Perineuronal nets within hypothalamic nuclei crucial for blood pressure regulation are altered during DOCA-salt hypertension

The paraventricular nucleus of the hypothalamus (PVN) and the perifornical area of the anterior hypothalamus (PeFAH) are crucial for the regulation of blood pressure. Hypertension is associated with increased sympathetic tone, partly resulting from over-activation of the PVN. The PeFAH, directly adjacent to the PVN, also contributes to an overall increase in sympathetic tone, though whether and how it contributes to the overall overexcitation of the PVN is not well understood. Several molecular mechanisms modulate neuronal activity including the deposition of perineuronal net (PNNs), lattice-like dynamic extracellular structures that surround the soma and proximal dendrites of neurons regulating their firing and contributing to circuit plasticity. These structures are of particular interest because changes in their deposition have been associated with multiple neurological disorders including Alzheimer’s disease for which hypertension is the highest modifiable vascular risk factor. However, whether PNNs are modulated during hypertension and whether they contribute to blood pressure regulation is not known. Therefore, this study aims to understand how hypertension modulates PNNs and thereby neuronal activity within the PVN and PeFAH. First, we created a comprehensive map of neuronal cell types surrounded by PNNs within the PVN from 3–5-month-old naïve female and male C57BL6 mice. We co-localized known neuronal populations within the PVN, including oxytocin, vasopressin, and neuronal nitric oxide synthase. (nNOS) and quantified the percentage of those neurons surrounded by PNNs. Then, we employed the DOCA-salt hypertension model to test the hypothesis that PNNs deposition is altered in both the PVN and the PeFAH during hypertension. To this end, 3-5-month old male C57BL6 mice were implanted with a subcutaneous (s.c.) deoxycorticosterone acetate (DOCA) pellet and received 0.9% NaCl in the drinking water. After 21-days of DOCA-salt, mice exhibited sustained increased blood pressure as compared to sham control and we found an increase in the number of PNNs within the PVN of DOCA-salt (n=8) vs control (n=9) (44.59 ± 5.37 PNNs/millimeter (mm) 2 in DOCA vs 23.81 ± 6.00 in control; p=0.0443). However, we observed no difference in the overall PVN area that was positive for PNNs (1.03 ± 0.11 % in DOCA vs 1.00 ± 0.03% in control, p = 0.5097). We found a significant decrease in the area that was positive for PNNs within the PeFAH (0.75 ± 0.03 % in DOCA vs 0.98 ± 0.005% in control, p = 0.0052). Taken together, we conclude that PNN number is increased in the PVN during DOCA-salt hypertension potentially activating previously ‘silenced’ neurons which could be a contributing mechanism to the overactivation of the PVN. Additionally, a decrease in the PNN coverage in the PeFAH, a highly inhibitory nucleus, may further contribute to the overactivation of the PVN by decreasing the firing of inhibitory neurons thereby disinhibiting the PVN. Ongoing studies are investigating which neuronal population has increased PNN deposition within the PVN and how PNNs contribute to sympathetic tone and blood pressure regulation during DOCA-salt hypertension. NINDS, D-SPAN/F99/K00 Award, K00 phase (K00NS130872), PI: Ismary Blanco NINDS/NIA Career Transition Award (K22 NS123507), PI: Monica M Santisteban This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.