Glutamatergic Neurotransmission Controls the Functional Lateralization of the mPFC in the Modulation of Anxiety Induced by Social Defeat Stress in Male Mice

Abstract

The rodent medial prefrontal cortex (mPFC) is anatomically divided into cingulate (Cg1), prelimbic (PrL), and infralimbic (IL) subareas. The left and right mPFC (L and RmPFC) process emotional responses induced by stress-related stimuli, and LmPFC and RmPFC inhibition elicit anxiogenesis and anxiolysis, respectively. Here we sought to investigate (i) the mPFC functional laterality on social avoidance/anxiogenic-like behaviors in male mice subjected to chronic social defeat stress (SDS), (ii) the effects of left prelimbic (PrL) inhibition (with local injection of CoCl2) on the RmPFC glutamatergic neuronal activation pattern (immunofluorescence assay), and (iii) the effects of the dorsal right mPFC (Cg1 + PrL) NMDA receptor blockade (with local injection of AP7) on the anxiety induced by left dorsal mPFC inhibition in mice exposed to the elevated plus maze (EPM). Results showed that chronic SDS induced anxiogenic-like behaviors followed by the rise of ΔFosB labeling and by ΔFosB + CaMKII double-labeling bilaterally in the Cg1 and IL subareas of the mPFC. Chronic SDS also increased ΔFosB and by ΔFosB + CaMKII labeling only on the right PrL. Also, the left PrL inhibition increased cFos + CaMKII labeling in the contralateral PrL and IL. Moreover, anxiogenesis induced by the left PrL inhibition was blocked by NMDA receptor antagonist AP7 injected into the right PrL. These findings suggest the lateralized control of the glutamatergic neurotransmission in the modulation of emotional-like responses in mice subjected to chronic SDS.

Daily Optogenetic Stimulation of the Left Infralimbic Cortex Reverses Extinction Impairments in Male Rats Exposed to Single Prolonged Stress

“…Moreover, bilateral IL continuous light stimulation over 60 min 1 day prior to testing reduced latency to eat in a novelty-suppressed feeding task, indicating an anxiolytic effect (Fuchikami et al, 2015), whereas acute left-IL optogenetic stimulation during behavioral tests enhanced anxiety-like behaviors (Berg et al, 2019) or did not disrupt anxiety-like responses (Covington et al, 2010). The present findings that left-IL optogenetic stimulation does not prevent the SPS-induced decrease in time spent exploring open arms of the EPM may be due to the functional differences between IL and dmPFC in the expression of anxiety-like behaviors (Santos- Costa et al, 2021), differences in unilateral vs. bilateral stimulation, or to differences in the timing of stimulation. Given the lack of a measurable effect of left IL stimulation on anxiety-like behavior in the present study, it is unlikely that the effect of optogenetic stimulation of the left IL on extinction is due to a general reduction in anxiety levels.…”

“…Exposure to SPS affected time spent in the open arms of the elevated plus maze, suggesting that the trauma of SPS increased anxiety-like behavior. Several findings suggest that left dorsal mPFC (dmPFC) can exert an inhibitory role over the right dmPFC, attenuating the anxiogenic effects driven by stressors (Cerqueira et al, 2008;Costa et al, 2016;Victoriano et al, 2020;Santos-Costa et al, 2021). However, other evidence suggests that enhanced excitability of the IL decreased time spent in the center of an open field and in open arms of an EPM (Bi et al, 2013) or had no effect (Suzuki et al, 2016).…”

“…Together, these findings indicate that IL hypofunctioning during the 7-day incubation period following SPS is associated with subsequent behavioral impairments, suggesting that increasing IL activity following SPS could prevent the impairments in anxiety and extinction. Moreover, previous findings indicate that stress can produce asymmetrical changes in the mPFC, and functional lateralization of mPFC affects emotional states following stress (Sullivan and Gratton, 1999;Cerqueira et al, 2008;Lee et al, 2015;Costa et al, 2016;Victoriano et al, 2020;Santos-Costa et al, 2021) and hemispheric asymmetry in volume of the hippocampus, amygdala, and cortex of PTSD patients has been reported (Adami et al, 2006;Karl et al, 2006;Morey et al, 2012;Zach et al, 2016;Cwik et al, 2020), suggesting that these SPSinduced changes may be lateralized. Previous studies have found that bilateral optogenetic stimulation of the IL or IL inputs to the basolateral amygdala during extinction training enhance extinction memories in rodents (Bukalo et al, 2015(Bukalo et al, , 2021Do-Monte et al, 2015).…”

Rearing in an Enriched Environment Ameliorates the ADHD-like Behaviors of Lister Hooded Rats While Suppressing Neuronal Activities in the Medial Prefrontal Cortex

“…Chronic stress alters neuronal activities in the mPFC in both humans and rodents [ 52 ]. Chronic social defeat stress induced elevated cFos expression in the mPFC of adolescent mice [ 61 ]. Acutely administered corticosterone increases expression of Fos and Arc in the mPFC [ 62 ].…”

Emotional- and cognitive-like responses induced by social defeat stress in male mice are modulated by the BNST, amygdala, and hippocampus

“…Subsequently, this paradigm was optimized and standardized to investigate various behavioral effects produced by chronic social defeats in mice ( Golden et al, 2011 ). Complementarily, our group has used the SDS to investigate the neuronal basis of defensive behaviors in the attacked mouse ( Faria et al, 2020 ; Victoriano et al, 2020 ; Santos-Costa et al, 2021 ).…”