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

项目概要/摘要 饥饿通常是由负能量平衡引起的，并导致一种增加的动力状态， 工作，吃食物。饥饿会使注意力偏向与食物相关的线索（例如糖果包装纸）， 为了恢复能量平衡，可以找到并食用高热量食物。增强的行为 对食物线索的敏感性仍然是涉及食物限制的减肥计划的主要障碍， 甚至持续存在于患有肥胖症或饮食失调的饱食个体中。尽管临床上的重要性， 这种现象，细胞和电路机制，饥饿偏见的认知处理， 食物预测的线索在很大程度上仍然是未知的。一个关键的大脑区域，已知整合信息的内部 具有外部感觉线索的身体状态（如饥饿）驱动目标导向行为的是岛叶皮层 （IC）.对人类的神经成像研究一直发现， 视觉食物线索的刺激值与IC中食物线索诱发反应的增加相关。在啮齿类动物中， 完整的IC对于学习食物预测线索以诱导寻食行为至关重要，这可能是由于其在 这些线索的激励价值的检索。该提案的首要目标是定义神经网络 饥饿选择性地增强IC对食物线索的反应的途径。一个有希望的起点， 这条通路是下丘脑刺豚鼠相关蛋白（AgRP）神经元的集合， 负能量平衡的信号。饥饿相关的行为在饱足的小鼠中通过激活这些 神经元此外，饥饿相关的食物线索反应增强在饱足的人中得到恢复。 通过全身注射生长素释放肽（一种激活AgRP神经元的饥饿刺激激素）来刺激受试者。我们将 联合收割机可逆操纵AgRP神经元活动与一种新的成像方法，我们开发了长期- 在缓慢变化的动机状态下，小鼠IC中单个神经元活动的长期成像。在 目的1，我们将测试在特定的IC神经元亚群的视觉食物线索反应是否（i）选择性 通过食物限制增强，（ii）通过饱腹感强烈减弱，和（iii）通过化学发生激活恢复， AgRP神经元。在目标2中，我们将确定IC中的基底外侧杏仁核轴突（BLAà-IC）是否是一个神经元。 通过长期成像和光遗传学沉默，饥饿依赖性食物提示信息的必要来源 的神经轴突。在目的3中，我们将检验AgRP神经元投射到室旁核的假设， 丘脑（AgRP PVT）通过抑制PVT介导IC中食物线索反应的饥饿依赖性调节 输入到BLA，在脑切片和体内使用创新的电路映射技术， 刺激和沉默AgRPà pVT神经元。这项工作应该大大促进我们对 饥饿对IC中食物相关线索的加工产生有效影响的机制，最终 驾驶欲望，暴饮暴食和肥胖更一般地说，这些实验建立了一个框架， 了解身体的需求如何驱动IC中感官信息的灵活，目标导向的处理。

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.