Reversal learning impairments in the maternal immune activation rat model of schizophrenia.

Abstract

One of the cognitive symptoms observed in schizophrenia is decreased flexibility in several tasks, including reversal learning. Reversal learning has previously been tested in rats following maternal immune activation (MIA), a risk factor for schizophrenia, with varying results. Whereas some previous studies have shown that MIA rats are slower to learn a reversal, others have reported more rapid learning compared with controls. Several of these latter studies have, however, used a T-maze task with aversive, negative reinforcement as a motivating factor. Because most human studies use positive reinforcement in reversal tasks, here we tested whether reinforcement valence might be a critical factor. We ran male MIA and control rats in a T-maze reversal procedure that was very similar to previous studies except that positive, appetitive reinforcement was used for motivation. The results showed that MIA animals performed similarly to controls during training, but in contrast to the previous, aversively motivated T-maze studies, slower reversal learning was observed. These results show that MIA animals are impaired in reversal learning under conditions of positive reinforcement, consistent with the effects observed in individuals with schizophrenia.

Maternal immune activation alters the sequential structure of ultrasonic communications in male rats

“…Furthermore, there was no between-group difference in the proportion of call types and the transition scores themselves were normalised to allow for the fact that calls with a high overall rate are more likely to occur after other calls. Interestingly, one of the significant changes in transition (step down to step down) involved increased repetition of the step-down call type, which suggests that this effect might result from perseveration, which has previously been described in MIA animals ( Kleinmans and Bilkey, 2018 ).…”

“…To induce MIA, female Sprague-Dawley rats were mated at approximately 3-months of age. On gestational day 15, pregnant dams were anesthetised with isoflurane (5% in oxygen) and randomly selected to receive a tail vein injection of either saline dissolved poly I:C (4.0 ​mg/kg) or an equivalent dosage of saline as per our previous studies ( Kleinmans and Bilkey, 2018 ; Wolff and Bilkey, 2015 ). Weaning of their male offspring occurred at week three after parturition, with four to six males retained from each dam.…”

“…MIA has also been examined in animal models, which allow for a more thorough examination of the brain changes that might underlie the disorder. In rodent models, a number of schizophrenia-like changes in behaviour and brain activity, function and neurochemistry have been previously described in the adult offspring of MIA-challenged dams ( Brown and Meyer, 2018 ; Dickerson et al., 2010 ; Estes and McAllister, 2016 ; Kleinmans and Bilkey, 2018 ; Wolff and Bilkey, 2015 ). This includes alterations in interval timing ( Deane et al., 2017 ).…”

Sensory filtering disruption caused by poly I:C - Timing of exposure and other experimental considerations

“…Litter variability has been a topic of discussion in toxicology and neurodevelopmental models for several decades, specifically in relation to models that investigate prenatal exposures such as poly I:C ( Golub and Sobin, 2020 )). Within the poly I:C literature, there is a trend towards increasing the number of litters and reducing the number of pups used per litter, typically 1–2 animals are used per litter (e.g see recent poly I:C literature: Clark et al., 2019 , De Felice et al., 2018 , Di Biase et al., 2020 , Haida et al., 2019 , Kleinmans and Bilkey, 2018 , Purves-Tyson et al., 2019 ; Zhang et al., 2019 ). In this case, within-litter variability has implications for whether the chosen rats are representative of the litter’s phenotype.…”

Disorganization of Oscillatory Activity in Animal Models of Schizophrenia

“…A range of behavioral abnormalities that match the symptomatic profile of schizophrenia have also been observed, including several cognitive deficits that have also been associated with disorganized oscillatory activity (Fatemi and Folsom, 2009;Meyer et al, 2009a,b;Brown and Derkits, 2010), These include reduced PPI (Ozawa et al, 2006;Wolff and Bilkey, 2010;Howland et al, 2012;Zhang and van Praag, 2015;Luchicchi et al, 2016), reduced behavioral flexibility (Zuckerman and Weiner, 2005;Bitanihirwe et al, 2010;Savanthrapadian et al, 2013;Ballendine et al, 2015;Kleinmans and Bilkey, 2018), temporal processing disturbances (Deane et al, 2017), and spatial memory impairments (Meyer et al, 2008;Wolff et al, 2011;Murray et al, 2017).…”