Neural signalling of gut mechanosensation in ingestive and digestive processes.

Eating and drinking generate sequential mechanosensory signals along the digestive tract. These signals are communicated to the brain for the timely initiation and regulation of diverse ingestive and digestive processes - ranging from appetite control and tactile perception to gut motility, digestive fluid secretion and defecation - that are vital for the proper intake, breakdown and absorption of nutrients and water. Gut mechanosensation has been investigated for over a century as a common pillar of energy, fluid and gastrointestinal homeostasis, and recent discoveries of specific mechanoreceptors, contributing ion channels and the well-defined circuits underlying gut mechanosensation signalling and function have further expanded our understanding of ingestive and digestive processes at the molecular and cellular levels. In this Review, we discuss our current understanding of the generation of mechanosensory signals from the digestive periphery, the neural afferent pathways that relay these signals to the brain and the neural circuit mechanisms that control ingestive and digestive processes, focusing on the four major digestive tract parts: the oral and pharyngeal cavities, oesophagus, stomach and intestines. We also discuss the clinical implications of gut mechanosensation in ingestive and digestive disorders.

A forebrain neural substrate for behavioral thermoregulation.

Thermoregulatory behavior is a basic motivated behavior for body temperature homeostasis. Despite its fundamental importance, a forebrain region or defined neural population required for this process has yet to be established. Here, we show that Vgat-expressing neurons in the lateral hypothalamus (LHVgat neurons) are required for diverse thermoregulatory behaviors. The population activity of LHVgat neurons is increased during thermoregulatory behavior and bidirectionally encodes thermal punishment and reward (P&R). Although this population also regulates feeding and caloric reward, inhibition of parabrachial inputs selectively impaired thermoregulatory behaviors and encoding of thermal stimulus by LHVgat neurons. Furthermore, two-photon calcium imaging revealed a subpopulation of LHVgat neurons bidirectionally encoding thermal P&R, which is engaged during thermoregulatory behavior, but is largely distinct from caloric reward-encoding LHVgat neurons. Our data establish LHVgat neurons as a required neural substrate for behavioral thermoregulation and point to the key role of the thermal P&R-encoding LHVgat subpopulation in thermoregulatory behavior.

Lateral Septum Somatostatin Neurons are Activated by Diverse Stressors.

The lateral septum (LS) is a forebrain structure that has been implicated in a wide range of behavioral and physiological responses to stress. However, the specific populations of neurons in the LS that mediate stress responses remain incompletely understood. Here, we show that neurons in the dorsal lateral septum (LSd) that express the somatostatin gene (hereafter, LSdSst neurons) are activated by diverse stressors. Retrograde tracing from LSdSst neurons revealed that these neurons are directly innervated by neurons in the locus coeruleus (LC), the primary source of norepinephrine well-known to mediate diverse stress-related functions in the brain. Consistently, we found that norepinephrine increased excitatory synaptic transmission onto LSdSst neurons, suggesting the functional connectivity between LSdSst neurons and LC noradrenergic neurons. However, optogenetic stimulation of LSdSst neurons did not affect stress-related behaviors or autonomic functions, likely owing to the functional heterogeneity within this population. Together, our findings show that LSdSst neurons are activated by diverse stressors and suggest that norepinephrine released from the LC may modulate the activity of LSdSst neurons under stressful circumstances.

A neural circuit mechanism for mechanosensory feedback control of ingestion.

Mechanosensory feedback from the digestive tract to the brain is critical for limiting excessive food and water intake, but the underlying gut-brain communication pathways and mechanisms remain poorly understood1-12. Here we show that, in mice, neurons in the parabrachial nucleus that express the prodynorphin gene (hereafter, PBPdyn neurons) monitor the intake of both fluids and solids, using mechanosensory signals that arise from the upper digestive tract. Most individual PBPdyn neurons are activated by ingestion as well as the stimulation of the mouth and stomach, which indicates the representation of integrated sensory signals across distinct parts of the digestive tract. PBPdyn neurons are anatomically connected to the digestive periphery via cranial and spinal pathways; we show that, among these pathways, the vagus nerve conveys stomach-distension signals to PBPdyn neurons. Upon receipt of these signals, these neurons produce aversive and sustained appetite-suppressing signals, which discourages the initiation of feeding and drinking (fully recapitulating the symptoms of gastric distension) in part via signalling to the paraventricular hypothalamus. By contrast, inhibiting the same population of PBPdyn neurons induces overconsumption only if a drive for ingestion exists, which confirms that these neurons mediate negative feedback signalling. Our findings reveal a neural mechanism that underlies the mechanosensory monitoring of ingestion and negative feedback control of intake behaviours upon distension of the digestive tract.