Communication Impairment in Ultrasonic Vocal Repertoire during the Suckling Period of Cd157 Knockout Mice: Transient Improvement by Oxytocin

Fujisaku

2020

J Neuroendocrinology

Autism spectrum disorder (ASD) is a neurodevelopmental disorder estimated by the World Health Organization to occur in one of 160 children worldwide. No pharmaceutical treatments are available to improve the deficits in social communication that are common symptoms of ASD. Recent clinical trials have focused on the nasal application of oxytocin, a neuronal peptide known to regulate a variety of social behaviours. However, the effect of oxytocin on this deficit is inconclusive. By contrast, evidence from ASD animal model studies indicates that when animals are treated with oxytocin during early development, improvements in social deficits are observed in adulthood. Thus, it is necessary to examine the effect of therapeutic target medication prescribed in early development. Mice prenatally exposed to valproic acid (VPA) are widely used as an animal model of ASD. However, many behavioural studies have been conducted during adulthood rather than early development. To establish a screening system to identify therapeutic drugs that are effective when delivered during the early postnatal period, it is important to examine the early developmental changes in their communicative behaviours. In the present study, we examined the ultrasonic vocalisation (USV) of VPA-exposed mice pups during their early postnatal developmental days. USV rates were comparable to those of the controls until the first week of their life but declined more on postnatal day 11. We checked the expression of oxytocin system in the hypothalamus and found the down-regulation of oxytocin and CD38, and up-regulation of oxytocin receptor in the VPA pups. Acute administration of oxytocin on postnatal day 11 increased the call rate of VPA pups.Taken together, we have demonstrated there was a deficiency in the oxytocinergic signalling in the VPA pups and also shown the existence of time periods that are effective with respect to screening the therapeutic drugs. K E Y W O R D Sautism spectrum disorder, early neurodevelopment, oxytocin, valproic acid mouse model

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Oxytocin ameliorates maternal separation‐induced ultrasonic vocalisation calls in mouse pups prenatally exposed to valproic acid

Fujisaku

2020

J Neuroendocrinology

Genes Brain and Behavior

“…Similar to Nrxn1α mice, Reeler mutant pups produced a narrowed repertoire of calls, specifically on PND 6 and 8, limiting their vocal repertoire to the two‐components , chevron and complex calls ; while Dab1 mutant pups showed a limited call pattern restricted to short and downward calls . A poor USV repertoire also has been detected in Cd157 KO pups from PND 3 until 10 compared with a rich repertoire in WT mice . These seemingly conflicting findings may simply indicate that the animal models reflect the diversity observed in patients across the different ASD, including the atypical vocalizations.…”

Section: Discussionmentioning

confidence: 99%

Assessing the developmental trajectory of mouse models of neurodevelopmental disorders: Social and communication deficits in mice with Neurexin 1α deletion

Armstrong

Caruso

Servadio

et al. 2019

Neurexin 1α mutations are strongly associated with neurodevelopmental disorders such as autism spectrum disorders and schizophrenia in humans. Studies using the Neurexin 1α knock‐out mouse have showed behavioral abnormalities of relevance to these disorders and baseline deficits in excitatory synaptic function have been described. However, little is known about the effect of Neurexin 1α deletion on behavior during development. This study examined the effects of Neurexin 1α deletion on behavior across a range of developmental time points to determine whether potential abnormalities follow a developmental trajectory. Pups lacking Neurexin 1α emitted a reduced number of ultrasonic vocalizations early in development combined with a restricted repertoire of calls indicative of a loss in complexity in vocal production and showed delays in reaching certain developmental milestones. Behavioral testing showed that juvenile and adult male Neurexin 1α knock‐out mice exhibited social deficits and increased levels of aggression, confirming previous findings. No increases in repetitive behaviors or deficits in motor learning or olfaction were seen. In conclusion, this research showed that Neurexin 1α deletion does result in social and communication deficits that follow a developmental trajectory. These are the first experimental data that associate a deletion of Neurexin 1α with alterations in behaviors relevant to autism spectrum disorder across development and highlight the importance of assessing the developmental trajectory in mouse models of neurodevelopmental disorders.

“…Importantly, an oxytocin analogue has long lasting effects on anxiety behavior in a CD157 knockout mouse (51) and communication impairment during the suckling period is restored by oxytocin in the CD157 knockout (52). CD157 and CD38 knockouts show decreased plasma oxytocin levels (53) suggesting a role for both, CD157 as well as CD38 in oxytocin (OT) release and thus as putative regulators of complex behaviors (53).…”

Section: Introductionmentioning

confidence: 99%

The Creative Mind: Blending Oxytocinergic, Dopaminergic and Personality

Chong

Becker

Angeles

et al. 2019

Preprint

In a fast-changing world, creative thinking (CT) is an extraordinary currency.Oxytocin (OT) is associated with CT and release of OT depends on ADP ribosyl-cyclases (CD38 and CD157). Moreover, CT as well as OT's mechanism of action are mediated via central dopaminergic pathways. Consequently, we evaluate the roles of CD38, CD157, dopamine receptor D2 (DRD2) and catechol-O-methyltransferase (COMT) peripheral gene expression in CT. Two principal domains of CT, divergent thinking and insight solving problems, were assessed using validated behavioral assessments. To facilitate discriminant validity, two established correlates of CT, trait Openness and fluid intelligence as well as age and sex were included in the regression model. In women, significant main effects (p<0.01) were positively associated with the expression CD38, CD15, and their interaction CD38 x CD157 controlling for Openness, fluid intelligence and age. Subsequent analysis on the subscale-level revealed significant main effects for CD157 and CD38 x CD157 in men specifically for divergent thinking. In women, significant (p<0.01) results are also observed for dopaminergic expression (DRD2, COMT, DRD2 x COMT). The full model (oxytocinergic and dopaminergic gene expressions, Openness, and fluid intelligence) explains a sizable 39% of the variance in females. Significant main effects are observed for CD38, CD157, DRD2 and COMT as well as their interactions (CD38xCD157 and DRD2xCOMT). In conclusion, we show that oxytocinergic and dopaminergic gene expression contribute significantly to the complex CT phenotype suggesting the notion that the perspective gained from examining the peripheral transcriptome meaningfully adds to understanding the landscape of creative thinking. Word count 249/250Significance Statement: Creative thinking (CT) is a powerful driving force galvanizing progress and civilization. Towards better understanding the neurobiology of CT, we implement a gene expression strategy that is considered to capture not only genomic elements but also environmental signatures. We employ laboratory measures of CT (alternative uses test and insight problem solving), controlling for fluid intelligence and the personality trait of Openness. We focus on oxytocinergic and dopaminergic genes that contribute to the molecular architecture of CT. Oxytocinergic and dopaminergic gene expression significantly explains a robust 39% of the variance in CT. Notably, this study demonstrates the potential of the peripheral transcriptome towards tracing gene pathways underlying some complex cognitive behaviors such as creative thinking.Word count 114/120 significantly correlated with IPS in females: Openness to experience (b = 0.01, p = 0.004), RPM (b = 0.1, p = 0.03) and age (b = 0.2, p = 0.02). Table 3, Models Subscale analyses of CT, with both oxytocinergic and dopaminergic gene expressions, Table 4, Models 5-10. Subscale analyses of CT, with dopaminergic gene expressions,