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    A Population of Indirect Pathway Striatal Projection Neurons Is Selectively Entrained to Parkinsonian Beta Oscillations. Sharott Andrew,Vinciati Federica,Nakamura Kouichi C,Magill Peter J The Journal of neuroscience : the official journal of the Society for Neuroscience Classical schemes of basal ganglia organization posit that parkinsonian movement difficulties presenting after striatal dopamine depletion stem from the disproportionate firing rates of spiny projection neurons (SPNs) therein. There remains, however, a pressing need to elucidate striatal SPN firing in the context of the synchronized network oscillations that are abnormally exaggerated in cortical-basal ganglia circuits in parkinsonism. To address this, we recorded unit activities in the dorsal striatum of dopamine-intact and dopamine-depleted rats during two brain states, respectively defined by cortical slow-wave activity (SWA) and activation. Dopamine depletion escalated striatal net output but had contrasting effects on "direct pathway" SPNs (dSPNs) and "indirect pathway" SPNs (iSPNs); their firing rates became imbalanced, and they disparately engaged in network oscillations. Disturbed striatal activity dynamics relating to the slow (∼1 Hz) oscillations prevalent during SWA partly generalized to the exaggerated beta-frequency (15-30 Hz) oscillations arising during cortical activation. In both cases, SPNs exhibited higher incidences of phase-locked firing to ongoing cortical oscillations, and SPN ensembles showed higher levels of rhythmic correlated firing, after dopamine depletion. Importantly, in dopamine-depleted striatum, a widespread population of iSPNs, which often displayed excessive firing rates and aberrant phase-locked firing to cortical beta oscillations, preferentially and excessively synchronized their firing at beta frequencies. Conversely, dSPNs were neither hyperactive nor synchronized to a large extent during cortical activation. These data collectively demonstrate a cell type-selective entrainment of SPN firing to parkinsonian beta oscillations. We conclude that a population of overactive, excessively synchronized iSPNs could orchestrate these pathological rhythms in basal ganglia circuits. Chronic depletion of dopamine from the striatum, a part of the basal ganglia, causes some symptoms of Parkinson's disease. Here, we elucidate how dopamine depletion alters striatal neuron firing , with an emphasis on defining whether and how spiny projection neurons (SPNs) engage in the synchronized beta-frequency (15-30 Hz) oscillations that become pathologically exaggerated throughout basal ganglia circuits in parkinsonism. We discovered that a select population of so-called "indirect pathway" SPNs not only fire at abnormally high rates, but are also particularly prone to being recruited to exaggerated beta oscillations. Our results provide an important link between two complementary theories that explain the presentation of disease symptoms on the basis of changes in firing rate or firing synchronization/rhythmicity. 10.1523/JNEUROSCI.0658-17.2017
    Striatal Direct Pathway Targets Npas1 Pallidal Neurons. Cui Qiaoling,Du Xixun,Chang Isaac Y M,Pamukcu Arin,Lilascharoen Varoth,Berceau Brianna L,García Daniela,Hong Darius,Chon Uree,Narayanan Ahana,Kim Yongsoo,Lim Byung Kook,Chan C Savio The Journal of neuroscience : the official journal of the Society for Neuroscience The classic basal ganglia circuit model asserts a complete segregation of the two striatal output pathways. Empirical data argue that, in addition to indirect-pathway striatal projection neurons (iSPNs), direct-pathway striatal projection neurons (dSPNs) innervate the external globus pallidus (GPe). However, the functions of the latter were not known. In this study, we interrogated the organization principles of striatopallidal projections and their roles in full-body movement in mice (both males and females). In contrast to the canonical motor-promoting response of dSPNs in the dorsomedial striatum (dSPNs), optogenetic stimulation of dSPNs in the dorsolateral striatum (dSPNs) suppressed locomotion. Circuit analyses revealed that dSPNs selectively target Npas1 neurons in the GPe. In a chronic 6-hydroxydopamine lesion model of Parkinson's disease, the dSPN-Npas1 projection was dramatically strengthened. As dSPN-Npas1 projection suppresses movement, the enhancement of this projection represents a circuit mechanism for the hypokinetic symptoms of Parkinson's disease that has not been previously considered. In sum, our results suggest that dSPN input to the GPe is a critical circuit component that is involved in the regulation of movement in both healthy and parkinsonian states. In the classic basal ganglia model, the striatum is described as a divergent structure: it controls motor and adaptive functions through two segregated, opposing output streams. However, the experimental results that show the projection from direct-pathway neurons to the external pallidum have been largely ignored. Here, we showed that this striatopallidal subpathway targets a select subset of neurons in the external pallidum and is motor-suppressing. We found that this subpathway undergoes changes in a Parkinson's disease model. In particular, our results suggest that the increase in strength of this subpathway contributes to the slowness or reduced movements observed in Parkinson's disease. 10.1523/JNEUROSCI.2306-20.2021
    Genetic tools to study complexity of striatal function. Ciriachi Chiara,Svane-Petersen David,Rickhag Mattias Journal of neuroscience research As the main input structure of the basal ganglia (BG), the striatum collects and integrates information from several brain areas and funnels them forward to other BG nuclei. The striatal projection neurons are medium-sized spiny neurons classified in two main subpopulations, based on their neurochemical characterization and projection targets. These subpopulations are segregated into two distinct circuits, the direct and the indirect pathway, which originate in the striatum and interconnect the BG, ultimately reaching their output nuclei. In this review, we discuss current opinions on the striatal circuit and present different strategies to decipher this circuit complexity by utilizing cell ablation, opto- and chemogenetics, tetanus toxin-induced neuronal silencing, and calcium imaging techniques. We also describe genetically encoded biosensors to monitor signaling dynamics in the striatal circuit with high spatial and temporal resolution by targeting both glutamate and dopamine transmission together with downstream signaling effectors. Recent findings revealing transcriptional, functional diversity, and regionally distinct signaling properties of spiny projection neurons argue that refined interrogation will be pertinent for a deeper understanding of this circuit. Moreover, future mapping the G-protein-coupled receptor repertoire in SPNs will potentially enable pathway-specific modulation of SPN activity and provide a novel framework for targeting BG diseases. Overall, these tools will be critical for designing next-generation treatments for BG diseases. 10.1002/jnr.24479
    Functional organization of the basal ganglia: therapeutic implications for Parkinson's disease. Obeso Jose A,Rodríguez-Oroz Maria Cruz,Benitez-Temino Beatriz,Blesa Franscisco J,Guridi Jorge,Marin Concepció,Rodriguez Manuel Movement disorders : official journal of the Movement Disorder Society The basal ganglia (BG) are a highly organized network, where different parts are activated for specific functions and circumstances. The BG are involved in movement control, as well as associative learning, planning, working memory, and emotion. We concentrate on the "motor circuit" because it is the best understood anatomically and physiologically, and because Parkinson's disease is mainly thought to be a movement disorder. Normal function of the BG requires fine tuning of neuronal excitability within each nucleus to determine the exact degree of movement facilitation or inhibition at any given moment. This is mediated by the complex organization of the striatum, where the excitability of medium spiny neurons is controlled by several pre- and postsynaptic mechanisms as well as interneuron activity, and secured by several recurrent or internal BG circuits. The motor circuit of the BG has two entry points, the striatum and the subthalamic nucleus (STN), and an output, the globus pallidus pars interna (GPi), which connects to the cortex via the motor thalamus. Neuronal afferents coding for a given movement or task project to the BG by two different systems: (1) Direct disynaptic projections to the GPi via the striatum and STN. (2) Indirect trisynaptic projections to the GPi via the globus pallidus pars externa (GPe). Corticostriatal afferents primarily act to inhibit medium spiny neurons in the "indirect circuit" and facilitate neurons in the "direct circuit." The GPe is in a pivotal position to regulate the motor output of the BG. Dopamine finely tunes striatal input as well as neuronal striatal activity, and modulates GPe, GPi, and STN activity. Dopaminergic depletion in Parkinson's disease disrupts the corticostriatal balance leading to increased activity the indirect circuit and reduced activity in the direct circuit. The precise chain of events leading to increased STN activity is not completely understood, but impaired dopaminergic regulation of the GPe, GPi, and STN may be involved. The parkinsonian state is characterized by disruption of the internal balance of the BG leading to hyperactivity in the two main entry points of the network (striatum and STN) and excessive inhibitory output from the GPi. Replacement therapy with standard levodopa creates a further imbalance, producing an abnormal pattern of neuronal discharge and synchronization of neuronal firing that sustain the "off" and "on with dyskinesia" states. The effect of levodopa is robust but short-lasting and converts the parkinsonian BG into a highly unstable system, where pharmacological and compensatory effects act in opposing directions. This creates a scenario that substantially departs from the normal physiological state of the BG. 10.1002/mds.22062
    Pedunculopontine Glutamatergic Neurons Provide a Novel Source of Feedforward Inhibition in the Striatum by Selectively Targeting Interneurons. Assous Maxime,Dautan Daniel,Tepper James M,Mena-Segovia Juan The Journal of neuroscience : the official journal of the Society for Neuroscience The main excitatory inputs to the striatum arising from the cortex and the thalamus innervate both striatal spiny projection neurons and interneurons. These glutamatergic inputs to striatal GABAergic interneurons have been suggested to regulate the spike timing of striatal projection neurons via feedforward inhibition. Understanding how different excitatory inputs are integrated within the striatal circuitry and how they regulate striatal output is crucial for understanding basal ganglia function and related behaviors. Here, using VGLUT2 mice from both sexes, we report the existence of a glutamatergic projection from the mesencephalic locomotor region to the striatum that avoids the spiny neurons and selectively innervates interneurons. Specifically, optogenetic activation of glutamatergic axons from the pedunculopontine nucleus induced monosynaptic excitation in most recorded striatal cholinergic interneurons and GABAergic fast-spiking interneurons. Optogenetic stimulation in awake head-fixed mice consistently induced an increase in the firing rate of putative cholinergic interneurons and fast-spiking interneurons. In contrast, this stimulation did not induce excitatory responses in spiny neurons but rather disynaptic inhibitory responses and a decrease in their firing rate , suggesting a feedforward mechanism mediating the inhibition of spiny projection neurons through the selective activation of striatal interneurons. Furthermore, unilateral stimulation of pedunculopontine nucleus glutamatergic axons in the striatum induced ipsilateral head rotations consistent with the inhibition of striatal output neurons. Our results demonstrate the existence of a unique interneuron-specific midbrain glutamatergic input to the striatum that exclusively recruits feedforward inhibition mechanisms. Glutamatergic inputs to the striatum have been shown to target both striatal projection neurons and interneurons and have been proposed to regulate spike timing of the projection neurons in part through feedforward inhibition. Here, we reveal the existence of a midbrain source of glutamatergic innervation to the striatum, originating in the pedunculopontine nucleus. Remarkably, this novel input selectively targets striatal interneurons, avoiding the projection neurons. Furthermore, we show that this selective innervation of interneurons can regulate the firing of the spiny projection neurons and inhibit the striatal output via feedforward inhibition. Together, our results describe a unique source of excitatory innervation to the striatum which selectively recruits feedforward inhibition of spiny neurons without any accompanying excitation. 10.1523/JNEUROSCI.2913-18.2019
    Normal functional imaging of the basal ganglia. Lehéricy Stéphane,Gerardin Emmanuel Epileptic disorders : international epilepsy journal with videotape In non-human primates, all cortical projections into the striatum are topographically organized in discrete parallel circuits. These circuits are involved in distinct behavioral functions. In humans, functional imaging data support a similar organization of the striatum. The representation of the different elements of a motor act (such as movement learning, selection, mental representation, preparation and execution) are represented differentially along distinct cortico-basal ganglia circuits. Saccadic eye movements are predominantly represented in the caudate nucleus. Motivational processes are represented in the ventral part of the striatum. Thus, functional imaging data suggest that the human striatum is organized in parallel motor circuits similar to those found in animal studies.
    The Role of Human Primary Motor Cortex in the Production of Skilled Finger Sequences. Yokoi Atsushi,Arbuckle Spencer A,Diedrichsen Jörn The Journal of neuroscience : the official journal of the Society for Neuroscience Human primary motor cortex (M1) is essential for producing dexterous hand movements. Although distinct subpopulations of neurons are activated during single-finger movements, it remains unknown whether M1 also represents sequences of multiple finger movements. Using novel multivariate functional magnetic resonance imaging (fMRI) analysis techniques and combining evidence from both 3T and 7T fMRI data, we found that after 5 d of intense practice, premotor and parietal areas encoded the different movement sequences. There was little or no evidence for a sequence representation in M1. Instead, activity patterns in M1 could be fully explained by a linear combination of patterns for the constituent individual finger movements, with the strongest weight on the first finger of the sequence. Using passive replay of sequences, we show that this first-finger effect is due to neuronal processes involved in the active execution, rather than to a hemodynamic nonlinearity. These results suggest that M1 receives increased input from areas with sequence representations at the initiation of a sequence, but that M1 activity itself relates to the execution of component finger presses only. These results improve our understanding of the representation of finger sequences in the human neocortex after short-term training and provide important methodological advances for the study of long-term skill development. There is clear evidence that human primary motor cortex (M1) is essential for producing individuated finger movements, such as pressing a button. Over and above its involvement in movement execution, it is less clear whether M1 also plays a role in learning and controlling sequences of multiple finger movements, such as when playing the piano. Using cutting-edge multivariate fMRI analysis and carefully controlled experiments, we demonstrate here that, while premotor areas clearly show a sequence representation, activity patterns in M1 can be fully explained from the patterns for individual finger movements. The results provide important new insights into the interplay of M1 and premotor cortex for learning of sequential movements. 10.1523/JNEUROSCI.2798-17.2017
    Distinct striatal regions for planning and executing novel and automated movement sequences. Jankowski J,Scheef L,Hüppe C,Boecker H NeuroImage The basal ganglia-thalamo-cortical circuits are viewed as segregated parallel feed back loops crucially involved in motor control, cognition, and emotional processing. Their role in planning novel, as compared to overlearned movement patterns is as yet not well defined. We tested for the involvement of the associative striatum (caudate/anterior putamen) in the generation of novel movement patterns, which is a critical cognitive requirement for non-routine motor behavior. Using event related functional MRI in 14 right-handed male subjects, we analyzed brain activity in the planning phase of four digit finger sequences. Subjects either executed a single overlearned four digit sequence (RECALL), or self-determined four digit sequences of varying order (GENERATE). In both conditions, RECALL and GENERATE, planning was associated with activation in mesial/lateral premotor cortices, motor cingulate cortex, superior parietal cortex, basal ganglia, insula, thalamus, and midbrain nuclei. When contrasting the planning phase of GENERATE with the planning phase of RECALL, there was significantly higher activation within this distributed network. At the level of the basal ganglia, the planning phase of GENERATE was associated with differentially higher activation located specifically within the associative striatum bilaterally. On the other hand, the execution phase during both conditions was associated with a shift of activity towards the posterior part of the putamen. Our data show the specific involvement of the associative striatum during the planning of non-routine movement patterns and illustrate the propagation of activity from rostral to dorsal basal ganglia sites during different stages of motor processing. 10.1016/j.neuroimage.2008.10.059
    Dopamine depletion induces neuron-specific alterations of GABAergic transmission in the mouse striatum. Boccalaro Ida Luisa,Schwerdel Cornelia,Cristiá-Lara Leonardo,Fritschy Jean-Marc,Rubi Lena The European journal of neuroscience Lack of dopamine (DA) in the striatum and the consequential dysregulation of thalamocortical circuits are major causes of motor impairments in Parkinson's disease. The striatum receives multiple cortical and subcortical afferents. Its role in movement control and motor skills learning is regulated by DA from the nigrostriatal pathway. In Parkinson's disease, DA loss affects striatal network activity and induces a functional imbalance of its output pathways, impairing thalamocortical function. Striatal projection neurons are GABAergic and form two functionally antagonistic pathways: the direct pathway, originating from DA receptor type 1-expressing medium spiny neurons (D R-MSN), and the indirect pathway, from D R-MSN. Here, we investigated whether DA depletion in mouse striatum also affects GABAergic function. We recorded GABAergic miniature IPSCs (mIPSC) and tonic inhibition from D R- and D R-MSN and used immunohistochemical labeling to study GABA R function and subcellular distribution in DA-depleted and control mice. We observed slower decay kinetics and increased tonic inhibition in D R-MSN, while D R-MSN had increased mIPSC frequency after DA depletion. Perisomatic synapses containing the GABA R subunits α or α were not affected, but there was a strong decrease in non-synaptic GABA Rs containing these subunits, suggesting altered receptor trafficking. To broaden these findings, we also investigated GABA Rs in GABAergic and cholinergic interneurons and found cell type-specific alterations in receptor distribution, likely reflecting changes in connectivity. Our results reveal that chronic DA depletion alters striatal GABAergic transmission, thereby affecting cellular and circuit activity. These alterations either result from pathological changes or represent a compensatory mechanism to counteract imbalance of output pathways. 10.1111/ejn.14886
    The Effects of Working Memory Updating Training in Parkinson's Disease: A Feasibility and Single-Subject Study on Cognition, Movement and Functional Brain Response. Walton Lois,Domellöf Magdalena Eriksson,Boraxbekk Carl-Johan,Domellöf Erik,Rönnqvist Louise,Bäckström David,Forsgren Lars,Stigsdotter Neely Anna Frontiers in psychology In Parkinson's disease (PD), the fronto-striatal network is involved in motor and cognitive symptoms. Working memory (WM) updating training engages this network in healthy populations, as observed by improved cognitive performance and increased striatal BOLD signal. This two-part study aimed to assess the feasibility of WM updating training in PD and measure change in cognition, movement and functional brain response in one individual with PD after WM updating training. A feasibility and single-subject (FL) study were performed in which patients with PD completed computerized WM updating training. The outcome measures were the pre-post changes in criterion and transfer cognitive tests; cognitive complaints; psychological health; movement kinematics; and task-related BOLD signal. Participants in the feasibility study showed improvements on the criterion tests at post-test. FL displayed the largest improvements on the criterion tests and smaller improvements on transfer tests. Furthermore, FL reported improved cognitive performance in everyday life. A shorter onset latency and smoother upper-limb goal-directed movements were measured at post-test, as well as increased activation within the striatum and decreased activation throughout the fronto-parietal WM network. This two-part study demonstrated that WM updating training is feasible to complete for PD patients and that change occurred in FL at post-test in the domains of cognition, movement and functional brain response. 10.3389/fpsyg.2020.587925
    CRISPR/Cas9 Edited sRAGE-MSCs Protect Neuronal Death in Parkinson’s Disease Model. Lee Jaesuk,Bayarsaikhan Delger,Arivazhagan Roshini,Park Hyejung,Lim Byungyoon,Gwak Peter,Jeong Goo-Bo,Lee Jaewon,Byun Kyunghee,Lee Bonghee International journal of stem cells BACKGROUND AND OBJECTIVES:Parkinson’s disease (PD) is a fatal and progressive degenerative disease of the nervous system. Until recently, its promising treatment and underlying mechanisms for neuronal death are poorly understood. This study was investigated to identify the molecular mechanism of neuronal death in the substantia nigra and corpus striatum of PD. METHODS:The soluble RAGE (sRAGE) secreting Umbilical Cord Blood-derived Mesenchymal Stem Cell (UCB-MSC) was generated by gene editing method using clustered regularly interspaced short palindromic repeats/CRISPR associated protein 9 (CRISPR/Cas9). These cells were transplanted into Corpus Striatum of rotenone-induced PD animal models then behavioral test, morphological analysis, and immunohistochemical experiments were performed to determine the neuronal cell death and recovery of movement. RESULTS:The neuronal cell death in Corpus Striatum and Substantia Nigra was dramatically reduced and the movement was improved after sRAGE secreting UCB-MSC treatment in PD mice by inhibition of RAGE in neuronal cells. CONCLUSIONS:We suggest that sRAGE secreting UCB-MSC based therapeutic approach could be a potential treatment strategy for neurodegenerative disease including PD. 10.15283/ijsc18110
    Chemogenetic Targeting of Dorsomedial Direct-pathway Striatal Projection Neurons Selectively Elicits Rotational Behavior in Mice. Bay Kønig Andreas,Ciriachi Chiara,Gether Ulrik,Rickhag Mattias Neuroscience The striatum of the basal ganglia is pivotal for voluntary movements and is implicated in debilitating movement disorders such as Parkinsonism and dystonia. Striatum projects to downstream nuclei through direct (dSPN) and indirect (iSPN) pathway projection neurons thought to exert opposite effects on movement. In rodent models of striatal function, unilateral dopamine deprivation induces ipsiversive rotational behavior. The dSPNs of the dorsal striatum are believed to engage distinct motor programs but underlying mechanisms remain unclear. Here, we show by employing chemogenetics [Designer Receptors Exclusively Activated by Designer Drugs (DREADDs)] that unilateral inhibition of dorsomedial dSPNs is sufficient to selectively impair contraversive movement and elicit ipsiversive rotational behavior in mice. Adeno-associated virus (AAV) encoding Cre-dependent G-coupled DREADD was injected unilaterally into the dorsomedial striatum of Drd1-Cre mice, resulting in expression of the modified human M4 muscarinic receptor (hM4Di) in ∼20% of dorsostriatal dSPNs. Upon hM4Di activation, a striking positive linear correlation was found between turn ratio and viral expression, which corroborates a relationship between unilateral inhibition of dorsomedial dSPNs and rotational behavior. Bursts of ipsiversive rotations were interspersed with normal ambulation. However, partial unilateral inhibition of ∼20% of dorsostriatal dSPNs did not affect horizontal and vertical locomotion or forelimb use preference. Overall, our results substantiate a unique role of dSPNs in promoting response bias in rotational behavior and show this to be a highly sensitive measure of dSPN performance. 10.1016/j.neuroscience.2019.01.013
    Dorsal striatal dopamine induces fronto-cortical hypoactivity and attenuates anxiety and compulsive behaviors in rats. Casado-Sainz Agata,Gudmundsen Frederik,Baerentzen Simone L,Lange Denise,Ringsted Annemette,Martinez-Tejada Isabel,Medina Siria,Lee Hedok,Svarer Claus,Keller Sune H,Schain Martin,Kjaerby Celia,Fisher Patrick M,Cumming Paul,Palner Mikael Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology Dorsal striatal dopamine transmission engages the cortico-striato-thalamo-cortical (CSTC) circuit, which is implicated in many neuropsychiatric diseases, including obsessive-compulsive disorder (OCD). Yet it is unknown if dorsal striatal dopamine hyperactivity is the cause or consequence of changes elsewhere in the CSTC circuit. Classical pharmacological and neurotoxic manipulations of the CSTC and other brain circuits suffer from various drawbacks related to off-target effects and adaptive changes. Chemogenetics, on the other hand, enables a highly selective targeting of specific neuronal populations within a given circuit. In this study, we developed a chemogenetic method for selective activation of dopamine neurons in the substantia nigra, which innervates the dorsal striatum in the rat. We used this model to investigate effects of targeted dopamine activation on CSTC circuit function, especially in fronto-cortical regions. We found that chemogenetic activation of these neurons increased movement (as expected with increased dopamine release), rearings and time spent in center, while also lower self-grooming. Furthermore, this activation increased prepulse inhibition of the startle response in females. Remarkably, we observed reduced [F]FDG metabolism in the frontal cortex, following dopamine activation in the dorsal striatum, while total glutamate levels- in this region were increased. This result is in accord with clinical studies of increased [F]FDG metabolism and lower glutamate levels in similar regions of the brain of people with OCD. Taken together, the present chemogenetic model adds a mechanistic basis with behavioral and translational relevance to prior clinical neuroimaging studies showing deficits in fronto-cortical glucose metabolism across a variety of clinical populations (e.g. addiction, risky decision-making, compulsivity or obesity). 10.1038/s41386-021-01207-y
    Anti-Dopamine Receptor 2 Antibody-Positive Encephalitis in Adolescent. Dai Xuejiao,Kuang Lilu,Feng Li,Yi Xiaoping,Tang Weiting,Liao Qiao,Long Xiaoyan,Wang Junling,Li Jing,Yang Huan,Xiao Bo,Li Guoliang,Chen Si Frontiers in neurology Autoimmune encephalitic syndromes include mutism, somnolence, movement disorder, and behavioral, or psychiatric symptoms. When paired with bilateral basal ganglia lesions on magnetic resonance imaging, these support the diagnosis of basal ganglia encephalitis (BGE). BGE is a rare but distinct entity of putative autoimmune etiology, with specific basal ganglia inflammation and acute movement disorders. A previous study identified dopamine-2 receptors (D2R) antibody to be positive in most BGE children, indicating that the D2R antibody may trigger the downstream pathological process in BGE patients. The highest levels of D2R are found in the striatum, the nucleus accumbens, and the olfactory tubercle. D2R antibody-positive BGE is widely reported in children. Here we present a 17-year-old girl with a typical clinical feature of basal ganglia encephalitis, who benefited from immune therapy. 10.3389/fneur.2020.00471
    Differential associations of dopamine synthesis capacity with the dopamine transporter and D2 receptor availability as assessed by PET in the living human brain. Yamamoto Yasuharu,Takahata Keisuke,Kubota Manabu,Takano Harumasa,Takeuchi Hiroyoshi,Kimura Yasuyuki,Sano Yasunori,Kurose Shin,Ito Hiroshi,Mimura Masaru,Higuchi Makoto NeuroImage BACKGROUND:The dopamine (DA) neurotransmission has been implicated in fundamental brain functions, exemplified by movement controls, reward-seeking, motivation, and cognition. Although dysregulation of DA neurotransmission in the striatum is known to be involved in diverse neuropsychiatric disorders, it is yet to be clarified whether components of the DA transmission, such as synthesis, receptors, and reuptake are coupled with each other to homeostatically maintain the DA neurotransmission. The purpose of this study was to investigate associations of the DA synthesis capacity with the availabilities of DA transporters and D2 receptors in the striatum of healthy subjects. METHODS:First, we examined correlations between the DA synthesis capacity and DA transporter availability in the caudate and putamen using PET data with L-[β-C]DOPA and [F]FE-PE2I, respectively, acquired from our past dual-tracer studies. Next, we investigated relationships between the DA synthesis capacity and D2 receptor availability employing PET data with L-[β-C]DOPA and [C]raclopride, respectively, obtained from other previous dual-tracer assays. RESULTS:We found a significant positive correlation between the DA synthesis capacity and DA transporter availability in the putamen, while no significant correlations between the DA synthesis capacity and D2 receptor availability in the striatum. CONCLUSION:The intimate association of the DA synthesis rate with the presynaptic reuptake of DA indicates homeostatic maintenance of the baseline synaptic DA concentration. In contrast, the total abundance of D2 receptors, which consist of presynaptic autoreceptors and postsynaptic modulatory receptors, may not have an immediate relationship to this regulatory mechanism. 10.1016/j.neuroimage.2020.117543
    Non-Cell Autonomous and Epigenetic Mechanisms of Huntington's Disease. International journal of molecular sciences Huntington's disease (HD) is a rare neurodegenerative disorder caused by an expansion of CAG trinucleotide repeat located in the exon 1 of gene in human chromosome 4. The HTT protein is ubiquitously expressed in the brain. Specifically, mutant HTT (mHTT) protein-mediated toxicity leads to a dramatic degeneration of the striatum among many regions of the brain. HD symptoms exhibit a major involuntary movement followed by cognitive and psychiatric dysfunctions. In this review, we address the conventional role of wild type HTT (wtHTT) and how mHTT protein disrupts the function of medium spiny neurons (MSNs). We also discuss how mHTT modulates epigenetic modifications and transcriptional pathways in MSNs. In addition, we define how non-cell autonomous pathways lead to damage and death of MSNs under HD pathological conditions. Lastly, we overview therapeutic approaches for HD. Together, understanding of precise neuropathological mechanisms of HD may improve therapeutic approaches to treat the onset and progression of HD. 10.3390/ijms222212499
    Combination Effects of Forced Mild Exercise and GABA Receptor Agonist on Spatial Learning, Memory, and Motor Activity in Striatum Lesion Rats. Modaberi Shaghayegh,Heysieattalab Soomaayeh,Shahbazi Mehdi,Naghdi Nasser Journal of motor behavior Basal ganglia (BG) lesions cause impairments of different mammalian's movement and cognition behaviors. Motor circuit impairment has a dominant role in the movement disorders. An inhibitory factor in BG is GABA neurotransmitter, which is released from striatum. Lesions in GABAergic neurons could trigger movement and cognition disorders. Previous evidence showed that GABA receptor agonist (Baclofen) administration in human improves movement disorders and exercise can improve neurodegenerative and cognitive decline; however, the effects of both Baclofen and mild forced treadmill exercise on movement disorders are not well known. The main objective of this study is to investigate the combined effects of mild forced treadmill exercise and microinjection of Baclofen in the internal Globus Pallidus on striatum lesion-induced impairments of spatial learning and motor activity. We used Morris water maze and open filed tests for studying spatial learning, and motor activity, respectively. Results showed that mild exercise and Baclofen microinjection could not lonely affect the spatial learning, and motor activity impairments while the combination of them could alleviate spatial learning, and motor activity impairments in striatum-lesion animals. Our results suggest that striatum lesion-induced memory and motor activity impairments can improve with combination interaction of GABA receptor agonist and exercise training. 10.1080/00222895.2018.1505711
    Striatal direct pathway neurons play leading roles in accelerating rotarod motor skill learning. iScience Dorsal striatum is important for movement control and motor skill learning. However, it remains unclear how the spatially and temporally distributed striatal medium spiny neuron (MSN) activity in the direct and indirect pathways (D1 and D2 MSNs, respectively) encodes motor skill learning. Combining miniature fluorescence microscopy with an accelerating rotarod procedure, we identified two distinct MSN subpopulations involved in accelerating rotarod learning. In both D1 and D2 MSNs, we observed neurons that displayed activity tuned to acceleration during early stages of trials, as well as movement speed during late stages of trials. We found a distinct evolution trajectory for early-stage neurons during motor skill learning, with the evolution of D1 MSNs correlating strongly with performance improvement. Importantly, optogenetic inhibition of the early-stage neural activity in D1 MSNs, but not D2 MSNs, impaired accelerating rotarod learning. Together, this study provides insight into striatal D1 and D2 MSNs encoding motor skill learning. 10.1016/j.isci.2022.104245
    Further Characterization of Intrastriatal Lipopolysaccharide Model of Parkinson's Disease in C57BL/6 Mice. Deng Isaac,Corrigan Frances,Garg Sanjay,Zhou Xin-Fu,Bobrovskaya Larisa International journal of molecular sciences Parkinson's disease (PD) is the most common movement disorder, characterized by progressive degeneration of the nigrostriatal pathway, which consists of dopaminergic cell bodies in substantia nigra and their neuronal projections to the striatum. Moreover, PD is associated with an array of non-motor symptoms such as olfactory dysfunction, gastrointestinal dysfunction, impaired regulation of the sleep-wake cycle, anxiety, depression, and cognitive impairment. Inflammation and concomitant oxidative stress are crucial in the pathogenesis of PD. Thus, this study aimed to model PD via intrastriatal injection of the inflammagen lipopolysaccharide (LPS)to investigate if the lesion causes olfactory and motor impairments, inflammation, oxidative stress, and alteration in synaptic proteins in the olfactory bulb, striatum, and colon. Ten µg of LPS was injected unilaterally into the striatum of 27 male C57BL/6 mice, and behavioural assessment was conducted at 4 and 8 weeks post-treatment, followed by tissue collection. Intrastriatal LPS induced motor impairment in C57BL/6 mice at 8 weeks post-treatment evidenced by reduced latency time in the rotarod test. LPS also induced inflammation in the striatum characterized by increased expression of microglial marker Iba-1 and astrocytic marker GFAP, with degeneration of dopaminergic neuronal fibres (reduced tyrosine hydroxylase immunoreactivity), and reduction of synaptic proteins and DJ-1 protein. Additionally, intrastriatal LPS induced inflammation, oxidative stress and alterations in synaptic proteins within the olfactory bulb, although this did not induce a significant impairment in olfactory function. Intrastriatal LPS induced mild inflammatory changes in the distal colon, accompanied by increased protein expression of 3-nitrotyrosine-modified proteins. This model recapitulated the major features of PD such as motor impairment and degeneration of dopaminergic neuronal fibres in the striatum, as well as some pathological changes in the olfactory bulb and colon; thus, this model could be suitable for understanding clinical PD and testing neuroprotective strategies. 10.3390/ijms22147380
    Implications of the putamen in pain and motor deficits in complex regional pain syndrome. Azqueta-Gavaldon Monica,Youssef Andrew M,Storz Claudia,Lemme Jordan,Schulte-Göcking Heike,Becerra Lino,Azad Shahnaz C,Reiners Anselm,Ertl-Wagner Birgit,Borsook David,Upadhyay Jaymin,Kraft Eduard Pain Complex regional pain syndrome (CRPS) develops after-limb injury, with persistent pain and deficits in movement frequently co-occurring. The striatum is critical for mediating multiple mechanisms that are often aberrant in CRPS, which includes sensory and pain processing, motor function, and goal-directed behaviors associated with movement. Yet, much remains unknown with regards to the morphological and functional properties of the striatum and its subregions in this disease. Thus, we investigated 20 patients (15 female, age 58 ± 9 years, right-handed) diagnosed with chronic (6+ months of pain duration) CRPS in the right hand and 20 matched, healthy controls with anatomical and resting-state, functional magnetic resonance imaging. In addition, a comprehensive clinical and behavioral evaluation was performed, where each participant's pain, motor function, and medical history were assessed. Complex regional pain syndrome patients harbored significant abnormalities in hand coordination, dexterity, and strength. These clinical pain- and movement-related findings in CRPS patients were concomitant with bilateral decreases in gray matter density in the putamen as well as functional connectivity increases and decreases among the putamen and pre-/postcentral gyri and cerebellum, respectively. Importantly, higher levels of clinical pain and motor impairment were associated with increased putamen-pre-/postcentral gyri functional connectivity strengths. Collectively, these findings suggest that putaminal alterations, specifically the functional interactions with sensorimotor structures, may underpin clinical pain and motor impairment in chronic CRPS patients. 10.1097/j.pain.0000000000001745
    Comparative Performance of 99mTc-TRODAT-1 SPECT/CT and 18F-FDOPA PET/CT Imaging in Patients With Parkinson's Disease, Parkinson-Plus Syndrome, and Essential Tremor. Sood Apurva,Shukla Jaya,Shree Ritu,Vatsa Rakhee,Modi Manish,Mittal Bhagwant Rai Clinical nuclear medicine PURPOSE:The aim of this study was to assess the utility of presynaptic dopaminergic imaging using 99mTc-TRODAT-1 SPECT/CT and 18F-FDOPA PET/CT and compare their performance in Parkinson's disease (PD), Parkinson-plus syndrome (PPS), and essential tremor (ET). PATIENTS AND METHODS:A total of 103 patients (PD = 48, PPS = 19, and ET = 36) were enrolled prospectively. Hoehn and Yahr (H&Y) staging and MDS-UPDRS (Movement Disorder Society-Sponsored Revision of Unified Parkinson's Disease Rating Scale) were done for PD and PPS cases. All the patients underwent 99mTc-TRODAT-1 SPECT/CT and 18F-FDOPA PET/CT brain scan. The scans were analyzed visually and semiquantitatively. Average pixel count and SUVmean of the striatum were calculated in SPECT and PET images, respectively, to calculate the specific uptake ratio of striatum (SUR). Comparison of scan findings and SURs among different groups and correlation with clinical characteristics was done. RESULTS:Symmetrical comma-shaped uptake was seen in bilateral striatum in ET cases with mean SURs significantly higher than in cases of early PD (H&Y stage I and II, n = 37), PD and PPS both on SPECT and PET images (P ≤ 0.001). The mean SURs between PD and PPS showed no significant difference (SPECT, P = 0.17; PET, P = 0.61). Substantial agreement (weighted κ = 0.659) was found between 99mTc-TRODAT-1 and 18F-FDOPA for the detection of presynaptic dopaminergic dysfunction. Specific uptake ratio of striatum correlation between SPECT and PET was statistically significant (r = 0.67; P < 0.01). A negative but nonsignificant correlation was found between the SURs and H&Y staging/MDS-UPDRS. CONCLUSIONS:Both 99mTc-TRODAT-1 SPECT/CT and 18F-FDOPA PET/CT showed substantial agreement and proved to be potential imaging biomarker for the detection of dopaminergic dysfunction, thus assisting in differentiating early PD/PD and PPS from ET cases. 10.1097/RLU.0000000000003409
    Striatal synaptic adaptations in Parkinson's disease. Shen Weixing,Zhai Shenyu,Surmeier D James Neurobiology of disease The striatum is densely innervated by mesencephalic dopaminergic neurons that modulate acquisition and vigor of goal-directed actions and habits. This innervation is progressively lost in Parkinson's disease (PD), contributing to the defining movement deficits of the disease. Although boosting dopaminergic signaling with levodopa early in the course of the disease alleviates these deficits, later this strategy leads to the emergence of debilitating dyskinesia. Here, recent advances in our understanding of how striatal cells and circuits adapt to this progressive de-innervation and to levodopa therapy are discussed. First, we discuss how dopamine (DA) depletion triggers cell type-specific, homeostatic changes in spiny projection neurons (SPNs) that tend to normalize striatal activity but also lead to disruption of the synaptic architecture sculpted by experience. Second, we discuss the roles played by cholinergic and nitric oxide-releasing interneurons in these adaptations. Third, we examine recent work in freely moving mice suggesting that alterations in the spatiotemporal dynamics of striatal ensembles contributes to PD movement deficits. Lastly, we discuss recently published evidence from a progressive model of PD suggesting that contrary to the classical model, striatal pathway imbalance is necessary but not sufficient to produce frank parkinsonism. 10.1016/j.nbd.2022.105686
    Neuro-Immune Cross-Talk in the Striatum: From Basal Ganglia Physiology to Circuit Dysfunction. Mancini Andrea,Ghiglieri Veronica,Parnetti Lucilla,Calabresi Paolo,Di Filippo Massimiliano Frontiers in immunology The basal ganglia network is represented by an interconnected group of subcortical nuclei traditionally thought to play a crucial role in motor learning and movement execution. During the last decades, knowledge about basal ganglia physiology significantly evolved and this network is now considered as a key regulator of important cognitive and emotional processes. Accordingly, the disruption of basal ganglia network dynamics represents a crucial pathogenic factor in many neurological and psychiatric disorders. The striatum is the input station of the circuit. Thanks to the synaptic properties of striatal medium spiny neurons (MSNs) and their ability to express synaptic plasticity, the striatum exerts a fundamental integrative and filtering role in the basal ganglia network, influencing the functional output of the whole circuit. Although it is currently established that the immune system is able to regulate neuronal transmission and plasticity in specific cortical areas, the role played by immune molecules and immune/glial cells in the modulation of intra-striatal connections and basal ganglia activity still needs to be clarified. In this manuscript, we review the available evidence of immune-based regulation of synaptic activity in the striatum, also discussing how an abnormal immune activation in this region could be involved in the pathogenesis of inflammatory and degenerative central nervous system (CNS) diseases. 10.3389/fimmu.2021.644294
    Voluntary Exercise Boosts Striatal Dopamine Release: Evidence for the Necessary and Sufficient Role of BDNF. The Journal of neuroscience : the official journal of the Society for Neuroscience Physical exercise improves motor performance in individuals with Parkinson's disease and elevates mood in those with depression. Although underlying factors have not been identified, clues arise from previous studies showing a link between cognitive benefits of exercise and increases in brain-derived neurotrophic factor (BDNF). Here, we investigated the influence of voluntary wheel-running exercise on BDNF levels in the striatum of young male wild-type (WT) mice, and on the striatal release of a key motor-system transmitter, dopamine (DA). Mice were allowed unlimited access to a freely rotating wheel (runners) or a locked wheel (controls) for 30 d. Electrically evoked DA release was quantified in corticostriatal slices from these animals using fast-scan cyclic voltammetry. We found that exercise increased BDNF levels in dorsal striatum (dStr) and increased DA release in dStr and in nucleus accumbens core and shell. Increased DA release was independent of striatal acetylcholine (ACh), and persisted after a week of rest. We tested a role for BDNF in the influence of exercise on DA release using mice that were heterozygous for BDNF deletion (BDNF). In contrast to WT mice, evoked DA release did not differ between BDNF runners and controls. Complementary pharmacological studies using a tropomyosin receptor kinase B (TrkB) agonist in WT mouse slices showed that TrkB receptor activation also increased evoked DA release throughout striatum in an ACh-independent manner. Together, these data support a causal role for BDNF in exercise-enhanced striatal DA release and provide mechanistic insight into the beneficial effects of exercise in neuropsychiatric disorders, including Parkinson's, depression, and anxiety. Exercise has been shown to improve movement and cognition in humans and rodents. Here, we report that voluntary exercise for 30 d leads to an increase in evoked DA release throughout the striatum and an increase in BDNF in the dorsal (motor) striatum. The increase in DA release appears to require BDNF, indicated by the absence of DA release enhancement with running in BDNF mice. Activation of BDNF receptors using a pharmacological agonist was also shown to boost DA release. Together, these data support a necessary and sufficient role for BDNF in exercise-enhanced DA release and provide mechanistic insight into the reported benefits of exercise in individuals with dopamine-linked neuropsychiatric disorders, including Parkinson's disease and depression. 10.1523/JNEUROSCI.2273-21.2022
    Discrete finger sequences are widely represented in human striatum. Andersen Kasper Winther,Madsen Kristoffer H,Siebner Hartwig Roman Scientific reports Research in primates and rodents ascribes the striatum a critical role in integrating elementary movements into unitary action sequences through reinforcement-based learning. Yet it remains to be shown whether the human striatum represents action sequence-specific information. Young right-handed volunteers underwent functional magnetic resonance imaging while they performed four discrete finger sequences with their right hand, consisting of five button presses. Specific finger sequences could be discriminated based on the distributed activity patterns in left and right striatum, but not by average differences in single-voxel activity. Multiple bilateral clusters in putamen and caudate nucleus belonging to motor, associative, parietal and limbic territories contributed to classification sensitivity. The results show that individual finger movement sequences are widely represented in human striatum, supporting functional integration rather than segregation. The findings are compatible with the idea that the basal ganglia simultaneously integrate motor, associative and limbic aspects in the control of complex overlearned behaviour. 10.1038/s41598-020-69923-x
    Dynamic Changes of Arc Expression in Dorsal Striatum of Mice After Self-Administration of Sucrose. Li Xue,Zhao Jing-Wang,Ding Qian,Wu Cheng,Li Wan-Qi,Guo Yan-Chen,Wang Di,Xu Guang-Qing,Yuan Ti-Fei,Gong Wan-Kun,Lan Yue Frontiers in cellular neuroscience Region-specific plasticity in the striatal circuit plays an important role in the development and long-term maintenance of skills and sequential movement procedures. Studies investigating the molecular substrates that contribute to the plasticity changes during motor skill processes have documented a transition in expression from the dorsomedial striatum (DMS) to the dorsolateral striatum (DLS); however, few studies have explored the expression pattern of molecular substrates in the dorsal striatum during progression of instrumental learning. To address this issue, the activity-regulated cytoskeleton-associated protein (Arc) expressions in the subregional dorsal striatum were analyzed during the early and late learning phases of the 10-day sucrose self-administration process. We found that Arc protein is primarily detected in the DMS only in the initial learning stage; however, it is expressed in the DLS during both early and late learning stages. Moreover, Arc expression in the DMS correlated with the number of rewards received later in the training. These data indicated that the Arc expression in subregions of the dorsal striatum shows region-specific transfer and that Arc expression in the DMS contributes to obtaining reward in later learning stage during the process of instrumental learning. 10.3389/fncel.2021.654521
    Direct-Pathway Spiny Projection Neuron Inhibition Evokes Transient Circuit Imbalance Manifested as Rotational Behavior. Christensen Maria,Nørr Søren Emil,Gether Ulrik,Rickhag Mattias Neuroscience The striatum collects and integrates information from many different areas of the brain and propels this forward to the basal ganglia (BG) output structures. In this way, the striatum is playing a pivotal role in control of voluntary movements and is implicated in debilitating movement disorders such as Parkinson's disease. The functional backbone of the striatum is represented by direct pathway (dSPN) Drd1-expressing and indirect pathway (iSPN) Drd2-expressing spiny projection neurons (SPN), exerting opposite effects on movement. In rodent models of striatal function, unilateral dopamine deprivation is known to induce ipsilateral rotational behavior. To further study imbalance of the BG circuit and striatal domain influence on behavioral outcome, we employed a viral approach based on tetanus toxin light chain (TeLC) activity for permanent inhibition of dSPN activity in dorsomedial striatum (DMS). Cre-dependent TeLC injected unilaterally into the DMS of Drd1-Cre mice resulted in robust expression of TeLC in the dSPN cell populations as shown by immunohistochemistry. In the TeLC expressing mice, but not in control mice, we observed ipsilateral rotations that were enhanced upon administration of amphetamine to augment striatal dopamine levels. We argue that the observed single turns of ipsilateral rotations occur because of TeLC-mediated silencing of dSPN activity in one hemisphere, causing unresponsiveness to dopamine transients during movement initiation. This evokes a temporal BG circuit imbalance manifested as short bursts of rotations, particular evident during extrinsic dopaminergic modulation. 10.1016/j.neuroscience.2020.11.035
    Leucine-Rich Repeats and Transmembrane Domain 2 Controls Protein Sorting in the Striatal Projection System and Its Deficiency Causes Disturbances in Motor Responses and Monoamine Dynamics. Frontiers in molecular neuroscience The striatum is involved in action selection, and its disturbance can cause movement disorders. Here, we show that leucine-rich repeats and transmembrane domain 2 (Lrtm2) controls protein sorting in striatal projection systems, and its deficiency causes disturbances in monoamine dynamics and behavior. The Lrtm2 protein was broadly detected in the brain, but it was enhanced in the olfactory bulb and dorsal striatum. Immunostaining revealed a strong signal in striatal projection output, including GABAergic presynaptic boutons of the SNr. In subcellular fractionation, Lrtm2 was abundantly recovered in the synaptic plasma membrane fraction, synaptic vesicle fraction, and microsome fraction. Lrtm2 KO mice exhibited altered motor responses in both voluntary explorations and forced exercise. Dopamine metabolite content was decreased in the dorsal striatum and hypothalamus, and serotonin turnover increased in the dorsal striatum. The prefrontal cortex showed age-dependent changes in dopamine metabolites. The distribution of glutamate decarboxylase 67 (GAD67) protein and gamma-aminobutyric acid receptor type B receptor 1 (GABA R1) protein was altered in the dorsal striatum. In cultured neurons, wild-type Lrtm2 protein enhanced axon trafficking of GAD67-GFP and GABA R1-GFP whereas such activity was defective in sorting signal-abolished Lrtm2 mutant proteins. The topical expression of hemagglutinin-epitope-tag (HA)-Lrtm2 and a protein sorting signal abolished HA-Lrtm2 mutant differentially affected GABA R1 protein distribution in the dorsal striatum. These results suggest that Lrtm2 is an essential component of striatal projection neurons, contributing to a better understanding of striatal pathophysiology. 10.3389/fnmol.2022.856315
    Dopamine denervation in the functional territories of the striatum: a new MR and atlas-based I-FP-CIT SPECT quantification method. Villain Nicolas,Béra G,Habert M-O,Kas A,Aubert J,Jaubert O,Valabregue R,Fernandez-Vidal S,Corvol J-C,Mangone G,Lehéricy S,Vidailhet M,Grabli D, Journal of neural transmission (Vienna, Austria : 1996) Current quantification methods of I-FP-CIT SPECT rely on anatomical parcellation of the striatum. We propose here to implement a new method based on MRI segmentation and functional atlas of the basal ganglia (MR-ATLAS) that could provide a reliable quantification within the sensorimotor, associative, and limbic territories of the striatum. Patients with Parkinson's disease (PD), idiopathic rapid eye movement sleep behavioral disorder (iRBD), and healthy controls underwent I-FP-CIT SPECT, MRI, motor, and cognitive assessments. SPECT data were corrected for partial volume effects and registered to a functional atlas of the striatum to allow quantification in every functional region of the striatum (nucleus accumbens, limbic, associative, and sensorimotor parts of the striatum). The MR-ATLAS quantification method is proved to be reliable in every territory of the striatum. In addition, good correlations were found between cognitive dysexecutive tests and the binding within the functional (limbic) territories of the striatum using the MR-ATLAS method, slightly better than correlations found using the anatomical quantification method. This new MR-ATLAS method provides a robust and useful tool for studying the dopaminergic system in PD, particularly with respect to cognitive functions. It may also be relevant to further unravel the relationship between dopaminergic denervation and cognitive or behavioral symptoms. 10.1007/s00702-021-02434-9
    Heterogenous electrophysiological responses of functionally distinct striatal subregions to circadian and sleep-related homeostatic processes. Fifel Karim,Deboer Tom Sleep Basal ganglia (BG) are a set of subcortical nuclei that are involved in the control of a wide variety of motor, cognitive, and affective behaviors. Although many behavioral abnormalities associated with BG dysfunction overlap with the clinical picture precipitated by the lack of sleep, the impact of sleep alterations on neuronal activity in BG is unknown. Using wild-type C57BI mice, we investigated the circadian and sleep-related homeostatic modulation of neuronal activity in the three functional subdivisions of the striatum (i.e. sensorimotor, associative, and limbic striatum). We found no circadian modulation of activity in both ventral and dorsomedial striatum while the dorsolateral striatum displayed a significant circadian rhythm with increased firing rates during the subjective dark, active phase. By combining neuronal activity recordings with electroencephalogram (EEG) recordings, we found a strong modulation of neuronal activity by the nature of vigilance states with increased activity during wakefulness and rapid eye movement sleep relative to nonrapid eye movement sleep in all striatal subregions. Depriving animals of sleep for 6 h induced significant, but heterogenous alterations in the neuronal activity across striatal subregions. Notably, these alterations lasted for up to 48 h in the sensorimotor striatum and persisted even after the normalization of cortical EEG power densities. Our results show that vigilance and sleep states as well as their disturbances significantly affect neuronal activity within the striatum. We propose that these changes in neuronal activity underlie both the well-established links between sleep alterations and several disorders involving BG dysfunction as well as the maladaptive changes in behavior induced in healthy participants following sleep loss. 10.1093/sleep/zsab230
    Ventral striatum links motivational and motor networks during operant-conditioned movement in rats. Hori Yuki,Ihara Naoki,Sugai Chiaki,Ogura Jun,Honda Manabu,Kato Koichi,Isomura Yoshikazu,Hanakawa Takashi NeuroImage Voluntary actions require motives. It is already known that the medial prefrontal cortex (MPFC) assess the motivational values. However, it remains unclear how the motivational process gains access to the motor execution system in the brain. Here we present evidence that the ventral striatum (VS) plays a hub-like role in mediating motivational and motor processing in operant behavior. We used positron emission tomography (PET) to detect the neural activation areas associated with motivational action. Using obtained regions, partial correlation analysis was performed to examine how the motivational signals propagate to the motor system. The results revealed that VS activity propagated to both MPFC and primary motor cortex through the thalamus. Moreover, muscimol injection into the VS suppressed the motivational behavior, supporting the idea of representations of motivational signals in VS that trigger motivational behavior. These results suggest that the VS-thalamic pathway plays a pivotal role for both motivational processing through interactions with the MPFC and for motor processing through interactions with the motor BG circuits. 10.1016/j.neuroimage.2018.10.018
    Movement Disorder in Copper Toxicity Rat Model: Role of Inflammation and Apoptosis in the Corpus Striatum. Kalita Jayantee,Kumar Vijay,Misra Usha K,Bora Himangsu K Neurotoxicity research The pattern of copper (Cu) toxicity in humans is similar to Wilson disease, and they have movement disorders and frequent involvement of corpus striatum. The extent of cell deaths in corpus striatum may be the basis of movement disorder and may be confirmed in the experimental study. To evaluate the extent of apoptosis and glial activation in corpus striatum following Cu toxicity in a rat model, and correlate these with spontaneous locomotor activity (SLA), six male Wistar rats were fed normal saline (group I) and another six were fed copper sulfate 100 mg/kgBWt/daily orally (group II). At 1 month, neurobehavioral studies including SLA, rotarod, and grip strength were done. Corpus striatum was removed and was subjected to glial fibrillary acidic protein (GFAP) and caspase-3 immunohistochemistry. The concentration of tissue Cu, total antioxidant capacity (TAC), glutathione (GSH), malondialdehyde (MDA), and glutamate were measured. Group II rats had higher expression of caspase-3 (Mean ± SEM 32.67 ± 1.46 vs 4.47 ± 1.08; p < 0.01) and GFAP (41.81 ± 1.68 vs 31.82 ± 1.27; p < 0.01) compared with group I. Neurobehavioral studies revealed reduced total distance traveled, time moving, the number of rearing, latency to fall on the rotarod, grip strength, and increased resting time compared with group I. The expression of GFAP and caspase-3 correlated with SLA parameters, tissue Cu, GSH, MDA, TAC, and glutamate levels. The impaired locomotor activity in Cu toxicity rats is due to apoptotic and inflammatory-mediated cell death in the corpus striatum because of Cu-mediated oxidative stress and excitotoxicity. 10.1007/s12640-019-00140-9
    Coordination of rapid cholinergic and dopaminergic signaling in striatum during spontaneous movement. Howe Mark,Ridouh Imane,Allegra Mascaro Anna Letizia,Larios Alyssa,Azcorra Maite,Dombeck Daniel A eLife Interplay between dopaminergic and cholinergic neuromodulation in the striatum is crucial for movement control, with prominent models proposing pro-kinetic and anti-kinetic effects of dopamine and acetylcholine release, respectively. However, the natural, movement-related signals of striatum cholinergic neurons and their relationship to simultaneous variations in dopamine signaling are unknown. Here, functional optical recordings in mice were used to establish rapid cholinergic signals in dorsal striatum during spontaneous movements. Bursts across the cholinergic population occurred at transitions between movement states and were marked by widespread network synchronization which diminished during sustained locomotion. Simultaneous cholinergic and dopaminergic recordings revealed distinct but coordinated sub-second signals, suggesting a new model where cholinergic population synchrony signals rapid changes in movement states while dopamine signals the drive to enact or sustain those states. 10.7554/eLife.44903
    Direct and indirect pathway neurons in ventrolateral striatum differentially regulate licking movement and nigral responses. Chen Zhaorong,Zhang Zhi-Yu,Zhang Wen,Xie Taorong,Li Yaping,Xu Xiao-Hong,Yao Haishan Cell reports Drinking behavior in rodents is characterized by stereotyped, rhythmic licking movement, which is regulated by the basal ganglia. It is unclear how direct and indirect pathways control the lick bout and individual spout contact. We find that inactivating D1 and D2 receptor-expressing medium spiny neurons (MSNs) in the ventrolateral striatum (VLS) oppositely alters the number of licks in a bout. D1- and D2-MSNs exhibit different patterns of lick-sequence-related activity and different phases of oscillation time-locked to the lick cycle. On the timescale of a lick cycle, transient inactivation of D1-MSNs during tongue protrusion reduces spout contact probability, whereas transiently inactivating D2-MSNs has no effect. On the timescale of a lick bout, inactivation of D1-MSNs (D2-MSNs) causes rate increase (decrease) in a subset of basal ganglia output neurons that decrease firing during licking. Our results reveal the distinct roles of D1- and D2-MSNs in regulating licking at both coarse and fine timescales. 10.1016/j.celrep.2021.109847
    Exercise and Cognitive Function. Loprinzi Paul D,Lovorn Ashley Journal of clinical medicine Cognitive function is associated with longevity and is of critical importance for optimal daily functioning[...]. 10.3390/jcm8101707
    [Cognitive Function and Calcium. Cerebral calcium oscillation: functional implication toward cognitive functions]. Osanai Makoto Clinical calcium Calcium is universal and versatile signal transduction molecule. Intracellular calcium is precisely regulated by various cellular mechanisms, making it possible to contribute to normal neuronal functions. Recently, the relationship between calcium and neuronal functions including cognitive functions has been investigated. This paper reviews normal and abnormal functions of calcium in a perspective of raveling the pathophysiology of neuropsychiatric disorders, such as Alzheimer's disease and Parkinson's disease. And, I introduce the slow calcium oscillation in striatum, which lasted more than 100 s, and discuss the pathophysiological function of the slow calcium oscillation in the neuropsychiatric disorder, especially in Parkinson's disease. CliCa1502217225
    Neurophysiology and cognitive functions of the striatum. Rolls E T Revue neurologique The striatum receives inputs from different areas of the cerebral cortex, including association cortical areas far on in the hierarchy of cortical information processing as well as the sensori-motor cortex, and has connections via the globus pallidus and substantia nigra to the thalamus and thence to premotor and prefrontal cortical areas. Recordings of the activity of neurons in different parts of the striatum of primates show that they have the following properties: 1) neurons in much of the putamen, which receives inputs from the sensori-motor cortex, have activity related to movements; 2) neurons in the caudate nucleus, which receives from the association cortex, have activity related for example to environmental stimuli which signal preparation for or initiation of behavioral responses; 3) neurons in the tail of the caudate nucleus, which receives strongly from the inferior temporal visual cortex, respond when a patterned visual stimulus changes; 4) some neurons in the posterior ventral putamen, which receives from the inferior temporal visual cortex and the prefrontal cortex, respond in a visual short term memory task, delayed match to sample. The neurons responded in the delay period, or differentially to match and non-match stimuli. These neurons did not respond in an auditory delayed match to sample task, so that their activity was not related to movement per se, but was instead more closely related to visual inputs relevant to a memory task; 5) some neurons in the ventral striatum (including the nucleus accumbens), which receives from limbic structures such as the amygdala and hippocampus, respond to stimuli associated with reinforcement or to novel stimuli. It is concluded that there is considerable segregation of function within the striatum. It is suggested that there is an opportunity for inputs which originate from different parts of the cerebral cortex to interact, via a first stage of convergence in the striatum, and by a further stage of convergence on the dendrites of single neurons in the globus pallidus and substantia nigra; and that both these parts of the basal ganglia may learn associations between the different signals they receive. The result of this convergence and learning is that the basal ganglia provide a way for cortical areas far on in the hierarchy of information processing to become linked during motor learning to particular sequences of movements, and thus to be involved in the execution of motor programs.
    Parallel associative processing in the dorsal striatum: segregation of stimulus-response and cognitive control subregions. Devan Bryan D,Hong Nancy S,McDonald Robert J Neurobiology of learning and memory Although evidence suggests that the dorsal striatum contributes to multiple learning and memory functions, there nevertheless remains considerable disagreement on the specific associative roles of different neuroanatomical subregions. We review evidence indicating that the dorsolateral striatum (DLS) is a substrate for stimulus-response habit formation - incremental strengthening of simple S-R bonds - via input from sensorimotor neocortex while the dorsomedial striatum (DMS) contributes to behavioral flexibility - the cognitive control of behavior - via prefrontal and limbic circuits engaged in relational and spatial information processing. The parallel circuits through dorsal striatum interact with incentive/affective motivational processing in the ventral striatum and portions of the prefrontal cortex leading to overt responding under specific testing conditions. Converging evidence obtained through a detailed task analysis and neurobehavioral assessment is beginning to illuminate striatal subregional interactions and relations to the rest of the mammalian brain. 10.1016/j.nlm.2011.06.002
    Glibenclamide alters serotonin and dopamine levels in the rat striatum and hippocampus, reducing cognitive impairment. Psychopharmacology RATIONALE:Glibenclamide (GD) is a widely used medical drug; therefore, identifying the mechanisms underlying its pleiotropic effects in the central nervous system is urgent. OBJECTIVES:The aim of this work was to determine the ability of GD to modulate serotonin (5-hydroxytryptamine, 5-HT) and dopamine (DA) transmission and to assess the dose-dependent effect of GD on cognitive function in rats during natural ageing. METHODS:In Experiment 1, rats received 10, 25, or 50 μg/kg GD intraperitoneally for 10 days. In Experiment 2, rats received 50 μg/kg GD intraperitoneally for 30 days. Spatial and working memory was assessed in the MWM and Y-maze tests, respectively. In both experiments, the levels of DA and 5-HT, their metabolites, and turnover rate were analysed by HPLC-ED in the rat hippocampus and striatum. RESULTS:Changes in DA and 5-HT levels occurred only with a dose of 50 μg/kg GD. Therefore, in the second experiment, we administered a dose of 50 μg/kg GD. At this dose, GD prevented the development of impairments in spatial and working memory. The hippocampal concentrations of DA and DOPAC decreased, and the striatal concentrations of DA, DOPAC, 5-HT, and 5-HIAA increased. CONCLUSION:One of the possible mechanisms of the precognitive effect of GD is its ability to modulate monoamine transmission. Thus, in translating our results to humans, GD can be recommended as a prophylactic agent for natural ageing to reduce the risk of developing cognitive impairments. 10.1007/s00213-022-06159-9
    Differential Contributions of Ventral and Dorsal Striatum to Early and Late Phases of Cognitive Set Reconfiguration. Sleezer Brianna J,Hayden Benjamin Y Journal of cognitive neuroscience Flexible decision-making, a defining feature of human cognition, is typically thought of as a canonical pFC function. Recent work suggests that the striatum may participate as well; however, its role in this process is not well understood. We recorded activity of neurons in both the ventral (VS) and dorsal (DS) striatum while rhesus macaques performed a version of the Wisconsin Card Sorting Test, a classic test of flexibility. Our version of the task involved a trial-and-error phase before monkeys could identify the correct rule on each block. We observed changes in firing rate in both regions when monkeys switched rules. Specifically, VS neurons demonstrated switch-related activity early in the trial-and-error period when the rule needed to be updated, and a portion of these neurons signaled information about the switch context (i.e., whether the switch was intradimensional or extradimensional). Neurons in both VS and DS demonstrated switch-related activity at the end of the trial-and-error period, immediately before the rule was fully established and maintained, but these signals did not carry any information about switch context. We also observed associative learning signals (i.e., specific responses to options associated with rewards in the presentation period before choice) that followed the same pattern as switch signals (early in VS, later in DS). Taken together, these results endorse the idea that the striatum participates directly in cognitive set reconfiguration and suggest that single neurons in the striatum may contribute to a functional handoff from the VS to the DS during reconfiguration processes. 10.1162/jocn_a_01011
    Associations between dopamine D2-receptor binding and cognitive performance indicate functional compartmentalization of the human striatum. Cervenka Simon,Bäckman Lars,Cselényi Zsolt,Halldin Christer,Farde Lars NeuroImage Based on pharmacological, neuroanatomical, and lesion studies in animals, a functional compartmentalization of the striatal complex has been proposed. However, this has not been convincingly demonstrated in human subjects. Most functions ascribed to the striatum have been linked to its dense dopaminergic innervation, from motor control to higher-order brain functions (e.g., cognition), making the dopamine system a suitable probe for striatal function. Limbic striatum, a region involved in reward processing, has recently been implicated also in episodic memory function. Here we examined striatal dopamine D2-receptor binding in 16 healthy subjects using PET and the radioligand [(11)C]raclopride, in relation to cognitive performance. Receptor availability in limbic striatum was related to performance in tests of episodic memory, but not to tests of verbal fluency and general knowledge. By contrast, D2 binding in associative and sensorimotor striatum was less strongly related to episodic memory, but showed associations to the non-episodic tasks. These findings provide biochemical evidence for a functional compartmentalization of human striatum, and serve as a starting point for a more detailed investigation of striatal biomarkers in the normal brain as well as in neurodegenerative disorders. 10.1016/j.neuroimage.2007.12.063
    Resting-state functional connectivity of the striatum in early-stage Parkinson's disease: Cognitive decline and motor symptomatology. Manza Peter,Zhang Sheng,Li Chiang-Shan R,Leung Hoi-Chung Human brain mapping Parkinson's disease is a neurodegenerative disorder characterized by changes to dopaminergic function in the striatum and a range of cognitive and motor deficits. Neuroimaging studies have repeatedly shown differences in activation and functional connectivity patterns of the striatum between symptomatic individuals with Parkinson's disease and healthy controls. However, the presence and severity of cognitive and motor symptoms seem to differ dramatically among individuals with Parkinson's disease at the early-stages. To investigate the neural basis of such heterogeneity, we examined the resting state functional connectivity patterns of caudate and putamen subdivisions in relation to cognitive and motor impairments among 62 early-stage individuals with Parkinson's disease (21 females, 23 drug naive, ages 39-77 years, average UPDRS motor scores off medication = 18.56, average H&Y stage = 1.66). We also explored how changes in striatal connectivity relate to changes in symptomatology over a year. There are two main findings. First, higher motor deficit rating was associated with weaker coupling between anterior putamen and midbrain including substantia nigra. Intriguingly, steeper declines in functional connectivity between these regions were associated with greater declines in motor function over the course of 1 year. Second, decline in cognitive function, particularly in the memory and visuospatial domains, was associated with stronger coupling between the dorsal caudate and the rostral anterior cingulate cortex. These findings remained significant after controlling for age, medication, gender, and education. In sum, our findings suggest that cognitive decline and motor deficit are each associated with a differentiable pattern of functional connectivity of striatal subregions. Hum Brain Mapp 37:648-662, 2016. © 2015 Wiley Periodicals, Inc. 10.1002/hbm.23056
    Down-regulation of dorsal striatal αCaMKII causes striatum-related cognitive and synaptic disorders. Wang Qi,Yin Pengcheng,Yu Bin,Zhao Zheng,Richter-Levin Gal,Yu Lu,Cao Xiaohua Experimental neurology Alpha calcium/calmodulin dependent protein kinase II (αCaMKII) is a serine/threonine protein kinase which is expressed abundantly in dorsal striatum and is highly involved in the corticostriatal synaptic plasticity. Nevertheless, it currently remains unclear whether and how αCaMKII plays a in the striatum-related neural disorders. To address the above issue, lentivirus-mediated short hairpin RNA (shRNA) was used to silence the expression of αCaMKII gene in the dorsal striatum of mice. As a consequence of down-regulation of dorsal striatal αCaMKII expression, we observed defective motor skill learning in accelerating rotarod and response learning in water cross maze. Furthermore, impaired corticostriatal basal transmission and long-term potentiation (LTP), which correlated with the deficits in dorsal striatum-related cognition, were also detected in the αCaMKII-shRNA mice. Consistent with the above results, αCaMKII-shRNA mice exhibited a remarkable decline in GluA1-Ser831 and GluA1-Ser845 phosphorylation levels of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR), and a decline in the expression levels of N-methyl-d-aspartic acid receptor (NMDAR) subunits NR1, NR2A and NR2B. Taken together, αCaMKII down-regulation caused dorsal striatum-related cognitive disorders by inhibiting corticostriatal synaptic plasticity, which resulted from dysfunction of AMPARs and NMDARs. Our findings demonstrate for the first time an important role of αCaMKII in striatum-related neural disorders and provide further evidence for the proposition that corticostriatal LTP underlies aspects of dorsal striatum-related cognition. 10.1016/j.expneurol.2017.09.004
    Dopamine release in the human striatum: motor and cognitive tasks revisited. Lappin Julia M,Reeves Suzanne J,Mehta Mitul A,Egerton Alice,Coulson Mark,Grasby Paul M Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism Striatal dopamine (DA) release has been shown during behavioural tasks, but the relative contribution of motor, reward, and cognitive components is unclear. Dopamine release was quantified using [(11)C]-raclopride in two studies using a triple-scan approach, comprising active task, motor control, and rest. In the first, bolus radiotracer was delivered during a sequential motor learning paradigm; in the second, a spatial planning task, bolus plus constant infusion was applied. [(11)C]-raclopride binding potentials (BP(ND)s) in striatal functional subdivisions were compared across conditions. [(11)C]-raclopride BP(ND) was significantly reduced in active task compared with rest in both the sensorimotor and associative striatum in both studies, because of differences between rest and motor control conditions. In both regions, the motor control BP(ND) fell between the rest and active task in the planning study, but the difference between motor control and active task conditions was not significant. No such changes were observed in the limbic striatum. Using rigorous methodology, this study validates earlier evidence that striatal DA release occurs during behavioural challenges. Increased DA release during movement was reliably detected in the sensorimotor and associative striatum, supporting use of the functional subdivision model in humans. No additional DA release was observed specific to the cognitive component of either task. 10.1038/jcbfm.2008.146