Fasting-activated ventrolateral medulla neurons regulate T cell homing and suppress autoimmune disease in mice.

Dietary fasting markedly influences the distribution and function of immune cells and exerts potent immunosuppressive effects. However, the mechanisms through which fasting regulates immunity remain obscure. Here we report that catecholaminergic (CA) neurons in the ventrolateral medulla (VLM) are activated during fasting in mice, and we demonstrate that the activity of these CA neurons impacts the distribution of T cells and the development of autoimmune disease in an experimental autoimmune encephalomyelitis (EAE) model. Ablation of VLM CA neurons largely reversed fasting-mediated T cell redistribution. Activation of these neurons drove T cell homing to bone marrow in a CXCR4/CXCL12 axis-dependent manner, which may be mediated by a neural circuit that stimulates corticosterone secretion. Similar to fasting, the continuous activation of VLM CA neurons suppressed T cell activation, proliferation, differentiation and cytokine production in autoimmune mouse models and substantially alleviated disease symptoms. Collectively, our study demonstrates neuronal control of inflammation and T cell distribution, suggesting a neural mechanism underlying fasting-mediated immune regulation.

Projections from D2 Neurons in Different Subregions of Nucleus Accumbens Shell to Ventral Pallidum Play Distinct Roles in Reward and Aversion.

The nucleus accumbens shell (NAcSh) plays an important role in reward and aversion. Traditionally, NAc dopamine receptor 2-expressing (D2) neurons are assumed to function in aversion. However, this has been challenged by recent reports which attribute positive motivational roles to D2 neurons. Using optogenetics and multiple behavioral tasks, we found that activation of D2 neurons in the dorsomedial NAcSh drives preference and increases the motivation for rewards, whereas activation of ventral NAcSh D2 neurons induces aversion. Stimulation of D2 neurons in the ventromedial NAcSh increases movement speed and stimulation of D2 neurons in the ventrolateral NAcSh decreases movement speed. Combining retrograde tracing and in situ hybridization, we demonstrated that glutamatergic and GABAergic neurons in the ventral pallidum receive inputs differentially from the dorsomedial and ventral NAcSh. All together, these findings shed light on the controversy regarding the function of NAcSh D2 neurons, and provide new insights into understanding the heterogeneity of the NAcSh.

A Vagal-NTS Neural Pathway that Stimulates Feeding.

A fundamental question of physiology is how gut-brain signaling stimulates appetite. While many studies have emphasized the importance of vagal afferents to the brain in inducing satiation, little is known about whether and how the vagal-mediated gut-brain pathway senses orexigenic signals and stimulates feeding. Here, we identified a previously uncharacterized population of fasting-activated catecholaminergic neurons in the nucleus of the solitary tract (NTS). After characterizing the anatomical complexity among NTS catecholaminergic neurons, we surprisingly found that activation of NTS epinephrine (ENTS) neurons co-expressing neuropeptide Y (NPY) stimulated feeding, whereas activation of NTS norepinephrine (NENTS) neurons suppressed feeding. Monosynaptic tracing/activation experiments then showed that these NTS neurons receive direct vagal afferents from nodose neurons. Moreover, activation of the vagal→NPY/ENTS neural circuit stimulated feeding. Our study reveals an orexigenic role of the vagal→NTS pathway in controlling feeding, thereby providing important insights about how gut-brain signaling regulates feeding behavior.

Neuronal Organization in the Inferior Colliculus Revisited with Cell-Type-Dependent Monosynaptic Tracing.

The inferior colliculus (IC) is a critical integration center in the auditory pathway. However, because the inputs to the IC have typically been studied by the use of conventional anterograde and retrograde tracers, the neuronal organization and cell-type-specific connections in the IC are poorly understood. Here, we used monosynaptic rabies tracing and in situ hybridization combined with excitatory and inhibitory Cre transgenic mouse lines of both sexes to characterize the brainwide and cell-type-specific inputs to specific neuron types within the lemniscal IC core and nonlemniscal IC shell. We observed that both excitatory and inhibitory neurons of the IC shell predominantly received ascending inputs rather than descending or core inputs. Correlation and clustering analyses revealed two groups of excitatory neurons in the shell: one received inputs from a combination of ascending nuclei, and the other received inputs from a combination of descending nuclei, neuromodulatory nuclei, and the contralateral IC. In contrast, inhibitory neurons in the core received inputs from the same combination of all nuclei. After normalizing the extrinsic inputs, we found that core inhibitory neurons received a higher proportion of inhibitory inputs from the ventral nucleus of the lateral lemniscus than excitatory neurons. Furthermore, the inhibitory neurons preferentially received inhibitory inputs from the contralateral IC shell. Because IC inhibitory neurons innervate the thalamus and contralateral IC, the inhibitory inputs we uncovered here suggest two long-range disinhibitory circuits. In summary, we found: (1) dominant ascending inputs to the shell, (2) two subpopulations of shell excitatory neurons, and (3) two disinhibitory circuits.SIGNIFICANCE STATEMENT Sound undergoes extensive processing in the brainstem. The inferior colliculus (IC) core is classically viewed as the integration center for ascending auditory information, whereas the IC shell integrates descending feedback information. Here, we demonstrate that ascending inputs predominated in the IC shell but appeared to be separated from the descending inputs. The presence of inhibitory projection neurons is a unique feature of the auditory ascending pathways, but the connections of these neurons are poorly understood. Interestingly, we also found that inhibitory neurons in the IC core and shell preferentially received inhibitory inputs from ascending nuclei and contralateral IC, respectively. Therefore, our results suggest a bipartite domain in the IC shell and disinhibitory circuits in the IC.

Somatostatin Neurons in the Basal Forebrain Promote High-Calorie Food Intake.

Obesity has become a global issue, and the overconsumption of food is thought to be a major contributor. However, the regulatory neural circuits that regulate palatable food consumption remain unclear. Here, we report that somatostatin (SOM) neurons and GABAergic (VGAT) neurons in the basal forebrain (BF) play specific roles in regulating feeding. Optogenetic stimulation of BF SOM neurons increased fat and sucrose intake within minutes and promoted anxiety-like behaviors. Furthermore, optogenetic stimulation of projections from BF SOM neurons to the lateral hypothalamic area (LHA) selectively resulted in fat intake. In addition, activation of BF VGAT neurons rapidly induced general food intake and gnawing behaviors. Whole-brain mapping of inputs and outputs showed that BF SOM neurons form bidirectional connections with several brain areas important in feeding and regulation of emotion. Collectively, these results suggest that BF SOM neurons play a selective role in hedonic feeding.

A Central Catecholaminergic Circuit Controls Blood Glucose Levels during Stress.

Stress-induced hyperglycemia is a fundamental adaptive response that mobilizes energy stores in response to threats. Here, our examination of the contributions of the central catecholaminergic (CA) neuronal system to this adaptive response revealed that CA neurons in the ventrolateral medulla (VLM) control stress-induced hyperglycemia. Ablation of VLM CA neurons abolished the hyperglycemic response to both physical and psychological stress, whereas chemogenetic activation of these neurons was sufficient to induce hyperglycemia. We further found that CA neurons in the rostral VLM, but not those in the caudal VLM, cause hyperglycemia via descending projections to the spinal cord. Monosynaptic tracing experiments showed that VLM CA neurons receive direct inputs from multiple stress-responsive brain areas. Optogenetic studies identified an excitatory PVN-VLM circuit that induces hyperglycemia. This study establishes the central role of VLM CA neurons in stress-induced hyperglycemia and substantially expands our understanding of the central mechanism that controls glucose metabolism.