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Deciphering the striatal interneuron diversity is key to understanding the basal ganglia circuit and to untangling the complex neurological and psychiatric diseases affecting this brain structure. We performed snRNA-seq and spatial transcriptomics of postmortem human caudate nucleus and putamen samples to elucidate the diversity and abundance of interneuron populations and their inherent transcriptional structure in the human dorsal striatum. We propose a comprehensive taxonomy of striatal interneurons with eight main classes and fourteen subclasses, providing their full transcriptomic identity and spatial expression profile as well as additional quantitative FISH validation for specific populations. We have also delineated the correspondence of our taxonomy with previous standardized classifications and shown the main transcriptomic and class abundance differences between caudate nucleus and putamen. Notably, based on key functional genes such as ion channels and synaptic receptors, we found matching known mouse interneuron populations for the most abundant populations, the recently described PTHLH and TAC3 interneurons. Finally, we were able to integrate other published datasets with ours, supporting the generalizability of this harmonized taxonomy., (© 2024. The Author(s).)

Corticosterone (CORT), the principal glucocorticoid in rodents, is released after stressful experiences such as training with high foot-shock intensities in the inhibitory avoidance task (IA). CORT reaches the glucocorticoid receptor (GR) located in almost all brain cells; the GR is subsequently phosphorylated at serine 232 (pGRser232). This has been reported as an indicator of ligand-dependent activation of the GR, as well as a requirement for its translocation into the nucleus for its transcription factor activity. The GR is present in the hippocampus with a high concentration in CA1 and dentate gyrus (DG), and a smaller proportion in CA3, and sparsely present in the caudate putamen (CPu); both structures are involved in memory consolidation of IA. To study the participation of CORT in IA, we quantified the ratio of pGR-positive neurons in both dorsal hippocampus (CA1, CA3 and DG) and dorsal and ventral regions of CPu of rats trained in IA, using different foot-shock intensities. Brains were dissected 60 min after training for immunodetection of pGRser232 positive cells. The results show that the groups trained with 1.0 and 2.0 mA had higher retention latencies than the 0.0 mA or 0.5 mA groups. An increase in the ratio of pGR-positive neurons was found in CA1 and ventral region of CPu only for the 2.0 mA trained group. These findings suggest that activation of GRs in CA1 and ventral CPu is involved in the consolidation of a stronger memory of IA, possibly through the modulation of gene expression., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

Previous studies suggest that signaling by the gamma-aminobutyric acid (GABA) type B receptor (GABA B R) is involved in the regulation of binge eating, a disorder which might contribute to the development of obesity. Here, we show that intermittent access to a high fat diet (HFD) induced binge-like eating behavior with activation of dopamine receptor d1 (drd1)-expressing neurons in the caudate putamen (CPu) and nucleus accumbens (NAc) in wild-type (WT) mice. The activation of drd1-expressing neurons during binge-like eating was substantially increased in the CPu, but not in the NAc, in corticostriatal neuron-specific GABA B R-deficient knockout (KO) mice compared to WT mice. Treatment with the GABA B R agonist, baclofen, suppressed binge-like eating behavior in WT mice, but not in KO mice, as reported previously. Baclofen also suppressed the activation of drd1-expressing neurons in the CPu, but not in the NAc, during binge-like eating in WT mice. Thus, our data suggest that GABA B R signaling in CPu neurons expressing drd1 suppresses binge-like consumption during a HFD in mice., (© 2021. The Author(s).)

Multiple system atrophy (MSA) is a progressive neurodegenerative disorder characterized by the accumulation of pathogenic phosphorylated α-synuclein in oligodendrocytes. In brains affected by MSA, severe astrogliosis is also observed, but its precise role in MSA pathogenesis remains largely unknown. Recently, the stimulator of interferon genes (STING) pathway and type I interferons, its downstream molecules, have been reported to be involved in the neurodegenerative process and to be activated in astrocytes. This study aimed to investigate the role of the STING pathway in the pathogenesis of MSA using postmortem brains. Samples used for immunohistochemical analysis included 6 cases of MSA parkinsonism type (MSA-P), 6 cases of MSA cerebellar type (MSA-C), and 7 age-matched controls. In MSA-P cases, astrocytes immunopositive for STING and TANK-binding kinase 1 (TBK1), its downstream molecule, were abundantly observed in the putamen and the substantia nigra. Moreover, these molecules colocalized with glial fibrillary acidic protein (GFAP) in reactive astrocytes, and the density of STING-positive astrocytes correlated with that of GFAP-positive reactive astrocytes in the brains of patients with MSA-P. These results suggest that the upregulated expression of STING pathway-related proteins in astrocytes and the subsequent inflammation may contribute to the pathogenesis in MSA-P and could provide novel therapeutic targets for the treatment of MSA., (Copyright © 2021. Published by Elsevier B.V.)

Human reproduction is controlled by ~2000 hypothalamic gonadotropin-releasing hormone (GnRH) neurons. Here, we report the discovery and characterization of additional ~150,000-200,000 GnRH-synthesizing cells in the human basal ganglia and basal forebrain. Nearly all extrahypothalamic GnRH neurons expressed the cholinergic marker enzyme choline acetyltransferase. Similarly, hypothalamic GnRH neurons were also cholinergic both in embryonic and adult human brains. Whole-transcriptome analysis of cholinergic interneurons and medium spiny projection neurons laser-microdissected from the human putamen showed selective expression of GNRH1 and GNRHR1 autoreceptors in the cholinergic cell population and uncovered the detailed transcriptome profile and molecular connectome of these two cell types. Higher-order non-reproductive functions regulated by GnRH under physiological conditions in the human basal ganglia and basal forebrain require clarification. The role and changes of GnRH/GnRHR1 signaling in neurodegenerative disorders affecting cholinergic neurocircuitries, including Parkinson's and Alzheimer's diseases, need to be explored., Competing Interests: KS, MS, IF, BG, ST, ÉR, VV, CV, GR, AM, NS, SP, BT, FE, GS, MC, CA, LC, VP, PG, EH No competing interests declared, (© 2021, Skrapits et al.)

In the macaque brain, projections from distant, interconnected cortical areas converge in specific zones of the striatum. For example, specific zones of the motor putamen are targets of projections from frontal motor, inferior parietal, and ventrolateral prefrontal hand-related areas and thus are integral part of the so-called "lateral grasping network." In the present study, we analyzed the laminar distribution of corticostriatal neurons projecting to different parts of the motor putamen. Retrograde neural tracers were injected in different parts of the putamen in 3 Macaca mulatta (one male) and the laminar distribution of the labeled corticostriatal neurons was analyzed quantitatively. In frontal motor areas and frontal operculum, where most labeled cells were located, almost everywhere the proportion of corticostriatal labeled neurons in layers III and/or VI was comparable or even stronger than in layer V. Furthermore, within these regions, the laminar distribution pattern of corticostriatal labeled neurons largely varied independently from their density and from the projecting area/sector, but likely according to the target striatal zone. Accordingly, the present data show that cortical areas may project in different ways to different striatal zones, which can be targets of specific combinations of signals originating from the various cortical layers of the areas of a given network. These observations extend current models of corticostriatal interactions, suggesting more complex modes of information processing in the basal ganglia for different motor and nonmotor functions and opening new questions on the architecture of the corticostriatal circuitry. SIGNIFICANCE STATEMENT Projections from the ipsilateral cerebral cortex are the major source of input to the striatum. Previous studies have provided evidence for distinct zones of the putamen specified by converging projections from specific sets of interconnected cortical areas. The present study shows that the distribution of corticostriatal neurons in the various layers of the primary motor and premotor areas varies depending on the target striatal zone. Accordingly, different striatal zones collect specific combinations of signals from the various cortical layers of their input areas, possibly differing in terms of coding, timing, and direction of information flow (e.g., feed-forward, or feed-back)., (Copyright © 2021 the authors.)

Objective: Different anesthetics have distinct effects on the interstitial fluid (ISF) drainage in the extracellular space (ECS) of the superficial rat brain, while their effects on ISF drainage in the ECS of the deep rat brain still remain unknown. Herein, we attempt to investigate and compare the effects of propofol and isoflurane on ECS structure and ISF drainage in the caudate-putamen (CPu) and thalamus (Tha) of the deep rat brain. Methods: Adult Sprague-Dawley rats were anesthetized with propofol or isoflurane, respectively. Twenty-four anesthetized rats were randomly divided into the propofol-CPu, isoflurane-CPu, propofol-Tha, and isoflurane-Tha groups. Tracer-based magnetic resonance imaging (MRI) and fluorescent-labeled tracer assay were utilized to quantify ISF drainage in the deep brain. Results: The half-life of ISF in the propofol-CPu and propofol-Tha groups was shorter than that in the isoflurane-CPu and isoflurane-Tha groups, respectively. The ECS volume fraction in the propofol-CPu and propofol-Tha groups was much higher than that in the isoflurane-CPu and isoflurane-Tha groups, respectively. However, the ECS tortuosity in the propofol-CPu and propofol-Tha groups was much smaller than that in isoflurane-CPu and isoflurane-Tha groups, respectively. Conclusions: Our results demonstrate that propofol rather than isoflurane accelerates the ISF drainage in the deep rat brain, which provides novel insights into the selective control of ISF drainage and guides selection of anesthetic agents in different clinical settings, and unravels the mechanism of how general anesthetics function., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

There is increasing evidence to support the notion that oligodendrocyte and myelin abnormalities may contribute to the functional dysconnectivity found in the major psychiatric disorders. The putamen, which is an important hub in the cortico-striato-thalamo-cortical loop, has been implicated in a broad spectrum of psychiatric illnesses and is a central target of their treatments. Previously we reported a reduction in the numerical density of oligodendrocytes and oligodendrocyte clusters in the prefrontal and parietal cortex in schizophrenia. Oligodendrocyte clusters contain oligodendrocyte progenitors and are involved in functionally dependent myelination. We measured the numerical density (Nv) of oligodendrocytes and oligodendrocyte clusters in the putamen in schizophrenia, bipolar disorder (BPD) and major depressive disorder (MDD) as compared to healthy controls (15 cases per group). Optical disector was used to estimate the Nv of oligodendrocytes and oligodendrocyte clusters. A significant reduction in both the Nv of oligodendrocytes (- 34%; p < 0.01) and the Nv of oligodendrocyte clusters (- 41%; p < 0.05) was found in the schizophrenia group as compared to the control group. Sexual dimorphism for both measurements was found only within the control group. The Nv of oligodendrocytes was significantly lower in male schizophrenia cases as compared to the male control cases. However, the Nv of oligodendrocyte clusters was significantly lower in all male clinical cases as compared to the male control group. The data suggest that lowered density of oligodendrocytes and oligodendrocyte clusters may contribute to the altered functional connectivity in the putamen in subjects with schizophrenia.

Measurement of long-term functional and anatomical outcomes in the same animal is considered a powerful strategy for correlating structure with function. In a neonatal animal model of hypoxic-ischemic brain injury that is relevant to cerebral palsy, long-term functional deficits on the staircase test and long-term anatomical deficits in the absolute number of medium-spiny projection neurons in the caudate-putamen were reported in different animals due to logistical constraints. Here, we investigated if these functional and anatomical measures were correlated when measured in the same animals. The medium-spiny projection neurons were investigated because (1) they comprise the vast majority (>97%) of all neurons in the caudate-putamen and (2) motor deficits observed during staircase testing are likely to involve these striatal medium-spiny projection neurons through their connections. We found that long-term skilled forepaw capability on the staircase test was correlated with the absolute number of DARPP-32-positive medium-spiny projection neurons in the caudate-putamen. Specifically, deficits in skilled forepaw ability for the number of sugar pellets eaten and retrieved, and for the maximum staircase level reached, were significantly correlated with a lower absolute neuronal number. We also found that skilled forepaw ability on the staircase test was not correlated with the neuronal density (i.e., number per unit volume) of DARPP-32-positive medium-spiny projection neurons. Since neuronal density is an indirect measure of neuronal survival that is used in the literature, and absolute neuronal number is a direct measure, the results also highlight the scientific value of measuring absolute neuronal number. Anat Rec, 302:2040-2048, 2019. © 2019 American Association for Anatomy., (© 2019 American Association for Anatomy.)

The basal ganglia, especially the circuits originating from the putamen, are essential for controlling normal body movements. Notably, the putamen receives inputs not only from motor cortical areas but also from multiple sensory cortices. However, how these sensory signals are processed in the putamen remains unclear. We recorded the activity of tentative medium spiny neurons in the caudal part of the putamen when the monkey viewed many fractal objects. We found many neurons that responded to these objects, mostly in the ventral region. We called this region "putamen tail" (PUTt), as it is dorsally adjacent to "caudate tail" (CDt). Although PUTt and CDt are mostly separated by a thin layer of white matter, their neurons shared several features. Almost all of them had receptive fields in the contralateral hemifield. Moreover, their responses were object selective (i.e., variable across objects). The object selectivity was higher in the ventral region (i.e., CDt > PUTt). Some neurons above PUTt, which we called the caudal-dorsal putamen (cdPUT), also responded to objects, but less selectively than PUTt. Next, we examined whether these visual neurons changed their responses based on the reward outcome. We found that many neurons encoded the values of many objects based on long-term memory, but not based on short-term memory. Such stable value responses were stronger in PUTt and CDt than in cdPUT. These results suggest that PUTt, together with CDt, controls saccade/attention among objects with different historical values, and may control other motor actions as well. SIGNIFICANCE STATEMENT Although the putamen receives inputs not only from motor cortical areas but also from sensory cortical areas, how these sensory signals are processed remains unclear. Here we found that neurons in the caudal-ventral part of the putamen (putamen tail) process visual information including spatial and object features. These neurons discriminate many objects, first by their visual features and later by their reward values as well. Importantly, the value discrimination was based on long-term memory, but not on short-term memory. These results suggest that the putamen tail controls saccade/attention among objects with different historical values and might control other motor actions as well., (Copyright © 2019 the authors 0270-6474/19/391709-11$15.00/0.)

Dopamine (DA) transmission in the medial preoptic area (mPOA) plays a critical role in the control of appetitive sexual behaviour in the female rat. We have shown previously that a DA D1 receptor (D1R)-mediated excitatory state appears to occur in females primed with estradiol benzoate (EB) and progesterone (P), whereas a DA D2 receptor (D2R)-mediated inhibitory state appears to occur in females primed only with EB. The present experiment employed three techniques to better understand what changes occur to DA receptors (DARs) in the mPOA under different hormonal profiles. Ovariectomized females were randomly assigned to one of three steroid treatment groups: EB + P (10 and 500 μg, respectively), EB + Oil, or the control (Oil + Oil), with hormone injections administered at 48 and 4 h prior to euthanizing. First, the number of neurons in the mPOA that contained D1R or D2R was assessed using immunohistochemistry. Second, the mPOA and two control areas (the prelimbic cortex and caudate putamen) were analysed for DAR protein levels using western blot, and DAR functional binding levels using autoradiography. Ovarian steroid hormones affected the two DAR subtypes in opposite ways in the mPOA. All three techniques supported previous behavioural findings that females primed with EB have a lower D1R : D2R ratio, and thus a D2R-mediated system, and females primed with EB + P have a higher D1R : D2R ratio, and thus a D1R-mediated system. This provides strong evidence for a DA-driven pathway of female sexual motivation, desire, and behaviour that is modified by different hormone priming regimens., (© 2015 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

The medial parabrachial nucleus (MPB) and external part of the medial parabrachial nucleus (MPBE) relay gustatory, oral mechanosensory and other visceral information in the rat brain and reportedly project not only to the parvicellular part of the posteromedial ventral thalamic nucleus (VPMpc) but also to the ventrocaudal part of the intralaminar thalamic nuclei. Generally, the intralaminar thalamic nuclei project topographically to the caudate putamen (CPu); however, it is unclear where the ventrocaudal part of the intralaminar thalamic nuclei projects within the CPu. Thus, we visualized neural pathways from the MPB and MPBE to the CPu via the ventrocaudal part of the intralaminar thalamic nuclei using an anterograde tracer, biotinylated dextran amine, and a retrograde tracer, cholera toxin B subunit. We found that the MPB and MPBE sent a relatively stronger input to the ventrocaudal part of the intralaminar thalamic nuclei such as the oval paracentral thalamic nucleus (OPC), central medial thalamic nucleus (CM) and parafascicular thalamic nucleus (PF) and retroreuniens area (RRe) as compared to the VPMpc. In turn, these thalamic nuclei projected to the ventral part of the CPu with the topographical arrangement as follows: the OPC to the ventrocentral part of the CPu; ventrolateral part of the PF to the ventrolateral part of the CPu; and the caudal part of the CM, ventromedial part of the PF and RRe to the ventromedial part of the CPu. Further, we found that the VPMpc rather projected to the interstitial nucleus of the posterior limb of the anterior commissure than the CPu. The ventral part of the CPu is reported to be involved in jaw movement as well as food and water intake functions. Therefore, these parabrachio-thalamo-striatal pathways that we demonstrated here suggest that gustatory and oral mechanosensory information affects feeding behavior within the ventral part of the CPu., (Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.)

Gamma (γ) and beta (β) oscillations seem to play complementary functions in the cortico-basal ganglia-thalamo-cortical circuit (CBGT) during motor behavior. We investigated the time-varying changes of the putaminal spiking activity and the spectral power of local field potentials (LFPs) during a task where the rhythmic tapping of monkeys was guided by isochronous stimuli separated by a fixed duration (synchronization phase), followed by a period of internally timed movements (continuation phase). We found that the power of both bands and the discharge rate of cells showed an orderly change in magnitude as a function of the duration and/or the serial order of the intervals executed rhythmically. More LFPs were tuned to duration and/or serial order in the β- than the γ-band, although different values of preferred features were represented by single cells and by both bands. Importantly, in the LFPs tuned to serial order, there was a strong bias toward the continuation phase for the β-band when aligned to movements, and a bias toward the synchronization phase for the γ-band when aligned to the stimuli. Our results suggest that γ-oscillations reflect local computations associated with stimulus processing, whereas β-activity involves the entrainment of large putaminal circuits, probably in conjunction with other elements of CBGT, during internally driven rhythmic tapping.

Day-to-day variability in performance is a common experience. We investigated its neural correlate by studying learning behavior of monkeys in a two-alternative forced choice task, the two-armed bandit task. We found substantial session-to-session variability in the monkeys' learning behavior. Recording the activity of single dorsal putamen neurons we uncovered a dual function of this structure. It has been previously shown that a population of neurons in the DLP exhibits firing activity sensitive to the reward value of chosen actions. Here, we identify putative medium spiny neurons in the dorsal putamen that are cue-selective and whose activity builds up with learning. Remarkably we show that session-to-session changes in the size of this population and in the intensity with which this population encodes cue-selectivity is correlated with session-to-session changes in the ability to learn the task. Moreover, at the population level, dorsal putamen activity in the very beginning of the session is correlated with the performance at the end of the session, thus predicting whether the monkey will have a "good" or "bad" learning day. These results provide important insights on the neural basis of inter-temporal performance variability.

Striatal cholinergic interneurons (ChIs) are involved in reward-dependent learning and the regulation of attention. The activity of these neurons is modulated by intrinsic and extrinsic γ-aminobutyric acid (GABA)ergic and glutamatergic afferents, but the source and relative prevalence of these diverse regulatory inputs remain to be characterized. To address this issue, we performed a quantitative ultrastructural analysis of the GABAergic and glutamatergic innervation of ChIs in the postcommissural putamen of rhesus monkeys. Postembedding immunogold localization of GABA combined with peroxidase immunostaining for choline acetyltransferase showed that 60% of all synaptic inputs to ChIs originate from GABAergic terminals, whereas 21% are from putatively glutamatergic terminals that establish asymmetric synapses, and 19% from other (non-GABAergic) sources of symmetric synapses. Double pre-embedding immunoelectron microscopy using substance P and Met-/Leu-enkephalin antibodies to label GABAergic terminals from collaterals of "direct" and "indirect" striatal projection neurons, respectively, revealed that 47% of the indirect pathway terminals and 36% of the direct pathway terminals target ChIs. Together, substance P- and enkephalin-positive terminals represent 24% of all synapses onto ChIs in the monkey putamen. These findings show that ChIs receive prominent GABAergic inputs from multiple origins, including a significant contingent from axon collaterals of direct and indirect pathway projection neurons., (Copyright © 2013 Wiley Periodicals, Inc.)

The objective of this study was to compare the functional connectivity of the lateral and medial thalamocortical pain pathways by investigating the blood oxygen level-dependent (BOLD) activation patterns in the forebrain elicited by direct electrical stimulation of the ventroposterior (VP) and medial (MT) thalamus. An MRI-compatible stimulation electrode was implanted in the VP or MT of α-chloralose-anesthetized rats. Electrical stimulation was applied to the VP or MT at various intensities (50 µA to 300 µA) and frequencies (1 Hz to 12 Hz). BOLD responses were analyzed in the ipsilateral forelimb region of the primary somatosensory cortex (iS1FL) after VP stimulation and in the ipsilateral cingulate cortex (iCC) after MT stimulation. When stimulating the VP, the strongest activation occurred at 3 Hz. The stimulation intensity threshold was 50 µA and the response rapidly peaked at 100 µA. When stimulating the MT, The optimal frequency for stimulation was 9 Hz or 12 Hz, the stimulation intensity threshold was 100 µA and we observed a graded increase in the BOLD response following the application of higher intensity stimuli. We also evaluated c-Fos expression following the application of a 200-µA stimulus. Ventroposterior thalamic stimulation elicited c-Fos-positivity in few cells in the iS1FL and caudate putamen (iCPu). Medial thalamic stimulation, however, produced numerous c-Fos-positive cells in the iCC and iCPu. The differential BOLD responses and c-Fos expressions elicited by VP and MT stimulation indicate differences in stimulus-response properties of the medial and lateral thalamic pain pathways.

In response to hypoxia, tissues have to implement numerous mechanisms to enhance oxygen delivery, including the activation of angiogenesis. This work investigates the angiogenic response of the hypoxic caudate putamen after several recovery times. Adult Wistar rats were submitted to acute hypoxia and analysed after 0 h, 24 h and 5 days of reoxygenation. Expression of hypoxia-inducible factor-1 alfa (HIF-1 alpha) and angiogenesis-related genes including vascular endothelial growth factor (VEGF), adrenomedullin (ADM) and transforming growth factor-beta 1 (TGF- beta 1) was determined by both RT-PCR and ELISA. For vessel labelling, lectin location and expression were analysed using histochemical and image processing techniques (fractal dimension). Expression of Hif-1 alpha, Vegf, Adm and Tgf- beta 1 mRNA rose immediately after hypoxia and this increase persisted in some cases after 5 days post-hypoxia. While VEGF and TGF-beta 1 protein levels increased parallel to mRNA expression, ADM remained unaltered. The quantification of the striatal vessel network showed a significant augmentation at 24 h of reoxygenation. These results reveal that not only short-term hypoxia, but also the subsequent reoxygenation period, up-regulate the angiogenic pathway in the rat caudate putamen as a neuroprotective mechanism to hypoxia that seeks to maintain a proper blood supply to the hypoxic tissue, thereby minimizing the adverse effects of oxygen deprivation.

Information is encoded in the nervous system through the discharge and synchronization of single neurons. The striatum, the input stage of the basal ganglia, is divided into three territories: the putamen, the caudate, and the ventral striatum, all of which converge onto the same motor pathway. This parallel organization suggests that there are multiple and competing systems in the basal ganglia network controlling behavior. To explore which mechanism(s) enables the different striatal domains to encode behavioral events and to control behavior, we compared the neural activity of phasically active neurons [medium spiny neurons (MSNs), presumed projection neurons] and tonically active neurons (presumed cholinergic interneurons) across striatal territories from monkeys during the performance of a well practiced task. Although neurons in all striatal territories displayed similar spontaneous discharge properties and similar temporal modulations of their discharge rates to the behavioral events, their correlation structure was profoundly different. The distributions of signal and noise correlation of pairs of putamen MSNs were strongly shifted toward positive correlations and these two measures were correlated. In contrast, MSN pairs in the caudate and ventral striatum displayed symmetrical, near-zero signal and noise correlation distributions. Furthermore, only putamen MSN pairs displayed different noise correlation dynamics to rewarding versus neutral/aversive cues. Similarly, the noise correlation between tonically active neuron pairs was stronger in the putamen than in the caudate. We suggest that the level of synchronization of the neuronal activity and its temporal dynamics differentiate the striatal territories and may thus account for the different roles that striatal domains play in behavioral control.

Astrocytosis, a process in which astrocytes undergo proliferation and enhancement of glial fibrillary acidic protein (GFAP) expression, has been suggested to play important roles in the maintenance of dependence to amphetamine and its derivatives. It was previously shown that mice with genetic deletion of pleiotrophin (PTN), a neurotrophic factor upregulated in different brain areas after administration of amphetamine, show a longer lasting amphetamine-induced conditioned place preference (CPP) when compared to wild type mice. In this work, we aimed to pursue the possibility of a different astrocytic response induced by amphetamine in PTN-/- and PTN+/+ mice, which could underlie the higher vulnerability of PTN-/- mice to maintain amphetamine CPP. In confirmation of previous studies, we found that PTN-/- mice significantly maintained amphetamine (3mg/kg)-induced CPP 5 days after the last drug administration compared to PTN+/+ mice. Interestingly, the number of astrocytes in nucleus accumbens (NAcc), cingulate cortex (CG) and caudate putamen (CPu) did not differ between mice that maintained and did not maintain amphetamine-induced CPP independently of the genotype considered. However, we found that PTN-/- mice showed significantly decreased numbers of astrocytes in CG and CPu compared to PTN+/+ mice independently of whether they maintained amphetamine-induced CPP 5 days after the last drug administration or not. The data demonstrate that maintenance of amphetamine-induced CPP depends on the endogenous expression of PTN. The data tend to discard a correlation between activated astrocytes and maintenance of amphetamine conditioning effects and suggest PTN as a potential modulator of activation of astrocytes after amphetamine treatment., (Copyright © 2012 Elsevier B.V. All rights reserved.)

A qualitative analysis of the morphology of human putamen nerve cells involves a detailed description of the structure and features of neurons and, accordingly, their classification into already defined classes and types. In our sample of 301 neurons, 64.78 % (195) were spiny and 35.22 % (106) aspiny cells. By analyzing cell bodies and dendritic trees, we subdivided spiny cells into two types (I and II) and aspiny cells into three types (III, IV and V). Our sample of neurons, classified according to the previously described scheme, consisted of 80 type I, 115 type II, 16 type III, 42 type IV and 48 type V nerve cells. In the present study, after qualitative analysis of microscopic images of the Golgi impregnated neurons of the putamen, we measured/quantified five morphological properties, i.e., the sizes of the soma and dendritic field, shape of the neuron, straightness of individual dendrites and the branching complexity of the dendritic tree, using eight morphometric parameters. Hence, we identify five types of nerve cells in the human putamen: type I-small spiny neurons; type II-large spiny neurons; type III-large aspiny neurons; type IV-neurons with a large soma and a medium dendritic field; and type V-small aspiny neurons. By performing an adequate statistical analysis on these parameters, we point out that the proposed types differ enough in their morphology to warrant our qualitative classification.

The putamen has classically been considered to be primarily a motor structure. It is involved in a broad range of roles and its neurons have been postulated to function as pattern classifiers of behaviourally significant events. However, its specific role in motor and sensory processing is still unclear. For the purpose of better categorizing putamen neurons, we trained two rhesus monkeys to perform multisensory operant tasks by using complex stimuli such as short videoclips. Trials involved image or soundtrack or both. Some stimuli required a motor response associated to reward, whereas others did not require response and produced no reward. We found that neurons in the putamen showed pure visual responses, action-related activity, and reward responses. Insofar as action-related activity, preparation of movement, movement execution, and withholding of movement involved three different putamen neuron populations. Moreover, our data suggest an involvement of putamen neurons in processing primary rewards and visual events in a complex task, which may contribute to reinforcement learning through stimulus-reward association., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Many measurements in biology follow distributions that can be approximated well by the normal distribution. The normal distribution plays an extremely important role in probability theory. However, some of the experimental data in biology are distributed asymmetrically. In order to transform such an asymmetrical distribution into a normal distribution, for which the standard statistical tables can be used for probability analysis of the available data, one must choose suitable transformation functions. We have met this problem when we qualitatively classified the spiny neurons in the adult human putamen. But, if one tries to test a qualitative classification of neurons quantitatively, a considerable class overlap between cells occurs as well as asymmetry often appears in the distributions of the data. We have already offered a method to overcome the overlapping problem when the data distributions are normal. In order to resolve the asymmetry problem in data distribution, we transformed our asymmetrically distributed data into an approximately normal distribution using a family of simple power functions and on a basis of appropriate probability analysis we propose a more acceptable classification scheme for the spiny neurons. The significance of our results in terms of current classifications of neurons in the adult human putamen is discussed., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

We have previously shown that persistent α-synuclein overexpression in ventral midbrain of marmoset leads to a distinctive neurodegenerative process and motor defects. The neurodegeneration was confined to caudate putamen dopaminergic fibers in animals overexpressing wild-type (wt) α-synuclein. However, A53T α-synuclein overexpression induced neurodegeneration that resulted in nigral dopaminergic cell death. Here, we analyze the microglia population in the midbrain of these animals by stereological quantification of Iba1+ cells. Our data here show that monkeys overexpressing A53T α-synuclein showed a long-term increase in microglia presenting macrophagic morphology. However, wt α-synuclein overexpression, despite the absence of dopaminergic cell death, resulted in a permanent robust increase of the microglia population characterized by a range of distinct morphological types that persisted after 1 year. These results confirm that the microglial response differs depending on the type of α-synuclein (wt/A53T) and/or whether α-synuclein expression results in cell death or not, suggesting that microglia may play different roles during disease progression. Furthermore, the microglial response is modulated by events related to α-synuclein expression in substantia nigra and persists in the long term. The data presented here is in agreement with that previously observed in a recombinant adeno-associated virus (rAAV) α-synuclein rat model, thereby validating both the findings and the model, and highlighting the translational potential of the rodent model to higher species closer to humans., (Copyright © 2012 IBRO. Published by Elsevier Ltd. All rights reserved.)

An optical coherence tomography (OCT) system employing a microelectromechanical system (MEMS) mirror was used to measure the refractive index (RI) of anatomically different regions in acute brain tissue slices, in which viability was maintained. RI was measured in white-matter and grey-matter regions, including the cerebral cortex, putamen, hippocampus, thalamus and corpus callosum. The RI in the corpus callosum was found to be ~4% higher than the RIs in other regions. Changes in RI with tissue deformation were also measured in the cerebral cortex and corpus callosum under uniform compression (20-80% strain). For 80% strain, measured RIs increased nonlinearly by up to 70% and 90% in the cerebral cortex and corpus callosum respectively. Knowledge of RI in heterogeneous tissues can be used to correct distorted optical images caused by RI variations between different regions. Also deformation-dependent changes in RI can be applied to OCT elastography or to mechanical tests based on optical imaging such as indentation tests.

Background: The afferent projections of the striatum (caudate nucleus and putamen) are segregated in three territories: associative, sensorimotor and limbic. Striatal interneurons are in part responsible for the integration of these different types of information. Among them, GABAergic interneurons are the most abundant, and can be sorted in three populations according to their content in the calcium binding proteins calretinin (CR), parvalbumin (PV) and calbindin (CB). Conversely, striatal dopaminergic cells (whose role as interneurons is still unclear) are scarce. This study aims to analyze the interneuron distribution in the striatal functional territories, as well as their organization regarding to the striosomal compartment., Methodology/principal Findings: We used immunohistochemical methods to visualize CR, PV, CB and tyrosine hydroxylase (TH) positive striatal neurons. The interneuronal distribution was assessed by stereological methods applied to every striatal functional territory. Considering the four cell groups altogether, their density was higher in the associative (2120±91 cells/mm(3)) than in the sensorimotor (959±47 cells/mm(3)) or limbic (633±119 cells/mm(3)) territories. CB- and TH-immunoreactive(-ir) cells were distributed rather homogeneously in the three striatal territories. However, the density of CR and PV interneurons were more abundant in the associative and sensorimotor striatum, respectively. Regarding to their compartmental organization, CR-ir interneurons were frequently found in the border between compartments in the associative and sensorimotor territories, and CB-ir interneurons abounded at the striosome/matrix border in the sensorimotor domain., Conclusions/significance: The present study demonstrates that the architecture of the human striatum in terms of its interneuron composition varies in its three functional territories. Furthermore, our data highlight the importance of CR-ir striatal interneurons in the integration of associative information, and the selective role of PV-ir interneurons in the motor territory. On the other hand, the low density of dopaminergic cells casts doubts about their role in the normal human striatum.

Matrix metalloproteinases (MMPs) are implicated in diverse processes, such as neuroinflammation, leakiness of the blood-brain barrier (BBB) and direct cellular damage in neurodegenerative and other CNS diseases. Tissue destruction by MMPs is regulated by their endogenous tissue inhibitors (TIMPs). TIMPs prevent excessive MMP-related degradation of extracellular matrix components. In a rat model of human immunodeficiency virus (HIV)-related encephalopathy, we described MMP-2 and MMP-9 upregulation by HIV-1 envelope gp120, probably via gp120-induced reactive oxygen species. Antioxidant gene delivery blunted gp120-induced MMP production. We also studied the effect of gp120 on TIMP-1 and TIMP-2 production. TIMP-1 and TIMP-2 levels increased 6 h after gp120 injection into rat caudate-putamen (CP). TIMP-1 and TIMP-2 colocalized mainly with neurons (92 and 95%, respectively). By 24 h, expression of these protease inhibitors diverged, as TIMP-1 levels remained high but TIMP-2 subsided. Gene delivery of the antioxidant enzymes Cu/Zn superoxide dismutase or glutathione peroxidase into the CP before injecting gp120 there reduced levels of gp120-induced TIMP-1 and TIMP-2, recapitulating the effect of antioxidant enzymes on gp120-induced MMP-2 and MMP-9. A significant correlation was observed between MMP/TIMP upregulation and BBB leakiness. Thus, HIV-1 gp120 upregulated TIMP-1 and TIMP-2 in the CP. Prior antioxidant enzyme treatment mitigated production of these TIMPs, probably by reducing MMP expression., (© 2011 The Authors. European Journal of Neuroscience © 2011 Federation of European Neuroscience Societies and Blackwell Publishing Ltd.)

We studied whether combinations of botanical extracts enriched in either Δ(9)-tetrahydrocannabinol (Δ(9)-THC) or cannabidiol (CBD), which are the main constituents of the cannabis-based medicine Sativex, provide neuroprotection in rat models of Huntington's disease (HD). We used rats intoxicated with 3-nitropropionate (3NP) that were given combinations of Δ(9)-THC- and CBD-enriched botanical extracts. The issue was also studied in malonate-lesioned rats. The administration of Δ(9)-THC- and CBD-enriched botanical extracts combined in a ratio of 1:1 as in Sativex attenuated 3NP-induced GABA deficiency, loss of Nissl-stained neurons, down-regulation of CB(1) receptor and IGF-1 expression, and up-regulation of calpain expression, whereas it completely reversed the reduction in superoxide dismutase-1 expression. Similar responses were generally found with other combinations of Δ(9)-THC- and CBD-enriched botanical extracts, suggesting that these effects are probably related to the antioxidant and CB(1) and CB(2) receptor-independent properties of both phytocannabinoids. In fact, selective antagonists for both receptor types, i.e., SR141716 and AM630, respectively, were unable to prevent the positive effects on calpain expression caused in 3NP-intoxicated rats by the 1:1 combination of Δ(9)-THC and CBD. Finally, this combination also reversed the up-regulation of proinflammatory markers such as inducible nitric oxide synthase observed in malonate-lesioned rats. In conclusion, this study provides preclinical evidence in support of a beneficial effect of the cannabis-based medicine Sativex as a neuroprotective agent capable of delaying disease progression in HD, a disorder that is currently poorly managed in the clinic, prompting an urgent need for clinical trials with agents showing positive results in preclinical studies., (Copyright © 2011 Wiley-Liss, Inc.)

Background: Environmental cues associated with cocaine evoke craving and seeking. This process, termed cue reactivity, is a critical element of cocaine addiction. Although glutamatergic neurotransmission has been implicated in this effect of cocaine, the precise subtype and localization in the brain of the glutamatergic receptor critical for cocaine cue reactivity is not well-understood., Methods: We used a conditional N-methyl-D-aspartic acid receptor (NMDAR) knockout mouse whose NMDAR gene was deleted by Cre expression restricted to striatal neurons. To evaluate the role of NMDAR in cocaine cue reactivity, conditional knockout mice and control mice (n = 5-8/group) were conditioned for place preference with cocaine (5 and 10 mg/kg SC) for 3 days. Their subsequent place preference was examined in a drug-free state., Results: Although control mice developed cocaine conditioned place preference, mice deficient for NMDAR on striatal neurons failed to develop conditioned place preference., Conclusions: The NMDAR on striatal neurons is essential for the development of cocaine cue reactivity in the place conditioning paradigm. Our finding identifies a brain region whose constitutive NMDAR level serves as a determinant for susceptibility to this aspect of cocaine addiction., (Copyright 2010 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Decision making and action selection are influenced by the values of benefit, reward, cost, and punishment. Mapping of the positive and negative values of external events and actions occurs mainly via the discharge rates of neurons in the cerebral cortex, the amygdala, and the basal ganglia. However, it remains unclear how the reward values of external events and actions encoded in the basal ganglia are integrated into reward value-based control of limb-movement actions through the corticobasal ganglia loops. To address this issue, we investigated the activities of presumed projection neurons in the putamen of macaque monkeys performing a visually instructed GO-NOGO button-press task for large and small rewards. Regression analyses of neuronal discharge rates, actions, and reward values revealed three major categories of neurons. First, neurons activated during the preinstruction delay period were selective to either the GO(large reward)-NOGO(small reward) or NOGO(large reward)-GO(small reward) combinations, although the actions to be instructed were not predictable. Second, during the postinstruction epoch, GO and NOGO action-related activities were highly selective to reward size. The pre- and postinstruction activities of a large subset of neurons were also selective to cue position or GO-response direction. Third, neurons activated during both the pre- and postinstruction epochs were selective to both action and reward size. The results support the view that putamen neurons encode reward value and direction of actions, which may be a basis for mediating the processes leading from reward-value mapping to guiding ongoing actions toward their expected outcomes and directions.

Assessment of axonal infiltration and guidance within neural tissue engineering scaffolds, along with the characterisation of the inflammatory response, is critical in determining these scaffolds' potential for facilitating neural repair. In this study, the extent of microglial and astrocytic response was measured following implantation of electrospun poly(epsilon-caprolactone) (PCL) scaffolds into the caudate putamen of the adult rat brain. The inflammation peaked at around 4 days (microglia) and 7 days (astrocytes) and subsided to homeostatic levels by 60 days. There was no evidence of microglial encapsulation and indeed neurites had infiltrated the implants, evidence of scaffold-neural integration. Whilst the inflammatory response was uninfluenced by the degree of PCL fibre alignment, the extent of neurite entry was. Large porosity, as was the case with the randomly orientated polymer fibres, enabled neurite infiltration and growth within the scaffold. However, neuronal processes could not penetrate scaffolds when fibres were partially aligned and instead, preferentially grew perpendicular to the direction of PCL fibre alignment at the implant-tissue interface i.e. perpendicular, not parallel, contact guidance was provided. This investigation shows that electrospun PCL fibres are compatible with brain tissue and provide preliminary insights regarding the influence of microglia and astrocytes in neural integration within such scaffolds.

Aims: Parkinson's disease (PD) affects the nigrostriatal projections leading to micturition disturbance in most cases. Overactive bladder (OAB) symptoms such as urinary urgency or urgent urinary incontinence are common amongst PD patients. Several urodynamic studies have revealed that detrusor overactivity causes OAB symptoms in PD patients. We assert that striatal dysfunction might contribute to the pathogenesis of detrusor overactivity in PD patients. However, the role of the striatum in bladder contraction remains unclear., Methods: We generated spontaneous isovolumetric bladder contractions in 12 ketamine-anesthetized adult male cats and subsequently performed electrical stimulation and extracellular single-unit recording in the striatum., Results: Electrical stimulation applied to the posterior ventral caudate nucleus and the adjacent putamen reduced inhibition of the spontaneous bladder contraction. None of the responses were facilitatory. Electrical stimulation was most effective at an amplitude of 70-400 microA. Forty-six neurons that exhibited correlation to spontaneous bladder contraction were recorded in the striatum. Thirty-five neurons were found to be tonically active throughout the bladder relaxation phase, and the remaining 11 neurons were active during the bladder contraction phase. These particular neurons were located within the area in which spontaneous bladder contraction was inhibited by electrical stimulation., Conclusions: Electrical stimulation was found to inhibit bladder contraction, and a correlation was observed between spontaneous bladder relaxation/contraction and neuronal firing in the posterior ventral striatum., ((c) 2009 Wiley-Liss, Inc.)

Chronic nicotine upregulates central nicotinic acetylcholine receptors (nAChRs), a plasticity process thought to contribute to its addictive properties. To analyze this process in vivo, we chronically exposed mice to nicotine using minipump delivering nicotine at concentrations close to those found in tobacco smokers. Binding studies show upregulation of high-affinity nAChRs after 21 days of treatment in cortical areas, caudate putamen, nucleus accumbens, hippocampus, ventral tegmental area, and superior colliculi. No upregulation was observed in thalamus and discrete cortical areas. Using wild type and alpha 6-/- mice, we observed a downregulation of alpha 6*-nAChRs in superior colliculi and no effects in other structures. The complex pattern of upregulation/downregulation observed in this study depends on both nAChR composition and regional distribution.

Development of drug addiction is accompanied by the induction of long-lasting neurobiological changes. Dopamine D1 receptors are involved in mediating cocaine-induced neuroadaptation, yet the underlying intracellular mechanisms remain less clear. Using a genetically modified mouse in which Fos is primarily mutated in D1 receptor-bearing neurons in the brain, we examined a potential role of the immediate early gene Fos, which is rapidly induced by cocaine via D1 receptors, in mediating cocaine-induced persistent neurobiological changes. We found that the composition of AP-1 transcription complexes and expression levels of AP-1 complexes, and several transcription factors, neurotransmitter receptors as well as intracellular signaling molecules following repeated cocaine administration are altered in Fos-deficient brains. Moreover, dendritic reorganization of medium spiny neurons induced by repeated exposure to cocaine is attenuated in the mutant brains. The mutant mice also exhibit reduced behavioral sensitization after repeated cocaine administration. These findings suggest that c-Fos expressed in D1 receptor-bearing neurons mediates cocaine-induced persistent changes.

Evidence supporting a role of the caudate and putamen nuclei in associative learning is present. We recorded the activity of 21 caudate and 26 putamen cells in one macaque monkey while performing a visuomotor task, which involved a visual stimulus and the execution of a motor response. Ninety-one percent of caudate cells and 65% of putamen cells showed changes in activity while the monkey was performing the task. Approximately half of the caudate cells and one third of the putamen cells showed changes in activity without a motor response. Our results show that caudate and putamen cells are activated regardless of the presence or absence of a motor action. These findings are consistent with the idea that these nuclei may play a role in associative learning.

GPR56, a member of the G-protein-coupled receptor family, plays a role in the formation of the frontal and parietal brain lobes and cortical lamination in the embryonic stage. A recent report indicated the existence of GPR56 transcripts in the subventricular zone (SVZ) and hippocampal subgranular zone (SGZ) of the adult mouse brain. Both these regions are known to continually produce neural progenitor cells in the adult brain. Here, we demonstrate abundant GPR56 protein expression in the ependymal cell layer and SVZ as well as its reciprocal translational regulation by a 12-day behavioral stress paradigm and 10-day electroconvulsive seizure (ECS) treatment. Our study revealed that GPR56 transcript expression in the hippocampus was regulated by stress and seizure in a manner identical to that in the SVZ. GPR56 expression was downregulated by stress and upregulated by the ECS treatment in both regions, whereas nestin expression showed no changes. Western blot analysis revealed a robust ECS-induced increase in brain-derived neurotrophic factor expression in the wall of the lateral ventricle including the ependymal cell layer and the SVZ, which may provide a possible regulatory mechanism for GPR56 expression. We consider that GPR56 is expressed in the ependymal cell layer and in immature progenitor cells and that its expression is regulated by functional stimulation.

Animals optimize behaviors by predicting future critical events based on histories of actions and their outcomes. When behavioral outcomes like reward and aversion are signaled by current external cues, actions are directed to acquire the reward and avoid the aversion. The basal ganglia are thought to be the brain locus for reward-based adaptive action planning and learning. To understand the role of striatum in coding outcomes of forthcoming behavioral responses, we addressed two specific questions. First, how are the histories of reward and aversion used for encoding forthcoming outcomes in the striatum during a series of instructed behavioral responses? Second, how are the behavioral responses and their instructed outcomes represented in the striatum? We recorded discharges of 163 presumed projection neurons in the striatum while monkeys performed a visually instructed lever-release task for reward, aversion, and sound outcomes, whose occurrences could be estimated by their histories. Before outcome instruction, discharge rates of a subset of neurons activated in this epoch showed positive or negative regression slopes with reward history (24/44), that is, to the number of trials since the last reward trial, which changed in parallel with reward probability of current trials. The history effect was also observed for the aversion outcome but in far fewer neurons (3/44). Once outcomes were instructed in the same task, neurons selectively encoded the outcomes before and after behavioral responses (reward, 46/70; aversion, 6/70; sound, 6/70). The history- and current instruction-based coding of forthcoming behavioral outcomes in the striatum might underlie outcome-oriented behavioral modulation.

CB(1) cannabinoid receptors are expressed in many neurons in the caudate-putamen. However, it is not known how the activation of these receptors influences synaptic transmission between different neuron classes. The aim was to establish a method for studying identified synaptic connections in the caudate-putamen, and to determine the effects of cannabinoids on these connections. Brain slices were prepared from transgenic mice expressing enhanced green fluorescent protein (EGFP) in parvalbumin-positive fast spiking interneurons (PV-FSNs). PV-FSNs were identified based on their fluorescence. Non-fluorescent medium-sized neurons were considered to be medium spiny neurons (MSNs). Synaptic transmission was studied by simultaneous patch-clamp recording from identified neuron pairs. In the case of PV-FSN --> MSN neurotransmission, the synthetic cannabinoid receptor agonist WIN55212-2 lowered the success rate of transmission and the amplitude of successful postsynaptic events. Analysis of miniature inhibitory postsynaptic currents indicated that WIN55212-2 inhibited synaptic transmission presynaptically. WIN55212-2 did not elicit somatodendritic effects in PV-FSNs: membrane potential, membrane current and evoked firing were not changed. WIN55212-2 also depressed the MSN --> MSN neurotransmission. The inhibitory synaptic input to MSNs was only weakly suppressed by endocannabinoids released by depolarized postsynaptic MSNs. The results show that the combined use of transgenic animals and paired-recording techniques allows the study of synaptic connections between rare neurons. Using these techniques, we showed that activation of CB(1) receptors on axon terminals of (i) PV-FSNs and (ii) MSNs leads to presynaptic inhibition of GABAergic synaptic transmission between these axons and their postsynaptic targets, the MSNs. The cannabinoids acted preferentially on axon terminals without effects on the somatodendritic region of the neurons.

The apoptotic death of putaminal neurons and glia in a patient with hereditary ferritinopathy is studied immunohistochemically with antibodies to p53, activated caspase-3, PUMA, BAX, cytochrome c, and inducible nitric oxide synthase. In addition to the overexpression of ferritin and the iron accumulations assumed to result from the genetically incompetent ferritin molecule, additional contributions to the iron, heme, and hyaline deposits in this disease are sought with antibodies to 2 recently discovered globins in humans, neuroglobin and cytoglobin. The "pathognomonic" swollen to vacuolated nuclei are immunoreactive for both p53 and activated caspase-3, indicating the intervention of the p53-mediated apoptotic pathway. The immunohistochemical demonstration of neuroglobin in the swollen nuclei and both globins in the hyaline deposits highlights the potential pathogenic importance of 2 other iron-containing proteins in this disease that is largely restricted to brain. Hereditary ferritinopathy is the first human disease in which abnormalities in these heme-containing proteins are demonstrated.

The dynamics of tonic neuron activity of the putamen and prefrontal cortex of monkey's brain is researched by studying sequential stages of executive behavior program. It is determined that tonic responses in both structures are classified in separate blocks. The blocks are timed to key moments of behavior connected with intermediate goals framed by a common task. As to the structures of the aforesaid blocks of tonic activity in cortex and striatum, they are different in instructive part of the program and similar in executive one. More differential attitude of cortex is revealed to the sequence of executive behavior activity.

A previous study found that as monkeys learned novel mappings between visual cues and responses, neuronal activity patterns evolved at approximately the same time in both the dorsal premotor cortex (PMd) and the putamen. Here we report that, in both regions, the population activity for novel mappings came to resemble that for familiar ones as learning progressed. Both regions showed activity differences on trials with correct responses versus those with incorrect ones. In addition to these common features, we observed two noteworthy differences between PMd and putamen activity during learning. After a response choice had been made, but prior to feedback about the correctness of that choice (reward or nonreward), the putamen showed a sustained activity increase in activity, whereas PMd did not. Also in the putamen, this prereward activity was highly selective for the specific visuomotor mapping that had just been performed, and this selectivity was maintained until the time of the reward. After performance reached an asymptote, the degree of this selectivity decreased markedly to the level typical for familiar visuomotor mappings. These findings support the hypothesis that neurons in the striatum play a pivotal role in associative learning.

Previous examination of binge cocaine self-administration and 2 week withdrawal from cocaine self-administration on ionotropic glutamate receptor subunit (iGluRs) protein levels revealed significant alterations in iGluR protein levels that differed between the mesocorticolimbic and nigrostriatal pathways. The present study was undertaken to extend the examination of cocaine-induced alterations in iGluR protein expression by assessing the effects of acute withdrawal (15-16 h) from limited access cocaine self-administration (8 h/day, 15 days). Western blotting was used to compare levels of iGluR protein expression (NR1-3B, GluR1-7, KA2) in the mesolimbic (ventral tegmental area, VTA; nucleus accumbens, NAc; and prefrontal cortex, PFC) and nigrostriatal pathways (substantia nigra, SN and dorsal caudate-putamen, CPu). Within the mesolimbic pathway, reductions were observed in NR1 and GluR5 immunoreactivity in the VTA although no significant alterations were observed in any iGluR subunits in the NAc. In the PFC, NR1 was significantly upregulated while GluR2/3, GluR4, GluR5, GluR6/7, and KA2 were decreased. Within the nigrostriatal pathway, NR1, NR2A, NR2B, GluR1, GluR6/7 and KA2 were increased in the dorsal CPu, whereas no significant changes were observed in the SN. The results demonstrate region- and pathway-specific alterations in iGluR subunit expression following limited cocaine self-administration and suggest the importance for the activation of pathways that are substrates of the reinforcing and motoric effects of cocaine.

The current model of basal ganglia rests on the idea that the striatofugal system is composed of two separate (direct and indirect) pathways originating from distinct cell populations in the striatum. The striatum itself is divided into two major compartments, the striosomes and the matrix, which differ by their neurochemical makeup and input/output connections. Here, neurons located in either striosomes or the extrastriosomal matrix in squirrel monkeys were injected with biotin dextran amine, and their labeled axons were entirely reconstructed with a camera lucida. Twenty-four of 27 reconstructed axons arborized into the three main striatal targets (external pallidum, globus pallidus, and substantia nigra pars reticulata), a finding that is at odds with the concept of a dual striatofugal system. Axons of striosomal neurons formed several columnar terminal fields in the substantia nigra pars reticulata. These data indicate that the substantia nigra pars compacta is neither the only nor the main target of striosomal neurons, a finding that calls for a reevaluation of the organization of the striatonigral projection system.

The cortical masticatory area (CMA) elicits rhythmic jaw movements in response to repetitive stimulation and is involved in the control of mastication. Based on jaw movement patterns, the CMA is divided into two parts. One is the part of the CMA in which a T-pattern similar to jaw movements during food transport in natural mastication is evoked by electrical stimulation. The other is more dorsomedially located, and during chewing a C-pattern similar to jaw movements can be induced. However, it is still not known which region of the putamen receives projections from the CMA and whether projections originate from both parts of the CMA. In this study, electrophysiological and histological experiments were undertaken in rabbits to investigate projections from the CMA to the putamen. Both experiments showed that the ventral region of the putamen received projections from the CMA. The density of the projections from the CMA area inducing the T-pattern seemed to be higher than that from the area inducing the C-pattern. Furthermore, the peak latency of the evoked potentials from stimulation of the CMA area inducing the T-pattern was shorter than that from stimulation of the area inducing the C-pattern. The data obtained from the present study indicate the functional role of the ventral region of the putamen in the regulation of mastication, and further suggest that the corticostriatal pathway is involved in the transition between behavioral jaw movement patterns.

The dopamine (DA) inputs to the caudate putamen, the nucleus accumbens, and the amygdala in rats are sensitive to circulating estrogens and androgens. One mechanism for the hormone modulation of these systems may be via actions at cognate intracellular estrogen and androgen receptors. However, although it is known that specific subsets of midbrain DA neurons are immunopositive for estrogen receptor beta (ERbeta) or androgen receptors (ARs), it is not known where these receptor-bearing cells project. To address this issue, we combined double-label immunocytochemistry with retrograde tract tracing to identify the forebrain projections of ERbeta- or AR-immunoreactive (IR) midbrain neurons. Specifically, Fluoro-Gold and/or cholera toxin were injected into discrete subregions of the caudate-putamen, the nucleus accumbens, or the amygdala. Evaluations of the resultant midbrain labeling revealed that ERbeta-IR neurons sent collateral projections mainly to both the ventral caudate-putamen and the amygdala, but not to the dorsal caudate or nucleus accumbens. In contrast, AR-IR neurons projected either to the amygdala or the nucleus accumbens but not to the caudate-putamen. The organization of these forebrain projections concurs with some of the known hormone sensitivities of mesostriatal and mesolimbic DA systems in rats and provides an anatomical model that predicts separate influences for androgens and estrogens over mesostriatal and mesolimbic DA systems.

Previous evidence has suggested that glutamate-driving neurotransmission and glutamate-excitotoxicity are modulated by substance P in the basal ganglia, but the assembly of glutamate receptors mediating this process remains to be delineated. By using a double immunofluorescence, cellular expression of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptor subunits (GluR1-4) in substance P receptor (SPR)-containing neurons was examined in the striatum of rats. It revealed that distribution of SPR-immunoreactive neurons completely overlapped with that of GluR1, 2, 3 or 4-immunoreactive neurons in the caudate-putamen. Neurons showing both SPR and AMPA receptor subunits (except of GluR3)-immunoreactivity were observed: all (100%) of SPR-positive neurons displayed GluR1-, GluR2- or GluR4-immunoreactivity, and the double-labeled neurons constituted about 33, 3 or 29% of total GluR-positive ones. In contrast, the neurons exhibiting both SPR- and GluR3-immunoreactivity were not detected, though numerous GluR3-positive neurons were still distributed in the caudate-putamen regions. Co-localization of SPR and distinct AMPA receptor subunits in the striatal neurons has provided a basis for functional modulation of neuronal APMA receptors by substance P in the caudate-putamen of rodents. Taken together with previous observations, this study has also suggested that, through interaction with AMPA receptors composed of subunits 1, 2 and 4, substance P or neurokinin peptides may play important roles in regulating neuronal properties and protecting neurons from excitotoxicity in the basal ganglia of mammals.

To achieve a goal, animals procure immediately available rewards, escape from aversive events, or endure the absence of rewards. The neuronal substrates for these goal-directed actions include the limbic system and the basal ganglia. In the striatum, tonically active neurons (TANs), presumed cholinergic interneurons, were originally shown to respond to reward-associated stimuli and to evolve their activity through learning. Subsequent studies revealed that they also respond to aversive event-associated stimuli such as an airpuff on the face and that they are less selective to whether the stimuli instruct reward or no reward. To address this paradox, we designed a set of experiments in which macaque monkeys performed a set of visual reaction time tasks while expecting a reward, during escape from an aversive event, and in the absence of a reward. We found that TANs respond to instruction stimuli associated with motivational outcomes (312 of 390; 80%) but not to unassociated ones (51 of 390; 13%), and that they mostly differentiate associated instructions (217 of 312; 70%). We also found that a higher percentage of TANs in the caudate nucleus respond to stimuli associated with motivational outcomes (118 of 128; 92%) than in the putamen (194 of 262; 74%), whereas a higher percentage of TANs in the putamen respond to go signals for the lever release (112 of 262; 43%) than in the caudate nucleus (27 of 128; 21%), especially for an action expecting a reward. These findings suggest a distinct, pivotal role of TANs in the caudate nucleus and putamen in encoding instructed motivational contexts for goal-directed action planning and learning.

Comparative analysis of neuron activity in the monkey putamen during multistep behavior showed that putamen neurons are active during all the animal's behavioral actions. The difference between the number of active neurons at a given step of the behavior as compared with the preceding step was found to be significantly smaller than the number of neurons reorganizing their activity at this step. Reorganization of neuron activity in the putamen is regarded as a reflection of the efferent code controlling the behavior, while the extent of reorganization is regarded as a measure of the change in this code in association with the organization of a sequential behavioral action. Changes in the numbers of active neurons at different stage of behavior and reorganization of their activity occurred independently of each other. This may be associated with the two afferent systems of the striatum: that ascending from the brainstem and the corticofugal, which carries differential information to the neural network of the striatum from various parts of the cortex.

Retrograde axonal transport of markers was used to study the afferent projections arising from functionally diverse cortical and subcortical structures and running to various segments of the caudate nucleus, nucleus accumbens, and putamen of the dog brain. The characteristics of the spatial organization of these projections were used to analyze the morphological aspects of the segregated and convergent conduction and processing of information in the striatum which underlie striatal function.

Background: Studies have shown that neuroleptics regulate expression of the transcription factor FosB/DeltaFosB in the striatum, including the accumbens and caudate-putamen; however, the striatum is also divided into another structural dimension, the striosome and matrix compartments. The precise distribution of FosB/DeltaFosB induced by chronic neuroleptics in these striatal compartments is poorly understood., Methods: Rats received either single acute injections or chronic injections of clozapine (0 or 20 mg/kg, intraperitoneally [IP]), olanzapine (0 or 5 mg/kg, IP), or haloperidol (0 or 1.5 mg/kg, IP) for 25 days. The levels and compartmental distribution of FosB/DeltaFosB were examined., Results: Chronic clozapine induced clustered FosB/DeltaFosB expression within striosomes of the caudate-putamen. This pattern was due to increased levels of FosB/DeltaFosB in striosomes within the ventrolateral caudate-putamen and reduced levels of basal FosB/DeltaFosB in the matrix in the entire caudate-putamen. In contrast, chronic haloperidol increased FosB/DeltaFosB equally within the matrix and striosomes throughout the entire caudate-putamen. Chronic olanzapine induced an intermediate pattern., Conclusions: The relative absence of FosB/DeltaFosB expression in the matrix correlates with the lack of parkinsonism of atypical neuroleptics. Expression of FosB/DeltaFosB in the matrix may contribute to parkinsonism of typical neuroleptics.

Spike activity was recorded from three zones of the putamen in monkeys trained to bimanual operant activity during performance of an alternative spatial selection task. Neuron responses were analyzed using the following criteria: a) differentiation of the side providing reinforcement (differentiating/non-differentiating responses); b) response duration (tonic/phasic); c) response laterality (contralateral/ipsilateral hemispheres); d) baseline activity frequency. The differentiating activity of cells was found to show the closest correlation with behavioral aspects of the program, particularly the tonic part and, even more so, contralateral tonic responses. It is suggested that differentiating activity, as opposed to non-differentiating activity, is less a reflection of the morphological and neurochemical characteristics of the neural elements of the putamen than of their functional homogeneity in relation to external determinants of behavior.