Sunday, May 11, 2025
5/11/2025
POm and its role in striatal circuitry modulation - Project Summary/Abstract Learned behaviors require the processing and transformation of sensory stimuli into motor actions, a process known as sensorimotor integration. Disruption of sensorimotor integration in key brain areas, such as the striatum, is implicated in movement disorders such as Parkinson’s disease, Huntington’s disease, Tourette’s syndrome, and dystonia. The striatum receives widespread inputs from numerous cortical and thalamic areas and recent published data from the Margolis lab demonstrate that primary motor cortex (M1) and primary somatosensory cortex (S1) have distinct striatal innervation patterns and opposing influence on behavioral performance in mice. However, the functional striatal innervation patterns and behavioral roles of most other inputs are unknown. One such input comes from the posterior medial nucleus (POm) of the thalamus, which has direct synaptic connections with S1, M1 and dorsolateral striatum. My proposal, using a combination of in vivo and ex vivo approaches, pursues the hypothesis that POm may function as an important “gain modulator” by enhancing the signal-to-noise of whisker-related sensory information in the striatum before sensory information arrives from other cortical and subcortical areas. A Go/NoGo whisker-based decision- making task with optogenetic manipulation (both gain-of-function and loss-of-function) in behaving mice will be employed in Specific Aim 1. This paradigm will assess the effects of bidirectional optogenetic manipulation of POm terminals in the striatum on behavioral responding. The Go/NoGo task is combined with in vivo fiber photometry in Specific Aim 2. This paradigm will determine the natural dynamics of thalamostriatal signaling across the learning of this sensory-guided task. Specific Aim 3 will use ex vivo whole-cell patch-clamp electrophysiology with optogenetic stimulation to assess if POm preferentially innervates any of three striatal neuron subtypes. This combined approach will define the circuit mechanisms of POm-striatal signaling in sensory-guided behavior, which may have implications for understanding circuit dysfunction in movement disorders. The proposed fellowship will provide the trainee with a solid foundation for a career as an independent systems neuroscientist. The training environment incorporates a robust education, ample professional development opportunities, and multiple faculty-student mentorships in domains vital to the project including electrophysiology, behavior, optogenetics, and fiber photometry. Overall, this NRSA fellowship has significant potential to elucidate the neural circuitry of sensorimotor integration and provide essential training for me to become a valuable member of the systems neuroscience community.
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