A Rodent Model of Anxiety: The Effect of Perinatal Immune Challenges on Gastrointestinal Inflammation and Integrity

Abstract

Objectives: Gastrointestinal (GI) inflammation and GI integrity deficits are common comorbidities of neuropsychiatric disorders. Ongoing research suggests that these aberrations may be contributing to heightened immune signals that have the potential to disrupt neuronal homeostasis and exacerbate behavioural deficits. The current study aimed to determine whether the well-characterized animal model of neuropsychopathology, the maternal immune activation (MIA) model, produced GI inflammation and integrity disruptions in association with anxiety-like behaviour. Methods: Pregnant Wistar rats were exposed to the viral mimetic polyriboinosinic:polyribocytidilic acid (polyI:C) on gestational days (GD) 10 and 19. Evidence of ANS activation, GI inflammation, and GI barrier integrity was assessed in both neonatal (postnatal day, P7) and adult (P84) offspring. Anxiety-like behaviour was assessed at P100. Results: Neonatal MIA offspring exhibited an altered intestinal inflammatory profile and evidence of an increase in lymphoid aggregates. MIA neonates also displayed disruptions to GI barrier tight junction protein mRNA. In addition, adult MIA offspring exhibited an increase in anxiety-like behaviours. Conclusion: These results indicate that the MIA rat model, which is well documented to produce behavioural, neurochemical, and neuroanatomical abnormalities, also produces GI inflammation and integrity disruptions. We suggest that this model may be a useful tool to elucidate biological pathways associated with neuropsychiatric disorders.

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

“…These findings may demonstrate an amelioration in microbiotic alterations by adulthood. As previous research suggests, a decrease in this bacteria could possibly account for the increased levels of circulating corticosterone and IL6 and CRHR1 mRNA found in the adolescent female MIA-ACE offspring in this study ( Cussotto et al., 2018 ; Hollins et al., 2018 ; Neuman et al., 2015 ).…”

“…In the hypothalamus, the neurotrophin brain-derived neurotrophic factor (BDNF) along with glucocorticoid signalling maintain CRH and glucocorticoid bioavailability ( Jeanneteau et al., 2012 ). Of particular interest, research has found that gut microbiota are involved in regulating the expression of BDNF ( Nemani et al., 2015 ), with alterations in both BDNF expression and gut microbiota found in patients with schizophrenia (reviewed in ( Hollins et al., 2018 )). Research shows that the bacteria B. longum can increase BDNF levels ( Alam et al., 2017 ), decrease circulating corticosterone levels, and reduce schizophrenia-like behaviour ( Orikasa et al., 2016 ).…”

“…Further evidence of a dysregulated GBA in schizophrenia comes from research identifying altered gut bacteria, also a crucial component of the GBA, in patients with the disorder ( Zheng et al., 2019 ). Studies also indicate that gut bacteria can affect the development and regulation of the HPA axis and in turn, influence brain function and behaviour, including neuroendocrine responses to stress ( Hollins et al., 2018 ). Although this may occur via many different mechanisms, one possible option is that this may arise through a weakened intestinal barrier, with evidence of increased markers of intestinal inflammation and bacterial translocation in schizophrenia patients ( Dickerson et al., 2017 ; Nemani et al., 2015 ).…”

“…This in turn can trigger a neural response which then acts in a feedback loop. Figure adapted from ( Hollins et al., 2018 ). …”

The poly(I:C)-induced maternal immune activation model; a systematic review and meta-analysis of cytokine levels in the offspring

“…(2011) Rats Sprague Dawley M Post-weaning (P44) 0.5 IP 15–18 Serum 6 TNF-α Han et al. (2017) Mice ddY NR Post-weaning (P70) 5 IP 12–17 Hip, nucleus accumbens, CA1, CA3, dentate gyrus 5–6 C1q Hollins et al. (2018) Rats Wistar M Pre-weaning (P7)/Post-weaning (P84) 5 IV 10,19 Colon 6 IL-1β, IL-6, TNF-α Horváth et al.…”