Acute optogenetic activation of the subfornical organ produces sympathetically mediated increases in blood pressure

Introduction: The subfornical organ (SFO) is a vital blood pressure-controlling region that elicits blood pressure changes likely via an excitatory (or glutamatergic) projection to the paraventricular nucleus of the hypothalamus (PVN). However, the role of this SFO-PVN pathway in blood pressure control has been poorly defined in the literature. As such, the present study aimed to examine the functional connectivity between the SFO neurons and the PVN and how they intersect to control blood pressure. Methods: In Lewis rats (n = 10), glutamatergic SFO neurons (SFO^glut) were transduced with channelrhodopsin via a CaMKIIa-promotor vector (pAAV9-CaMKIIa-hChR2(H134R)-EYFP). Under urethane anaesthesia, changes in blood pressure and renal and splanchnic nerve activities were recorded in response to photostimulation of SFO^glut neurons before and after administration of an intravenous ganglionic blocker and V1a receptor antagonism and inhibition of the PVN via muscimol microinjection. Immunohistochemistry was used to examine the projections between the SFO and PVN. Results: Photostimulation of SFO^glut neurons produced a frequency-dependent pressor response that was abolished by sympathetic ganglionic blockade but not by inhibiting the vasoactive hormone vasopressin. This pressor response depends on ongoing neuronal transmission within the PVN as it is abolished by bilateral PVN inhibition. Confirming this, we found dense projections from SFO^glut neurons to magnocellular and parvocellular PVN neurons. Finally, photostimulation of SFO^glut neurons elicited a peak increase in sympathetic nerve activity that was reversibly abolished by phenylephrine administration and abolished by inhibition of the PVN, suggesting that the neuronal circuitry underpinning this response is barosensitive. Conclusion: The pressor response elicited by SFO^glut neurons is largely mediated by barosensitive sympathetic nerve activity and dependent on the PVN.