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How Smooth Muscle Contractions Shape the Developing Enteric Nervous System.

ABSTRACT: Neurons and glia of the enteric nervous system (ENS) are constantly subject to mechanical stress stemming from contractions of the gut wall or pressure of the bolus, both in adulthood and during embryonic development. Because it is known that mechanical forces can have long reaching effects on neural growth, we investigate here how contractions of the circular smooth muscle of the gut impact morphogenesis of the developing fetal ENS, in chicken and mouse embryos. We find that the number of enteric ganglia is fixed early in development and that subsequent ENS morphogenesis consists in the anisotropic expansion of a hexagonal honeycomb (chicken) or a square (mouse) lattice, without de-novo ganglion formation. We image the deformations of the ENS during spontaneous myogenic motility and show that circular smooth muscle contractile waves induce longitudinal strain on the ENS network; we rationalize this behavior by mechanical finite element modeling of the incompressible gut wall. We find that the longitudinal anisotropy of the ENS vanishes when contractile waves are suppressed in organ culture, showing that these contractile forces play a key role in sculpting the developing ENS. We conclude by summarizing different key events in the fetal development of the ENS and the role played by mechanics in the morphogenesis of this unique nerve network.

SUBMITTER: Chevalier NR

PROVIDER: S-EPMC8206791 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The enteric nervous system (ENS) contains millions of neurons essential for organization of motor behavior of the intestine. It is well established that the large intestine requires ENS activity to drive propulsive motor behaviors. However, the firing pattern of the ENS underlying propagating neurogenic contractions of the large intestine remains unknown. To identify this, we used high-resolution neuronal imaging with electrophysiology from neighboring smooth muscle. Myoelectric activity underlying propagating neurogenic contractions along murine large intestine [also referred to as colonic migrating motor complexes, (CMMCs)] consisted of prolonged bursts of rhythmic depolarizations at a frequency of ∼2 Hz. Temporal coordination of this activity in the smooth muscle over large spatial fields (∼7 mm, longitudinally) was dependent on the ENS. During quiescent periods between neurogenic contractions, recordings from large populations of enteric neurons, in mice of either sex, revealed ongoing activity. The onset of neurogenic contractions was characterized by the emergence of temporally synchronized activity across large populations of excitatory and inhibitory neurons. This neuronal firing pattern was rhythmic and temporally synchronized across large numbers of ganglia at ∼2 Hz. ENS activation preceded smooth muscle depolarization, indicating rhythmic depolarizations in smooth muscle were controlled by firing of enteric neurons. The cyclical emergence of temporally coordinated firing of large populations of enteric neurons represents a unique neural motor pattern outside the CNS. This is the first direct observation of rhythmic firing in the ENS underlying rhythmic electrical depolarizations in smooth muscle. The pattern of neuronal activity we identified underlies the generation of CMMCs.SIGNIFICANCE STATEMENT How the enteric nervous system (ENS) generates neurogenic contractions of smooth muscle in the gastrointestinal (GI) tract has been a long-standing mystery in vertebrates. It is well known that myogenic pacemaker cells exist in the GI tract [called interstitial cells of Cajal (ICCs)] that generate rhythmic myogenic contractions. However, the mechanisms underlying the generation of rhythmic neurogenic contractions of smooth muscle in the GI tract remains unknown. We developed a high-resolution neuronal imaging method with electrophysiology to address this issue. This technique revealed a novel pattern of rhythmic coordinated neuronal firing in the ENS that has never been identified. Rhythmic neuronal firing in the ENS was found to generate rhythmic neurogenic depolarizations in smooth muscle that underlie contraction of the GI tract.

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How Smooth Muscle Contractions Shape the Developing Enteric Nervous System.

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