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.
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