Mechanisms underlying impaired hippocampal physiology in Fragile X Syndrome

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PROJECT SUMMARY Fragile X Syndrome (FXS) is a neurodevelopmental disorder that can cause impaired spatial memory and atypical spatial behaviors such as “elopement,” or wandering around and becoming lost. Current treatments for FXS are limited and do not treat underlying neurological changes that may be associated with these symptoms. Activity in the CA1 subregion of the hippocampus supports spatial memory and spatial cognition, making it an important candidate to study in the context of FXS; however, research into whether differences in neurophysiological activity in CA1 in FXS contribute to impaired spatial behaviors and memory is lacking. The goal of this project is to examine whether the activity in CA1 that supports spatial memory formation is impaired in a rat model of FXS. The studies will use in vivo electrophysiology to record the activity of spatially modulated CA1 neurons after introduction to a novel environment as a model of spatial memory formation in a rat model of FXS (Fmr1 knockout, hereafter “FXS rats”) and wildtype (WT) control rats. Specific Aim 1 will test whether the modulation of individual neurons by the extracellular 6-10 Hz theta rhythm is normal in FXS rats. This Aim will assess whether this modulation is present from the onset of exposure to a novel environment in FXS rats as it is in WT rats. Specific Aim 2 will test whether coding of spatial paths by coordinated ensembles of spatially modulated CA1 neurons, which develops with experience in novel environments in WT rats, fails to develop at the same rate in FXS rats. Specific Aim 3 will examine the reactivation of previously active CA1 neuron ensembles during waking rest and sleep in FXS and WT rats. This Aim will test the hypothesis that CA1 neuronal ensembles representing novel environments are not preferentially reactivated during rest and sleep in FXS rats in contrast to results from WT rats. The results from these proposed experiments may reveal specific impairments in hippocampal mechanisms that support spatial memory in FXS and may suggest novel treatment targets for FXS. This fellowship will allow me to develop the necessary technical and professional skills to pursue a career as a principal investigator performing independent research. I believe my choice of institution and sponsor is ideal for completing my proposed project as well as the training necessary to pursue my long-term career goals. The Institute for Neuroscience at UT Austin offers a rigorous PhD program, a collaborative work environment where I am regularly able to present my work and receive feedback, and opportunities to teach and mentor students. Through the college’s career services for graduate students, I am also able to attend courses in subjects such as science communication, data management, and planning rigorous and reproducible science, as well as to meet individually with a career counselor. Through this fellowship, I will develop the skills necessary to continue onto future academic positions and continue to research network impairments in cognitive disorders.