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Purpose In our previous study, we developed an assay system to evaluate antisocial maltreating behavior of conspecific mice using a perpetrator–victim paradigm. We also generated a mouse model for the maltreating behavior by mimicking child maltreatment or abuse. Here, we further investigate the antisocial behavior using anti-aggressive and antipsychotic drugs. Methods Model mice sequentially subjected to maternal separation (MS), social defeat (SD), and social isolation (SI) in that order (MS/SD/SI model) were subjected to a maltreating behavioral task. The MS/SD/SI mice were treated with oxytocin (OXY), clozapine (CLZ), haloperidol (HAL), and 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT). Western blotting and enzyme-linked immunosorbent assay were used for protein analysis. Results A substantial portion of the MS/SD/SI model mice (46% of males and 40% of females) showed a higher number of nose pokes than the control. OXY or 8-OH-DPAT treatment reduced the high number of nose pokes by the MS/SD/SI mice, whereas HAL increased it. CLZ did not affect the number of nose pokes by the MS/SD/SI mice. Interestingly, although the OXY level in the MS/SD/SI mice was similar to that in the control, the amount of OXY receptor was lower in the MS/SD/SI mice. The amount of 5-HT1A receptor was also decreased in the MS/SD/SI mice. Conclusion Chronic social stress in childhood might predispose a mouse to antisocial behavior. Our maltreating behavior assay system, including the MS/SD/SI model, is a good animal system for research on and drug screening for brain disorders associated with antisocial or psychotic behavior.

Purpose Febrile seizures at a young age can provoke late-onset temporal lobe epilepsy. Since recent evidence has suggested that the gut microbiome affects central nervous system pathology across the blood-brain barrier, we hypothesized that febrile seizures alter the composition of the gut microbiome to provoke epilepsy. Methods Third-generation C57BL/6 mice were separated into two groups (n = 5 each), and hot air was applied to only one group to cause febrile seizures. After two weeks of heat challenge, the fecal pellets acquired from each group were analyzed. Results The gut microbiota of fecal pellets from each group revealed five taxa at the genus level and eight taxa at the species level that were significantly different in proportion between the groups. Conclusion Although there was no significant difference in the overall diversity of the gut microbiota between the two groups, the identified heterogeneity may imply the pathognomonic causative relevance of febrile seizures and the development of epilepsy.

Purpose Early-life stress can cause brain inflammation and affect social behavior in adulthood. In humans, maltreated (abused or neglected) children often exhibit antisocial behavior, including violent and sadistic behavior, in adulthood. However, it is unknown whether maltreatment behavior occurs in rodents. Here, we developed an assay system to evaluate conspecific maltreatment behavior in the mouse. Methods To assess maltreatment behavior, we devised a two-chamber apparatus separated by a transparent partition, in which one chamber was provided with a nose-poking hole that would trigger foot shocks onto the other. Lidocaine was used to inhibit neural activity in vivo. Brain oscillations were investigated by electroencephalograph. Enzyme-linked immunosorbent assay was used for protein assay. The mouse model was sequentially subjected to maternal separation (MS), social defeat (SD), and social isolation (SI) in that order (MS/SD/SI model). Results Inactivation of the anterior cingulate cortex and medial prefrontal cortex increased the level of nose-poking. Maltreatment behavior provoked changes in oxytocin, corticosterone, and brain-derived neurotrophic factor levels. MS/SD/SI mice exhibited more sustained nose-poking behavior during the experiment, resulting in increased foot shocks to the mouse in the opposite chamber. Abnormal brain oscillations were observed in the MS/SD/SI mice. Conclusion The MS/SD/SI model and maltreatment-behavior assay may be useful not only to study the relationship between social stress in childhood and antisocial behavior in adulthood, but also for study of etiology, pathology, or treatment for brain disorders, such as psychopathy.

Purpose Chronic social stress is known to induce inflammation in the brain, and early-life stress affects the brain and social behavior in adulthood. To study the relationship between social stress in childhood development and social behavior in adulthood, we subjected mice to a sequential early-life social stresses and characterized their adult behavioral phenotypes. Methods C57BL/6 mice were sequentially subjected to maternal separation (MS), social defeat (SD), and social isolation (SI) in that order. The body weights of the MS/SD/SI mice were measured. Behavioral tasks related to anxiety, depression, locomotion, learning/memory, and repetitive/compulsive-like behavior were conducted. Social behaviors suggesting sociability, social interaction, aggression, and social fear were investigated. Results MS/SD/SI mice weighed less than the control mice. At 7 and 8 weeks of age. These mice displayed normal behaviors in anxiety-, depression-, and learning/memory-related tasks, but they exhibited increased locomotor activity and a low level of repetitive/compulsive-like behavior. Notably, they exhibited increased social interaction, impaired empathy-related fear, reduced predator fear, and increased defensive aggressiveness. Conclusion Social stress during childhood development resulted in behavioral alterations, and MS/SD/SI mice generated by mimicking child abuse or maltreatment showed unique abnormalities in social behaviors. MS/SD/SI mice might be useful not only to study the relationship between social stress and brain inflammation but also psychosocial behaviors observed in individuals with brain disorders, such as psychopaths.

Purpose Suicidality can be a serious feature of psychiatric symptoms in encephalitis. Investigating the psychiatric behavior associated with suicidality in animal models of encephalitis is important; thus, determining whether normal laboratory animals are aware of death is necessary. Methods To examine the behavioral and brain activity changes associated with death of conspecifics, laboratory mice were exposed to a cadaveric mouse or an anesthetized mouse. Behavioral tasks associated with anxiety and locomotion were conducted after repeated exposure. Neural activity in the medial prefrontal cortex during the cadaver exploration was investigated using electroencephalographic recordings. Results During repeated exposure, mice in the cadaver group showed a gradual decrease in time exploring the cadaver, which was not observed in mice in the anesthesia group. The cadaver group also exhibited increased levels of anxiety in the light/dark transition and elevated plus maze tasks and displayed increased locomotor activity in the open field test. In an electrophysiological study, different brain oscillations were observed when mice were exposed to a cadaveric mouse and an anesthetized mouse. Enhanced delta-band activity and reduced theta- and alpha-band activities were observed during cadaver exploration. Conclusion The present study results showed that experiences involving dead conspecifics strongly affect mouse behavior and brain activity. These findings may be helpful in treating patients with psychiatric symptoms and aid in understanding the concept of death recognition/awareness in laboratory animals.