Date of Award
12-1-2025
Degree Name
Doctor of Philosophy
Department
Pharmacology
First Advisor
Richardson, Benjamin
Abstract
Adverse Childhood Experiences (ACEs) have been associated with many neurodevelopmental and affective disorders, including attention deficit hyperactivity disorder (ADHD) and generalized anxiety disorder (GAD), with more exposures increasing negative risks. Sex and genetic background are biological variables involved in adverse psychiatric outcomes due to ACE exposure(s). Few preclinical studies have properly powered each sex to determine the interaction between sex and genetics on stress-impacting behavior, especially in early life. Females generally have an increased prevalence of stress-related psychopathologies beginning after adolescence, indicative of the adolescent time period as a female-specific sensitive period. To understand the underlying neuronal components responsible for this relationship between sex, stress/trauma, and cognitive/affective behaviors, we are focused on understanding changes in and involvement of the norepinephrine (NE)-releasing locus coeruleus (LC) for several reasons. The LC has a key role in attention and memory modulation with LC neuronal activity displaying sex differences in excitability and neuropeptide responses. Genes involved in monoaminergic metabolism and transport are also involved in neurodevelopmental and affective behavior disorder risks. Corticotropin-releasing hormone/factor (CRF), the neuropeptide responsible for central stress signaling, has been shown to directly alter LC neuron firing, thereby providing one mechanism by which stress may modulate noradrenergic function. Genes associated with CRF signaling are also shown to increase the risk for affective disorder outcomes, especially after ACEs. In addition, LC neurons in female mice and rats have increased CRF sensitivity due to increased CRF receptor expression, Gs coupling, decreased receptor internalization, and increased NE release in the LC when compared to males. Despite the role of NE in modulating attention and sex differences in NE dynamics and sensitivity to stress, the role of early life stress on neurodevelopment impacting persistent cognitive behavioral changes in females had not been explored. In this dissertation, we first assessed behavioral outcomes depending on sex and genetic background due to stress in early life in two different inbred mouse strains. Secondly, we identified the effect of early life stress on physiological changes persisting in adult LC neurons and determined the causal relationship between cellular level changes and persistent behavioral changes. Thirdly, we have assessed sex differences in LC neuron responses ex vivo to CRF in both naïve and stress-exposed groups.
Access
This dissertation is Open Access and may be downloaded by anyone.