Targeted Cortical Circuit Manipulation in Parkinson's Disease

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PROJECT SUMMARY/ABSTRACT This exploratory project is a collaboration between Parkinson's disease (PD) researchers and BRAIN tool developers and will utilize novel interventional tools for changing neural circuit dynamics to ameliorate motor and nonmotor deficits in PD. In PD, degeneration of midbrain dopamine neurons promotes an exaggeratedly synchronized burst firing in the cortico-basal ganglia-thalamocortical circuitry, disrupts its normal function, and causes both motor and affective dysfunction. Targeted neural modulation at different entry points in this circuitry is a promising strategy for improving the treatment of PD symptoms. Emerging findings from patients and mouse models of PD demonstrate the cortex as a potential target for neuromodulation yielding beneficial effects for PD patients. The primary motor cortex (M1) exhibits adaptive changes that play a critical role in generating aberrant cortical output in PD. Our studies identified four circuit elements that can contribute to the emergence of aberrant M1 activity: (1) decreased pyramidal tract (PT) neuron excitability, (2) increased excitability of M1 parvalbumin- expressing interneurons (PV-INs), (3) increased thalamic excitation of M1 PV-INs, and (4) synchronized nigrothalamic synaptic activity. This project will explore modulating specific M1 microcircuits in the PD brain using tools developed under the BRAIN initiative. Our central hypothesis is that manipulation of the firing activity within and the synaptic drive towards key neuron populations in the M1 microcircuit normalizes network activity and ameliorates motor and nonmotor deficits. We will test our hypothesis in two Specific Aims (SA), reflecting the identified entry points. SA1 will define the physiological and behavioral impact of modulating intrinsic excitability of cortical neuron populations by decreasing and increasing excitability of PT neurons (SA1.1) and PV-INs (SA1.2), respectively. SA2 will probe the impact of modulating synaptic activity of thalamocortical circuits by determining whether manipulations of thalamic inputs to M1 PV-INs (SA2.1) and nigrothalamic synapses (SA2.2) rescue pathophysiological and behavioral phenotypes of PD mice. Our major goal will be to determine which of these key entry points provides the most efficacious strategy for mitigating the behavioral deficits in a mouse model of advanced PD. For manipulation of neuronal activity this project will utilize the bioluminescent optogenetic (BL-OG) platform that employs light emitting luciferases to activate light sensing opsins, including the recently developed ‘interluminescence’ approach that enables controlling synaptic transmission by expressing the light emitter and sensor in pre- and post-synaptic partners, respectively. To achieve our goals, we are combining expertise in circuit manipulation tool development and PD mouse model behavioral research towards a more refined understanding of the brain mechanisms underlying complex behaviors. At the same time our project will drive translational progress toward potential novel therapeutic purposes. In addition to the impact on PD research our results are expected to have a significant impact on approaching other neurodegenerative diseases that show circuit imbalances.