Functional identification of vagal sensory neurons innervating the liver

内感受信号通过迷走神经从器官到大脑的正确整合和运输似乎对各种感觉和情绪到动机和适应行为的心理体验至关重要。患有心理障碍的个体，包括抑郁症和双相情感障碍，除了情绪低落外，还会经历饮食行为的变化。人们认为，在患有心理障碍和物质滥用障碍的个体中，食欲的丧失或增加是由于中枢奖赏和内感受神经回路的中断。该提案将使用神经解剖学追踪结合迷走神经感觉神经回路的生理和行为分析来进行功能分析，迷走神经感觉神经回路感知并整合肝脏中的内感受信号。 每个迷走神经感觉神经元都有一个中央脑干终末。孤束核（NTS）中的一群儿茶酚胺能细胞接受来自肝脏投射的迷走神经传入神经元的输入。这些儿茶酚胺能神经元控制葡萄糖消耗。此外，NTS中的抑制性神经元的子集通过节前副交感神经元调节肝葡萄糖产生。肝脏投射迷走神经感觉神经元的一个亚群可以对血糖的变化做出反应，并将此信息传递给NTS中的神经元。有趣的是，下丘脑弓状核中的食欲神经元群和臂旁核中的食欲抑制神经元亚群从NTS中的儿茶酚胺能神经元接收突触输入。这些调节食欲的神经元似乎投射到与抑郁和情绪有关的结构。因此，我们提出肝脑神经回路对摄食行为至关重要，并且这种神经回路在大脑功能中也起着至关重要的作用，特别是心理障碍，包括抑郁症和双相情感障碍。 目标1的研究将确定肝脏投射迷走神经感觉神经元的分子和细胞特性。目标2中的实验将检查肝脑神经回路功能丧失的功能后果。我们的建议将有可能提供新的信息，如何营养和激素迷走神经传入信号从肝脏作用于中枢神经系统，以驱动食欲和消费方面的动机喂养和奖励行为。

Proper integration and transportation of interoceptive signals from organs to the brain via the vagus nerve appear to be critical for psychological experiences ranging from a variety of feelings and emotions to motivations and adaptive behaviors. Individuals with psychological disorders, including depression and bipolar disorder experience changes in eating behavior in addition to low mood. It has been thought that loss or increase of appetite in individuals with psychological disorders and substance abuse disorders results from disruptions in central reward and interoceptive neurocircuits. This proposal will perform functional analysis using neural anatomical tracing combined with physiological and behavioral analysis of the vagal sensory neural circuit that senses and integrates interoceptive signals in the liver. Each vagal sensory neuron has a central brainstem terminal. A population of catecholaminergic cells in the nucleus tractus solitarius (NTS) receives input from liver-projecting vagal afferent neurons. These catecholaminergic neurons control glucoprivic feeding. Additionally, a subset of inhibitory neurons in the NTS regulate hepatic glucose production via preganglionic parasympathetic neurons. A subgroup of liver-projecting vagal sensory neurons can respond to changes in blood glucose and transmit this information to the neurons in the NTS. Intriguingly, a population of orexigenic neurons in the arcuate nucleus of the hypothalamus and a subgroup of appetite-suppressing neurons in the parabrachial nucleus receive synaptic inputs from catecholaminergic neurons in the NTS. These appetite-regulating neurons appear to project to the structures implicated in depression and emotion. Therefore, we propose that a liver-brain neural circuit is essential for ingestive behaviors and that this neural circuit also plays a vital role in brain functions, particularly psychological disorders, including depression and bipolar disorder. Studies in Aim 1 will determine the molecular and cellular identity of liver-projecting vagal sensory neurons. Experiments in Aim 2 will examine the functional consequences of the loss-of-function of a liver-brain neural circuit. Our proposal will have the potential to provide novel information on how nutrient and hormonal vagal afferent signals from the liver act on the CNS to drive appetitive and consummatory aspects of motivated feeding and reward behavior.