Increased temporal discounting after chronic stress in CHL1-deficient mice is reversed by 5-HT2C agonist Ro 60-0175

Abstract

Schizophrenia is a neurodevelopmental disorder in which impaired decision-making and goal-directed behaviors are core features. One of the genes associated with schizophrenia is the Close Homolog of L1 (CHL1); CHL1-deficient mice are considered a model of schizophrenia-like deficits, including sensorimotor gating, interval timing and spatial memory impairments. Here we investigated temporal discounting in CHL1-deficient (KO) mice and their wild-type littermates. Although no discounting differences were found under baseline conditions, CHL1-KO mice showed increased impulsive choice following chronic unpredictable stress (fewer % larger-later choices, and reduced area under the discounting curve). Stressed CHL1-KO mice also showed decreased neuronal activation (number of cFos positive neurons) in the discounting task in the prelimbic cortex and dorsal striatum, areas thought to be part of executive and temporal processing circuits. Impulsive choice alterations were reversed by the 5-HT2C agonist Ro 60-0175. Our results provide evidence for a gene x environment, double-hit model of stress-related decision-making impairments, and identify CHL1-deficient mice as a mouse model for these deficits in regard to schizophrenia-like phenotypes.

Keywords: cFos; intertemporal decision making; prefrontal cortex; schizophrenia; serotonin; striatum.

Fig.1. Increased discounting after chronic stress in CHL1-deficient mice

Average %LL choices (± SEM) in CHL1- KO mice (n=16) and WT controls (n=16) under baseline conditions (left) and after chronic unpredictable stress (right). * p<0.05, ** p<0.01.

Fig.2. Increased impulsivity after chronic stress in CHL1-deficient mice

(A) Average normalized %LL choices (± SEM) in CHL1-KO mice (n=16) and WT controls (n=16) under baseline conditions (left) and after chronic unpredictable stress (right). (B) Average %AUC (± SEM) in CHL1-KO mice and WT controls under baseline and stress conditions. * p<0.05, ** p<0.01.

Fig.3. Neural activation during TD in stressed CHL1-deficient mice and stressed WT controls

Average number of cFos+ neurons (± SEM) in CHL1-KO (n=6) and WT controls (n=6) in the stress condition in prelimbic cortex (PrL), medial OFC (OFC-med), ventrolateral OFC (OFC-vlat), nucleus accumbens core (Acb-core), nucleus accumbens shell (Acb-shell), dorsomedial striatum (DS-med), and dorsolateral striatum (DS-lat). * p<0.05; ** p<0.01.

Fig.4. Systemic administration of Ro 60-0175 reverses impulsivity in stressed CHL1-deficient mice and WT controls

(A) Average %AUC (± SEM) in CHL1-KO mice (n=10) and WT controls (n=10) under Ro 60-0175 (0.6mg/kg, 1.2mg/kg) and saline (SAL) control. (B) Average normalized %LL choices (± SEM) in CHL1-KO mice (n=10, right) and WT controls (n=10, left) under Ro 60-0175 0.6mg/kg and saline (SAL) control. * p<0.05, ** p<0.01.