Prefrontal Cortical Control of Food binging, Novelty Seeking and Impulsive Behavior

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Abstract – The neuronal basis of diseases of disordered feeding, such as bulimia, anorexia and binge eating disorder, is poorly understood. Dysfunction of the medial prefrontal cortex (mPFC), however, has been suggested to play a causative role, as altered mPFC activity correlates with changes in novelty seeking and impulsivity in people with diseases of disordered feeding. Unfortunately, little is known about the behavioral significance of neurons within the mPFC that regulate behavioral output. Recent evidence suggests that two important interneuron subtypes that express either somatostatin (SST) or vasoactive intestinal peptide (VIP) in conjunction with GABA is responsible for gating information flow within the cortex. Specifically, while SST positive interneuron activation directly reduces pyramidal cell activity, VIP interneurons produce the opposite effect by inhibiting SST interneurons, causing pyramidal neurons to experience disinhibition and enhanced activity. Although this circuit is poised to contribute significantly to the regulation of binge feeding, novelty seeking and the regulation of impulsivity, through the integration of intra- and extra- cortical inputs, no studies have yet explored this possibility. Subsequently, this crucial knowledge gap presents as a critical barrier to the field, as it limits our understanding of the neuronal basis behind the expression of these behaviors. To better understand how changes in the VIP-SST interneuron circuit can lead to mPFC a change in behavior, two fundamental questions need to be addressed: 1. What role do disinhibitory VIP interneurons that increase excitatory tone in pyramidal neurons of the mPFC play in regulating binge feeding, novelty seeking and impulsivity? 2. What role do SST interneurons that interact with VIP neurons and specialize in inhibiting output from the mPFC play in regulating binge feeding, novelty seeking and impulsivity? In Aim 1, we will determine whether VIP expressing interneurons are necessary and sufficient to regulate binge food intake, novelty seeking and impulsivity. To test the sufficiency of these neurons, we will excite the mPFC VIP neurons optogenetically in either the prelimbic or infralimbic cortex. To examine the necessity of these neurons, we will deliver a caspase protein selectively to ablate the mPFC VIP neurons in either the prelimbic or infralimbic cortex. Following excitation or ablation, we will examine the effect of the manipulation on animal behavior. In Aim 2, we will repeat these same studies to excite or ablate SST expressing neurons of the prelimbic and infralimbic cortex. In conclusion, our proposed work will significantly enhance our understanding of how neurons that control frontal cortical excitation subsequently regulate behaviors associated with diseases of disordered feeding and drug addiction.