Functional organization of neural circuits underlying movement control

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DESCRIPTION (provided by applicant): The striatum is the main input zone of the basal ganglia, which integrates the sensory and motor information conveyed by cortical and thalamic inputs. The integrity of this circuitry is critical for a variety of functions, including locomotion, motor learning and action selection. The current model of how motor command is processed through basal ganglia circuits has been built upon the theory that two complementary pathways (direct and indirect pathways) mediate different aspects of information for motor control through relays of specific synaptic connections. However, virtually nothing is known about how specific synaptic connections are formed during development in direct and indirect pathway MSNs. It is also unclear if anatomically related striatal neurons form functional modules like those seen in cortical columns, where radial clones of excitatory cortical neurons preferentially develop specific synaptic connections. Dysfunction of basal ganglia neural network activity leads to a plethora of psychomotor disorders, including Parkinson's disease (PD), Huntington's disease (HD), and addiction. One of the most indispensable neuromodulators for normal striatal function is dopamine (DA) as suggested by loss of dopaminergic neurons in substantia nigra parc compacta (SNc) in PD, where motor command initiation and execution are severely impaired. The long-term objectives of this study are to define mechanisms that regulate function of the specific synaptic connection in the neural circuit and the underlying molecular and cellular mechanism that governs the specificity of synapse formation during developement. I am currently a postdoctoral fellow at Dr. Bernardo Sabatini laboratory at Department of Neurobiology, Harvard Medical School. The department offers a great environment for me to conduct the research projects proposed here. During mentored phase of this proposal, we try to address two specific aims: 1. To characterize the modulation of neuronal excitability in striatal neurons following selective activation of dopamine axons. 2: To characterize the modulation of LTS-interneuron mediated GABAergic inhibition by dopaminergic afferents in striatal MSNs. Although it is generally accepted that DA acts through D1 receptors to excite the direct pathway and through D2 receptors to inhibit the indirect pathway, precisely how dopamine modulates the different pathway striatal function remains enigmatic. We aim to by using a combination of electrophysiological, imaging, optogenetic techniques and various genetic manipulations to identify properties of specific synaptic connections in the striatum. During the Independent phase, we aim to implement the cutting-edge techniques that I have learned during the mentored phase to tackle fundamental questions in our understanding of development and formation of functional neural circuits underlying voluntary movement control. To address these questions, we propose to address specific aims: 3: To investigate the molecular mechanism governing formation of specific glutamatergic synaptic connectivity in the striatum. 4: To characterize the organization of basic functional modules in the striatum. The proposed studies will be pursued by same set of electrophysiological, imaging tools and viral gene manipulation tools applied to identified neurons either in transgenic BAC mice and conditional KO mice. Detailed electrophysiological analyses of these synapse function and subsequent characterization of the circuit function in conditional KO mice should provide a basic understanding of mechanisms regulating synapse formation and a framework for understanding the neural substrate for fine motor control and action selection. The proposed studies here will provide training experience that will be critical for transition from postdoc to independent PI. With this proposed training plan, I will not only gain important training in developing techniques necessary for experiments, but also managerial skills for running a successful lab at a major research institution. I have been and will continue to discuss with Dr. Sabatini on every aspect of these goals and get advice on grant writing and finding a faculty position. PUBLIC HEALTH RELEVANCE: Parkinson's disease (PD) is the second most common neurodegenerative disorder, which is caused by loss of dopaminergic innervations from the Substantia nigra pars compacta. Following loss of dopamine, the adaptations of synaptic connectivity in striatal neurons are prominent, but molecular mechanisms governing synapse formation/maintenance and how precisely dopamine regulates striatal function remain unclear. The insights gained from the proposed should provide a framework for understanding the neural substrate for fine motor control and pathophysiological changes occurring in PD.