Search

The striatum of humans and other mammals is divided into macroscopic compartments made up of a labyrinthine striosome compartment embedded in a much larger surrounding matrix compartment. Anatomical and snRNA-Seq studies of the Huntington’s disease (HD) postmortem striatum suggest a preferential decline of some striosomal markers, and mRNAs studies of HD model mice concur. Here, by immunohistochemical methods, we examined the distribution of the canonical striosomal marker, mu-opioid receptor 1 (MOR1), in the striatum of the Q175 knock-in mouse model of HD in a postnatal time series extending from 3 to 19 months. We demonstrate that, contrary to the loss of many markers for striosomes, there is a pronounced up-regulation of MOR1 in these Q175 knock-in mice. We show that in heterozygous Q175 knock-in model mice [~192 cytosine-adenine-guanine (CAG) repeats], this MOR1 up-regulation progressed with advancing age and disease progression, and was particularly remarkable at caudal levels of the striatum. Given the known importance of MOR1 in basal ganglia signaling, our findings, though in mice, should offer clues to the pathogenesis of psychiatric features, especially depression, reinforcement sensitivity, and involuntary movements in HD.

The striatum is the neural interface between dopamine reward signals and cortico-basal ganglia circuits responsible for value assignments, decisions, and actions. Medium spiny neurons (MSNs) make up the vast majority of striatal neurons and are traditionally classified as two distinct types: direct- and indirect-pathway MSNs. The direct- and indirect-pathway model has been useful for understanding some aspects of striatal functions, but it accounts for neither the anatomical heterogeneity, nor the functional diversity of the striatum. Here, we use single nucleus RNA-sequencing and Fluorescent In-Situ Hybridization to explore MSN diversity in the Rhesus macaque striatum. We identified MSN subtypes that correspond to the major subdivisions of the striatum. These include dorsal striatum subtypes associated with striosome and matrix compartments, as well as ventral striatum subtypes associated with the shell of the nucleus accumbens. We also describe a cell type that is anatomically restricted to "Neurochemically Unique Domains in the Accumbens and Putamen (NUDAPs)". Together, these results help to advance nonhuman primate studies into the genomics era. The identified cell types provide a comprehensive blueprint for investigating cell type-specific information processing, and the differentially expressed genes lay a foundation for achieving cell type-specific transgenesis in the primate striatum.

Corticostriatal synaptic integration is partitioned among striosome (patch) and matrix compartments of the dorsal striatum, allowing compartmentalized control of discrete aspects of behavior. Despite the significance of such organization, it's unclear how compartment-specific striatal output is dynamically achieved, particularly considering new evidence that overlap of afferents is substantial. We show that dopamine oppositely shapes responses to convergent excitatory inputs in mouse striosome and matrix striatal spiny projection neurons (SPNs). Activation of postsynaptic D1 dopamine receptors promoted the generation of long-lasting synaptically evoked "up-states" in matrix SPNs but opposed it in striosomes, which were more excitable under basal conditions. Differences in dopaminergic modulation were mediated, in part, by dendritic voltage-gated calcium channels (VGCCs): pharmacological manipulation of L-type VGCCs reversed compartment-specific responses to D1 receptor activation. These results support a novel mechanism for the selection of striatal circuit components, where fluctuating levels of dopamine shift the balance of compartment-specific striatal output.

The glutamate receptor delta 1 (GluD1) is strongly expressed in the striatum. Knockout of GluD1 expression in striatal neurons elicits cognitive deficits and disrupts the thalamostriatal system in mice. To understand the potential role of GluD1 in the primate striatum, we compared the cellular and subcellular localization of striatal GluD1 immunoreactivity (GluD1-IR) in mice and monkeys. In both species, striatal GluD1-IR displayed a patchy pattern of distribution in register with the striosome/matrix compartmentation, but in an opposite fashion. While GluD1 was more heavily expressed in the striosomes than the matrix in the monkey caudate nucleus, the opposite was found in the mouse striatum. At the electron microscopic level, GluD1-IR was preferentially expressed in dendritic shafts (47.9 ± 1.2%), followed by glia (37.7 ± 2.5%), and dendritic spines (14.3 ± 2.6%) in the matrix of the mouse striatum. This pattern was not statistically different from the labeling in the striosome and matrix compartments of the monkey caudate nucleus, with the exception of a small amount of GluD1-positive unmyelinated axons and axon terminals in the primate striatum. Immunogold staining revealed synaptic and perisynaptic GluD1 labeling at putative axo-dendritic and axo-spinous glutamatergic synapses, and intracellular labeling on the surface of mitochondria. Confocal microscopy showed that GluD1 is preferentially colocalized with thalamic over cortical terminals in both the striosome and matrix compartments. These data provide the anatomical substrate for a deeper understanding of GluD1 regulation of striatal glutamatergic synapses, but also suggest possible extrasynaptic, glial, and mitochondrial GluD1 functions.

Substantia nigra (SNc) dopaminergic neurons respond to aversive stimuli with inhibitory pauses in firing followed by transient rebound activation. We tested integration of inhibitory synaptic inputs onto SNc neurons from genetically defined populations in dorsal striatum (striosome and matrix) and external globus pallidus (GPe; parvalbumin- and Lhx6-positive), and examined their contribution to pause-rebound firing. Activation of striosome projections, which target "dendron bouquets" in the pars reticulata (SNr), consistently quiets firing and relief from striosome inhibition triggers rebound activity. Striosomal inhibitory postsynaptic currents (IPSCs) display a prominent GABA-B receptor-mediated component that strengthens the impact of SNr dendrite synapses on somatic excitability and enables rebounding. By contrast, GPe projections activate GABA-A receptors on the soma and proximal dendrites but do not result in rebounding. Lastly, optical mapping shows that dorsal striatum selectively inhibits the ventral population of SNc neurons, which are intrinsically capable of rebounding. Therefore, we define a distinct striatonigral circuit for generating dopamine rebound.

The basal ganglia, best known for processing information required for multiple aspects of movement, is also part of a network which regulates reward and cognition. The major output nucleus of the basal ganglia is the striatum, and its functions are dependent on neuronal compartmentation, including striosomes and matrix, which are selectively affected in disease. Striatal projection neurons are GABAergic medium spiny neurons (MSNs), all of which share basic molecular signatures but are subtyped by selective expression of receptors, neuropeptides, and other gene families. Neurogenesis of the striosome and matrix occurs in separate waves, but the factors regulating terminal neuronal differentiation following migration are largely unidentified. We performed RNA- and ATAC-seq on sorted murine striosome and matrix cells at postnatal day 3. Focusing on the striosomal compartment, we validated the localization and role of transcription factors and their regulator(s), previously not known to be associated with striatal development, including Irx1, Foxf2, Olig2 and Stat1/2. In addition, we validated the enhancer function of a striosome-specific open chromatin region located 15Kb downstream of the Olig2 gene. These data and data bases provide novel tools to dissect and manipulate the networks regulating MSN compartmentation and differentiation and thus provide new approaches to establishing MSN subtypes from human iPSCs for disease modeling and drug discovery.

The purpose of this review is to bridge the gap between earlier literature on striatal cholinergic interneurons and mechanisms of microcircuit interaction demonstrated with the use of newly available tools. It is well known that the main source of the high level of acetylcholine in the striatum, compared to other brain regions, is the cholinergic interneurons. These interneurons provide an extensive local innervation that suggests they may be a key modulator of striatal microcircuits. Supporting this idea requires the consideration of functional properties of these interneurons, their influence on medium spiny neurons, other interneurons, and interactions with other synaptic regulators. Here, we underline the effects of intrastriatal and extrastriatal afferents onto cholinergic interneurons and discuss the activation of pre‐ and postsynaptic muscarinic and nicotinic receptors that participate in the modulation of intrastriatal neuronal interactions. We further address recent findings about corelease of other transmitters in cholinergic interneurons and actions of these interneurons in striosome and matrix compartments. In addition, we summarize recent evidence on acetylcholine‐mediated striatal synaptic plasticity and propose roles for cholinergic interneurons in normal striatal physiology. A short examination of their role in neurological disorders such as Parkinson's, Huntington's, and Tourette's pathologies and dystonia is also included.

In this study, we examined the cellular distribution of encephalopsin (opsin 3; OPN3) expression in the striatum of non-human primates. In addition, because of our long standing interest in Parkinson's disease and neuroprotection, we examined whether parkinsonian (MPTP; 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) insult and/or photobiomodulation (670 nm) had any impact on encephalopsin expression in this key area of the basal ganglia. Striatal sections of control naïve monkeys, together with those that were either MPTP- and/or photobiomodulation-treated were processed for immunohistochemistry. Our results revealed two populations of striatal interneurones that expressed encephalopsin, one of which was the giant, choline acetyltransferase-containing, cholinergic interneurones. The other population had smaller somata and was not cholinergic. Neither cell group expressed the calcium-binding protein, parvalbumin. There was also rich encephalopsin expression in a set of terminals forming striosome-like patches across the striatum. Finally, we found that neither parkinsonian (MPTP) insult nor photobiomodulation had any effect on encephalopsin expression in the striatum. In summary, our results revealed an extensive network of encephalopsin containing structures throughout the striatum, indicating that external light is in a position to influence a range of striatal activities at both the interneurone and striosome level.

Preliminary evidence from postmortem studies of X-linked dystonia-parkinsonism (XDP) suggests tissue loss may occur first and/or most severely in the striatal striosome compartment, followed later by cell loss in the matrix compartment. However, little is known about how this relates to pathogenesis and pathophysiology. While MRI cannot visualize these striatal compartments directly in humans, differences in relative gradients of afferent cortical connectivity across compartments (weighted toward paralimbic versus sensorimotor cortex, respectively) can be used to infer potential selective loss in vivo. In the current study we evaluated relative connectivity of paralimbic versus sensorimotor cortex with the caudate and putamen in 17 individuals with XDP and 17 matched controls. Although caudate and putamen volumes were reduced in XDP, there were no significant reductions in either “matrix-weighted”, or “striosome-weighted” connectivity. In fact, paralimbic connectivity with the putamen was elevated, rather than reduced, in XDP. This was driven most strongly by elevated putamen connectivity with the anterior insula. There was no relationship of these findings to disease duration or striatal volume, suggesting insula and/or paralimbic connectivity in XDP may develop abnormally and/or increase in the years before symptom onset., Highlights • Previous work suggested striosomes might degenerate preferentially in early XDP. • We developed a DTI tractography method to assess striosome and matrix integrity. • Striosomal afferents to putamen were elevated in XDP, despite reduced putamen volume. • Connectivity was particularly elevated from the insula (two to three-fold). • Striosome connectivity strength was not associated with disease duration.

The striatum comprises two neurochemical compartments: striosomes and the matrix. Striosomal and matrix compartments receive inputs from limbic system-related and sensorimotor cortices, respectively. Here, we investigate the impact on the corticostriosomal pathway in the valproic acid (VPA)-induced autism spectrum disorder mouse model. VPA administration during the neurogenesis time windows of striosomes, but not the matrix, resulted in aberrant compartmentation [i.e., maternal VPA injections at embryonic day (E)12.75 decreased μ-opioid receptor-positive striosomes, but increased calbindin-positive matrix in the rostral striatum]. VPAE12.75 treatment also impaired the aggregation of cells pulse labeled with 5-bromo-2'-deoxyuridine at E12.75 into striosomal cell clusters, which suggests defective segregation of striosomal cells from matrix cells. This possibility was supported by our findings that VPAE12.75 treatment altered the expression of ephrinA5 and EphA4, two molecules that are related to compartmental segregation. In the VPAE12.75 neocortex, Foxp2-positive neurons were decreased in layer VI, but increased in layer V, which projects to the striosomal compartment. We also investigated VPA effects on the corticostriosomal pathway. VPAE12.75 treatment decreased the putative corticostriosomal synapses of striosomal neurons and induced an aberrant pattern of isolation stress-induced ultrasonic vocalizations. Of interest, risperidone treatments conjointly improved ultrasonic vocalizations and restored the striosomal compartment in VPAE12.75 pups. Collectively, dysfunctional corticostriatal pathways, particularly via the aberrant striosomal compartment, may be involved in autism spectrum disorder pathophysiology.-Kuo, H.-Y., Liu, F.-C. Valproic acid induces aberrant development of striatal compartments and corticostriatal pathways in a mouse model of autism spectrum disorder.

The striosome compartment within the dorsal striatum has been implicated in reinforcement learning and regulation of motivation, but how striosomal neurons contribute to these functions remains elusive. Here, we show that a genetically identified striosomal population, which expresses the Teashirt family zinc finger 1 (Tshz1) and belongs to the direct pathway, drives negative reinforcement and is essential for aversive learning in mice. Contrasting a "conventional" striosomal direct pathway, the Tshz1 neurons cause aversion, movement suppression, and negative reinforcement once activated, and they receive a distinct set of synaptic inputs. These neurons are predominantly excited by punishment rather than reward and represent the anticipation of punishment or the motivation for avoidance. Furthermore, inhibiting these neurons impairs punishment-based learning without affecting reward learning or movement. These results establish a major role of striosomal neurons in behaviors reinforced by punishment and moreover uncover functions of the direct pathway unaccounted for in classic models.

Many diseases are linked to dysregulation of the striatum. Striatal function depends on neuronal compartmentation into striosomes and matrix. Striatal projection neurons are GABAergic medium spiny neurons (MSNs), subtyped by selective expression of receptors, neuropeptides, and other gene families. Neurogenesis of the striosome and matrix occurs in separate waves, but the factors regulating compartmentation and neuronal differentiation are largely unidentified. We performed RNA- and ATAC-seq on sorted striosome and matrix cells at postnatal day 3, using the Nr4a1-EGFP striosome reporter mouse. Focusing on the striosome, we validated the localization and/or role of Irx1, Foxf2, Olig2, and Stat1/2 in the developing striosome and the in vivo enhancer function of a striosome-specific open chromatin region 4.4 Kb downstream of Olig2. These data provide novel tools to dissect and manipulate the networks regulating MSN compartmentation and differentiation, including in human iPSC-derived striatal neurons for disease modeling and drug discovery.

Substania nigra (SNc) dopaminergic neurons show a pause-rebound firing pattern in response to aversive events. Because these neurons integrate information from predominately inhibitory brain areas, it is important to determine which inputs functionally inhibit the dopamine neurons and whether this pause-rebound firing pattern can be produced by a solely inhibitory input. Here, we functionally map genetically-defined inhibitory projections from the dorsal striatum (striosome and matrix) and globus pallidus (GPe; parvalbumin and Lhx6) onto SNc neurons. We find that GPe and striosomal inputs both pause firing in SNc neurons, but rebound firing only occurs after inhibition from striosomes. Indeed, we find that striosomes are synaptically optimized to produce rebound and preferentially inhibit a subpopulation of ventral, intrinsically rebound-ready SNc dopaminergic neurons on their reticulata dendrites. Therefore, we describe a self-contained dendrite-specific striatonigral circuit that can produce pause-rebound firing in the absence of excitatory input.

The striatum plays a central role in guiding numerous complex behaviors, ranging from motor control to action selection and reward learning. The diverse responsibilities of the striatum are reflected by the complexity of its organization. In this review, we will summarize what is currently known about the compartmental layout of the striatum, an organizational principle that is crucial for allowing the striatum to guide such a diverse array of behaviors. We will focus on the anatomical and functional properties of striosome (patch) and matrix compartments of the striatum, and how the engagement of these compartments is uniquely controlled by their afferents, intrinsic properties, and neuromodulation. We will give examples of how advances in technology have opened the door to functionally dissecting the striatum's compartmental design, and close by offering thoughts on the future and relevance for human disease.

SUMMARY One long-standing model of striatal function divides the striatum into compartments called striosome and matrix. While some anatomical evidence suggests that these populations represent distinct striatal pathways with differing inputs and outputs, functional investigation has been limited by the methods for identifying and manipulating these populations. Here, we utilize hs599CreER mice as a new tool for targeting striosome projection neurons and testing their functional connectivity. Extending anatomical work, we demonstrate that striosome neurons receive greater synaptic input from prelimbic cortex, whereas matrix neurons receive greater input from primary motor cortex. We also identify functional differences in how striosome and matrix neurons process excitatory input, providing the first electrophysiological method for delineating striatal output neuron subtypes. Lastly, we provide the first functional demonstration that striosome neurons are the predominant striatal output to substantia nigra pars compacta dopamine neurons. These results identify striosome and matrix as functionally distinct striatal pathways., Graphical Abstract, In Brief McGregor et al. utilize a novel transgenic mouse line to dissect the functional circuitry and electrophysiology of striatal striosome and matrix neurons. They report that striosome and matrix neurons receive distinct synaptic input and that striosome neurons represent the major striatal population innervating substantia nigra pars compacta dopamine neurons.

The striatum mediates habit formation and reward association. The striatum can be divided into the patch and matrix compartment, which are two distinct regions that sub-serve different aspects of behavior. The patch compartment may mediate reward-related behaviors, while the matrix compartment may mediate adaptive motor functions. Previous studies indicate that enhanced relative activation of the patch versus matrix compartment is associated with inflexible behaviors, such as stereotypy. Habitual behaviors are also inflexible in nature, but whether enhanced activation of the patch compartment contributes to habitual behavior is not known. The goal of the current study was to examine the role of patch compartment in the development of habit formation. We used dermorphin-saporin to ablate neurons of the patch compartment in the dorsolateral striatum prior to training animals to self-administer sucrose on a random interval schedule of reinforcement. Our data showed that patch compartment lesions in the dorsolateral striatum reduced the reinstatement of sucrose self-administration after sucrose devaluation, indicating that destruction of this region prevented the development of habitual behavior. Additionally, in animals with patch compartment lesions in the DLS that did not develop habitual behavior, activation of the dorsolateral striatum and sensorimotor cortex was diminished, while activity in the dorsomedial striatum and prefrontal cortex was increased, suggesting less engagement of regions that mediate habitual behaviors and heightened engagement of regions that mediate goal-directed behaviors occurs with reduced habit formation. These data indicate that the dorsolateral patch compartment may mediate habit formation by altering information flow through basal ganglia circuits.

Summary The striatum contains neurochemically defined compartments termed patches and matrix. Previous studies suggest patches preferentially receive limbic inputs and project to dopamine neurons in substantia nigra pars compacta (SNc), whereas matrix neurons receive sensorimotor inputs and do not innervate SNc. Using BAC-Cre transgenic mice with viral tracing techniques, we mapped brain-wide differences in the input-output organization of the patch/matrix. Findings reveal a displaced population of striatal patch neurons termed "exo-patch," which reside in matrix zones but have neurochemistry, connectivity, and electrophysiological characteristics resembling patch neurons. Contrary to previous studies, results show patch/exo-patch and matrix neurons receive both limbic and sensorimotor information. A novel inhibitory projection from bed nucleus of the stria terminalis to patch/exo-patch neurons was revealed. Projections to SNc were found to originate from patch/exo-patch and matrix neurons. These findings redefine patch/matrix beyond traditional neurochemical topography and reveal new principles about their input-output connectivity, providing a foundation for future functional studies.

Learning valence-based responses to favorable and unfavorable options requires judgments of the relative value of the options, a process necessary for species survival. We have found, using engineered mice, that circuit connectivity and function of the striosome compartment of the striatum are critical for this type of learning. Calcium imaging during valence-based learning exhibited a selective correlation between learning and striosomal, but not matrix, signals. This striosomal activity encoded discrimination learning and was correlated with task engagement, which could, in turn, be regulated by chemogenetic excitation and inhibition. Striosomal function during discrimination learning was disturbed with aging, and severely so in a mouse model of Huntington’s disease. Anatomical and functional connectivity of parvalbumin-positive, putative fast-spiking interneurons (FSIs) to striatal projection neurons was enhanced in striosomes compared to matrix in mice that learned. Computational modeling of these findings suggests that FSIs can modulate striosomal signal-to-noise ratio, crucial for discrimination and learning.

Genetic and clinical studies of speech and language disorders are providing starting points to unravel underlying neurobiological mechanisms. The gene encoding the transcription factorFOXP2has been the first example of a gene involved in the development and evolution of this human-specific trait. A number of autosomal-dominantFOXP2mutations are associated with developmental speech and language deficits indicating that gene dosage plays an important role in the disorder. Comparative genomics studies suggest that two human-specific amino acid substitutions in FOXP2 might have been positively selected during human evolution. A knock-in mouse model carrying these two amino acid changes in the endogenous mouseFoxp2gene(Foxp2hum/hum)shows profound changes in striatum-dependent behaviour and neurophysiology, supporting a functional role for these changes. However, how this affects Foxp2 expression patterns in different striatal regions and compartments has not been assessed. Here, we characterized Foxp2 protein expression patterns in adult striatal tissue inFoxp2hum/hummice. Consistent with prior reports in wildtype mice, we find that striatal neurons inFoxp2hum/hummice and wildtype littermates express Foxp2 in a range from low to high levels. However, we observe a shift towards more cells with higher Foxp2 expression levels inFoxp2hum/hummice, significantly depending on the striatal region and the compartment. As potential behavioural readout of these shifts in Foxp2 levels across striatal neurons, we employed a morphine sensitization assay. While we did not detect differences in morphine-induced hyperlocomotion during acute treatment, there was an attenuated hyperlocomotion plateau during sensitization inFoxp2hum/hummice. Taken together, these results suggest that the humanizedFoxp2allele in a mouse background is associated with a shift in striatal Foxp2 protein expression pattern.

Objective X-linked dystonia-parkinsonism (XDP) is a neurodegenerative disease with adult onset dystonia and subsequent parkinsonism. Postmortem and imaging studies revealed remarkable striatal pathology, with a predominant involvement of the striosomal compartment in the early phase. Here, we aimed to disentangle sequential neurodegeneration in the striatum of XDP patients, provide evidence for preferential loss of distinct striatal areas in the early phase, and investigate whether iron accumulation is present. Methods We used multimodal structural magnetic resonance imaging (voxel-based morphometry and relaxometry) in 18 male XDP patients carrying a TAF1 mutation and 19 age-matched male controls. Results Voxel-based relaxometry and morphometry revealed (1) a cluster in the anteromedial putamen showing high iron content and severe atrophy (-55%) and (2) a cluster with reduced relaxation rates as a marker for increased water levels and a lower degree of atrophy (-20%) in the dorsolateral putamen. Iron deposition correlated with the degree of atrophy (ρ = -0.585, p = 0.011) and disease duration (ρ = 0.632, p = 0.005) in the anteromedial putamen. In the dorsolateral putamen, sensorimotor putamen atrophy correlated with disease severity (ρ = -0.649, p = 0.004). Interpretation This multimodal approach identified a patchy pattern of atrophy within the putamen. Atrophy is advanced and associated with iron accumulation in rostral regions of the striatum, whereas neurodegeneration is moderate and still ongoing in dorsolateral areas. Given the short disease duration and predominant dystonic phenotype, these results are well in line with early and preferential degeneration of striosome-rich striatal areas in XDP. ANN NEUROL 2019;86:517-526.

The neostriatum has a mosaic organization consisting of striosome and matrix compartments. It receives glutamatergic excitatory afferents from the cerebral cortex and thalamus. Recent behavioral studies in rats revealed a selectively active medial prefronto-striosomal circuit during cost-benefit decision-making. However, clarifying the input/output organization of striatal compartments has been difficult because of its complex structure. We recently demonstrated that the source of thalamostriatal projections are highly organized in striatal compartments. This finding indicated that the functional properties of striatal compartments are influenced by their cortical and thalamic afferents, presumably with different time latencies. In addition, these afferents likely support the unique dynamics of striosome and matrix compartments. In this manuscript, we review the anatomy of basal ganglia networks with regard to striosome/matrix structure. We place specific focus on thalamostriatal projections at the population and single neuron level.

This perspective article provides observations supporting the view that nigro-striatal dopamine neurons and meso-limbic dopamine neurons mainly communicate through short distance volume transmission in the um range with dopamine diffusing into extrasynaptic and synaptic regions of glutamate and GABA synapses. Based on this communication it is discussed how volume transmission modulates synaptic glutamate transmission onto the D1R modulated direct and D2R modulated indirect GABA pathways of the dorsal striatum. Each nigro-striatal dopamine neuron was first calculated to form large numbers of neostriatal DA nerve terminals and then found to give rise to dense axonal arborizations spread over the neostriatum, from which dopamine is released. These neurons can through DA volume transmission directly influence not only the striatal GABA projection neurons but all the striatal cell types in parallel. It includes the GABA nerve cells forming the island-/striosome GABA pathway to the nigral dopamine cells, the striatal cholinergic interneurons and the striatal GABA interneurons. The dopamine modulation of the different striatal nerve cell types involves the five dopamine receptor subtypes, D1R to D5R receptors, and their formation of multiple extrasynaptic and synaptic dopamine homo and heteroreceptor complexes. These features of the nigro-striatal dopamine neuron to modulate in parallel the activity of practically all the striatal nerve cell types in the dorsal striatum, through the dopamine receptor complexes allows us to understand its unique and crucial fine-tuning of movements, which is lost in Parkinson's disease. Integration of striatal dopamine signals with other transmitter systems in the striatum mainly takes place via the receptor-receptor interactions in dopamine heteroreceptor complexes. Such molecular events also participate in the integration of volume transmission and synaptic transmission. Dopamine modulation of the glutamate synapses on the dorsal striato-pallidal GABA pathway involves D2R heteroreceptor complexes such as D2R-NMDAR, A2AR-D2R, and NTSR1-D2R heteroreceptor complexes. The dopamine modulation of glutamate synapses on the striato-entopeduncular/nigral pathway takes place mainly via D1R heteroreceptor complexes such as D1R-NMDAR, A2R-D1R, and D1R-D3R heteroreceptor complexes. Dopamine modulation of the island/striosome compartment of the dorsal striatum projecting to the nigral dopamine cells involve D4R-MOR heteroreceptor complexes. All these receptor-receptor interactions have relevance for Parkinson's disease and its treatment.

doctoral thesis

Presynaptic cannabinoid-1 receptors (CB1-R) bind endogenous and exogenous cannabinoids to modulate neurotransmitter release. CB1-Rs are expressed throughout the basal ganglia, including striatum and substantia nigra, where they play a role in learning and control of motivated actions. However, the pattern of CB1-R expression across different striatal compartments, microcircuits and efferent targets, and the contribution of different CB1-R-expressing neurons to this pattern, are unclear. We use a combination of conventional techniques and novel genetic models to evaluate CB1-R expression in striosome (patch) and matrix compartments of the striatum, and in nigral targets of striatal medium spiny projection neurons (MSNs). CB1-R protein and mRNA follow a descending dorsolateral-to-ventromedial intensity gradient in the caudal striatum, with elevated expression in striosomes relative to the surrounding matrix. The lateral predominance of striosome CB1-Rs contrasts with that of the classical striosomal marker, the mu opioid receptor (MOR), which is expressed most prominently in rostromedial striosomes. The dorsolateral-to-ventromedial CB1-R gradient is similar to Drd2 dopamine receptor immunoreactivity and opposite to Substance P. This topology of CB1-R expression is maintained downstream in the globus pallidus and substantia nigra. Dense CB1-R-expressing striatonigral fibers extend dorsally within the substantia nigra pars reticulata, and colocalize with bundles of ventrally extending, striosome-targeted, dendrites of dopamine-containing neurons in the substantia nigra pars compacta (striosome-dendron bouquets). Within striatum, CB1-Rs colocalize with fluorescently labeled MSN collaterals within the striosomes. Cre recombinase-mediated deletion of CB1-Rs from cortical projection neurons or MSNs, and MSN-selective reintroduction of CB1-Rs in knockout mice, demonstrate that the principal source of CB1-Rs in dorsolateral striosomes is local MSN collaterals. These data suggest a role for CB1-Rs in caudal dorsolateral striosome collaterals and striosome-dendron bouquet projections to lateral substantia nigra, where they are anatomically poised to mediate presynaptic disinhibition of both striosomal MSNs and midbrain dopamine neurons in response to endocannabinoids and cannabinomimetics.

SUMMARYThe circuitry of the striatum is characterized by two organizational plans: the division into striosome and matrix compartments, thought to mediate evaluation and action, and the direct and indirect pathways, thought to promote or suppress behavior. The developmental origins of and relationships between these organizations are unknown, leaving a conceptual gap in understanding the cortico-basal ganglia system. Through genetic fate mapping, we demonstrate that striosome-matrix compartmentalization arises from a lineage program embedded in lateral ganglionic eminence radial glial progenitors mediating neurogenesis through two distinct types of intermediate progenitors (IPs). The early phase of this program produces striosomal spiny projection neurons (SPNs) through fate-restricted apical IPs (aIPSs) with limited capacity; the late phase produces matrix SPNs through fate-restricted basal IPs (bIPMs) with expanded capacity. Remarkably, direct and indirect pathway SPNs arise within both aIPSand bIPMpools, suggesting that striosome-matrix architecture is the fundamental organizational plan of basal ganglia circuitry organization.

Corticostriatal synaptic integration is partitioned among striosome (patch) and matrix compartments of the dorsal striatum, allowing compartmentalized control of discrete aspects of behavior. Despite the significance of such organization, it is unclear how compartment-specific striatal output is dynamically achieved, particularly considering new evidence that overlap of afferents is substantial. Here we show that dopamine oppositely modulates glutamatergic synaptic integration in striosome and matrix striatal spiny projection neurons (SPNs). Activation of postsynaptic D1-type dopamine receptors promoted the generation of long-lasting synaptically-evoked “up-states” in matrix SPNs but opposed it in striosomes, which were more excitable under basal conditions. Compartment-specific differences in dendritic L-type voltage gated calcium channel (L-VGCC) availability determined the direction of dopaminergic modulation: manipulating L-VGCC engagement could reverse compartment-specific responses to D1 receptor activation. These results support a novel mechanism for the selection of striatal circuit components, where fluctuating levels of dopamine will shift the balance of compartment-specific striatal output.

X-linked dystonia-parkinsonism is a neurodegenerative movement disorder characterized by adult-onset dystonia combined with parkinsonism over the disease course. Previous imaging and pathological findings indicate exclusive striatal atrophy with predominant pathology of the striosomal compartment in the dystonic phase of X-linked dystonia-parkinsonism. The striosome occupies 10-15% of the entire striatal volume and the density of striosomes follows a rostrocaudal gradient with the rostral striatum being considered striosome-rich. Recent quantitative MRI analyses provided evidence for an additional involvement of the white matter and the pallidum. In this study, we aimed to (i) disentangle the degree of atrophy in the different subdivisions of the striatum; (ii) investigate changes of cortical morphology; and (iii) elucidate the role of the cerebellum in X-linked dystonia-parkinsonism. T1-weighted MRI scans were acquired in 17 male X-linked dystonia-parkinsonism patients with predominant dystonia (40.1 ± 7.5 years) and 17 ethnicity-matched male healthy controls (35.2 ± 7.4 years). Voxel-based morphometry used a region of interest-based approach for the basal ganglia and primary motor cortex, whole brain analysis, and a separate analysis of the cerebellum. Cortical thickness and subcortical volume were measured. Volume loss in X-linked dystonia-parkinsonism affected all parts of the striatum (-29% voxel intensity) but was most pronounced in the associative subdivision (-41%; P < 0.001). The volume loss also involved the external and internal pallidum, albeit to a lesser extent than the striatum (-19% and -12%, P

Striosomes were discovered several decades ago as neurochemically identified zones in the striatum, yet technical hurdles have hampered the study of the functions of these striatal compartments. Here we used 2-photon calcium imaging in neuronal birthdate-labeled Mash1-CreER;Ai14 mice to image simultaneously the activity of striosomal and matrix neurons as mice performed an auditory conditioning task. With this method, we identified circumscribed zones of tdTomato-labeled neuropil that correspond to striosomes as verified immunohistochemically. Neurons in both striosomes and matrix responded to reward-predicting cues and were active during or after consummatory licking. However, we found quantitative differences in response strength: striosomal neurons fired more to reward-predicting cues and encoded more information about expected outcome as mice learned the task, whereas matrix neurons were more strongly modulated by recent reward history. These findings open the possibility of harnessing in vivo imaging to determine the contributions of striosomes and matrix to striatal circuit function.

Effective evaluation of costs and benefits is a core survival capacity that in humans is considered as optimal, “rational” decision-making. This capacity is vulnerable in neuropsychiatric disorders and in the aftermath of chronic stress, in which aberrant choices and high-risk behaviors occur. We report that chronic stress exposure in rodents produces abnormal evaluation of costs and benefits resembling non-optimal decision-making in which choices of high-cost/high-reward options are sharply increased. Concomitantly, alterations in the task-related spike activity of medial prefrontal neurons correspond with increased activity of their striosome-predominant striatal projection neuron targets and with decreased and delayed striatal fast-firing interneuron activity. These effects of chronic stress on prefronto-striatal circuit dynamics could be blocked or be mimicked by selective optogenetic manipulation of these circuits. We suggest that altered excitation-inhibition dynamics of striosome-based circuit function could be an underlying mechanism by which chronic stress contributes to disorders characterized by aberrant decision-making under conflict., National Institute of Mental Health (Grant R01 MH060379), CHDI Foundation (Award A-5552), Army Research Office (Contract W911NF-10-1-0059)