Date of Award

Spring 4-4-2025

Embargo Period

4-28-2025

Document Type

Dissertation

Degree Name

Doctor of Philosophy (Medical Science)

Department

Neuroscience

College

College of Graduate Studies

Additional College

College of Medicine

First Advisor

Christopher Cowan

Second Advisor

Makoto Taniguchi

Abstract

Emotional experiences often evoke neural plasticity that supports adaptive changes in behavior, including maladaptive plasticity associated with mood and substance use disorders. These adaptations are supported in part by experience-dependent activation of immediate-early response genes, such as Npas4. We discovered that a conserved, long non-coding enhancer RNA (lnc-eRNA) transcribed from an activity-sensitive enhancer produces DNA-RNA hybrid R-loop structures that support 3D chromatin-looping of the enhancer and proximal promoter and stimulus-induced, rapid Npas4 gene induction. We also show that this Npas4 lnceRNA and its R-loops are required for the development of behavioral adaptations produced by chronic psychosocial stress or cocaine exposure, revealing a critical role for this new genomic regulatory mechanism in the transmission of emotional experiences, such as stress or drug use, to adaptive behavioral responses.

Rights

Copyright is held by the author. All rights reserved.

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