Biology subjects

Lever, T. E.

Publications and source records attributed to Lever, T. E..

3 recordsLinked to original sources

bioRxiv2026

Functional segregation of body-brain signals in the area postrema

Nausea arises from activation of specialized neurons in the area postrema (AP)1-8. The AP also mediates much of the satiety produced by GLP1R agonists9-12, suggesting a broader role in non-aversive physiology, yet the functions of AP cell types are not well understood. Here, we have used optical recordings in behaving mice to systematically define the natural regulation of an array of AP neurons, including the cell types that are principal targets of widely-used weight loss drugs. We discover that neurons expressing GFRAL, the receptor for the sickness-related hormone GDF15, are unexpectedly activated when mice consume food rich in fat. This fat-specific GFRAL neuron activation is required for fat satiation but does not involve GDF15 or canonical gut-brain pathways. Instead, "anti-nausea" neurons expressing GIPR, which directly inhibit GFRAL neurons, are selectively activated by sugar, enabling macronutrient-specific gating of GFRAL responses. In addition, we show that CALCR neurons link intestinal hyperosmolality to the suppression of feeding, whereas PRLHR neurons respond to changes in blood volume and pressure. These findings reveal a broad role for AP cell types in sensing and responding to physiologic signals unrelated to nausea. They also reveal that GFRAL and GIPR neurons, which are key targets of the weight-loss drug tirzepatide, have a natural function in sensing ingestion of fat and sugar, respectively.

neuroscience↗

bioRxiv2025

Brainstem sensing of multiple body signals during food consumption

Studies of body-to-brain communication often examine one stimulus or organ at a time, yet the brain must integrate many body signals during behavior. For example, food consumption generates diverse oral and post-oral chemical and mechanical signals transduced by well-characterized peripheral neuronal pathways. Far less is known about how these and other bodily signals are integrated and organized in the brainstem lateral parabrachial nucleus (LPBN), a key interoceptive sensory hub. We established methods to image the activity of 1000s of neurons throughout a large region of mouse LPBN. Food consumption drove a seconds-long wave of activity across LPBN, with dynamics mirroring the movement of food through the upper gastrointestinal tract observed using X-ray fluoroscopy. By imaging the same neurons across days, we found that spatially clustered subsets of neurons encoded oral signals, stomach filling, visceral malaise, arousal, and/or body movement. Moreover, only certain subsets were modulated by cortical input. Together, these experiments reveal a functional specialization in the LPBN that integrates contextual information from the body to guide behavior.

neuroscience↗

bioRxiv2022

Prox2+ and Runx3+ neurons regulate esophageal motility

Sensory neurons of the vagus nerve monitor distention and stretch in the gastrointestinal tract. Major efforts are underway to assign physiological functions to the many distinct subtypes of vagal sensory neurons. Here, we used genetically guided anatomical tracing, optogenetics and electrophysiology to identify and characterize three vagal sensory neuronal subtypes expressing Prox2 and Runx3. We show that these neuronal subtypes innervate the esophagus and stomach where they display regionalized innervation patterns. Their electrophysiological analysis showed that they are all low threshold mechanoreceptors, but possess different adaptation properties. Lastly, genetic ablation of Prox2+ and Runx3+ neurons demonstrated their essential roles for esophageal peristalsis and swallowing in freely behaving animals. Our work reveals the identity and function of the vagal neurons that provide mechanosensory feedback from the esophagus to the brain, and could lead to better understanding and treatment of esophageal motility disorders.

neuroscience↗