Prenatal poly(I:C) exposure, rather than altered maternal care, causes offspring behavioural and cognitive deficits in a rat model of neurodevelopmental disorders

IF 8.8 2区医学 Q1 IMMUNOLOGY

Brain, Behavior, and Immunity Pub Date : 2025-06-06 DOI:10.1016/j.bbi.2025.06.005

Harry G. Potter , Rebecca M. Woods , Jarred M. Lorusso , Grace Revill , Michael K. Harte , Jocelyn D. Glazier , Joanna C. Neill , Reinmar Hager

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引用次数: 0

Abstract

Background

Cognitive deficits are core features of neurodevelopmental disorders (NDD), arising from interacting genetic and environmental (GxE) factors. Maternal immune activation (MIA) is an established environmental risk factor, differentially affecting offspring cognition depending on exposure timing and severity. Maternal pro-inflammatory cytokines (e.g. tumor necrosis factor-alpha, TNFα) and altered maternal-offspring interactions are both implicated in MIA-induced NDD pathogenesis, but their relative impact on offspring cognition remains unclear. Understanding these mechanisms is crucial for developing targeted therapies for NDD-related cognitive deficits.

Methods

We used a split-litter cross-fostering design in a validated rat MIA model to examine prenatal and postnatal maternal influences on NDD-related cognitive traits. MIA was induced in pregnant Wistar dams (N = 22; gestational day 15) followed by cross-fostering (postnatal day (PD)1). Maternal behaviours, offspring ultrasonic vocalisations (USV), and cognition were assessed in both sexes. Phenotypic clustering of USV and cognitive traits was performed, and high-throughput Western blot quantified glutamic acid decarboxylase-67 (GAD67) and parvalbumin (PVALB) expression in the adult prefrontal cortex (PFC).

Results

Prenatal MIA, but not postnatal rearing, increased offspring USVs, maternal care behaviours, and impaired adult cognitive flexibility without affecting sociability. Offspring clustered into three groups based on PD10 USVs, with high USVs associated with reduced PD100 sociability. MIA did not alter PFC GAD67/PVALB expression.

Conclusions

The prenatal maternal response to MIA drives developmental and cognitive deficits. Offspring USVs influenced maternal care behaviours, but postnatal rearing did not affect cognitive development. USV trait clustering predicted adult social deficits, highlighting its potential for identifying at-risk and resilient offspring in NDDs.

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在神经发育障碍大鼠模型中，产前多（I:C）暴露，而不是改变的母性护理，导致后代行为和认知缺陷。

背景：认知缺陷是神经发育障碍（NDD）的核心特征，由遗传和环境因素相互作用引起。母体免疫激活（MIA）是一种既定的环境风险因素，根据暴露时间和严重程度对后代认知产生不同的影响。母体促炎因子（如肿瘤坏死因子α， TNFα）和改变的母婴相互作用都与mia诱导的NDD发病有关，但它们对后代认知的相对影响尚不清楚。了解这些机制对于开发针对ndd相关认知缺陷的靶向治疗至关重要。方法：我们在一个经过验证的MIA大鼠模型中采用分窝交叉饲养设计来研究产前和产后母亲对ndd相关认知特征的影响。妊娠Wistar母鼠诱导MIA (N = 22；妊娠期第15天)，然后进行交叉培养（产后第1天）。母鼠行为、子代超声发声（USV）和认知能力在两性中进行了评估。对USV和认知性状进行表型聚类，并用高通量Western blot定量测定成人前额皮质（PFC）中谷氨酸脱羧酶-67 （GAD67）和小白蛋白（PVALB）的表达。结果：产前MIA，而不是产后抚养，增加了后代usv，产妇护理行为和成人认知灵活性受损，但不影响社交能力。后代根据PD10 usv分为三组，高usv与低PD100社交性相关。MIA未改变PFC GAD67/PVALB的表达。结论：孕妇对MIA的产前反应导致发育和认知缺陷。后代usv影响母亲的护理行为，但产后抚养不影响认知发展。USV特征聚类预测了成人社会缺陷，突出了其在ndd中识别风险和适应力强的后代的潜力。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Brain, Behavior, and Immunity 医学-免疫学

CiteScore

29.60

自引率

2.00%

发文量

290

审稿时长

28 days

期刊介绍： Established in 1987, Brain, Behavior, and Immunity proudly serves as the official journal of the Psychoneuroimmunology Research Society (PNIRS). This pioneering journal is dedicated to publishing peer-reviewed basic, experimental, and clinical studies that explore the intricate interactions among behavioral, neural, endocrine, and immune systems in both humans and animals. As an international and interdisciplinary platform, Brain, Behavior, and Immunity focuses on original research spanning neuroscience, immunology, integrative physiology, behavioral biology, psychiatry, psychology, and clinical medicine. The journal is inclusive of research conducted at various levels, including molecular, cellular, social, and whole organism perspectives. With a commitment to efficiency, the journal facilitates online submission and review, ensuring timely publication of experimental results. Manuscripts typically undergo peer review and are returned to authors within 30 days of submission. It's worth noting that Brain, Behavior, and Immunity, published eight times a year, does not impose submission fees or page charges, fostering an open and accessible platform for scientific discourse.