Linking hypothalamic and amygdalar circuits underlying attention to food cues

 描述(由申请者提供)：饥饿选择性地增强了人们对与食物相关的线索的关注，这可能导致暴饮暴食和肥胖。我们的实验室试图建立一个遗传的小鼠模型，以检查饥饿依赖注意食物线索的神经通路。我们提出的电路包括在下丘脑的弓状核(感知内部状态)、杏仁核(更新感觉线索的值并编码动机突出性)以及接受选择性杏仁核输入的高级视觉皮质区域(物体识别)表达刺鼠相关蛋白(AgRP)的神经元。我们提出的饥饿依赖注意力模型是，下丘脑AgRP神经元的活动反映了寻找食物的动力。杏仁核将这些内感线索与有关感觉环境的外感线索(通过来自高级视觉皮质区域的输入)结合起来，以识别与动机相关的线索。 并为这些线索分配额外的感觉处理。我假设，随着动物饥饿状态的改变，食物暗示的动机相关性或“价值”也会改变，这一过程取决于下丘脑和杏仁核的活动。为了支持这一点，在大量的人类神经成像研究中，接受杏仁核输入的杏仁核和腹侧视觉皮质区域在饥饿但不饱的状态下，始终显示出对视觉食物提示的更高反应，这一效果可能是由于下丘脑(也可能是直接的荷尔蒙)对这些区域的影响。然而，这些研究缺乏细胞分辨率来剖析饥饿依赖注意力所涉及的基本微电路。与人类神经成像研究不同，我们对行为正常的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。我将检查我们提议的电路中的两个节点。在目标1中，我将使用下丘脑弓状核中光遗传学定义的神经元类别的电生理记录来测量状态依赖的神经对食物相关和中性视觉线索的反应。在目标2中，我将使用双光子钙成像来测量杏仁核轴突在相同任务中投射到高级视觉皮质的状态依赖的神经反应。我们的初步数据表明，AgRP细胞和杏仁核向高级视觉皮质的投射都显示出饥饿依赖的神经对食物线索的偏见。最后，我将通过测试对AgRP神经元的光遗传刺激是否足以概括神经元对食物线索的偏见，来确定下丘脑通路在饥饿依赖注意食物线索中的贡献(目标3)。在……里面 通过这种方式，我可以开始定义潜在的寻找食物的冲动和那些将这种冲动转化为对特定感觉线索的选择性认知处理的回路之间的关系。总而言之，我的建议将剖析从下丘脑到皮层的神经通路，这些神经通路对于饥饿依赖的对食物暗示的注意非常重要，并为合理设计新的治疗方法提供了重要的一步，以减少过度注意和对美味食物的上瘾。

 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.