Regulation of Subfornical Organ Neurons by the Neuropeptide Neurotensin

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The central nervous system of vertebrates is protected by a blood brain barrier. This barrier allows exchange of materials such as oxygen and glucose between the blood and the fluid surrounding neurons, but prevents exchange of most other materials, including hormones and signaling molecules. Specialized areas called sensory circumventricular organs (CVOs), however, have leaky capillaries, and lack a blood brain barrier. Sensory CVOs contain specialized neurons to detect circulating hormones, concentration of ions in the plasma such as Na+, and numerous metabolites. This information is then transmitted to other brain centres which ultimately regulate homeostasis. ******My research focuses on an area of the brain called the subfornical organ (SFO), a sensory CVO with well-established roles in regulating thirst, salt appetite, cardiovascular function and energy balance. The goals of the proposed research aim to deliver a better understanding of the fundamental regulation of SFO neurons and how their electrical properties are modulated by hormones.******One of the investigations enabled by my previous Discovery Grant was a transcriptomic analysis of rat SFO. In carrying out this work, my trainees and I were able to construct a list of all the ion channels and receptors expressed by the SFO. By examining the complement of expressed ion channels and receptors, we have begun to gain a better understanding of the physiological roles of SFO neurons. The present application has three research objectives: (1) investigate how a hormone called neurotensin alters electrical activity of SFO neurons; (2) determine if neurotensin, like many other hormones, acts at the SFO to regulate blood pressure and/or heart rate; (3) investigate the roles of a specific group of ion channels called Ca++ channels in shaping electrical properties of SFO neurons. I aim to provide training for 4 graduate-level and 10 undergraduate-level HQP.******Significance: The SFO has been intensely studied as a brain centre critical to regulation of numerous homeostatic functions. Neurotensin is a hormone that converges on many of the same homeostatic processes as SFO. It has been proposed that errors in processing of electrical information at the SFO, or in detecting hormones may result in departures from homeostasis such as abnormal regulation of feeding and/or cardiovascular output. My trainees and I have gathered preliminary data to indicate that the SFO is a previously undescribed site of action for neurotensin. This research will provide detailed cellular and molecular mechanisms of action for neurotensin at the SFO, and provide physiological context at the level of whole animal physiology. The work will be of importance to those who are interested in regulation of basic homeostatic functions by the central nervous system, sensory circumventricular organs and neurotensin. The work will also be of importance to those interested in the biology of energy balance and cardiovascular regulation.**