization associated with compulsive-like behavior in APP/PS1 mice

Mild behavioral impairment (MBI), which can include compulsive behavior, is an early sign of Alzheimer's disease (AD), but its underlying neural mechanisms remain unclear. Here, we show that 3–5-month-old APP/PS1 mice display obsessive-compulsive disorder (OCD)-like behavior. The number of parvalbumin-positive (PV) interneurons and level of high gamma (γhigh) oscillation are significantly decreased in the striatum of AD mice. This is accompanied by enhanced β-γhigh coupling and firing rates of putative striatal projection neurons (SPNs), indicating decorrelation between PV interneurons and SPNs. Local field potentials (LFPs) simultaneously recorded in prefrontal cortex (PFC) and striatum (Str) demonstrate a decrease in γhigh-band coherent activity and spike-field coherence in corticostriatal circuits of APP/PS1 mice. Furthermore, levels of GABAB receptor (GABABR), but not GABAA receptor (GABAAR), and glutamatergic receptors, were markedly reduced, in line with presymptomatic AD-related behavioral changes. These findings suggest that MBI occurs as early as 3–5 months in APP/PS1 mice and that altered corticostriatal synchronization may play a role in mediating the behavioral phenotypes observed.

Complete representation of action space and value in all dorsal striatal pathways.

The dorsal striatum plays a central role in the selection, execution, and evaluation of actions. An emerging model attributes action selection to the matrix and evaluation to the striosome compartment. Here, we use large-scale cell-type-specific calcium imaging to determine the activity of striatal projection neurons (SPNs) during motor and decision behaviors in the three major outputs of the dorsomedial striatum: Oprm1+ striosome versus D1+ direct and A2A+ indirect pathway SPNs. We find that Oprm1+ SPNs show complex tunings to simple movements and value-guided actions, which are conserved across many sessions in a single task but remap between contexts. During decision making, the SPN tuning profiles form a complete representation in which sequential SPN activity jointly encodes task progress and value. We propose that the three major output pathways in the dorsomedial striatum share a similarly complete representation of the entire action space, including task- and phase-specific signals of action value and choice.

Duplex optogenetic stimulation system modulates compulsive behaviors bidirectionally

Decisions enable us to consider our actions while adjusting behaviors to a relentlessly changing environment. Since conscious decision making requires our full attention and is therefore expensive, we use a cheaper system for everyday and repetitive tasks that run automatically without conscious evaluations, commonly described as habits. The combination of these two systems is highly adaptive. However, if there is a disruption in these systems’ balance, mental illnesses such as Obsessive-Compulsive Disorders (OCD) or addiction may arise. Now, how does a newly acquired memory or behavior transition to a habit? We know that the striatum’s dorsolateral region (DLS) plays a significant role in sustaining successful behaviors and habits manifestation. Furthermore, it has been shown that the micro-circuitry of the DLS is organized into two functional opposing pathways that consist of the direct pathway striatal spiny projection neurons (dSPNs), which facilitate movement, and the indirect pathway SPNs, which inhibit actions. Already Freud wrote in the letters to his friend Fliess that memory and motive are inseparable, and its recollection would have no force or meaning unless it would be coupled to a motive or emotion. Therefore, we hypothesize that emotional-associated cues would directly prime the DLS through the amygdala to turn newly acquired behaviors into habits. We are adding new supporting insight for this hypothesis by using a duplex optogenetic stimulation system of the amygdala input in the DLS, modulating specific compulsive behaviors bidirectionally. These behavior modulations were accompanied by spine density modulations and intrinsic excitability changes in the SPNs of the DLS. Keywords: Compulsions; Habits; Optogenetics; Neuromodulation; Dorsolateral striatum; Amygdala.

Dietary Phytoestrogens: Neuroprotective Role in Parkinson's Disease.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by progressive damage of mesencephalic dopaminergic neurons of the substantia nigra and the striatal projections. Recent studies suggest that estrogen and estrogen-like chemicals have beneficial effects on neurodegenerative diseases, particularly PD. Animal studies demonstrate that estrogen influences dopamine's synthesis, release, and metabolism. In vivo studies have also shown the significant beneficial effects of estrogen in shielding the brain from neurodegenerative processes like PD. Moreover, the expression and function of dopamine receptors can be modified by estrogen. Phytoestrogens are non-steroidal compounds derived from plants present in a large spectrum of foods, most specifically soy and in numerous dietary supplements. Phytoestrogens share structural and functional similarities with 17β-estradiol and can be used as an alternative treatment for PD because of estrogen's undesirable effects, such as the increased risk of breast and endometrial cancer, ischemic disorders, and irregular bleeding. Despite the beneficial effects of phytoestrogens, their impact on human health may depend on age, health status, and even the presence or absence of specific gut microflora. In addition to their antioxidant properties, soy products or phytoestrogens also exhibit neuroprotective activity in patients with PD via the interaction with estrogen receptors (ER) α and β, with a higher affinity for ERβ. Phytoestrogens offer a valuable model for fully exploring the biological effects of endocrine disruptors in general. However, observational studies and randomized controlled trials in humans have resulted in inconclusive findings within this domain. This review considered the evidence in animal models and human epidemiological data as to whether developmental exposure to various phytoestrogen classes adversely or beneficially impacts the neurobehavioral programming in PD.

Prediction of Neural Diameter From Morphology to Enable Accurate Simulation.

Accurate neuron morphologies are paramount for computational model simulations of realistic neural responses. Over the last decade, the online repository NeuroMorpho.Org has collected over 140,000 available neuron morphologies to understand brain function and promote interaction between experimental and computational research. Neuron morphologies describe spatial aspects of neural structure; however, many of the available morphologies do not contain accurate diameters that are essential for computational simulations of electrical activity. To best utilize available neuron morphologies, we present a set of equations that predict dendritic diameter from other morphological features. To derive the equations, we used a set of NeuroMorpho.org archives with realistic neuron diameters, representing hippocampal pyramidal, cerebellar Purkinje, and striatal spiny projection neurons. Each morphology is separated into initial, branching children, and continuing nodes. Our analysis reveals that the diameter of preceding nodes, Parent Diameter, is correlated to diameter of subsequent nodes for all cell types. Branching children and initial nodes each required additional morphological features to predict diameter, such as path length to soma, total dendritic length, and longest path to terminal end. Model simulations reveal that membrane potential response with predicted diameters is similar to the original response for several tested morphologies. We provide our open source software to extend the utility of available NeuroMorpho.org morphologies, and suggest predictive equations may supplement morphologies that lack dendritic diameter and improve model simulations with realistic dendritic diameter.

Reduced Expression of GABA A Receptor Alpha2 Subunit Is Associated With Disinhibition of DYT-THAP1 Dystonia Patient-Derived Striatal Medium Spiny Neurons.

DYT-THAP1 dystonia (formerly DYT6) is an adolescent-onset dystonia characterized by involuntary muscle contractions usually involving the upper body. It is caused by mutations in the gene THAP1 encoding for the transcription factor Thanatos-associated protein (THAP) domain containing apoptosis-associated protein 1 and inherited in an autosomal-dominant manner with reduced penetrance. Alterations in the development of striatal neuronal projections and synaptic function are known from transgenic mice models. To investigate pathogenetic mechanisms, human induced pluripotent stem cell (iPSC)-derived medium spiny neurons (MSNs) from two patients and one family member with reduced penetrance carrying a mutation in the gene THAP1 (c.474delA and c.38G > A) were functionally characterized in comparison to healthy controls. Calcium imaging and quantitative PCR analysis revealed significantly lower Ca2+ amplitudes upon GABA applications and a marked downregulation of the gene encoding the GABAA receptor alpha2 subunit in THAP1 MSNs indicating a decreased GABAergic transmission. Whole-cell patch-clamp recordings showed a significantly lower frequency of miniature postsynaptic currents (mPSCs), whereas the frequency of spontaneous action potentials (APs) was elevated in THAP1 MSNs suggesting that decreased synaptic activity might have resulted in enhanced generation of APs. Our molecular and functional data indicate that a reduced expression of GABAA receptor alpha2 subunit could eventually lead to limited GABAergic synaptic transmission, neuronal disinhibition, and hyperexcitability of THAP1 MSNs. These data give pathophysiological insight and may contribute to the development of novel treatment strategies for DYT-THAP1 dystonia.

Anatomical study of the striatal and cortical projections arising from the posterior intralaminar thalamic nucleus neurons in the mouse.

Anatomical study of the striatal and cortical projections arising from the posterior intralaminar thalamic nucleus neurons in the mouse.

Anatomical study of the striatal and cortical projections arising from the posterior intralaminar thalamic nucleus neurons in the mouse.

Anatomical study of the striatal and cortical projections arising from the posterior intralaminar thalamic nucleus neurons in the mouse.

Rescue of striatal long-term depression by chronic mGlu5 receptor negative allosteric modulation in distinct dystonia models

An impairment of long-term synaptic plasticity is considered as a peculiar endophenotype of distinct forms of dystonia, a common, disabling movement disorder. Among the few therapeutic options, broad-spectrum antimuscarinic drugs are utilized, aimed at counteracting abnormal striatal acetylcholine-mediated transmission, which plays a crucial role in dystonia pathophysiology. We previously demonstrated a complete loss of long-term synaptic depression (LTD) at corticostriatal synapses in rodent models of two distinct forms of isolated dystonia, resulting from mutations in the TOR1A (DYT1), and GNAL (DYT25) genes. In addition to anticholinergic agents, the aberrant excitability of striatal cholinergic cells can be modulated by group I metabotropic glutamate receptor subtypes (mGlu1 and 5). Here, we tested the efficacy of the negative allosteric modulator (NAM) of metabotropic glutamate 5 (mGlu) receptor, dipraglurant (ADX48621) on striatal LTD. We show that, whereas acute treatment failed to rescue LTD, chronic dipraglurant rescued this form of synaptic plasticity both in DYT1 mice and GNAL rats. Our analysis of the pharmacokinetic profile of dipraglurant revealed a relatively short half-life, which led us to uncover a peculiar time-course of recovery based on the timing from last dipraglurant injection. Indeed, striatal spiny projection neurons (SPNs) recorded within 2 h from last administration showed full expression of synaptic plasticity, whilst the extent of recovery progressively diminished when SPNs were recorded 4–6 h after treatment.Our findings suggest that distinct dystonia genes may share common signaling pathway dysfunction. More importantly, they indicate that dipraglurant might be a potential novel therapeutic agent for this disabling disorder.

Developmental Characterization of Schizophrenia-Associated Gene Zswim6 in Mouse Forebrain

Schizophrenia is a devastating neuropsychiatric disease with a globally 1% life-long prevalence. Clinical studies have linked Zswim6 mutations to developmental and neurological diseases, including schizophrenia. Zswim6’s function remains largely unknown. Given the involvement of Zswim6 in schizophrenia and schizophrenia as a neurodevelopmental disease, it is important to understand the spatiotemporal expression pattern of Zswim6 in the developing brain. Here, we performed a comprehensive analysis of the spatiotemporal expression pattern of Zswim6 in the mouse forebrain by in situ hybridization with radioactive and non-radioactive-labeled riboprobes. Zswim6 mRNA was detected as early as E11.5 in the ventral forebrain. At E11.5–E13.5, Zswim6 was highly expressed in the lateral ganglionic eminence (LGE). The LGE consisted of two progenitor populations. Dlx+;Er81+ cells in dorsal LGE comprised progenitors of olfactory bulb interneurons, whereas Dlx+;Isl1+ progenitors in ventral LGE gave rise to striatal projection neurons. Zswim6 was not colocalized with Er81 in the dorsal LGE. In the ventral LGE, Zswim6 was colocalized with striatal progenitor marker Nolz-1. Zswim6 was highly expressed in the subventricular zone (SVZ) of LGE in which progenitors undergo the transition from proliferation to differentiation. Double labeling showed that Zswim6 was not colocalized with proliferation marker Ki67 but was colocalized with differentiation marker Tuj1 in the SVZ, suggesting Zswim6 expression in early differentiating neurons. Zswim6 was also expressed in the adjacent structures of medial and caudal ganglionic eminences (MGE, CGE) that contained progenitors of cortical interneurons. At E15.5 and E17.5, Zswim6 was expressed in several key brain regions that were involved in the pathogenesis of schizophrenia, including the striatum, cerebral cortex, hippocampus, and medial habenular nucleus. Zswim6 was persistently expressed in the postnatal brain. Cell type analysis indicated that Zswim6 mRNA was colocalized with D1R-expressing striatonigral and D2R-expressing striatopallidal neurons of the adult striatum with a higher colocalization in striatopallidal neurons. These findings are of particular interest as striatal dopamine D2 receptors are known to be involved in the pathophysiology of schizophrenia. In summary, the comprehensive analysis provides an anatomical framework for the study of Zswim6 function and Zswim6-associated neurological disorders.

Striatal cholinergic transmission. Focus on nicotinic receptors' influence in striatal circuits.

The critical role of acetylcholine (ACh) in the basal ganglia is evident from the effect of cholinergic agents in patients suffering from several related neurological disorders, such as Parkinson's disease, Tourette syndrome, or dystonia. The striatum possesses the highest density of ACh markers in the basal ganglia underlying the importance of ACh in this structure. Striatal cholinergic interneurons (CINs) are responsible for the bulk of striatal ACh, although extrinsic cholinergic afferents from brainstem structures may also play a role. CINs are tonically active, and synchronized pause in their activity occurs following the presentation of salient stimuli during behavioral conditioning. However, the synaptic mechanisms involved are not fully understood in this physiological response. ACh modulates striatal circuits by acting on muscarinic and nicotinic receptors existing in several combinations both presynaptically and postsynaptically. While the effects of ACh in the striatum through muscarinic receptors have received particular attention, nicotinic receptors function has been less studied. Here, after briefly reviewing relevant results regarding muscarinic receptors expression and function, I will focus on striatal nicotinic receptor expressed presynaptically on glutamatergic and dopaminergic afferents and postsynaptically on diverse striatal interneurons populations. I will also review recent evidence suggesting the involvement of different GABAergic sources in two distinct nicotinic-receptor-mediated striatal circuits: the disynaptic inhibition of striatal projection neurons and the recurrent inhibition among CINs. A better understanding of striatal nicotinic receptors expression and function may help to develop targeted pharmacological interventions to treat brain disorders such as Parkinson's disease, Tourette syndrome, dystonia, or nicotine addiction.

Morphological Study of the Cortical and Thalamic Glutamatergic Synaptic Inputs of Striatal Parvalbumin Interneurons in Rats.

Parvalbumin-immunoreactive (Parv+) interneurons is an important component of striatal GABAergic microcircuits, which receive excitatory inputs from the cortex and thalamus, and then target striatal projection neurons. The present study aimed to examine ultrastructural synaptic connection features of Parv+ neruons with cortical and thalamic input, and striatal projection neurons by using immuno-electron microscopy (immuno-EM) and immunofluorescence techniques. Our results showed that both Parv+ somas and dendrites received numerous asymmetric synaptic inputs, and Parv+ terminals formed symmetric synapses with Parv- somas, dendrites and spine bases. Most interestingly, spine bases targeted by Parv+ terminals simultaneously received excitatory inputs at their heads. Electrical stimulation of the motor cortex (M1) induced higher proportion of striatal Parv+ neurons express c-Jun than stimulation of the parafascicular nucleus (PFN), and indicated that cortical- and thalamic-inputs differentially modulate Parv+ neurons. Consistent with that, both Parv + soma and dendrites received more VGlut1+ than VGlut2+ terminals. However, the proportion of VGlut1+ terminal targeting onto Parv+ proximal and distal dendrites was not different, but VGlut2+ terminals tended to target Parv+ somas and proximal dendrites than distal dendrites. These functional and morphological results suggested excitatory cortical and thalamic glutamatergic inputs differently modulate Parv+ interneurons, which provided inhibition inputs onto striatal projection neurons. To maintain the balance between the cortex and thalamus onto Parv+ interneurons may be an important therapeutic target for neurological disorders.

Striatal Direct Pathway Targets Npas1+ Pallidal Neurons.

The classic basal ganglia circuit model asserts a complete segregation of the two striatal output pathways. Empirical data argue that, in addition to indirect-pathway striatal projection neurons (iSPNs), direct-pathway striatal projection neurons (dSPNs) innervate the external globus pallidus (GPe). However, the functions of the latter were not known. In this study, we interrogated the organization principles of striatopallidal projections and their roles in full-body movement in mice (both males and females). In contrast to the canonical motor-promoting response of dSPNs in the dorsomedial striatum (DMSdSPNs), optogenetic stimulation of dSPNs in the dorsolateral striatum (DLSdSPNs) suppressed locomotion. Circuit analyses revealed that dSPNs selectively target Npas1+ neurons in the GPe. In a chronic 6-hydroxydopamine lesion model of Parkinson's disease, the dSPN-Npas1+ projection was dramatically strengthened. As DLSdSPN-Npas1+ projection suppresses movement, the enhancement of this projection represents a circuit mechanism for the hypokinetic symptoms of Parkinson's disease that has not been previously considered. In sum, our results suggest that dSPN input to the GPe is a critical circuit component that is involved in the regulation of movement in both healthy and parkinsonian states.SIGNIFICANCE STATEMENT In the classic basal ganglia model, the striatum is described as a divergent structure: it controls motor and adaptive functions through two segregated, opposing output streams. However, the experimental results that show the projection from direct-pathway neurons to the external pallidum have been largely ignored. Here, we showed that this striatopallidal subpathway targets a select subset of neurons in the external pallidum and is motor-suppressing. We found that this subpathway undergoes changes in a Parkinson's disease model. In particular, our results suggest that the increase in strength of this subpathway contributes to the slowness or reduced movements observed in Parkinson's disease.