早期逆境导致青春期小鼠穿孔通路连通性和情境记忆的性别特异性缺陷

IF 4.9 2区 医学 Q1 ENDOCRINOLOGY & METABOLISM Biology of Sex Differences Pub Date : 2024-05-07 DOI:10.1186/s13293-024-00616-0
Rafiad Islam, Jordon D White, Tanzil M Arefin, Sameet Mehta, Xinran Liu, Baruh Polis, Lauryn Giuliano, Sahabuddin Ahmed, Christian Bowers, Jiangyang Zhang, Arie Kaffman
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引用次数: 0

摘要

背景:在不同物种中,早期生活逆境会损害海马的发育和功能。虽然最初的证据表明雄性和雌性之间存在潜在的差异,但还需要进一步的研究来验证这些观察结果,并更好地了解导致这些性别差异的潜在机制。此外,大多数啮齿类动物的临床前研究都是在成年雄性动物中进行的,只有少数研究对青春期的性别差异进行了研究,而青春期的性别差异显得更为明显。为了解决这些问题,我们研究了小鼠早期逆境模型--有限垫料(LB)对青春期前和青春期雌雄小鼠海马发育的影响:方法:采用RNA测序、共聚焦显微镜和电子显微镜评估LB和性别对出生后第17天(P17)青春期前小鼠海马发育的影响。另外还对 P29-36 岁的青春期小鼠进行了研究,包括情境恐惧条件反射、逆行追踪和体外弥散磁共振成像(dMRI):结果:与雌性小鼠相比,青春期前和青春期枸橼酸雄性小鼠穿孔通路的轴突神经支配和髓鞘化缺陷更为严重。这些性别差异是由于位于外侧内侧皮层(LEC)的髓鞘蛋白阳性神经元未能通过穿孔通路支配男性海马背侧,而枸杞雌性海马背侧的髓鞘蛋白阳性神经元未能通过穿孔通路支配男性海马背侧,并且与情境恐惧条件反射的缺陷密切相关:结论:LB损害了位于LEC的reelin阳性细胞对LB雄性仔鼠海马背侧的投射和神经支配能力,而LB雌性仔鼠则没有这种能力。鉴于这些投射在支持海马正常功能方面发挥的关键作用,LEC与海马背侧之间未能建立适当的连接提供了一个令人信服的新机制,以解释在青少年男性LB中发现的更严重的髓鞘化和情境冻结缺陷。
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Early adversity causes sex-specific deficits in perforant pathway connectivity and contextual memory in adolescent mice.

Background: Early life adversity impairs hippocampal development and function across diverse species. While initial evidence indicated potential variations between males and females, further research is required to validate these observations and better understand the underlying mechanisms contributing to these sex differences. Furthermore, most of the preclinical work in rodents was performed in adult males, with only few studies examining sex differences during adolescence when such differences appear more pronounced. To address these concerns, we investigated the impact of limited bedding (LB), a mouse model of early adversity, on hippocampal development in prepubescent and adolescent male and female mice.

Methods: RNA sequencing, confocal microscopy, and electron microscopy were used to evaluate the impact of LB and sex on hippocampal development in prepubescent postnatal day 17 (P17) mice. Additional studies were conducted on adolescent mice aged P29-36, which included contextual fear conditioning, retrograde tracing, and ex vivo diffusion magnetic resonance imaging (dMRI).

Results: More severe deficits in axonal innervation and myelination were found in the perforant pathway of prepubescent and adolescent LB males compared to LB female littermates. These sex differences were due to a failure of reelin-positive neurons located in the lateral entorhinal cortex (LEC) to innervate the dorsal hippocampus via the perforant pathway in males, but not LB females, and were strongly correlated with deficits in contextual fear conditioning.

Conclusions: LB impairs the capacity of reelin-positive cells located in the LEC to project and innervate the dorsal hippocampus in LB males but not female LB littermates. Given the critical role that these projections play in supporting normal hippocampal function, a failure to establish proper connectivity between the LEC and the dorsal hippocampus provides a compelling and novel mechanism to explain the more severe deficits in myelination and contextual freezing found in adolescent LB males.

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来源期刊
Biology of Sex Differences
Biology of Sex Differences ENDOCRINOLOGY & METABOLISM-GENETICS & HEREDITY
CiteScore
12.10
自引率
1.30%
发文量
69
审稿时长
14 weeks
期刊介绍: Biology of Sex Differences is a unique scientific journal focusing on sex differences in physiology, behavior, and disease from molecular to phenotypic levels, incorporating both basic and clinical research. The journal aims to enhance understanding of basic principles and facilitate the development of therapeutic and diagnostic tools specific to sex differences. As an open-access journal, it is the official publication of the Organization for the Study of Sex Differences and co-published by the Society for Women's Health Research. Topical areas include, but are not limited to sex differences in: genomics; the microbiome; epigenetics; molecular and cell biology; tissue biology; physiology; interaction of tissue systems, in any system including adipose, behavioral, cardiovascular, immune, muscular, neural, renal, and skeletal; clinical studies bearing on sex differences in disease or response to therapy.
期刊最新文献
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