The goal of this project is to understand the mechanisms which allow neurons to integrate diverse regulatory signals into functional responses. Vasopressin (VP) neurons of the hypothalamo-neurohypophseal system (HNS) will serve as the model neuron in these studies, because they respond to wide ranging afferents, and integrate this information into a physiologically appropriate rate of hormone secretion. In addition to responding to afferents from the brainstem, hypothalamus, and forebrain that utilize an array of neurotransmitters and neuropeptides, the VP neurons also respond to non-synaptic signals such as osmolality of the extracellular fluid and steroid hormones. The proposed experiments will address two hypotheses: 1) Agonists of ionotropic receptors represent the primary regulators of VP neurons, and the action of these neurotransmitters is modulated via agonists of G-protein linked receptors and steroid hormones. 2) G-protein linked agonists also regulate VP gene expression and/or mRNA stability independent of ionotropic receptor agonists.
The specific aims of the proposal are: 1. To evaluate the role of excitatory amino acids (EAA) in the regulation of VP release and VPmRNA. 2. To evaluate the relationship between EAA ionotropic receptor agonists and G-protein linked receptor agonists. 3. To evaluate modulation of EAA stimulation by steroid hormones. 4. To evaluate the autoregulation of neurohypophyseal hormone secretion by VP and OT. Explants of the HNS will be used in all of the proposed experiments. These explants respond to a slow increase in osmolality with a sustained increase in VP release and an increase in VPmRNA content. VP release from these explants is also stimulated by EAA agonists, ATP and GABAergic antagonists. Where appropriate, HNS explants from mice strains with null mutations in specific genes of interest to this proposal will be used.
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