BRAIN-DERIVED NEUROTROPHIC FACTOR IN NEURONS EXPRESSING CORTICOTROPIN-RELEASING HORMONE MEDIATES THE RESPONSE TO CHRONIC STRESS.
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 ... read more(CRH) 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