Antagonism of metabotropic glutamate receptor type 5 prevents levodopa-induced dyskinesia development in a male rat model of Parkinson's disease: Electrophysiological evidence.

Levodopa-induced dyskinesia (LID) is a common complication in patients with advanced Parkinson's disease (PD) undergoing treatment with levodopa. Glutamate receptor antagonists can suppress LID; however, the underlying mechanisms remain unclear. Here, we aimed to evaluate the effect of 3-((2-methyl-1,3-thiazol-4-yl)ethynyl)pyridine (MTEP), a metabotropic glutamate receptor 5 (mGluR5) antagonist, on dyskinesia. We recorded the neuronal activity of the entopeduncular nucleus and examined responses to cortical electric stimulation in the control group (n = 6) and three groups of rats (male PD model). Saline was intraperitoneally administered to dopamine lesioned (DL) rats (n = 6), levodopa/benserazide (L/B) was administered to LID rats (n = 8), and L/B combined with MTEP was administered to MTEP rats (n = 6) twice daily for 14 days. We administered L/B to LID and MTEP rats 48 h after the final administration of MTEP to examine the chronic effect of MTEP. The control and DL groups did not have LID. The MTEP group had less LID than the LID group (p < .01) on day 1 and day 18. The control group had a typical triphasic pattern consisting of early excitation (early-Ex), inhibition, and late excitation (late-Ex). However, the inhibition phase disappeared, was partially observed, and was fully suppressed in the DL, LID, and MTEP groups, respectively. The cortico-striato-entopeduncular pathway is important in the pathophysiology of LID. mGluR5 antagonism suppresses LID progression by preventing physiological changes in the cortico-striato-entopeduncular pathway. Future studies are required to validate these results.

Clinical features of bipolar disorder with idiopathic basal ganglia calcification: a review of case reports in the literature.

Although idiopathic basal ganglia calcification (IBGC) is associated with various neuropsychiatric disturbances including several cases of bipolar disorder (BD), there has been no systematic review of clinical features of patients with BD and comorbid IBGC. We undertook a literature search to identify case reports of these patients. Most cases showed complex syndromes comprising not only mood disturbance but also cognitive disability and motor symptoms limited to depressive state and had favorable treatment response. These patients should have a careful and repeated psychiatric, neurological, and cognitive assessment to determine an optimal diagnostic and treatment approaches at each clinical stage.

Transgenic tools targeting the basal ganglia reveal both evolutionary conservation and specialization of neural circuits in zebrafish.

The cortico-basal ganglia circuit mediates decision making. Here, we generated transgenic tools for adult zebrafish targeting specific subpopulations of the components of this circuit and utilized them to identify evolutionary homologs of the mammalian direct- and indirect-pathway striatal neurons, which respectively project to the homologs of the internal and external segment of the globus pallidus (dorsal entopeduncular nucleus [dEN] and lateral nucleus of the ventral telencephalic area [Vl]) as in mammals. Unlike in mammals, the Vl mainly projects to the dEN directly, not by way of the subthalamic nucleus. Further single-cell RNA sequencing analysis reveals two pallidal output pathways: a major shortcut pathway directly connecting the dEN with the pallium and the evolutionarily conserved closed loop by way of the thalamus. Our resources and circuit map provide the common basis for the functional study of the basal ganglia in a small and optically tractable zebrafish brain for the comprehensive mechanistic understanding of the cortico-basal ganglia circuit.

Altered functional connectivity associated with striatal dopamine depletion in Parkinson's disease.

We aimed to clarify whether dopamine depletion in the posterior dorsal striatum in early-stage Parkinson's disease (PD) alters synchronized activity in the cortico-basal ganglia motor circuit. In sum, 14 PD patients and 16 matched healthy controls (HC) underwent [11C]-2-ß-carbomethoxy-3-ß-(4-fluorophenyl) tropane positron emission tomography to identify striatal dopamine-depleted areas. The identified map was applied to functional magnetic resonance imaging (fMRI) to discover abnormalities in functional connectivity (FC) during motor-task and rest-state in PD patients in the drug-off state relative to HC. Striatal dopamine-depleted areas formed synchronized fMRI activity that largely corresponded to the cortico-basal ganglia motor circuit. Group comparisons revealed that striatal dopamine-depleted areas exhibited decreased FC with the medial premotor cortex during motor-task and with the medial, lateral premotor and primary motor cortices during rest-state. Striatal dopamine-depleted areas also elucidated decreased FC in the subthalamic nucleus (STN) in PD both during motor-task and rest-state. The STN regions that exhibited reduced FC with striatal dopamine-depleted areas demonstrated excessive FC with the lateral premotor and primary motor cortices in PD only during rest-state. Our findings suggest that striatal dopamine-depleted area reduced synchronized activity with the motor cortices and STN, which, in turn, induces an abnormal increase in coupling between the areas in PD.

Episodic memory governs choices: An RNN-based reinforcement learning model for decision-making task.

Typical methods to study cognitive function are to record the electrical activities of animal neurons during the training of animals performing behavioral tasks. A key problem is that they fail to record all the relevant neurons in the animal brain. To alleviate this problem, we develop an RNN-based Actor-Critic framework, which is trained through reinforcement learning (RL) to solve two tasks analogous to the monkeys' decision-making tasks. The trained model is capable of reproducing some features of neural activities recorded from animal brain, or some behavior properties exhibited in animal experiments, suggesting that it can serve as a computational platform to explore other cognitive functions. Furthermore, we conduct behavioral experiments on our framework, trying to explore an open question in neuroscience: which episodic memory in the hippocampus should be selected to ultimately govern future decisions. We find that the retrieval of salient events sampled from episodic memories can effectively shorten deliberation time than common events in the decision-making process. The results indicate that salient events stored in the hippocampus could be prioritized to propagate reward information, and thus allow decision-makers to learn a strategy faster.

Altered Prefrontal-Basal Ganglia Effective Connectivity in Patients With Poststroke Cognitive Impairment.

We investigated the association between poststroke cognitive impairment and a specific effective network connectivity in the prefrontal-basal ganglia circuit. The resting-state effective connectivity of this circuit was modeled by employing spectral dynamic causal modeling in 11 poststroke patients with cognitive impairment (PSCI), 8 poststroke patients without cognitive impairment (non-PSCI) at baseline and 3-month follow-up, and 28 healthy controls. Our results showed that different neuronal models of effective connectivity in the prefrontal-basal ganglia circuit were observed among healthy controls, non-PSCI, and PSCI patients. Additional connected paths (extra paths) appeared in the neuronal models of stroke patients compared with healthy controls. Moreover, changes were detected in the extra paths of non-PSCI between baseline and 3-month follow-up poststroke, indicating reorganization in the ipsilesional hemisphere and suggesting potential compensatory changes in the contralesional hemisphere. Furthermore, the connectivity strengths of the extra paths from the contralesional ventral anterior nucleus of thalamus to caudate correlated significantly with cognitive scores in non-PSCI and PSCI patients. These suggest that the neuronal model of effective connectivity of the prefrontal-basal ganglia circuit may be sensitive to stroke-induced cognitive decline, and it could be a biomarker for poststroke cognitive impairment 3 months poststroke. Importantly, contralesional brain regions may play an important role in functional compensation of cognitive decline.

Brain structural correlates of depressive symptoms in Parkinson's disease patients at different disease stage.

Parkinson's disease (PD) pathology may damage emotion circuit and cause depression. We investigated whether the neural basis of depressive symptoms varies at different PD stages. Seventy-six healthy controls (HC) and 98 PD patients (divided into early and middle stage groups) underwent brain magnetic resonance imaging (MRI) and general neuropsychological tests. Voxel-based morphometry and tract-based analysis were used to study the association between brain structural alterations and the Hamilton Depression Scale 17 Item (HAMD-17) scores in different groups. Comparing with HC group, PD patients showed widespread brain alterations in both gray and white matter. The HAMD-17 scores were positively correlated with GM volume in the right pre-central gyrus of early PD patients. In the middle stage group, HAMD-17 scores were positively correlated with GM volume in midbrain and right superior temporal gyrus, and negatively associated with GM volume in left anterior cingulate and superior frontal gyrus. In white matter analysis, The HAMD-17 scores were positively correlated with fractional anisotropy value of the bilateral inferior fronto-occipital fasciculus in the early stage group, but not the middle stage group. We concluded that the neural basis of depressive symptoms might be distinct in different stages of PD, implying the need for differential treatments.

Dynamic Modulation of a Learned Motor Skill for Its Recruitment.

Humans learn motor skills (MSs) through practice and experience and may then retain them for recruitment, which is effective as a rapid response for novel contexts. For an MS to be recruited for novel contexts, its recruitment range must be extended. In addressing this issue, we hypothesized that an MS is dynamically modulated according to the feedback context to expand its recruitment range into novel contexts, which do not involve the learning of an MS. The following two sub-issues are considered. We previously demonstrated that the learned MS could be recruited in novel contexts through its modulation, which is driven by dynamically regulating the synergistic redundancy between muscles according to the feedback context. However, this modulation is trained in the dynamics under the MS learning context. Learning an MS in a specific condition naturally causes movement deviation from the desired state when the MS is executed in a novel context. We hypothesized that this deviation can be reduced with the additional modulation of an MS, which tunes the MS-produced muscle activities by using the feedback gain signals driven by the deviation from the desired state. Based on this hypothesis, we propose a feedback gain signal-driven tuning model of a learned MS for its robust recruitment. This model is based on the neurophysiological architecture in the cortico-basal ganglia circuit, in which an MS is plausibly retained as it was learned and is then recruited by tuning its muscle control signals according to the feedback context. In this study, through computational simulation, we show that the proposed model may be used to neurophysiologically describe the recruitment of a learned MS in novel contexts.

The Role of Group II Metabotropic Glutamate Receptors in the Striatum in Electroacupuncture Treatment of Parkinsonian Rats.

AIMS: Glutamatergic transmission may play a critical role in the pathogenesis of Parkinson's disease (PD). Electroacupuncture (EA) has been demonstrated to effectively alleviate PD symptoms. In this study, a potential glutamate-dependent mechanism underlying the therapeutic action of EA was investigated. METHODS: The effects of EA stimulation on motor behaviors, dopamine contents, glutamate release, and group II metabotropic glutamate receptor (mGluR2/3) expression in unilateral 6-hydroxydopamine (6-OHDA)-lesioned rats were examined. RESULTS: Unilateral 6-OHDA lesions of the nigrostriatal system caused a marked increase in glutamate content in the ipsilateral cortex and striatum. mGluR2/3 protein expression and mGluR3 mRNA expression were reduced in the striatum. Noticeably, prolonged EA stimulation at 100 Hz significantly reversed these changes in the striatal glutamate system. Behaviorally, EA improved the motor deficits induced by 6-OHDA lesions. Intrastriatal infusion of an mGluR2/3 antagonist APICA blocked the improving effect of EA. CONCLUSIONS: These data collectively demonstrate that the group II mGluR-mediated glutamatergic transmission in the striatum is sensitive to dopamine depletion and may serve as a substrate of EA for mediating the therapeutic effect of EA in a rat model of PD.

Roles of Multiple Globus Pallidus Territories of Monkeys and Humans in Motivation, Cognition and Action: An Anatomical, Physiological and Pathophysiological Review.

The globus pallidus (GP) communicates with widespread cortical areas that support various functions, including motivation, cognition and action. Anatomical tract-tracing studies revealed that the anteroventral GP communicates with the medial prefrontal and orbitofrontal cortices, which are involved in motivational control; the anterodorsal GP communicates with the lateral prefrontal cortex, which is involved in cognitive control; and the posterior GP communicates with the frontal motor cortex, which is involved in action control. This organization suggests that distinct subdivisions within the GP play specific roles. Neurophysiological studies examining GP neurons in monkeys during behavior revealed that the types of information coding performed within these subdivisions differ greatly. The anteroventral GP is characterized by activities related to motivation, such as reward seeking and aversive avoidance; the anterodorsal GP is characterized by activity that reflects cognition, such as goal decision and action selection; and the posterior GP is characterized by activity associated with action preparation and execution. Pathophysiological studies have shown that GABA-related substances or GP lesions result in abnormal activity in the GP, which causes site-specific behavioral and motor symptoms. The present review article discusses the anatomical organization, physiology and pathophysiology of the three major GP territories in nonhuman primates and humans.