Clozapine prevented social interaction deficits and reduced c-Fos immunoreactivity expression in several brain areas of rats exposed to acute restraint stress

Abstract

In the present study, we evaluate the effect of acute restraint stress (15 min) of male Wistar rats on social interaction measurements and c-Fos immunoreactivity (c-Fos-ir) expression, a marker of neuronal activity, in areas involved with the modulation of acute physical restraint in rats, i.e., the paraventricular nucleus of the hypothalamus (PVN), median raphe nucleus (MnR), medial prefrontal cortex (mPFC), cingulate prefrontal cortex (cPFC), nucleus accumbens (NaC), hippocampus (CA3), lateral septum (LS) and medial amygdala (MeA). We considered the hypothesis that restraint stress exposure could promote social withdrawal induced by the activation of the hypothalamic-pituitary-adrenocortical (HPA) axis, and increase c-Fos expression in these limbic forebrain areas investigated. In addition, we investigated whether pretreatment with the atypical antipsychotic clozapine (5 mg/kg; I.P.) could attenuate or block the effects of restraint on these responses. We found that restraint stress induced social withdrawal, and increased c-Fos-ir in these areas, demonstrating that a single 15 min session of physical restraint of rats effectively activated the HPA axis, representing an effective tool for the investigation of neuronal activity in brain regions sensitive to stress. Conversely, pretreatment with clozapine, prevented social withdrawal and reduced c-Fos expression. We suggest that treatment with clozapine exerted a preventive effect in the social interaction deficit, at least in part, by blocking the effect of restraint stress in brain regions that are known to regulate the HPA-axis, including the cerebral cortex, hippocampus, hypothalamus, septum and amygdala. Further experiments will be done to confirm this hypothesis.

The gut metabolite indole-3-propionic acid activates ERK1 to restore social function and hippocampal inhibitory synaptic transmission in a 16p11.2 microdeletion mouse model

“…The hippocampal and medial prefrontal cortex (mPFC) are critical brain regions involved in social cognition and episodic memory [ 42 – 44 ]. Neuroactivity abnormalities in these regions can lead to impaired social interactions [ 45 ]. To investigate potential changes in neural activity in these regions, we examined the expression of c-Fos, an immediate-early gene marker for neuronal activity, after exposing 16p11.2 +/- mice to social stimuli (i.e., TCT) (Fig.…”

The gut metabolite indole-3-propionic acid activates ERK1 to restore social function and hippocampal inhibitory synaptic transmission in a 16p11.2 microdeletion mouse model

“…Impaired inhibitory synaptic transmission in hippocampal dentate gyrus in 16p11.2 +/mice The hippocampal and medial prefrontal cortex (mPFC) are critical brain regions involved in social cognition and episodic memory [42][43][44]. Neuroactivity abnormalities in these regions can lead to impaired social interactions [45]. To investigate potential changes in neural activity in these regions, we examined the expression of c-Fos, an immediate-early gene marker for neuronal activity, after exposing 16p11.2 +/mice to social stimuli (i.e.…”

“…The hippocampus and mPFC are essential brain regions that regulate social novelty and new object recognition [43,65,66]. Excessive activation of neurons in the hippocampus has been reported to impair social interaction [45]. In 16p11.2 +/rats, Yang et al reported abnormal activation of the hippocampal CA1 somatostatin positive interneurons [67].…”

Differential expression of Dusp1 and immediate early response genes in the hippocampus of rats, subjected to forced swim test

“…Introduction of diazepam reduces induction of this expression 62 . Clozapine restores normal social interactions in rats subjected to acute restraint stress and reduces Fos expression in several parts of the brain 53 . Short-term fluoxetine treatment reduces Fos expression in the lymbic system of rats subjected to acute forced restraint stress 59 .…”

“…Stress induces Fos expression in several regions of the brain involved in stress reaction and regulation of the stress—the hippocampus 52 – 56 ; hypothalamus, amygdala, and nucleus accumbens 52 – 54 , 56 – 60 ; HPA-axis 58 ; and PFC 53 , 57 , 61 . Ingestion of antidepressants and anxiolytics reduces the induction of Fos expression.…”