Social adversity not only causes severe psychological diseases but also may improve people’s ability to learn and grow. However, the beneficial effects of social adversity are often ignored. In this ...study, we investigated whether and how social adversity affects learning and memory in a mouse social defeat stress (SDS) model. A total of 652 mice were placed in experimental groups of six to 23 mice each. SDS enhanced spatial, novelty, and fear memory with increased synaptosome associated protein 25 (SNAP-25) level and dendritic spine density in hippocampal neurons among young but not middle-aged mice. Chemogenetic inhibition of hippocampal CaMK2A+ neurons blocked SDS-induced enhancement of learning or memory. Knockdown of SNAP-25 or blockade of N-methyl-D-aspartate (NMDA) receptor subunit GluN2B in the hippocampus prevented SDS-induced learning memory enhancement in an emotion-independent manner. These findings suggest that social adversity promotes learning and memory ability in youths and provide a neurobiological foundation for biopsychological antifragility.
•Mice were exposed to emotional stress by witnessing the defeat of a conspecific.•Only ES mice showed anhedonia and only PS mice showed increased anxiety.•Emotional stress induced immune system ...changes 1 month after stress exposure.•Fasudil did not suppress behavioral changes induced by emotional stress.•The effects of emotional stress are not identical to those of physical stress.
In this study, we investigated the effects of emotional stress and physical stress using the social defeat stress (SDS) model in mice. Male C57BL/6 J mice were attacked by male non-retired ICR mice for 10 min daily for 10 days (physical stress; PS), while the other cohort of mice witnessed the defeat (emotional stress; ES). As a result, both PS and ES mice exhibited decreased social behavior in the social interaction test (SIT) and increased immobility in the forced swim test (FST). Interestingly, only ES mice exhibited decreased sucrose preference, and only PS mice exhibited decreased time spent in the open arms in the elevated plus-maze test. ES mice did not exhibit increased levels of corticosterone and epinephrine after a single stress exposure, but showed a decrease in plasma CXCL16 levels 1 month after stress exposure. Finally, a RhoA/Rho kinase inhibitor, fasudil, which has been reported to attenuate the effects of chronic stress, suppressed the increased immobility in the FST in PS mice, but not in ES mice. These results demonstrate that, although ES and PS mice shared many characteristics, the effects of emotional stress are not identical to those of physical stress in mice.
The study of depression in humans depends on animal models that attempt to mimic specific features of the human syndrome. Most studies focus on one or a few behavioral domains, with time and ...practical considerations prohibiting a comprehensive evaluation. Although machine learning has enabled unbiased analysis of behavior in animals, this has not yet been applied to animal models of psychiatric disease.
We performed chronic social defeat stress (CSDS) in mice and evaluated behavior with PsychoGenics’ SmartCube, a high-throughput unbiased automated phenotyping platform that collects >2000 behavioral features based on machine learning. We evaluated group differences at several times post-CSDS and after administration of the antidepressant medication imipramine.
SmartCube analysis after CSDS successfully separated control and defeated-susceptible mice, and defeated-resilient mice more resembled control mice. We observed a potentiation of CSDS effects over time. Treatment of susceptible mice with imipramine induced a 40.2% recovery of the defeated-susceptible phenotype as assessed by SmartCube.
High-throughput analysis can simultaneously evaluate multiple behavioral alterations in an animal model for the study of depression, which provides a more unbiased and holistic approach to evaluating group differences after CSDS and perhaps can be applied to other mouse models of psychiatric disease.
•Vicarious social defeat stress diminishes cell survival rate in the hippocampus.•Vicarious social defeat stress produces no effect on cell proliferation rate.•Psychological stress influences ...new-born neuronal cell survival in the hippocampus.•Antidepressant fluoxetine rescues deficiencies in social behaviors and neurogenesis.•Validities of vicarious social defeat stress as a depression model is reinforced.
Increasing evidence has shown that adult hippocampal neurogenesis is closely related to the pathophysiological condition of depressive disorders. Recently, chronic social defeat stress paradigms have been regarded as important animal models of depression, accompanied with neural plastic changes in the hippocampus. However, little is known about influences of non-physical stress on neurogenesis. In the present study, we focused on the chronic vicarious social defeat stress paradigm and examined the effect of psychological stress on mouse hippocampal neurogenesis. Immediately after the chronic psychological stress, the cell survival rate in the dentate gyrus of the hippocampus was significantly diminished without modifying the cell proliferation rate. The decreased ratio in cell survival persisted for 4 weeks after the stress-loading period, while the differentiation and maturity of new-born neurons were identical to control groups. Furthermore, treatment with the chronic antidepressant fluoxetine reversed the social behavioral deficits and promoted new-born neurons survival. These results demonstrate that emotional stress in the vicarious social defeat stress paradigm influences neuronal cell survival in the hippocampus, which reinforces its validity as an animal model of depression.
Chronic stress is the leading risk factor of a broad range of severe psychopathologies. Nonetheless, the molecular mechanisms triggering these pathological processes are not well understood. In our ...study, we investigated the effects of 15-day social defeat stress (SDS) on the genome-wide landscape of trimethylation at the 4th lysine residue of histone H3 (H3K4me3) and on the transcriptome in the prefrontal cortex of mice that were reared normally (group SDS) or subjected to maternal separation early in life (group MS+SDS). The mice with the history of stress early in life showed increased susceptibility to SDS in adulthood and demonstrated long-lasting genome-wide alterations in gene expression and splicing as well as in the H3K4me3 epigenetic landscape in the prefrontal cortex. Thus, the high-throughput techniques applied here allowed us to simultaneously detect, for the first time, genome-wide epigenetic and transcriptional changes in the murine prefrontal cortex that are associated with both chronic SDS and increased susceptibility to this stressor.
•Mice with a history of stress early in life showed increased susceptibility to SDS in adulthood•Stress early in life caused specific alterations in gene transcription, alternative splicing, and the H3K4me3 landscape in the prefrontal cortex under SDS in adulthood•The changes in the epigenetic landscape after SDS did not correlate with the level of gene expression
Ganoderic Acid A (GAA), a primary bioactive component in Ganoderma, has demonstrated ameliorative effects on depressive-like behaviors in a Chronic Social Defeat Stress (CSDS) mouse model. This study ...aims to elucidate the underlying molecular mechanisms through proteomic analysis.
C57BL/6 J mice were allocated into control (CON), chronic social defeat stress (CSDS), GAA, and imipramine (IMI) groups. Post-depression induction via CSDS, the GAA and IMI groups received respective treatments of GAA (2.5 mg/kg) and imipramine (10 mg/kg) for five days. Behavioral assessments utilized standardized tests. Proteins from the prefrontal cortex were analyzed using LC-MS, with further examination via bioinformatics and PRM for differential expression. Western blot analysis confirmed protein expression levels.
Chronic social defeat stress (CSDS) induced depressive-like behaviors in mice, which were significantly alleviated by GAA treatment, comparably to imipramine (IMI). Proteomic analysis identified distinct proteins in control (305), GAA-treated (949), and IMI-treated (289) groups. Enrichment in mitochondrial and synaptic proteins was evident from GO and PPI analyses. PRM analysis revealed significant expression changes in proteins crucial for mitochondrial and synaptic functions (namely, Naa30, Bnip1, Tubgcp4, Atxn3, Carmil1, Nup37, Apoh, Mrpl42, Tprkb, Acbd5, Dcx, Erbb4, Ppp1r2, Fam3c, Rnf112, and Cep41). Western blot validation in the prefrontal cortex showed increased levels of Mrpl42, Dcx, Fam3c, Ppp1r2, Rnf112, and Naa30 following GAA treatment.
GAA exhibits potential antidepressant properties, with its action potentially tied to the modulation of synaptic functions and mitochondrial activities.
•Ganoderic Acid A shows antidepressant effects similar to imipramine in mice, suggesting its therapeutic potential.•Proteomic analysis indicates changes in mitochondrial and synaptic proteins in the prefrontal cortex.•The study links specific proteins (e.g., Mrpl42, Ppp1r2, Dcx, Fam3c, Rnf112, Naa30) to Ganoderic Acid A's mood-regulation effects.
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.
•Repeated OT treatment prevented CSDS-induced increases of anxiety-like behaviors and social avoidance•CSDS and Repeated OT treatment produced no effects on depression-like behavior in males.•Repeated OT treatment prevented reduction of OT receptors in the NAc induced by CSDS only in females.•Activation of PVN-NAcs pathway during or after CSDS reduced adverse effects of CSDS on behaviors.
Normative error theorists aim to defend an error theory which says that normative judgments ascribe normative properties, and such properties, including reasons for belief, are never instantiated. ...Many philosophers have raised objections to defending a theory which entails that we cannot have reason to believe it. Spencer Case objects that error theorists simply cannot avoid self-defeat. Alternatively, Bart Streumer argues that we cannot believe normative error theory but that, surprisingly, this helps its advocates defend it against these objections. I think that if Streumer’s argument is successful, it provides error theorists an escape from Case’s self-defeat objection. However, I build upon and improve Case’s argument to show that we could never even successfully defend normative error theory whether we can believe it or not. So, self-defeat remains. I close by offering some reasons for thinking our inability to defend normative error theory means that we should reject it, which, in turn, would mean that it’s false.
Normativni teoretičari pogreške nastoje braniti teoriju pogreške koja kaže da normativni sudovi pripisuju normativna svojstva, a takva svojstva, uključujući razloge za vjerovanje, nikada nisu instancirana. Mnogi filozofi su iznijeli prigovore obrani teorije koja podrazumijeva da ne možemo imati razloga vjerovati u nju. Spencer Case prigovara da teoretičari pogreške jednostavno ne mogu izbjeći samopobijanje. S druge strane, Bart Streumer tvrdi da ne možemo vjerovati u normativnu teoriju pogreške, ali da to, pomalo iznenađujuće, pomaže njenim zagovornicima da je obrane od ovih prigovora. Smatram da, ako je Streumerov argument uspješan, on omogućuje teoretičarima pogreške izbjegavanje Caseovog prigovora o samopobijanju. Međutim, nadograđujem i poboljšavam Caseov argument kako bih pokazao da nikada ne bismo mogli uspješno obraniti normativnu teoriju pogreške, bez obzira na to možemo li vjerovati u nju ili ne. Dakle, samopobijanje ostaje. Rad zaključujem nudeći neke razloge za mišljenje da naša nesposobnost da obranimo normativnu teoriju pogreške znači da bismo je trebali odbaciti, što bi posljedično značilo da je ona neistinita.
The serotonergic (5-HTergic) system is closely involved in the pathophysiology of mood and anxiety disorders and the responsibility of this system may differ for each symptom. In this study, we ...examined the relationship between the dysfunction of the 5-HTergic system and abnormal behaviors in the social defeat stress model, an animal model of mood and anxiety disorders and in mice with knockdown of Slc6a4, the gene encoding SERT. Monoamine content, serotonin (5-HT) release, 5-HT uptake, 5-HT transporter (SERT) protein levels, and behaviors were investigated in mice subjected to chronic social defeat stress and in mice with knockdown of Slc6a4, in 5-HTergic neurons projecting to the prefrontal cortex (PFC). Furthermore, DNA methylation of Slc6a4 was examined in mice subjected to chronic social defeat stress. Increased turnover, increased extracellular basal levels, decreased release and decreased uptake of 5-HT, and decreased SERT protein levels were observed in the PFC of the stressed mice. The decreased 5-HT uptake correlated with anxiety-like behavior characterized by decreased time spent in the open arms of the elevated plus maze. DNA methylation was increased in the CpG island of Slc6a4 in 5-HTergic neurons projecting to the PFC of the stressed mice. Similar to the stressed mice, mice with Slc6a4 knockdown in 5-HTergic neurons projecting to the PFC also showed decreased release and uptake of 5-HT in the PFC and increased anxiety-like behavior. Chronic stress may induce anxiety due to dysfunction in the prefrontal 5-HTergic system via decreased SERT expression in the PFC.
•Anxiety-like behavior and reduced prefrontal serotonin uptake are correlated.•Stress methylated Slc6a4 gene in serotonergic neurons projecting to the PFC.•Slc6a4 knockdown in the PFC induces anxiety-like behavior.
•Mild early life stress primes microglia and alters its later response to stress.•Mild ELS reduces PPARγ expression in the hippocampus.•Mild ELS followed by CSD induces PPARγ expression in the ...hippocampus.•Chronic social defeat affects microglia in the amygdala.•CSD increases IL-1b and TNFα in the hippocampus and the amygdala.
Exposure to early life stress affects the development and function of the brain and when followed by adversities in adulthood, the negative effects of stress are enhanced. Microglia has been proposed as a potential mediator of this phenomenon. In the present study, we investigated the long-term effects of mild early life stress, the consequences of a stressor in adulthood as well as their interaction on microglial and cytokine (PPARγ, IL-1β and TNFα) levels in the brain of adult male rats. As an early life stress we used a model of maternal neglect, in which the dam is present but non-accessible to the pup for 15 min during postnatal days 10–13; as a stressor in adulthood we exposed animals to chronic social defeat (CSD) for 3 weeks. We determined in the hippocampus, prefrontal cortex and amygdala, the number of Iba-1+ microglial cells, the number of PPARγ+ cells as well as the relative expression of PPARγ, IL-1β and TNFα mRNA by qPCR. Following exposure to CSD, the number of Iba-1+ cells was increased in the hippocampus and the prefrontal cortex of adult animals exposed to mild early life stress, while in the absence of CSD no such difference was observed. Moreover, following CSD PPARγ levels were increased in the hippocampus of adult males exposed as neonates to “maternal neglect”. Our findings support the notion that early life stress, even a mild one, primes microglia and enhances its reactivity to a second stressful event, later in life, in accord with the “two-hit” hypothesis.
