Glucocorticoids (GCs) a hormone released from the adrenal glands during the stress response modulates hippocampal function, a brain region important for memory and learning. The modulatory affects of GCs on hippocampal function are thought to be mediated by the mineralocorticoid receptor (MR) and the glucocorticoid receptor (GR). The GRs plays a critical role in mediating the impairing effects of GCs on hippocampal function. Conversely, activation of MRs facilitates hippocampal function. Mineralocorticoid receptors (MRs) have extremely high affinity for corticosteroid and are consequently tonically occupied. As a result of MRs' high affinity and tonic occupation its functional dynamic range was considered to be minimal. Thus, the contribution of this receptor in modulating the cognitive effects of stress was considered to be trivial. An important question addressed by my thesis was: (1) is it possible to modulate the dynamic range of a receptor that is tonically occupied and (2) if so what are the functional consequences of increasing MR's dynamic range during the acquisition, consolidation, and retrieval phase of a spatial and non spatial hippocampal-dependent task, during basal and high corticosteroid conditions. Using herpes simplex vectors, simultaneously manipulated both MR and GR signaling in the dentate gyrus of the hippocampus, which in turn increased MR signaling. My studies revealed an enhancement in spatial and nonspatial memory consolidation in animals overexpressing MR protein. Moreover, rats overexpressing MR or a negative transdominant GR (TD) were spared from the disruptive effects of high GCs on the retrieval of spatial and nonspatial memory. Thus, this thesis illustrates the potential of viral vectors overexpressing MR to mediate cognitive function. In addition, I evaluated the functional impact of an increase in MR's dynamic range on measures of anxiety. Anxiety-related disorders are closely linked to stress. GCs, acting through GR or MR can influence neuropsychiatric disorders. In the present thesis, I bilaterally over-expressed either one or two copies of the MR gene in the dentate gyrus of the hippocampus and determined its effect on the open field (OF) and elevated plus maze (EPM), two established models of anxiety. I demonstrated that overexpression of two copies of MR ("MR/MR") blocked the stress induced decline in open arm exploration. These results demonstrate that over-expression of MR in the hippocampus blocks the anxiolytic effects of stress and suggest that MR may serve as a potential molecular target for novel therapeutic agents. The results from my thesis support the use of viral vectors to safely and efficiently deliver selective genes to the CNS of living animals; facilitating the study of very sensitive behaviors such as learning/memory and anxiety.
|School Location:||United States -- California|
|Source:||DAI-B 69/10, Dissertation Abstracts International|
|Keywords:||Anxiety, Cognition, Gene therapy, Memory impairments, Stress|
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