The gastrointestinal (GI) tract is the only abdominal organ that has evolved with its own enteric nervous system
(ENS) fully contained within the gut wall, also known as the “second brain” in the gut. Our long-term goal is to
understand how the intrinsic primary sensory neurons (IPANs) in the ENS detect and respond to both physical
and chemical cues in the gut lumen and control propulsion of content in the colon.
Although known for about 25 years, the IPANs are still a subset of the most mysterious neurons in the ENS
because how they participate in coordinated muscle movements (motility), regulate immune cell function
(immunity) and maintain integrity of intestinal barrier is not completely understood. Equally as mysterious is
whether the IPANs can fulfil the function as a “pattern generator” and can control the rhythmicity of cyclical
propagating contractions along the colon. This is largely due to a lack of tools that can be used to selectively
manipulate the excitability of specific classes of enteric neurons and any drugs that have been tried to
stimulate or block activity in IPANs will likely act on many other types of neurons (or non-neuronal cells),
making interpretation of the results unclear.
In pilot studies, we have generated critical resources enabling us to identify and selectively targeting the ß-
CGRP-expressing (ß-CGRP+) IPANs. By using these unique resources, we will be able to ask important
questions regarding the roles of the ß-CGRP+ IPANs in the ENS: What role the ß-CGRP+ IPANs have in the
propagation of neural activity along the gut? Are these IPANs activated by both mechanical and chemical cues
in the gut lumen? Can these IPANs serve as cellular sensors for distinct microbiota-derived metabolites?
This proposal represents a major technical advance by using cutting-edge neurogenetic approaches which
make it possible to genetically target and determine the functionality of the ß-CGRP+ IPANs in the ENS both
ex vivo and in vivo, providing the first insights into how selective activation and inhibition of the ß-CGRP+
IPANs in the ENS affects GI-motility. This information will advance our understanding of the inner workings of
the ENS and shed new insights on the development of novel strategies for the treatment of motility-related GI
disorders by targeting the IPANs in the ENS.