Oxytocin receptor knockout prairie voles generated by CRISPR/Cas9 editing show reduced preference for social novelty and exaggerated repetitive behaviors

Horie, Katsutoshi; Inoue, Kiyoshi; Suzuki, Shingo; Adachi, Saki; Yada, Saori; Hirayama, Takashi; Hidema, Shizu; Young, Larry J.; Nishimori, Katsuhiko

doi:10.1016/j.yhbeh.2018.10.011

Cited by 64 publications

(59 citation statements)

References 72 publications

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“…Mutant oxtr ( −/− ) fish showed no impairment of social preference, although they did exhibit a significant impairment in both social and non‐social memory recognition. These findings suggest that, in zebrafish, OXT‐like peptides act on particular aspects of social behaviour, more specifically on cognitive rather than on motivational functions of sociality, which has also been observed in other species . Moreover, our findings also show that these effects of OXT on memory recognition are not specific to the social domain but, instead, they are of the general domain, also affecting object recognition.…”

Section: Discussionsupporting

confidence: 80%

“…Although we have observed a normal social preference in our oxtr ( −/− ) mutants, we did observe that an impaired oxytocinergic signalling affected social recognition, comprising a cognitive function that has been shown consistently to be affected by OXT in other species . It has already been reported that the zebrafish is able to discriminate between novel and familiar conspecifics, exhibiting social recognition memory, and, in the present study, for the first time, we have shown that this mechanism is regulated by OXT signalling, suggesting a conserved mechanism across species . Interestingly, a conditional deletion of OXTR in lateral septum of mice impairs social memory but not social approach .…”

Section: Discussionsupporting

confidence: 52%

“…There are some studies showing that different aspects of sociality may be differently affected by OXT; however, these results are not consistent throughout the literature. For example, although prairie voles exhibiting a dysfunctional OXT receptor (OXTR) display normal approach to conspecifics, they show an impairment in social recognition . The same results have been observed using a conditional lateral septum‐specific OXTR‐deficient mice, showing deficits in social recognition, although not in social preference .…”

Section: Introductionsupporting

confidence: 54%

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Oxytocin receptor signalling modulates novelty recognition but not social preference in zebrafish

Ribeiro

Nunes

Gliksberg

et al. 2020

J Neuroendocrinology

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| INTRODUC TI ONNonapeptides are known to be important players in the regulation of social behaviour across taxa. 1 They evolved from a common ancestral molecule, the arginine vasotocin, after a gene duplication event in early-jawed fish. 2 One copy originated the vasopressin-like peptides, which retained the most primitive functions of the ancestral molecule, namely the regulation of osmotic balance. The other originated the oxytocin (OXT)-like peptides, which have greatly diverged across species, being recruited for diverse homeostatic processes, including parturition and lactation in mammals. Throughout evolution, these nonapeptides have also been involved in the regulation of social behaviours, with vasopressin being more involved in aggression and agonistic behaviours and OXT in affiliative behaviours and sociality. 3 AbstractSociality is a complex phenomenon that involves the individual´s motivation to approach their conspecifics, along with social cognitive functions that enable individuals to interact and survive. The nonapeptide oxytocin (OXT) is known to regulate sociality in many species. However, the role of OXT in specific aspects of sociality is still not well understood. In the present study, we investigated the contribution of the OXT receptor (OXTR) signalling in two different aspects of zebrafish social behaviour: social preference, by measuring their motivation to approach a shoal of conspecifics, and social recognition, by measuring their ability to discriminate between a novel and familiar fish, using a mutant zebrafish lacking a functional OXTR. Although oxtr mutant zebrafish displayed normal attraction to a shoal of conspecifics, they exhibited reduced social recognition. We further investigated whether this effect would be social-domain specific by replacing conspecific fish by objects. Although no differences were observed in object approach, oxtr mutant fish also exhibited impaired object recognition. Our findings suggest that OXTR signalling regulates a more general memory recognition of familiar vs novel entities, not only in social but also in a non-social domain, in zebrafish. K E Y W O R D Sautism spectrum disorders, oxytocin, social preference, social recognition, zebrafish S U PP O RTI N G I N FO R M ATI O NAdditional supporting information may be found online in the Supporting Information section.

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Section: Discussionsupporting

confidence: 80%

Section: Discussionsupporting

confidence: 52%

Section: Introductionsupporting

confidence: 54%

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Oxytocin receptor signalling modulates novelty recognition but not social preference in zebrafish

Ribeiro

Nunes

Gliksberg

et al. 2020

J Neuroendocrinology

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“…In addition, we demonstrate a novel role of dopamine receptor activity in the MeA in approach/avoidance response following social defeat stress. With the recent emergence of transgenic prairie voles (Horie et al, 2018), this species may continue to rise as an attractive model in the study of neural mechanisms underlying stress-induced alterations in adaptive and maladaptive behavior. All together, these findings Table S1.…”

Section: Discussionmentioning

confidence: 99%

“…While the closely related Mandarin vole (Microtus mandarinus) has recently been used to model social defeat, a direct comparison of males and females has yet to be performed (Li et al, 2018;Wang et al, 2018). Additionally, recent Tickerhoof (Manuscript) 5 work in developing transgenic prairie voles has begun to examine the effects of developmental gene manipulation on prairie vole sociality (Horie et al, 2018), increasing the utility of this species in examining the neurobiology connecting stress and social behavior as more tools become available. These reasons taken together present the prairie vole as an attractive model in further examining the role of dopamine in the impact of social defeat stress.…”

Section: Introductionmentioning

confidence: 99%

Regulation of defeat-induced social avoidance by medial amygdala DRD1 in male and female prairie voles

Tickerhoof

Hale

Smith

2019

Preprint

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Social interaction with unfamiliar individuals is necessary for species-preserving behaviors such as finding mates and establishing social groups. However, social conflict is a potential negative outcome to interaction with a stranger that can be distressing enough to cause an individual to later avoid interactions with other unfamiliar conspecifics. Unfortunately, stress research using a prominent model of social conflict, social defeat stress, has largely omitted female subjects. This has left a void in the literature regarding social strain on female stress biology and adequate comparison of the effect of sex in stress pathways. The prairie vole (Microtus ochrogaster) exhibits aggressive behavior in both sexes, making voles an attractive candidate to model social defeat in both sexes. This study sought to establish a model of social defeat stress in both male and female prairie voles, characterize behavioral changes in response to this stressor, and investigate the role of dopamine signaling in the response to social defeat stress. Defeated male and female prairie voles displayed social avoidance as well as an increase in expression of dopamine receptor D1 (DRD1) in the medial amygdala (MeA). Pharmacological manipulation of DRD1 signaling in the MeA revealed that increased DRD1 signaling is sufficient to induce a social avoidant state, and could be a necessary component in the defeat-induced social avoidance response. These findings provide the prairie vole as a model of social defeat in both sexes, and implicate the MeA in avoidance of unfamiliar conspecifics after a distressing social encounter.

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Oxytocin receptors are widely distributed in the prairie vole (Microtus ochrogaster) brain: Relation to social behavior, genetic polymorphisms, and the dopamine system

Inoue

Ford

Horie

et al. 2022

J of Comparative Neurology

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Oxytocin regulates social behavior via direct modulation of neurons, regulation of neural network activity, and interaction with other neurotransmitter systems. The behavioral effects of oxytocin signaling are determined by the species‐specific distribution of brain oxytocin receptors. The socially monogamous prairie vole has been a useful model organism for elucidating the role of oxytocin in social behaviors, including pair bonding, response to social loss, and consoling. However, there has been no comprehensive mapping of oxytocin receptor‐expressing cells throughout the prairie vole brain. Here, we employed a highly sensitive in situ hybridization, RNAscope, to construct an exhaustive, brain‐wide map of oxytocin receptor mRNA‐expressing cells. We found that oxytocin receptor mRNA expression was widespread and diffused throughout the brain, with specific areas displaying a particularly robust expression. Comparing receptor binding with mRNA revealed that regions of the hippocampus and substantia nigra contained oxytocin receptor protein but lacked mRNA, indicating that oxytocin receptors can be transported to distal neuronal processes, consistent with presynaptic oxytocin receptor functions. In the nucleus accumbens, a region involved in oxytocin‐dependent social bonding, oxytocin receptor mRNA expression was detected in both the D1 and D2 dopamine receptor‐expressing subtypes of cells. Furthermore, natural genetic polymorphisms robustly influenced oxytocin receptor expression in both D1 and D2 receptor cell types in the nucleus accumbens. Collectively, our findings further elucidate the extent to which oxytocin signaling is capable of influencing brain‐wide neural activity, responses to social stimuli, and social behavior. Key points Oxytocin receptor mRNA is diffusely expressed throughout the brain, with strong expression concentrated in certain areas involved in social behavior. Oxytocin receptor mRNA expression and protein localization are misaligned in some areas, indicating that the receptor protein may be transported to distal processes. In the nucleus accumbens, oxytocin receptors are expressed on cells expressing both D1 and D2 dopamine receptor subtypes, and the majority of variation in oxytocin receptor expression between animals is attributable to polymorphisms in the oxytocin receptor gene.

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Oxytocin receptor knockout prairie voles generated by CRISPR/Cas9 editing show reduced preference for social novelty and exaggerated repetitive behaviors

Cited by 64 publications

References 72 publications

Oxytocin receptor signalling modulates novelty recognition but not social preference in zebrafish

Oxytocin receptor signalling modulates novelty recognition but not social preference in zebrafish

Regulation of defeat-induced social avoidance by medial amygdala DRD1 in male and female prairie voles

Oxytocin receptors are widely distributed in the prairie vole (Microtus ochrogaster) brain: Relation to social behavior, genetic polymorphisms, and the dopamine system

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