Circuit-specific enteric #glia regulate #intestinal motor neurocircuits

Neurons have long been considered the main active cell type within the circuitry of the enteric nervous system (ENS), giving rise to a neurocentric paradigm that has tended to overlook the role of enteric glia as key regulators of gut motility. Understanding how simple synapse-level interactions give rise to complex, network-level behaviors remains a fundamental problem in neurogastroenterology. We show that enteric glia and neurons interact in a cell- and network-specific manner and that enteric glia display functional heterogeneity based on selective signaling with particular neuron subtypes and circuits belonging to overlapping ascending, descending, and circumferential pathways of the ENS. Enteric glia thus function as logic gates to modify neural network activity through purinergic and cholinergic mechanisms.

Glia in the central nervous system exert precise spatial and temporal regulation over neural circuitry on a synapse-specific basis, but it is unclear if peripheral glia share this exquisite capacity to sense and modulate circuit activity. In the enteric nervous system (ENS), glia control gastrointestinal motility through bidirectional communication with surrounding neurons. We combined glial chemogenetics with genetically encoded calcium indicators expressed in enteric neurons and glia to study network-level activity in the intact myenteric plexus of the proximal colon. Stimulation of neural fiber tracts projecting in aboral, oral, and circumferential directions activated distinct populations of enteric glia. The majority of glia responded to both oral and aboral stimulation and circumferential pathways, while smaller subpopulations were activated only by ascending and descending pathways.

Cholinergic signaling functionally specifies glia to the descending circuitry, and this network plays an important role in repressing the activity of descending neural pathways, with some degree of cross-inhibition imposed upon the ascending pathway. Glial recruitment by purinergic signaling functions to enhance activity within ascending circuit pathways and constrain activity within descending networks. Pharmacological manipulation of glial purinergic and cholinergic signaling differentially altered neuronal responses in these circuits in a sex-dependent manner.

Collectively, our findings establish that the balance between purinergic and cholinergic signaling may differentially control specific circuit activity through selective signaling between networks of enteric neurons and glia. Thus, enteric glia regulate the ENS circuitry in a network-specific manner, providing profound insights into the functional breadth and versatility of peripheral glia.