Project Summary
The decision on when and how much to eat is fundamental to an animal’s ability to live, and regulation of feeding
behavior is dictated by complex communications between the gut and the brain. Research on gut-brain neural
communication for the control of feeding behavior has focused almost exclusively on signaling via the vagus
nerve, the fibers of which innervate the gut viscera and project to the hindbrain to influence key brain regions
that drive hunger and satiation. While the vagus nerve plays a fundamental and significant role in nutrient
sensing, it is not the only mechanism through which nutritional information is relayed to the brain. Indeed,
pseudo-unipolar neurons in the dorsal root ganglia (DRG) directly innervate the intestines and relay sensory
input to the spinal cord via the splanchnic nerve. However, compared to the vagus, the role of spinal afferent
pathways in energy balance control is poorly understood and represents a major unexplored area that could lead
to better understanding of gut-brain communication. My Sponsor lab (Alhadeff) recently demonstrated that
blocking spinal afferent signaling decreases in vivo neural activity changes elicited by intestinal glucose in
hypothalamic hunger neurons. Furthermore, our pilot data indicate that DRG neurons are dose-dependently
activated by glucose infused in to the intestine. While these data reveal a spinal gut-brain pathway that is involved
in glucose sensing, the mechanisms through which spinal afferent-mediated nutrient detection occur are
unknown, and there is a critical gap in knowledge regarding the connectivity between the gut and the DRG. As
the first nutrient-sensing site in the intestine, the duodenum sits at a critical junction to sense nutrients and quickly
modulate food intake. Therefore, this proposal investigates the involvement of duodenum-projecting DRG
neurons in intestinal nutrient detection. In the first aim, I will use anatomical tracing to map duodenum to dorsal
root ganglion connections along the thoracic and lumbar regions of the spinal cord. The results from these
experiments will provide important anatomical groundwork to comprehensively characterize nutrient sensing by
spinal afferents. In Aim 2, I will test the specificity with which DRG neurons respond to nutrients. Here, I will use
in vivo 2-photon calcium imaging of DRG neurons in response to infusions of different nutrients into the gut. The
results of these experiments will provide precise temporal information and population dynamics on how DRG
neurons are tuned to detect specific nutrients. The combined expertise of Alhadeff (Sponsor) and Luo (Co-
Sponsor) labs, along with my mentorship committee, will give me ample support and expertise to address the
proposed experiments. These complementary aims will uncover fundamental roles for nutrient sensing by DRG
neurons, a neural population which has previously been underappreciated for its contribution to energy balance
and feeding behavior.
