KP. Median preoptic nucleus and subfornical organ drive renal sympathetic nerve activity via a glutamatergic mechanism within the paraventricular nucleus. Am J Physiol Regul Integr Comp Physiol 302: R424 -R432, 2012. First published December 7, 2011 doi:10.1152/ajpregu.00403.2011The paraventricular nucleus (PVN) of the hypothalamus is involved in the neural control of sympathetic drive, but the precise mechanism(s) that influences the PVN is not known. The activation of the PVN may be influenced by input from higher forebrain areas, such as the median preoptic nucleus (MnPO) and the subfornical organ (SFO). We hypothesized that activation of the MnPO or SFO would drive the PVN through a glutamatergic pathway. Neuroanatomical connections were confirmed by the recovery of a retrograde tracer in the MnPO and SFO that was injected bilaterally into the PVN in rats. Microinjection of 200 pmol of N-methyl-D-aspartate (NMDA) or bicucullineinduced activation of the MnPO and increased renal sympathetic activity (RSNA), mean arterial pressure, and heart rate in anesthetized rats. These responses were attenuated by prior microinjection of a glutamate receptor blocker AP5 (4 nmol) into the PVN (NMDA Ϫ ⌬RSNA 72 Ϯ 8% vs. 5 Ϯ 1%; P Ͻ 0.05). Using single-unit extracellular recording, we examined the effect of NMDA microinjection (200 pmol) into the MnPO on the firing activity of PVN neurons. Of the 11 active neurons in the PVN, 6 neurons were excited by 95 Ϯ 17% (P Ͻ 0.05), 1 was inhibited by 57%, and 4 did not respond. The increased RSNA after activation of the SFO by ANG II (1 nmol) or bicuculline (200 pmol) was also reduced by AP5 in the PVN (for ANG II Ϫ ⌬RSNA 46 Ϯ 7% vs. 17 Ϯ 4%; P Ͻ 0.05). Prior microinjection of ANG II type 1 receptor blocker losartan (4 nmol) into the PVN did not change the response to ANG II or bicuculline microinjection into the SFO. The results from this study demonstrate that the sympathoexcitation mediated by a glutamatergic mechanism in the PVN is partially driven by the activation of the MnPO or SFO. glutamate; angiotensin II; sympathetic drive; cardiovascular THE PARAVENTRICULAR NUCLEUS (PVN) of the hypothalamus is involved in the neural control of the cardiovascular system (10, 23). Previous researchers from this laboratory (7,23,25) and others (4, 5) have observed that the activity of PVN neurons associated with sympathoexcitation is due to an increase in glutamatergic mechanisms within the PVN. Specifically, we have shown that the parvocellular neurons of the PVN are involved in mediating the neural component of cardiovascular reflexes by influencing renal sympathetic nerve activity (RSNA) (7,23,25). We have also demonstrated that the PVN is involved in baroreflex regulation of lumbar sympathetic nerve activity (23). Neuroanatomically, the parvocellular neurons of the PVN have been shown to connect to the nucleus of the solitary tract (10), as well as project to sympathetic preganglionic neurons within the intermediolateral cell column (IML) of the spinal cord directly or via the rostral vent...