The mammalian hypothalamus is privy to relatively uncensored information provided by certain brainstem and, circumventricular cell groups that process neurogenic and circulating indices of perturbations in cardiovascular homeostasis. Hypothalamic neurosecretory and autonomic- related effector neurons participate directly in adaptive reflex adjustments to hemodynamic insult. Relative levels of messenger RNAs encoding major signalling molecules used by neurons at nodal points along these pathways, and immediate-early gene products that serve as inducible indices of cellular activation, will followed, in situ, in response to challenges that differentially affect blood pressure and volume in order to define and characterize functional circuits mediating integrated multi- organ responses to disturbances in the circulatory milieu. An initial set of studies will determine the manner and time course with which cardiovascular challenges affect specific hypothalamic neuroendocrine and autonomic-related effector neuron pools. Discrete unilateral knife cuts will be used to estimate the participation of ascending afferents provided by medullary catecholamine cell groups, and descending projections from circumventricular structures of the lamina terminalis, in individual components of the integrated hypothalamic response. More circumscribed ablation approaches will be used in a similar context to attempt a more exacting localization of function. A second set of studies will use primarily anatomical methods to clarify the manner in which amino acid neurotransmitters may participate in the hemodynamic control of hypothalamic visceromotor neurons. Sensitive histochemical techniques will be used to pursue indications that the lamina terminalis is a major source of inhibitory, GABA-containing, projections. Combined transmitter-specific and non-specific retrograde labeling methods will be used to determine how excitatory amino acid containing afferents to the hypothalamus map onto major known sources conveying hemodynamic input. Candidate projections uncovered by this approach will be characterized at the ultrastructural level. A final study will explore the manner in which cardiovascular information is processed through medullary catecholamine cell groups that project to the hypothalamus. Peripheral denervations will be used to assess the role of transsynaptic mechanisms in challenge effects on transmitter-related gene expression. The significance of the multiple biologically active molecules synthesized by these neurons will be probed by determining whether mRNAs encoding coexisting molecules are regulated differentially by variations in the strength or modality of cardiovascular input. Light and electron microscopic analyses will seek to characterize the organization of local brainstem circuits by which blood pressure- related information is conveyed to hypothalamically-projecting aminergic cell groups. The neural systems under scrutiny here subserve indispensable physiologic functions, and relate directly to health problems associated with cardiovascular and renal disease, trauma, hypertension, and stress.
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