Subthalamic Activity for Motor Execution and Cancelation in Monkeys.

The subthalamic nucleus (STN) receives cortical inputs via the hyperdirect and indirect 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 (Macaca fuscata, both sexes) who performed a goal-directed reaching task with a delay that included Go, Cancel, and NoGo trials. We first examined responses to the stimulation of the forelimb regions in the primary motor cortex and/or supplementary motor area. STN neurons with motor cortical inputs were found in the dorsal somatomotor region of the STN. All these STN neurons showed activity changes in Go trials, suggesting their involvement in execution of movements. Part of them exhibited activity changes in Cancel trials and sustained activity during delay periods, suggesting their involvement in cancelation of planed movements and preparation of movements, respectively. The STN neurons rarely showed activity changes in NoGo trials. Go- and Cancel-related activity was selective to the direction of movements, and the selectivity was higher in Cancel trials than in Go trials. Changes in Go- and Cancel-related activity occurred early enough to initiate and cancel movements, respectively. These results suggest that the dorsal somatomotor region of the STN, which receives motor cortical inputs, is involved in preparation and execution of movements and cancelation of planned movements.

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. On the other hand, many studies have so far been performed in monkeys to clarify the functions of the basal ganglia in the healthy and diseased states, but have not paid much attention to such classification and functional differences of GPe neurons. In this minireview, we consider the knowledge on the rodent GPe and discuss its impact on the understanding of the basal ganglia circuitry in monkeys.

LGI1-ADAM22-MAGUK configures transsynaptic nanoalignment for synaptic transmission and epilepsy prevention.

Physiological functioning and homeostasis of the brain rely on finely tuned synaptic transmission, which involves nanoscale alignment between presynaptic neurotransmitter-release machinery and postsynaptic receptors. However, the molecular identity and physiological significance of transsynaptic nanoalignment remain incompletely understood. Here, we report that epilepsy gene products, a secreted protein LGI1 and its receptor ADAM22, govern transsynaptic nanoalignment to prevent epilepsy. We found that LGI1-ADAM22 instructs PSD-95 family membrane-associated guanylate kinases (MAGUKs) to organize transsynaptic protein networks, including NMDA/AMPA receptors, Kv1 channels, and LRRTM4-Neurexin adhesion molecules. Adam22ΔC5/ΔC5 knock-in mice devoid of the ADAM22-MAGUK interaction display lethal epilepsy of hippocampal origin, representing the mouse model for ADAM22-related epileptic encephalopathy. This model shows less-condensed PSD-95 nanodomains, disordered transsynaptic nanoalignment, and decreased excitatory synaptic transmission in the hippocampus. Strikingly, without ADAM22 binding, PSD-95 cannot potentiate AMPA receptor-mediated synaptic transmission. Furthermore, forced coexpression of ADAM22 and PSD-95 reconstitutes nano-condensates in nonneuronal cells. Collectively, this study reveals LGI1-ADAM22-MAGUK as an essential component of transsynaptic nanoarchitecture for precise synaptic transmission and epilepsy prevention.

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. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

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. After cortico-STN elimination, cortically evoked early excitation in the SNr was diminished, while the cortically evoked inhibition and late excitation, which are delivered through the direct and indirect pathways, respectively, were unchanged. In addition, locomotor activity was significantly increased after bilateral cortico-STN elimination, and apomorphine-induced ipsilateral rotations were observed after unilateral cortico-STN elimination, suggesting that cortical activity was increased. These results are compatible with the notion that the cortico-STN-SNr hyperdirect pathway quickly conveys cortical excitation to the output station of the basal ganglia, resets or suppresses the cortical activity related to ongoing movements, and prepares for the forthcoming movement.SIGNIFICANCE STATEMENT The basal ganglia play a pivotal role in the control of voluntary movements, and their malfunctions lead to movement disorders, such as Parkinson's disease and dystonia. Understanding their functions is important to find better treatments for such diseases. Here we used a photodynamic technique to selectively eliminate the projection from the motor cortex to the subthalamic nucleus, the input station of the basal ganglia, and found greatly reduced early excitatory signals from the cortex to the output station of the basal ganglia and motor hyperactivity. These results suggest that the neuronal signals through the cortico-subthalamic hyperdirect pathway reset or suppress ongoing movements and that blockade of this pathway may be beneficial for Parkinson's disease, which is characterized by oversuppression of movements.

Abnormal Cortico-Basal Ganglia Neurotransmission in a Mouse Model of l-DOPA-Induced Dyskinesia.

l-3,4-dihydroxyphenylalanine (l-DOPA) is an effective treatment for Parkinson's disease (PD); however, long-term treatment induces l-DOPA-induced dyskinesia (LID). To elucidate its pathophysiology, we developed a mouse model of LID by daily administration of l-DOPA to PD male ICR mice treated with 6-hydroxydopamine (6-OHDA), and recorded the spontaneous and cortically evoked neuronal activity in the external segment of the globus pallidus (GPe) and substantia nigra pars reticulata (SNr), the connecting and output nuclei of the basal ganglia, respectively, in awake conditions. Spontaneous firing rates of GPe neurons were decreased in the dyskinesia-off state (≥24 h after l-DOPA injection) and increased in the dyskinesia-on state (20-100 min after l-DOPA injection while showing dyskinesia), while those of SNr neurons showed no significant changes. GPe and SNr neurons showed bursting activity and low-frequency oscillation in the PD, dyskinesia-off, and dyskinesia-on states. In the GPe, cortically evoked late excitation was increased in the PD and dyskinesia-off states but decreased in the dyskinesia-on state. In the SNr, cortically evoked inhibition was largely suppressed, and monophasic excitation became dominant in the PD state. Chronic l-DOPA treatment partially recovered inhibition and suppressed late excitation in the dyskinesia-off state. In the dyskinesia-on state, inhibition was further enhanced, and late excitation was largely suppressed. Cortically evoked inhibition and late excitation in the SNr are mediated by the cortico-striato-SNr direct and cortico-striato-GPe-subthalamo-SNr indirect pathways, respectively. Thus, in the dyskinesia-on state, signals through the direct pathway that release movements are enhanced, while signals through the indirect pathway that stop movements are suppressed, underlying LID.SIGNIFICANCE STATEMENT Parkinson's disease (PD) is caused by progressive loss of midbrain dopaminergic neurons, characterized by tremor, rigidity, and akinesia, and estimated to affect around six million people world-wide. Dopamine replacement therapy is the gold standard for PD treatment; however, control of symptoms using l-3,4-dihydroxyphenylalanine (l-DOPA) becomes difficult over time because of abnormal involuntary movements (AIMs) known as l-DOPA-induced dyskinesia (LID), one of the major issues for advanced PD. Our electrophysiological data suggest that dynamic changes in the basal ganglia circuitry underlie LID; signals through the direct pathway that release movements are enhanced, while signals through the indirect pathway that stop movements are suppressed. These results will provide the rationale for the development of more effective treatments for LID.

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. In the normal state, cortical stimulation induced a triphasic response composed of early excitation, inhibition, and late excitation in the GPi and GPe. In the PD state, cortically evoked inhibition in the GPi mediated by the cortico-striato-GPi "direct" pathway was largely diminished, whereas late excitation in the GPe mediated by the cortico-striato-GPe-subthalamo (STN)-GPe pathway was elongated. l-DOPA treatment ameliorated PD signs, particularly akinesia/bradykinesia, and normalized cortically evoked responses in both the GPi and GPe. STN blockade by muscimol injection ameliorated the motor deficit and unmasked cortically evoked inhibition in the GPi. These results suggest that information flow through the direct pathway responsible for the initiation of movements is largely reduced in PD and fails to release movements, resulting in akinesia/bradykinesia. Restoration of the information flow through the direct pathway recovers execution of voluntary movements.

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. Thus, clarifying how STN neuronal activity is controlled by the two inputs is crucial. Cortical stimulation evokes early excitation and late excitation in STN neurons, intervened by a short gap. Here, to examine the origin of each component of this biphasic response, we recorded neuronal activity in the STN, combined with electrical stimulation of the motor cortices and local drug application in two male monkeys (Macaca fuscata) in the awake state. Local application of glutamate receptor antagonists, a mixture of an AMPA/kainate receptor antagonist and an NMDA receptor antagonist, into the vicinity of recorded STN neurons specifically diminished early excitation. Blockade of the striatum (putamen) or GPe with local injection of a GABAA receptor agonist, muscimol, diminished late excitation in the STN. Blockade of striato-GPe transmission with local injection of a GABAA receptor antagonist, gabazine, into the GPe also abolished late excitation. These results indicate that cortically evoked early and late excitation in the STN is mediated by the cortico-STN glutamatergic hyperdirect and the cortico-striato-GPe-STN indirect pathways, respectively.SIGNIFICANCE STATEMENT Here we show that the subthalamic nucleus (STN), an input station of the basal ganglia, receives cortical inputs through the cortico-STN hyperdirect and cortico-striato-external pallido-STN indirect pathways. This knowledge is important for understanding not only the normal functions of the STN, but also the pathophysiology of STN-related disorders and therapy targeting the STN. Lesions or application of high-frequency stimulation in the STN ameliorates parkinsonian symptoms. These procedures could affect all components in the STN, such as afferent inputs through the hyperdirect and indirect pathways, and STN neuronal activity. If we can understand which component is most affected by such procedures, we may be able to identify more effective manipulation targets or methods to treat Parkinson's disease.

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. On the other hand, coincident spikes among neurons, that is, correlated activity, may also contribute to motor control. To address this issue, we first identified multiple pallidal neurons receiving inputs from the forelimb regions of the primary motor cortex and supplementary motor area, recorded neuronal activity of these neurons simultaneously, and analyzed their spike correlations while monkeys performed a hand-reaching task. Most (79%) pallidal neurons exhibited task-related firing rate changes, whereas only a small fraction (20%) showed significant but small and short correlated activity during the task performance. These results suggest that motor control signals are conveyed primarily by firing rate changes in the external and internal segments of the globus pallidus and that the contribution of correlated activity may play only a minor role in the healthy state.

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. To address the questions whether the disruption of Dst in Schwann cells induces movement disorders and how much impact does it have on dt phenotypes, we generated Dst conditional knockout (cKO) mice using P0-Cre transgenic mice and Dst gene trap mice. First, we assessed the P0-Cre transgene-dependent Cre recombination using tdTomato reporter mice and then confirmed the preferential tdTomato expression in Schwann cells. In the Dst cKO mice, Dst mRNA expression was significantly decreased in Schwann cells, but it was intact in most of the sensory neurons in the dorsal root ganglion. Next, we analyzed the phenotype of Dst cKO mice. They exhibited a normal motor phenotype during juvenile periods, and thereafter, started exhibiting an ataxia. Behavioral tests and electrophysiological analyses demonstrated impaired motor abilities and slowed motor nerve conduction velocity in Dst cKO mice, but these mice did not manifest dystonic movements. Electron microscopic observation of the PNS of Dst cKO mice revealed significant numbers of hypomyelinated axons and numerous infiltrating macrophages engulfing myelin debris. These results indicate that Dst is important for normal PNS myelin organization and Dst disruption in Schwann cells induces late-onset neuropathy and sensory ataxia. MAIN POINTS: Dystonin (Dst) disruption in Schwann cells results in late-onset neuropathy and sensory ataxia. Dst in Schwann cells is important for normal myelin organization in the peripheral nervous system.

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. Light stimulation typically induced a triphasic response composed of early excitation, inhibition, and late excitation in GP/EPN neurons. Other response patterns lacking 1 or 2 of the components were also observed. The distribution of the cortical sites whose stimulation induced a triphasic response was confined, whereas stimulation of the large surrounding areas induced early and late excitation without inhibition. Our results suggest that cortical inputs to the GP/EPN are organized in a "local inhibitory and global excitatory" manner. Such organization seems to be the neuronal basis for information processing through the cortico-basal ganglia pathways, that is, releasing and terminating necessary information at an appropriate timing, while simultaneously suppressing other unnecessary information.

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. To investigate whether Dst is the causative gene of the novel mutant phenotype, we crossed the mutant with Dst gene trap (DstGt) mice. Compound heterozygotes showed a typical dt phenotype with sensory degeneration and progressive motor symptoms. DNA sequencing analysis identified a nonsense mutation within the spectrin repeats of the plakin domain. The novel mutant allele was named dt23Rbrc. Motor abnormalities in homozygous dt23Rbrc/dt23Rbrc mice are not as severe as homozygous DstGt/DstGt mice. Histological analyses showed abnormal neurofilament (NF) accumulation in the nervous system of homozygous dt23Rbrc/dt23Rbrc mice, which is characteristic of the dt phenotype. We mapped the distribution of abnormal NF-accumulated neurons in the brain and found that they were located specifically in the brainstem, spinal cord, and in regions such as the vestibular nucleus, reticular nucleus, and red nucleus, which are implicated in posture and motor coordination pathways. The quantification of abnormal NF accumulation in the cytoplasm and spheroids (axons) of neurons showed that abnormal NF immunoreactivity was lower in homozygous dt23Rbrc/dt23Rbrc mice than in homozygous DstGt/DstGt mice. Therefore, we have identified a novel hypomorphic allele of dt, which causes histological abnormalities in the central nervous system that may account for the abnormal motor phenotype. This novel spontaneously occurring mutant may become a good model of hereditary sensory and autonomic neuropathy type 6, which is caused by mutations in the human DST gene.

Dopamine D1 Receptor-Mediated Transmission Maintains Information Flow Through the Cortico-Striato-Entopeduncular Direct Pathway to Release Movements.

In the basal ganglia (BG), dopamine plays a pivotal role in motor control, and dopamine deficiency results in severe motor dysfunctions as seen in Parkinson's disease. According to the well-accepted model of the BG, dopamine activates striatal direct pathway neurons that directly project to the output nuclei of the BG through D1 receptors (D1Rs), whereas dopamine inhibits striatal indirect pathway neurons that project to the external pallidum (GPe) through D2 receptors. To clarify the exact role of dopaminergic transmission via D1Rs in vivo, we developed novel D1R knockdown mice in which D1Rs can be conditionally and reversibly regulated. Suppression of D1R expression by doxycycline treatment decreased spontaneous motor activity and impaired motor ability in the mice. Neuronal activity in the entopeduncular nucleus (EPN), one of the output nuclei of the rodent BG, was recorded in awake conditions to examine the mechanism of motor deficits. Cortically evoked inhibition in the EPN mediated by the cortico-striato-EPN direct pathway was mostly lost during suppression of D1R expression, whereas spontaneous firing rates and patterns remained unchanged. On the other hand, GPe activity changed little. These results suggest that D1R-mediated dopaminergic transmission maintains the information flow through the direct pathway to appropriately release motor actions.

High-frequency pallidal stimulation disrupts information flow through the pallidum by GABAergic inhibition.

To elucidate the mechanism of deep brain stimulation (DBS) targeting the internal segment of the globus pallidus (GPi), neuronal activity of the GPi and the external segment of the globus pallidus (GPe) was examined during local electrical microstimulation in normal awake monkeys. Single-pulse stimulation of the GPi evoked brief inhibition in neighboring GPi neurons, which was mediated by GABA(A) receptors. High-frequency stimulation of the GPi completely inhibited spontaneous firings of GPi neurons by activation of GABA(A) and GABA(B) receptors. Local single-pulse stimulation directly excited some GPi neurons. Such directly evoked responses were also inhibited by high-frequency stimulation through GABA(A) receptors. In contrast to the GPi, single-pulse and high-frequency stimulation of the GPe induced complex responses composed of GABAergic inhibition and glutamatergic excitation in neighboring GPe neurons. Cortically evoked triphasic responses of GPi neurons were completely inhibited during high-frequency GPi stimulation. These findings suggest that GPi-DBS dissociates inputs and outputs in the GPi by intense GABAergic inhibition and disrupts information flow through the GPi.

Signals through the striatopallidal indirect pathway stop movements by phasic excitation in the substantia nigra.

The striatum and subthalamic nucleus (STN) are the input stations of the basal ganglia and receive excitatory afferents from the cerebral cortex. The basal ganglia control voluntary movements through three parallel pathways mediated by the input stations: the hyperdirect pathway, which conveys direct cortical inputs to the substantia nigra pars reticulata (SNr), the output nucleus, through the STN; the direct pathway, which arises from striatal neurons expressing dopamine D1 receptors and projects to the SNr; and the indirect pathway, which arises from striatal neurons expressing dopamine D2 receptors (D2Rs) and projects indirectly to the SNr by way of the globus pallidus (GP) and STN. Our previous study showed that immunotoxin-mediated cell targeted ablation of D2R-expressing striatal neurons in mice induced motor hyperactivity. To elucidate the mechanism underlying the hyperactivity, here we examined neuronal activity in the GP and SNr. The ablation of D2R-expressing striatal neurons had little effect on spontaneous activity in the GP and SNr, but induced dramatic changes in the cortically evoked triphasic response composed of early excitation, inhibition, and late excitation in the GP and SNr (i.e., reduced inhibition in the GP, and reduced late excitation in the GP and SNr). In contrast, the ablation of striatal cholinergic interneurons, which also express D2Rs, did not show such effects. Therefore, the reduction of the cortically evoked late excitation in the SNr seems to be responsible for hyperactivity. These observations suggest that phasic late excitation in the SNr through the striatopallidal indirect pathway plays a key role in stopping movements.

Disruption of actin-binding domain-containing Dystonin protein causes dystonia musculorum in mice.

The Dystonin gene (Dst) is responsible for dystonia musculorum (dt), an inherited mouse model of hereditary neuropathy accompanied by progressive motor symptoms such as dystonia and cerebellar ataxia. Dst-a isoforms, which contain actin-binding domains, are predominantly expressed in the nervous system. Although sensory neuron degeneration in the peripheral nervous system during the early postnatal stage is a well-recognised phenotype in dt, the histological characteristics and neuronal circuits in the central nervous system responsible for motor symptoms remain unclear. To analyse the causative neuronal networks and roles of Dst isoforms, we generated novel multipurpose Dst gene trap mice, in which actin-binding domain-containing isoforms are disrupted. Homozygous mice showed typical dt phenotypes with sensory degeneration and progressive motor symptoms. The gene trap allele (Dst(Gt) ) encodes a mutant Dystonin-LacZ fusion protein, which is detectable by X-gal (5-bromo-4-chloro-3-indolyl-ß-D-galactoside) staining. We observed wide expression of the actin-binding domain-containing Dystonin isoforms in the central nervous system (CNS) and peripheral nervous system. This raised the possibility that not only secondary neuronal defects in the CNS subsequent to peripheral sensory degeneration but also cell-autonomous defects in the CNS contribute to the motor symptoms. Expression analysis of immediate early genes revealed decreased neuronal activity in the cerebellar-thalamo-striatal pathway in the homozygous brain, implying the involvement of this pathway in the dt phenotype. These novel Dst(Gt) mice showed that a loss-of-function mutation in the actin-binding domain-containing Dystonin isoforms led to typical dt phenotypes. Furthermore, this novel multipurpose Dst(Gt) allele offers a unique tool for analysing the causative neuronal networks involved in the dt phenotype.

[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. Among three components, cortically induced inhibition, which is mediated by the direct pathway, releases an appropriate movement at an appropriate time by disinhibiting thalamic and cortical activity, whereas early and late excitation, which is mediated by the hyperdirect and indirect pathways, resets on-going cortical activity and stops movements, respectively. Cortically induced triphasic response patterns are systematically altered in various movement disorder models and could well explain the pathophysiology of their motor symptoms. In monkey and mouse models of Parkinson's disease, cortically induced inhibition is reduced and prevents the release of movements, resulting in akinesia/bradykinesia. On the other hand, in a mouse model of dystonia, cortically induced inhibition is enhanced and releases unintended movements, inducing involuntary muscle contractions. Moreover, after blocking the subthalamic nucleus activity in a monkey model of Parkinson's disease, cortically induced inhibition is recovered and enables voluntary movements, explaining the underlying mechanism of stereotactic surgery to ameliorate parkinsonian motor signs. The "dynamic activity model" gives us a more comprehensive view of the pathophysiology underlying motor symptoms of movement disorders and clues for their novel therapies.

Exposure to the cytokine EGF leads to abnormal hyperactivity of pallidal GABA neurons: implications for schizophrenia and its modeling.

Previous studies on a cytokine model for schizophrenia reveal that the hyperdopaminergic innervation and neurotransmission in the globus pallidus (GP) is involved in its behavioral impairments. Here, we further explored the physiological consequences of the GP abnormality in the indirect pathway, using the same schizophrenia model established by perinatal exposure to epidermal growth factor (EGF). Single-unit recordings revealed that the neural activity from the lateral GP was elevated in EGF-treated rats in vivo and in vitro (i.e., slice preparations), whereas the central area of the GP exhibited no significant differences. The increase in the pallidal activity was normalized by subchronic treatment with risperidone, which is known to ameliorate their behavioral deficits. We also monitored extracellular GABA concentrations in the substantia nigra, one of the targets of pallidal efferents. There was a significant increase in basal GABA levels in EGF-treated rats, whereas high potassium-evoked GABA effluxes and glutamate levels were not affected. A neurotoxic lesion in the GP of EGF-treated rats normalized GABA concentrations to control levels. Corroborating our in vivo results, GABA release from GP slices was elevated in EGF-treated animals. These findings suggest that the hyperactivity and enhanced GABA release of GP neurons represent the key pathophysiological features of this cytokine-exposure model for schizophrenia.

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. Systemic administration of chemogenetic ligands prolongs movement time and increases spike train variability in the pallidum, but only slightly affects firing rate modulations. Across-trial analyses reveal that the irregular discharges in the pallidum coincides with prolonged movement time. Reduction of subthalamic activity also induces excessive abnormal movements in the contralateral forelimb, which are preceded by subthalamic and pallidal phasic activity changes. Our results suggest that the subthalamic nucleus stabilizes pallidal spike trains and achieves stable movements.

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. We trained two monkeys to perform an upper limb reaching task and rendered them parkinsonian with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Bipolar intracortical recording electrodes were implanted in the M1, and a recording chamber was attached to access the STN. In aDBS, the M1 LFPs were recorded, filtered into the γ2 band, and discretized into logic pulses by a window discriminator, and the pulses were used to modulate the interval and amplitude of DBS pulses. In constant DBS (cDBS), constant stimulus intervals and amplitudes were used. Reaction and movement times during the task were measured and compared between aDBS and cDBS. The M1-γ2 activities were increased before and during movements in parkinsonian monkeys and these activities modulated the aDBS pulse interval, amplitude, and dispersion. With aDBS and cDBS, reaction and movement times were significantly decreased in comparison to DBS-OFF. The electric charge delivered was lower with aDBS than cDBS. M1-γ2 aDBS in parkinsonian monkeys resulted in clinical benefits that did not exceed those from cDBS. However, M1-γ2 aDBS achieved this magnitude of benefit for only two thirds of the charge delivered by cDBS. In conclusion, M1-γ2 aDBS is an effective therapeutic approach which requires a lower electrical charge delivery than cDBS for comparable clinical benefits.