背景:早期生活逆境会损害不同物种的海马发育和功能。虽然最初的证据表明男性和女性之间存在潜在的差异,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,大多数啮齿动物的临床前工作是在成年男性中进行的,只有少数研究研究青春期的性别差异,因为这种差异显得更加明显。为了解决这些问题,我们调查了有限垫层(LB)的影响,早期逆境的小鼠模型,青春期前和青春期雄性和雌性小鼠海马发育的研究。
方法:RNA测序,共聚焦显微镜,和电子显微镜用于评估LB和性别对青春期前出生后第17天(P17)小鼠海马发育的影响。对年龄在P29-36岁的青春期小鼠进行了其他研究,其中包括上下文恐惧条件,逆行追踪,和离体扩散磁共振成像(dMRI)。
结果:与LB女性同窝相比,在青春期前和青春期LB男性的穿通途径中发现轴突神经支配和髓鞘形成更严重的缺陷。这些性别差异是由于位于外侧内嗅皮层(LEC)中的reelin阳性神经元未能通过雄性穿通途径支配背侧海马,但不是LB女性,并且与上下文恐惧条件的缺陷密切相关。
结论:LB损害了位于LEC中的reelin阳性细胞投射和神经支配LB雄性而不是雌性LB同窝的背侧海马的能力。鉴于这些投射在支持正常海马功能中起着关键作用,未能在LEC和背侧海马之间建立适当的连接,这提供了一种令人信服的新机制来解释在青少年LB男性中发现的更严重的髓鞘形成和上下文冻结缺陷.
童年的逆境,例如严重的剥夺和忽视,导致人脑发育的结构变化,这与学习缺陷和行为困难有关。在暴露于儿童逆境的个体中,一些最一致的发现是海马体积减少和海马功能异常。这很重要,因为海马体是学习和记忆所必需的,它在抑郁和焦虑中起着至关重要的作用。尽管最初的研究表明男性海马缺陷更明显,需要更多的研究来证实这些发现,并阐明导致这些性别差异的机制.我们发现,暴露于早期贫困和剥夺的雄性和雌性小鼠表现出与被剥夺儿童相似的结构变化。有趣的是,青春期雄性老鼠,但不是女性,当放在一个盒子里,他们的冻结能力表现出严重的缺陷,他们之前感到震惊。将“震惊/危险”与“盒子/地方”相关联的能力被称为上下文恐惧条件,并且需要内嗅皮层和海马体之间的正常连接。我们发现,这些联系在暴露于贫困条件的雄性小鼠中无法正常形成,但女性只受到最小的影响。这些发现似乎解释了为什么暴露于贫困条件会损害雄性小鼠而不是雌性小鼠的上下文恐惧条件。需要做更多的工作来确定在遭受忽视和剥夺的青少年中是否也观察到这些联系中类似的性别特定变化。
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.
Childhood adversity, such as severe deprivation and neglect, leads to structural changes in human brain development that are associated with learning deficits and behavioral difficulties. Some of the most consistent findings in individuals exposed to childhood adversity are reduced hippocampal volume and abnormal hippocampal function. This is important because the hippocampus is necessary for learning and memory, and it plays a crucial role in depression and anxiety. Although initial studies suggested more pronounced hippocampal deficits in men, additional research is needed to confirm these findings and to elucidate the mechanisms responsible for these sex differences. We found that male and female mice exposed to early impoverishment and deprivation exhibit similar structural changes to those observed in deprived children. Interestingly, adolescent male mice, but not females, display severe deficits in their ability to freeze when placed back in a box where they were previously shocked. The ability to associate “shock/danger” with a “box/place” is referred to as contextual fear conditioning and requires normal connections between the entorhinal cortex and the hippocampus. We found that these connections did not form properly in male mice exposed to impoverished conditions, but they were only minimally affected in females. These findings appear to explain why exposure to impoverished conditions impairs contextual fear conditioning in male mice but not in female mice. Additional work is needed to determine whether similar sex-specific changes in these connections are also observed in adolescents exposed to neglect and deprivation.