The basal ganglia network is the motor switchboard of the brain and the output of this macrocircuit is dependent on the balance of two opposing pathways, i.e. the direct and indirect pathways. The disruption of this crucial interplay underlies the debilitating effects observed in movement disorders, such as Parkinson's disease. Emerging evidence suggests that the external globus pallidus, traditionally thought to once function as a mere relay nucleus, is believed to be more complex than previously thought. The external globus pallidus is connected with other neurons in the indirect pathway through complex recurrent feedback loops, suggesting its key role in indirect pathway function. Our work, along with others, has suggested a complex cellular makeup of the globus pallidus. In this upcoming grant period, we seek to better characterize how these types of neurons are connected with the rest of the basal ganglia. The proposed multidisciplinary research strategy will use a combination of electrophysiological, optogenetic, transgenic, viral, transcriptomic, and anatomical techniques in a 6-OHDA, chronic mouse model of Parkinson's disease.
In Aim 1, using a Cre/lox approach, subtypes of globus pallidus neurons will be identified and either FACS-purified or patch-clamped. The intrinsic properties of globus pallidus neuron subtypes will be measured and correlated with molecular profiling of ion channel expression.
In Aim 2, the connectivity of globus pallidus neuron subtypes with the subthalamic nucleus will be studied. Using an electrophysiological approach, biophysical properties and receptor complement of the subthalamopallidal input will be measured. Pharmacological methods, transcriptomic analysis, and genetic approaches will be used in conjunction to corroborate the inferences drawn from electrophysiological studies.
In Aim 3, using an optogenetic approach, the functional properties of the pallidostriatal input will be studied. Identified striatal neurons will be patch-clamped and signaling mechanisms involved in pallidostriatal transmission will be studied. Pharmacological, immunocytochemical, and genetic knockdown approaches will complement this effort.
In Aim 4 we will determine how subcircuits of the indirect pathway are altered in a chronic dopamine depletion model that mimics Parkinson's disease. Transcriptomic, electrophysiological, and anatomical analyses will be performed.
The overactivity of the basal ganglia indirect pathway is implicated in the motor symptoms associated with Parkinson's disease. The proposed studies will determine the organization principles of this pathway. The knowledge gained will in turn provide a framework for novel therapeutic strategies for Parkinson's disease.
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