Mechanisms and Functional Roles of Orexins’Cardiovascular Effects in the Dorsomedial Hypothalamus

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 orexin system has been proved to mediate cardiovascular response of defense reaction, but the neural circuits involved in orexin’s actions remains unknown. The dorsomedial hypothalamus (DMH) is the defense center and mediates stress-induced cardiovascular response. It receives orexinergic innervation and expresses orexinergic receptors. But, the physiological role of orexinergic activity within the DMH remains unknown. With the support from the Ministry of Science and Technology, our recent study demonstrates that orexins elevated arterial pressure and heart rate in anesthetized rats through their action in the DMH and these effects were likely either OX1R/OX2R-mediated or OX1R-mediated at different sites in the DMH. Considering the essential roles that the DMH and orexin system play in regulating cardiovascular response to stress, these findings raise the possibility that the orexinergic activity within the DMH is involved in cardiovascular regulation during stress response. The proposed study aims to discover the neural circuits affected by orexins and to verify the possible involvement of orexinergic activity within the DMH in cardiovascular response to stress. The rostral ventrolateral medulla (RVLM) and raphe pallidus are known structures that relay the signal of stress or DMH activation to systemic vasoconstrictor and tachycardia responses, respectively. We hypothesize that orexins can modulate neuronal activities of the DMH neurons that project to the RVLM or raphe pallidus, and the effects of orexins in the DMH are involved in stress-relevant cardiovascular response. Two specific aims are proposed to examine the hypothesis: aim 1, to evaluate the effects and mechanisms of orexins on the DMH neurons that project to the RVLM or raphe pallidus; and aim 2, to evaluate the contribution of the orexinergic activity within the DMH in cardiovascular response to stress. For the studies of the aim 1, electrophysiological approaches will be employed to assess neuronal activity and synaptic activity and retrograde tracing techniques will be used to identify the DMH neurons that send projections to the RVLM or raphe pallidus. In studies of the aim 2, the role of orexinergic activity within the DMH in stress-related cardiovascular regulation will be confirmed in conscious rats. Preliminary findings that orexin A directly excited RVLM-projecting and raphe pallidus-projecting DMH neurons in a concentration dependent-like manner support our hypothesis. The depolarization was likely mediated by a decrease of potassium or chloride conductance, an increase of cation conductance, and/or activation of sodium-calcium exchanger. Preliminary data also show that all techniques required for the proposed studies are established in our laboratory. The completion of this study will lead to a better understanding of orexinergic neural pathways involving in stress-related cardiovascular regulation and support the training of a student to become future scientists in academic neural electrophysiology.