Gene therapy against conditioned fear

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DESCRIPTION (provided by applicant): It is clear that repeated exposure to stress increases the risk of developing and expressing symptoms of human disorders of fear and anxiety, however little is known about the mechanisms by which this occurs. Numerous studies have shown that the hippocampus is profoundly affected by chronic stress. Accordingly, patients with disorders of fear and anxiety often exhibit reduced hippocampal activity, and impairments in hippocampus-dependent learning and memory. In contrast, such patients are reported to exhibit increases in amygdala activity and enhancement of amygdala-dependent learning and memory. Because the amygdala plays an essential role in both innate and learned fear, this region may be a locus of stress-related changes that underlie fear and anxiety disorders. However, almost no work has examined the impact of chronic stress on the amygdala. In the proposed research, we will characterize stress-related changes in the amygdala in rats, using functional measures (behavior and synaptic plasticity) for which stress-related impairments in hippocampal neurons are well documented. We hypothesize that a regimen of chronic stress that negatively impacts hippocampal function across multiple measures will facilitate amygdala function along those same measures, thereby modeling the relationship between stress and disorders of fear and anxiety in humans. We will then examine the efficacy of two gene therapeutic interventions in reversing stress-related enhancement of fear. We will generate stress-inducible herpes simplex-1 viral amplicons designed to express an activity-dependent potassium channel (Kv1. 1), a calcium-dependent potassium channel (SK), the enzyme 11-beta-hydroxysteroid dehydrogenase-2 (11B), or a transdominant negative glucocorticoid receptor (Td). We will examine the impact of overexpressing these proteins in two amygdaloid regions (the basolateral complex or central nucleus) during stress to determine whether reducing either neuronal excitability (Kv1.1 and SK) or the actions of glucocorticoids (11B or Td) in the amygdala during stress restores normative function across behavioral and electrophysiological measures. These studies will be among the first to probe the feasibility of gene therapy in treating models of psychiatric disorders, and will provide important and novel insights into the mechanisms by which chronic stress impacts amygdala function.