Structural, Functional, and Behavioral Outcomes of Stimulus-Dependent Transcription in Nucleus Accumbens Parvalbumin-Expressing Interneurons

Abstract

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.