Biomedical Sciences ETDs

Publication Date

Fall 12-13-2025

Abstract

Adolescence represents a critical window of frontal cortex (FC) maturation and corticolimbic circuit refinement that supports stress and emotion regulation. Disruption of these processes by early-life insults such as prenatal alcohol exposure (PAE) or adolescent stress increases vulnerability to anxiety and mood disorders, in part through circadian–immune dysregulation. The circadian transcription factor Bmal1 and the proinflammatory cytokine tumor necrosis factor-alpha (TNFα) have emerged as key regulators of neuroimmune signaling and synaptic communication, yet their interactions across developmental risk contexts remain poorly understood. This dissertation examined the effects of mild adolescent isolation stress, with and without PAE, on anxiety-like behaviors and gene expression within corticolimbic regions of male and female mice. Behavioral assessments revealed that both adolescent stress and PAE increased anxiety-like responses in a sex-dependent manner, with PAE females displaying heightened freezing and reduced exploratory activity and PAE males showing impaired adaptive coping. Molecular analyses demonstrated that adolescent stress elevated Bmal1 expression while suppressing TNFα and downstream inflammatory mediators in the FC, consistent with an anti-inflammatory role for Bmal1 that may disrupt TNFα-dependent homeostatic synaptic signaling. PAE interacted with stress to produce region- and sex-specific transcriptional changes, including elevated Bmal1 and corticotropin-releasing hormone (CRH) in the hippocampus (HIPP) and amygdala (AMG) of stressed PAE females and blunted Per2 responses in PAE males. These findings identify Bmal1–TNFα–Per2 signaling as a convergent pathway through which PAE and adolescent stress impair circadian, immune, and stress regulatory systems, providing new insight into mechanisms of sex-specific vulnerability to anxiety and highlighting potential targets for intervention in fetal alcohol spectrum disorder and adolescent stress-related psychopathology.

Keywords

Prenatal alcohol exposure (PAE), Corticotropin-releasing hormone (CRH); Circadian transcription factors (Bmal1 and Per2); Tumor necrosis factor-alpha (TNFα); corticolimbic regions; chemokine ligand 2 (CCL2).

Document Type

Dissertation

Language

English

Degree Name

Biomedical Sciences

Level of Degree

Doctoral

Department Name

Biomedical Sciences Graduate Program

First Committee Member (Chair)

David Linsenbardt

Second Committee Member

Erin Milligan

Third Committee Member

Kiran Bhaskar

Fourth Committee Member

Nora Bizorrero

Fifth Committee Member

Jason Weick

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