Illuminating a Gut-Brain Neural Path for Sensory Signaling and Pathogens

Lay Summary

Could eating and anxiety disorders be treated by targeting a neural circuit in the gut?

The Investigators will use two optical imaging technologies in mice to explore whether a neural circuit that connects the gut to the brain may be the source of eating and anxiety-like disorders.

The vagus nerve, the longest nerve in the human body, connects the brain with the gut. Investigators recently discovered that the vagus nerve forms a sensory circuit with a specific population of hormone-producing cells in the gut. The cells are called enteroendocrine and appear to send electrochemical signals, via the vagus nerve, into an area of the brain’s hypothalamus that controls eating and mood behaviors. These discoveries provide the opportunity to determine how stimuli from food and gut microbes may alter basic brain behaviors, such as the desire to eat or mood disorders.

The investigators hypothesize that sensory signals from the enteroendocrine cells are converted into electrochemical signals, passed to the vagus nerve and sent to the hypothalamus where these signals modify eating and anxiety-like behaviors. They will test this hypothesis in mice using optical imaging techniques, traditionally used to study brain neural circuits, now adapted to study gut neural circuits.

One technique is two-photon imaging. Two-photon microscopy, in conjunction genetically encoded calcium indicators, allows imaging the function of specific cells of a neural circuit in awake, behaving animals. The other technique is optogenetics. It allows to control specific cells by light to dissect their contribution to the behavior. Using both two-photon microscopy and optogenetics, the investigators will define the neurotransmission between enteroendocrine cells and the vagus nerve, and establish the role of this circuit in food intake, food preference, and anxiety-like behaviors in the animal model. The findings would be a scientific platform for future translation into human treatment studies.

Significance: If their hypotheses are confirmed, the results would spur a fundamental shift towards identifying experimental therapies that target this neural circuit in the gut to modulate eating and anxiety-like behavioral disorders of the brain.

Abstract

Illuminating a gut-brain neural path for sensory signaling and pathogens

The gut-brain connection is emerging as a target to treat brain diseases and behavioral disorders. Mood and anxiety behaviors are clearly associated with vagal nerve fibers. Indeed, chronic depression is often treated by broad electrical stimulation of the entire vagal nerve. Unfortunately, the procedure is not selective and unwanted side effects often eclipse its benefits. Therapies therefore depend on a deeper understanding of the sensory neural circuits transducing stimuli from the surface of the gut to the brain. Our brain senses stimuli from surfaces of the body through innervated epithelial transducers. For example, skin Merkel cells synapse with somatosensory afferents to allow us to discriminate fine textures. Likewise, tongue taste cells synapse with facial and vagal nerve fibers to allow us to perceive flavor. But in the gut’s surface, stimuli are thought to be transduced to nerves only by hormones, such as cholecystokinin (CCK) and peptide YY (PYY), and not through direct innervation of an epithelial sensor. The source of these hormones, and hence the name, is the enteroendocrine cell. Recently, we discovered that the vagus forms a neuroepithelial circuit with a specific population of enteroendocrine cells. We uncovered this novel gut-to-brain neural circuit using the neurotropic rabies virus. This finding opened the possibility that this neural circuit may serve as a gut portal for pathogens to enter the brain. Here, we propose to define the physiological function of this gut-to-brain neural circuit in eating and anxiety-like behaviors. The rationale is that by defining the function of the circuit in the context of behavior, subsequent studies could focus on targeting a neural circuit in the gut to modulate behavioral disorders of the brain. Our hypothesis is that sensory transduction between enteroendocrine cells and the vagus nerve modulate eating and anxiety-like behaviors. We will test this hypothesis in two specific aims: first, we will define the neurotransmission between enteroendocrine cells and the vagus nerve; and second, we will establish the role of the circuit in food intake, food preference, and anxiety-like behaviors. Our methods include optogenetic stimulation and intra-vital multiphoton imaging, which are two advanced optical methods for the study of neural circuits. These methods were developed to study brain neural circuits and we have adapted them to the study of this gut-to-brain neural circuit.