Date of Award

2026

Degree Name

Biomedical Research

College

Joan C. Edwards School of Medicine

Type of Degree

Ph.D.

Document Type

Dissertation

First Advisor

Dr. Price Dickson

Second Advisor

Dr. Daniel Morgan

Third Advisor

Dr. Brandon Henderson

Fourth Advisor

Dr. Alejandro Nato

Fifth Advisor

Dr. James Denvir

Abstract

Environmental impoverishment is a model of early life stress with direct consequences across a wide range of neurological and physiological conditions. Neuron morphology and density as well as anxiety disorders and addiction have shown to have significant relationships with environmental impoverishment models. Conversely, environmental enrichment confers therapeutic benefits that are protective across these conditions. There is an observed spectrum of resistance or vulnerability to the effects of housing conditions across populations, indicating genetics as an influential factor. Understanding this interaction is critical for deepening our knowledge of how genes and environment interact in ways that confer resistance or vulnerability, and contribute to the deeper understanding of these complex conditions. The objective of these studies is to investigate how changes in gene expression caused by environmental enrichment or impoverishment vary across genetically diverse populations. The first project used three different housing contexts: environmental enrichment, standard housing, and isolation housing. Using recombinant inbred lines in these studies increases the genetic diversity in the population, allowing for the inclusion of novel gene combinations. Recombinant inbred lines also provide the potential for genetic mapping. The C57BL/6J and DBA/2J are the founder strains of the BXD recombinant inbred lines and, as such, were chosen as the two strains used in this first study. Mice were separated into the housing conditions at weaning and remained there for 10 weeks. Striatum samples were then collected and processed for ribonucleic acid (RNA) sequencing. The striatum plays a significant role in dopamine reward pathways, making it a valuable target for understanding the effects of environmental enrichment. Samples were then analyzed both within and across strains to quantify the strain-based influence of housing condition. The findings from this first study were significant, with the DBA/2J strain exhibiting differential expression across different housing contexts. This differential expression was primarily between environmental enrichment and isolation housing groups. The second study refined the housing conditions down to the most informative contexts, namely the enriched and isolated conditions, while expanding into eight different strains and an additional brain region. A combination of Collaborative Cross (CC) strains and their founders were selected for this follow-up study. The CC mouse lines are another recombinant inbred panel that expands on the concepts of the BXD panel by incorporating a greater breadth of founder strains, increasing the genetic diversity found within the individual CC strains. The hippocampus is primarily associated with learning and memory, and alterations in its gene expression can provide insights into how environmental enrichment influences these processes. For this reason, the hippocampus was added as an additional tissue for sequencing and evaluation in the second study. Evaluating changes in the transcriptome through RNA sequencing in the second study identified a broad spectrum of differential gene expression, revealing distinct patterns of strain and tissue-specific vulnerability and resistance. These findings present a complex relationship between genetics and variability in environmental quality, with advanced mouse crosses proving to be an invaluable tool to disentangle this complex relationship. Together, these studies deepen our understanding of this complex gene-by-environment interaction and demonstrate how advanced mouse models can be better used to investigate these interactions.

Subject(s)

Genetics.

Biology -- Research.

Medicine -- Research.

Gene expression.

Laboratory animals -- Housing.

Morphology.

Therapeutics.

Mental illness -- Genetic aspects.

Hippocampus (Brain)

RNA.

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