Probes for INS

The ventral pallidum (VP) lies at the interface between sensory, motor, and cognitive processing-with a particular role in mounting behavioral responses to rewards. Though the VP is predominantly GABAergic, glutamate neurons were recently identified, though their relative abundances and respective roles are unknown. Here, we show that VP glutamate neurons are concentrated in the rostral ventromedial VP and project to qualitatively similar targets as do VP GABA neurons. At the functional level, we used optogenetics to show that activity in VP GABA neurons can drive positive reinforcement, particularly through projections to the ventral tegmental area (VTA). On the other hand, activation of VP glutamate neurons leads to behavioral avoidance, particularly through projections to the lateral habenula. These findings highlight cell-type and projection-target specific roles for VP neurons in behavioral reinforcement, dysregulation of which could contribute to the emergence of negative symptoms associated with drug addiction and other neuropsychiatric disease.

Adaptation of liver to the postprandial state requires coordinated regulation of protein synthesis and folding aligned with changes in lipid metabolism. Here we demonstrate that sensory food perception is sufficient to elicit early activation of hepatic mTOR signaling, Xbp1 splicing, increased expression of ER-stress genes, and phosphatidylcholine synthesis, which translate into a rapid morphological ER remodeling. These responses overlap with those activated during refeeding, where they are maintained and constantly increased upon nutrient supply. Sensory food perception activates POMC neurons in the hypothalamus, optogenetic activation of POMC neurons activates hepatic mTOR signaling and Xbp1 splicing, whereas lack of MC4R expression attenuates these responses to sensory food perception. Chemogenetic POMC-neuron activation promotes sympathetic nerve activity (SNA) subserving the liver, and norepinephrine evokes the same responses in hepatocytes in vitro and in liver in vivo as observed upon sensory food perception. Collectively, our experiments unravel that sensory food perception coordinately primes postprandial liver ER adaption through a melanocortin-SNA-mTOR-Xbp1s axis.

The ventral pallidum (VP) is a critical component of the basal ganglia neurocircuitry regulating learning and decision making; however, its precise role in controlling associative learning of environmental stimuli conditioned to appetitive or aversive outcomes is still unclear. Here, we investigated the expression of preproenkephalin, a polypeptide hormone previously shown to be expressed in nucleus accumbens neurons controlling aversive learning, within GABAergic and glutamatergic VP neurons. Next, we explored the behavioral consequences of chemicogenetic inhibition or excitation of preproenkephalin-expressing VP neurons on associative learning of reward- or aversion-paired stimuli in autoshaping and inhibitory avoidance tasks, respectively. We reveal for the first time that preproenkephalin is expressed predominantly in GABAergic rather than glutamatergic VP neurons, and that excitation of these preproenkephalin-expressing VP neurons was sufficient to impair inhibitory avoidance learning. These findings indicate the necessity for inhibition of preproenkephalin-expressing VP neurons for avoidance learning, and suggest these neurons as a potential therapeutic target for psychiatric disorders associated with maladaptive aversive learning.

Molecular characterization of neurons across brain regions has revealed new taxonomies for understanding functional diversity even among classically defined neuronal populations. Neuronal diversity has become evident within the brain serotonin (5-HT) system, which is far more complex than previously appreciated. However, until now it has been difficult to define subpopulations of 5-HT neurons based on molecular phenotypes. We demonstrate that the MET receptor tyrosine kinase (MET) is specifically expressed in a subset of 5-HT neurons within the caudal part of the dorsal raphe nuclei (DRC) that is encompassed by the classic B6 serotonin cell group. Mapping from embryonic day 16 through adulthood reveals that MET is expressed almost exclusively in the DRC as a condensed, paired nucleus, with an additional sparse set of MET+ neurons scattered within the median raphe. Retrograde tracing experiments reveal that MET-expressing 5-HT neurons provide substantial serotonergic input to the ventricular/subventricular region that contains forebrain stem cells, but do not innervate the dorsal hippocampus or entorhinal cortex. Conditional anterograde tracing experiments show that 5-HT neurons in the DRC/B6 target additional forebrain structures such as the medial and lateral septum and the ventral hippocampus. Molecular neuroanatomical analysis identifies 14 genes that are enriched in DRC neurons, including 4 neurotransmitter/neuropeptide receptors and 2 potassium channels. These analyses will lead to future studies determining the specific roles that 5-HTMET+ neurons contribute to the broader set of functions regulated by the serotonergic system.