Dysfunction of the hypothalamo-pituitary-adrenocortical (HPA) axis is a common feature of major affective illnesses. Neuroendocrine disturbances are typically manifest as cortisol hypersecretion and glucocorticoid negative feedback resistance, both of which expose individuals to excessive levels of stress hormones and their deleterious sequelae. The mechanism underlying glucocorticoid hypersecretion is currently ill-defined. Work from our laboratories as well as others indicate that pathologically elevated glucocorticoids are likely due to hyperactivity of central stress-integrative neurons in the parvocellular PVN, which represent the final common pathway for HPA axis activation. In this proposal, we use a rat chronic stress model of depression to test the novel hypothesis that stress-related illnesses frequently characterized by sustained activation of HPA outflow result from the induction of biochemical and/or structural neuroplastic changes in hypophysiotropic regions of the paraventricular nucleus. This hypothesis will be tested in three Specific Aims.
The first Aim will test the hypothesis that chronic stress induces functional plasticity of post-synaptic receptor expression in the HPA effector neurons in the paraventricular nucleus. Experiments will evaluate the prediction that chronic stress reconfigures receptor populations to favor excitatory neurotransmission over inhibition, test for chronic stress enhancement of excitatory neurotransmitter actions on glucocorticoid secretion, and use a genomics-guided approach to provide an integrated analysis of stress-induced receptor changes in paraventricular nucleus neurons.
The second Aim will test the hypothesis that chronic stress disrupts glucocorticoid feedback sensitivity in paraventricular nucleus neurons controlling HPA axis responses. These experiments will determine if chronic stress reduces the capacity for nuclear glucocorticoid receptor signaling, and assess stress effects on feedback efficacy at the level of the PVN.
The third Aim will test the hypothesis that chronic stress induces morphological changes in the parvocellular PVN that predict enhanced excitability. These studies will determine whether chronic stress enhances excitatory vs. inhibitory neurotransmitter innervation of paraventricular CRH neurons, assess the ability of stress to affect paraventricular neuronal morphology, and use a genomics-guided approach to probe for possible molecular mechanisms underlying stress plasticity. Overall, this project will provide critical new information on hypothalamic mechanisms mediating neuroendocrine dysfunction in affective disease states.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
3R01MH069725-04S1
Application #
7675895
Study Section
Special Emphasis Panel (ZRG1-IFCN-D (02))
Program Officer
Desmond, Nancy L
Project Start
2005-04-08
Project End
2010-03-31
Budget Start
2008-09-01
Budget End
2009-03-31
Support Year
4
Fiscal Year
2008
Total Cost
$117,000
Indirect Cost
Name
University of Cincinnati
Department
Psychiatry
Type
Schools of Medicine
DUNS #
041064767
City
Cincinnati
State
OH
Country
United States
Zip Code
45221
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Evanson, Nathan K; Herman, James P (2015) Role of Paraventricular Nucleus Glutamate Signaling in Regulation of HPA Axis Stress Responses. Interdiscip Inf Sci 21:253-260
Solomon, Matia B; Loftspring, Matthew; de Kloet, Annette D et al. (2015) Neuroendocrine Function After Hypothalamic Depletion of Glucocorticoid Receptors in Male and Female Mice. Endocrinology 156:2843-53
Evanson, Nathan K; Herman, James P (2015) Metabotropic glutamate receptor-mediated signaling dampens the HPA axis response to restraint stress. Physiol Behav 150:2-7
Myers, Brent; Mark Dolgas, C; Kasckow, John et al. (2014) Central stress-integrative circuits: forebrain glutamatergic and GABAergic projections to the dorsomedial hypothalamus, medial preoptic area, and bed nucleus of the stria terminalis. Brain Struct Funct 219:1287-303
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Herman, James P (2012) Neural pathways of stress integration: relevance to alcohol abuse. Alcohol Res 34:441-7
Myers, Brent; McKlveen, Jessica M; Herman, James P (2012) Neural Regulation of the Stress Response: The Many Faces of Feedback. Cell Mol Neurobiol :

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