Developmental exposure to selective serotonin reuptake inhibitor (SSRI) increases the risk of Autism Spectrum Disorder (ASD), however, the underlying neurobiology of this effect is not fully understood. Here we used the socially monogamous prairie vole as a translational model of developmental SSRI exposure. Paired female prairie voles (n = 20) were treated with 5 mg/kg subcutaneous fluoxetine (FLX) or saline (SAL) daily from birth of the second litter until the day of birth of the 4th litter. This design created three cohorts of FLX exposure: postnatal exposure in litter 2, both prenatal and postnatal exposure in litter 3, and prenatal exposure in litter 4. Post-weaning, subjects underwent behavioral testing to detect changes in sociality, repetitive behavior, pair-bond formation, and anxiety-like behavior. Quantitative receptor autoradiography was performed for oxytocin, vasopressin 1a, and serotonin 1a receptor density in a subset of brains. We observed increased anxiety-like behavior and reduced sociality in developmentally FLX exposed adults. FLX exposure decreased oxytocin receptor binding in the nucleus accumbens core and central amygdala, and vasopressin 1a receptor binding in the medial amygdala. FLX exposure did not affect serotonin 1A receptor binding in any areas examined. Changes to oxytocin and vasopressin receptors may underlie the behavioral changes observed and have translational implications for the mechanism of the increased risk of ASD subsequent to prenatal SSRI exposure.

The prosocial hormone oxytocin (OXT) has become a new target for research on the etiology and treatment of autism spectrum disorder (ASD), a condition characterized by deficits in social function. However, it remains unknown whether there are alterations in OXT receptor (OXTR) levels in the ASD brain. This study quantified the density of OXTR and of the structurally related vasopressin 1a receptor (AVPR1a) in postmortem brain tissue from individuals with ASD and typically developing individuals. We analyzed two regions known to contain OXTR across all primates studied to date: the nucleus basalis of Meynert (NBM), which mediates visual attention, and the superior colliculus, which controls gaze direction. In the NBM specimens, we also analyzed the neighboring ventral pallidum (VP) and the external segment of the globus pallidus. In the superior colliculus specimens, we also analyzed the adjacent periaqueductal gray. We detected dense OXTR binding in the human NBM and VP and moderate to low OXTR binding in the human globus pallidus, superior colliculus, and periaqueductal gray. AVPR1a binding was negligible across all five regions in all specimens. Compared to controls, ASD specimens exhibited significantly higher OXTR binding in the NBM and significantly lower OXTR binding in the VP, an area in the mesolimbic reward pathway. There was no effect of ASD on OXTR binding in the globus pallidus, superior colliculus, or periaqueductal gray. We also found a significant negative correlation between age and OXTR binding in the VP across all specimens. Further analysis revealed a peak in OXTR binding in the VP in early childhood of typically developing individuals, which was absent in ASD. This pattern suggests a possible early life critical period, which is lacking in ASD, where this important reward area becomes maximally sensitive to OXT binding. These results provide unique neurobiological insight into human social development and the social symptoms of ASD.

Intranasal oxytocin (IN OXT) has been proposed as a treatment for autism spectrum disorder (ASD); however, little is known about the effects of long-term exposure. This is the first study in a non-human primate species to examine how developmental exposure to chronic IN OXT affects juveniles interactions with family members, social preference for parents versus strangers, anxiety-like behavior, and cerebral glucose metabolism. Titi monkeys are socially monogamous and biparental; their family bonds share important characteristics with human family bonds. Fourteen males and 15 females were treated intranasally with saline (n = 14) or 0.8 IU/kg OXT (n = 15), daily from 12 to 18 months of age. Compared to SAL-treated animals, OXT-treated animals of both sexes spent significantly more time grooming other family members (F1 = 8.97, p = 0.006). Overall, OXT-treated subjects were more social (F1 = 8.35, p = 0.005) during preference tests. OXT-treated females displayed an enhanced preference for their parents (t = 2.265, p = 0.026). OXT-treated males had a blunted preference for their parents and an increase in the time spent near unfamiliar pairs (F1 = 10.89, p = 0.001). During anxiety tests, OXT-treated males refused to complete the task more often than SAL-treated males and had longer latencies (p < 0.0001). Neuroimaging studies revealed that OXT-treated animals had higher glucose uptake across the social salience network as a whole after one month of treatment (F1,9 = 1.07, p = 0.042). Our results suggest moderate prosocial effects of chronic IN OXT, that did not depend on anxiolytic properties. We also found important sex differences that should be considered in a translational context.

Intranasal oxytocin (IN OXT) has been proposed as a treatment for autism spectrum disorder (ASD); however, little is known about the effects of long-term exposure. This is the first study in a non-human primate species to examine how developmental exposure to chronic IN OXT affects juvenile's interactions with family members, social preference for parents versus strangers, anxiety-like behavior, and cerebral glucose metabolism. Titi monkeys are socially monogamous and biparental; their family bonds share important characteristics with human family bonds. Fourteen males and 15 females were treated intranasally with saline (n = 14) or 0.8 IU/kg OXT (n = 15), daily from 12 to 18 months of age. Compared to SAL-treated animals, OXT-treated animals of both sexes spent significantly more time grooming other family members (F₁ = 8.97, p = 0.006). Overall, OXT-treated subjects were more social (F₁ = 8.35, p = 0.005) during preference tests. OXT-treated females displayed an enhanced preference for their parents (t = 2.265, p = 0.026). OXT-treated males had a blunted preference for their parents and an increase in the time spent near unfamiliar pairs (F1 = 10.89, p = 0.001). During anxiety tests, OXT-treated males refused to complete the task more often than SAL-treated males and had longer latencies (p < 0.0001). Neuroimaging studies revealed that OXT-treated animals had higher glucose uptake across the social salience network as a whole after one month of treatment (F_1,9 = 1.07, p = 0.042). Our results suggest moderate prosocial effects of chronic IN OXT, that did not depend on anxiolytic properties. We also found important sex differences that should be considered in a translational context.

Oligodendrocytes derive from progenitors (OPCs) through the interplay of epigenomic and transcriptional events. By integrating high-resolution methylomics, RNA-sequencing, and multiple transgenic lines, this study defines the role of DNMT1 in developmental myelination. We detected hypermethylation of genes related to cell cycle and neurogenesis during differentiation of OPCs, yet genetic ablation of Dnmt1 resulted in inefficient OPC expansion and severe hypomyelination associated with ataxia and tremors in mice. This phenotype was not caused by lineage switch or massive apoptosis but was characterized by a profound defect of differentiation associated with changes in exon-skipping and intron-retention splicing events and by the activation of an endoplasmic reticulum stress response. Therefore, loss of Dnmt1 in OPCs is not sufficient to induce a lineage switch but acts as an important determinant of the coordination between RNA splicing and protein synthesis necessary for myelin formation.

Intranasal oxytocin (IN OXT) administration has been proposed as a pharmacological treatment for a range of biomedical conditions including neurodevelopmental disorders. However, studies evaluating the potential long-lasting effects of chronic IN OXT during development are still scarce. Here we conducted a follow-up study of a cohort of adult titi monkeys that received intranasal oxytocin 0.8 IU/kg (n = 15) or saline (n = 14) daily for six months during their juvenile period (12 to 18 months of age), with the goal of evaluating the potential long-lasting behavioral and neural effects one year post-treatment. Subjects were paired with an opposite-sex mate at 30 months of age (one year post-treatment). We examined pair affiliative behavior in the home cage during the first four months and tested for behavioral components of pair bonding at one week and four months post-pairing. We assessed long-term changes in brain glucose uptake using ¹⁸FDG positron emission tomography (PET) scans. Our results showed that OXT-treated animals were more affiliative across a number of measures, including tail twining, compared to SAL treated subjects (tail twining is considered the "highest" type of affiliation in titi monkeys). Neuroimaging showed no treatment differences in glucose uptake between SAL and OXT-treated animals; however, females showed higher glucose uptake in whole brain at 23 months, and in both the whole brain and the social salience network at 33 months of age compared to males. Our results suggest that chronic IN OXT administration during development can have long-term effects on adult social behavior.

Peer review is an important part of the scientific process, but traditional peer review at journals is coming under increased scrutiny for its inefficiency and lack of transparency. As preprints become more widely used and accepted, they raise the possibility of rethinking the peer-review process. Preprints are enabling new forms of peer review that have the potential to be more thorough, inclusive, and collegial than traditional journal peer review, and to thus fundamentally shift the culture of peer review toward constructive collaboration. In this Consensus View, we make a call to action to stakeholders in the community to accelerate the growing momentum of preprint sharing and provide recommendations to empower researchers to provide open and constructive peer review for preprints.