title: The role of the paraventricular nucleus of the hypothalamus in the central control of the autonomic nervous system
Creators: name: Feetham, Claire
Publisher: name: University of Liverpool Repository
Year: 2015

description: The paraventricular nucleus (PVN) is a region of the hypothalamus considered the “master controller” of the autonomic nervous system. A subregion of the PVN, the parvocellular subnucleus, is believed to be involved in autonomic control, but its physiological importance is not fully understood. This thesis aimed to investigate the role of the parvocellular PVN in autonomic control and the underlying mechanisms responsible. In slice cell-attached patch action current recordings showed that putative parvocellular neurones are sensitive to osmolality and that a member of the mechanosensitive transient receptor potential ion channel (TRP) family TRPV4 plays a role in this osmosensing. TRPV4 agonists gave a similar reduction in action current frequency (ACf) to hypotonic challenge, which was reversed by selective TRPV4 inhibitors. Single-channel recordings identified a TRP-like channel on parvocellular neurones, and the activity of this channel was increased by the TRPV4 agonist 4αPDD. Intracellular calcium recordings showed increases in Ca2+ in response to either hypotonic challenge or 4αPDD. Furthermore, a role for TRPV4 was verified in central osmosensing at the whole animal level; central injections of hypotonic solution decreased blood pressure; an effect ablated by a TRPV4 inhibitor. Functional coupling between TRPV4 channels and Ca2+-activated K+ (KCa) channels was also explored. The effect of hypotonic challenge was reversed by inhibition of the small-conductance KCa (SK) channel. Since the effects of TRPV4 could also be blocked by an SK inhibitor, it is proposed that TRPV4 is coupled to SK to modulate neuronal activity. During calcium recordings Aaplication of a TRPV4 agonist in the presence of an SK inhibitor showed a reduced, but sustained Ca2+ rise compared to TRPV4 agonist application alone, suggesting feedback mechanisms are also in play. These mechanisms were also verified, quantitatively, with a mathematical model written in the NEURON simulation environment and incorporating experimentally derived parameters. A role for this area of the PVN in temperature sensing was also discovered, with ACf decreasing with an increase in temperature from 25oC to 37oC. Pharmacological investigation identified another TRP channel, TRPM2, to be central for the PVN response to temperature. ECG recordings from rats implanted with telemeters confirmed roles for neurokinin 1 receptor (NK1) expressing neurones in the PVN in the cardiovascular response to psychological stress and in the setting of circadian heart rate. Heart rate variability analysis showed that increases in the sympathetic activity indicator, “LF/HF”, in response to handling stress were ablated by specific lesioning of the NK1 neurones in the PVN. In addition these animals had a significant shift in the daily variation of their average day/night heart rate. In conclusion this thesis identifies the mechanisms underlying several different functional roles for parvocellular PVN neurones and indicates the PVN may be a multifunctional homeostatic “detector”.