Sensory neurons promote immune homeostasis in the lung.

Cytokines employ downstream Janus kinases (JAKs) to promote chronic inflammatory diseases. JAK1-dependent type 2 cytokines drive allergic inflammation, and patients with JAK1 gain-of-function (GoF) variants develop atopic dermatitis (AD) and asthma. To explore tissue-specific functions, we inserted a human JAK1 GoF variant (JAK1GoF) into mice and observed the development of spontaneous AD-like skin disease but unexpected resistance to lung inflammation when JAK1GoF expression was restricted to the stroma. We identified a previously unrecognized role for JAK1 in vagal sensory neurons in suppressing airway inflammation. Additionally, expression of Calcb/CGRPß was dependent on JAK1 in the vagus nerve, and CGRPß suppressed group 2 innate lymphoid cell function and allergic airway inflammation. Our findings reveal evolutionarily conserved but distinct functions of JAK1 in sensory neurons across tissues. This biology raises the possibility that therapeutic JAK inhibitors may be further optimized for tissue-specific efficacy to enhance precision medicine in the future.

"Goodnight" from the heart: A cardiovascular circuit that promotes sleep.

The baroreflex is essential for blood pressure homeostasis. In this issue of Neuron, Yao et al.1 uncover a novel role of brainstem barosensitive neurons in promoting non-REM (NREM) sleep, providing a direct link between the cardiovascular system and sleep-wake states.

A multidimensional coding architecture of the vagal interoceptive system.

Interoception, the ability to timely and precisely sense changes inside the body, is critical for survival1-4. Vagal sensory neurons (VSNs) form an important body-to-brain connection, navigating visceral organs along the rostral-caudal axis of the body and crossing the surface-lumen axis of organs into appropriate tissue layers5,6. The brain can discriminate numerous body signals through VSNs, but the underlying coding strategy remains poorly understood. Here we show that VSNs code visceral organ, tissue layer and stimulus modality-three key features of an interoceptive signal-in different dimensions. Large-scale single-cell profiling of VSNs from seven major organs in mice using multiplexed projection barcodes reveals a 'visceral organ' dimension composed of differentially expressed gene modules that code organs along the body's rostral-caudal axis. We discover another 'tissue layer' dimension with gene modules that code the locations of VSN endings along the surface-lumen axis of organs. Using calcium-imaging-guided spatial transcriptomics, we show that VSNs are organized into functional units to sense similar stimuli across organs and tissue layers; this constitutes a third 'stimulus modality' dimension. The three independent feature-coding dimensions together specify many parallel VSN pathways in a combinatorial manner and facilitate the complex projection of VSNs in the brainstem. Our study highlights a multidimensional coding architecture of the mammalian vagal interoceptive system for effective signal communication.

Vagal sensory neurons and gut-brain signaling.

Our understanding of the gut system has been revolutionized over the past decade, in particular regarding its role in immune control and psychological regulation. The vagus nerve is a crucial link between gut and brain, transmitting diverse gut-derived signals, and has been implicated in many gastrointestinal, neurological, and immunological disorders. Using state-of-the-art technologies including single-cell genomic analysis, real-time neural activity recording, trans-synaptic tracing, and electron microscopy, novel physiological functions of vagal gut afferents have been uncovered, and new gut-to-brain pathways have been revealed. Here, we review the most recent findings on vagal sensory neurons and the gut-brain signaling, focusing on the anatomical basis and the underlying molecular and cellular mechanisms. Such new discoveries explain some of the old puzzling problems and also raise new questions in this exciting and rapidly growing field.