ABSTRACT
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.
ABSTRACT
The rising global prevalence of microplastics (MPs) has highlighted their diverse toxicological effects. The oxytocin (OT) system in mammals, deeply intertwined with social behaviors, is recognized to be vulnerable to environmental stressors. We hypothesized that MP exposure might disrupt this system, a topic not extensively studied. We investigated the effects of MPs on behavioral neuroendocrinology via the gut-brain axis by exposing adolescent male C57BL/6 mice to varied sizes (5 µm and 50 µm) and concentrations (100 µg/L and 1000 µg/L) of polystyrene MPs over 10 weeks. The results demonstrated that exposure to 50 µm MPs significantly reduced colonic mucin production and induced substantial alterations in gut microbiota. Notably, the 50 µm-100 µg/L group showed a significant reduction in OT content within the medial prefrontal cortex and associated deficits in sociality, along with damage to the blood-brain barrier. Importantly, blocking the vagal pathway ameliorated these behavioral impairments, emphasizing the pivotal role of the gut-brain axis in mediating neurobehavioral outcomes. Our findings confirm the toxicity of MPs on sociality and the corresponding neuroendocrine systems, shedding light on the potential hazards and adverse effects of environmental MPs exposure on social behavior and neuroendocrine frameworks in social mammals, including humans.
Subject(s)
Brain-Gut Axis , Brain , Mice, Inbred C57BL , Microplastics , Oxytocin , Polystyrenes , Social Behavior , Animals , Oxytocin/metabolism , Mice , Male , Polystyrenes/toxicity , Microplastics/toxicity , Brain/drug effects , Brain/metabolism , Brain-Gut Axis/physiology , Brain-Gut Axis/drug effects , Gastrointestinal Microbiome/drug effectsABSTRACT
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.
Subject(s)
Arvicolinae , Behavior, Animal , Gyrus Cinguli , Paternal Deprivation , Animals , Female , Male , Anxiety/metabolism , Arvicolinae/physiology , Gyrus Cinguli/metabolism , Paraventricular Hypothalamic Nucleus/metabolism , Receptors, Oxytocin/metabolism , Receptors, Oxytocin/genetics , Social BehaviorABSTRACT
Cardiac function is under neural regulation; however, brain regions in the cerebral cortex responsible for regulating cardiac function remain elusive. In this study, retrograde trans-synaptic viral tracing is used from the heart to identify a specific population of the excitatory neurons in the primary motor cortex (M1) that influences cardiac function in mice. Optogenetic activation of M1 glutamatergic neurons increases heart rate, ejection fraction, and blood pressure. By contrast, inhibition of M1 glutamatergic neurons decreased cardiac function and blood pressure as well as tyrosine hydroxylase (TH) expression in the heart. Using viral tracing and optogenetics, the median raphe nucleus (MnR) is identified as one of the key relay brain regions in the circuit from M1 that affect cardiac function. Then, a mouse model of cardiac injury is established caused by myocardial infarction (MI), in which optogenetic activation of M1 glutamatergic neurons impaired cardiac function in MI mice. Moreover, ablation of M1 neurons decreased the levels of norepinephrine and cardiac TH expression, and enhanced cardiac function in MI mice. These findings establish that the M1 neurons involved in the regulation of cardiac function and blood pressure. They also help the understanding of the neural mechanisms underlying cardiovascular regulation.
Subject(s)
Disease Models, Animal , Motor Cortex , Myocardial Infarction , Neurons , Optogenetics , Animals , Myocardial Infarction/metabolism , Myocardial Infarction/physiopathology , Myocardial Infarction/genetics , Mice , Motor Cortex/metabolism , Motor Cortex/physiopathology , Optogenetics/methods , Neurons/metabolism , Male , Heart/physiopathology , Glutamic Acid/metabolism , Mice, Inbred C57BL , Blood Pressure/physiologyABSTRACT
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.
Subject(s)
Dorsal Raphe Nucleus , Preoptic Area , Humans , Animals , Male , Preoptic Area/metabolism , Fathers , Behavior, Animal/physiology , ArvicolinaeABSTRACT
Social isolation (SI) can lead to devastating behavioral effects. Increasing evidence has demonstrated that physical activity can improve sociability and brain functions, but whether voluntary exercise can ameliorate SI-induced abnormalities in social behavior and its underlying neuronal mechanisms remains unknown. The present study found that SI during adulthood increased aggression in the resident-intruder test and motivation for social exploration in the three-chamber test. Voluntary wheel running (VWR) could reverse the alterations in social behavior induced by SI in male mice. In addition, SI increased the number of c-Fos-immunoreactive neurons and c-Fos/AVP-labeled neurons in the PVN, reduced c-Fos/TPH2-labeled neurons in the DRN. These alterations could be reversed by VWR. Together, our results reveal that voluntary exercise could ameliorate SI-induced negative effects on social behavior, possibly via alterations of neuronal activation in the brain. This finding provides a potential therapy and targets to prevent or treat the psychological diseases associated with abnormalities in social behaviors.
Subject(s)
Motor Activity , Social Behavior , Mice , Animals , Male , Brain , Social Isolation , AggressionABSTRACT
Juveniles of cooperative breeding species usually remain in the natal area and provide care to younger siblings, a behavior considered one form of alloparenting in the natural condition. Previous studies have demonstrated the effects of providing or receiving alloparental care on adult behaviors, including anxiety-like behavior, social interaction, and parental behavior, but little is known about the influences on species-typical bonding behaviors, such as pair-bond formation. In this study, we explored this concept using socially monogamous mandarin voles (Lasiopodomys mandarinus). As the oxytocin (OT) and dopamine systems are involved in alloparental and pair-bonding behaviors, we also examined the levels of central OT and tyrosine hydroxylase (TH), as well as OT receptor (OTR) and dopamine D1-type and D2-type receptors (D1R and D2R) mRNA expression in the nucleus accumbens (NAcc) and amygdala to investigate the underlying mechanisms. Our results show that mandarin voles providing alloparental care to younger siblings displayed facilitation of partner preference formation, lower levels of OT expression in the paraventricular nucleus of the hypothalamus (PVN) and lateral hypothalamus (LH), and increased OTR and D2R mRNA expression in the NAcc compared to controls. Individuals receiving alloparental care also demonstrated facilitation of partner preference formation in adult voles. Additionally, alloparental care enhanced OT expression in the PVN, anterior medial preoptic nucleus (MPOAa), medial amygdala (MeA), and TH expression in the ventral tegmental area (VTA) and zona incerta (ZI). Furthermore, males displayed decreased D1R mRNA expression in the NAcc, whereas females showed slightly increased D2R expression in the amygdala. These results demonstrate that providing or received alloparental care can promote partner preference formation in monogamous species and that these changes are associated with altered OT and dopamine levels and their receptors in specific brain regions.
Subject(s)
Dopamine , Oxytocin , Humans , Male , Animals , Female , Oxytocin/pharmacology , Oxytocin/metabolism , Dopamine/metabolism , Receptors, Oxytocin/genetics , Receptors, Oxytocin/metabolism , Receptors, Dopamine D2/genetics , Receptors, Dopamine D2/metabolism , Nucleus Accumbens/metabolism , Arvicolinae/metabolism , RNA, Messenger/metabolism , Social BehaviorABSTRACT
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.
Subject(s)
Depressive Disorder, Major , Empathy , Rats , Animals , Behavior, Animal , Emotions/physiology , Anxiety , Stress, Psychological , Disease Models, Animal , DepressionABSTRACT
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.
Subject(s)
Oxytocin , Paraventricular Hypothalamic Nucleus , Female , Male , Animals , Oxytocin/metabolism , Paraventricular Hypothalamic Nucleus/metabolism , Nucleus Accumbens , Social Defeat , Social Behavior , Arvicolinae , Stress, Psychological/metabolismABSTRACT
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.
Subject(s)
Renal Insufficiency, Chronic , Ureteral Obstruction , Animals , Humans , Mice , Apoptosis , Cell Line, Tumor , Collagen Type I/metabolism , Down-Regulation , Fatty Acids , Fibrosis , G2 Phase Cell Cycle Checkpoints , Hypoxia/pathology , Kidney/pathology , Lipids , Renal Insufficiency, Chronic/pathology , Transforming Growth Factor beta1/metabolism , Ureteral Obstruction/metabolismABSTRACT
Social contacts play an important role in the development and survival of social animals. Social isolation (SI) at adolescence often induces abnormalities in many kinds of behaviors. This study assessed whether five weeks of continuous SI at adulthood could alter social behaviors and whether dorsal raphe nucleus (DR) to medial prefrontal cortex (mPFC) 5-HT neural projections were involved in this alteration in C57BL/6J adult male mice. The present study found that five weeks chronic social isolation (CSI) at adulthood increased mounting and sniffing behaviors in resident-intruder test, and lengthened duration staying in interaction zone of stranger cage in the three-chamber social preference test. CSI also reduced the release of 5-HT in the mPFC detected by 5-HT 1.0 sensor and measured by in vivo fiber photometry test. Meanwhile, the c-Fos expression indicated that CSI reduced the activity of serotonergic neurons. Chemogenetic activation of DR-mPFC 5-HTergic projection reduced sniffing of CSI mice in the resident-intruder test, but didn't significantly affect mounting behavior. It also decreased the interaction time during the three-chamber social preference test. Thus, 5-HT neural projections from the DR to the mPFC are involved in changes of social exploration behaviors induced by CSI at adulthood.
Subject(s)
Prefrontal Cortex , Serotonin , Animals , Male , Mice , Mice, Inbred C57BL , Prefrontal Cortex/metabolism , Serotonin/metabolism , Social Behavior , Social IsolationABSTRACT
Stable and positive social bonds are pretty vital to the development of animals. Instability and disruptions of social bonds, such as maternal separation and social isolation, always produce disastrous influence on physiology, neuroendocrine and behaviors. Pair bond is one of the most important social bonds in adulthood. But the different effects of pair bond interruption between males and females are rarely studied. In the present study, the monogamous mandarin voles (Microtus mandarinus) were used to confirm the time window of pair bond formation. After that, voles were separated from their partner for 1 or 2 weeks. Then anxiety- and depression-like behaviors were investigated by using open field test, light-dark box test, tail suspension test and forced swimming test, respectively. The results showed that: (1) cohabitation for 5 days is sufficient and necessary for mandarin voles to form pair bond; (2) loss of partner is always crucial for the effects of pair bond interruption, while social isolation works in certain behavioral tests.; (3) pair bond interruption for 2 weeks significantly increased the level of anxiety and depression in adult males, but not female mandarin voles. Overall, this research suggested that loss of partner plays a key role in pair bond interruption in male mandarin voles.
Subject(s)
Maternal Deprivation , Pair Bond , Animals , Anxiety , Arvicolinae , Depression , Female , Male , Social BehaviorABSTRACT
Like mothers, fathers play a vital role in the development of the brain and behavior of offspring in mammals with biparental care. Unlike mothers, fathers do not experience the physiological processes of pregnancy, parturition, or lactation before their first contact with offspring. Whether pup exposure can induce the onset of paternal behavior and the underlying neural mechanisms remains unclear. By using Slc:ICR male mice exhibiting maternal-like parental care, the present study found that repeated exposure to pups for six days significantly increased the total duration of paternal behavior and shortened the latency to retrieve and care for pups. Repeated pup exposure increased c-Fos-positive neurons and the levels of dopamine- and TH-positive neurons in the nucleus accumbens (NAc). In addition, inhibition of dopamine projections from the ventral tegmental area to the NAc using chemogenetic methods reduced paternal care induced by repeated pup exposure. In conclusion, paternal behavior in virgin male ICR mice can be initiated by repeated pup exposure via sensitization, and the dopamine system may be involved in this process.
Subject(s)
Behavior, Animal/physiology , Dopamine/metabolism , Nucleus Accumbens/metabolism , Paternal Behavior/physiology , Animals , Male , Maternal Behavior/physiology , Mice , Mice, Inbred ICRABSTRACT
Paternal care plays a critical role in the development of brain and behaviors in offspring in monogamous species. However, the neurobiological mechanisms, especially the neuronal circuity, underlying paternal care is largely unknown. Using socially monogamous male mandarin voles (Microtus mandarinus) with high levels of paternal care, we found that paraventricular nucleus of the hypothalamus (PVN) to ventral tegmental area (VTA) or nucleus accumbens (NAc) oxytocin (OT) neurons are activated during paternal care. Chemogenetic activation/inhibition of the PVN OT projection to VTA promoted/decreased paternal care, respectively. Chemogenetic inhibition of the PVN to VTA OT pathway reduced dopamine (DA) release in the NAc of male mandarin voles during licking and grooming of pups as revealed by in vivo fiber photometry. Optogenetic activation/inhibition of the VTA to NAc DA pathway possibly enhanced/suppressed paternal behaviors, respectively. Furthermore, chemogenetic activation/inhibition of PVN to NAc OT circuit enhanced/inhibited paternal care. This finding is a first step toward delineating the neuronal circuity underlying paternal care and may have implications for treating abnormalities in paternal care associated with paternal postpartum depression or paternal abuse.SIGNIFICANCE STATEMENT Paternal behavior is essential for offspring survival and development in some mammalian species. However, the circuit mechanisms underlying the paternal brain are poorly understood. We show that manipulation of paraventricular nucleus of the hypothalamus (PVN) to ventral tegmental area (VTA) oxytocin (OT) projections as well as VTA to nucleus accumbens (NAc) DA projections promote paternal behaviors. Inhibition the PVN to VTA OT pathway reduces DA release in the NAc during pup licking and grooming. PVN to NAc OT circuit is also essential for paternal behaviors. Our findings identify two new neural circuits that modulate paternal behaviors.
Subject(s)
Behavior, Animal/physiology , Neural Pathways/metabolism , Oxytocin/metabolism , Paraventricular Hypothalamic Nucleus/metabolism , Paternal Behavior/physiology , Animals , Arvicolinae , MaleABSTRACT
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.
Subject(s)
Arvicolinae , Corticotropin-Releasing Hormone , Stress, Psychological , Animals , Arvicolinae/metabolism , Corticotropin-Releasing Hormone/metabolism , Gyrus Cinguli/metabolism , Prefrontal Cortex/metabolism , Receptors, Corticotropin-Releasing Hormone/metabolismABSTRACT
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.
Subject(s)
Behavior, Animal , Dorsal Raphe Nucleus/physiology , Gyrus Cinguli/physiology , Serotonergic Neurons/physiology , Serotonin/metabolism , Social Behavior , Animals , Arvicolinae , Dorsal Raphe Nucleus/metabolism , Female , Grooming , Gyrus Cinguli/metabolism , Male , Motor Activity , Neural Pathways/metabolism , Neural Pathways/physiology , Optogenetics , Receptor, Serotonin, 5-HT1A/metabolism , Serotonergic Neurons/metabolism , Time FactorsABSTRACT
In the regulation of emotional and social behaviors, both oxytocin (OT) and vasopressin (AVP) are sex specific. Although significant sex differences have been reported in the context of behavioral and hormonal responses to social stress, such differences in response to chronic social defeat stress (CSDS) and the underlying neural mechanisms remain largely unknown. By investigating monogamous mandarin voles (Microtus mandarinus), CSDS was found to decrease the percentages of time spent in the central area of the open field, in the open arms of the elevated plus maze, as well as in the light area of the light and dark boxes in both male and female voles. CSDS also increased the observed level of social withdrawal in both sex groups. However, CSDS exposure increased the percentages of immobile time in both the tail suspension test and the forced swim test and reduced the locomotor activity in the open field (in females only). Along with these behavioral changes, the oxytocin receptor (OTR) levels in the nucleus accumbens (NAc) were significantly lower in CSDS-exposed voles of both sexes; however, in males, the levels of OTR in the paraventricular nucleus (PVN) were reduced. CSDS-exposed males showed lower levels of V1aR in the NAc than CSDS-exposed females. Furthermore, induced by a single social defeat event, CSDS reduced c-Fos and OT double labeling in the PVN of females but increased c-Fos and AVP double-labeled neurons in the PVN of males exposed to a single social defeat event. Collectively, the present study indicates that OT and AVP systems may play important regulatory roles in the sex differences of behavioral performances in response to CSDS. These findings suggest mandarin voles as a useful animal model for studying sex-specific behavioral performance and the underlying neurobiological mechanisms of stress-related mental disorders in preclinical studies.
ABSTRACT
In the early stage of life, experiencing social isolation can generate long-lasting deleterious effects on behaviors and brain development. However, the effects of chronic social isolation during adolescence on social behaviors and its underlying neurobiological mechanisms remain unclear. The present study found that four weeks of social isolation during adolescence impaired social recognition ability in the three-chamber test and five-trial social recognition test, and increased aggressive-like behaviors, but reduced environmental exploration, as showed in the social interaction test. Chronic social isolation decreased levels of dopamine D2 receptor in the shell of the nucleus accumbens (NAcc) and medial prefrontal cortex. It also reduced TH in the NAcc. Using in vivo fiber photometry, it was also found that isolated mice displayed a reduction in NAcc shell activity upon exploring unfamiliar social stimuli. An injection of a 100 ng dose of the D2R agonist quinpirole into the shell of the NAcc reversed behavioral abnormalities induced by chronic social isolation. These data suggest that the dopamine system is involved in alterations in social behaviors induced by chronic social isolation. This finding sheds light on the mechanism underlying abnormalities in social behavior induced by adolescent chronic social isolation and provides a promising target to treat mental diseases relevant to social isolation.
Subject(s)
Dopamine/metabolism , Social Behavior , Social Isolation/psychology , Animals , Behavior, Animal/drug effects , Brain/metabolism , Dopamine/pharmacology , Dopamine Agonists/pharmacology , Male , Mice , Mice, Inbred C57BL , Nucleus Accumbens/metabolism , Prefrontal Cortex/metabolism , Receptors, Dopamine D2/genetics , Receptors, Dopamine D2/metabolismABSTRACT
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.
Subject(s)
Dopaminergic Neurons , Social Defeat , Animals , Mice , Mice, Inbred C57BL , Motor Activity , Stress, Psychological , Tyrosine 3-Monooxygenase , Ventral Tegmental AreaABSTRACT
Chlordecone (CD) is one of the common persistent organic pollutants in nature and has a profound impact on the environment and on public health. Accumulating evidence has demonstrated that neonatal exposure of CD influences adult physiology and behavior due to its estrogenic properties. Using socially monogamous mandarin voles as an experimental animal model, the present study aimed to evaluate the impact of neonatal exposure to CD on female social behaviors and central estrogen receptor alpha (ERα) expression in adulthood. After receiving a single subcutaneous injection with sesame seed oil (female control group), 17 beta-estradiol (E2 group), or CD group on postnatal Day 1, the social behaviors of adult animals and ERα expression in specific brain regions were assessed. The data indicated that CD or E2-treated female animals displayed increased affiliative behaviors and decreased aggressive behaviors with regard to the unfamiliar females in the social interaction test. In addition, CD or E2-treated female voles exhibited significant preferences to females over males in the sexual preference test. Moreover, CD-treated female animals exhibited higher levels of ERα expression in the bed nucleus of the stria terminalis, the central amygdala, the medial amygdala and the medial preoptic area compared with those of the control voles. The results suggested that neonatal exposure to CD may masculinize female social behaviors, possibly via CD-induced changes in the ERα expression of relevant brain regions.