Modeling psychotic and cognitive symptoms of affective disorders: Disrupted latent inhibition and reversal learning deficits in highly stress reactive mice

Abstract

Increased stress reactivity has repeatedly been reported in patients suffering from psychiatric diseases including schizophrenia and major depression. These disorders also have other symptoms in common, such as cognitive deficits and psychotic-like behavior. We have therefore investigated if increased stress reactivity is associated with these phenotypic endpoints in an animal model of affective disorders. The stress reactivity mouse model used in this study consists of three CD-1-derived mouse lines, that have been selectively bred for high (HR), intermediate (IR) or low (LR) stress reactivity. Male mice from these three breeding lines were subjected to a reversal learning task and latent inhibition (Li) was assessed using a conditioned taste aversion paradigm. Furthermore, as the dopaminergic system is involved in both Li and reversal learning, the dopamine 1 receptor (D1R), dopamine 2 receptor (D2R) and dopamine transporter (DAT) mRNA expression levels were assessed in relevant brain areas of these animals. The results demonstrate that HR mice show perseveration in the reversal learning task and have disrupted Li. Furthermore, compared to LR mice, HR mice have decreased D2R mRNA levels in the ventral tegmental area, as well as decreased D1R mRNA levels in the cingulate cortex, and an increased expression of D2R mRNA in the nucleus accumbens. Taken together, these results demonstrate that the HR mice display cognitive deficits associated with psychotic-like behavior, similar to those observed in patients suffering from schizophrenia and major depression and could be utilized in the search for better treatment strategies for these symptoms of psychiatric disorders.

Introduction

Although many treatment strategies are available, major depression (MD) is not a fully treatable disorder (Holsboer and Ising, 2010, Wong and Licinio, 2001). This particularly applies to the symptoms in the cognitive realm that often subside when the affective symptoms of the disease have successfully been treated (Reppermund et al., 2009, Reppermund et al., 2007). Typical antidepressants also lack the capacity to treat the psychotic symptoms of major MD (Holtzheimer & Nemeroff, 2006). It is therefore of great importance to better understand the mechanisms underlying these cognitive deficits and psychotic symptoms and to explore new potential targets for their treatment.

Drugs focusing on the dopaminergic system, such as atypical antipsychotics, have shown great promise in treating depressed patients who do not respond to typical antidepressants (Quintin & Thomas, 2004). Atypical antipsychotics are believed to exert their effect by increasing dopaminergic activity in the prefrontal cortex (PFC) implicating the dopaminergic system in these symptoms (Ichikawa et al., 2002, Kuroki et al., 1999, Rollema et al., 1997). The dopaminergic system subserves an optimal neuronal function in the PFC (Cropley, Fujita, Innis, & Nathan, 2006), which plays a key role in executive functioning tasks (Carpenter et al., 2000, Petrides, 1994, Robbins and Arnsten, 2009). Fittingly, executive functioning tasks are the cognitive tasks that depressed patients and schizophrenic patients display the most deficits in (Austin et al., 2001, Porter et al., 2003, Rabin et al., 2009, Reppermund et al., 2007, Reppermund et al., 2009, Shirayama et al., 2009). Thus, it appears that psychotic MD and schizophrenia (SZ) share certain symptoms and possibly have similar underlying biological underpinnings causing these symptoms. It was therefore our aim to study these symptoms as phenotypic endpoint relevant to both disorders. The focus of this study was the dopaminergic system and the behaviors likely to be subserved by the dopaminergic system in the context of these symptoms.

Dopamine plays a key role in the regulation of latent inhibition (Li). Li is the phenomenon whereby pre-exposure to the to-be conditioned stimulus retards the learning of subsequent pairing of the unconditioned stimulus (US) and the conditioned stimulus (CS) (Lubow, 1973). Disrupted Li is strongly associated with an increased dopaminergic activity in the mesolimbic area (Lubow, 2005, Solomon and Staton, 1982, Weiner, 1990, Young et al., 1993) and is considered to be a model of the inability to ignore irrelevant stimuli associated with schizotypy (Baruch et al., 1988, Guterman et al., 1996, Rascle et al., 2001, Schmidt-Hansen et al., 2009).

In addition to the affective and cognitive symptoms, dysregulation of the hypothalamus–pituitary–adrenal (HPA) axis is commonly observed in patients suffering from MD (de Kloet et al., 2005, Holsboer, 2000, Holsboer and Ising, 2010, Ising et al., 2005), but has also been reported in patients suffering from SZ (Gallagher et al., 2007, Muck-Seler et al., 2004, Ritsner et al., 2007, Ryan et al., 2004). An animal model of affective disorders, the “stress reactivity” mouse model, was therefore established using a selective breeding approach to generate mice with high, intermediate or low stress reactivity (Touma et al., 2008). Briefly, a founder population of CD-1 mice was subjected to a standardized stressor (15-min restraint), and the increase of plasma corticosterone concentrations in response to this stressor was determined. Males and females with very high stress reactivity (HR) were then mated, as were males and females with very low stress reactivity (LR). Their offspring were tested for their stress reactivity in the same manner and so forth for each generation to come (for details see (Touma et al., 2008)). An intermediate reactivity (IR) line was additionally established to serve as a control group with the same inbreeding status as the other two lines. The IR mice present a corticosterone response similar to the mean of the founder population of CD-1 mice (Touma et al., 2008). In this study, these three mouse lines have been utilized to investigate the effect of a hyperactive vs. hypoactive HPA axis reactivity on the dopaminergic system as well as behaviors subserved by the dopaminergic system that are relevant to the psychotic and cognitive deficits observed in MD and SZ. Ultimately, we aim to provide a mouse model for cognitive deficits and psychotic symptoms that could be utilized in the search for better treatment options for these symptoms.

To this end, mice from the stress reactivity model were subjected to a reversal learning task, and Li was assessed in a conditioned taste aversion paradigm. The brains of these animals were subsequently analyzed via in situ hybridization to measure dopamine 1 receptor (D1R), dopamine receptor 2 (D2R) and dopamine transporter (DAT) mRNA levels in relevant brain areas.