Testosterone in puberty regulates emotional contagion and consolation via the AVP system in the ACC of C57BL/6J mice.

INTRODUCTION: Empathy is the ability of an individual to present and respond to the emotions of others and is thought to originate from parental behavior. Testosterone could promote aggression and inhibit biparental behavior and vasopressin (AVP) could promote aggression. Given levels of aggression and parental care are closely associated with levels of empathy, we hypothesized that testosterone may influence empathetic behavior via the AVP system. METHODS: We examined testosterone levels and tested social, empathic, and anxiety-like behaviors after castration surgery to pubertal mice, and subsequently examined the molecular levels of AVP, V1aR in different brain regions. Finally, pharmacological experiments were used to test the effects on empathic behavior by injecting testosterone in combination with V1aR antagonist. RESULTS: Here, we show that pubertal castration reduced serum testosterone levels, increased empathetic behavior and sociality, and reduced anxiety-like behaviors in male C57 mice. The pubertal castration also reduced AVP and vasopressin receptor (V1aR) protein levels, and AVP mRNA levels in the PVN. It also reduced the number of AVP-positive neurons in the PVN. In addition, pubertal subcutaneous injection of testosterone reduced emotional contagion and consolation of castrated mice, while concomitant injection of V1aR antagonists into the ACC reversed the downregulation of emotional contagion and consolation induced by testosterone. CONCLUSION: It is suggested that testosterone in puberty regulates empathetic behavior in C57 mice possibly via the AVP system in the ACC. These findings help us to understand the neuroendocrine mechanisms underlying empathetic behavior and provide potential targets for the treatment of psychiatric disorders associated with low empathy.

Effects of paternal deprivation on empathetic behavior and the involvement of oxytocin receptors in the anterior cingulate cortex.

Paternal deprivation (PD) impairs social cognition and sociality and increases levels of anxiety-like behavior. However, whether PD affects the levels of empathy in offspring and its underlying mechanisms remain unknown. The present study found that PD increased anxiety-like behavior in mandarin voles (Microtus mandarinus), impaired sociality, reduced the ability of emotional contagion, and the level of consolation behavior. Meanwhile, PD reduced OT neurons in the paraventricular nucleus (PVN) in both male and female mandarin voles. PD decreased the level of OT receptor (OTR) mRNA in the anterior cingulate cortex (ACC) of male and female mandarin voles. Besides, OTR overexpression in the ACC reversed the PD-induced changes in anxiety-like behavior, social preference, emotional contagion, and consolation behavior. Interference of OTR expression in the ACC increased levels of anxiety-like behaviors, while it reduced levels of sociality, emotional contagion, and consolation. These results revealed that the OTR in the ACC is involved in the effects of PD on empathetic behaviors, and provide mechanistic insight into how social experiences affect empathetic behaviors.

Involvement of Serotonergic Projections from the Dorsal Raphe to the Medial Preoptic Area in the Regulation of the Pup-Directed Paternal Response of Male Mandarin Voles.

Male mammals display different paternal responses to pups, either attacking or killing the young offspring, or contrastingly, caring for them. The neural circuit mechanism underlying the between-individual variation in the pup-directed responsiveness of male mammals remains unclear. Monogamous mandarin voles were used to complete the present study. The male individuals were identified as paternal and infanticidal voles, according their behavioral responses to pups. It was found that the serotonin release in the medial preoptic area (MPOA), as well as the serotonergic neuron activity, significantly increased upon licking the pups, but showed no changes after attacking the pups, as revealed by the in vivo fiber photometry of the fluorescence signal from the 5-HT 1.0 sensor and the calcium imaging indicator, respectively. It was verified that the 5-HTergic neural projections to the MPOA originated mainly from the ventral part of the dorsal raphe (vDR). Furthermore, the chemogenetic inhibition of serotonergic projections from the vDR to the MPOA decreased the paternal behaviors and shortened the latency to attack the pups. In contrast, the activation of serotonergic neurons via optogenetics extended the licking duration and inhibited infanticide. Collectively, these results elucidate that the serotonergic projections from the vDR to the MPOA, a previously unrecognized pathway, regulate the paternal responses of virgin male mandarin voles to pups.

Chronic stress and stressful emotional contagion affect the empathy-like behavior of rats.

Empathy is a potential motivation for prosocial behaviors that is related to many psychiatric diseases, such as major depressive disorder; however, its neural mechanisms remain unclear. To elucidate the relationship between empathy and stress, we established a chronic stress contagion (SC) procedure combined with chronic unpredictable mild stress (CUMS) to investigate (1) whether depressive rats show impaired empathy-like behavior toward fearful conspecifics, (2) whether frequent social contact with normal familiar conspecifics (social support) alleviates the negative effects of CUMS, and (3) the effect of long-term exposure to a depressed partner on emotional and empathic responses in normal rats. We found that the CUMS group showed less empathy-like behavior in the social transfer of fear model (STFM), as indicated by less social interaction with the demonstrator and reduced freezing behavior in the fear-expression test. Social contact partially alleviated depression-like behaviors and the negative effect of CUMS in the fear-transfer test. The normal rats who experienced stress contagion from daily exposure to a depressed partner for 3 weeks showed lower anxiety and increased social response in the fear-transfer test than the control group. We concluded that chronic stress impairs empathy-like behaviors, while social contact partially buffers the effect of CUMS. Thus, social contact or contagion of stress is mutually beneficial to both stressed individuals and nonstressed partners. Higher dopamine and lower norepinephrine levels in the basolateral amygdala probably contributed to these beneficial effects.

Oxytocin treatments or activation of the paraventricular nucleus-the shell of nucleus accumbens pathway reduce adverse effects of chronic social defeat stress on emotional and social behaviors in Mandarin voles.

Chronic social stress can cause psychological disease. Although oxytocin (OT) has been showed to modulate effects of chronic social defeat stress (CSDS) on emotional and social behaviors, however, how OT circuits mediate effects of CSDS on emotional and social abnormalities remains unclear. Here, we found that repeated intraperitoneal OT administration in the process of CSDS buffered adverse effects of CSDS on emotional and social behaviors in mandarin voles (Microtus mandarinus) of both sexes except no effect on depression-like behavior of males. Repeated OT treatments during CSDS prevented decrease of oxytocin receptors in nucleus accumbens (NAc) in females, but produced no effects on males. Furthermore, using designer receptors exclusively activated by designer drugs (DREADDs)-based chemogenetic tools, we determined that the activation of the paraventricular nucleus (PVN)-the shell of NAc (NAcs) projections before social defeat during CSDS process significantly prevented the increase of the anxiety-like behaviors and social avoidance induced by CSDS in both sexes, and reversed the depressive-like behaviors induced by CSDS only in females. Besides, optogenetic activation of PVN-NAcs projections after CSDS reduced anxiety-like behaviors and increased levels of sociality. Collectively, we suggest that PVN-NAcs projections modulate emotional and social behaviors during or after the process of CSDS sex-specifically, although AAV viruses did not specifically infect OT neurons. These findings offer potential targets for preventing or treating emotional and social disorders induced by chronic stress.

Downregulation of fatty acid oxidation led by Hilpda increases G2/M arrest/delay-induced kidney fibrosis.

Hypoxia-regulated proximal tubular epithelial cells (PTCs) G2/M phase arrest/delay was involved in production of renal tubulointerstitial fibrosis (TIF). TIF is a common pathological manifestation of progression in patients with chronic kidney disease (CKD), and is often accompanied by lipid accumulation in renal tubules. However, cause-effect relationship between hypoxia-inducible lipid droplet-associated protein (Hilpda), lipid accumulation, G2/M phase arrest/delay and TIF remains unclear. Here we found that overexpression of Hilpda downregulated adipose triglyceride lipase (ATGL) promoted triglyceride overload in the form of lipid accumulation, leading to defective fatty acid ß-oxidation (FAO), ATP depletion in a human PTC cell line (HK-2) under hypoxia and in mice kidney tissue treated with unilateral ureteral obstruction (UUO) and unilateral ischemia-reperfusion injury (UIRI). Hilpda-induced lipid accumulation caused mitochondrial dysfunction, enhanced expression of profibrogenic factors TGF-ß1, α-SMA and Collagen I elevation, and reduced expression of G2/M phase-associated gene CDK1, as well as increased CyclinB1/D1 ratio, resulted in G2/M phase arrest/delay and profibrogenic phenotypes. Hilpda deficiency in HK-2 cell and kidney of mice with UUO had sustained expression of ATGL and CDK1 and reduced expression of TGF-ß1, Collagen I and CyclinB1/D1 ratio, resulting in the amelioration of lipid accumulation and G2/M arrest/delay and subsequent TIF. Expression of Hilpda correlated with lipid accumulation, was positively associated with tubulointerstitial fibrosis in tissue samples from patients with CKD. Our findings suggest that Hilpda deranges fatty acid metabolism in PTCs, which leads to G2/M phase arrest/delay and upregulation of profibrogenic factors, and consequently promote TIF which possibly underlie pathogenesis of CKD.

Phencynonate hydrochloride exerts antidepressant effects by regulating the dendritic spine density and altering glutamate receptor expression.

Phencynonate hydrochloride (PCH) is a drug that crosses the blood-brain barrier. Cellular experiments confirmed that PCH protects against glutamate toxicity and causes only weak central inhibition and limited side effects. As shown in our previous studies, PCH alleviates depression-like behaviours induced by chronic unpredictable mild stress (CUMS). Here we administered PCH at three different doses (4, 8 and 16 mg/kg) to male rats for two continuous days after CUMS and conducted behavioural tests to assess the dose-dependent antidepressant effects of PCH and its effects on the neuroplasticity in the hippocampus and medial prefrontal cortex (mPFC). Meanwhile, we measured the spine density and expression of related proteins to illustrate the mechanism of PCH. PCH treatment (8 mg/kg) significantly alleviated depression-like behaviours induced by CUMS. All doses of PCH treatment reversed the spine loss in prelimbic and CA3 regions induced by CUMS. Kalirin-7 expression was decreased in the hippocampus and mPFC of the CUMS group. The expression of the NR1 and NR2B subunits in the hippocampus, and NR2B in mPFC are increased by CUMS. PCH treatment (8 and 16 mg/kg) reversed all of these changes of Kalirin-7 in PFC and hippocampus, as well as NR1 and NR2B expression in the hippocampus. PCH is expected to be developed as a new type of rapid antidepressant. Its antidepressant effect may be closely related to the modulation of dendritic spine density in the prelimbic and CA3 regions and the regulation of Kalilin-7 and N-methyl-D-aspartic acid receptor levels in the hippocampus.

Different baseline physical activity predicts susceptibility and resilience to chronic social defeat stress in mice: Involvement of dopamine neurons.

Physical inactivity, the fourth leading mortality risk factor worldwide, is associated with chronic mental illness. Identifying the mechanisms underlying different levels of baseline physical activity and the effects of these levels on the susceptibility to stress is very important. However, whether different levels of baseline physical activity influence the susceptibility and resilience to chronic social defeat stress (CSDS), and the underlying mechanisms in the brain remain unclear. The present study segregated wild-type mice into low baseline physical activity (LBPA) and high baseline physical activity (HBPA) groups based on short term voluntary wheel running (VWR). LBPA mice showed obvious susceptibility to CSDS, while HBPA mice were resilient to CSDS. In addition, the expression of tyrosine hydroxylase (TH) in the ventral tegmental area (VTA) was lower in LBPA mice than in HBPA mice. Furthermore, activation of TH neurons in the VTA of LBPA mice by chemogenetic methods increased the levels of VWR and resilience to CSDS. In contrast, inhibiting TH neurons in the VTA of HBPA mice lowered the levels of VWR and increased their susceptibility to CSDS. Thus, this study suggests that different baseline physical activities might be mediated by the dopamine system. This system also affects the susceptibility and resilience to CSDS, possibly via alteration of the baseline physical activity. This perspective on the neural control and impacts on VWR may aid the development of strategies to motivate and sustain voluntary physical activity. Furthermore, this can maximize the impacts of regular physical activity toward stress-reduction and health promotion.