Our long term goal is to understand how sex steroids regulate G protein-coupled receptor mediated neurotransmission that underlies hormonal activation of behavior. We have demonstrated that membrane-initiated estradiol signaling (MIES) activates a circuit regulating lordosis behavior, a measure of sexual receptivity. Estradiol sequentially activates estrogen receptor-a (ERa), releasing NPY onto NPY-Y1 receptors in the ARH, which stimulates ?-endorphin release into the medial preoptic nucleus activating ?-opioid receptors (MORs). The present proposal builds on our discovery that MIES requires the metabotropic glutamate receptor, mGluR1a, to initiate cell signaling and that estradiol modulates membrane levels of ERa. We propose to test the hypothesis that MIES, which allows for hormonal-neural integration, regulates ERa trafficking to and from the membrane, and spinogenesis needed for sexual receptivity.
Three Specific Aims are proposed: 1) MIES modulates ERa-mGluR1a levels in the membrane which will be tested through a series of pharmacological studies that systematically block or activate MIES and intracellular pathways. 2) Lordosis behavior depends on MIES-induced trafficking of ERa-mGluR1a to the membrane. Manipulations that alter ERa-mGluR1a trafficking in the ARH will be tested on MOR internalization, a measure of circuit activation, and lordosis behavior. 3) MIES integrates hormonal and neuronal signals inducing morphological reorganization of the ARH underlying sexual receptivity. We will determine how estradiol, by activating different intracellular signaling pathways, induces dendritic spine formation and maturation needed for lordosis behavior. These experiments have salience for understanding not only reproductive behavior, but estradiol cell signaling throughout the nervous system through their interaction with mGluRs.

Public Health Relevance

Membrane-initiated estradiol signaling (MIES) has been directly implicated neural events underlying drug addiction, neuroprotection, cognition and reproductive physiology. Regulation of estrogen action in the brain requires an understanding of mechanisms that modulate MIES by altering levels of membrane estrogen receptors that transactivate metabotropic glutamate receptors initiating cell signaling.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA013185-13
Application #
8628089
Study Section
Neuroendocrinology, Neuroimmunology, Rhythms and Sleep Study Section (NNRS)
Program Officer
Pilotte, Nancy S
Project Start
2001-03-01
Project End
2017-02-28
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
13
Fiscal Year
2014
Total Cost
$334,950
Indirect Cost
$117,450
Name
University of California Los Angeles
Department
Neurosciences
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Micevych, P; Sinchak, K (2013) Temporal and concentration-dependent effects of oestradiol on neural pathways mediating sexual receptivity. J Neuroendocrinol 25:1012-23
Sinchak, Kevin; Dewing, Phoebe; Ponce, Laura et al. (2013) Modulation of the arcuate nucleus-medial preoptic nucleus lordosis regulating circuit: a role for GABAB receptors. Horm Behav 64:136-43
Christensen, Amy; Micevych, Paul (2013) A Novel Membrane Estrogen Receptor Activated by STX Induces Female Sexual Receptivity through an Interaction with mGluR1a. Neuroendocrinology 97:363-8
Dominguez, Reymundo; Dewing, Phoebe; Kuo, John et al. (2013) Membrane-initiated estradiol signaling in immortalized hypothalamic N-38 neurons. Steroids 78:607-13
Micevych, Paul E; Kelly, Martin J (2012) Membrane estrogen receptor regulation of hypothalamic function. Neuroendocrinology 96:103-10
Kuo, John; Micevych, Paul (2012) Neurosteroids, trigger of the LH surge. J Steroid Biochem Mol Biol 131:57-65
Christensen, Amy; Dewing, Phoebe; Micevych, Paul (2011) Membrane-initiated estradiol signaling induces spinogenesis required for female sexual receptivity. J Neurosci 31:17583-9
Chaban, Victor; Li, Jichang; McDonald, John S et al. (2011) Estradiol attenuates the adenosine triphosphate-induced increase of intracellular calcium through group II metabotropic glutamate receptors in rat dorsal root ganglion neurons. J Neurosci Res 89:1707-10
Micevych, Paul; Bondar, Galyna; Kuo, John (2010) Estrogen actions on neuroendocrine glia. Neuroendocrinology 91:211-22
Dominguez, Reymundo; Micevych, Paul (2010) Estradiol rapidly regulates membrane estrogen receptor alpha levels in hypothalamic neurons. J Neurosci 30:12589-96

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