Behavioural Brain Research 224 (2011) 180–188 Contents lists available at ScienceDirect Behavioural Brain Research j ourna l ho me pa ge: www.elsevier.com/locate/bbr Research report Differential effects of maternal immune activation and juvenile stress on anxiety-like behaviour and physiology in adult rats: No evidence for the “double-hit hypothesis” Nicole Yee a,∗ , Adema Ribic a , Christina Coenen de Roo b , Eberhard Fuchs a,c a Clinical Neurobiology Laboratory, German Primate Center, Leibniz Institute for Primate Research, Kellnerweg 4, Göttingen 37077, Germany b Harlan Laboratories B.V., P.O. Box 553, 5800 AN Venray, The Netherlands c Department of Neurology, Medical School, University of Göttingen, Göttingen, Germany a r t i c l e i n f o Article history: Received 27 April 2011 Received in revised form 27 May 2011 Accepted 31 May 2011 Keywords: Maternal immune activation Poly I:C Juvenile stress Double-hit hypothesis Anxiety Depression a b s t r a c t Environmental disruptions can influence neurodevelopment during pre- and postnatal periods. Given such a large time window of opportunity for insult, the “double-hit hypothesis” proposes that exposure to an environmental challenge may impact development such that an individual becomes vulnerable to developing a psychopathology, which then manifests upon exposure to a second challenge later in life. The present study in male rats utilized the framework of the “double-hit hypothesis” to investigate potential compounding effects of maternal immune activation (MIA) during pregnancy and exposure of offspring to stress during juvenility on physiological and behavioural indications of anxiety in adulthood. We used an established rat model of MIA via maternal treatment with polyinosinic:polycytidylic acid (poly I:C) on gestation day 15 in combination with a model of juvenile stress (applied ages 27–29 d) in offspring to explore potential interacting/additive effects. First, we confirmed our employment of the MIA model by replicating previous findings that prenatal treatment with poly I:C caused deficits in sensorimotor gating in adult offspring, as measured by prepulse inhibition. Juvenile stress, on the other hand, had no effect on prepulse inhibition. In terms of anxiety-related behaviour and physiology, we found that prenatal poly I:C alone or in combination with juvenile stress had no effects on body weight, adrenal weight, and plasma concentration of corticosterone and cytokines in adult rats. MIA and juvenile stress increased anxiety-related behaviour on the elevated plus maze, but did so independently of each other. In all, our findings do not support an interaction between MIA and juvenile stress in terms of producing marked changes related to anxiety-like behaviour in adulthood. © 2011 Elsevier B.V. All rights reserved. 1. Introduction Disturbances experienced by a maternal host during pregnancy directly affect the fetal environment and can negatively influence the normal development, physiology and behaviour of offspring [1]. Specifically, these disturbances are forms of prenatal stress, and examples include maternal psychological stress, malnutri- tion or immune activation due to infection. In such situations of extreme challenge, the placental barrier may become compromised and expose the developing fetus to elevated cytokine concentra- tions and stress hormones [1]. This can lead to long-lasting and/or permanent consequences in terms of postnatal brain function in the offspring. Abnormalities in neurodevelopment may predispose individuals to various psychopathologies, including schizophrenia, autism and mood/affective disorders [2]. ∗ Corresponding author. Tel.: +49 551 3851 135; fax: +49 551 3851 307. E-mail address: nyee@cnl-dpz.de (N. Yee). Epidemiological studies show that maternal infection during pregnancy, in particular, enhances the risk for a number of neu- ropsychiatric disorders in offspring, most notably schizophrenia [3]. As such, maternal immune activation (MIA) models have been developed in rodents in attempt to underpin a causal relationship between in utero immune activation and the emergence of adult psychopathology [4,5]. The majority of these studies utilized prena- tal exposure to various immunostimulatory agents (e.g., bacterial endotoxins, lipopolysaccharide, influenza virus) to demonstrate the induction of abnormalities associated with a schizophrenia- related phenotype [6]. Polyinosinic:polycytidylic acid (poly I:C) is a viral mimic that is increasingly being used in studies as an immunostimulatory agent due to its ease of usability from a biosafety standpoint and its precise time-window of action [7]. Poly I:C is a synthetically made double-stranded RNA used to mimic viral exposure because it evokes an immune response without causing the full spectrum of immune reaction normally observed after viral infection (e.g., production of antiviral antibodies). In animals, poly I:C treatment causes acute sickness behaviour, fever and weight 0166-4328/$ – see front matter © 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.bbr.2011.05.040