Chronic mild stress impairs latent inhibition and induces region-specific neural activation in CHL1-deficient mice, a mouse model of schizophrenia

Abstract

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.

Impaired Latent Inhibition in GDNF-Deficient Mice Exposed to Chronic Stress

“…Using an “on baseline” within-subject CER LI procedure developed in our lab (Buhusi et al, 2017 ), the current study found that WT mice showed LI, consistent with previous findings (Gould and Wehner, 1999 ). Additionally, results indicated that GDNF HET mice in C57BL/6J background showed LI under baseline, no-stress conditions.…”

“…LI was assessed using an “on baseline” conditioned emotional response (CER) procedure consisting of baseline, pre-exposure, conditioning, rebaseline and test phases (i.e., allowing the mouse to eat during the all stages of the LI paradigm; Buhusi et al, 2017 ). Mice were assigned either to a PE tone/NPE click or PE click/NPE tone in a counterbalanced manner.…”

“…During a 30-min test session, mice were presented with 3-min PE and NPE stimuli with an 8-min ISI. Mouse behavior was video recorded and the duration of freezing behavior was estimated using FreezeScan software (CleverSys Inc., Reston, VA, USA; Buhusi et al, 2017 ).…”

PsyCoP – A Platform for Systematic Semi-Automated Behavioral and Cognitive Profiling Reveals Gene and Environment Dependent Impairments of Tcf4 Transgenic Mice Subjected to Social Defeat

“…It is known that the effects of stress in adolescence are sex dependent, so it would be important to be able to test both sexes. For that reason, we are evaluating other paradigms such as unpredictable chronic mild stress (Buhusi et al, 2017 ; Page and Coutellier, 2018 ).…”

Real-time in vivo two-photon imaging study reveals decreased cerebro-vascular volume and increased blood-brain barrier permeability in chronically stressed mice

“…Adverse effects on the brain system of chronic stress include stroke, vascular dementia and cognitive dysfunction 4 – 6 . Especially, the detrimental effects of chronic stress on neuronal activation has been extensively studied over the past few decades, and decreased activation of the hippocampus, amygdala, pre-frontal cortex, in chronically stressed animals has been reported 7 – 10 . Because neuronal activation is tightly linked to brain hemodynamics, reduction in hemodynamics can be used as a measure of the decreased level of neuronal activation due to chronic stress.…”