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SUMMARY Opioids are powerful addictive agents that alter dopaminergic influence on reward signaling in medium spiny neurons (MSNs) of the nucleus accumbens. Repeated opioid exposure triggers adaptive changes, shifting reward valuation to the allostatic state underlying tolerance. However, the cellular substrates and molecular logic underlying such allostatic changes are not well understood. Here, we report that the plasticity of dopamine-induced cyclic AMP (cAMP) signaling in MSNs serves as a cellular substrate for drug-induced allostatic adjustments. By recording cAMP responses to optically evoked dopamine in brain slices from mice subjected to various opioid exposure paradigms, we define profound neuronal-type-specific adaptations. We find that opioid exposure pivots the initial hyper-responsiveness of D1-MSNs toward D2-MSN dominance as dependence escalates. Presynaptic dopamine transporters and postsynaptic phosphodiesterases critically enable cell-specific adjustments of cAMP that control the balance between opponent D1-MSN and D2-MSN channels. We propose a quantitative model of opioid-induced allostatic adjustments in cAMP signal strength that balances circuit activity., In Brief Muntean et al. examine how opioid exposure influences cyclic AMP (cAMP) responses to dopamine in striatal medium spiny neurons (MSNs). They describe allostatic adaptations in the processing of dopaminergic signals by D1-MSN and D2-MSN populations as opioid administration progresses from acute exposure to chronic use, and they define molecular elements contributing to the process., Graphical Abstract

The striatum is an essential component of the basal ganglia that regulatessensory processing, motor, cognition, and behavior. Depending on the species, the striatum shows a unique structure called caudate-putamen as in mice, or its separation into two regions called caudate and lenticular nuclei, the latter formed by putamen and globus pallidus areas, as in primates. These structures have two compartments, striosome and matrix. We investigated the structural organization, GABAergic and tyrosine hydroxylase (TH) expression in the striatum and globus pallidus of the South American plains vizcacha, Lagostomus maximus. Its striatum showed regionalization arising from the presence of an internal capsule, and a similar organization to a striosome-matrix compartmentalization. GABAergic neurons in the matrix of caudate exhibited parvalbumin, calretinin, calbindin, GAD65, and NADPH-d-immunoreactivity. These were also expressed in cells of the putamen with the exception of calretinin showing neurofibers localization. Globus pallidus showed parvalbumin- and GAD65-immunoreactive cells, and calretinin- and calbindin-immunoreactive neuropil, plus GABA-A-immunoreactive neurofibers. NADPH-d-, GAD65- and GABA-A-immunoreactive neurons were larger than parvalbumin-, calretinin-, and calbindin-immunoreactive cells, whereas calbindin-immunoreactive cells were the most abundant. In addition, TH-immunoreactive neuropil was observed in the matrix of the striatum. A significant larger TH-immunoreactive area and neuron number was found in females compared to males. The presence of an internal capsule suggests an adaptive advantage concerning motor and cognitive abilities favoring reaction time in response to predators. In an anatomy-evolutive perspective, the striatum of vizcacha seems to be closer to that of humans than to that of laboratory traditional models such as mouse.

Background The most prevalent inherited form of generalized dystonia is caused by a mutation in torsinA (DYT1, ∆GAG) with incomplete penetrance. Rodent models with mutated torsinA do not develop dystonic symptoms, but previous ex vivo studies indicated abnormal excitation of cholinergic interneurons (ChI) and increased striatal acetylcholine. Methods We used in vivo optogenetics to exacerbate this endophenotype in order to determine its capacity to trigger dystonic symptoms in freely behaving mice. Tor1a+/Δgag DYT1 mice and wildtype littermates expressing channelrhodopsin2 under the Chat promotor were implanted bilaterally with optical LED cannulae and stimulated with blue light pulses of varied durations. Findings Six months old DYT1 KI mice but not wildtype controls responded with hyperactivity to blue light specifically at 25 ms pulse duration, 10 Hz frequency. Neuronal activity (c-Fos) in cholinergic interneurons was increased immediately after light stimulation and persisted only in DYT1 KI over 15 min. Substance P was increased specifically in striosome compartments in naive DYT1 KI mice compared to wildtype. Under optogenetic stimulation substance P increased in wildtype to match levels in Dyt1 KI, and acetylcholinesterase was elevated in the striatum of stimulated DYT1 KI. No signs of dystonic movements were observed under stimulation of up to one hour in both genotypes and age groups, and the sensorimotor deficit previously observed in 6 months old DYT1 KI mice persisted under stimulation. Interpretation Overall this supports an endophenotype of dysregulated cholinergic activity in DYT1 dystonia, but depolarizing cholinergic interneurons was not sufficient to induce overt dystonia in DYT1 KI mice.

Learning about positive and negative outcomes of actions is crucial for survival and underpinned by conserved circuits including the striatum. How associations between actions and outcomes are formed is not fully understood, particularly when the outcomes have mixed positive and negative features. We developed a novel foraging (‘bandit’) task requiring mice to maximize rewards while minimizing punishments. By 2-photon Ca++ imaging, we monitored activity of 5831 identified anterodorsal striatal striosomal and matrix neurons. Surprisingly, we found that action-outcome associations for reward and punishment were combinatorially encoded rather than being integrated as overall outcome value. Single neurons could, for one action, encode outcomes of opposing valence. Striosome compartments consistently exhibited stronger representations of reinforcement outcomes than matrix, especially for high reward or punishment prediction errors. These findings demonstrate a remarkable multiplexing of action-outcome contingencies by single identified striatal neurons and suggest that striosomal neurons are differentially important in action-outcome learning.

Medium spiny neurons (MSNs) constitute the vast majority of striatal neurons and the principal interface between dopamine reward signals and functionally diverse cortico-basal ganglia circuits. Information processing in these circuits is dependent on distinct MSN types – cell types that are traditionally defined according to their projection targets or dopamine receptor expression. Single cell transcriptional studies have revealed greater MSN heterogeneity than predicted by traditional circuit models, but the transcriptional landscape in the primate striatum remains unknown. Here, we set out to establish molecular definitions for MSN subtypes in Rhesus monkeys, and to explore the relationships between transcriptionally defined subtypes and anatomical subdivisions of the striatum. Our results suggest at least nine MSN subtypes, including dorsal striatum subtypes associated with striosome and matrix compartments, ventral striatum subtypes associated with the nucleus accumbens shell and olfactory tubercle, and an MSN-like cell type restricted to μ-opioid receptor rich islands in the ventral striatum. Although each subtype was demarcated by discontinuities in gene expression, continuous variation within subtypes defined gradients corresponding to anatomical locations and, potentially, functional specializations. These results lay the foundation for achieving cell-type-specific transgenesis in the primate striatum and provide a blueprint for investigating circuit specific information processing.

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.

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.

The striatum comprises a mosaic structure of striosomal and matrix compartments. Imbalanced neuronal activity between striosomes and matrix is implicated in neurological deficits in psychomotor and limbic functions. Because patients with autism spectrum disorder (ASD) are impaired in social communication and psychomotor function, it raises the possibility that abnormal striatal compartments may contribute to ASD pathogenesis. Here, we provide pathological evidence from human postmortem brains to support this hypothesis. Because ASD is a neurodevelopmental disease that emerges early in childhood, we analyzed juvenile and adolescent brains. Distinct patterns of PRODYNORPHIN-positive and calbindin-poor striosomes were detected in the caudate nucleus of control brains by in situ hybridization and immunohistochemistry. By contrast, PRODYNORPHIN-positive and calbindin-poor striosomes were decreased in the caudate nucleus of young ASD brains. Moreover, calbindin, a matrix marker, was aberrantly increased in the striosomal compartment, obscuring the boundaries between calbindin-poor striosomes and calbindin-rich matrix in ASD caudate nucleus. Calbindin-positive cells were decreased in the ASD matrix compartment. Collectively, our study has uncovered for the first time that aberrant striatal compartments occur in the caudate nucleus of human ASD brains, which suggests abnormal striatal compartmentation as a pathological signature that has previously been underestimated in ASD pathogenesis.

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 striatum is critically involved in execution of appropriate behaviors, but its internal structures remain unmapped due to its unique structural organization, leading to ambiguity when interpreting heterogeneous properties of striatal neurons that differ by location. We focused on site-specific diversity of striosomes/matrix compartmentalization to draw the striatum map. Five types of striosomes were discriminated according to diverse immunoreactivities for the µ-opioid receptor, substance P (SP) and enkephalin, and each type occupied a particular domain inside the striatum. Furthermore, there was an additional domain lacking striosomes. This striosome-free space was located at the dorsolateral region and received afferents preferentially from the primary motor and sensory cortices, whereas the striosome-rich part received afferents from associational/limbic cortices, with topography inside both innervations. The proportion of dopamine D1 receptor-expressing, presumptive striatonigral neurons was approximately 70% in SP-positive striosomes, 40% in SP-deficient striosomes, 30% in the striosome-free space, and 50% in the matrix. In contrast, the proportion of D2 receptor-expressing, presumptive striatopallidal neurons was complementary to that of D1 receptor-expressing cells, indicating a close relationship between the map and the direct and indirect parallel circuitry. Finally, the most caudal part of the striatum lacked compartmentalization and consisted of three lamina characterized by intense and mutually exclusive immunoreactivities for SP and enkephalin. This tri-laminar part also received specific afferents from the cortex. The newly obtained map will facilitate broad fields of research in the basal ganglia with higher resolution of the three-dimensional anatomy of the striatum. Electronic supplementary material The online version of this article (10.1007/s00429-018-1749-3) contains supplementary material, which is available to authorized users.

The mammalian striatum is comprised of intermingled tissue compartments, matrix and striosome. Though indistinguishable by routine histological techniques, matrix and striosome have distinct embryologic origins, afferent/efferent connections, surface protein expression, intra-striatal location, susceptibilities to injury, and functional roles in a range of animal behaviors. Distinguishing the compartments previously required post-mortem tissue and/or genetic manipulation; we aimed to identify matrix/striosome non-invasively in living humans. We used diffusion MRI (probabilistic tractography) to identify human striatal voxels with connectivity biased towards matrix-favoring or striosome-favoring regions (determined by prior animal tract-tracing studies). Segmented striatal compartments replicated the topological segregation and somatotopic organization identified in animal matrix/striosome studies. Of brain regions mapped in prior studies, our human brain data confirmed 93% of the compartment-selective structural connectivity demonstrated in animals. Test-retest assessment on repeat scans found a voxel classification error rate of 0.14%. Fractional anisotropy was significantly higher in matrix-like voxels, while mean diffusivity did not differ between the compartments. As mapped by the Talairach human brain atlas, 460 regions were significantly biased towards either matrix or striosome. Our method allows the study of striatal compartments in human health and disease, in vivo, for the first time.

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.

The complex neuroanatomical connections of the inferior colliculus (IC) and its major subdivisions offer a juxtaposition of segregated processing streams with distinct organizational features. While the tonotopically layered central nucleus (CNIC) is well-documented, less is known about functional compartments in the neighboring lateral cortex (LCIC). In addition to a laminar framework, LCIC afferent-efferent patterns suggest a multimodal mosaic, consisting of a patchy modular network with surrounding extramodular domains. The present study utilizes several neurochemical markers that reveal an emerging LCIC modular-extramodular microarchitecture. In newborn and post-hearing C57BL/6J and CBA/CaJ mice, histochemical and immunocytochemical stains were performed for acetylcholinesterase (AChE), nicotinamide adenine dinucleotide phosphate-diaphorase (NADPH-d), glutamic acid decarboxylase (GAD), cytochrome oxidase (CO), and calretinin (CR). Discontinuous layer 2 modules are positive for AChE, NADPH-d, GAD, and CO throughout the rostrocaudal LCIC. While not readily apparent at birth, discrete cell clusters emerge over the first postnatal week, yielding an identifiable modular network prior to hearing onset. Modular boundaries continue to become increasingly distinct with age, as surrounding extramodular fields remain largely negative for each marker. Alignment of modular markers in serial sections suggests each highlight the same periodic patchy network throughout the nascent LCIC. In contrast, CR patterns appear complementary, preferentially staining extramodular LCIC zones. Double-labeling experiments confirm that NADPH-d, the most consistent developmental modular marker, and CR label separate, non-overlapping LCIC compartments. Determining how this emerging modularity may align with similar LCIC patch-matrix-like Eph/ephrin guidance patterns, and how each interface with, and potentially influence developing multimodal LCIC projection configurations is discussed. This article is protected by copyright. All rights reserved.

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.

The intricate neuronal architecture of the striatum plays a pivotal role in the functioning of the basal ganglia circuits involved in the control of various aspects of motor, cognitive, and emotional functions. Unlike the cerebral cortex, which has a laminar structure, the striatum is primarily composed of two functional subdivisions (i.e., the striosome and matrix compartments) arranged in a mosaic fashion. This review addresses whether striatal compartmentalization is present in non-mammalian vertebrates, in which simple cognitive and behavioral functions are executed by primitive sensori-motor systems. Studies show that neuronal subpopulations that share neurochemical and connective properties with striosomal and matrix neurons are present in the striata of not only anamniotes (fishes and amphibians), but also amniotes (reptiles and birds). However, these neurons do not form clearly segregated compartments in these vertebrates, suggesting that such compartmentalization is unique to mammals. In the ontogeny of the mammalian forebrain, the later-born matrix neurons disperse the early-born striosome neurons into clusters to form the compartments in tandem with the development of striatal afferents from the cortex. We propose that striatal compartmentalization in mammals emerged in parallel with the evolution of the cortex and possibly enhanced complex processing of sensory information and behavioral flexibility phylogenetically.

The striatum, the largest nucleus of the basal ganglia controlling motor and cognitive functions, can be characterized by a labyrinthine mosaic organization of striosome/matrix compartments. It is unclear how striosome/matrix mosaic formation is spatially and temporally controlled at the cellular level during the striatal development. Here, by combining in vivo electroporation and brain slice cultures, we set up a prospective experimental system where we differentially labeled striosome and matrix cells from the time of birth and followed their distributions and migratory behaviors. Our results showed that, at an initial stage of striosome/matrix mosaic formation, striosome cells were mostly stationary, whereas matrix cells actively migrated in multiple directions irrespective of the presence of striosome cells. The mostly stationary striosome cells were still able to associate to form patchy clusters via attractive interactions. Our results suggested that the restricted migratory capability of striosome cells may only allow them to cluster together when they happen to be located in close proximity to each other and are not separated by actively migrating matrix cells. The way the mutidirectionally migrating matrix cells intermingle with the mostly stationary striosome cells may therefore determine the topographical features of striosomes. At later stages, the actively migrating matrix cells began to repulse the patchy clusters of striosomes, presumably enhancing the striosome cluster formation and the segregation and eventual formation of dichotomous homogeneous striosome/matrix compartments. Taken altogether, our study revealed temporally distinct migratory behaviors of striosome/matrix cells, which may underlie the sequential steps of mosaic formation in the developing striatum. This article is protected by copyright. All rights reserved.

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.

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.

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.

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.

Aldehyde dehydrogenase 1 (ALDH1A1)–positive dopaminergic (DA) neurons at the ventral substantia nigra pars compacta (SNpc) preferentially degenerate in Parkinson’s disease (PD). Their projection pattern and dopamine release properties, however, remains uncharacterized. Here we show that ALDH1A1–positive axons project predominantly to the rostral two–thirds of dorsal striatum. A portion of these axons converge on a small fraction of striosome compartments restricted to the dorsolateral striatum (DLS), where less dopamine release was measured compared to the adjacent matrix enriched with the ALDH1A1–negative axons. Genetic ablation of Aldh1a1 substantially increases the dopamine release in striosomes, but not in matrix. Additionally, the presence of PD-related human α-synuclein A53T mutant or dopamine transporter (DAT) blockers also differentially affects the dopamine output in striosomes and matrix. Together, these results demonstrate distinct dopamine release characteristics of ALDH1A1–positive DA fibers, supporting a regional specific function of ALDH1A1 in regulating dopamine availability/release in striatum.

The GABAergic medium-size spiny neuron (MSN), the striatal output neuron, may be classified into striosome, also known as patch, and matrix, based on neurochemical differences between the two compartments. At this time, little is known regarding the regulation of the development of the two compartments.Nr4a1, primarily described as a nuclear receptor/immediate early gene involved in the homeostasis of the dopaminergic system, is a striosomal marker. UsingNr4a1-overexpressing andNr4a1-null mice, we sought to determine whether Nr4a1 is necessary and/or sufficient for striosome development. We report thatin vivoandin vitro,Nr4a1andOprm1mRNA levels are correlated. In the absence of Nr4a, there is a decrease in the percentage of striatal surface area occupied by striosomes. Alterations inNr4a1expression leads to dysregulation of multiple mRNAs of members of the dopamine receptor D1signal transduction system. Constitutive overexpression ofNr4a1decreases both the induction of phosphorylation of ERK after a single cocaine exposure and locomotor sensitization following chronic cocaine exposure.Nr4a1overexpression increases MSN excitability but reduces MSN long-term potentiation. In the resting state, type 5 adenylyl cyclase (AC5) activity is normal, but the ability of AC5 to be activated by Drd1 G-protein-coupled receptor inputs is decreased. Our results support a role forNr4a1in determination of striatal patch/matrix structure and in regulation of dopaminoceptive neuronal function.

Repeated psychostimulant exposure induces persistent gene expression modifications that contribute to enduring changes in striatal GABAergic spiny projecting neurons (SPNs). However, it remains unclear whether changes in the control of mRNA translation are required for the establishment of these durable modifications. Here we report that repeated exposure to D-amphetamine decreases global striatal mRNA translation. This effect is paralleled by an enhanced phosphorylation of the translation factors, eIF2α and eEF2, and by the concomitant increased translation of a subset of mRNAs, among which the mRNA encoding for the activity regulated cytoskeleton-associated protein, also known as activity regulated gene 3.1 (Arc/Arg3.1). The enrichment of Arc/Arg3.1 mRNA in the polysomal fraction is accompanied by a robust increase of Arc/Arg3.1 protein levels within the striatum. Immunofluorescence analysis revealed that this increase occurred preferentially in D1R-expressing SPNs localized in striosome compartments. Our results suggest that the decreased global protein synthesis following repeated exposure to D-amphetamine favors the translation of a specific subset of mRNAs in the striatum.

The striatum is key for action-selection and the motivation to move. Dopamine and acetylcholine release sites are enriched in the striatum and are cross-regulated, possibly to achieve optimal behavior. Drugs of abuse, which promote abnormally high dopamine release, disrupt normal action-selection and drive restricted, repetitive behaviors (stereotypies). Stereotypies occur in a variety of disorders including obsessive-compulsive disorder, autism, schizophrenia and Huntington's disease, as well as in addictive states. The severity of drug-induced stereotypy is correlated with induction of c-Fos expression in striosomes, a striatal compartment that is related to the limbic system and that directly projects to dopamine-producing neurons of the substantia nigra. These characteristics of striosomes contrast with the properties of the extra-striosomal matrix, which has strong sensorimotor and associative circuit inputs and outputs. Disruption of acetylcholine signaling in the striatum blocks the striosome-predominant c-Fos expression pattern induced by drugs of abuse and alters drug-induced stereotypy. The activity of striatal cholinergic interneurons is associated with behaviors related to sensory cues, and cortical inputs to striosomes can bias action-selection in the face of conflicting cues. The neurons and neuropil of striosomes and matrix neurons have observably separate distributions, both at the input level in the striatum and at the output level in the substantia nigra. Notably, cholinergic axons readily cross compartment borders, providing a potential route for local cross-compartment communication to maintain a balance between striosomal and matrix activity. We show here, by slice electrophysiology in transgenic mice, that repetitive evoked firing patterns in striosomal and matrix striatal projection neurons (SPNs) are interrupted by optogenetic activation of cholinergic interneurons either by the addition or the deletion of spikes. We demonstrate that this cholinergic modulation of projection neurons is blocked in brain slices taken from mice exposed to amphetamine and engaged in amphetamine-induced stereotypy, and lacking responsiveness to salient cues. Our findings support a model whereby activity in striosomes is normally under strong regulation by cholinergic interneurons, favoring behavioral flexibility, but that in animals with drug-induced stereotypy, this cholinergic signaling breaks down, resulting in differential modulation of striosomal activity and an inability to bias action-selection according to relevant sensory cues., National Institutes of Health (U.S.) (Grants R01 MH060379), National Institutes of Health (U.S.) (Grants R37 HD028341), Saks-Kavanaugh Foundation, Massachusetts Institute of Technology. Poitras Center for Affective Disorders Research, Simons Foundation, Broad Institute of MIT and Harvard. Stanley Center for Psychiatric Research

The dopamine systems of the brain powerfully influence movement and motivation. We demonstrate that striatonigral fibers originating in striosomes form highly unusual bouquet-like arborizations that target bundles of ventrally extending dopamine-containing dendrites and clusters of their parent nigral cell bodies. Retrograde tracing showed that these clustered cell bodies in turn project to the striatum as part of the classic nigrostriatal pathway. Thus, these striosome–dendron formations, here termed “striosome–dendron bouquets,” likely represent subsystems with the nigro–striato–nigral loop that are affected in human disorders including Parkinson’s disease. Within the bouquets, expansion microscopy resolved many individual striosomal fibers tightly intertwined with the dopamine-containing dendrites and also with afferents labeled by glutamatergic, GABAergic, and cholinergic markers and markers for astrocytic cells and fibers and connexin 43 puncta. We suggest that the striosome–dendron bouquets form specialized integrative units within the dopamine-containing nigral system. Given evidence that striosomes receive input from cortical regions related to the control of mood and motivation and that they link functionally to reinforcement and decision-making, the striosome–dendron bouquets could be critical to dopamine-related function in health and disease.

Introduction The basal ganglia (BG) have been implicated in different processes that control action such as the control of movement parameters but also in processing cognitive and emotional information from the environment. Here, we review existing anatomical data on the interaction between the BG and the limbic system that support implication of the BG in limbic functions. State of the art The BG form a system that is fairly different from the limbic system, but have strong ties, both anatomical and functional, to the latter. Different models have been proposed. In the parallel model, five segregated circuits from the frontal cortex are individualized and terminate in different regions of the BG and thalamus, before projecting back to their cortical area of origin. Based on the extrafrontal cortical projections, another model has been proposed. It subdivides the cortico-striatal projection into three functional territories: limbic, associative and sensorimotor. In a third spiral model, propagation is possible between limbic information processed by the most medial striatal neurons to motor information processed by the most lateral neurons. Perspectives Three main levels of interaction between the BG system and the limbic system are considered. (1) The BG receive direct afferences from several structures associated with the limbic system. Limbic cortical areas project to the striatum, of which the internal architecture is particularly complex, with significant cross-species differences: a compartmental striosome/matrix subdivision described mainly in primates, and a core/shell topographic subdivision of the nucleus accumbens more sharply marked in rodents. (2) Projections from the amygdala form a patchy dorso-ventral progressive gradient in the nucleus accumbens and ventral caudate. (3) Both shell and striosomes receive limbic information from cortical and subcortical limbic structures and project to the dopaminergic neurons of the substantia nigra pars compacta, which in turn modulates their activity. (4) There is a significant overlap between the ventral portions of the BG, nucleus accumbens and ventral pallidum, and the ventral subcortical structures of the limbic system, extended amygdala and nucleus basalis. Conclusion Important interactions exist between the limbic system and the BG system but questions remain about the role that this information plays in the functional organisation of this system. Is limbic information processed separately in the BG, or is it integrated to motor and cognitive information? Do pathological conditions such as obsessive-compulsive disorders or Tourette syndrome result from abnormal afferent limbic input to the BG or abnormal processing within the BG?

The neuron-specific isoform of the TAF1 gene (N-TAF1) is thought to be involved in the pathogenesis of DYT3 dystonia, which leads to progressive neurodegeneration in the striatum. To determine the expression pattern of N-TAF1 transcripts, we developed a specific monoclonal antibody against the N-TAF1 protein. Here we show that in the rat brain, N-TAF1 protein appears as a nuclear protein within subsets of neurons in multiple brain regions. Of particular interest is that in the striatum, the nuclei possessing N-TAF1 protein are largely within medium spiny neurons, and they are distributed preferentially, though not exclusively, in the striosome compartment. The compartmental preference and cell type-selective distribution of N-TAF1 protein in the striatum are strikingly similar to the patterns of neuronal loss in the striatum of DYT3 patients. Our findings suggest that the distribution of N-TAF1 protein could represent a key molecular characteristic contributing to the pattern of striatal degeneration in DYT3 dystonia., Japan. Ministry of Education, Culture, Sports, Science and Technology (Grant-in-aid for Scientific Research 20591025), Japan. Ministry of Education, Culture, Sports, Science and Technology (Grant-in-aid for Scientific Research 2139026900), National Institutes of Health (U.S.) (Grant P50 NS38372), National Institutes of Health (U.S.) (Grant R37 HD028341)

The rat neostriatum has a mosaic organization composed of striosome/patch compartments embedded in a more extensive matrix compartment, which are distinguished from each other by the input-output organization as well as by the expression of many molecular markers. The matrix compartment gives rise to the dual γ-aminobutyric acid (GABA)ergic striatofugal systems, i.e. direct and indirect pathway neurons, whereas the striosome compartment is considered to involve direct pathway neurons alone. Although the whole axonal arborization of matrix striatofugal neurons has been examined in vivo by intracellular staining, that of striosome neurons has never been studied at the single neuron level. In the present study, the axonal arborizations of single striosome projection neurons in rat neostriatum were visualized in their entirety using a viral vector expressing membrane-targeted green fluorescent protein, and compared with that of matrix projection neurons. We found that not only matrix but also striosome compartments contained direct and indirect pathway neurons. Furthermore, only striatonigral neurons in the striosome compartment projected directly to the substantia nigra pars compacta (SNc), although they sent a substantial number of axon collaterals to the globus pallidus, entopeduncular nucleus and/or substantia nigra pars reticulata. These results suggest that striosome neurons play a more important role in the formation of reward-related signals of SNc dopaminergic neurons than do matrix neurons. Together with data from previous studies in the reinforcement learning theory, our results suggest that these direct and indirect striosome-SNc pathways together with nigrostriatal dopaminergic neurons may help striosome neurons to acquire the state-value function.

There is a growing body of evidence that striosome-matrix dopamine systems are tightly linked with motor and behavioral brain functions and disorders. In this study, we used an immunohistochemical method to show differential expression of the olfactory type G-protein alpha subunit (Galphaolf) that involves in the coupling of dopamine D1 receptor with adenylyl cyclase in the striatal compartments of adult mice, and observed heightened density of Galphaolf labeling in the striosomes relative to the matrix compartment. Our findings suggest that Galphaolf could be one of the key molecules for controlling differential responses of the striosome and matrix compartments to dopamine D1 receptor signaling in the striatum of adult mice.

We have previously shown that docosahexaenoic acid (DHA) significantly reduced L-Dopa-induced dyskinesia (LID) in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) monkeys (Samadi et al., Ann. Neurol. 59:282-288, 2006). In the present study, we measured for the first time mRNA levels of Nur77, an orphan nuclear receptor that participates to adaptive and/or aberrant dopamine-related behaviors, and retinoid X receptor gamma1 (RXRgamma1), a putative brain receptor for DHA and transcriptional partner of Nur77, in MPTP monkeys treated with L-Dopa and DHA. The RXRgamma1 mRNA is strongly expressed in monkey caudate nucleus and putamen, but no change in levels of RXRgamma1 was observed following MPTP and L-Dopa treatments. On the other hand, denervation reduced Nur77 mRNA levels, whereas chronic L-Dopa treatment strongly induced Nur77 transcripts. These modulations are taking place in substance P positive cells and are associated with both caudate-putamen matrix and striosome compartments. Interestingly, combination of L-Dopa with DHA further increases Nur77 mRNA levels in the anterior caudate-putamen, and mainly in striosomes. This is accompanied by a significant inverse correlation between Nur77 mRNA levels and dyskinetic scores. Taken together, our results show that Nur77 expression is modulated following dopamine denervation and chronic L-Dopa therapy in a non-human primate model of Parkinson's disease, and suggest that strong modulation of Nur77 expression might be linked to a reduced risk to develop LIDs.

Basal ganglia striosomes, or patches, are rich in mu opioid receptors (MOR) and form a three-dimensional labyrinth of cells that extend throughout the mid- and anterior striatum in mice. Though previous studies have suggested that striosomes could affect drug-induced motor output in rodents, the functional role of these compartmentalized MOR-rich striosomes is not well understood. To investigate any relationship between the striosomes and motor behavior we used the toxin dermorphin-saporin (DS) to selectively ablate MOR-rich striosomal cells. FVB mice were bilaterally infused with DS in the midstriatum alone or in the mid- and anterior striatum, and were tested on three motor tasks and in an open field. Two volume measurement procedures and stereological cell counts were used to confirm the induced pathology. Mice that received DS injections showed significantly smaller volumes (-26% to -44%) and fewer cells (-30% to -49%) in the striosome compartment compared to mice that received control injections of saline or saporin. Striosome pathology was greatest in the dorsolateral striatum. The extrastriosomal matrix was not significantly affected, resulting in an imbalance in the ratio of striosome-to-matrix cells. Behaviorally, toxin injections caused deficits on an accelerating rotarod task and the deficit was worse in mice that received mid and anterior injections than those that received midstriatal injections alone. However, DS-injected mice did not differ from control mice on other motor tasks. We conclude that the MOR-rich cells of the striosomes are necessary for optimal rotarod performance, including learning and/or improvement on the task.

High-resolution 3D reconstruction and morphometric analysis of striosomes was carried out in macaque monkeys by using immunocytochemistry for the Kv4 potassium channel subunit potassium channel interacting protein 1 (KChIP1), a novel marker. The striosomes form a connected reticulum made up of two distinct planar sheets spanning several millimeters in the putamen, and long finger-like branches in the caudate nucleus and putamen. Although their spatial organization is variable, morphometric analysis of the striosomes, utilizing skeletonizations, reveals several quantitative invariant measures of striosome organization, including the following findings: 1) individual bifurcation-free striosome branches are 355 +/- 108.5 microm in diameter and 1,013 +/- 751 microm in length, and are both lognormally distributed; and 2) striosome branches exhibit three pronounced orientation preferences that are approximately orthogonal. The former finding suggests a fundamental anatomical and functional component of the striatum, whereas the latter indicates that striosomes are more lattice-like than their spatial variability suggests. The perceived variable spatial organization of the striosomes in primates belies many invariant features that may reflect striatal function, development, and pathophysiology.

Whether or not the striosome compartment of the neostriatum contained preproenkephalin (PPE)-expressing neurons remained unresolved. To address this question by developing a sensitive detection method, we generated transgenic mice expressing enhanced green fluorescent protein (GFP) under the specific transcriptional control of the PPE gene. Eight transgenic lines were established, and three of them showed GFP expression which was distributed in agreement with the reported localization of PPE mRNA in the central nervous system. Furthermore, in the matrix compartment of the neostriatum of the three lines, intense GFP immunoreactivity was densely distributed in the neuronal cell bodies and neuropil, and matrix neurons displayed > 94% co-localization for GFP and PPE immunoreactivities. In sharp contrast, GFP immunoreactivity was very weak in the striosome compartment, which was characterized by intense immunoreactivity for mu-opioid receptors (MOR). Although neostriatal neurons were divided into GFP-immunopositive and -negative groups in both the striosome and matrix compartments, GFP immunoreactivity of cell bodies was much weaker (~1/5) in GFP-positive striosomal neurons than in GFP-positive matrix neurons. A similar reciprocal organization of PPE and MOR expression was also suggested in the ventral striatum, because GFP immunoreactivity was weaker in intensely MOR-immunopositive regions than in the surrounding MOR-negative regions. As PPE-derived peptides are endogenous ligands for MOR in the neostriatum and few axon collaterals of matrix neurons enter the striosome compartment, the present results raised the question of the target of those peptides produced abundantly by matrix neurons.

Dopa-responsive dystonia (DRD) is a hereditary dystonia characterized by a childhood onset of fixed dystonic posture with a dramatic and sustained response to relatively low doses of levodopa. DRD is thought to result from striatal dopamine deficiency due to a reduced synthesis and activity of tyrosine hydroxylase (TH), the synthetic enzyme for dopamine. The mechanisms underlying the genesis of dystonia in DRD present a challenge to models of basal ganglia movement control, given that striatal dopamine deficiency is the hallmark of Parkinson's disease. We report here behavioral and anatomical observations on a transgenic mouse model for DRD in which the gene for 6-pyruvoyl-tetrahydropterin synthase is targeted to render selective dysfunction of TH synthesis in the striatum. Mutant mice exhibited motor deficits phenotypically resembling symptoms of human DRD and manifested a major depletion of TH labeling in the striatum, with a marked posterior-to-anterior gradient resulting in near total loss caudally. Strikingly, within the regions of remaining TH staining in the striatum, there was a greater loss of TH labeling in striosomes than in the surrounding matrix. The predominant loss of TH expression in striosomes occurred during the early postnatal period, when motor symptoms first appeared. We suggest that the differential striosome-matrix pattern of dopamine loss could be a key to identifying the mechanisms underlying the genesis of dystonia in DRD.

Diagnosis of dystonia is not difficult by recognizing the pattern of clinical presentation. Dopa-responsive dystonia (DRD) and Wilson disease are important in differential diagnosis because of their specific treatment. The most common are the focal dystonias, including blepharospasm and spasmodic torticollis. Dystonia comprises mobile involuntary movements and abnormal postures, the latter is better described as hypokinetic disorder. The pathogenesis of dystonia is now being clarified, and includes abnormal neuroplasticity caused by the relative excess of dopamine in the matrix compartment of the striatum, the possible primary lesion being the striosome. In a dopa-responsive dystonia model, dopaminergic projection is more deficient to the striosome than to the matrix, which could produce imbalance between the direct versus. indirect pathway activities. The treatment options include trihexyphenidyl, minor tranquilizers, botulinum toxin injection, and deep brain stimulation.

Observations of disease-associated changes in the basal ganglia are key to our current understanding of cortico-thalamo-basal ganglia circuits. Postmortem findings of imbalances between the direct and indirect striatal output pathways led to mechanistic hypotheses that are now being directly tested in animal models by genetic engineering to enable cell-type-specific expression of opsins, DREADDs (designer receptors exclusively activated by designer drugs), calcium indicators, and disease–gene constructs. Such methods have confirmed but also questioned aspects of the direct–indirect pathway circuit model for how we select distinct movements and inhibit competitive movements. Disease-associated imbalances are also found between the striosome and matrix compartments of the striatum, which overlap but are distinct from the direct–indirect pathways. Here, we review evidence that striosomes are enriched in limbic loops that include direct connections to dopamine-containing neurons in the substantia nigra, and how this pivotal position of striosomes could relate to striosome–matrix imbalances in human disorders affecting mood, motivation, and action–selection.

In earlier work, we proposed a theoretical model of dorsal striatal function in which the dorsolateral striatum (DLS) contributes to simple stimulus–response habit formation through reinforcement-based, incremental strengthening of simple S–R bonds via sensorimotor neocortical afferents, whereas the dorsomedial striatum (DMS) contributes to flexible behavior through the cognitive control of responding via inputs from prefrontal and limbic circuits engaged in relational and spatial information processing (Devan et al. 2011). In this chapter, we expand on the original evidence supporting the main hypotheses by further reviewing the neuroanatomical evidence, with particular attention focused on the tripartite model of parallel motor, associate, and limbic loops of the basal ganglia and the open-interconnected circuits allowing for interactions between striatal subregions. In particular, we discuss the idea that blockade of the striosome/patch compartment of the striatum may weaken the integration of higher-order habits based on associative and limbic cortical interactions with the motor-related matrix region. Many recent discoveries support interactive functions of striatal subregions at multiple levels of organization. These interactions modulate different associative learning and performance mechanisms of simple habits and higher-order [(S-S) → R] cognitive–habit integration and behavioral flexibility of associative/limbic interactions with response output and cognitive control function. Neurobehavioral findings show that the striosome/patch compartment within the DMS may normally contribute to the expression of higher-order habit formation that allows cognitive place information acquired through hippocampal/limbic-striatal interaction to access matrix-related reinforcement/response processing under circumstances that promote a cooperative interaction between memory systems. In the second part of the chapter, we review electrophysiological techniques in freely behaving animals. Finally, we present a discussion of Bayesian approaches to the understanding of goal-directed behavior. The role of the dorsal striatum in instrumental learning is particularly amenable to computational models because there are two disparate learning strategies that are posited to be subserved by different neural circuits. Model-free or habit learning has been thought to be primarily mediated by the DLS, whereas model-based or goal directed learning has been thought to rely on the DMS. We review seminal model-free and model-based computations with the goal of integrating them with rodent and human data. We also discuss data suggesting how habit- and goal-directed controllers might interact and finish by highlighting instances that challenge the classic dogma for perceived DLS and DMS function.

A fundamental organizing principle of the striatum is the striosome/matrix system that is defined by inputs/outputs and neurochemical markers. The thalamostriatal projection is highly heterogeneous originating in many subnuclei of the thalamus including the midline (ML) and intralaminar (IL) nuclei. We examined the dendritic morphology and axonal trajectory of 15 ML and 11 IL neurons by single-neuron labeling with viral vectors in combination with mu-opioid receptor immunostaining in rat brains. Dendritic and axonal morphology defined ML neurons as type II cells consisting of at least two subclasses according to the presence or absence of striatal axon collaterals. In the striatum, ML neurons preferentially innervated striosomes, whereas parafascicular neurons preferentially innervated the matrix. Almost all single thalamostriatal neurons favoring striosome or matrix compartments also innervated the cerebral cortical areas that supplied cortical input to the same striatal compartment. We thus revealed that thalamostriatal projections are highly organized 1) by the similarity in morphological characteristics and 2) their preference for the striatal compartments and cortical areas. These findings demonstrate that the functional properties of striatal compartments are influenced by both their cortical and thalamic afferents presumably with a different time latency and support selective dynamics for the striosome and matrix compartments.