Optogenetic screening of the gut-brain axis via an internal light source

The gut-brain axis is implicated in many essential physiological and psychological functions, ranging from feeding, emotion, motivation, to memory. As a critical component of the gut-brain axis, vagal sensory neurons exhibit distinct projection patterns to target specific visceral organs. Electrical stimulation of afferent vagal nerves has been demonstrated to regulate the movement of the gastrointestinal tract, implying the underlying role of the gut-brain axis. However, it remains unknown whether specific projections of vagal sensory neurons in different regions of the gut have distinct functions or synergistically cooperate in the gut-brain axis. A substantial challenge in dissecting the gut-brain axis arises from limited tools for manipulating vagal sensory projections with target specificity in the gut. Therefore, new technologies that can selectively stimulate vagal nerve terminals at different visceral organs are required to fill the knowledge gap of how distinct vagal projections in the gut contribute uniquely to the gut functions via the gut-brain axis.

We aim to conduct optogenetic screening in the gut and dissect the gut-brain axis, by transforming the conventional paradigm of in-vivo light delivery with an internal systemic light source. A noninvasive, implant-free, and tether-free in-vivo light source for optogenetic screening will be developed based on tissue-penetrant near-infrared light and systemically delivered nanoparticles that convert near-infrared light to visible light. Leveraging the endogenous circulatory system, intravenously injected NPs will function as the intravascular light source throughout the entire systemic circulation including the gut. By spatiotemporally controlling visible emission in different regions of the gut, we can selectively stimulate and screen different vagal sensory neurons to identify their independent vs. synergistic contributions to the gut functions. The in-vivo screening platform can be broadly applied to the periphery nervous system, thus potentially leading to a new paradigm for dissecting different neuron subtypes underlying complex functions and behaviors.