Date of Award


Document Type

Campus Access Dissertation

Degree Name

Doctor of Philosophy (PhD)


Developmental and Brain Sciences

First Advisor

Richard G. Hunter

Second Advisor

Ed Tronick

Third Advisor

Susan Zup


Stress represents an ubiquitous environmental stimuli, one both perceived an adapted to by the brain. Colloquially, stress carries a negative connotation and stress has certainly been associated with pathogenesis of numerous neuropsychiatric disorders. Stress, however, can produce positive effects on brain and behavior. These seemingly diametrically opposed actions of stress can be reconciled by considering the duration, frequency and context of stress stimuli. Physiologically stress stimuli produce a (WORD CHOICE) signaling cascade through hypothalamic-pituitary-adrenal axis activation, ultimately resulting in the release of glucocorticoids which can diffuse throughout and act on receptors within the brain and body. Canonical actions of glucocorticoids include binding to cytosolic receptors that upon ligand binding, translocate to the nucleus and interact with genomic response elements to influence transcription. Yet, this view of glucocorticoid action has not fully explained stress-induced changes in brain and behavior nor have single- or poly-genic mutations of genes associated with glucocorticoid signaling. For instance, a number of anxiety disorder subtypes are considered “stress-related.” A large focus of research has been on the epigenetic and anxiety-like behavioral consequences of stress. Animal models of anxiety-related disorders have provided strong evidence for the role of stress on the epigenetic control of the hypothalamic-pituitary-adrenal axis and of stress responsive brain regions. Neuroepigenetics may continue to explain individual variation in susceptibility to environmental perturbations and consequently anxious behavior. Behavioral and pharmacological interventions aimed at targeting affecting epigenetic marks associated with anxiety may prove fruitful in treatment. With the advent of next-generation sequencing technologies, large swathes of the non-coding genome have been identified and a role for the deep genome in governing the neural response to stress has been outlined. For instance, in the hippocampus heterochromatin remodeling is observed in gene deserts, here, marking repetitive retrotransposable elements selectively for transcriptional silencing. Aberrant retroelement expression is predicted to contribute to functional deficits in stress-sensitive brain regions. Though not yet fully realized, this “junk” represents a novel frontier in stress physiology relevant to the many stress-related pathologies.


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