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

项目摘要/摘要 饥饿通常是由负能量平衡引起的，并导致一种更有动力去寻找的状态， 为之工作，吃东西。饥饿使人们的注意力偏向与食物有关的暗示(例如糖果包装纸)，因此 为了恢复能量平衡，可以找到并消费高热量食物。增强的行为 对食物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，而且可能 甚至在饱受肥胖症或饮食失调之苦的人身上也是如此。尽管它在临床上很重要 这一现象，即饥饿使认知加工偏向于 预测食物的线索在很大程度上仍然是未知的。已知的一个关键的大脑区域整合关于大脑内部的信息 身体状态，如饥饿，加上外部感觉线索来驱动目标导向行为，则是岛叶皮质 (IC)。人类的神经成像研究一直发现，依赖饥饿的人 视觉食物线索的激励价值与IC中食物线索诱发反应的增加相关。在啮齿动物中， 完整的IC对于习得的食物预测线索诱导觅食行为至关重要，这可能是因为它在 检索这些线索的激励价值。这项提议的首要目标是定义神经 在IC中，饥饿选择性地增强对食物线索的反应的途径。一个很有希望的起点是 这条通路是下丘脑刺鼠相关蛋白(AgRP)神经元的集合，它整合了内感 能量负平衡的信号。在饱足的小鼠中，通过激活这些基因，可以恢复饥饿相关的行为 神经元。此外，在饱足的人类中，IC中与饥饿相关的食物线索反应的增强也得到了恢复 受试者全身注射Ghrelin，这是一种激活AgRP神经元的饥饿刺激激素。我们会 将AgRP神经元活动的可逆操作与我们长期开发的一种新的成像方法相结合- 小鼠大脑中单个神经元在缓慢变化的动机状态下的活动的术语成像。在……里面 目标1，我们将测试视觉食物提示反应是否在特定的神经元亚群中是(I)选择性的 通过食物限制而增强，(Ii)因饱腹感而强烈减弱，以及(Iii)通过化学生成激活 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)是否是一种 饥饿依赖食物线索信息的必要来源，通过长期成像和光遗传沉默 BlaàIC轴突。在目标3中，我们将检验AgRP神经元投射到脑室旁的假设。 丘脑(AgrpàPVT)通过抑制PVT介导饥饿依赖的IC食物线索反应的调制 在脑片和活体中使用创新的电路映射技术，以及光遗传技术，将信息输入BLA 室旁核神经元的刺激和沉默。这项工作应该会极大地促进我们对 饥饿最终对IC中食物相关线索的加工产生强大影响的机制 导致食欲、暴饮暴食和肥胖。更广泛地说，这些实验建立了一个框架 了解身体需求如何驱动IC中灵活的、面向目标的感官信息处理。

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.