Neural Pathway Linking Nutritional State To Food-Cue Responses In Insular Cortex

连接岛叶皮层营养状态与食物提示反应的神经通路

• 批准号: 9754119
• 负责人: Mark L Andermann
• 金额: $ 43.25万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-19 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9754119
• 关键词: ART protein; Address; Advertisements; Affect; Amygdaloid structure; Animals; Area; Attenuated; Automobile Driving; Axon; Behavior; Behavioral; Brain; Brain imaging; Brain region; Calcium; Calories; Candy; Chronic; Clinical; Cognitive; Color; Consumption; Cues; Discrimination; Eating; Eating Disorders; Food; Food Processing; Goals; Hormones; Human; Hunger; Hypothalamic structure; Image; Incentives; Individual; Injections; Interneurons; Label; Lead; Link; Mediating; Motivation; Mus; Neural Pathways; Neurons; Nutritional; Obesity; Palate; Pathway interactions; Peptides; Population; Rabies; Retrieval; Rodent; Role; Satiation; Sensory; Signal Transduction; Slice; Source; Structure of nucleus infundibularis hypothalami; Techniques; Testing; Thalamic structure; Variant; Visual; Visual Cortex; Work; attentional bias; behavioral response; brain pathway; cell type; craving; energy balance; experimental study; feeding; flexibility; food craving; food restriction; ghrelin; human subject; imaging approach; imaging modality; imaging study; in vivo; incentive salience; innovation; neuroimaging; new therapeutic target; novel; optogenetics; relating to nervous system; response; two-photon; weight loss program

Project Summary/Abstract Hunger is typically elicited by negative energy balance, and causes a state of increased motivation to seek out, work for, and eat food. Hunger biases attention toward food-associated cues (e.g. candy bar wrappers) so that calorie-dense foods can be found and consumed in order to restore energy balance. Enhanced behavioral sensitivity to food cues remains a major obstacle to weight-loss programs involving food restriction, and can even persist in satiated individuals suffering from obesity or eating disorders. Despite the clinical importance of this phenomenon, the cellular and circuit mechanisms by which hunger biases cognitive processing towards food-predicting cues remain largely unknown. A key brain area known to integrate information about internal bodily states such as hunger with external sensory cues to drive goal-directed behavior is the insular cortex (IC). Neuroimaging studies in humans have consistently found that hunger-dependent increases in the incentive value of visual food cues correlates with increased food-cue-evoked responses in IC. In rodents, an intact IC is critical for learned food-predicting cues to induce food-seeking behavior, potentially due to its role in the retrieval of the incentive value of these cues. The overarching goal of this proposal is to define the neural pathways by which hunger selectively enhances responses to food cues in IC. One promising starting point for this pathway is the set of hypothalamic agouti-related protein (AgRP) neurons that integrates interoceptive signals of negative energy balance. Hunger-related behaviors are restored in sated mice by activation of these neurons. Moreover, hunger-related enhancement of food-cue responses in IC are restored in sated human subjects by systemic injection of ghrelin, a hunger-stimulating hormone that activates AgRP neurons. We will combine reversible manipulation of AgRP neuron activity with a new imaging approach we developed for long- term imaging of the activity of individual neurons in mouse IC across slowly-changing motivational states. In Aim 1, we will test whether visual food cue responses in specific subsets of IC neurons are (i) selectively enhanced by food restriction, (ii) strongly attenuated by satiety, and (iii) restored by chemogenetic activation of AgRP neurons. In Aim 2, we will determine whether basolateral amygdala axons in IC (BLAàIC) are a necessary source of hunger-dependent food-cue information, via long-term imaging and optogenetic silencing of BLAàIC axons. In Aim 3, we will test the hypothesis that AgRP neurons projecting to the paraventricular thalamus (AgRPàPVT) mediate hunger-dependent modulation of food-cue responses in IC by inhibiting PVT inputs to BLA, using innovative circuit mapping techniques in brain slices and in vivo, together with optogenetic stimulation and silencing of AgRPàPVT neurons. This work should greatly advance our understanding of the mechanisms by which hunger exerts its potent effects on processing of food-related cues in IC, ultimately driving cravings, excessive eating, and obesity. More generally, these experiments establish a framework for understanding how the needs of the body drive flexible, goal-oriented processing of sensory information in IC.

项目摘要/摘要 饥饿通常是通过负能量平衡引起的，并引起人们提高动力的状态 工作，吃食物。饥饿会偏向于食物相关的提示（例如糖果吧包装纸），以便 可以找到和消耗卡路里的食物，以恢复能量平衡。增强的行为 对食品提示的敏感性仍然是涉及食物限制的减肥计划的主要障碍，并且可以 甚至仍然存在于患有肥胖或饮食失调的人。尽管临床重要性 这种现象，饥饿偏向认知处理的细胞和电路机制 粮食预测的提示仍然在很大程度上未知。已知的关键大脑区域，该区域旨在整合有关内部的信息 身体状态，例如具有外部感觉线索以推动目标指导行为的饥饿是岛状皮层 （我知道了）。在人类中的神经影像学研究一直发现饥饿依赖性的增加在 视觉食品提示的激励价值与IC中的食物库诱发的反应增加相关。在啮齿动物中，一个 完整的IC对于学习的食物预测线索至关重要 这些提示的激励价值的检索。该提议的总体目标是定义中性 饥饿有选择地增强对IC中食品线索的反应的途径。一个人承诺起点 该途径是下丘脑Agouti相关蛋白（AGRP）神经元的一组，它整合了互感 负能量平衡的信号。与饥饿相关的行为通过激活这些行为在小鼠中恢复 神经元。此外，与饥饿相关的饮食 - 提示反应增强IC中的人类响应已恢复 通过全身注射生长素素的受试者，这是一种激活AGRP神经元的饥饿刺激性的。我们将 将AGRP神经元活性的可逆操纵与我们为长期开发的新成像方法结合在一起 小鼠IC中单个神经元在缓慢变化的动机状态中的活性的术语成像。在 AIM 1，我们将测试IC神经元特定子集中的视觉食品提示反应是否为（i） 通过食物限制增强，（ii）强烈通过饱腹感减弱，（iii）通过化学遗传激活恢复 AGRP神经元。在AIM 2中，我们将确定IC（BlaàIC）中的基底外侧杏仁核是否是 通过长期成像和光学遗传沉默，依赖饥饿的食物库信息的必要来源 blaà -iC轴突。在AIM 3中，我们将检验以下假设，即AGRP神经元投射到阶室 通过抑制PVT，丘脑（agrpàpvt）介导了IC中食品证明反应的饥饿依赖性调制 使用脑切片和体内的创新电路映射技术输入到BLA，并与光遗传学一起 刺激和沉默agrpàpvt神经元。这项工作应该很好地提高我们对 最终 驾驶渴望，多余的饮食和肥胖症。更一般地，这些实验为 了解身体的需求如何推动IC中感觉信息的灵活，面向目标的处理。