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

摘要-进食障碍疾病的神经基础，如暴食症、厌食症和暴食。 无序，人们对此知之甚少。然而，内侧前额叶皮质(MPFC)的功能障碍 建议发挥诱因作用，因为mPFC活动的改变与新奇寻求和 进食障碍患者的冲动。不幸的是，人们对此知之甚少 调节行为输出的mPFC内神经元的行为意义。最近的证据 提示两种重要的中间神经元亚型表达生长抑素(SST)或血管活性物质 肠肽(VIP)与GABA一起负责控制皮质内的信息流。 具体地说，虽然SST阳性中间神经元的激活直接降低了锥体细胞的活动，但VIP中间神经元 通过抑制SST中间神经元产生相反的效果，导致锥体神经元经历 去抑制和增强活性。尽管这一巡回法庭准备对调节 暴饮暴食，寻求新奇和调节冲动，通过内外整合-- 大脑皮层输入，目前还没有研究探索这种可能性。随后，这一关键的知识鸿沟出现了 作为该领域的关键障碍，因为它限制了我们对表达背后的神经元基础的理解 这些行为。为了更好地了解VIP-SST中间神经元回路的变化如何导致mPFC a 行为的改变需要解决两个基本问题：1.抑制VIP的作用是什么 MPFC锥体神经元增加兴奋性张力的中间神经元在调节狂欢中发挥作用 摄食、寻求新奇和冲动？2.与VIP相互作用的SST中间神经元起什么作用 神经元和专门抑制mPFC的输出在调节狂欢进食中发挥作用，新奇 追求和冲动？在目标1中，我们将确定是否需要表达VIP的中间神经元 并足以控制暴饮暴食、追求新奇和冲动。为了测试这些功能的充分性 对于神经元，我们将以光遗传学的方式兴奋前额叶或下缘皮质中的mPFC VIP神经元。至 研究这些神经元的必要性，我们将选择性地传递caspase蛋白来消融mPFC VIP 前额叶或下缘皮质中的神经元。在激发或消融后，我们将检查其影响。 对动物行为的操纵。在目标2中，我们将重复这些相同的研究来刺激或消融SST 前缘皮质和下缘皮质神经元的表达。总而言之，我们提议的工作将显著 加深我们对控制额叶皮质兴奋的神经元随后如何调节的理解 与饮食失调和吸毒成瘾等疾病相关的行为。

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.