DAM RESPONSE TO TREATMENT, RATHER THAN TREATMENT GROUP, PREDICTS OFFSPRING SPATIAL MEMORY DEFICITS IN A RAT MODEL OF NEURODEVELOPMENTAL DISORDERS

Exposure to prenatal stressors such as maternal immune activation (MIA) conveys increased risk for neurodevelopmental disorders. MIA is modelled preclinically via gestational administration of the viral mimetic polyinosinic:polycytidylic acid (PIC), impairing cognition in susceptible offspring. Here, we investigated how individual responses to prenatal stressors affects spatial memory in adolescent rats. Seven pregnant Wistar dams were injected with PIC (10mg/kg in 0.9% saline; N=3) or vehicle (0.9% saline; N=4) on gestational day (GD)15, followed by tail-vein blood sampling 3h post-injection. Four additional untreated control dams underwent neither procedure. Treatment response severity was inferred from dam weight-change measured 24h post-injection. Object Location (OL) testing was conducted on postnatal day (PND)42-50: offspring (N=92) explored two identical objects (5 min) before removal to a holding box (5 min) and returning to the testing area (3 min) where one object had moved. The ratio of time spent exploring novel versus familiar object locations was calculated as Discrimination Index (DI), with DI>0 indicating novelty preference, thus intact spatial memory. One-sample t-tests compared group DIs to zero, finding significant novelty preference in untreated controls (t(21)=3.189, p=0.004) but not vehicle or PIC. Linear mixed model analysis found significant effects of offspring sex (F(1,29)=4.268,p=0.042) and dam weight-loss (F(1,89)=5.321,p=0.023) on offspring OL DI. Dam weight-loss significantly predicted OL DI in males (r=0.321,p=0.026) but not females. Dam treatment response, rather than treatment group, was significantly associated with offspring spatial memory, highlighting the role of individual responses to prenatal stressors and the susceptibility of this cognitive domain to disruption following prenatal stress.