In this application, we propose to investigate the specific neural systems underlying the mechanisms that may lead to long-term sensitization of one of the 'anxiety regulating networks'. The overall hypothesis for the current proposal is that the state of 'anxiety' (measured by behavioral an physiological responses) in an animal is dependent upon sensitization of a distributed forebrain neural network (that includes the basolateral and central nuclei of the amygdala, bed nucleus of the stria terminalis and others) and a topographically organized serotonergic system in the caudal dorsal raph_ nucleus. The experiments described below have been designed to test this hypothesis under four Specific Aims: 1) To demonstrate that the critical components of the proposed neuronal network, specifically, the corticotropin releasing factor (CRF) containing neurons of BLA, CeA, BNST, and the serotonergic neurons of the dorsal raph_nucleus (DRN), are activated (as measured by c-fos activation) in a variety of 'anxiety' states. 2) To determine that repeated stimulation of CRF receptors, either CRF type 1 or 2 receptors (CRFR1 and CRFR2, respectively) within the above network results in 'priming' of chronic anxiety/stress states. 3) To characterize, using combined anatomical and electrophysiological techniques, the effects of stimulating the CRF receptors on the 5-HT neurons of the caudal DRN in control versus chronically anxious (such as those after repeated CRF stimulation) rate. 4) To determine the effects of early life events such as neonatal lipopolysaccharide (LPS) stress on the BLA, CeA, BNST and DRN network functions. All these studies will be utilizing the following methods: a) whole animal behavioral and physiological responses; b) microinjection and immunohistochemical studies to elucidate pathways; c) patch-clamp studies to determine electrophysiological changes at the neuronal level; as well as d) pharmacological and molecular methods to understand regulation of messenger RNA levels that may contribute to long-term changes in cellular function. This proposal is a direct result of a NIMH research network development grant, HPA Regulation: Cross-Disciplinary Research Networks (RO3 MH 60825) and has provided us with an opportunity to demonstrate the feasibility of this proposed international collaboration. ? ?
Showing the most recent 10 out of 62 publications
