The long-term goal of these experiments is to define the organization of the neural networks responsible for anorexia in rats. The rationale is that understanding how these networks are constructed and interact during the adverse challenges that cause anorexia in animals will help us begin considering how the brain is involved with clinically-important anorexias. Increasing evidence suggests that animal anorexias can be categorized into two groups depending on whether or not they are sensitive to exogenous NPY treatment. Experiments are designed to address the neural circuits and mechanisms underlying the second group. To generate anorexia experimentally, the project will use the chronic dehydration that follows drinking hypertonic saline. This well-documented model has the advantage that its development and intensity can be simply and reliably controlled. Furthermore, the anorexia is quickly reversed when the animal drinks water. The theoretical basis for how underlying circuits are functionally organized is that the brain contains a tripartite system of neural networks that either stimulates, inhibits or disinhibits feeding. Three hypotheses will be addressed by five specific aims. These hypotheses are: 1) An inhibitory network generates anorexia during dehydration when its constituent neurons increase their expression of anorexic neuropeptides. Some of these neurons are located in the lateral hypothalamus (LHA) and bed nucleus of the stria terminalis (BST). 2) During dehydration this inhibitory network generates anorexia by masking the effects of a leptin-sensitive NPY-containing neural networks that normally stimulate eating. 3) Sensory signals derived from drinking water activate a third network that generates compensatory feeding by disinhibiting the output of the leptin-sensitive stimulatory network. The constituents of this third network are currently unknown. Experiments will use excitotoxic lesions specifically targeted to the LHA and BST, central neuropeptide infusions, and neuroanatomical mapping of markers of rapid cellular activation. The goal is to correlate these manipulations and variables to behavioral end points associated with anorexia development and reversal. In situ hybridization will be used as a tool for exploring the dynamics of neuropeptide genes during anorexia, as a neuroanatomical probe for clarifying circuit organization, and for monitoring the extent of the excitotoxic lesions. Collectively, the experiments in this project are designed to make major contributions towards elucidating the organization and function of the neural circuits responsible for anorexia in animals in a way that will ultimately help to clarify the neural substrates of clinically important anorexias.
