Clustering of cognitive phenotypes identifies susceptible and resilient offspring in a rat model of maternal immune activation and early-life stress

Maternal Immune Activation Induces Adolescent Cognitive Deficits Preceded by Developmental Perturbations in Cortical Reelin Signalling

“…While the use of IVCs has been shown to increase spontaneous abortion rate and attenuate offspring behavioural effects in GD9 mouse models of poly(I:C)-induced MIA, induction on GD12 using IVCs resulted in no increase in MIA-induced spontaneous abortion, but still induced offspring deficits in working memory, sociability and mean PPI, akin to open-cage-housed GD9 models [ 53 ]. GD12 in mice reflects a developmental period closer to GD15 in rats [ 9 ], illustrating a comparable timing to our established model [ 14 , 15 , 16 , 17 , 49 ]. Further, previous analyses within our group have identified no effects on maternal rearing behaviour or offspring cognition from the use of IVCs [ 54 ].…”

“…All animal procedures adhered to the Animals in Scientific Procedures Act (ASPA) 1986 and were approved by the Animal Welfare and Ethical Review Body (AWERB) at the University of Manchester. All animal work was conducted at the Biological Services Facility (BSF) at the University of Manchester as described previously [ 14 , 15 , 16 , 17 , 49 ]. Briefly, adult Wistar rats were obtained from Charles River Laboratories and housed in single-sex groups within individually ventilated cages (IVCs, Double-Decker Cage, Tecniplast, Buguggiate, Italy) under standard conditions: 12 h light/dark cycles (07:00–19:00/19:00–07:00), 21 ± 2 °C, 55 ± 5% humidity, with ad libitum access to food and water.…”

“…In this context, it is important to appreciate the role that housing may play in any expression changes seen presently. Despite these considerations, and much like the use of IVCs, this methodology has imparted significant effects of MIA on offspring cognition in our group [ 17 , 49 ].…”

“…Further, no studies to date have evaluated epigenetic changes in the Reelin pathway in a MIA model [ 9 ], despite this finding being evidenced in schizophrenia postmortem studies [ 27 , 29 , 30 ]. Hence, following our previous work, which validated a PFC-mediated cognitive deficit in adult female rats exposed to MIA [ 17 ], as well as sex-independent deficits in recognition memory [ 49 ], our aim here was to evaluate the possible role of the Reelin pathway in contributing to these cognitive deficits. Given the wide range of functional roles for Reelin across neurodevelopment, we sought to explore the pathway across both early and late neurodevelopment to determine if, and when, pathological changes occur.…”

Maternal behaviours and adult offspring behavioural deficits are predicted by maternal TNFα concentration in a rat model of neurodevelopmental disorders

“…Surprisingly, there were no effects of MIA on NOR or EPM performance. A recent study has suggested evidence for distinct clustering of cognitive phenotypes in our MIA model, indicating that effects on NOR performance in 'high-risk' individuals may be masked by those with resilience factors born to poly I:C dams (Lorusso et al, 2022). It may be important for future analyses to consider clustering of phenotypes, rather than limiting analysis by treatment group, to identify such effects as well as risk and resilience factors in MIA models.…”