Increased sociability and gene expression of oxytocin and its receptor in the brains of rats affected prenatally by valproic acid

Štefánik, Peter; Olexová, Lucia; Kršková, Lucia

doi:10.1016/j.pbb.2015.01.021

Cited by 37 publications

(32 citation statements)

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“…Raza et al [ 67 ] found that prenatal VPA exposure impaired motor behavior and decreased closed-arm time exclusively in female rats. Stefánik et al [ 68 ] reported increased social interaction in females prenatally exposed to VPA. However, Roullet et al [ 59 ] reported male and female mice exposed prenatally to VPA were similarly impaired in sociability scores and nest-seeking responses.…”

Section: Discussionmentioning

confidence: 99%

Developmental disruption of amygdala transcriptome and socioemotional behavior in rats exposed to valproic acid prenatally

et al. 2017

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BackgroundThe amygdala controls socioemotional behavior and has consistently been implicated in the etiology of autism spectrum disorder (ASD). Precocious amygdala development is commonly reported in ASD youth with the degree of overgrowth positively correlated to the severity of ASD symptoms. Prenatal exposure to VPA leads to an ASD phenotype in both humans and rats and has become a commonly used tool to model the complexity of ASD symptoms in the laboratory. Here, we examined abnormalities in gene expression in the amygdala and socioemotional behavior across development in the valproic acid (VPA) rat model of ASD.MethodsRat dams received oral gavage of VPA (500 mg/kg) or saline daily between E11 and 13. Socioemotional behavior was tracked across development in both sexes. RNA sequencing and proteomics were performed on amygdala samples from male rats across development.ResultsEffects of VPA on time spent in social proximity and anxiety-like behavior were sex dependent, with social abnormalities presenting in males and heightened anxiety in females. Across time VPA stunted developmental and immune, but enhanced cellular death and disorder, pathways in the amygdala relative to saline controls. At postnatal day 10, gene pathways involved in nervous system and cellular development displayed predicted activations in prenatally exposed VPA amygdala samples. By juvenile age, however, transcriptomic and proteomic pathways displayed reductions in cellular growth and neural development. Alterations in immune pathways, calcium signaling, Rho GTPases, and protein kinase A signaling were also observed.ConclusionsAs behavioral, developmental, and genomic alterations are similar to those reported in ASD, these results lend support to prenatal exposure to VPA as a useful tool for understanding how developmental insults to molecular pathways in the amygdala give rise to ASD-related syndromes.Electronic supplementary materialThe online version of this article (doi:10.1186/s13229-017-0160-x) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Developmental disruption of amygdala transcriptome and socioemotional behavior in rats exposed to valproic acid prenatally

et al. 2017

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“…The location and causative nature of hypothalamic OT action in this model remains undetermined, however. Hypothalamic OTergic fibers project to many distinct brain regions (medial prefrontal cortex, piriform cortex, basolateral and basomedial amygdala, and hippocampus (Choleris et al, 2013;Štefánik et al, 2015)) involved in the regulation of social behavior. Given the low central availability of peripherally administered OTR antagonists (Viero et al, 2010), future experiments requiring local OT infusion into these diverse brain regions will address this question.…”

Section: Discussionmentioning

confidence: 99%

Moderate Stress-Induced Social Bonding and Oxytocin Signaling are Disrupted by Predator Odor in Male Rats

Muroy

Long

Kaufer

et al. 2016

Neuropsychopharmacol

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In times of stress, social support can serve as a potent buffering mechanism that enhances resilience. In humans, stress can promote protective affiliative interactions and prosocial behavior. Yet, stress also precipitates psychopathologies characterized by social withdrawal such as post-traumatic stress disorder (PTSD) and depression. The factors that drive adaptive vs maladaptive social responses to stress are not yet clear. Rodent studies have focused on pair-bonded, opposite-sex mates and suggest that a variety of stressors can induce social support-like behaviors. However, between same-sex conspecifics-particularly males-stress effects on social bonding are less understood and often associated with aggression and social unrest. We thus sought to investigate if a moderate stressor-3 h of acute immobilizationimpacts social-support behaviors differently when experienced in a neutral vs more innately threatening context (ie, paired with predator odor). We found that moderate stress increased social support-seeking behavior in rat cagemates and facilitated long-term sharing of a limited water resource, decreased aggression, and strongly defined dominance ranks (an indicator of home cage stability). In contrast, experiencing the same stressor in the presence of predator odor eliminated the positive behavioral effects of moderate stress. Importantly, hypothalamic oxytocin (OT) signaling increased coincident with stress in a neutral-but not a predator odor-context. Our results define a novel rodent model of divergent stress effects on social affiliation and OT signaling dependent on odor context with particularly strong relevance to stress-related disorders such as PTSD, which are characterized by a disrupted ability to seek and maintain social bonds.

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“…While the oxytocin system has been studied and found affected in Fragile X mice (Francis et al, 2014), to date there are no studies characterizing this system as it relates to social deficits in the VPA model. Strikingly, Stefanik et al (2015) have recently observed increased sociability in rats exposed in utero to VPA. This observation contrasts with most reports so far and it is possible that differences are due to VPA dosing or exposure time at gestation.…”

Section: Environmental Modelsmentioning

confidence: 99%

Oxytocin in animal models of autism spectrum disorder

Peñagarikano

2017

Developmental Neurobiology

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Autism spectrum disorder is a behavioral disorder characterized by impairments in social interaction and communication together with the presence of stereotyped behaviors and restricted interests. Although highly genetic, its etiology is complex which correlates with the extensive heterogeneity found in its clinical manifestation, adding to the challenge of understanding its pathophysiology and develop targeted pharmacotherapies. The neuropeptide oxytocin is part of a highly conserved system involved in the regulation of social behavior, and both animal and human research have shown that variation in the oxytocin system accounts for interindividual differences in the expression of social behaviors in mammals. In autism, recent studies in human patients and animal models are starting to reveal that alterations in the oxytocin system are more common than previously anticipated. Genetic variation in the key players involved in the system (i.e., oxytocin receptor, oxytocin, and CD38) has been found associated with autism in humans, and animal models of the disorder converge in an altered oxytocin system and/or dysfunction in oxytocin related biological processes. Furthermore, oxytocin administration exerts a behavioral and neurobiological response, and thus, the oxytocin system has become a promising potential therapeutical target for autism. Animal models represent a valuable tool to aid in the research into the potential therapeutic use of oxytocin. In this review, I aim to discuss the main findings related to oxytocin research in autism with a focus on findings in animal models. © 2016 Wiley Periodicals, Inc. Develop Neurobiol 77: 202-213, 2017.

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Increased sociability and gene expression of oxytocin and its receptor in the brains of rats affected prenatally by valproic acid

Cited by 37 publications

References 64 publications

Developmental disruption of amygdala transcriptome and socioemotional behavior in rats exposed to valproic acid prenatally

Developmental disruption of amygdala transcriptome and socioemotional behavior in rats exposed to valproic acid prenatally

Moderate Stress-Induced Social Bonding and Oxytocin Signaling are Disrupted by Predator Odor in Male Rats

Oxytocin in animal models of autism spectrum disorder

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