Neuro-inflammation has been shown to play a critical role in the development of depression. Beta-hydroxybutyrate (BHB) is a ketone body and has recently been reported to exert anti-inflammatory effects via inhibition of NLRP3 inflammasome. Here, we investigated the potential antidepressant and anti-inflammatory effects of BHB on rats exposed to acute and chronic stress. We examined the influence of repeated BHB administration on depressive and anxiety behaviors in a rodent model of chronic unpredictable stress (CUS). Additionally, the influence of acute immobilization (IMM) stress and single BHB administration on hippocampal interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) were assessed. Repeated administration of BHB attenuated CUS-induced depressive- and anxiety-related behaviors. IMM stress increased levels of IL-1β in the hippocampus, while a single pre-administration of BHB attenuated this increase. Although no effect was observed on hippocampal TNF-α levels after 1 h of IMM stress, a single BHB pre-administration reduced hippocampal TNF-α. Our previous report showed that the release of IL-1β and TNF-α caused by stress is tightly regulated by NLRP3 inflammasome. These findings demonstrate that BHB exerts antidepressant-like effects, possibly by inhibiting NLRP3-induced neuro-inflammation in the hippocampus, and that BHB may be a novel therapeutic candidate for the treatment of stress-related mood disorders.

Olig2 is a basic helix-loop-helix (bHLH) transcription factor essential for development of motoneurons and oligodendrocytes. It is known that Olig2(+) cells persist in the central nervous system (CNS) from embryonic to adult stages and that the number of Olig2(+) progenitors increases in the injured adult CNS. Recent studies have demonstrated an inhibitory action of Olig2 on neurogenesis in adult CNS, but the fate of Olig2(+) cells in the injured state remains largely unknown. To trace directly the fate of Olig2 cells in the adult cerebral cortex after injury, we employed the CreER/loxP system to target the olig2 locus. In this genetic tracing study, green fluorescent protein (GFP) reporter-positive cells labeled after cryoinjury coexpressed glial fibrillary acidic protein (GFAP), an astrocytic marker. Electron microscopy also showed that GFP(+) cells have the ultrastructural characteristics of astrocytes. Furthermore, GFP(+) cells labeled before injury, most of which had been NG2 cells, also produced bushy astrocytes. Here we show direct evidence that Olig2(+) cells preferentially differentiate into astrocytes, which strongly express GFAP, in response to injury in the adult cerebral cortex. These results suggest that reactive astrocytes, known to be the main contributors to glial scars, originate, at least in part, from Olig2(+) cells.

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Epidemiological data suggest a relationship between maternal infection and a high incidence of schizophrenia in offspring. An animal model based on this hypothesis was made by injecting double-stranded RNA, polyinosinic-polycytidylic acid (poly-I:C), into early pregnant mice, and their offspring were examined for biochemical and histological abnormalities. Mouse brains were examined with special reference to oligodendrocytes, which have been implicated in several neurodevelopmental disorders. We detected a significant decrease of myelin basic protein (MBP) mRNA and protein at early postnatal periods in poly-I:C mice. MBP immunocytochemistry and electron microscopy revealed that the hippocampus of juvenile poly-I:C mice was less myelinated than in PBS mice, with no significant loss of oligodendrocytes. In addition, axonal diameters were significantly smaller in juvenile poly-I:C mice than in control mice. These abnormalities reverted to normal levels when the animals reached the adult stage. These findings suggest that retarded myelination and axonal abnormalities in early postnatal stages caused by maternal immune activation could be related to schizophrenia-related behaviors in adulthood.

Enriched environments enhance hippocampal neurogenesis, synaptic efficacy, and learning and memory functions. Recent studies have demonstrated that enriched environments can restore learning behavior and long-term memory after significant brain atrophy and neural loss. Emotional and anxiety-related behaviors were also improved by enriched stimuli, but the effect of enriched environments on the amygdala, one of the major emotion-related structures in the central nervous system, remains largely unknown. In this study, we have focused on the effects of an enriched environment on cell proliferation and differentiation in the murine amygdala. The enriched environment increased bromodeoxyuridine (BrdU)-positive (newborn) cell numbers in the amygdala, almost all of which, immediately after a 1-week period of enrichment, expressed the oligodendrocyte progenitor marker Olig2. Furthermore, enriched stimuli significantly suppressed cell death in the amygdala. Some of the BrdU-positive cells in mice exposed to the enriched environment, but none in animals housed in the standard environment, later differentiated into astrocytes. Our findings, taken together with previous behavioral studies, suggest that progenitor proliferation and differentiation in the amygdala may contribute to the beneficial aspects of environmental enrichment such as anxiolytic effects.

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Social isolation is an important factor in the development of psychiatric disorders. It is necessary to develop an effective psychological treatment, such as cognitive rehabilitation, for children who have already suffered from social isolation, such as neglect and social rejection. We used socially isolated mice to validate whether elaborate re-socialization after juvenile social isolation can restore hypomyelination in the medial prefrontal cortex (mPFC) and the attendant functions manifested in socially isolated mice. While mice who underwent re-socialization with socially isolated mice after juvenile social isolation (Re-IS mice) demonstrated less mPFC activity during exposure to a strange mouse, as well as thinner myelin in the mPFC than controls, mice who underwent re-socialization with socially housed mice after juvenile social isolation (Re-SH mice) caught up with the controls in terms of most mPFC functions, as well as myelination. Moreover, social interaction of Re-IS mice was reduced as compared to controls, but Re-SH mice showed an amount of social interaction comparable to that of controls. These results suggest that the mode of re-socialization after juvenile social isolation has significant effects on myelination in the mPFC and the attendant functions in mice, indicating the importance of appropriate psychosocial intervention after social isolation.