CRF-CRFR1 system within the dorsal medial prefrontal cortex are involved in consolation deficits under acute restraint stress in mandarin voles.

Consolation is a complex empathic behavior that has recently been observed in some socially living rodents. Despite the growing body of literature suggesting that stress affects some simple form of empathy, the relationship between stress and consolation remains largely understudied. Using monogamous mandarin voles, we found that an acute restraint stress exposure significantly reduced consolation-like behaviors and induced anxiety-like behaviors. Along with these behavioral changes, corticotropin-releasing factor (CRF) and CRF receptor 1 (CRFR1) neurons were activated within the anterior cingulate cortex (ACC) and prelimbic cortex (PrL) but not within the infralimbic cortex (IL). Chemogenetic activation of CRF neurons in the ACC and PrL, recaptured acute stress-induced behavioral dysfunctions. We further observed that intracellular PKA and PKC signaling pathways mediate CRF-induced behavioral dysfunctions, but they work in a regional-specific, sex-biased manner. Together, these results suggest that the local CRF-CRFR1 system within the ACC and PrL is involved in the consolation deficits and anxiety induced by acute stress.

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

Consolation is a common response to the distress of others in humans and some social animals, but the neural mechanisms underlying this behavior are not well characterized. By using socially monogamous mandarin voles, we found that optogenetic or chemogenetic inhibition of 5-HTergic neurons in the dorsal raphe nucleus (DR) or optogenetic inhibition of serotonin (5-HT) terminals in the anterior cingulate cortex (ACC) significantly decreased allogrooming time in the consolation test and reduced sociability in the three-chamber test. The release of 5-HT within the ACC and the activity of DR neurons were significantly increased during allogrooming, sniffing, and social approaching. Finally, we found that the activation of 5-HT1A receptors in the ACC was sufficient to reverse consolation and sociability deficits induced by the chemogenetic inhibition of 5-HTergic neurons in the DR. Our study provided the first direct evidence that DR-ACC 5-HTergic neural circuit is implicated in consolation-like behaviors and sociability.

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.

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

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.

Voluntary Wheel Running Reverses Deficits in Social Behavior Induced by Chronic Social Defeat Stress in Mice: Involvement of the Dopamine System.

Voluntary exercise has been reported to have a therapeutic effect on many psychiatric disorders and social stress is known to impair social interaction. However, whether voluntary exercise could reverse deficits in social behaviors induced by chronic social defeat stress (CSDS) and the underlying mechanism remain unclear. The present study shows CSDS impaired social preference and induced social interaction deficiency in susceptible mice. Voluntary wheel running (VWR) reversed these effects. In addition, CSDS decreased the levels of tyrosine hydroxylase in the ventral tegmental area and the D2 receptor (D2R) in the nucleus accumbens (NAc) shell. These changes can be recovered by VWR. Furthermore, the recovery effect of VWR on deficits in social behaviors in CSDS mice was blocked by the microinjection of D2R antagonist raclopride into the NAc shell. Thus, these results suggest that the mechanism underlying CSDS-induced social interaction disorder might be caused by an alteration of the dopamine system. VWR may be a novel means to treat CSDS-induced deficits in social behaviors via modifying the dopamine system.

Involvement of oxytocin and GABA in consolation behavior elicited by socially defeated individuals in mandarin voles.

Consolation, which entails comforting contact directed toward a distressed party, is a common empathetic response in humans and other species with advanced cognition. Here, using the social defeat paradigm, we provide empirical evidence that highly social and monogamous mandarin voles (Microtus mandarinus) increased grooming toward a socially defeated partner but not toward a partner who underwent only separation. This selective behavioral response existed in both males and females. Accompanied with these behavioral changes, c-Fos expression was elevated in many of the brain regions relevant for emotional processing, such as the anterior cingulate cortex (ACC), bed nucleus of the stria terminalis, paraventricular nucleus (PVN), basal/basolateral and central nucleus of the amygdala, and lateral habenular nucleus in both sexes; in the medial preoptic area, the increase in c-Fos expression was found only in females, whereas in the medial nucleus of the amygdala, this increase was found only in males. In particular, the GAD67/c-Fos and oxytocin (OT)/c-Fos colocalization rates were elevated in the ACC and PVN, indicating selective activation of GABA and OT neurons in these regions. The "stressed" pairs matched their anxiety-like behaviors in the open-field test, and their plasma corticosterone levels correlated well with each other, suggesting an empathy-based mechanism. This partner-directed grooming was blocked by pretreatment with an OT receptor antagonist or a GABAA receptor antagonist in the ACC but not by a V1a subtype vasopressin receptor antagonist. We conclude that consolation behavior can be elicited by the social defeat paradigm in mandarin voles, and this behavior may be involved in a coordinated network of emotion-related brain structures, which differs slightly between the sexes. We also found that the endogenous OT and the GABA systems within the ACC are essential for consolation behavior in mandarin voles.

Aerobic exercise inhibits sympathetic nerve sprouting and restores ß-adrenergic receptor balance in rats with myocardial infarction.

BACKGROUND: Cardiac sympathetic nerve sprouting and the dysregulation of ß-adrenergic receptor (ß-AR) play a critical role in the deterioration of cardiac function after myocardial infarction (MI). Growing evidence indicates that exercise provides protection against MI. The aims of this study were to investigate whether aerobic exercise following MI could inhibit sympathetic nerve sprouting and restore the balance of ß3-AR/ß1-AR. METHODS: Male Sprague-Dawley rats were divided into three groups: sham-operated control group (SC), MI group (MI), and MI with aerobic exercise group (ME). The rats in ME group were assigned to 8 weeks of exercise protocol (16 m/min, 50 min/d, 5 d/wk). The expression of nerve growth factor (NGF), the sympathetic nerve marker-tyrosine hydroxylase (TH), the nerve sprouting marker-growth associated protein 43 (GAP43), and ß1- and ß2-AR expression in the peri-infarct area of the left ventricle (LV) were measured by Western blot and immunohistochemistry, while ß3-AR expression was determined by Western blot and immunofluorescence. Endothelial nitric oxide synthase (NOS2), phospho-NOS2 (p-NOS2), and neuronal nitric oxide synthase (NOS1) were measured by Western blot. RESULTS: MI increased LV end-diastolic pressure (LVEDP), and decreased LV systolic pressure (LVSP). Compared with the MI group, aerobic exercise significantly decreased LVEDP and increased LVSP. The protein expression of TH, GAP43 and NGF was significantly increased after MI, which was normalized by exercise. Compared with the SC group, the ratios of ß2-AR/ß1-AR and ß3-AR/ß1-AR were elevated in the MI group, and the protein expression of ß3-AR and NOS1 increased after MI. Compared with the MI group, the ratios of ß2-AR/ß1-AR and ß3-AR/ß1-AR were normalized in the ME group, while the protein expression of ß3-AR and NOS1 significantly increased, and NOS2 was activated by exercise. CONCLUSIONS: Aerobic exercise inhibits cardiac sympathetic nerve sprouting, restores ß3-AR/ß1-AR balance and increases ß3-AR expression through the activation of NOS2 and NOS1 after myocardial infarction.

[Exercise intervention in skeletal muscle endocrine function].

As a new secretory organ skeletal muscle, which could secrete a variety of biological active substances, plays an important role in biological function and clinical medicine, and has important research value and application scenarios in the field of sports medicine. Different mode and intensity of exercise would give different influences on skeletal muscle endocrine function. Exercise intervention could improve the chronic disease, such as metabolic disease (obesity, diabetes) and muscle atrophy by changing endocrine function of the skeletal muscle. It will be great valuable to explore the mechanisms of exercise-induced skeletal muscle endocrine, seek for the appropriate biomarker, make exercise prescription, which would give improtant theoretical value and application prospect for the exercise system function improvement metabolic disease grevention and exercise rehabilitation of the systemic diseases.