Abstract

The neural circuitry that gives rise to the rewarding effects of goal-objects and goal-directed behaviors can be directly studied with the use of brain stimulation reward (BSR). Brief trains of electrical stimulation to some brain regions produces a highly rewarding effect that rats will learn to self-administer. Stimulation of some sites in the lateral hypothalamus (LH) has been linked to the regulation of energy balance, supporting the notion that brain reward circuitry is subdivided along functional lines. Finding from the Master's thesis showed that the rewarding effect of the stimulation is enhanced by chronic food restriction and weight loss in some rats. In contrast, a short-term period of food deprivation was unable to increase BSR in these same subjects. The adipose hormone, leptin, mimicked the effect of fattening by opposing the effect of food restriction on BSR. The present body of work examines whether the neurons supporting BSR comprise functionally distinct subcomponents and characterizes a subset of reward neurons that respond to weight loss and leptin. Alterations in the reward effectiveness of LH stimulation were measured following different manipulations of energy state by examining the willingness of the rat to work (lever-press) for varying strengths of stimulation. The first set of experiments in Chapter Two examines the contribution of some neuropeptides known to mediate the actions of leptin on restriction-sensitive and -insensitive reward circuitry. The divergent effect of corticotropin-releasing hormone (CRH) and agouti-related peptide (AgRP) on BSR obtained at restriction-sensitive versus -insensitive sites further suggests that there are separate subpopulations of reward neurons with distinct neurochemical profiles. That CRH, AgRP, neuropeptide Y and melanin-concentrating hormone largely fail to alter BSR at restriction-sensitive sites suggest that these peptides are not involved in the modulation of BSR by food restriction. In Chapter Three, the ability of food restriction to enhance BSR in a leptin-resistant rat strain suggests that there may be other peripheral signals mediating the actions of weight loss on restriction-sensitive reward circuitry. Finally, data presented in Chapter Four demonstrate that the effect of food restriction on BSR is contingent on the placement of the electrode amongst a functionally heterogeneous population of directly-activated neurons. This evidence provides a basis for the distinction between restriction-sensitive and -insensitive stimulation sites. Together, these data describe a subcomponent of reward circuitry that carries reward signals relevant to the maintenance of long-term energy balance. Unraveling the identity, function and neurochemistry of these neurons will increase our understanding of the neural mechanisms underlying body weight regulation and may shed light on the development of metabolic disorders such as obesity.