Linking hypothalamic and amygdalar circuits underlying attention to food cues

连接下丘脑和杏仁核回路是对食物线索的关注的基础

• 批准号: 9142058
• 负责人: Rohan Ramesh
• 金额: $ 3.11万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-30 至 2018-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9142058
• 关键词: ART protein; Amygdaloid structure; Animals; Area; Attention; Automobile Driving; Axon; Behavior; Behavioral; Binge Eating; Biological Neural Networks; Brain; Calcium; Cells; Chronic; Cues; Data; Drops; Eating; Electrophysiology (science); Environment; Fasting; Feedback; Feeding behaviors; Food; Food Processing; Genetic; Head; Hormonal; Hour; Human; Hunger; Hypothalamic structure; Image; Individual; Lead; Link; Liquid substance; Measures; Modeling; Motivation; Mus; Neural Pathways; Neurons; Obesity; Operant Conditioning; Outcome; Pathway interactions; Performance; Population; Process; Quinine; Resolution; Rewards; Role; Satiation; Sensory; Sensory Process; Signal Transduction; Structure; Structure of nucleus infundibularis hypothalami; Task Performances; Testing; Training; Translating; Update; Visual; Visual Cortex; Work; addiction; cognitive process; design; experience; extrastriate visual cortex; feeding; food surveillance; imaging modality; in vivo; insight; mouse model; neuroimaging; novel therapeutics; object recognition; optogenetics; public health relevance; rational function; relating to nervous system; research study; response; sensory input; therapy development; tool; two-photon; visual learning

 DESCRIPTION (provided by applicant): Hunger selectively enhances attention to food-associated cues, which can lead to excessive eating and obesity. Our lab seeks to establish a genetic mouse model to examine the neural pathways underlying hunger- dependent attention to food-cues. Our proposed circuit includes neurons expressing agouti-related protein (AgRP) in the arcuate nucleus of the hypothalamus (sensing internal state), the amygdala (updating the value of sensory cues and encoding motivational salience), and the higher visual cortical areas that receive selective amygdalar input (object recognition). Our proposed model for hunger-dependent attention is that hypothalamic AgRP neuron activity mirrors a drive to seek food. The amygdala integrates these interoceptive cues with exteroceptive cues about the sensory environment (via inputs from higher visual cortical areas) to identify motivationally relevant cues in the environment and allocate additional sensory processing to these cues. I hypothesize that as the hunger state of the animal changes, so does the motivational relevance or `value' of food-cues, a process dependent on activity in both the hypothalamus and the amygdala. In support of this, in a large number of human neuroimaging studies, the amygdala and ventral visual cortical areas that receive amygdalar input consistently show increased responses to visual food cues during hungry, but not sated, states, an effect likely due to indirect hypothalamic (and possibly direct hormonal) influences on these areas. These studies, however, lack the cellular resolution to dissect the basic microcircuits involved in hunger- dependent attention. Unlike in human neuroimaging studies, our studies in behaving mice involve the simultaneous recording, at single cell resolution, of genetically-identified neurons, across natural and induced states of hunger. I will examine two nodes in our proposed circuit. In Aim 1, I will use electrophysiological recordings in optogenetically-defined classes of neurons in the arcuate nucleus of the hypothalamus to measure state-dependent neural responses to food-associated and neutral visual cues. In Aim 2, I will use two-photon calcium imaging to measure the state-dependent neural responses of amygdala axons projecting to higher visual cortex in an identical task. Our preliminary data suggests that, both AgRP cells and the amygdalar projections to higher visual cortex show hunger-dependent neural biases to food-cues. Finally, I will determine the contribution of hypothalamic pathways in hunger-dependent attention to food-cues by testing whether optogenetic stimulation of AgRP neurons, a manipulation known to drive food-seeking behavior, is sufficient to recapitulate neuronal biases to food-cues (Aim 3). In this way, I can begin to define the relationship between circuits underlying the drive to seek food, and those translating this drive into selective cognitive processing of specific sensory cues. In summary, my proposal will dissect the neural pathways from hypothalamus to cortex important for hunger-dependent attention to food cues, and provide an important step towards the rational design of novel therapies for reducing over-attention and addiction to highly palatable foods.

 描述（由申请人提供）：饥饿选择性地增强对食物相关线索的注意力，这可能导致过度进食和肥胖。我们的实验室试图建立一个遗传小鼠模型，以研究饥饿依赖性注意食物线索的神经通路。我们提出的电路包括在下丘脑弓状核（感知内部状态），杏仁核（更新感官线索的价值和编码动机显着性），和更高的视觉皮层区域，接收选择性杏仁输入（对象识别）表达刺鼠相关蛋白（AgRP）的神经元。我们提出的饥饿依赖性注意力模型是下丘脑AgRP神经元活动反映了寻找食物的驱动力。杏仁核将这些内感受性线索与感觉环境的外感受性线索（通过来自高级视觉皮层区域的输入）整合起来，以识别与动机相关的线索 并为这些线索分配额外的感官处理。我假设，作为饥饿状态的动物的变化，所以没有动机的相关性或“价值”的食物线索，一个过程依赖于活动在下丘脑和杏仁核。为了支持这一点，在大量的人类神经影像学研究中，接受杏仁核输入的杏仁核和腹侧视觉皮层区域在饥饿但不饱足的状态下对视觉食物线索的反应一致地显示出增加，这种效应可能是由于下丘脑对这些区域的间接影响（也可能是直接的激素）。然而，这些研究缺乏细胞分辨率来剖析饥饿依赖性注意力的基本微电路。与人类神经成像研究不同，我们对行为小鼠的研究涉及在自然和诱导饥饿状态下以单细胞分辨率同时记录遗传识别的神经元。我将研究我们提出的电路中的两个节点。在目标1中，我将使用光遗传学定义的下丘脑弓状核神经元类别的电生理记录来测量对食物相关和中性视觉线索的状态依赖性神经反应。在目标2中，我将使用双光子钙成像来测量在相同的任务中杏仁核轴突投射到高级视觉皮层的状态依赖性神经反应。我们的初步数据表明，AgRP细胞和杏仁核的高级视觉皮层的投射显示饥饿依赖的神经偏向的食物线索。最后，我将通过测试AgRP神经元的光遗传学刺激（一种已知的驱动食物寻找行为的操作）是否足以概括神经元对食物线索的偏好来确定下丘脑通路在饥饿依赖性注意中对食物线索的贡献（目标3）。在 通过这种方式，我可以开始定义在寻找食物的驱动力之下的电路之间的关系，以及那些将这种驱动力转化为特定感官线索的选择性认知处理的电路。总之，我的建议将解剖从下丘脑到皮层的神经通路，这对饥饿依赖性注意食物线索很重要，并为合理设计新疗法以减少过度注意和对美味食物成瘾迈出了重要一步。