Any condition that threatens homeostasis such as tissue injury, hemorrhage, hypoxia, infection, hypothermia, or psychological stress elicits changes in autonomic nervous system (ANS) function and specific behaviors. These changes can be beneficial for survival if transient but pathogenic if sustained, as in hypertension. The main new idea tested is that C1 neurons, a group of catecholaminergic/glutamatergic neurons within the rostral ventrolateral medulla of all mammals, including humans, are a nodal point for expression of these stress responses. That is, C1 neurons function like a switchboard enabling the expression of a large variety of ANS responses to acute physical and psychological stresses mediated by both sympathetic and parasympathetic divisions the ANS. The proposed experiments will use innovative methods (e.g. intersectional genetics, optogenetics, pharmacogenetics) designed to test key aspects of this theory, with particular emphasis on such novel topics as anti-inflammation, the prevention of hypoxic tissue damage and behavioral effects elicited by C1 cell activation. This knowledge is central to our understanding of how blood pressure and other physiological functions are regulated by the autonomic nervous system in healthy, diseased or stressed states.
The specific aims tested are: 1: Is C1 cell stimulation sufficient to elicit physiological and behavioral signs of stress? Do C1 cells produce these effects by releasing glutamate or a catecholamine? Activation of C1 cells with optogenetics in unanesthetized transgenic mice is expected to result in signs of stress. 2: Are C1 cells necessary for responses to physiological or psychological stressors? Using loss of function optogenetics (archaerhodopsin) C1 cell activation is expected to be necessary to maintain BP and HR in awake rats subjected to non-hypotensive hemorrhage, hypoxia or bacterial infection. We will also test whether C1 cells are required for the autonomic (e.g. cardiovascular, respiratory, GI and anti-inflammatory components) and behavioral manifestations of restraint stress in conscious mice by either inhibiting (pharmacogenetically) or selectively destroying these neurons. 3: Which C1 cells regulate blood pressure? Using mouse intersectional genetics and Boolean vectors, subgroups of C1 cells defined by peptide expression or CNS projection will be transduced to selectively express ChannelRhodopsin2. These subgroups are expected to have distinct projections and their optogenetic activation is expected to elicit highly specific physiological and behavioral responses.
Any condition that threatens homeostasis such as tissue injury, hemorrhage, hypoxia, infection, hypothermia, or psychological stress elicits changes in autonomic nervous system function and behavior. These changes can be beneficial for survival if transient but pathogenic if sustained, as in hypertension. The proposed research focuses on neurons in the brainstem of humans and other mammals that are activated by physical and psychological stresses and will test whether these neurons are indispensable to the production of adaptive autonomic nervous system responses to stress and essential for certain behaviors associated with stress such as anxiety or sleep disruption. These neurons could be a productive focus of therapeutic intervention for conditions in which the autonomic nervous system is inappropriately activated e.g., hypertension, irritable bowel syndrome, heart failure or obstructive sleep apnea.
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