Reduced Consolation Behaviors in Physically Stressed Mandarin Voles: Involvement of Oxytocin, Dopamine D2, and Serotonin 1A Receptors Within the Anterior Cingulate Cortex

Abstract

Background Consolation is a type of empathy-like behavior that has recently been observed in some socially living rodents. Despite the growing body of literature suggesting that stress affects empathy, the relationship between stress and consolation remains understudied at the preclinical level. Here, we examined the effects of chronic emotional stress or physical stress exposure on consolation and emotional behaviors by using the socially monogamous mandarin vole (Microtus mandarinus) in both males and females. Method/Results Physical stress voles were exposed to 14-day social defeat stress, whereas emotional stress voles vicariously experienced the defeat of their partners. We found that physical stress, but not emotional stress, voles showed reduced grooming toward their defeated partners and increased anxiety- and despair-like behaviors. Meanwhile, physical stress voles exhibited decreased neural activity in the anterior cingulate cortex, which is centrally involved in empathy. The densities of oxytocin receptors, dopamine D2 receptors, and serotonin 1A-receptors within the anterior cingulate cortex were significantly decreased in the physical stress group compared with controls. All the behavioral and physiological changes were similar between the sexes. Finally, we found that the reduced consolation behavior and some anxiety-like syndromes in physical stress voles could be alleviated by pretreatment with an oxytocin receptor, D2 receptors, or serotonin 1A-receptor agonist within the anterior cingulate cortex, whereas injections of corresponding receptor antagonists to the control voles decreased the consolation behavior and increased some anxiety-like behaviors. Conclusions Our results indicated that chronic physical stress exposure impaired consolation and induced anxiety-like behaviors in mandarin voles and oxytocin receptors, 5-HT1A receptors, and D2 receptors within the anterior cingulate cortex may play important roles in these processes.

Paraventricular thalamic nucleus plays a critical role in consolation and anxious behaviors of familiar observers exposed to surgery mice

“…The lack of consolation in surgery mice is conceivable because these mice were sick and suffered from pain and distress. Consistent with this possibility, physically stressed Mandarin voles have reduced consolation toward their social defeated partners 8 .…”

“…Consistent with our findings, orexin has been found to regulate anxiety and adaptation to stress 37 , 38 . Orexin signaling may be involved in consolation of Mandarin voles toward socially defeated partners 8 , 39 Orexinergic modulation of PVT neurons is reported from lateral hypothalamic area 19 , 34 . Our findings imply a role of lateral hypothalamic area in the consolation and anxious behaviors of familiar observers.…”

Dorsal raphe nucleus to anterior cingulate cortex 5-HTergic neural circuit modulates consolation and sociability

“…Increasing evidence indicates that these two types of receptors exert opposite effects within the mPFC (Celada et al, 2013;Puig and Gulledge, 2011). In our previous study, we indicated that ACC administration of a 5HT1AR agonist (8-OH-DPAT) rescued the impaired consolation and sociability induced by social defeat (Li et al, 2020). To further examine which receptor mediates consolation-like behaviors within the ACC, we directly infused 8-OH-DPAT (200 nL/side; 1.5 mg/mL) or a 5-HT2AR antagonist (MDL 100907, 200 nL/side; 1 mg/mL) into the ACC along with chemogenetic inhibition of DR 5-HT neurons before conducting behavioral assays ( Figure 6A & B).…”

“…The digital videos were viewed and quantified using J Watcher software (http://www.jwatcher.ucla.edu/). According to previous studies (Burkett et al, 2016; Li et al, 2019), allogrooming is designated as behavioral indicators of consolation, which defined as head contact with the body or head of their partner, accompanied by a rhythmic head movement.…”

“…The injector tips remained in situ for another 2 min for drug diffusions. The dose and timing of drug administration were chosen based on previous studies with 8-OH-DPAT (Cooper et al, 2008;Li et al, 2020) and MDL 100907 (Ishii et al, 2015;Pockros et al, 2011), which adjusted according to preliminary studies. In chemogenetic studies, CNO (1 mg/kg) was dissolved in saline and delivered intraperitoneally 30 min before the behavioral test.…”