Abstract
Zebrafish are highly social teleost fish and an excellent model to study social behavior. The neuropeptide Oxytocin is associated different social behaviors as well as disorders resulting in social impairment like autism spectrum disorder. However, how Oxytocin receptor signaling affects the development and expression kinetics of social behavior is not known. In this study we investigated the role of the two oxytocin receptors, Oxtr and Oxtrl, in the development and maintenance of social preference and shoaling behavior in 2- to 8-week-old zebrafish. Using CRISPR/Cas9 mediated oxtr and oxtrl knock-out fish, we found that the development of social preference is accelerated if one of the Oxytocin receptors is knocked-out and that the knock-out fish reach significantly higher levels of social preference. Moreover, oxtr−/− fish showed impairments in the maintenance of social preference. Social isolation prior to testing led to impaired maintenance of social preference in both wild-type and oxtr and oxtrl knock-out fish. Knocking-out either of the Oxytocin receptors also led to increased group spacing and reduced polarization in a 20-fish shoal at 8 weeks post fertilization, but not at 4. These results show that the development and maintenance of social behavior is influenced by the Oxytocin receptors and that the effects are not just pro- or antisocial, but dependent on both the age and social context of the fish.
Highlights
The association between Oxytocin and social behavior has been demonstrated in multiple s tudies[36–38] and the human Oxytocin receptor may influence social traits affected in neurodevelopmental disorders such as autism spectrum d isorder[39,40]
Isolation has been reported to reduce the activity of Oxytocin receptors (OTR) in the nucleus accumbens of rats[46] and to affect the expression of OTR in specific brain regions to different degrees: a four-week long social isolation of prairie voles led to reduced hypothalamic expression of O TR47, whereas six- and eight-week social isolation did not change the expression of OTR in murine h ippocampus[48]
The development of social preference was significantly (p = 2.09 × 1 0−4) altered in the oxtrl−/− fish, which exhibited an early onset of social preference, reaching a peak precociously at 3 wpf (Fig. 1b,c)
Summary
Many species, including humans, live in groups to enhance their fitness—their lifetime reproductive success. Gilles and Polston[44] reported that a two-week isolation of rats starting after weaning (postnatal day 21) led to increased pro- and antisocial behavior They further described an inverse correlation between the number of oxytocinergic neurons in the anterior parvicellular division of the hypothalamic paraventricular nucleus (PVN) and the level of antisocial behavior[44]. Several s tudies[51–53] investigated how Oxytocin receptors influence social recognition or social preference in adult zebrafish by blocking both Oxtr and Oxtrl with a ntagonists[51,52] or knocking out the oxtr[53]. Often these studies came to contradictory conclusions, underscoring the complexity of Oxytocin’s effects. The discrete impact of Oxtr or Oxtrl on the development and maintenance of social behavior in socially or isolation reared zebrafish remains to be elucidated
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