Abnormal Ontogeny and Cortical Function in a Mouse Model

一种小鼠模型的个体发育和皮质功能异常 早期的压力经历被认为是心理健康病因学的重要因素 精神分裂症和情绪障碍等障碍。早期的压力经历导致永久性的 老年人肾上腺皮质下丘脑[HPA]反应的变化。在啮齿动物模型中，从长期来看， 出生后早期母体分离[MS](3-24小时)会导致严重的HPA对压力的高反应 在晚年，伴随着焦虑的增加和认知的受损。然而，早期的、短期的“处理” 幼鼠(10-15分钟)会导致长期的压力反应迟钝，减少焦虑并改善 认知能力，显然是因为被处理的幼崽在返回时增加了母体的修饰。完毕 在目前的资助期，我们开发了一种新生的多发性硬化症小鼠分离范例，基于 分排式垃圾桶设计。来自这些公升的应激雄性小鼠[STR]会发展成认知障碍，增加 成年后的焦虑和攻击性，以及皮质宽度的变化，这是可以通过经验改变的。 令人惊讶的是，没有压力的产仔雄性[LMC]也会发生皮质变化和认知和 情绪障碍，尽管水平略低于年龄匹配的对照组[AMC]小鼠 没有任何压力暴露的垃圾。初步数据显示，LMC的母亲美容减少 与STR幼崽相比。这项提议旨在验证以下假设：1)STR的母体美容 LMC幼鼠对早期HPA轴的反应性有不同程度的影响 将单胺能神经支配改为皮质和海马区。此外，基于对新生儿的影响 5-羟色胺[5-羟色胺]和多巴胺[DA]缺乏对皮质形态发生和可塑性的影响 2)与AMC小鼠相比，STR和LMC的皮质形态差异是由于 5-羟色胺和/或多巴胺神经支配改变导致的皮质形态发生和可塑性受损； 反过来，形态的变化可能会导致行为的改变。这项竞争的长期目标是 更新应用是在细胞神经生物学水平上了解发育相互作用 环境诱因和遗传脆弱性之间的关系可以引起认知功能的改变，类似于 可见于各种精神健康障碍。

Abnormal Ontogeny and Cortical Function in a Mouse Model Early stress experience is regarded as powerfully contributing factor in the etiology of mental health disorders such as schizophrenia and mood disorders. Early stress experience leads to permanent alterations in the adreno-cortical-hypothalamic [HPA] response in later life. In rodent models, long-term, early postnatal maternal separation [MS] (3-24 hours) leads to profound HPA hyper-responsiveness to stress in later life, along with increased anxiety and impaired cognition. However, early, short term "handling" of pups (10-15 minutes) results in long-term stress hypo-responsiveness, decreased anxiety and improved cognition, apparently as result of increased maternal grooming of the handled pups upon their return. Over the current funding period, we have developed a neonatal MS separation paradigm in mouse, based on a split-litter design. Stressed male mice [STR] from these liters develop cognitive impairments, increased anxiety and aggression by adulthood, and, altered cortical width, that is modifiable by experience. Surprisingly, non-stressed litter-mate males [LMC] also develop cortical changes and cognitive and emotional impairments, albeit at somewhat lower levels, compared to age matched control [AMC] mice from litters without any stress exposure. Preliminary data suggest decreased maternal grooming of LMC compared to STR pups. This proposal aims to test the hypotheses that 1) maternal grooming of the STR and LMC pups induces graded effects on early HPA axes responsiveness that subsequently, differentially alter the monoaminergic innervation to cortex and hippocampus. Furthermore, based on effects of neonatal serotonin [5-HT] and dopamine [DA] depletions on cortical morphogenesis and plasticity, we hypothesize that 2) cortical morphological differences in both STR and LMC, compared to AMC mice, are the result of impaired cortical morphogenesis and plasticity resulting from altered 5-HT and/or DA innervation; such morphological changes, in turn, may precipitate altered behavior. The long-term goal of this competitive renewal application is to understand, on the level of cellular neurobiology, how developmental interactions between environmental triggers and genetic vulnerabilities can induce altered cognitive function akin to those seen in a variety of mental health disorders.