The long-term objective of our studies is to define the biological role of the hypothalamic-pituitary-adrenal (HPA) axis and signaling through the glucocorticoid receptor (GR) in both the normal stress response and in psychiatric disease. Dysfunction HPA axis, the endocrine stress response, is specifically associated with vulnerability to major depression, bipolar disorder, anxiety disorders, and schizophrenia. The amygdala is a key nodal forebrain structure for integrating neuroendocrine and behavioral responses to stress, and amygdalar hyperactivity occurs in human depression and HPA hypersecretory states. Moreover, glucocorticoid action in the central nucleus of the amygdala (CeA) has been implicated in mediating a positive feedback loop that potentiates activity of the HPA axis, anxiety, and acquisition or expression of emotionally salient memory. The mechanisms by which these processes occur remain poorly understood, in part because of inadequately specific means for genetic manipulation of CeA function. We will test the hypotheses that glucocorticoid receptors in the CeA regulate behavioral and adrenal responses to stress by control of corticotropin-releasing hormone (CRH) gene expression at this site.
Our specific aims will seek to establish a novel CeA-specific GR knockout system, determine the phenotypic consequences of loss of GR function in the CeA for HPA axis regulation and behavior, and determine whether alteration in CRH expression contributes to the resulting behavioral and adrenal axis changes by regional replacement of CRH. Ultimately, our efforts aim to further the understanding of neuroendocrine circuits relevant for psychiatric diseases and promote development of novel therapeutic approaches for these major health disorders.

Public Health Relevance

An estimated 40 million people in the United States suffer from a psychiatric disorder, generating an enormous societal and public health burden. The results of our planned studies on the role of glucocorticoid receptor function in the amygdala hold promise for new insights into brain pathways regulating the responses to stress and the genesis and treatment of mental illness.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
7R01MH079010-04
Application #
8204986
Study Section
Neuroendocrinology, Neuroimmunology, and Behavior Study Section (NNB)
Program Officer
Desmond, Nancy L
Project Start
2009-02-13
Project End
2013-12-31
Budget Start
2012-01-01
Budget End
2012-12-31
Support Year
4
Fiscal Year
2012
Total Cost
$387,478
Indirect Cost
$125,656
Name
Cincinnati Children's Hospital Medical Center
Department
Type
DUNS #
071284913
City
Cincinnati
State
OH
Country
United States
Zip Code
45229
Arnett, Melinda G; Muglia, Lisa M; Laryea, Gloria et al. (2016) Genetic Approaches to Hypothalamic-Pituitary-Adrenal Axis Regulation. Neuropsychopharmacology 41:245-60
Nahar, Jebun; Haam, Juhee; Chen, Chun et al. (2015) Rapid Nongenomic Glucocorticoid Actions in Male Mouse Hypothalamic Neuroendocrine Cells Are Dependent on the Nuclear Glucocorticoid Receptor. Endocrinology 156:2831-42
Laryea, Gloria; Muglia, Lisa; Arnett, Melinda et al. (2015) Dissection of glucocorticoid receptor-mediated inhibition of the hypothalamic-pituitary-adrenal axis by gene targeting in mice. Front Neuroendocrinol 36:150-64
Arnett, M G; Pan, M S; Doak, W et al. (2015) The role of glucocorticoid receptor-dependent activity in the amygdala central nucleus and reversibility of early-life stress programmed behavior. Transl Psychiatry 5:e542
Laryea, Gloria; Arnett, Melinda; Muglia, Louis J (2015) Ontogeny of hypothalamic glucocorticoid receptor-mediated inhibition of the hypothalamic-pituitary-adrenal axis in mice. Stress 18:400-7
Laryea, Gloria; Arnett, Melinda G; Wieczorek, Lindsay et al. (2013) Site-specific modulation of brain glucocorticoid receptor and corticotropin-releasing hormone expression using lentiviral vectors. Mol Cell Endocrinol 371:160-5
Laryea, Gloria; Schutz, Gunther; Muglia, Louis J (2013) Disrupting hypothalamic glucocorticoid receptors causes HPA axis hyperactivity and excess adiposity. Mol Endocrinol 27:1655-65
Laryea, Gloria; Arnett, Melinda G; Muglia, Louis J (2012) Behavioral Studies and Genetic Alterations in Corticotropin-Releasing Hormone (CRH) Neurocircuitry: Insights into Human Psychiatric Disorders. Behav Sci (Basel) 2:135-71
Kocalis, Heidi E; Turney, Maxine K; Printz, Richard L et al. (2012) Neuron-specific deletion of peroxisome proliferator-activated receptor delta (PPARδ) in mice leads to increased susceptibility to diet-induced obesity. PLoS One 7:e42981
Wieczorek, L; Majumdar, D; Wills, T A et al. (2012) Absence of Ca2+-stimulated adenylyl cyclases leads to reduced synaptic plasticity and impaired experience-dependent fear memory. Transl Psychiatry 2:e126

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