Impaired contextual fear-conditioning in MAM rodent model of schizophrenia

Abstract

The methylazoxymethanol acetate (MAM) rodent neurodevelopmental model of schizophrenia exhibits aberrant dopamine system activation attributed to hippocampal dysfunction. Context discrimination is a component of numerous behavioral and cognitive functions and relies on intact hippocampal processing. The present study explored context processing behaviors, along with dopamine system activation, during fear learning in the MAM model. Male offspring of dams treated with MAM (20mg/kg, i.p.) or saline on gestational day 17 were used for electrophysiological and behavioral experiments. Animals were tested on the immediate shock fear conditioning paradigm, with either different pre-conditioning contexts or varying amounts of context pre-exposure (0-10 sessions). Amphetamine-induced locomotor activity and dopamine neural activity was measured 1-week after fear conditioning. Saline, but not MAM animals, demonstrated enhanced fear responses following a single context pre-exposure in the conditioning context. One week following fear learning, saline rats with 2 or 7min of context pre-exposure prior to fear conditioning also demonstrated enhanced amphetamine-induced locomotor response relative to MAM animals. Dopamine neuron recordings showed fear learning-induced reductions in spontaneous dopamine neural activity in MAM rats that was further reduced by amphetamine. Apomorphine administration confirmed that reductions in dopamine neuron activity in MAM animals resulted from over excitation, or depolarization block. These data show a behavioral insensitivity to contextual stimuli in MAM rats that coincide with a less dynamic dopamine response after fear learning.

Fear extinction disruption in a developmental rodent model of schizophrenia correlates with an impairment in basolateral amygdala-medial prefrontal cortex plasticity

“…Moreover, we demonstrated that MAM-treated rats have no alteration in contextual fear conditioning. A recent study from our group suggests that MAM-treated animals have a deficiency in context discrimination to predict a future aversive situation [29]. In the contextual fear conditioning experiment, we observed a similar expression of conditioned response between saline and MAMtreated animals.…”

Cannabidiol Administered During Peri-Adolescence Prevents Behavioral Abnormalities in an Animal Model of Schizophrenia

“…In the SHR strain, the contextual fear conditioning deficit is specifically reversed by the administration of antipsychotic drugs ( Calzavara et al, 2009 ), being suggested as a model for the cognitive symptoms of schizophrenia. Contextual fear conditioning deficits are also seen in other animal models for schizophrenia ( Duffy et al, 2010 ; Gill et al, 2017 ; Latusz et al, 2017 ). Our findings therefore point to beneficial effects of CBD on the cognitive impairments and are in accordance with a recent work showing that prolonged treatment with CBD improves the deficits on recognition and working memory in the poly I:C model ( Osborne et al, 2017 ).…”

Development of the MAM model of schizophrenia in mice: Sex similarities and differences of hippocampal and prefrontal cortical function

“…Additionally, these animals show deficits in social behavior (Flagstad et al 2004;Le Pen et al 2006;Hazane et al 2009) equivalent to the negative symptoms, as well as in cognitive tasks, including impairments in spatial learning and memory (Gourevitch et al 2004;Hazane et al 2009;Ratajczak et al 2015;Gastambide et al 2015;Gill et al 2017), cognitive flexibility (Moore et al 2006) and problem-solving (Featherstone et al 2007). MAM-17 rats also have reduced thickness in cortical and subcortical regions (Moore et al 2006;Flagstad et al 2004;Featherstone et al 2007;Matricon et al 2010;Hradetzky et al 2012), dysregulated dopamine (DA) system (Grace 2017) and parvalbumin (PV) loss in ventral subicullum, HPC and PFC (Penschuck et al 2006;Lodge et al 2009;Gill & Grace 2014).…”