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Estrogen Regulation of the Hypothalamo-Pituitary-Adrenal Axis

雌激素对下丘脑-垂体-肾上腺轴的调节

基本信息

批准号：
9040279
负责人：
Robert J Handa
金额：
$ 33.02万
依托单位：
COLORADO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-05 至 2019-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9040279
关键词：
Acute Adrenal Glands Adult Agonist Amygdaloid structure Androgens Androstanes Beds Behavior Binding Brain Cell Nucleus Chronic Corticosterone Corticotropin Corticotropin-Releasing Hormone Data Disease Estradiol Estrogen Receptor alpha Estrogen Receptor beta Estrogen Receptors Estrogens FOS gene Female Gap Junctions Gene Expression Glucocorticoids Glycols Goals Gonadal Hormones Gonadal Steroid Hormones Hemagglutinin Homeostasis Hormonal Hormone Receptor Hormones Hypothalamic structure Immediate-Early Genes Immune Sera Immunoprecipitation Individual Differences Injection of therapeutic agent Knock-out Knockout Mice Ligands Location Mammals Measures Medial Messenger RNA Molecular Monitor Mus Neurobiology Neurologic Neurons Neuropeptides Neurotransmitters Output Oxytocin Pathway interactions Phenotype Pituitary Gland Pituitary-Adrenal System Play Polyribosomes Population Preparation Recovery Regulation Reporter Ribosomal Proteins Rodent Role Sex Characteristics Shapes Slice Stress Suid Herpesvirus 1 Synapses Testing Testosterone Three-Dimensional Image Tissues Tracer Transgenic Mice Transgenic Organisms Translating Vasopressins Wild Type Mouse anxiety-related behavior base biological adaptation to stress gamma-Aminobutyric Acid insight male mouse Cre recombinase mouse model neural circuit neurobiological mechanism neurobiotin neuropsychiatry new therapeutic target novel paraventricular nucleus public health relevance reproductive response restraint stress reactivity stressor stria terminalis

项目摘要

DESCRIPTION (provided by applicant): The long-term goal of this project is to determine the neurobiological mechanisms that underlie effects of estrogen on the adult hypothalamo-pituitary-adrenal (HPA) axis. HPA axis activation in mammals is a basic response to environmental perturbations that threaten homeostasis and such responses, although beneficial in the short-term, have deleterious consequences under chronic conditions. Prolonged elevations of adrenal glucocorticoids (GCs) are neuroendangering and alter behaviors. Moreover, a dysregulation of the HPA activity accompanies neuropsychiatric disorders. In rodents, females show a more robust HPA axis response to stress than do males, partly because of sex-differences in circulating estradiol (E2) levels. Thus, the overarching postulate of this application is that individual differences in adult stress-responses arise from differential E actions on the stress-circuitry. Our studies focus predominantly on estrogen receptor beta (ERβ). Rodent studies show that the alpha form of ER (ERα) increases adrenal corticosterone (CORT) and pituitary adrenocorticotropic hormone (ACTH) response to stressors whereas activation of ERβ inhibits HPA activity. Importantly, ERβ is highly expressed in neurons of the PVN of both male and female mice, allows integration of gonadal hormone levels with stress-related inputs. Using novel transgenic mouse models, we will identify stress responsive ERβ-ergic neural circuitry of the mouse hypothalamus, and determine if activation of PVN ERβ reduces HPA drive through OTergic pathways. Specific aim 1 will assess populations of ERβ and ERα neurons that are incorporated into the stress circuitry of the mouse brain. Aim 2 will test the hypothesis that activation of ERβ in male and female PVN neurons inhibits HPA axis function through 1) synaptic connections between ERβ and CRH neurons or 2) through reciprocal projections to the Bed n. of the Stria Terminalis (BST) or medial Amygdala (mAmg). Aim 3 will elucidate molecular changes and sex differences that occur in PVN ERβ neurons in response to stress or ER (α / β) agonist treatment. Aim 4 will directly test whether OT is requird for ERβ regulation of PVN function. The results of these studies will provide novel insight into the role played by PVN ERβ neurons in controlling hypophysiotrophic function with hopes of identifying novel targets for therapeutic approaches to treating stress and associated neurological deficits.