Primary motor cortex of the parkinsonian monkey: differential effects on the spontaneous activity of pyramidal tract-type neurons.
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ABSTRACT:
SUBMITTER: Pasquereau B
PROVIDER: S-EPMC3097989 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Abnormalities in the movement-related activation of the primary motor cortex (M1) are thought to be a major contributor to the motor signs of Parkinson's disease. The existing evidence, however, variably indicates that M1 is under-activated with movement, overactivated (due to a loss of functional specificity) or activated with abnormal timing. In addition, few models consider the possibility that distinct cortical neuron subtypes may be affected differently. Those gaps in knowledge were addressed by studying the extracellular activity of antidromically-identified lamina 5b pyramidal-tract type neurons (n = 153) and intratelencephalic-type corticostriatal neurons (n = 126) in the M1 of two monkeys as they performed a step-tracking arm movement task. We compared movement-related discharge before and after the induction of parkinsonism by administration of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) and quantified the spike rate encoding of specific kinematic parameters of movement using a generalized linear model. The fraction of M1 neurons with movement-related activity declined following MPTP but only marginally. The strength of neuronal encoding of parameters of movement was reduced markedly (mean 29% reduction in the coefficients from the generalized linear model). This relative decoupling of M1 activity from kinematics was attributable to reductions in the coefficients that estimated the spike rate encoding of movement direction (-22%), speed (-40%), acceleration (-49%) and hand position (-33%). After controlling for MPTP-induced changes in motor performance, M1 activity related to movement itself was reduced markedly (mean 36% hypoactivation). This reduced activation was strong in pyramidal tract-type neurons (-50%) but essentially absent in corticostriatal neurons. The timing of M1 activation was also abnormal, with earlier onset times, prolonged response durations, and a 43% reduction in the prevalence of movement-related changes beginning in the 150-ms period that immediately preceded movement. Overall, the results are consistent with proposals that under-activation and abnormal timing of movement-related activity in M1 contribute to parkinsonian motor signs but are not consistent with the idea that a loss of functional specificity plays an important role. Given that pyramidal tract-type neurons form the primary efferent pathway that conveys motor commands to the spinal cord, the dysfunction of movement-related activity in pyramidal tract-type neurons is likely to be a central factor in the pathophysiology of parkinsonian motor signs.
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Project description:Exaggeration of the long-latency stretch reflex (LLSR) is a characteristic neurophysiologic feature of Parkinson's disease (PD) that contributes to parkinsonian rigidity. To explore one frequently-hypothesized mechanism, we studied the effects of fast muscle stretches on neuronal activity in the macaque primary motor cortex (M1) before and after the induction of parkinsonism by unilateral administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). We compared results from the general population of M1 neurons and two antidromically-identified subpopulations: distant-projecting pyramidal-tract type neurons (PTNs) and intra-telecenphalic-type corticostriatal neurons (CSNs). Rapid rotations of elbow or wrist joints evoked short-latency responses in 62% of arm-related M1 neurons. As in PD, the late electromyographic responses that constitute the LLSR were enhanced following MPTP. This was accompanied by a shortening of M1 neuronal response latencies and a degradation of directional selectivity, but surprisingly, no increase in single unit response magnitudes. The results suggest that parkinsonism alters the timing and specificity of M1 responses to muscle stretch. Observation of an exaggerated LLSR with no change in the magnitude of proprioceptive responses in M1 is consistent with the idea that the increase in LLSR gain that contributes to parkinsonian rigidity is localized to the spinal cord.
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Project description:Deep brain stimulation (DBS), a surgical therapy for advanced Parkinson's disease (PD), is known to change neuronal activity patterns in the pallidothalamic circuit. Whether these effects translate to the motor cortex and, if so, how they might modulate the functional responses of individual neurons in primary motor cortex remains uncertain. A 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkey was implanted with a DBS lead spanning internal and external segments of globus pallidus. During therapeutic stimulation (135 Hz) for rigidity and bradykinesia, neurons in primary motor cortex (M1) exhibited an inhibitory phase-locking (2-5 ms) to the stimulus, an overall decrease in mean discharge rate, and an increase in response specificity to passive limb movement. Sub-therapeutic DBS (30 Hz) still produced entrainment to the stimulation, but the mean discharge rate and specificity to movement were not changed. Lower stimulation intensities (at 135 Hz), which no longer improved motor symptoms, had little effect on M1 activity. These findings suggest that DBS improves parkinsonian motor symptoms by inducing global changes in firing pattern and rate along the pallido-thalamocortical sensorimotor circuit.
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Project description: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.
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