Date of Award

7-2026

Embargo Period

7-27-2028

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biomedical Sciences

Additional Department

Natural Resources

College

College of Graduate Studies

First Advisor

Patrick Mulholland

Second Advisor

Jennifer Rinker

Abstract

Alcohol dependence facilitates the emergence of cognitive deficits that perpetuate continued misuse. While circuitry underlying executive dysfunction in alcohol use disorder (AUD) has historically focused on the cortex and hippocampus, other regions critical for cognitive circuitry remain understudied.

The nucleus reuniens (RE) is a midline thalamic nucleus essential for enabling cortical hippocampal communication, maintaining cognitive function, and is involved in affective behaviors. Despite its relevancy to behavioral domains critically impaired by alcohol dependence, the RE is highly understudied.

In chapter two, we established a model of alcohol dependence-induced cognitive deficits. Male and female C57BL/6J mice underwent baseline working memory testing before undergoing the chronic intermittent ethanol (CIE) model of alcohol dependence. Following 72 hours after the final vapor exposure session, mice were retested, and CIE-exposed mice exhibited significantly worse working memory.

In chapter three, bulk RNA-seq was performed on male and female C57BL/6J mice, and spatial transcriptomics was performed on female mice to determine molecular adaptations within the RE following CIE exposure. Baseline sex differences were identified, and differentially expressed genes (DEGs) were sex divergently modulated by CIE exposure. Gene ontology (GO) enrichment analysis identified DEGs implicated in neuronal excitability, GABAergic synapses, and AUD-related behavioral phenotypes. Spatial transcriptomics identified distinct spatially restricted glutamatergic subtypes that exhibited similar GO adaptations as the bulk seq. Genetic adaptations to glia and endothelial tissue were also identified.

Within chapter four, physiological adaptations were identified in the RE after CIE. Slice electrophysiology measured evoked action potential firing and synaptic transmission. Neurons from CIE-exposed males had reduced action potential firing, while RE neurons from CIE-exposed females showed increased evoked firing. The amplitude of spontaneous inhibitory postsynaptic currents was increased by CIE exposure in both sexes.

In chapter five, RE modulation during spatial working memory and anxiety like behavior were assessed following CIE exposure. Chemogenetic inhibition of the RE restored working memory and reduced CIE-induced negative affect.

In conclusion, alcohol dependence-induced molecular and physiological adaptations within the RE after CIE exposure that may contribute to working memory impairment. The RE may serve as a novel target for treatment of AUD-related behavioral deficit.

Rights

Copyright is held by the author. All rights reserved.

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