Functional identification of vagal sensory neurons innervating the liver

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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.