Approximately 33% of adults in the United States are obese. These individuals have an increased susceptibility to a number of obesity-associated health risks, including coronary heart disease, type 2 diabetes, hypertension, stroke, and several cancers. Compounding the problem, as of 2008 the estimated medical care costs of obesity in the United States alone were $147 billion. The obesity epidemic therefore carries grave consequences for both afflicted individuals and the nation at large. To combat this epidemic we need to understand the biological pathways that underlie the development of obesity. Many factors are known to contribute to the development of obesity, and excessive caloric intake is clearly one of them. The act of food consumption is fundamentally a neural process;therefore, dysregulated neuronal control of food intake can be a major contributor to the development of obesity. A complex network of neural systems regulates metabolic homeostasis and food intake. The prefrontal cortex (PFC) is an integral part of this network. The PFC likely regulates food intake through bottom-up integration of cue salience and metabolic status, combined with top- down control of motivation, reward evaluation, and behavioral decision making. However, the pathways that accomplish this processing at the cellular and circuit level are largely unknown, representing a significant barrier to progress. This proposal seeks to elucidate the cellular and circuit mechanisms that drive overconsumption and thereby contribute to a state of obesity. To accomplish this, two specific aims are proposed. First, I will use a pharmacogenetic approach to drive activity in mPFC-resident pyramidal neurons, which are the principal output cells of the mPFC. By targeting the infralimbic and prelimbic subdivisions of the mPFC individually with this approach, I will determine the sufficiency of these subregions for modulating food intake. As part of this Aim I will also target the individual projection from the mPFC to the nucleus accumbens, which plays a role in reward evaluation.
This aim will potentially clarify apparently contradictory data showing that both hyperactivity and hypoactivity in the mPFC are correlated with increased food consumption. Second, I will use optogenetics to drive activity in mPFC pyramidal neurons in order to determine whether excitatory mPFC output is sufficient to modulate both contingent and non-contingent food intake. Optogenetic stimulation of the mPFC differs from chemogenetic stimulation, and produces different behavioral outcomes. We hypothesize that this is linked to variation in changes in cortical rhthymicity produced by the two stimuli. Therefore, in addition to assessing the various roles of the mPFC in regulating food intake, this proposal will also provide the first comparison of opto- and chemogenetic stimulation techniques, broadening the impact of this work. Both independently and in concert, these two aims will clarify the role of prefrontal cortica output in modulating food intake. This will result in an improved understanding of the neural regulatory networks that control food intake and energy balance, and thereby have direct influence over the development of obesity.
Obesity is at epidemic levels, and incidence is increasing. This disease carries a number of health risks with consequences ranging from decreased quality of life to potentially lethal. This study will investigate the neural regulatory networks tat control food intake, and are therefore likely to be involved in the development of obesity. The study will contribute to the understanding of the neurological basis of food intake and obesity, potentially leading to identification of therapeutic and behavioral modifications to avert and trea obesity.
|Gaykema, Ronald P; Newmyer, Brandon A; Ottolini, Matteo et al. (2017) Activation of murine pre-proglucagon-producing neurons reduces food intake and body weight. J Clin Invest 127:1031-1045|
|Warthen, Daniel M; Lambeth, Philip S; Ottolini, Matteo et al. (2016) Activation of Pyramidal Neurons in Mouse Medial Prefrontal Cortex Enhances Food-Seeking Behavior While Reducing Impulsivity in the Absence of an Effect on Food Intake. Front Behav Neurosci 10:63|