[An emotional stress model using witnessing social defeat scenes in mice].

Chronic exposure to stress can lead to a variety of mental disorders such as depression. There are many treatment-resistant patients who do not respond adequately to the standard pharmacological treatments. Therefore, the development of novel therapeutic agents is highly expected. In rodents, socially defeated animals that were exposed to repeated physical aggression from other individuals are widely used in this field of research. The social defeat is considered as a stress that mimics human social stress. On the other hand, emotional stress, but not physical stress, is likely to contribute to the pathogenesis and etiology of depression in human. Therefore, there is a gap between the process of pathogenesis and the animal models, and this is one of the reasons why the development of new psychotropic drugs to treat depression has been difficult. Recently, a novel stress model has been introduced, in which mice are subjected to emotional stress without physical distress by witnessing social defeat scenes of their conspecifics. We have investigated the mechanisms by which emotional stress is transmitted by witnessing social defeat in mice, focusing on the insular cortex. In this article, we summarize and discuss the recent advancements in the neural basis of behavioral changes induced by emotional stress.

Adolescent social isolation induces distinct changes in the medial and lateral OFC-BLA synapse and social and emotional alterations in adult mice.

Early-life social isolation is associated with social and emotional problems in adulthood. However, neural mechanisms underlying how social deprivation impairs social and emotional development are poorly understood. Recently, the orbitofrontal cortex (OFC) and basolateral amygdala (BLA) have been highlighted as key nodes for social and emotional functions. Hence, we hypothesize that early social deprivation disrupts the information processing in the OFC-BLA pathway and leads to social and emotional dysfunction. Here, we examined the effects of adolescent social isolation on the OFC-BLA synaptic transmission by optogenetic and whole-cell patch-clamp methods in adult mice. Adolescent social isolation decreased social preference and increased passive stress-coping behaviour in adulthood. Then, we examined excitatory synaptic transmissions to BLA from medial or lateral subregions of the OFC (mOFC or lOFC). Notably, adolescent social isolation decreased the AMPA/NMDA ratio in the mOFC-BLA synapse in adulthood, while the ratio was increased in the lOFC-BLA synapse. Furthermore, we optogenetically manipulated the mOFC-BLA or lOFC-BLA transmission in behaving mice and examined the effects on social and stress-coping behaviours. Optogenetic manipulation of the mOFC-BLA transmission altered social behaviour without affecting passive stress-coping behaviour, while optogenetic manipulation of the lOFC-BLA transmission altered passive stress-coping behaviour without affecting social behaviour. Our results suggest that adolescent social isolation induces distinct postsynaptic changes in the mOFC-BLA and lOFC-BLA synapses, and these changes may separately contribute to abnormalities in social and emotional development.

Indirect exposure to socially defeated conspecifics using recorded video activates the HPA axis and reduces reward sensitivity in mice.

Rodents perceive the emotional states of conspecifics using vision. In the present study, we demonstrated that exposure to the video-recorded distress of conspecifics induces stress responses in male C57BL/6J mice. A single exposure to a video-recorded scene of the social defeat stress (SDS) increased plasma corticosterone levels in these mice. This physiological change was suppressed by blocking the visual information, suggesting that vision plays a crucial role in inducing stress responses. Furthermore, after exposure to the video, there were increased numbers of c-Fos-positive neurons in the anterior cingulate cortex and other brain areas that are associated with the negative valence and empathy systems, but not in the regions related to the pain signaling. In addition, repeated exposure to SDS videos induced an apparent reduction in reward sensitivity in the sucrose preference test, but did not affect avoidance behaviour in the social interaction test or immobility behaviour in the forced swim test. Reduced reward sensitivity in mice reflects anhedonia, which is a core symptom of depression in humans. Our video SDS model therefore provides a unique opportunity to not only understand the mechanisms underlying stress-induced anhedonia, but also to screen effective candidate molecules for stress-related disorders with greater reproducibility.

Early life stress from allergic dermatitis causes depressive-like behaviors in adolescent male mice through neuroinflammatory priming.

Allergic dermatitis (AD), associated with pruritus and itchiness, is one of the major stressful conditions early in life. AD also influences the incidence of neuropsychiatric disorders and developmental disorders through neuro-immune interactions. To the best of our knowledge, there is no report that assesses the effects of early childhood dermatitis on psychiatric disorders later in life using an animal model. Here, we developed an oxazolone (Ox)-induced AD model in the early life of male C57BL/6J mice whose ears were challenged by Ox repeatedly from postnatal days (PD) 2 to PD30. On PD30, the Ox-treated ears were remarkably thickened and showed epidermal hyperplasia coupled with increased expression of T helper 2 cytokines, interleukin (IL)-4, and IL-13 in the ear tissue. Additionally, serum immunoglobulin E levels and serum corticosterone levels were higher in the Ox-treated mice than those in the control mice. Although Ox-treated PD40 mice showed neither behavioral abnormalities nor increases in pro-inflammatory cytokine expression in the brain, this study revealed that they experienced downregulation of CD200R1 expression in the amygdala under basal conditions and that additional lipopolysaccharide (LPS) administration induced enhanced neuroinflammatory reaction as the priming effect was accompanied by an increase of Iba-1-positive microglia in the amygdala and hippocampus. Furthermore, the Ox-treated PD40 mice showed depressive-like behaviors 24 h after LPS administration, whereas the control mice did not. Interestingly, the expression of indoleamine 2,3-dioxygenase and kynurenine 3-monooxygenase, key rate-limiting enzymes of the kynurenine metabolism pathway, was upregulated in the hippocampus, prefrontal cortex, and amygdala of the Ox-treated mice 4 h after LPS administration. Based on these results, we suggest that early life stress from AD aggravates susceptibility to systemic inflammation in the adolescent brain, leading to depressive behaviors with abnormal kynurenine metabolism.

Benzothiazepines, diltiazem and JTV-519, exert an anxiolytic-like effect via neurosteroid biosynthesis in mice.

We investigated whether benzothiazepines could produce anxiolytic effects via allopregnanolone (ALLO) biosynthesis in mice. We compared the behavioral effects caused by benzothiazepines to those caused by carbamazepine and sodium valproate. We found that a pretreatment with finasteride (a 5 alpha-reductase inhibitor) suppressed carbamazepine-induced anxiolytic effects but not the effects of sodium valproate. Similar to carbamazepine, diltiazem and JTV-519 displayed anxiolytic effects that were suppressed by a pretreatment with finasteride. We clearly demonstrate that the benzothiazepines, diltiazem and JTV-519, exert an anxiolytic-like effect via ALLO biosynthesis in mice.

The effects of emotional stress are not identical to those of physical stress in mouse model of social defeat 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.

Degradation of 2,7-dichlorodibenzo-p-dioxin by Fe(3+)-H(2)O(2) mixed reagent.

Fe(3+)-H(2)O(2) mixed reagent, but not Fe(2+)-H(2)O(2), was found to be capable of degrading 2,7-dichlorodibenzo-p-dioxin (DCDD). A reaction mixture of FeCl(3) (8 mM) and H(2)O(2) (1%) caused approximately 50% degradation within 6 h and >90% degradation within 24 h at 27 degrees C. Increasing the temperature remarkably stimulated degradation: at 70 degrees C, approximately 100% degradation was achieved within 15 min. When DCDD-treated model soil (5 micrograms/g) was conducted, approximately 100% of the DCDD was degraded within 30 min at 70 degrees C (both reagents were added every 10 min). These results suggest that Fe(3+)-H(2)O(2) mixed reagent may be a new tool for combating persistent environmental pollutants such as dioxins and polychlorinated biphenyls.