Roles of Orexinergic Activity Within the Dorsomedial Hypothalamus in Cardiovascular Regulation

Stress response can be elicited in all mammals while encountering threats and helps the organism to survive. The response includes sympathetically mediated elevation of cardiovascular function, which may potentially link to emerging epidemic of cardiovascular disorders in modern societies. Understanding the mechanism of stress-related cardiovascular regulation is, therefore, important. The dorsomedial hypothalamus (DMH) is the defense center and mediates stress-induced cardiovascular response through pathways that descend to two brainstem nuclei. The orexin system has been proved to mediate cardiovascular response of defense reaction, but the neural circuits involved in orexin’s actions remains unknown. The DMH receives orexinergic innervation and expresses orexinergic receptors. Whether orexins can affect cardiovascular function through their action in the DMH has not been examined. Our preliminary finding of a depressor effect elicited by intra-DMH blockade of orexin 2 receptor implicates that orexins can regulate cardiovascular functions by acting in the DMH. Therefore, we hypothesize that orexins can regulate cardiovascular function by acting in the DMH and these effects of orexins are involved in cardiovascular response to stress. Three specific aims are proposed to examine the hypothesis and also to explore the underlying mechanisms: aim 1, to evaluate cardiovascular effects of intra-DMH injected orexins and identify the site of action (compared with stress-related sites) and type of receptor involved; aim 2, to identify the types of neurons and cellular mechanisms underlying orexins’ action in the DMH; and aim 3, to evaluate the contribution of DMH-orexinergic activity in cardiovascular response to stress. Studies of aim 1 will be performed in anesthetized rats. For aim 2, electrophysiological approaches will be employed to assess neuronal activity and synaptic activity and retrograde tracing techniques will be used to identify the DMH neurons mediating stress response. In aim 3, the role of DMH-orexinergic activity in stress-related cardiovascular regulation will be confirmed in conscious rats. Several preliminary findings support our hypothesis. The completion of this study will lead to a better understanding toward orexinergic neural pathways involving in stress-related cardiovascular regulation.