Central Viscerosensory Circuits-Structure and Function

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DESCRIPTION (provided by applicant): Sensory signals from within the body are delivered to brain regions that shape physiological and behavioral responses to stress and influence emotional learning. The research proposed in this R01 competing renewal application will provide new insights into the functional organization and development of viscerosensory inputs to the hypothalamus and limbic forebrain, with a focus on sensory signals from the gut. Experiments will test mechanistic hypotheses about the structure and function of noradrenergic (NA) and glucagon-like peptide-1 (GLP-1) signaling pathways that originate in the dorsal vagal complex (DVC) and target the paraventricular nucleus of the hypothalamus (PVN), lateral hypothalamic area (LHA), bed nucleus of the stria terminalis (BNST), and central nucleus of the amygdala (CeA). Hypotheses to be tested are organized into three Specific Aims. Aim 1 will use anterograde transneuronal virus tracing to label viscerosensory pathways from the stomach to the forebrain. One set of experiments will test the hypothesis that NA and non-NA DVC neurons relay gastric viscerosensory signals to discrete subregions of the PVN, LHA, BNST, and CeA. Other experiments will test the hypothesis that gastric viscerosensory inputs to the forebrain undergo significant structural maturation in rats during the first two weeks postnatal. Aim 2 will determine the necessity of DVC NA neurons for hypothalamic and limbic forebrain responses to interoceptive stress. One study will test the hypothesis that DVC NA neurons are necessary for certain interoceptive stressors [i.e., cholecystokinin (CCK), lithium chloride (LiCl), and lipopolysaccharide (LPS)] to inhibit food intake, but are unnecessary for these stressors to support conditioned taste aversion learning. A related study will test the hypothesis that DVC NA neurons are necessary for CCK, LiCl and LPS to induce cFos expression in the PVN and LHA, but are unnecessary for these stressors to induce cFos expression in the CeA. A third study will test the hypothesis that the ability of systemic CCK, LiCl, and LPS to activate cFos expression in the PVN, LHA, BNST, and CeA emerges gradually in rats during the first two weeks postnatal. Aim 3 will use electron microscopy to determine whether separate populations of NA and GLP-1-positive axon terminals converge on common postsynaptic targets in the PVN, LHA, CeA, and BNST. Experimental outcomes will advance our understanding of how viscerosensory inputs to the hypothalamus and limbic forebrain might impact diverse conditions such as anxiety disorders, visceral malaise, dysregulation of the HPA stress axis, depression, and conditioned aversions.