Background-The paraventricular nucleus of the hypothalamus (PVN) has emerged as one of the most important autonomic control centers in the brain, with neurons playing essential roles in controlling stress, metabolism, growth, reproduction, immune, and other more traditional autonomic functions (gastrointestinal, renal and cardiovascular).Objectives-Traditionally the PVN was viewed very much as a nucleus in which afferent inputs from other regions were faithfully translated into changes in single specific outputs whether those were neuroendocrine or autonomic. Here we will present data which suggest that PVN in fact plays significant and essential roles in integrating multiple sources of afferent input and sculpting an integrated autonomic output by concurrently modifying the excitability of multiple output pathways. In addition we will highlight recent work which suggests that dysfunction of such intranuclear integrative circuitry may contribute to the pathology of conditions such as hypertension and congestive heart failure.Conclusions-This review highlights data showing that individual afferent inputs (SFO), signaling molecules (orexins, adiponectin), and interneurons (glutamate/GABA), all have the potential to influence (and thus coordinate) multiple PVN output pathways. We also highlight recent studies showing that modifications in this integrated circuitry may play significant roles in the pathology of diseases such as congestive heart failure and hypertension.

The area postrema is a medullary structure lying at the base of the fourth ventricle. The area postrema's privileged location outside of the blood-brain barrier make this sensory circumventricular organ a vital player in the control of autonomic functions by the central nervous system. By virtue of its lack of tight junctions between endothelial cells in this densely vascularized structure and the presence of fenestrated capillaries, peptide and other physiological signals borne in the blood have direct access to neurons that project to brain areas with important roles in the autonomic control of many physiological systems, including the cardiovascular system and systems controlling feeding and metabolism. However, the area postrema is not simply a conduit through which signals flow into the brain, but it is now being recognized as the initial site of integration for these signals as they enter the circuitry of the central nervous system.

Somatostatin is important in the regulation of diverse neuroendocrine functions. Based on bioinformatic analyses of evolutionarily conserved sequences, we predicted another peptide hormone in pro-somatostatin and named it neuronostatin. Immuno-affinity purification allowed the sequencing of an amidated neuronostatin peptide of 13 residues from porcine tissues. In vivo treatment with neuronostatin induced c-Fos expression in gastrointestinal tissues, anterior pituitary, cerebellum, and hippocampus. In vitro treatment with neuronostatin promoted the migration of cerebellar granule cells and elicited direct depolarizing actions on paraventricular neurons in hypothalamic slices. In a gastric tumor cell line, neuronostatin induced c-Fos expression, stimulated SRE reporter activity, and promoted cell proliferation. Furthermore, intracerebroventricular treatment with neuronostatin increased blood pressure but suppressed food intake and water drinking. Our findings demonstrate diverse neuronal, neuroendocrine, and cardiovascular actions of a somatostatin gene-encoded hormone and provide the basis to investigate the physiological roles of this endogenously produced brain/gut peptide.Originally discovered in 1972 based on its ability to inhibit pituitary growth hormone release (1, 2), somatostatin is one of the most extensively studied peptide hormones (3, 4). Somatostatin is widely expressed in neuronal, neuroendocrine, gastrointestinal, inflammatory, immune, and cancer cells and plays important roles in the regulation of neuromodulation, hormone secretion, gastrointestinal functions, immune responses, cell growth, and exocrine secretion (5). Two somatostatin isoforms, somatostatin-14 and somatostatin-28, activate five related G protein-coupled receptors with different affinity (6 -8). Somatostatin receptors are also activated by two cortistatin isoforms secreted from different brain regions (9). Based on bioinformatic analysis of evolutionarily conserved sequences in the pro-somatostatin protein, we predicted the existence of another peptide hormone encoded by the somatostatin gene. We generated antibodies against the putative peptide, isolated the endogenous peptide, and found it to be an amidated peptide of 13 residues. This peptide hormone, named neuronostatin, induced c-Fos and c-Jun expression in diverse brain/gut tissues, regulated neuronal functions in vitro, and modulated blood pressure as well as food intake and drinking behavior in vivo. EXPERIMENTAL PROCEDURESPeptide Hormones-All peptides used were synthesized by Phoenix Pharmaceuticals Inc. (Burlingame, CA) or the PAN facility at Stanford University. Peptide purity was verified by analytical reverse phase HPLC and matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) 4 mass spectrometry. Unless indicated otherwise, all functional tests utilized human amidated neuronostatin-13.Purification of Endogenous Neuronostatin-To purify endogenous neuronostatin, frozen porcine pancreas and spleen were obtained from Pel-Freez (Rogers, AK) and extracted ...

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