高柳 友紀

BACKGROUND: The flexibility to adjust actions and attitudes in response to varying social situations is a fundamental aspect of adaptive social behavior. Adaptive social behaviors influence an individual's vulnerability to social stress. While oxytocin has been proposed to facilitate active coping behaviors during social stress, the exact mechanisms remain unknown. METHODS: By using a social defeat stress paradigm in male mice, we identified the distribution of oxytocin receptor (OXTR)-expressing neurons in the ventrolateral part of the ventromedial hypothalamus (vlVMH) that are activated during stress by detection of c-Fos protein expression. We then investigated the role of vlVMH OXTR-expressing neurons in social defeat stress responses by chemogenetic methods or deletion of local OXTRs. The social defeat posture was measured for quantification of adaptive social behavior during repeated social stress. RESULTS: Social defeat stress activated OXTR-expressing neurons rather than estrogen type 1-expressing neurons in the rostral vlVMH. OXTR-expressing neurons in the vlVMH were glutamatergic. Chemogenetic activation of vlVMH OXTR-expressing neurons facilitated exhibition of the social defeat posture during exposure to social stress, while local OXTR deletion suppressed it. In contrast, over-activation of vlVMH-OXTR neurons induced generalized social avoidance after exposure to chronic social defeat stress. Neural circuits for the social defeat posture centered on OXTR-expressing neurons were identified by viral tracers and c-Fos mapping. CONCLUSIONS: VlVMH OXTR-expressing neurons are a functionally unique population of neurons that promote an active coping behavior during social stress, but their excessive and repetitive activation under chronic social stress impairs subsequent social behavior.

Rodent ultrasonic vocalisations can be used to assess social behaviour and have attracted increasing attention. Rats emit 50-kHz and 22-kHz calls during appetitive and aversive states, respectively. These calls induce behavioural and neural responses in the receiver by transmitting the internal states of the rats, thus serving communicative functions. Recently, we discovered that female Lewis rats emit 31-kHz calls under social isolation and inequality conditions; however, the biological significance of 31-kHz calls remains unknown. In the present study, we conducted three playback experiments to examine the behavioural effects of 31-kHz calls. In the first experiment, Lewis female rats were exposed to four types of sound: 22-kHz, 50-kHz, 31-kHz calls, and environmental noise. As a result, rats stayed significantly longer in the area with a sound-producing speaker, regardless of the sound type, than in the silent speaker area. The duration spent around the sound-producing speaker was particularly extended during the 50-kHz or 31-kHz call playback, compared to the environmental noise or 22-kHz call playback. In the second experiment, rats were exposed to refined versions of sound stimuli that were synthesised to preserve prominent frequency components while removing background noise from original calls. Rats significantly preferred to stay around the speaker for the synthesised 50-kHz and 31-kHz sounds, but not for the synthesised 22-kHz sound. However, in the third experiment, additional 31-kHz sound synthesised from calls emitted by a different rat did not elicit a significant preference for the source side. These results suggest that the rats paid attention to the 31-kHz call, although it is plausible that acoustic variability in the 31-kHz USV may affect their approach behaviour.

The cerebellum plays an important role in cognitive and social functioning. Childhood damage in the cerebellum increases the risk of autism spectrum disorder. Cerebellar inflammation induces social avoidance in mice. Oxytocin regulates social relationship and expression pattern of the oxytocin receptor in the brain is related to social behaviors. However, the expression patterns of the oxytocin receptor in the cerebellum remain controversial. Here, we report that the expression patterns of the oxytocin receptor in the cerebellum are highly variable among knock-in transgenic lines. We used Oxtr-Cre knock-in mice combined with a fluorescent reporter line and found that oxytocin receptor expression in Bergmann glia was more variable than that in Purkinje cells. We found that physical damage with inflammation induced the selective upregulation of the oxytocin receptor in Bergmann glia. Our findings indicate high variability in oxytocin receptor expression in the cerebellum and suggest that the oxytocin receptor can affect neural processing in pathological conditions, such as inflammation.

BACKGROUND: Fabry disease (FD) is an inherited lysosomal storage disease caused by deficiency of α-galactosidase A (α-Gal A) encoded by the GLA gene. The symptoms of FD occur as a result of the accumulation of globotriaosylceramide (Gb3), comprising a substrate of α-Gal A, in the organs. Adeno-associated virus (AAV)-mediated gene therapy is a promising treatment for FD. METHODS: α-Gal A knockout (GLAko) mice were injected intravenously with AAV2 (1 × 1011 viral genomes [vg]) or AAV9 (1 × 1011 or 2 × 1012 vg) vectors carrying human GLA (AAV-hGLA), and plasma, brain, heart, liver and kidney were tested for α-Gal A activity. The vector genome copy numbers (VGCNs) and Gb3 content in each organ were also examined. RESULTS: The plasma α-Gal A enzymatic activity was three-fold higher in the AAV9 2 × 1012 vg group than wild-type (WT) controls, which was maintained for up to 8 weeks after injection. In the AAV9 2 × 1012 vg group, the level of α-Gal A expression was high in the heart and liver, intermediate in the kidney, and low in the brain. VGCNs in the all organs of the AAV9 2 × 1012 vg group significantly increased compared to the phosphate-buffered-saline (PBS) group. Although Gb3 in the heart, liver and kidney of the AAV9 2 × 1012 vg was reduced compared to PBS group and AAV2 group, and the amount of Gb3 in the brain was not reduced. CONCLUSIONS: Systemic injection of AAV9-hGLA resulted in α-Gal A expression and Gb3 reduction in the organs of GLAko mice. To expect a higher expression of α-Gal A in the brain, the injection dosage, administration route and the timing of injection should be reconsidered.