Environmental enrichment mitigates the sex-specific effects of gestational inflammation on social engagement and the hypothalamic pituitary adrenal axis-feedback system

Connors, Eric J; Shaik, Abdul Naveed; Migliore, Mattia M.; Kentner, Amanda C.

doi:10.1016/j.bbi.2014.06.020

Cited by 62 publications

(82 citation statements)

References 81 publications

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“…Our study exposed a sex-specific effect of MIA; social recognition was affected in males only. The Connors et al (45) study in rats also found a male-specific effect of MIA, but they observed an overall decrease in social interactions, which we only see in the MIAexposed male KO mice, not in the WT mice, possibly accounted for by a species-specific effect of MIA.…”

Section: Resultsmentioning

confidence: 81%

Sex-specific gene–environment interactions underlying ASD-like behaviors

Schaafsma

Gagnidze

Reyes

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

106

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The male bias in the incidence of autism spectrum disorders (ASDs) is one of the most notable characteristics of this group of neurodevelopmental disorders. The etiology of this sex bias is far from known, but pivotal for understanding the etiology of ASDs in general. Here we investigate whether a "three-hit" (genetic load × environmental factor × sex) theory of autism may help explain the male predominance. We found that LPS-induced maternal immune activation caused male-specific deficits in certain social responses in the contactin-associated protein-like 2 (Cntnap2) mouse model for ASD. The three "hits" had cumulative effects on ultrasonic vocalizations at postnatal day 3. Hits synergistically affected social recognition in adulthood: only mice exposed to all three hits showed deficits in this aspect of social behavior. In brains of the same mice we found a significant three-way interaction on corticotropin-releasing hormone receptor-1 (Crhr1) gene expression, in the left hippocampus specifically, which co-occurred with epigenetic alterations in histone H3 N-terminal lysine 4 trimethylation (H3K4me3) over the Crhr1 promoter. Although it is highly likely that multiple (synergistic) interactions may be at work, change in the expression of genes in the hypothalamic-pituitary-adrenal/ stress system (e.g., Crhr1) is one of them. The data provide proof-of-principle that genetic and environmental factors interact to cause sex-specific effects that may help explain the male bias in ASD incidence.maternal immune activation | prenatal stress | sex differences | Cntnap2 | autism A utism spectrum disorders (ASDs) comprise a heterogeneous group of neurodevelopmental disorders. The core symptoms of ASD are deficits in social communication and social interactions (Diagnostic and Statistical Manual of Mental Disorders V) and one of the most noticeable biological constants in this group of disorders is the sex difference: ∼80% of the children diagnosed with an ASD are boys (1). Many genes have been implicated in the etiologies underlying ASD in humans and ASD-like behavior in animal models. Some of these genes are located on the sex chromosomes and many of these genes may be able to affect other sex-chromosomal genes or may otherwise indirectly lead to sex-specific effects (reviewed in ref.2). However, it seems unlikely that these genes can account for the full sex bias in incidence and it is becoming increasingly clear that environmental factors play a very important role as well (3), and that these factors can interact with one another (2, 4). Moreover, prenatal testosterone (an indirect genetic factor) affects human behavior (5, 6) and may increase the risk to develop an ASD (7).Although today it is commonly proposed that many neurodevelopmental disorders result from interactions between "nature" and "nurture," studies investigating the gene-environment interaction in the development of ASD are scarce.In this study we tested whether an interaction between an ASD-related genetic mutation and an environmental factor may be a...

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Section: Resultsmentioning

confidence: 81%

Sex-specific gene–environment interactions underlying ASD-like behaviors

Schaafsma

Gagnidze

Reyes

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

106

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“…However, social rejection following early-life challenge/injury in rodents is not without precedent; in a pediatric model of mild traumatic brain injury juvenile female rats received fewer play initiations from conspecifics (Mychasiuk et al, 2014). Moreover, recent work utilizing both gestational (Connors et al, 2014) and neonatal (MacRae et al, under review) lipopolysaccharide (LPS) has demonstrated that juvenile male rats had diminished social contact, mediated by a reduced level of interaction directed towards them. Since these animals initiated contact but received fewer approach/following behaviors from their conspecifics it is unlikely that they were merely being evasive, suggesting that there was another element underlying the reduced level of engagement.…”

Section: Introductionmentioning

confidence: 94%

“…Virgin female and male Sprague-Dawley rats from Charles River (Wilmington, MA) were pair-housed at 20°C on a 12 h light/dark cycle (0700-1900 light) with free access to food and water and bred as previously described (Connors et al, 2014). Experimental procedures were approved by the MCPHS Institutional Animal Care and Use Committee and were carried out in compliance with the Association for Assessment and Accreditation of Laboratory Animal Care.…”

Section: Animal Housing and Drug Treatmentmentioning

confidence: 99%

“…Prior to this test, rats were habituated to a black open field arena (40 cm Â 40 cm Â 28 cm), over three separate days, for 10 min daily (Connors et al, 2014). To evaluate social behavior, nLPS (n = 9) and nsaline (n = 9) treated rats were introduced to a novel conspecific of the same sex and age (n = 6) for 10 min, as previously described (Connors et al, 2014). Novel conspecifics were separate groups of nsaline rats raised under standard housing conditions.…”

Section: Social Behaviormentioning

confidence: 99%

“…The anxiolytic diazepam was therefore administered to juvenile nLPS animals to determine if the social contact they received from conspecifics would increase. Given that lower levels of social interaction following early administration of LPS tend to occur in males, more so than females (Connors et al, 2014;Taylor et al, 2012), we focused our investigations on the former sex.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Social rejection following neonatal inflammation is mediated by olfactory scent cues

MacRae

Kenkel

Kentner

2015

Brain, Behavior, and Immunity

Self Cite

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Differential effects of social and physical environmental enrichment on brain plasticity, cognition, and ultrasonic communication in rats

Brenes

Lackinger

Höglinger

et al. 2015

J of Comparative Neurology

133

107

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Environmental enrichment (EE) exerts beneficial effects on brain plasticity, cognition, and anxiety/depression, leading to a brain that can counteract deficits underlying various brain disorders. Because the complexity of the EE commonly used makes it difficult to identify causal aspects, we examined possible factors using a 2 × 2 design with social EE (two vs. six rats) and physical EE (physically enriched vs. nonenriched). For the first time, we demonstrate that social and physical EE have differential effects on brain plasticity, cognition, and ultrasonic communication. Expectedly, physical EE promoted neurogenesis in the dentate gyrus of the hippocampal formation, but not in the subventricular zone, and, as a novel finding, affected microRNA expression levels, with the activity-dependent miR-124 and miR-132 being upregulated. Concomitant improvements in cognition were observed, yet social deficits were seen in the emission of prosocial 50-kHz ultrasonic vocalizations (USV) paralleled by a lack of social approach in response to them, consistent with the intense world syndrome/theory of autism. In contrast, social EE had only minor effects on brain plasticity and cognition, but led to increased prosocial 50-kHz USV emission rates and enhanced social approach behavior. Importantly, social deficits following physical EE were prevented by additional social EE. The finding that social EE has positive whereas physical EE has negative effects on social behavior indicates that preclinical studies focusing on EE as a potential treatment in models for neuropsychiatric disorders characterized by social deficits, such as autism, should include social EE in addition to physical EE, because its lack might worsen social deficits.

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Environmental enrichment mitigates the sex-specific effects of gestational inflammation on social engagement and the hypothalamic pituitary adrenal axis-feedback system

Cited by 62 publications

References 81 publications

Sex-specific gene–environment interactions underlying ASD-like behaviors

Sex-specific gene–environment interactions underlying ASD-like behaviors

Social rejection following neonatal inflammation is mediated by olfactory scent cues

Differential effects of social and physical environmental enrichment on brain plasticity, cognition, and ultrasonic communication in rats

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