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Mechanisms of Interoceptive Signaling in Mouse Colon

Award Number: R01DK143587
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2026
PERIOD OF PERFORMANCE END DATE: 05/30/2030

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Mechanisms of Interoceptive Signaling in Mouse Colon - PROJECT SUMMARY/ABSTRACT The gastrointestinal (GI) tract is innervated by a complex network that includes the enteric nervous system (ENS), the autonomic nervous system, and the sensory nervous system, comprising both vagal and spinal afferents. Notably, while vagal afferents extensively modulate the upper GI tract, their influence on the distal colon and rectum is minimal. These lower regions are key hubs for generating gut-derived interoceptive signals. Our laboratories focus on uncovering the cellular and molecular mechanisms that mediate mechanosensitivity in the mouse distal colon. We have developed genetic tools that enable precise manipulation of molecularly distinct neuronal populations involved in gut motility, using techniques such as targeted cell ablation and optogenetic activation. Through these efforts, we have identified Piezo2 channels as specialized mechanoreceptors expressed in colon-innervating spinal visceral afferents. Preliminary studies demonstrate that both chemical and mechanical stimulation of the distal colon induce c-Fos expression in a subset of tachykinin receptor 3-positive neurons located in the spinal dorsal horn (Tacr3SDH neurons). Optogenetic stimulation of Tacr3SDH neurons at the L6–S1 spinal level evokes visceromotor responses and aversive behavior, without altering somatosensory processing, suggesting a selective role in visceral interoception. Moreover, similar colonic stimulations increase c-Fos activity in prodynorphin-expressing neurons of the parabrachial nucleus (PdynPBN neurons), implicating this region in processing visceral signals. These findings support our central hypothesis: that a distinct Tacr3SDH-PdynPBN neural circuit mediates interoceptive signaling from the colon. To test this hypothesis, we will investigate whether Tacr3SDH neurons form functional synaptic connections with colon-innervating spinal visceral afferents and project to PdynPBN neurons. We will employ a combination of neural tracing, electrophysiology, and in vivo calcium imaging to map and characterize this pathway. Additionally, we will use intersectional viral genetics to manipulate these neurons selectively and assess their necessity and sufficiency in driving both sensory and affective components of visceral interoception. Through these studies, we aim to delineate the functional architecture of the Tacr3SDH-PdynPBN neuraxis and its role in visceral interoception. The insights gained from these investigations will deepen our understanding of gut- brain communication and may reveal novel therapeutic targets for disorders rooted in disrupted visceral interoceptive processing.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $814,028 )
2026	2026	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	8/18/2026	NEW	$814,028
														Subtotal = $814,028

Grand Total All Awards = $814,028

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Mechanisms of Interoceptive Signaling in Mouse Colon

Award Number: R01DK143587

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/01/2026

PERIOD OF PERFORMANCE END DATE: 05/30/2030

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