Gene Therapy, Stress and Hippocampal Function

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DESCRIPTION (provided by applicant): The hippocampus has been studied for its synaptic plasticity, role in cognition, and the neurogenesis that occurs in the adult hippocampus. With this has come an appreciation of endocrine modulators of hippocampal function. Specifically, glucocorticoids (GCs), adrenal steroids secreted during stress, disrupt [or] impair facets of synaptic plasticity and cognition, and inhibit neurogenesis. Estrogen, in contrast, enhances plasticity, cognition and neurogenesis. There has also been progress in the use of viral vectors to deliver transgenes into the CNS. We will use herpes simplex virus-1 vectors in a gene therapy strategy to protect the hippocampus from the disruptive effects of GCs and of stress, and to divert some of those GC effects into salutary estrogenic ones. We have constructed and wish to explore the protective potential of vectors expressing a) an enzyme which degrades GCs; b) a dominant negative GC receptor; c) a chimeric steroid receptor which binds GCs but has the genomic actions of an estrogen receptor. In Aim 1, we will alter these vectors to make them inducible by stress and GCs, as a means to have their expression triggered by insults. We will then characterize their patterns of expression. We will then examine the protective potential of these vectors, examining if the first two spare neurons from adverse GC effects, and if the chimeric vector also generates the salutary estrogenic effects when exposed to GCs. In Aim 2, the endpoint will be long-term potentiation in hippocampal slices generated from rats with differing pre-mortem regimes of GC exposure or stress. In Aim 3, we will study the effects of GCs, stress, and these vectors upon a hippocampal-dependent cognitive task. In Aim 4, we will study neurogenesis in vitro and in the adult hippocampus. We will characterize the effects of GCs, stress and estrogen upon it. We will then determine whether these vectors can protect neurogenesis from the inhibitory effects of GCs and, in the case of the chimeric vector, harness this to produce stimulatory estrogenic effects.