Sensory-motor circuit is a therapeutic target for mice, a model of hereditary sensory and autonomic neuropathy 6.

Mutations in Dystonin (), which encodes cytoskeletal linker proteins, cause hereditary sensory and autonomic neuropathy 6 (HSAN-VI) in humans and the () phenotype in mice; however, the neuronal circuit underlying the HSAN-VI and phenotype is unresolved. mice exhibit dystonic movements accompanied by the simultaneous contraction of agonist and antagonist muscles and postnatal lethality. Here, we identified the sensory-motor circuit as a major causative neural circuit using a gene trap system that enables neural circuit-selective inactivation and restoration of by Cre-mediated recombination.

[Dynamic activity model of movement disorders: a unified view to understand their pathophysiology].

Malfunction of the basal ganglia leads to movement disorders such as Parkinson's disease, dystonia, Huntington's disease, dyskinesia, and hemiballism, but their underlying pathophysiology is still subject to debate. To understand their pathophysiology in a unified manner, we propose the "dynamic activity model", on the basis of alterations of cortically induced responses in individual nuclei of the basal ganglia. In the normal state, electric stimulation in the motor cortex, mimicking cortical activity during initiation of voluntary movements, evokes a triphasic response consisting of early excitation, inhibition, and late excitation in the output stations of the basal ganglia of monkeys, rodents, and humans.

Subthalamic Activity for Motor Execution and Cancelation in Monkeys.

The subthalamic nucleus (STN) receives cortical inputs via the and pathways, projects to the output nuclei of the basal ganglia, and plays a critical role in the control of voluntary movements and movement disorders. STN neurons change their activity during execution of movements, while recent studies emphasize STN activity specific to cancelation of movements. To address the relationship between execution and cancelation functions, we examined STN activity in two Japanese monkeys (, both sexes) who performed a goal-directed reaching task with a delay that included Go, Cancel, and NoGo trials.

External segment of the globus pallidus in health and disease: Its interactions with the striatum and subthalamic nucleus.

The external segment of the globus pallidus (GPe) has long been considered a homogeneous structure that receives inputs from the striatum and sends processed information to the subthalamic nucleus, composing a relay nucleus of the indirect pathway that contributes to movement suppression. Recent methodological revolution in rodents led to the identification of two distinct cell types in the GPe with different fiber connections. The GPe may be regarded as a dynamic, complex and influential center within the basal ganglia circuitry, rather than a simple relay nucleus.

Dynamic Activity Model of Movement Disorders: The Fundamental Role of the Hyperdirect Pathway.

Schematic illustration of cortically induced dynamic activity changes of the output nuclei of the basal ganglia (the internal segment of the globus pallidus, GPi and the substantia nigra pars reticulata, SNr) in the healthy and diseased states. The height of the dam along the time course controls the expression of voluntary movements. Its alterations could cause a variety of movement disorders, such as Parkinson's disease and hyperkinetic disorders.

Cerebro-cerebellar interactions in nonhuman primates examined by optogenetic functional magnetic resonance imaging.

Functional magnetic resonance imaging (fMRI) is a promising approach for the simultaneous and extensive scanning of whole-brain activities. Optogenetics is free from electrical and magnetic artifacts and is an ideal stimulation method for combined use with fMRI. However, the application of optogenetics in nonhuman primates (NHPs) remains limited.

Subthalamic nucleus stabilizes movements by reducing neural spike variability in monkey basal ganglia.

The subthalamic nucleus projects to the external and internal pallidum, the modulatory and output nuclei of the basal ganglia, respectively, and plays an indispensable role in controlling voluntary movements. However, the precise mechanism by which the subthalamic nucleus controls pallidal activity and movements remains elusive. Here, we utilize chemogenetics to reversibly reduce neural activity of the motor subregion of the subthalamic nucleus in three macaque monkeys (Macaca fuscata, both sexes) during a reaching task.

Subthalamic nucleus deep brain stimulation driven by primary motor cortex γ2 activity in parkinsonian monkeys.

In parkinsonism, subthalamic nucleus (STN) electrical deep brain stimulation (DBS) improves symptoms, but may be associated with side effects. Adaptive DBS (aDBS), which enables modulation of stimulation, may limit side effects, but limited information is available about clinical effectiveness and efficaciousness. We developed a brain-machine interface for aDBS, which enables modulation of stimulation parameters of STN-DBS in response to γ2 band activity (80-200 Hz) of local field potentials (LFPs) recorded from the primary motor cortex (M1), and tested its effectiveness in parkinsonian monkeys.

Transient Response of Basal Ganglia Network in Healthy and Low-Dopamine State.

The basal ganglia (BG) are crucial for a variety of motor and cognitive functions. Changes induced by persistent low-dopamine (e.g.

Altered Dynamic Information Flow through the Cortico-Basal Ganglia Pathways Mediates Parkinson's Disease Symptoms.

Parkinson's disease (PD) is a progressive neurodegenerative disorder caused by dopamine deficiency. To elucidate network-level changes through the cortico-basal ganglia pathways in PD, we recorded neuronal activity in PD monkeys treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. We applied electrical stimulation to the motor cortices and examined responses in the internal (GPi) and external (GPe) segments of the globus pallidus, the output and relay nuclei of the basal ganglia, respectively.

Elimination of the Cortico-Subthalamic Hyperdirect Pathway Induces Motor Hyperactivity in Mice.

The substantia nigra pars reticulata (SNr) is the output station of the basal ganglia and receives cortical inputs by way of the following three basal ganglia pathways: the cortico-subthalamo (STN)-SNr hyperdirect, the cortico-striato-SNr direct, and the cortico-striato-external pallido-STN-SNr indirect pathways. Compared with the classical direct and indirect pathways via the striatum, the functions of the hyperdirect pathway remain to be fully elucidated. Here we used a photodynamic technique to selectively eliminate the cortico-STN projection in male mice and observed neuronal activity and motor behaviors in awake conditions.

[Parkinson's Disease as a Network Disorder].

Network disorders of the basal ganglia may underlie the pathophysiology of movement disorders, such as Parkinson's disease and dystonia. The following models have been proposed to explain network disorders: (1) the firing rate model: an activity imbalance between the direct, indirect, and hyperdirect pathways induces changes in the mean firing rate of the output nuclei of the basal ganglia and causes hypokinetic or hyperkinetic movement disorders, (2) the firing pattern model: oscillatory and/or synchronized activity in the basal ganglia disturbs information processing in this area, resulting in motor symptoms and, (3) the dynamic activity model: abnormal neuronal modulations through the direct, indirect, and hyperdirect pathways disrupt the balance between movement-related inhibition and surrounding excitation in the output nuclei, which leads to motor symptoms. We present a critical analysis of these models in this review.

Cortical Control of Subthalamic Neuronal Activity through the Hyperdirect and Indirect Pathways in Monkeys.

The subthalamic nucleus (STN) plays a key role in the control of voluntary movements and basal ganglia disorders, such as Parkinson's disease and hemiballismus. The STN receives glutamatergic inputs directly from the cerebral cortex via the cortico-STN hyperdirect pathway and GABAergic inputs from the external segment of the globus pallidus (GPe) via the cortico-striato-GPe-STN indirect pathway. The STN then drives the internal segment of the globus pallidus, which is the output nucleus of the basal ganglia.

Weakly correlated activity of pallidal neurons in behaving monkeys.

The basal ganglia play a crucial role in the control of voluntary movements. Neurons in both the external and internal segments of the globus pallidus, the connecting and output nuclei of the basal ganglia, respectively, change their firing rates in relation to movements. Firing rate changes of movement-related neurons seem to convey signals for motor control.

Forelimb movements evoked by optogenetic stimulation of the macaque motor cortex.

Optogenetics has become an indispensable tool for investigating brain functions. Although non-human primates are particularly useful models for understanding the functions and dysfunctions of the human brain, application of optogenetics to non-human primates is still limited. In the present study, we generate an effective adeno-associated viral vector serotype DJ to express channelrhodopsin-2 (ChR2) under the control of a strong ubiquitous CAG promoter and inject into the somatotopically identified forelimb region of the primary motor cortex in macaque monkeys.

Disruption of dystonin in Schwann cells results in late-onset neuropathy and sensory ataxia.

Dystonin (Dst) is a causative gene for Dystonia musculorum (dt) mice, which is an inherited disorder exhibiting dystonia-like movement and ataxia with sensory degeneration. Dst is expressed in a variety of tissues, including the central nervous system and the peripheral nervous system (PNS), muscles, and skin. However, the Dst-expressing cell type(s) for dt phenotypes have not been well characterized.

Cerebellar outputs contribute to spontaneous and movement-related activity in the motor cortex of monkeys.

Cerebellar outputs originate from the dentate nucleus (DN), project to the primary motor cortex (M1) via the motor thalamus, control M1 activity, and play an essential role in coordinated movements. However, it is unclear when and how the cerebellar outputs contribute to M1 activity. To address this question, we examined the response of M1 neurons to electrical stimulation of the DN and M1 activity during performance of arm-reaching tasks.

Parkinsonism Differently Affects the Single Neuronal Activity in the Primary and Supplementary Motor Areas in Monkeys: An Investigation in Linear and Nonlinear Domains.

The changes in neuronal firing activity in the primary motor cortex (M1) and supplementary motor area (SMA) were compared in monkeys rendered parkinsonian by treatment with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. The neuronal dynamic was characterized using mathematical tools defined in different frameworks (rate, oscillations or complex patterns). Then, and for each cortical area, multivariate and discriminate analyses were further performed on these features to identify those important to differentiate between the normal and the pathological neuronal activity.

Local field potential dynamics in the primate cortex in relation to parkinsonism reveled by machine learning: A comparison between the primary motor cortex and the supplementary area.

The present study compares the cortical local field potentials (LFPs) in the primary motor cortex (M1) and the supplementary motor area (SMA) of non-human primates rendered Parkinsonian with administration of dopaminergic neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. The dynamic of the LFPs was investigated under several mathematical frameworks and machine learning was used to discriminate the recordings based on these features between healthy, parkinsonian with off-medication and parkinsonian with on-medication states. The importance of each feature in the discrimination process was further investigated.

Monitoring and Updating of Action Selection for Goal-Directed Behavior through the Striatal Direct and Indirect Pathways.

The basal ganglia play key roles in adaptive behaviors guided by reward and punishment. However, despite accumulating knowledge, few studies have tested how heterogeneous signals in the basal ganglia are organized and coordinated for goal-directed behavior. In this study, we investigated neuronal signals of the direct and indirect pathways of the basal ganglia as rats performed a lever push/pull task for a probabilistic reward.

Development of stereotaxic recording system for awake marmosets (Callithrix jacchus).

The common marmoset has been proposed as a potential alternative to macaque monkey as a primate model for neuroscience and medical research. Here, we have newly developed a stereotaxic neuronal recording system for awake marmosets under the head-fixed condition by modifying that for macaque monkeys. Using this system, we recorded neuronal activity in the cerebral cortex of awake marmosets and successfully identified the primary motor cortex by intracortical microstimulation.

Optogenetic Activation of the Sensorimotor Cortex Reveals "Local Inhibitory and Global Excitatory" Inputs to the Basal Ganglia.

To understand how information from different cortical areas is integrated and processed through the cortico-basal ganglia pathways, we used optogenetics to systematically stimulate the sensorimotor cortex and examined basal ganglia activity. We utilized Thy1-ChR2-YFP transgenic mice, in which channelrhodopsin 2 is robustly expressed in layer V pyramidal neurons. We applied light spots to the sensorimotor cortex in a grid pattern and examined neuronal responses in the globus pallidus (GP) and entopeduncular nucleus (EPN), which are the relay and output nuclei of the basal ganglia, respectively.

Characterization of novel dystonia musculorum mutant mice: Implications for central nervous system abnormality.

We identified a novel spontaneous mutant mouse showing motor symptoms that are similar to those of the dystonia musculorum (dt) mouse. The observations suggested that the mutant mice inherited the mild dt phenotype as an autosomal recessive trait. Linkage analysis showed that the causative gene was located near D1Mit373 and D1Mit410 microsatellite markers on chromosome 1, which are close to the dystonin (Dst) gene locus.