Immune Activation in Pregnant Rats Affects Brain Glucose Consumption, Anxiety-like Behaviour and Recognition Memory in their Male Offspring

Abstract

Purpose Prenatal infection during pregnancy is a risk factor for schizophrenia, as well as for other developmental psychiatric disorders, such as autism and bipolar disorder. Schizophrenia patients were reported to have altered brain metabolism and neuroinflammation. However, the link between prenatal infection, altered brain inflammation and metabolism, and schizophrenia remains unclear. In this project, we aimed to evaluate whether there are changes in brain glucose consumption and microglia activation in the offspring of pregnant rats exposed to maternal immune activation (MIA), and if so, whether these changes occur before or after the initiation of schizophrenia-like behaviour. Procedures Pregnant rats were treated with the viral mimic polyinosinic-polycytidylic acid (MIA group) or saline (control group) on gestational day 15. Static PET scans of the male offspring were acquired on postnatal day (PND) 21, 60, and 90, using [11C]-PK11195 and deoxy-2-[18F]fluoro-D-glucose ([18F]-FDG) as tracers to measure TSPO expression in activated microglia and brain glucose consumption, respectively. On PND60 and PND90, anxiety-like behaviour, recognition memory, and sensorimotor gating were measured using the open field test (OFT), novel object recognition test (NOR), and prepulse inhibition test (PPI). Results [18F]-FDG PET demonstrated that MIA offspring displayed higher brain glucose consumption in the whole brain after weaning (p = 0.017), and in the frontal cortex during late adolescence (p = 0.001) and adulthood (p = 0.037) than control rats. [11C]-PK11195 PET did not reveal any changes in TSPO expression in MIA offspring. Prenatal infection induced age-related behavioural alterations. Adolescent MIA offspring displayed a more anxious state in the OFT than controls (p = 0.042). Adult MIA offspring showed recognition memory deficits in the NOR (p = 0.003). Our study did not show any PPI deficits. Conclusions Our results suggest that prenatal immune activation changed neurodevelopment, resulting in increased brain glucose consumption, but not in microglia activation. The increased brain glucose consumption in the frontal cortex of MIA offspring remained until adulthood and was associated with increased anxiety-like behaviour during adolescence and recognition memory deficits in adulthood.

The Poly I:C maternal immune stimulation model shows unique patterns of brain metabolism, morphometry, and plasticity in female rats

“…Our results showed a significant effect of the PND factor in global brain metabolism, with higher values in PND100 vs. PND35, regardless of phenotype. These results are similar to that found by Guerrin et al ( 2022 ), showing a progressive increase of brain metabolism with age in the frontal cortex in MIS male offspring. Besides, voxel-wise results showed increased FDG uptake in the cerebellum of MIS adolescent females compared to Saline animals, but this modulation was not present in adulthood.…”

“…The cerebellar metabolic changes that we observed are relatively controversial. On the one hand, they mimic the hypermetabolism shown in males at PND21, which is not present in older ages (Guerrin et al, 2022) but highly contrast with the metabolic reduction found in males of the same age (i.e., PND35; Hadar et al, 2015). Therefore, the temporal nature of this metabolic feature could be indicative of the delayed neurodevelopmental impairment in females, implying a delay in achieving the same cerebellar metabolic reduction as observed in males.…”

“…In fact, this effect coincides with the well-known delay in the age of symptom onset in women compared to men (Riecher-Rossler and Häfner, 2000 ; Hafner, 2003 ), which has also been well-ratified in the MIS-Poly I:C model (Piontkewitz et al, 2012 ). This delayed neurodevelopmental impairment may also explain the reduced thalamic metabolism observed in adult females of the MIS group, which again contrasts with the hypermetabolic pattern observed in males in early adolescence and adulthood (Hadar et al, 2015 ; Guerrin et al, 2022 ). In this respect, thalamic hypermetabolism has been associated with psychotic/positive symptoms in schizophrenia and related disorders (Silbersweig et al, 1995 ; Soyka et al, 2005 ), and their absence in females may be related to the later onset of these symptoms (Piontkewitz et al, 2012 ).…”

Maternal immune activation induces sex-dependent behavioral differences in a rat model of schizophrenia

“…Even though the research results may differ across the specific Poly (I: C) schemes in different studies, the aberrant cognitive behaviors of offspring seemed to be manifested at a certain stage of growth (44,45). Thus, the existence of the behaviors related to cognitive dysfunction helped to confirm harmful factors from the previous maternal Poly (I: C) exposure that caused perturbed neurodevelopment in offspring.…”