Hypothalamic paraventricular nucleus neuronal nitric oxide synthase activity is a major determinant of renal sympathetic discharge in conscious Wistar rats.

NEW FINDINGS: What is the central question of this study? Does chronic reduction of neuronally generated nitric oxide in the hypothalamic paraventricular nucleus affect the set-point regulation of blood pressure and sympathetic activity destined to the kidneys? What is the main finding and its importance? Within the hypothalamic paraventricular nucleus, nitric oxide generated by neuronal nitric oxide synthase plays a major constitutive role in suppressing long term the levels of both ongoing renal sympathetic activity and arterial pressure in conscious Wistar rats. This finding unequivocally demonstrates a mechanism by which the diencephalon exerts a tonic influence on sympathetic discharge to the kidney and may provide the basis for both blood volume and osmolality homeostasis. ABSTRACT: The paraventricular nucleus (PVN) of the hypothalamus plays a crucial role in cardiovascular and neuroendocrine regulation. Application of nitric oxide donors to the PVN stimulates GABAergic transmission, and may suppress sympathetic nerve activity (SNA) to lower arterial pressure. However, the role of endogenous nitric oxide within the PVN in regulating renal SNA chronically remains to be established in conscious animals. To address this, we used our previously established lentiviral vectors to knock down neuronal nitric oxide synthase (nNOS) selectively in the PVN of conscious Wistar rats. Blood pressure and renal SNA were monitored simultaneously and continuously for 21 days (n = 14) using radio-telemetry. Renal SNA was normalized to maximal evoked discharge and expressed as a percentage change from baseline. The PVN was microinjected bilaterally with a neurone-specific tetracycline-controllable lentiviral vector, expressing a short hairpin miRNA30 interference system targeting nNOS (n = 7) or expressing a mis-sense as control (n = 7). Recordings continued for a further 18 days. The vectors also expressed green fluorescent protein, and successful expression in the PVN and nNOS knockdown were confirmed histologically post hoc. Knockdown of nNOS expression in the PVN resulted in a sustained increase in blood pressure (from 95 ± 2 to 104 ± 3 mmHg, P < 0.05), with robust concurrent sustained activation of renal SNA (>70%, P < 0.05). The study reveals a major role for nNOS-derived nitric oxide within the PVN in chronic set-point regulation of cardiovascular autonomic activity in the conscious, normotensive rat.

Reversible hippocampal inactivation partially dissociates how and where to search in the water maze.

To assess the interaction between spatial and procedural memory systems, the authors developed a learning protocol in the water maze using a rising "Atlantis" platform that requires rats to learn to swim to a specific location and, once there, to learn a "dwelling" response to raise the platform. In this protocol, the effects of temporal inactivation of the dorsal hippocampus with the AMPA/kainate receptor antagonist LY326325 on different memory phases were investigated. Hippocampal inactivation impaired acquisition of the searching task, mainly because of disruption of procedural learning. Inactivation also impeded consolidation and retrieval of spatial information, while leaving expression of dwelling responses intact. These findings challenge the idea of a sharp demarcation between spatial and procedural learning with respect to hippocampal involvement.