Date of Award
Doctor of Philosophy (PhD)
The following dissertation focuses on preclinical rodent feeding paradigms that were designed to examine the mechanisms by which the brain regulates caloric (homeostatic) and palatability (hedonic)-driven feeding. Taken together, my findings suggest differentially motivated feeding can, in part, signal through isolated non-overlapping mechanisms in the brain. Furthermore, some of these mechanisms occur in similar neurocircuits that have been implicated in other compulsive behaviors, such as drug abuse. In an effort to support the argument that binge eating disorder (BED) and substance abuse share similar behavioral and molecular targets, we first demonstrate that the development of BED in rodents is attenuated by both systemic and central administration of a cysteine pro-drug (N-acetylcysteine or NAC) which is a compound that targets the understudied glutamate system and is currently used to treat other disorders that have aspects of compulsion, such as trichotillomania or drug addiction (chapter II). Interestingly, NAC-induced hypophagia is specific to feeding stimulated by palatability as NAC did not produce any suppression of feeding in animals not maintained under a feeding paradigm that would produce binge behavior. In addition to studying differentially motivated feeding, a large component of this dissertation examines the mechanisms by which the neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) regulates feeding in the ventromedial nucleus of the hypothalamus (VMN) as well as the nucleus accumbens (NAc). Our results indicate that PACAP microinjected into the VMN suppresses feeding elicited specifically by food deprivation, as PACAP did not effecting feeding elicited by palatability. Interestingly, in the nucleus accumbens, a brain region important for reward related activity, PACAP suppresses palatably-driven feeding in satiated rats, while not effecting feeding driven by food deprivation (chapter III). The opposing behavioral effects of PACAP on feeding propelled the lab to further investigate the mechanism by which PACAP was working in these two regions. In the VMN, we demonstrate that PACAP interacts with leptin signaling as acute blockade of PACAP receptors (PAC1R) in the VMN inhibits the behavioral and molecular actions of leptin (chapter IV). In the nucleus accumbens, PACAP attenuates hedonic drive in a site-specific manner and we identified PACAP mRNA expressing striatal afferents originating in the prefrontal cortex (chapter V), which is significant as obese individuals display hypoactive medial prefrontal cortex and stimulation of this area decreases calories consumed and body weight. Taken together, the opposing behavioral effects of PACAP emphasize an important point that a signaling mechanism in one brain region can be significantly different in another.