DOI
https://doi.org/10.25772/8KEQ-KX64
Author ORCID Identifier
https://orcid.org/0000-0003-3602-607X
Defense Date
2025
Document Type
Dissertation
Degree Name
Doctor of Philosophy
Department
Neuroscience
First Advisor
Peter J. Hamilton
Abstract
Experiences represent a powerful influence on an individual and their behaviors. Different life experiences can lead to long term changes in both brain physiology and behavioral phenotypes (Rosenzweig & Bennett, 1996). Indeed, early life experiences have been well-documented to affect an individual through the duration of their life across multiple species (Kundakovic & Champagne, 2015). Yet, the neurobiological mechanisms through which experiences can drive beneficial versus maladaptive behavioral changes are incompletely understood.
It is common to examine the biological origins of behavior through the synapse. Neurons communicate through the release of neurotransmitters to activate receptors on the post-synaptic neuron, and this signal is terminated by neurotransmitter reuptake through transporter proteins on the pre-synaptic neuron. Seminal work by Donald Hebb posited that experience driven alterations to these synaptic machinery can lead to the development and strengthening of neural circuits, providing an anatomic model of learning and memory (Brown, 2020). This framework remains relevant today, and many of our current therapeutic strategies to treat neuropsychiatric syndromes build on this synaptic model by modulating neurotransmission in the brain (Braslow & Marder, 2019).
More recently, growing evidence suggests that the synapse is an incomplete explanation for how experiences influence behaviors. Rather, behavioral change reflects a series of processes ranging from intracellular molecular mechanisms to widespread neural circuitry integrating throughout the brain (Langille & Brown, 2018). It is therefore important to study behavioral adaptations to experience not only at the synapse, but also downstream of the synapse and through the lens of the cell body and nucleus.
Typically, following binding of a neurotransmitter to its receptor, a signal transduction cascade will transmit the stimulus through effector proteins within the neuron to transcription factors within the nucleus. In response to transcription factor activity, mRNA molecules are produced and exported to the cell body, where they are translated into proteins and trafficked to their destinations. In this manner, a stimulus can be processed and result in a net change to neuronal physiology through nucleus-dependent mechanisms. Indeed, early investigations towards nuclear mechanisms driving behavioral adaptations to environmental stimuli have elucidated several transcriptional and epigenetic mechanisms underlying both drug seeking behaviors and stress-induced behavioral maladaptations (Tsankova et al., 2007; D. M. Walker & Nestler, 2018; Lorsch et al., 2019a; Teague et al., 2023).
The contents of this dissertation aim to use synthetic biology and bioinformatics tools to examine the molecular mechanisms underlying the origins of maladaptive behaviors. We examined transcriptional changes driving a sex-specific capacity to choose to self-administer food and forego seeking drugs (Chapter 2). We investigated a chromatin biology mechanism involving a linker histone protein correlated with susceptibility to develop behavioral maladaptations to stress experience utilizing a synthetic overexpression vector in an attempt to artificially induce susceptibility to stress (Chapter 3). Finally, we utilized synthetic transcription factors to discover a transposable element-associated cis-regulatory mechanism necessary to maintain appropriate social behaviors (Chapter 4 and Chapter 5). By improving our understanding of the neuroepigenetic and molecular mechanisms driving behavioral maladaptations, we aim to identify behaviorally significant pathways and transcriptional process that represent potential targets to investigate as novel treatment strategies for neuropsychiatric syndromes.
Rights
© The Author
Is Part Of
VCU University Archives
Is Part Of
VCU Theses and Dissertations
Date of Submission
4-7-2025