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. 2017 Aug 30;333:1-8.
doi: 10.1016/j.bbr.2017.06.033. Epub 2017 Jun 21.

Chronic Mild Stress Impairs Latent Inhibition and Induces Region-Specific Neural Activation in CHL1-deficient Mice, a Mouse Model of Schizophrenia

Free PMC article

Chronic Mild Stress Impairs Latent Inhibition and Induces Region-Specific Neural Activation in CHL1-deficient Mice, a Mouse Model of Schizophrenia

Mona Buhusi et al. Behav Brain Res. .
Free PMC article


Schizophrenia is a neurodevelopmental disorder characterized by abnormal processing of information and attentional deficits. Schizophrenia has a high genetic component but is precipitated by environmental factors, as proposed by the 'two-hit' theory of schizophrenia. Here we compared latent inhibition as a measure of learning and attention, in CHL1-deficient mice, an animal model of schizophrenia, and their wild-type littermates, under no-stress and chronic mild stress conditions. All unstressed mice as well as the stressed wild-type mice showed latent inhibition. In contrast, CHL1-deficient mice did not show latent inhibition after exposure to chronic stress. Differences in neuronal activation (c-Fos-positive cell counts) were noted in brain regions associated with latent inhibition: Neuronal activation in the prelimbic/infralimbic cortices and the nucleus accumbens shell was affected solely by stress. Neuronal activation in basolateral amygdala and ventral hippocampus was affected independently by stress and genotype. Most importantly, neural activation in nucleus accumbens core was affected by the interaction between stress and genotype. These results provide strong support for a 'two-hit' (genes x environment) effect on latent inhibition in CHL1-deficient mice, and identify CHL1-deficient mice as a model of schizophrenia-like learning and attention impairments.

Keywords: Accumbens; Chronic mild stress; Close homolog to L1; Latent inhibition; Schizophrenia; c-Fos.


Fig. 1
Fig. 1. Latent inhibition by stress and genotype
Average duration of freezing (± SEM) to the pre-exposed (PE) and non-pre-exposed (NPE) stimulus in CHL1 knock-out (KO), heterozygotes (HET) and wild type littermate controls (WT) under no-stress (left) and chronic mild stress (right). A reliably latent inhibition (larger freezing to NPE than PE) was observed in all groups except in stressed CHL1 HET and KO mice. * = p<0.05; ** = p<0.01.
Fig. 2
Fig. 2. Neural activation during latent inhibition testing
A: Average c-Fos+ cell counts (± SEM) in prelimbic cortex (PrL), infralimbic cortex (IL), nucleus accumbens shell (Acb-shell), basolateral amygdala (BLA), ventral hippocampus (vHipp), and nucleus accumbens core (Acb-core) in the stress (S) and no-stress (NS) CHL1-deficient mice (KO) and wild-type littermate controls (WT). BCD: Correlations between latent inhibition (difference in freezing duration to the non-pre-exposed, NPE, and pre-exposed, PE, stimuli) and neural activation in Acb-shell (B) and Acb-core (CD). * = p<0.05.
Fig. 3
Fig. 3. Modulation of a putative latent inhibition circuit by stress or the CHL1 genotype
A putative circuit for latent inhibition (modified after [–39]) indicating the brain regions where activity was affected by stress and/or CHL1 genotype. PFC = prefrontal cortex; PrL = prelimbic cortex; IL = infralimbic cortex; BLA = basolateral amygdala; vHipp = ventral hippocampus; Acb = nucleus accumbens; Acb-core = nucleus accumbens core; Acb-shell = nucleus accumbens shell.

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