Serotonergic Modulation of Fast-Spiking Interneurons in Medial Prefrontal Cortex

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PROJECT SUMMARY/ABSTRACT The prefrontal cortex (PFC) is a highly evolved brain region that is responsible for directing higher order cognitive functions ranging from decision making to and social cognition. These complex behaviors emerge from the synchronous firing of individual neurons in the PFC, a process which gives rise to neuronal oscillations, or brain rhythms. Oscillations in the gamma frequency range (30 – 90Hz) may play a key role in information encoding in the PFC during behavior. Importantly, deficits in the generation of PFC gamma rhythms are observed in patients with schizophrenia, which implies that alterations in PFC gamma oscillations may contribute to the pathophysiology of this disorder, or act as a biomarker for disease. Fast-spiking interneurons (FSIs), a subset of inhibitory interneurons in the PFC, coordinate gamma rhythms by controlling the timing of excitatory neuron firing via somatic inhibition. To effectively integrate inputs, the PFC must flexibly regulate the power of gamma oscillations during behavior. Serotonin (5HT), a modulatory neurotransmitter that is produced in the brain stem and secreted throughout the brain, can influence the power of brain rhythms in other cortical regions but it is unclear if 5HT modulates PFC rhythms via FSIs. Both prefrontal and FSI dysfunction are prominent features of schizophrenia, and second-generation antipsychotic drugs target 5HT receptors with high affinity. Therefore, identifying how 5HT modulates prefrontal gamma oscillations via FSIs will broadly inform our understanding of the etiology of schizophrenia and potentially lead to novel therapies for this prevalent disorder. I will use a combination of in vitro electrophysiology coupled with cutting-edge optogenetic & chemogenetic tools, two-photon microscopy, glutamate uncaging, and in vivo physiology to determine the functional consequences of 5HT-mediated changes in FSI excitability at the cellular and network levels. Then I will use a behavioral assay to determine how changes in FSI excitability influence behavior in an animal model of schizophrenia.