New discovery challenges long-held views of the ‘second brain’

The findings may pave the way for better treatments for digestive problems.

after your gut. loss of your appetite Brave move. Although we often think of the intestine as merely a digestive tool, these common expressions reflect the central role the intestine plays in a much broader range of basic functions.

The entire digestive system is lined with the enteric nervous system (ENS), which is an extensive network of millions of neurons and glia, two basic cell types also found in the central nervous system. Although it is often called the second brain, the central nervous system not only generates the same neurotransmitters, but actually predates the development of the central nervous system in the brain.

Central nervous system functions are essential to life and extend well beyond digestion, as they regulate immunity and intestinal secretions, and enable the complex two-way communication between the gut and the brain. This is why a happy gut coexists with a happy brain, and why digestive issues can lead to changes in mood and behavior.

Since the mid-twenties^y In the 20th century, scientists believed that the central nervous system is derived from the neural crest before birth and remains unchanged thereafter. Now, in a paper published in the journal eLifeResearchers at Beth Israel Deaconess Medical Center (BIDMC) present a completely new model that describes a developmental pathway by which central nervous system development continues after birth in mice and human tissue samples.

This discovery overturns decades of scientific dogma about the basic biology of neuroscience and the central nervous system, by showing for the first time evidence of a non-ectodermal and mesoderm origin for large numbers of postnatally born enteric neurons. The results show the importance of these neurons in the maturation and aging of the central nervous system in health and disease.

“These findings indicate for the first time that the mesoderm is an important source of neurons in the body’s second largest nervous system,” said Subhash Kulkarni, PhD, a scientist at BIDMC and assistant professor in the Department of Neuroscience. Medical Sciences at Harvard Medical School. “How we mature and how we age is central to our understanding of health and disease in our rapidly aging population. An increased proportion of neurons from the mesoderm lineage is a natural consequence of maturation and aging; moreover, this lineage is expected to have points Obvious vulnerability to disease.

Using transgenic mouse models, high-resolution microscopy, and genetic analyses, Kulkarni and colleagues analyzed neuronal populations in the central nervous system in adult mice and human tissues. Using mouse models, the team found that although CNS cells after early birth were of the expected neural crest lineage, this pattern changed rapidly as the animal matured. Kulkarni and colleagues document the arrival and continued expansion of a new group of enteric neurons derived from the mesoderm, the same lineage that gives rise to muscle and heart cells.

This newly discovered population of mesoderm-derived neurons expanded with age, making up one-third of all enteric neurons in adolescent mice, half of all enteric neurons in adult mice, and eventually outnumbering the original enteric neurons derived from neural crest. in aging mice.

By evaluating the molecular signature of these neurons, the team identified novel cellular markers that have been used to identify this group of mesoderm-derived neurons in human intestinal tissue. These markers also provided drug targets, which the researchers used to not only manipulate the mesenchymal lineage of neurons in adolescent mice, but also to reduce their predominant ratios in the gut of aged mice to treat age-related slowing of bowel movements.

Kulkarni added: “We can now work to understand how these findings can be translated into human systems to provide a disease-modifying treatment for elderly patients whose main complaint often involves diseases of the gastrointestinal tract.” “By reversing one of the biggest dogmas in neuroscience, we are now in uncharted territory, and at the same time, we have a great opportunity to understand this hidden basic, translational, and clinical biology of neurons. Newly discovered neuronal lineages offer us potential new drug targets that could help numbers large number of patients.

Reference: “Age-Related Changes in Lineage Composition of the Enteric Nervous System Regulate Intestinal Health and Disease” by Subhash Kulkarni, Monali Saha, Jared Slossberg, Alpana Singh, Sushma Nagaraj, Laren Baker, Qingxiu Zhang, Alicia Bukowski, Chulon Wang, Jusheng Liu, Gina Lesser Mithra Kumar, Shriya Bakhshi, Matthew Anderson, Mark Lewandowski, Elizabeth Vincent, Loyal A. Jove and Pankaj Jay Pasrecha, Aug 7, 2023, Available here. eLife.
doi: 10.7554/eLife.88051.1

Co-authors included Monali Saha, Jared Slossberg, Alpana Singh, Sushma Nagaraj, Qingxiu Zhang, Alicia Bukowski, Zulun Wang, Guosheng Liu, Jenna Lesser, Mithra Kumar, Shriya Bakhshi, Elizabeth Vincent, Loyal A. Goff of the Johns Hopkins University School. from medicine; Laraine Baker and Stanford University School of Medicine; Matthew Anderson and Mark Lewandowski of the National Cancer Institute Cancer Research Center; and Pankaj Jay Pasresha of the Mayo Clinic.

Microscopy was performed on a Ross Imaging Core at the Johns Hopkins University Hopkins County Gastroenterology Center (P30DK089502) using an Olympus FV 3000rs (acquired with NIH-NIDDK grant S10 OD025244). 10X Genomics Chromium processing of scRNAseq was performed in GRCF Core and sequencing was performed in CIDR core at Johns Hopkins University. This work was supported by a grant from the Ludwig Foundation, a grant from the NIA (R01AG066768), a pilot award from the Hopkins Digestive Diseases Center for Basic and Translational Research grant (P30DK089502), a pilot award from the Diacomp Initiative through Augusta University; the Johns Hopkins Catalyst Prize; Maryland Genetics, Epidemiology, and Medicine Training Program sponsored by the Burroughs Welcome Fund; and the Hopkins County Gastroenterology Center at Johns Hopkins University (P30DK089502); Nidec (R01DK080920); Maryland Stem Cell Research Foundation (MSCRF130005), and a grant from the AMOS family.