Abstract

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Anomalies in neural connectivity due to structural modifications related to myelin is involved in a variety of neuropsychiatric disorders (NPDs), such as schizophrenia, autism depression, obsessive–compulsive disorder and attention-deficit hyperactivity disorder (Vanes et al., 2020). Myelin supports the efficiency and rapidity of neuronal signal conduction, facilitating effective functional integration during cognitive processing. Myelination proceeds throughout early life and into early adulthood, coinciding with the very period of enhanced risk for a range of psychiatric disorders (Vanes et al., 2019).

Although most NPDs are thought to arise because of neuronal impairment, increasing evidence also suggest the involvement of oligodendroglial dysfunction (Bøstrand et al., Life (Basel), 2021). The myelin proteome is known to be enriched with several myelin-specific proteins, including myelin basic protein (MBP), and proteolipid protein (PLP) that are abundant in the central, nervous system (CNS; Antontseva et al., 2020). The interaction between the enteric nervous system (ENS) and the CNS is currently starting to emerge. The abundance of immune cells in the gastrointestinal tract, the extensive connectivity of the ENS and its ability to communicate to the CNS make it likely that gut is primarily involved in NPDs development (Dora et al., 2021).

The ENS is composed of different cell populations, including neurons and glial cells. Enteric neurons, beside controlling gut function, have recently been identified as gatekeepers of immune response for their ability to release and respond to several factors which in turn can influence a variety of immune cells (Verheijden et al., 2018). Enteric glial cells (EGCs) not only insulate neurons, since their fibers are non-myelinated, but exert several neuroprotective and neuro-immunomodulatory functions to protect neuronal networks and guarantee gut activity (Cerantola et al., 2020). EGCs and CNS astrocytes exhibit molecular similarities in their electrophysiological properties and express GFAP and S100β proteins. However, EGCs differs from CNS astrocytes for the expression of the transcription factor Sox10, MBP and PLP1, implicated in myelin production, highlighting a genic signature more similar to that of oligodendrocytes and Schwann cells than to astrocytes (Spear et al., 2018; Coelho-Aguiar et al., 2019).

Interestingly, changes in gut microbiota composition have been revealed to affect ENS homeostasis as well as to modify the equilibrium between inflammatory and regulatory host responses. Innate immune response relies on Toll-like receptors (TLRs), which play critical roles in initiating inflammation and promoting adaptive immune responses due to their ability to recognize a wide range of conserved molecular motifs found in microbes (microbial-associated molecular patterns, MAMPs), or damaged cells (damage-associated molecular patterns, DAMPs; Caputi et al., 2017a and 2017b). Among all TLRs, TLR2, a key member of TLR family, is found to be widely expressed in glial cells and neurons and plays a pivotal role in neuroinflammation (Brun et al., 2013). TLR2 deficiency not only leads to neurobehavioral dysfunction (e.g., increased anxiety state and psychotic-like symptoms) but also results in various changes in brain structure and function, such as impaired myelination, and disrupted blood brain barrier integrity (Hu Y et al., 2021).

Following on these findings, we posit that gut dysbiosis causes enteric myelinization changes similar to those seen in NPDs, resulting in ENS neuroinflammation, altered GI motility and impaired cognition, and all these alterations are relying on host-microbiota interactions. In this first part of the proposed research, we have found that in adolescent male mice cuprizone administration causes enteric disrupted myelinization, neuroimmune changes and neuronal loss. These alterations were associated to disrupted morpho-functional gut activity with still no evident signs of cognition impairment.

The aim of the present study was to investigate the impact of the demyelinating process in the structural and functional integrity of the ENS. The demyelinating process was induced by administering normal rodent chow supplemented with 0.25% cuprizone (CPZ) to wild type mice whereas SHAM mice received normal rodent chow with no supplementation. SHAM and CPZ animals were then subjected to: i) in vivo evaluation of health status and intestinal motility, ii) ex vivo functional analysis of ileal excitatory and inhibitory neuromuscular contractility, iii) structural examination of ENS using confocal immunofluorescence, iv) in vivo analysis of behavioral and cognitive deficits.

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