Investigating the gut-brain axis in a neurodevelopmental rodent model of schizophrenia

Abstract

Background Although the aetiology of schizophrenia remains unknown, it has been suggested that it might occur in response to alterations in the gut-brain axis (GBA), the bi-directional communication system between the gut and the brain. The current study aimed to determine whether the “two-hit” animal model of neuropsychopathology (maternal immune activation combined with adolescent cannabinoid exposure), produced abnormalities in the GBA Method Pregnant Wistar rats were administered the viral mimetic polyI:C on gestational day 19 and offspring were administered the synthetic cannabinoid HU210 from postnatal days 35–48. Evidence of GBA activation was assessed in the hypothalamus, colon and fecal samples from male and female offspring at adolescence and adulthood Results Findings were sex-specific with adolescent female offspring exhibiting an increased hypothalamic inflammatory profile, increased hypothalamic CRHR1 mRNA, and decreased fecal expression of Bifidobacterium longum , however, no changes were detected in colonic inflammation or integrity. Conclusion These results indicate that the rat two-hit model, documented to produce behavioural and neuroanatomical abnormalities, also produces hypothalamic and microbiota abnormalities. The results also demonstrate significant sex differences, suggesting that this model may be useful for investigating the role of the GBA in the aetiology of neurodevelopmental disorders such as schizophrenia.

Understanding the Role of the Gut Microbiome in Brain Development and Its Association With Neurodevelopmental Psychiatric Disorders

“…MIA during pregnancy has reportedly caused an increase in mesencephalic dopaminergic neurons in the foetal brain, which is associated with excessive dopaminergic signaling in the midbrain area in SCZ ( Winter et al, 2009 ). Besides, in utero MIA precondition offspring exhibit, a triggered HPA-axis stress response when exposed to cannabinoids in adolescence and exhibit SCZ associated behavior in a sex-specific manner with a remarkable decline in Bifidobacterium longum gut abundance ( Katz-Barber et al, 2020 ). Exposure to viral or bacterial pathogens in-utero also has been reported to enhance the risk of developing SCZ.…”

Placental CRH as a Signal of Pregnancy Adversity and Impact on Fetal Neurodevelopment

“…MIA appears to induce dysregulation of the bi-directional gut-brain axis (GBA) in particular the gut microbiome and HPA axis. Pro-inflammatory cytokines can modulate the offspring’s HPA axis activity, in particular CRH-R1 expression shown in rodent environmental ‘two-hit’ insult models ( 94 ), or modify its neuroimmune function and gut microbial colonization ( 95 ). Many studies highlight the role of gut microbiome in health ( 96 ) and disease ( 97 ).…”

Microbiome Profiling Reveals Gut Dysbiosis in the Metabotropic Glutamate Receptor 5 Knockout Mouse Model of Schizophrenia

“…Additionally, the same study showed that adult MIA offspring displayed altered gut microbiota, with differential relative abundance between components of the gut microbiota, including Ruminococcaceae. Likewise, in Wistar rats, an animal model combining MIA with polyI:C and adolescent cannabinoid exposure demonstrated a sex-specific effect, with adolescent female offspring exhibiting decreased fecal levels of Bifidobacterium longum, measured using qPCR (Katz-Barber et al, 2020). While very promising, these aforementioned studies should be interpreted with caution, since recapitulating the complexity of SZ in an animal model is still a challenge, and each study has its own limitations.…”