Sex and gender bias in the experimental neurosciences: the case of the maternal immune activation model

Coiro, Pierluca; Pollak, Daniela D.

doi:10.1038/s41398-019-0423-8

Cited by 55 publications

(47 citation statements)

References 83 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The above results demonstrate that minocycline treatment during the juvenile period alleviated behavior deficits in locomotor activity, sensory gating, and cognitive ability induced by prenatal poly (I:C) insult, but not social withdrawal in male offspring. Considering the possibility of the sex-specific effects in animal behaviors of MIA, the female offspring were also used in behavior tests [ 45 – 47 ]. We found that the female mice exposed to MIA have similar behavior deficits as male mice, and minocycline treatment can prevent these behavior deficits effectively (Fig.…”

Section: Resultsmentioning

confidence: 99%

Modulating microglia activation prevents maternal immune activation induced schizophrenia-relevant behavior phenotypes via arginase 1 in the dentate gyrus

Xia

Zhang

Lin

et al. 2020

Neuropsychopharmacol.

View full text Add to dashboard Cite

Prenatal infection during pregnancy increases the risk for developing neuropsychiatric disorders such as schizophrenia. This is linked to an inflammatory microglial phenotype in the offspring induced by maternal immune activation (MIA). Microglia are crucial for brain development and maintenance of neuronal niches, however, whether and how their activation is involved in the regulation of neurodevelopment remains unclear. Here, we used a MIA rodent model in which polyinosinic: polycytidylic acid (poly (I:C)) was injected into pregnant mice. We found fewer parvalbumin positive (PV+) cells and impaired GABAergic transmission in the dentate gyrus (DG), accompanied by schizophrenia-like behavior in the adult offspring. Minocycline, a potent inhibitor of microglia activation, successfully prevented the above-mentioned deficits in the offspring. Furthermore, by using microglia-specific arginase 1 (Arg1) ablation as well as overexpression in DG, we identified a critical role of Arg1 in microglia activation to protect against poly (I:C) imparted neuropathology and altered behavior in offspring. Taken together, our results highlight that Arg1-mediated alternative activation of microglia are potential therapeutic targets for psychiatric disorders induced by MIA.

show abstract

Section: Resultsmentioning

confidence: 99%

Modulating microglia activation prevents maternal immune activation induced schizophrenia-relevant behavior phenotypes via arginase 1 in the dentate gyrus

Xia

Zhang

Lin

et al. 2020

Neuropsychopharmacol.

View full text Add to dashboard Cite

show abstract

“…In a related rat model of MIA, inflammation induced in lactating dams resulted in the development of distinct sex-dependent phenotypes in the suckling offspring, where the females offspring displayed a depressive phenotype and male offspring displayed a psychiatric phenotype (Arad et al, 2017). Taken together, the complicated and often conflicting results from these studies demonstrate the need for sex by treatment analyses in future MIA research (Coiro and Pollak, 2019; Kentner et al, 2019).…”

Section: Introductionmentioning

confidence: 92%

“…Offspring of treated dams display behavioral and neuropathological profiles consistent with psychiatric illness in humans (Brown and Meyer, 2018). The majority of MIA studies focus on the male offspring or lack consideration of sex as a biological variable despite policies by the National Institute of Health and other grant funding agencies that require the examination of sex as a factor in biomedical research (Clayton and Collins, 2014; Coiro and Pollak, 2019). This is particularly concerning for studies of MIA given the sex differences noted in the human psychiatric disorders associated with MIA as a risk factor (Klein and Corwin, 2002; Arad et al, 2017; Brown and Meyer, 2018; Coiro and Pollak, 2019).…”

Section: Introductionmentioning

confidence: 99%

Maternal Immune Activation during Pregnancy Alters the Behavior Profile of Female Offspring of Sprague Dawley Rats

Lins

Marks

Zabder

et al. 2019

eNeuro

View full text Add to dashboard Cite

Sex differences are documented in psychiatric and neurological disorders, yet most preclinical animal research has been conducted in males only. There is a need to better understand of the nature of sex differences in brain disease in order to meet the needs of psychiatric patients. We present the behavior profile of adult female offspring produced using a maternal immune activation (MIA) model where pregnant rats receive an immune stimulant and the offspring typically show various abnormalities consistent with psychiatric illnesses such as schizophrenia and autism. The results in female offspring were compared to a previously published cohort of their male siblings ( Lins et al., 2018 ). We examined prepulse inhibition (PPI), sociability, MK-801-induced locomotor activity, crossmodal object recognition (CMOR), and oddity discrimination; behaviors relevant to the positive, negative, and cognitive symptoms of schizophrenia. No between-treatment differences in PPI or locomotor activity were noted. Tactile memory was observed in the control and treated female offspring, visual recognition memory was deficient in the polyinosinic:polycytidylic acid (polyI:C) offspring only, and both groups lacked crossmodal recognition. PolyI:C offspring were impaired in oddity preference and had reduced preference for a stranger conspecific in a sociability assay. Systemic maternal CXCL1, IL-6, and TNF-a levels 3 h after polyI:C treatment were determined, but no relationship was found between these cytokines and the behavior seen in the adult female offspring. Overall, female offspring of polyI:C-treated dams display an array of behavior abnormalities relevant to psychiatric illnesses such as schizophrenia similar to those previously reported in male rats.

show abstract

“…In general, MIA associated behavioral and neurophysiological outcomes may appear differentially, or similar behavioral phenotypes can be mediated by separate underlying mechanisms (Sorge et al, 2015), as is probable with the social discrimination impairments observed here. Notably, the paucity of female impairments reported following MIA are likely due to experimental biases, leading to the exclusion of female animals in research (Coiro & Pollak, 2019) and deficits in the detection of such impairments.…”

Section: Discussionmentioning

confidence: 99%

Environmental influences on placental programming and offspring outcomes following maternal immune activation

Estevez

Rondón-Ortiz

Nguyen

et al. 2019

Preprint

View full text Add to dashboard Cite

Adverse experiences during pregnancy induce placental programming, affecting the fetus and its developmental trajectory. However, the influence of 'positive' maternal experiences on the placenta and fetus remain unclear. In animal models of early life stress, environmental enrichment (EE) has ameliorated and even prevented associated impairments in brain and behavior. Here, using a maternal immune activation (MIA) model in rats, we test whether EE attenuates maternal, placental and/or fetal responses to an inflammatory challenge, thereby offering a mechanism by which fetal programming may be prevented. Moreover, we evaluate life-long EE exposure on offspring development and examine a constellation of genes and epigenetic writers that may protect against MIA challenges. In our model, maternal plasma corticosterone and interleukin-1β were elevated 3 h after MIA, validating the maternal inflammatory response. Evidence for developmental programming was demonstrated by a simultaneous decrease in the placental enzymes Hsd11b2 and Hsd11b2/Hsd11b1, suggesting disturbances in glucocorticoid metabolism. Reductions of Hsd11b2 in response to challenge is thought to result in excess glucocorticoid exposure to the fetus and altered glucocorticoid receptor expression, increasing susceptibility to behavioral impairments later in life. The placental, but not maternal, glucocorticoid implications of MIA were attenuated by EE. There were also sustained changes in epigenetic writers in both placenta and fetal brain as a consequence of environmental experience and sex. Following MIA, both male and female juvenile animals were impaired in social discrimination ability. Life-long EE mitigated these impairments, in addition to the sex specific MIA associated disruptions in central Fkbp5 and Oprm1. These data provide the first evidence that EE protects placental functioning during stressor exposure, underscoring the importance of addressing maternal health and well-being throughout pregnancy. Future work must evaluate critical periods of EE use to determine if postnatal EE experience is necessary, or if prenatal exposure alone is sufficient to confer protection.

show abstract

Sex and gender bias in the experimental neurosciences: the case of the maternal immune activation model

Cited by 55 publications

References 83 publications

Modulating microglia activation prevents maternal immune activation induced schizophrenia-relevant behavior phenotypes via arginase 1 in the dentate gyrus

Modulating microglia activation prevents maternal immune activation induced schizophrenia-relevant behavior phenotypes via arginase 1 in the dentate gyrus

Maternal Immune Activation during Pregnancy Alters the Behavior Profile of Female Offspring of Sprague Dawley Rats

Environmental influences on placental programming and offspring outcomes following maternal immune activation

Contact Info

Product

Resources

About