? 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 how the medial prefrontal cortex regulates these behaviors. To gain a better understanding of how the mPFC functions and thus how dysfunction could lead to behavioral change, three important questions must be answered. 1. How do specific projections from the mPFC control binge feeding, novelty seeking and impulsivity? 2. What role do important modulatory interneurons that act within the mPFC play in regulating these same behaviors? 3. Do specific circuit alterations that produce changes in impulsivity and novelty seeking also coordinately modify binge feeding behavior? To address this knowledge gap, in Aim 1, we will test the necessity and sufficiency of projections from the prefrontal cortex to the rostral nucleus accumbens in the control of binge feeding, novelty seeking and impulsive behavior. In support of these studies, we have shown that this projection is necessary for the regulation of novelty seeking behavior. To test the sufficiency of the projection, a Cre recombinase expression dependent excitatory Designer Receptor Exclusively Activated by Designer Drugs (DREADD), delivered from an adeno associated virus, will be injected into the prefrontal cortex. To examine the necessity of the projection, a Cre recombinase expression dependent caspase protein, delivered from an adeno-associated virus, will be used. Specificity of targeting the cortex-acumbens projection will be achieved by the injection of a retrogradely transported virus, expressing cre recombinase, into the nucleus accumbens.
In Aim 2, we will determine whether a specific gabaergic interneuron population in the prefrontal cortex expressing vasoactive intestinal peptide is necessary and sufficient to regulate binge food intake, novelty seeking and impulsivity. Our studies are supported by preliminary data that shows how these cells are both necessary and sufficient to produce a change in binge feeding and novelty seeking. To test the sufficiency of these neurons in the control of binge feeding, impulsivity and novelty seeking, we will excite the mPFC VIP neurons optogenetically. Again, to examine the necessity of these neurons, we will deliver a caspase protein selectively to ablate the mPFC VIP neurons. Our proposed work will significantly enhance our understanding of how the frontal cortex regulates behaviors associated with diseases of disordered feeding and drug addiction.
PUBLICHEALTHRELEVANCE:Severalco-?morbidbehaviorshavebeensuggestedtounderliethe developmentofdiseasesofdisorderedfeeding,suchasanorexia,bulimiaandbingefeedingdisorder.The neurobiologicalbasisofthesebehavioralalterations,howeverremainsunknown.Ourworkwilldescribe howsubsetsofneuronsinthemedialprefrontalcortexcanregulatebingefoodintake,noveltyseeking andimpulsivebehavior,providingimportantinformationonhowbraindysfunctionmayleadto behavioralchange.Subsequently,webelievethatunderstandingtheneurobiologicalchangesthatresult inaberrantfeeding,noveltyseekingandimpulsivebehaviorwillallowustoidentifynoveltargetsfor futuretherapeuticintervention.
