吉田 匡秀

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.

Social stress has deteriorating effects on various psychiatric diseases. In animal models, exposure to socially dominant conspecifics (i.e., social defeat stress) evokes a species-specific defeat posture via unknown mechanisms. Oxytocin neurons have been shown to be activated by stressful stimuli and to have prosocial and anxiolytic actions. The roles of oxytocin during social defeat stress remain unclear. Expression of c-Fos, a marker of neuronal activation, in oxytocin neurons and in oxytocin receptor‒expressing neurons was investigated in mice. The projection of oxytocin neurons was examined with an anterograde viral tracer, which induces selective expression of membrane-targeted palmitoylated green fluorescent protein in oxytocin neurons. Defensive behaviors during double exposure to social defeat stress in oxytocin receptor‒deficient mice were analyzed. After social defeat stress, expression of c-Fos protein was increased in oxytocin neurons of the bed nucleus of the stria terminalis, supraoptic nucleus, and paraventricular hypothalamic nucleus. Expression of c-Fos protein was also increased in oxytocin receptor‒expressing neurons of brain regions, including the ventrolateral part of the ventromedial hypothalamus and ventrolateral periaqueductal gray. Projecting fibers from paraventricular hypothalamic oxytocin neurons were found in the ventrolateral part of the ventromedial hypothalamus and in the ventrolateral periaqueductal gray. Oxytocin receptor‒deficient mice showed reduced defeat posture during the second social defeat stress. These findings suggest that social defeat stress activates oxytocin-oxytocin receptor systems, and the findings are consistent with the view that activation of the oxytocin receptor in brain regions, including the ventrolateral part of the ventromedial hypothalamus and the ventrolateral periaqueductal gray, facilitates social defeat posture.

BACKGROUND: Social recognition underlies social behavior in animals, and patients with psychiatric disorders associated with social deficits show abnormalities in social recognition. Oxytocin is implicated in social behavior and has received attention as an effective treatment for sociobehavioral deficits. Secretin receptor-deficient mice show deficits in social behavior. The relationship between oxytocin and secretin concerning social behavior remains to be determined. METHODS: Expression of c-Fos in oxytocin neurons and release of oxytocin from their dendrites after secretin application were investigated. Social recognition was examined after intracerebroventricular or local injection of secretin, oxytocin, or an oxytocin receptor antagonist in rats, oxytocin receptor-deficient mice, and secretin receptor-deficient mice. Electron and light microscopic immunohistochemical analysis was also performed to determine whether oxytocin neurons extend their dendrites into the medial amygdala. RESULTS: Supraoptic oxytocin neurons expressed the secretin receptor. Secretin activated supraoptic oxytocin neurons and facilitated oxytocin release from dendrites. Secretin increased acquisition of social recognition in an oxytocin receptor-dependent manner. Local application of secretin into the supraoptic nucleus facilitated social recognition, and this facilitation was blocked by an oxytocin receptor antagonist injected into, but not outside of, the medial amygdala. In the medial amygdala, dendrite-like thick oxytocin processes were found to extend from the supraoptic nucleus. Furthermore, oxytocin treatment restored deficits of social recognition in secretin receptor-deficient mice. CONCLUSIONS: The results of our study demonstrate that secretin-induced dendritic oxytocin release from supraoptic neurons enhances social recognition. The newly defined secretin-oxytocin system may lead to a possible treatment for social deficits.

Gentle touching or stroking has anxiolytic actions and contributes to the establishment of an intimate relationship between individuals. Oxytocin administration also has anxiolytic actions and facilitates social behaviors. In this study, we examined effects of stroking stimuli on activation of oxytocin neurons and emission of 50-kHz ultrasonic vocalizations, an index of positive emotion, in rats. The number of oxytocin neurons expressing Fos protein was increased in the hypothalamus, especially in the dorsal zone of the medial parvicellular part of the paraventricular nucleus. The number of 50-kHz ultrasonic vocalizations was also increased. These findings suggest that pleasant sensory stimuli activate hypothalamic oxytocin neurons.

We previously generated oxytocin (OXT)-deficient mice and oxytocin receptor (OXTR)-deficient mice. Impaired social behaviors were observed in these mice, so they may be useful as animal models for studying the regulatory mechanism of social behavior by the OXT/OXTR system in the brain. In the present review, we aimed to overview our previous works to unravel the mechanism(s) by which OXTR deficiency leads to the impairment of social behaviors; for example, abnormalities in maternal behavior and/or social memory observed in mice deficient in the OXTR will be presented. By analyzing the brain of the OXTR-modified yellow fluorescent protein knock-in mice histologically, OXTR-expressing neurons were observed conspicuously in brain regions that are related to social behaviors. We focus on the characteristics of the regions containing neurons with prominent Oxtr gene expression in the present manuscript and discuss on the mechanisms through which OXT exerts its effects on social behaviors.

Oxytocin plays an essential role in milk ejection and parturition in mammals. Oxytocin has also been shown to be involved in the control of various behaviors, including anxiety-related behaviors, food intake and affiliative behaviors.<br>We previously showed that noxious stimuli or stimuli previously paired with noxious stimuli (conditioned fear stimuli) activate hypothalamic oxytocin neurons via activation of brainstem catecholaminergic/prolactin-releasing peptide (PrRP)-positive neurons. Oxytocin neurons are activated not only by noxious stimuli but also by non-noxious touch stimuli. Social contact has been suggested to activate oxytocin neurons. Non-noxious tactile stimuli induce 50-kHz ultrasonic vocalization, an index of positive states in rats, and activate hypothalamic oxytocin neurons, suggesting that pleasant tactile stimuli activate oxytocin neurons.<br>Physiological roles of oxytocin released during noxious or non-noxious tactile stimuli remain to be clarified. Noxious stimuli increase anxiety-related behavior, while pleasant sensory stimuli have pro-social actions. We have shown that endogenous oxytocin reduces anxiety-related behaviors, induces a decrease in amounts of food intake per meal, and facilitates social recognition via distinct neural pathways. Roles of oxytocin released during sensory stimuli may be dependent upon the sensory stimuli used, and oxytocin may contribute to the prevention of overreactions to noxious stimuli or mediate pro-social or anxiolytic actions of pleasant tactile stimuli.

Salt homeostasis is essential to survival, but brain mechanisms for salt-intake control have not been fully elucidated. Here, we found that the sensitivity of Na(x) channels to [Na(+)](o) is dose-dependently enhanced by endothelin-3 (ET-3). Na(x) channels began to open when [Na(+)](o) exceeded ~150 mM without ET-3, but opened fully at a physiological [Na(+)](o) (135–145 mM) with 1 nM ET-3. Importantly, ET-3 was expressed in the subfornical organ (SFO) along with Nax, and the level was robustly increased by dehydration. Pharmacological experiments revealed that endothelin receptor B (ET(B)R) signaling is involved in this modulation of Na(x) gating through protein kinase C and ERK1/2 activation. ET(B)R agonists increased the firing rate of GABAergic neurons via lactate in the SFO, and an ET(B)R antagonist attenuated salt aversion during dehydration. These results indicate that ET-3 expression in the SFO is tightly coupled with body-fluid homeostasis through modulation of the [Na(+)](o) sensitivity of Na(x).