Regulation of Subfornical Organ Neurons by the Novel Na+ leakage channel NALCN: Interactions with Neuropeptide Y

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The central nervous system of vertebrates is protected by a blood brain barrier. This barrier allows the exchange of some materials such as oxygen and glucose between the blood and the fluid surrounding neurons, but prevents the exchange of most other materials, including hormones. There are areas however called sensory circumventricular organs which have no blood brain barrier, and contain specialized neurons to detect levels of circulating hormones (reflecting physiological status) as well as properties of the circulation such as osmolarity (reflecting how dehydrated an animal may be) and sodium concentration. The information detected by these neurons is then transmitted to other centres of the central nervous system which regulate homeostasis. The subfornical organ (SFO) is one of the sensory circumventricular organs, and plays critical roles in regulating feeding, water and salt balance and cardiovascular output. My proposed research is focused on understanding biological effects of a signaling protein called neuropeptide Y (NPY) acting at the SFO. Within the central nervous system, NPY is a neurotransmitter that plays a key role in regulating feeding behavior and several other processes. NPY is also a peptide hormone which can be released into the bloodstream causing elevated heart rate and blood pressure. Our preliminary evidence (supported by our previously published data) indicates that SFO neurons express several types of receptor for NPY. Moreover, we observed that isolated SFO neurons become active when NPY is applied, apparently by activation of a very abundant ion channel called “Na+ leakage channel, non-selective” (NALCN), which is a powerful regulator of electrical activity of neurons. Therefore this proposed research has three objectives: (1) to characterize the electrical response of SFO neurons to NPY, including determining which subtype(s) of receptor are involved in the NPY-mediated activation and the identity of the molecules in the signaling pathway; (2) to use genetic tools to upregulate and downregulate NALCN to confirm its role in NPY mediated signaling and further investigate other biological functions of NALCN in SFO neurons and (3) to microinject NPY directly into the SFO of anesthetized rats to investigate its role in biological processes such as regulation of cardiovascular output. Therefore this research will provide insight into the biological roles of SFO and NPY using approaches that span molecular and cellular biology to whole animal physiology. Significance: The SFO has been the subject of intense investigation as a centre in the central nervous system that contributes to regulation of functions such as feeding behavior, water and salt balance and cardiovascular output. Similarly, NPY is a neuropeptide hormone that converges on many of the same homeostatic process as SFO. It has been proposed that errors in processing of information at the SFO, or in aberrant NPY signaling may result in abnormal regulation of feeding and/or cardiovascular output. Experiments in our proposal will explore our recent progress into the novel observation that SFO is a site of action for NPY. The data will provide detailed cellular and molecular mechanisms of action for NPY in SFO neurons. Moreover, while NPY’s ability to regulate cardiovascular output has historically been attributed to its action on peripheral tissue, this research will provide evidence to help shift this paradigm by revealing a site of action in the central nervous system. The work will be of great importance to those who are interested in regulation of basic homeostatic functions by SFO or NPY, as well as those interested in the biology of cardiovascular regulation in human disease.