Blood glucocorticoid levels rise in response to stress activation of the hypothalamic- pituitary-adrenal (HPA) axis. They feed back onto the brain, where they exert both rapid and delayed inhibitory effects on HPA axis activation, corresponding generally to non-genomic and genomic actions, respectively. Dysfunctional glucocorticoid negative feedback is associated with a wide variety of disorders, including stress disorders and metabolic syndrome. The general goal of this project is to determine the site and mechanisms of rapid glucocorticoid feedback actions. Our working hypothesis is that rapid glucocorticoid actions in the hypothalamus are important for the integration of neuroendocrine signaling during stress. During the first period of funding of this grant, we identified a novel rapid glucocorticoid action in hypothalamic paraventricular nucleus (PVN) neurons that involves the activation of a putative membrane G protein-coupled glucocorti in PVN parvocellular neurons and both retrograde endocannabinoid and NO release in magnocellular neurons. Endocannabinoids are also released and suppress excitatory inputs in response to depolarization of PVN neurons. Thus, glucocorticoids elicit multiple retrograde signals in PVN neurons, suggesting a divergence in membrane glucocorticoid receptor signaling pathways, and both glucocorticoids and electrical activity elicit endocannabinoid synthesis, suggesting a convergence in the signaling mechanisms activated by these stimuli. In this proposal, we will build on our previous findings with experiments that address the following aims:
Aim 1 is to study the intracellular signaling mechanisms engaged by membrane glucocorticoid receptor actions and depolarization that lead to endocannabinoid and NO synthesis;
Aim 2 is to investigate the role of glia in restricting the extracellular actions of endocannabinoids to glutamate synapses;
Aim 3 is to determine the role of glucocorticoid-indus-related disorders, including depression, hypertension and obesity. Corticosteroids represent a critical endocrine signal activated during the stress response, and they play various roles throughout the body that increase the chance for survival during stress. Corticosteroids have different mechanisms of action, both rapid and delayed, which are mediated ostensibly by different membrane and intracellular receptors. A clear understanding of the differences in the mechanisms and properties of these receptors will allow the development of pharmacological therapies for stress-related disorders, such as anxiety, depression and feeding disorders, with distinct pharmacodynamics and reduced side effects.

Public Health Relevance

Corticosteroids represent a critical endocrine signal activated during the stress response, and they play various roles throughout the body that increase the chance for survival during stress. Corticosteroids have different mechanisms of action, both rapid and delayed, which are mediated ostensibly by different membrane and intracellular receptors. A clear understanding of the differences in the mechanisms and properties of these receptors will allow the development of pharmacological therapies for stress-related disorders, such as anxiety, depression and feeding disorders, with distinct pharmacodynamics and reduced side effects. 1

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH066958-09
Application #
8414850
Study Section
Special Emphasis Panel (ZRG1-IFCN-A (03))
Program Officer
Desmond, Nancy L
Project Start
2003-06-01
Project End
2014-12-31
Budget Start
2013-01-01
Budget End
2014-12-31
Support Year
9
Fiscal Year
2013
Total Cost
$357,589
Indirect Cost
$91,471
Name
Tulane University
Department
Anatomy/Cell Biology
Type
Schools of Arts and Sciences
DUNS #
053785812
City
New Orleans
State
LA
Country
United States
Zip Code
70118
Morton, Linda A; Popescu, Ion R; Haam, Juhee et al. (2014) Short-term potentiation of GABAergic synaptic inputs to vasopressin and oxytocin neurones. J Physiol 592:4221-33
Di, Shi; Popescu, Ion R; Tasker, Jeffrey G (2013) Glial control of endocannabinoid heterosynaptic modulation in hypothalamic magnocellular neuroendocrine cells. J Neurosci 33:18331-42
Herman, J P; McKlveen, J M; Solomon, M B et al. (2012) Neural regulation of the stress response: glucocorticoid feedback mechanisms. Braz J Med Biol Res 45:292-8
Hill, M N; Tasker, J G (2012) Endocannabinoid signaling, glucocorticoid-mediated negative feedback, and regulation of the hypothalamic-pituitary-adrenal axis. Neuroscience 204:5-16
Tasker, Jeffrey G; Herman, James P (2011) Mechanisms of rapid glucocorticoid feedback inhibition of the hypothalamic-pituitary-adrenal axis. Stress 14:398-406
Wardman, Jonathan H; Berezniuk, Iryna; Di, Shi et al. (2011) ProSAAS-derived peptides are colocalized with neuropeptide Y and function as neuropeptides in the regulation of food intake. PLoS One 6:e28152
Evanson, Nathan K; Tasker, Jeffrey G; Hill, Matthew N et al. (2010) Fast feedback inhibition of the HPA axis by glucocorticoids is mediated by endocannabinoid signaling. Endocrinology 151:4811-9
Hill, Matthew N; Patel, Sachin; Campolongo, Patrizia et al. (2010) Functional interactions between stress and the endocannabinoid system: from synaptic signaling to behavioral output. J Neurosci 30:14980-6
Di, Shi; Maxson, Marc M; Franco, Alier et al. (2009) Glucocorticoids regulate glutamate and GABA synapse-specific retrograde transmission via divergent nongenomic signaling pathways. J Neurosci 29:393-401
Di, Shi; Tasker, Jeffrey G (2008) Rapid synapse-specific regulation of hypothalamic magnocellular neurons by glucocorticoids. Prog Brain Res 170:379-88

Showing the most recent 10 out of 17 publications