Glutamatergic neurons of the paraventricular nucleus are critical contributors to the development of neurogenic hypertension

Abstract

Neuro-cardiovascular dysregulation leads to increased sympathetic activity and neurogenic hypertension. The paraventricular nucleus (PVN) of the hypothalamus is a key hub for blood pressure (BP) control, producing or relaying the increased sympathetic tone in hypertension. We hypothesize that increased central sympathetic drive is caused by chronic over-excitation of glutamatergic PVN neurons. We tested how stimulation or lesioning of excitatory PVN neurons in conscious mice affects BP, baroreflex and sympathetic activity. Glutamatergic PVN neurons were unilaterally transduced with channelrhodopsin-2 using an adeno-associated virus (CamKII-ChR2-eYFP-AAV2) in wildtype mice (n = 7) to assess the impact of acute stimulation of excitatory PVN neurons selectively on resting BP in conscious mice. Stimulation of the PVN glutamatergic population resulted in an immediate frequency-dependent (2, 10 and 20 Hz) increase in BP from baseline by ∼9 mmHg at 20 Hz stimulation (P < 0.001). Additionally, in vGlut2-cre mice glutamatergic neurons of the PVN were bilaterally lesioned utilizing a cre-dependent caspase (AAV2-flex-taCASP3-TEVp). Resting BP and urinary noradrenaline (norepinephrine) levels were then recorded in conscious mice before and after DOCA-salt hypertension. Partial lesions of glutamatergic neurons of the PVN (39.3%, P < 0.05) resulted in an attenuated rise in BP following DOCA-salt treatment (P < 0.05 at 7 day time point, n = 8). Noradrenaline levels as an index of sympathetic activity between the lesion and wildtype groups showed a significant reduction after DOCA-salt treatment in the lesioned animals (P < 0.05). These experiments suggest that stimulation of PVN glutamatergic neurons is sufficient to cause autonomic dysfunction and drive the increase in BP.

Shining light on the paraventricular nucleus: the role of glutamatergic PVN neurons in blood pressure control

“…In this issue of The Journal of Physiology , authors Basting et al . () describe a series of experiments focused on demonstrating the necessity and sufficiency of glutamatergic neurons in the PVN towards sympathetically mediated control of blood pressure in conscious mice both in normal physiological function and in a model of neurogenic hypertension (Fig. ).…”

The Renin-Angiotensin System in the Central Nervous System and Its Role in Blood Pressure Regulation

“…These data suggest expression of PRR in specific brain regions controlling drinking behavior, such as the SFO is of physiological relevance. Recently, Souza and colleagues examined the role of PRR in the PVN, a key integratory nucleus involved in blood pressure control [77]. In this study, PVNtargeted ablation of PRR was induced in PRR-floxed mice by bilateral stereotactic microinjection of adeno-associated virus (AAV)-CRE-GFP.…”

The sympathetic role of glutamatergic paraventricular nucleus neurons in blood pressure regulation

“…However, it is still unknown how PVN glutamatergic neurons contribute to BP regulation. In a recent issue of The Journal of Physiology , Basting and colleagues () hypothesized that overexcitation of the PVN‐RVLM glutamatergic interneuronal population leads to excess sympathetic outflow, evoking an increase in baseline BP and contributing to hypertension.…”

“…To address the unknown role of PVN‐RVLM excitatory glutamatergic interneurons in the development of hypertension through overactivation of the sympathetic nervous system, Basting et al . () completed a set of experiments in mouse models that involved unilateral and bilateral manipulation of PVN‐RVLM excitatory glutamatergic interneurons, and assessed their role in both RVLM activity and BP. First, the researchers conducted an in vivo optogenetic procedure in conscious mice to investigate the effects of PVN‐RVLM glutamatergic interneuronal activation on BP using channelrhodopsin‐2 (ChR2) under the calcium/calmodulin‐dependent protein kinase type Iiα (CaMKIIα) promoter (AAV‐CamKIIα‐ChR2‐eYFP sero‐type 2) in a selective manner such that they would activate these neurons unilaterally.…”

“…Using optogenetic stimulation of the PVN‐RVLM excitatory glutamatergic interneurons, Basting and colleagues () showed that there is a clear and immediate positive relationship between the frequency of stimulation and increase in BP. The proposed mechanism for the observed frequency‐dependent BP increase is due to increased excitation of the RVLM, specifically through PVN‐RVLM excitatory interneurons.…”