Dysfunction of motor cortices in Parkinson's disease.

The cerebral cortex has long been thought to be involved in the pathophysiology of motor symptoms of Parkinson's disease. The impaired cortical function is believed to be a direct and immediate effect of pathologically patterned basal ganglia output, mediated to the cerebral cortex by way of the ventral motor thalamus. However, recent studies in humans with Parkinson's disease and in animal models of the disease have provided strong evidence suggesting that the involvement of the cerebral cortex is much broader than merely serving as a passive conduit for subcortical disturbances. In the present review, we discuss Parkinson's disease-related changes in frontal cortical motor regions, focusing on neuropathology, plasticity, changes in neurotransmission, and altered network interactions. We will also examine recent studies exploring the cortical circuits as potential targets for neuromodulation to treat Parkinson's disease.

Can Virtual Reality-Assisted Therapy Offer Additional Benefits to Patients With Vestibular Disorders Compared With Conventional Vestibular Physical Therapy? A Meta-analysis.

OBJECTIVE: To determine whether virtual reality-assisted therapy (VRAT) significantly improves the treatment of peripheral or central vestibular disorders when compared with conventional vestibular physical therapy (CVPT) alone. Indicators of vestibular symptoms are used to determine this. DATA SOURCES: Two reviewers independently searched PubMed, EMBASE, ClinicalTrials.gov, Web of Science, and the Cochrane Collaboration database from January 2010 to January 2022 for studies reporting on VRAT in vestibular disorders. STUDY SELECTION: Randomized controlled trials (RCTs) were included that mainly focused on the following measures: the Dizziness Handicap Inventory (DHI), Simulator Sickness Questionnaire, visual analog scale, and balance measures such as the Activities-specific Balance Confidence Scale (ABC), timed Up and Go test, sensory organization test, and center of pressure. The primary outcome was assessment of symptomatic changes before and after VRAT. DATA EXTRACTION: Two authors independently conducted the literature search and selection. After screening, meta-analysis was performed on the RCTs using RevMan 5.3 software. DATA SYNTHESIS: The results showed that VRAT produced significantly greater improvement than CVPT alone in scores of DHI-Total (standardized mean difference [SMD]: -7.09, 95% confidence interval [CI]: [-12.17, -2.00], P=.006), DHI-Functional (SMD=-3.66, 95% CI: [-6.34, -0.98], P=.007), DHI-Physical (SMD=-3.14, 95% CI: [-5.46, -0.83], P=.008), and DHI-Emotional (SMD=-3.10, 95% CI: [-5.13, -1.08], P=.003). ABC scores did not show improvement (SMD: 0.58, 95% CI: [-3.69, 4.85], P=.79). Subgroup analysis showed that DHI-Total between-group differences were insignificant for central vestibular disorders (SMD=-1.47, 95% CI: [-8.71, -5.78], P=.69), although peripheral disorders showed significant improvements (SMD=-9.58, 95% CI: [-13.92, -5.25], P<.0001). However, the included studies showed high heterogeneity (I2>75%). CONCLUSIONS: VRAT may offer additional benefits for rehabilitation from vestibular diseases, especially peripheral disorders, when compared with CVPT alone. However, because of high heterogeneity and limited data, additional studies with a larger sample size and more sensitive and specific measurements are required to conclusively determine the evidence-based utility of virtual reality.

Cell Type-Specific Decrease of the Intrinsic Excitability of Motor Cortical Pyramidal Neurons in Parkinsonism.

The hypokinetic motor symptoms of Parkinson's disease (PD) are closely linked with a decreased motor cortical output as a consequence of elevated basal ganglia inhibition. However, whether and how the loss of dopamine (DA) alters the cellular properties of motor cortical neurons in PD remains undefined. We induced parkinsonism in adult C57BL/6 mice of both sexes by injecting neurotoxin, 6-hydroxydopamine (6-OHDA), into the medial forebrain bundle. By using ex vivo patch-clamp recording and retrograde tracing approach, we found that the intrinsic excitability of pyramidal tract neurons (PTNs) in the primary motor cortical (M1) layer (L)5b was greatly decreased in parkinsonism; but the intratelencephalic neurons (ITNs) were not affected. The cell type-specific intrinsic adaptations were associated with a depolarized threshold and broadened width of action potentials (APs) in PTNs. Moreover, the loss of midbrain dopaminergic neurons impaired the capability of M1 PTNs to sustain high-frequency firing, which could underlie their abnormal pattern of activity in the parkinsonian state. We also showed that the decreased excitability in parkinsonism was caused by an impaired function of both persistent sodium channels and the large conductance, Ca2+-activated K+ channels. Acute activation of dopaminergic receptors failed to rescue the impaired intrinsic excitability of M1 PTNs in parkinsonian mice. Altogether, our data demonstrated a cell type-specific decrease of the excitability of M1 pyramidal neurons in parkinsonism. Thus, intrinsic adaptations in the motor cortex provide novel insight in our understanding of the pathophysiology of motor deficits in PD.SIGNIFICANCE STATEMENT The degeneration of midbrain dopaminergic neurons in Parkinson's disease (PD) remodels the connectivity and function of cortico-basal ganglia-thalamocortical network. However, whether and how dopaminergic degeneration and the associated basal ganglia dysfunction alter motor cortical circuitry remain undefined. We found that pyramidal neurons in the layer (L)5b of the primary motor cortex (M1) exhibit distinct adaptations in response to the loss of midbrain dopaminergic neurons, depending on their long-range projections. Besides the decreased thalamocortical synaptic excitation as proposed by the classical model of Parkinson's pathophysiology, these results, for the first time, show novel cellular and molecular mechanisms underlying the abnormal motor cortical output in parkinsonism.

Synaptic and cellular plasticity in Parkinson's disease.

Parkinson's disease (PD) is a progressive neurodegenerative disease, which causes a tremendous socioeconomic burden. PD patients are suffering from debilitating motor and nonmotor symptoms. Cardinal motor symptoms of PD, including akinesia, bradykinesia, resting tremor, and rigidity, are caused by the degeneration of dopaminergic neurons in the substantia nigra pars compacta. In addition, decreased amounts of dopamine (DA) level in the basal ganglia induces numerous adaptive changes at the cellular and synaptic levels in the basal ganglia circuits. These cellular and synaptic adaptations are believed to underlie the emergence and propagation of correlated, rhythmic pattern of activity throughout the interconnected cortico-basal ganglia-thalamocortical network. The widespread pathological pattern of brain activity is closely linked to the devastating motor symptoms of PD. Accumulating evidence suggests that both dopaminergic degeneration and the associated abnormal cellular and circuit activity in the basal ganglia drive the motor symptoms of PD. In this short review I summarize the recent advances in our understanding of synaptic and cellular alterations in two basal ganglia nuclei (i.e. the striatum and the subthalamic nucleus) following a complete loss of DA, and in our conceptual understanding of the cellular and circuit bases for the pathological pattern of brain activity in parkinsonian state.

Effects of SKF83959 on the excitability of hippocampal CA1 pyramidal neurons: a modeling study.

AIM: 3-Methyl-6-chloro-7,8-hydroxy-1-(3-methylphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine (SKF83959) have been shown to affect several types of voltage-dependent channels in hippocampal pyramidal neurons. The aim of this study was to determine how modulation of a individual type of the channels by SKF83959 contributes to the overall excitability of CA1 pyramidal neurons during either direct current injections or synaptic activation. METHODS: Rat hippocampal slices were prepared. The kinetics of voltage-dependent Na(+) channels and neuronal excitability and depolarization block in CA1 pyramidal neurons were examined using whole-cell recording. A realistic mathematical model of hippocampal CA1 pyramidal neuron was used to simulate the effects of SKF83959 on neuronal excitability. RESULTS: SKF83959 (50 µmol/L) shifted the inactivation curve of Na(+) current by 10.3 mV but had no effect on the activation curve in CA1 pyramidal neurons. The effects of SKF83959 on passive membrane properties, including a decreased input resistance and depolarized resting potential, predicted by our simulations were in agreement with the experimental data. The simulations showed that decreased excitability of the soma by SKF83959 (examined with current injection at the soma) was only observed when the membrane potential was compensated to the control levels, whereas the decreased dendritic excitability (examined with current injection at the dendrite) was found even without membrane potential compensation, which led to a decreased number of action potentials initiated at the soma. Moreover, SKF83959 significantly facilitated depolarization block in CA1 pyramidal neurons. SKF83959 decreased EPSP temporal summation and, of physiologically greater relevance, the synaptic-driven firing frequency. CONCLUSION: SKF83959 decreased the excitability of CA1 pyramidal neurons even though the drug caused the membrane potential depolarization. The results may reveal a partial mechanism for the drug's anti-Parkinsonian effects and may also suggest that SKF83959 has a potential antiepileptic effect.

Open-source platform for kinematic analysis of mouse forelimb movement.

Here we present an open-source behavioral platform and software solution for studying fine motor skills in mice performing reach-to-grasp task. We describe steps for assembling the box, training mice to perform the task, and processing the video with the custom software pipeline to analyze forepaw kinematics. The behavioral platform uses readily available and 3D-printed components and was designed to be affordable and universally reproducible. We provide the schematics, 3D models, code, and assembly instructions in the open GitHub repository.

Open-Source Platform for Kinematic Analysis of Mouse Forelimb Movement.

We present an open-source behavioral platform and software solution for studying fine motor skills in mice performing reach-to-grasp task. The behavioral platform uses readily available and 3D-printed components and was designed to be affordable and universally reproducible. The protocol describes how to assemble the box, train mice to perform the task and process the video with the custom software pipeline to analyze forepaw kinematics. All the schematics, 3D models, code and assembly instructions are provided in the open GitHub repository.

Loss of Midbrain Dopamine Neurons Does Not Alter GABAergic Inhibition Mediated by Parvalbumin-Expressing Interneurons in Mouse Primary Motor Cortex.

The primary motor cortex (M1) integrates sensory and cognitive inputs to generate voluntary movement. Its functional impairments have been implicated in the pathophysiology of motor symptoms in Parkinson's disease (PD). Specifically, dopaminergic degeneration and basal ganglia dysfunction entrain M1 neurons into the abnormally synchronized bursting pattern of activity throughout the cortico-basal ganglia-thalamocortical network. However, how degeneration of the midbrain dopaminergic neurons affects the anatomy, microcircuit connectivity, and function of the M1 network remains poorly understood. The present study examined whether and how the loss of dopamine (DA) affects the morphology, cellular excitability, and synaptic physiology of Layer 5 parvalbumin-expressing (PV+) cells in the M1 of mice of both sexes. Here, we reported that loss of midbrain dopaminergic neurons does not alter the number, morphology, and physiology of Layer 5 PV+ cells in M1. Moreover, we demonstrated that the number of perisomatic PV+ puncta of M1 pyramidal neurons as well as their functional innervation of cortical pyramidal neurons were not altered following the loss of DA. Together, the present study documents an intact GABAergic inhibitory network formed by PV+ cells following the loss of midbrain dopaminergic neurons.

Motor Cortical Neuronal Hyperexcitability Associated with α-Synuclein Aggregation.

Dysfunction of the cerebral cortex is thought to underlie motor and cognitive impairments in Parkinson disease (PD). While cortical function is known to be suppressed by abnormal basal ganglia output following dopaminergic degeneration, it remains to be determined how the deposition of Lewy pathology disrupts cortical circuit integrity and function. Moreover, it is also unknown whether cortical Lewy pathology and midbrain dopaminergic degeneration interact to disrupt cortical function in late-stage. To begin to address these questions, we injected α-synuclein (αSyn) preformed fibrils (PFFs) into the dorsolateral striatum of mice to seed αSyn pathology in the cortical cortex and induce degeneration of midbrain dopaminergic neurons. Using this model system, we reported that αSyn aggregates accumulate in the motor cortex in a layer- and cell-subtype-specific pattern. Particularly, intratelencephalic neurons (ITNs) showed earlier accumulation and greater extent of αSyn aggregates relative to corticospinal neurons (CSNs). Moreover, we demonstrated that the intrinsic excitability and inputs resistance of αSyn aggregates-bearing ITNs in the secondary motor cortex (M2) are increased, along with a noticeable shrinkage of cell bodies and loss of dendritic spines. Last, neither the intrinsic excitability of CSNs nor their thalamocortical input was altered by a partial striatal dopamine depletion associated with αSyn pathology. Our results documented motor cortical neuronal hyperexcitability associated with αSyn aggregation and provided a novel mechanistic understanding of cortical circuit dysfunction in PD.

Decreased cellular excitability of pyramidal tract neurons in primary motor cortex leads to paradoxically increased network activity in simulated parkinsonian motor cortex.

Decreased excitability of pyramidal tract neurons in layer 5B (PT5B) of primary motor cortex (M1) has recently been shown in a dopamine-depleted mouse model of parkinsonism. We hypothesized that decreased PT5B neuron excitability would substantially disrupt oscillatory and non-oscillatory firing patterns of neurons in layer 5 (L5) of primary motor cortex (M1). To test this hypothesis, we performed computer simulations using a previously validated computer model of mouse M1. Inclusion of the experimentally identified parkinsonism-associated decrease of PT5B excitability into our computational model produced a paradoxical increase in rest-state PT5B firing rate, as well as an increase in beta-band oscillatory power in local field potential (LFP). In the movement-state, PT5B population firing and LFP showed reduced beta and increased high-beta, low-gamma activity of 20-35 Hz in the parkinsonian, but not in control condition. The appearance of beta-band oscillations in parkinsonism would be expected to disrupt normal M1 motor output and contribute to motor activity deficits seen in patients with Parkinson's disease (PD).

Target-specific suppression of GABA release from parvalbumin interneurons in the basolateral amygdala by dopamine.

Dopamine (DA) in the basolateral amygdala (BLA) promotes fear learning by disinhibiting principal neurons (PNs) and enabling synaptic plasticity in their sensory inputs. While BLA interneurons (INs) are heterogeneous, it is unclear which interneuron subtypes decrease GABAergic input to PNs in the presence of DA. Here, using cell type-selective photostimulation by channelrhodopsin 2 in BLA slices from mouse brain, we examined the role of parvalbumin-positive INs (PV-INs), the major interneuronal subpopulation in BLA, in the disinhibitory effect of DA. We found that DA selectively suppressed GABAergic transmission from PV-INs to PNs by acting on presynaptic D(2) receptors, and this effect was mimicked by Rp-cAMP, an inhibitor of cAMP-dependent signaling. In contrast, DA did not alter GABA release from PV-INs to INs. Furthermore, neither suppressing cAMP-dependent signaling by Rp-cAMP nor enhancing it by forskolin altered GABA release from PV-INs to BLA INs. Overall, DA disinhibits BLA, at least in part, by suppressing GABA release from PV-INs in the target cell-specific manner that results from differential control of this release by cAMP-dependent signaling.

Reduced thalamic excitation to motor cortical pyramidal tract neurons in parkinsonism.

Degeneration of midbrain dopaminergic (DA) neurons alters the connectivity and functionality of the basal ganglia-thalamocortical circuits in Parkinson's disease (PD). Particularly, the aberrant outputs of the primary motor cortex (M1) contribute to parkinsonian motor deficits. However, cortical adaptations at cellular and synaptic levels in parkinsonism remain poorly understood. Using multidisciplinary approaches, we found that DA degeneration induces cell subtype- and input-specific reduction of thalamic excitation to M1 pyramidal tract (PT) neurons. At molecular level, we identified that N-methyl-d-aspartate (NMDA) receptors play a key role in mediating the reduced thalamocortical excitation to PT neurons. At circuit level, we showed that the reduced thalamocortical transmission in parkinsonian mice can be rescued by chemogenetically suppressing basal ganglia outputs. Together, our data suggest that cell subtype- and synapse-specific adaptations in M1 contribute to altered cortical outputs in parkinsonism and are important aspects of PD pathophysiology.

Synaptic location is a determinant of the detrimental effects of α-synuclein pathology to glutamatergic transmission in the basolateral amygdala.

The presynaptic protein α-synuclein (αSyn) has been suggested to be involved in the pathogenesis of Parkinson's disease (PD). In PD, the amygdala is prone to develop insoluble αSyn aggregates, and it has been suggested that circuit dysfunction involving the amygdala contributes to the psychiatric symptoms. Yet, how αSyn aggregates affect amygdala function is unknown. In this study, we examined αSyn in glutamatergic axon terminals and the impact of its aggregation on glutamatergic transmission in the basolateral amygdala (BLA). We found that αSyn is primarily present in the vesicular glutamate transporter 1-expressing (vGluT1+) terminals in the mouse BLA, which is consistent with higher levels of αSyn expression in vGluT1+ glutamatergic neurons in the cerebral cortex relative to the vGluT2+ glutamatergic neurons in the thalamus. We found that αSyn aggregation selectively decreased the cortico-BLA, but not the thalamo-BLA, transmission; and that cortico-BLA synapses displayed enhanced short-term depression upon repetitive stimulation. In addition, using confocal microscopy, we found that vGluT1+ axon terminals exhibited decreased levels of soluble αSyn, which suggests that lower levels of soluble αSyn might underlie the enhanced short-term depression of cortico-BLA synapses. In agreement with this idea, we found that cortico-BLA synaptic depression was also enhanced in αSyn knockout mice. In conclusion, both basal and dynamic cortico-BLA transmission were disrupted by abnormal aggregation of αSyn and these changes might be relevant to the perturbed cortical control of the amygdala that has been suggested to play a role in psychiatric symptoms in PD.

SKF83959 suppresses excitatory synaptic transmission in rat hippocampus via a dopamine receptor-independent mechanism.

Dopamine (DA) profoundly modulates excitatory synaptic transmission and synaptic plasticity in the brain. In the present study the effects of SKF83959, the selective agonist of phosphatidylinositol (PI)-linked D(1) -like receptor, on the excitatory synaptic transmission were investigated in rat hippocampus. SKF83959 (10-100 µM) reversibly suppressed the field excitatory postsynaptic potential (fEPSP) elicited by stimulating the Schaffer's collateral-commissural fibers in CA1 area of hippocampal slices. However, the inhibition was not blocked by the D(1) receptor antagonist SCH23390, the D(2) receptor antagonist raclopride, the 5-HT(2A/2C) receptor antagonist mesulergine, or the α(1) -adrenoceptor antagonist prazosin. In addition, SKF83959 inhibited the afferent volley and significantly reduced the paired-pulse facilitation ratios. In dissociated hippocampal CA1 pyramidal neurons, SKF83959 had no detectable effect on glutamate-induced currents but potently inhibited voltage-activated Na(+) current (IC50 value = 26.9 ± 1.0 µM), which was not blocked by SCH23390 or by intracellular dialysis of GDP-ß-S. These results demonstrate that SKF83959 suppressed the excitatory synaptic transmission in hippocampal CA1 area, which was independent of D(1) -like receptor. The mechanism underlying the effect could be mainly inhibition of Na(+) channel in the afferent fibers. The suppression of excitatory synaptic transmission and the Na(+) channel by SKF83959 may contribute to its therapeutic benefits in Parkinson's disease.

l-Stepholidine-induced excitation of dopamine neurons in rat ventral tegmental area is associated with its 5-HT(1A) receptor partial agonistic activity.

RATIONALE: l-Stepholidine (l-SPD), a tetrahydroprotoberberine alkaloid, possesses a pharmacological profile of a D1/5-HT(1A) agonist and a D2 antagonist. This unique pharmacological profile makes it a promising novel antipsychotic candidate. Preliminary clinical trials and animal experiments suggest that l-SPD improves both positive and negative symptoms of schizophrenia without producing significant extrapyramidal side effects. To further explore the antipsychotic mechanisms of the drug, we studied the effects of l-SPD on the activity of dopamine (DA) neurons in the ventral tegmental area (VTA) using in vivo single-unit recording technique in rats. RESULT: We found that l-SPD increased VTA DA neurons firing rate and induced slow oscillation in firing pattern. Moreover, l-SPD, not clozapine, reversed d-amphetamine-induced inhibition which induced an excitation of VTA DA neurons. Furthermore, our data indicated that the excitatory effect of l-SPD is associated with its partial agonistic action for the 5-HT(1A) receptor since the 5-HT(1A) receptor antagonist WAY100635 could block the l-SPD-induced excitatory effect. However, activation of 5-HT(1A) receptor alone by specific agonist (±)-8-Hydroxy-2-(dipropylamino) tetralin (8-OH-DPAT) was insufficient to elicit excitation of VTA DA neurons, but the excitation of 8-OH-DPAT on VTA DA neurons was elicited in the presence of D2-like receptors antagonist raclopride. Collectively, these results indicate that l-SPD excited VTA DA neurons requiring its D2-like receptors antagonistic activity and 5-HT(1A) receptor agonistic activity. CONCLUSION: The present data demonstrate that D2 receptor antagonist/5-HT(1A) receptor agonistic dual properties modulate dopaminergic transmission in a unique pattern that may underlie the different therapeutic responses between l-SPD and other atypical antipsychotic drugs.

Hyperpolarization-activated, cyclic nucleotide-gated (HCN) channels in the regulation of midbrain dopamine systems.

Hyperpolarization-activated, cyclic nucleotide-gated channels (HCN channels) are expressed widely in the brain and invovled in various neuronal activities, including the control of neuronal rhythmic activity, setting the resting membrane potential, as well as dendritic integration. HCN channels also participate in the regulation of spontaneous activity of midbrain dopamine (DA) neurons to some extent. In slice preparations of midbrain, a hyperpolarization-activated non-selective cation current (Ih) mediated by the channels has been proposed as an electrophysiological marker to identify DA neurons. Recent evidence, however, shows that the functional roles of HCN channels in midbrain DA neurons are obviously underestimated. Here, we review the recent advances in the studies of the functional roles of Ih in midbrain DA neurons and further, their involvement in drug addiction and Parkinson's disease.

Maladaptive Downregulation of Autonomous Subthalamic Nucleus Activity following the Loss of Midbrain Dopamine Neurons.

Abnormal subthalamic nucleus (STN) activity is linked to impaired movement in Parkinson's disease (PD). The autonomous firing of STN neurons, which contributes to their tonic excitation of the extrastriatal basal ganglia and shapes their integration of synaptic input, is downregulated in PD models. Using electrophysiological, chemogenetic, genetic, and optical approaches, we find that chemogenetic activation of indirect pathway striatopallidal neurons downregulates intrinsic STN activity in normal mice but this effect is occluded in Parkinsonian mice. Loss of autonomous spiking in PD mice is prevented by STN N-methyl-D-aspartate receptor (NMDAR) knockdown and reversed by reactive oxygen species breakdown or KATP channel inhibition. Chemogenetic activation of hM3D(Gq) in STN neurons in Parkinsonian mice rescues their intrinsic activity, modifies their synaptic integration, and ameliorates motor dysfunction. Together these data argue that in PD mice increased indirect pathway activity leads to disinhibition of the STN, which triggers maladaptive NMDAR-dependent downregulation of autonomous firing.

Loss of Hyperdirect Pathway Cortico-Subthalamic Inputs Following Degeneration of Midbrain Dopamine Neurons.

The motor symptoms of Parkinson's disease (PD) are linked to abnormally correlated and coherent activity in the cortex and subthalamic nucleus (STN). However, in parkinsonian mice we found that cortico-STN transmission strength had diminished by 50%-75% through loss of axo-dendritic and axo-spinous synapses, was incapable of long-term potentiation, and less effectively patterned STN activity. Optogenetic, chemogenetic, genetic, and pharmacological interrogation suggested that downregulation of cortico-STN transmission in PD mice was triggered by increased striato-pallidal transmission, leading to disinhibition of the STN and increased activation of STN NMDA receptors. Knockdown of STN NMDA receptors, which also suppresses proliferation of GABAergic pallido-STN inputs in PD mice, reduced loss of cortico-STN transmission and patterning and improved motor function. Together, the data suggest that loss of dopamine triggers a maladaptive shift in the balance of synaptic excitation and inhibition in the STN, which contributes to parkinsonian activity and motor dysfunction.