In the female laboratory rodent, oxytocin (OT) is believed to be anxiolytic and to dampen the response of the hypothalamic-pituitary- adrenal axis to stress. Psychogenic stress or anxiety activates limbic regions of the rat or mouse brain, such as the amygdaloid nuclei and hippocampus. These regions project to the hypothalamic paraventricular nucleus (PVN), a major site of OT production in the brain. The PVN in turn innervates the limbic system. Brain pathways that are activated by psychogenic stressors or anxiety contain OT immunoreactivity (ir) and/or OT receptors (OTR). Preliminary studies in this proposal indicate that female OT deficient mice release more corticosterone following a psychogenic stress, have a greater stress-induced hyperthermic response to novel environment, and display more anxiety-related behavior than wild type mice. The enhanced anxiety in this genotype is accompanied by enhanced expression of Fos immunoreactivity (ir), a marker of neuronal activation, in the medial amygdala of null versus wild type mice. We hypothesize that central OT is necessary for attenuation of stress and anxiety. If OT pathways are absent, then limbic activation (as measured by Fos ir) will be altered and responses to psychogenic stress (e.g., corticosterone release or stress-induced hyperthermia) will be heightened.
The specific aims of this proposal are as follows: 1- Measure plasma corticosterone concentrations in OT null and wild type mice before and following either psychogenic or physical stressors and score anxiety-related behavior during tests of anxiety. Peripheral and brain indicators of the stress response and anxiety-related behavior will be measured to ascertain potential genotypic differences in compensatory homeostatic mechanisms. 2- Immunocytochemical localization of the immediate-early gene protein product, Fos, will be used to identify neurons activated after stress or anxiety testing in wild type and OT null mice. Single- and dual-labeling methods will be used to map the distribution and neurochemical phenotypes of activated neurons in the brain with a particular focus on neurons in the limbic system, which are believed to mediate psychogenic stress and anxiety-related behaviors. 3- Administer exogenous OT into the brain of OT null and wild type mice and measure anxiety-related behavior or corticosterone following stressful stimuli; and 4- Measure brain OT receptors by autoradiography pre and post anxiety and stress testing in wild type versus OT null mice.
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