Abnormal context–reward associations in an immune-mediated neurodevelopmental mouse model with relevance to schizophrenia

Abstract

Impairments in central reward processing constitute an important aspect of the negative symptoms of schizophrenia. Despite its clinical relevance, the etiology of deficient reward processing in schizophrenia remains largely unknown. Here, we used an epidemiologically informed mouse model of schizophrenia to explore the effects of prenatal immune activation on reward-related functions. The model is based on maternal administration of the viral mimic PolyI:C and has been developed in relation to the epidemiological evidence demonstrating enhanced risk of schizophrenia and related disorders following prenatal maternal infection. We show that prenatal immune activation induces selective deficits in the expression (but not acquisition) of conditioned place preference for a natural reward (sucrose) without changing hedonic or neophobic responses to the reward. On the other hand, prenatal immune activation led to enhanced place preference for the psychostimulant drug cocaine, while it attenuated the locomotor reaction to the drug. The prenatal exposure did not alter negative reinforcement learning as assessed using a contextual fear conditioning paradigm. Our findings suggest that the nature of reward-related abnormalities following prenatal immune challenge depends on the specificity of the reward (natural reward vs drug of abuse) as well as on the valence domain (positive vs negative reinforcement learning). Moreover, our data indicate that reward abnormalities emerging in prenatally immune-challenged offspring may, at least in part, stem from an inability to retrieve previously established context–reward associations and to integrate such information for appropriate goal-directed behavior.

Maternal infection and stress during pregnancy and depressive symptoms in adolescent offspring

“…Both animal and human studies suggest that maternal timing of infection during mid-gestation (i.e., the second trimester) may be particularly relevant to the development of psychopathology in offspring (reviewed in (Boksa, 2010)). In rodents, experiments using poly[I:C] models of MIA suggest discrete windows of in utero exposure to infection may determine specificity of subsequent disorders in offspring with exposure at times corresponding to the second trimester in humans linked to depressive phenotypes, such as anhedonia and negative symptoms (Bitanihirwe et al, 2010; Labouesse et al, 2015). …”

Phosphorylated SNAP25 in the CA1 regulates morphine‐associated contextual memory retrieval via increasing GluN2B‐NMDAR surface localization

“…; Zhai et al . ; Labouesse, Langhans, & Meyer ). The CPP apparatus is the same as mentioned previously.…”

Schizophrenia and drug addiction comorbidity: recent advances in our understanding of behavioural susceptibility and neural mechanisms

“…Mice prenatally exposed to Poly I:C exhibit enhanced cocaine reward in CPP, indicating stronger cocaine context-reward associations [91]. Despite elevated cocaine context-reward associations, Poly I:C treated mice exhibit reduced cocaine-induced locomotor activity, which may indicate lower dopamine transporter or dopamine receptor availability in brain regions such as the VTA or striatum [91]. Prenatal Poly I:C treatment in rats also enhances cross-sensitization to cocaine after behavioural sensitization to amphetamine, suggesting elevated susceptibility to other stimulant drugs following repeated amphetamine administration [89].…”

“…Mice prenatally exposed to Poly I:C exhibit enhanced cocaine reward in CPP, indicating stronger cocaine context-reward associations [91]. Despite elevated cocaine context-reward associations, Poly I:C treated mice exhibit reduced cocaine-induced locomotor activity, which may indicate lower dopamine transporter or dopamine receptor availability in brain regions such as the VTA or striatum [91].…”