BRAIN-DERIVED NEUROTROPHIC FACTOR IN NEURONS EXPRESSING CORTICOTROPIN-RELEASING HORMONE MEDIATES THE RESPONSE TO CHRONIC STRESS.
Gainey, Laura.
2015
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Abstract: Stress is an evolutionarily conserved process that allows for mitigation of environmental stimuli that threaten the individual's health and wellbeing. The response to a stressful stimulus is centrally governed by the Hypothalamic-Pituitary-Adrenal axis which begins by activation of neurons in the paraventricular hypothalamus (PVN) and their secretion of corticotropin-releasing factor (CR... read moreH) into the blood. CRH works down-stream of the PVN to cause secretion of adrenocorticotropic hormone (ACTH) which travels in the circulation to the adrenal cortex where it stimulates release of glucocorticoids (GCs) that travel throughout the body to cause sympathetic activation, increased arousal and vigilance and behavioral changes necessary for mitigation of a stressor. Stress can lead to neuropsychiatric disorders in vulnerable individuals and this vulnerability is thought to be conferred by a complex combination of genetic predisposition and environmental stressors. Among the candidate genetic factors contributing to stress-induced disease is the brain-derived neurotrophic factor (BDNF.) Genetic dysregulation of BDNF regulated secretion via the Val-66-Met single nucleotide polymorphism has been associated with disruption of mood and anxiety in humans and animal models. Both acute and chronic stress, as well as exogenous application of GCs, have been found to regulate BDNF expression in the PVN. Additionally, BDNF infusion to the lateral ventricles of rodents causes elevations of CRH transcript in the hypothalamus. In this thesis I present my investigation of the hypothesis that BDNF in CRH-expressing neurons is a critical regulator of the behavioral response to stress. I have shown that BDNF colocalizes with CRH in parvocellular neurons of the PVN and that targeted deletion of BDNF from CRH neurons throughout the brain results in altered behavioral response to stress. Specifically, I have shown that loss of BDNF from CRH neurons prevents stress-induced alterations in anxiety-like and exploratory behavior in the Open Field Test and Elevated Plus Maze but not the Light-Dark Box Test. Additionally, I have demonstrated that BDNF KO mice exposed to one week of chronic stress have elevated circulating GCs and reduced PVN expression of glucocorticoid receptor (GR) compared to stressed controls and to non-stressed controls and BDNF KOs. These findings imply that BDNF in CRH cells is necessary for chronic stress-induced changes in behavior and that these behavioral changes are mediated by BDNF-dependent inhibition of HPA-axis activity.
Thesis (Ph.D.)--Tufts University, 2015.
Submitted to the Dept. of Neuroscience.
Advisor: Maribel Rios.
Committee: Leon Reijmers, Emmanuel Pothos, and Tracey Petryshen.
Keyword: Neurosciences.read less - ID:
- jq085x74b
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