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.