Prospective Analysis of the Effects of Maternal Immune Activation on Rat Cytokines during Pregnancy and Behavior of the Male Offspring Relevant to Schizophrenia

Abstract

Influenza during pregnancy is associated with the development of psychopathology in the offspring. We sought to determine whether maternal cytokines produced following administration of viral mimetic polyinosinic-polycytidylic acid (polyI:C) to pregnant rats were predictive of behavioral abnormalities in the adult offspring. Timed-pregnant Sprague Dawley rats received a single intravenous injection of 4-mg/kg polyI:C or saline on gestational day (GD)15. Blood was collected 3 h later for serum analysis of cytokine levels with ELISA. Male offspring were tested in a battery of behavioral tests during adulthood and behavior was correlated with maternal cytokine levels. Maternal serum levels of CXCL1 and interleukin (IL)-6, but not tumor necrosis factor (TNF)-α or CXCL2, were elevated in polyI:C-treated dams. PolyI:C-treated dams experienced post-treatment weight loss and polyI:C pups were smaller than controls at postnatal day (PND)1. Various behavior alterations were seen in the polyI:C-treated offspring. Male polyI:C offspring had enhanced MK-801-induced locomotion, and reduced sociability. PolyI:C offspring failed to display crossmodal and visual memory, and oddity preference was also impaired. Set-shifting, assessed with a lever-based operant conditioning task, was facilitated while touchscreen-based reversal learning was impaired. Correlations were found between maternal serum concentrations of CXCL1, acute maternal temperature and body weight changes, neonatal pup mass, and odd object discrimination and social behavior. Overall, while the offspring of polyI:C-treated rats displayed behavior abnormalities, maternal serum cytokines were not related to the long-term behavior changes in the offspring. Maternal sickness effects and neonatal pup size may be better indicators of later effects of maternal inflammation in the offspring.

Impaired Cognitive Function after Perineuronal Net Degradation in the Medial Prefrontal Cortex

“…The battery of tasks used in the present study was developed from previous research conducted to assess behavioral effects in the offspring of rats subjected to treatment with polyI:C during pregnancy. As the offspring of polyI:C-treated dams display altered behavior in these tasks (Howland et al, 2012; Zhang et al, 2012; Ballendine et al, 2015; Lins et al, 2018) and have reduced PNNs in mPFC (Paylor et al, 2016), we reasoned it would be valuable to assess behavior in the same tasks following ChABC infusions in young adulthood. In general, behavior of the PEN-treated rats was similar to that previously reported for these tasks (Ballendine et al, 2015; Marks et al, 2016; Lins et al, 2018); thus, we are confident in our testing protocols for these groups of rats.…”

“…Odd object preference was reported as a percentage of the total time exploring the odd object. Note that 25% is chance performance in this task (Lins et al, 2018).…”

“…In Figure 5, in addition to unpaired Student’s t tests, we used one-sample t tests against chance performance to probe animals’ performance on object recognition. One-sample t tests to chance performance are frequently used in behavioral neuroscience to determine whether performance of a given group differs significantly from chance (Gervais et al, 2016; Jacklin et al, 2016; Lins et al, 2018).…”

“…This treatment has been used extensively to degrade CSPGs in PNNs and the surrounding interstitial matrix (Fawcett, 2015). After injection, we assessed cognitive function using tasks where performance is impaired in the offspring of rats subjected to polyI:C during pregnancy, including altered object oddity preference, recognition memory, sensorimotor gating, and cognitive flexibility [set-shifting (SS) and reversal learning; Bissonette et al, 2013; Yang et al, 2014; Ballendine et al, 2015; Latif-Hernandez et al, 2016; Kamiński et al, 2017; Lins et al, 2018]. We found that ChABC treatment reduced overall extracellular matrix staining within the mPFC as well as a reduced density of PNNs.…”

Environmental influences on placental programming and offspring outcomes following maternal immune activation

“…For example, using a poly I:C MIA model (Patrich et al, 2016), juvenile male rats showed depression in hippocampal excitatory transmission, an effect that did not appear in poly I:C exposed females until adulthood. Moreover, while male (but not female) exposed poly I:C offspring displayed disrupted startle responses to acoustic stimuli, both sexes showed impairments in sociability, visual discrimination and novel object preferences (Lins et al, 2018;Lins et al, 2019). Reported sex differences are likely due to timing of infection, since male and female brains do not develop at the same pace (Anderson, 2003).…”