Structural, Functional, and Behavioral Outcomes of Stimulus-Dependent Transcription in Nucleus Accumbens Parvalbumin-Expressing Interneurons
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Learning and memory are mediated by changes in synaptic and neuronal function within brain circuits, and is supported by dynamic waves of stimulus-dependent transcription in the nucleus of neurons. Stimulus-dependent transcription relies heavily on the epigenetic landscape of a given neuron, which is highly cell-type specific and can be further tuned by experience. Developments in genetic tools and methods to survey the entire transcriptome and epigenome have increased our ability to study stimulus-dependent transcription in diverse cell-types, including rare populations of interneurons. Application of these tools to addiction models, where long-lasting changes in behavior depend on stimulus-dependent transcription in diverse cell-types in multiple areas of the corticomesolimbic reward circuit, presents a particularly potent opportunity to increase our understanding of the functional consequences of stimulus-dependent transcription in diverse cell-types in a system that is highly relevant to human health. In the nucleus accumbens (NAc), parvalbumin-expressing (PV+) interneurons exert strong control over local circuit output and downstream behavior, including behavioral responses to drugs of abuse. Recent data from our lab suggest that perineuronal net (PNN) genes are a promising target for behaviorally-relevant, drug-dependent functional adaptations in this rare cell-type. In this dissertation, I use histological techniques in mouse tissue to validate in situ the heterogeneous transcriptional regulation of NAc PV+ interneurons and specific cell adhesion gene targets in response to psychostimulants, and explore the developmental and drug-dependent regulation of PNNs and the PNN gene Bcan. I use genetic and viral tools to specifically knockdown Bcan expression in NAc PV+ cells, and demonstrate that Bcan stabilizes their excitatory synaptic inputs even in adulthood and restricts the development of cocaine-context associations, showing that NAc PV+ interneurons and their PNNs play an important role in limiting the development of addiction-related behaviors. Finally, I use dCas9-mediated epigenetic editing to tune activity-dependent transcription of select rapid primary response genes, which are thought to interact with cell-type and cell-state dependent chromatin to coordinate later waves of stimulus-dependent transcription. I show that the fine details of activity-dependent transcription of rapid primary response genes resulting from chromatin state can lead to physiological changes in protein, and downstream neural physiology and behavior.
Hazlett, Mariah Faith (2022). Structural, Functional, and Behavioral Outcomes of Stimulus-Dependent Transcription in Nucleus Accumbens Parvalbumin-Expressing Interneurons. Dissertation, Duke University. Retrieved from https://hdl.handle.net/10161/26870.
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