Degree

Doctor of Philosophy (PhD)

Department

Environmental and Evolutionary Biology

Document Type

Dissertation

Abstract

Self-injurious behavior (SIB), also known as non-suicidal self-injury (NSSI), is characterized by deliberate infliction of harming one’s own body tissues without committing suicide, and persists in a group of captive rhesus macaques despite an enhanced enrichment program and pharmacological intervention with diazepam. The aim of this dissertation was to identify the neurobiological underpinnings of SIB by combining RNA-seq guided transcriptomic discovery and targeted candidate gene validation with unbiased histological and imaging analysis. The secondary aim was to employ a complementary mouse model to investigate the endogenous opioid system in response to diazepam. The amygdala transcriptome of primates with SIB (n = 9) was compared with that of monkeys without a history of SIB (n = 3) using bulk RNA-sequencing, and top differentially expressed gene candidates were validated further by DAB-chromogen based immunohistochemistry and unbiased stereology in independent cohorts. Transcriptomic approaches were extended to reward-circuit for identifying the dopaminergic signature by dopamine-transporter (DAT) immunoreactivity in the ventral tegmental area (VTA), and chronic diazepam intervention was framed in C57BL/6 mice (2 × 2 Sex × Treatment, n = 8/group) with anxiety phenotype and PDYN expression as downstream analysis in the limbic system. RNA-sequencing identified 26 differentially expressed genes, with vimentin and RARRES2 (chemerin) selected for histological validation. In the prefrontal cortex, vimentin⁺ cell morphology displayed a proportional shift toward reactive morphology in SIB animals (p < 0.001). In the central amygdala, all three SIB samples showed enhanced RARRES2 staining (d = 2.07; p = 0.069), and DAT-positive % area in the VTA was significantly reduced in SIB animals compared with controls (p = 0.020). Chronic diazepam reduces the open-field center time by 70% and light-dark-box light-zone time by 60% (both p ≤ 0.001), and selective sex-specific PDYN mRNA suppression in the male amygdala by 53% (p = 0.026), with no observed effect in females or in the hippocampus of either sex. Together, these findings suggest maladaptive changes among neuroimmune signaling, endogenous opioid neurochemistry and dopaminergic reward circuitry in SIB and provide evidence for a network-level model of SIB with translational relevance to NSSI in humans and related comorbid neuropsychiatric disorders.

Date

2-6-2026

DOI

https://proquest.com/docview/3347951613

First Committee Chair

Karen Müller Smith

First Committee Member

Erika M. Caramillo

Second Committee Member

François Villinger

Third Committee Member

Mirna Marinic

Fourth Committee Member

Ritwij Kulkarni

Download

Included in

Neurosciences Commons

Share

COinS