Amnesia is a consequence of enhancing GABAergic neurotransmission in clinical settings and GABA systems play a role in some forms of mental retardation but the precise role of GABA receptors in well-defined learning circuits is not well characterized. Stress and gonadal hormones also influence GABA function and learning processes but even less is known about the extent to which these factors converge on common brain mechanisms. Using learning preparations that have well characterized neural circuitry we will determine how stress and other alterations in the hormonal milieu act through GABA receptors to influence learning. A key focus of this work will be how hormonal factors impact learning and memory via neurosteroid action at d subunit containing GABA receptors. While d-subunits have limited distribution in the brain, two regions with especially high expression, the dentate gyrus of the hippocampus and granule cells of the cerebellum play a fundamental role in learning and memory. Therefore d subunit containing GABA receptors offer a site at which factors such as stress, can modulate learning systems. Our central hypothesis is that hormonal factors impact learning and memory via neurosteroid action at d subunit containing GABA receptors within the neural circuits mediating specific forms of memory. This hypothesis is based on 4 key findings: 1) Neurosteroids act on dGABARs. 2) dGABARs are strategically placed within well-defined learning/memory circuits. 3) Factors such as stress and estrus cycle influence both hormonal background and learning and memory. 4) d subunit knockout mice are not responsive to neurosteroids. Hormonal variation associated with the estrus cycle will provide one avenue for addressesing these issues. A second will be an animal model of past-traumatic stress disorder, where prior stress enhances certain forms of learning. We seek to determine how both of these factors converge to modulate learning and memory by action an delta containing GABAA receptors.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Program Projects (P01)
Project #
2P01NS035985-06A1
Application #
6946688
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Project Start
2005-04-01
Project End
2010-03-31
Budget Start
2005-04-01
Budget End
2006-03-31
Support Year
6
Fiscal Year
2005
Total Cost
$218,903
Indirect Cost
Name
University of California Los Angeles
Department
Type
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
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Meera, Pratap; Wallner, Martin; Otis, Thomas S (2011) Molecular basis for the high THIP/gaboxadol sensitivity of extrasynaptic GABA(A) receptors. J Neurophysiol 106:2057-64
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