Glucocorticoid and Stress Induced Cerebellar Neural Progenitor Cell Apoptosis

描述（由申请人提供）：有相当多的证据表明，围产期糖皮质激素（GC）暴露，无论是从药物管理或在极端围产期应激期间，可以产生神经发育缺陷，导致永久性神经精神疾病。在我们的初步结果中，我们发现，急性注射GC和暴露于新生儿应激都可以在发育中的啮齿动物小脑中产生相同模式的神经祖细胞（NFC）凋亡变性。因此，阐明这种毒性的潜在机制有可能为围产期保健和神经发育的基本机制提供重要信息。虽然小脑传统上与神经运动功能有关，但最近的研究已经确定它在认知和情感行为中起着关键作用。因此，这项研究也可能表明GC诱导的小脑功能障碍在一个 各种神经精神病与这一观点一致，与生理盐水对照组相比，暴露于GC的早产儿已被发现出现认知和神经运动缺陷。同样重要的是，暴露于围产期应激与认知和情感功能障碍有关，并与各种神经精神疾病有关。在目标1中，申请人将测试潜在安全剂药物锂防止GC诱导的NPC细胞凋亡的能力及其在小脑中的长期作用。在目标2中，申请人将确定与增加的皮质酮释放相关的围产期应激范例是否可以在小脑NPC中急性产生细胞凋亡并在小脑颗粒细胞中产生长期减少。最后，在目的3中，申请人将利用Cre/lox重组系统选择性敲除小脑NPC中的GC受体，以确定它们在该毒性和小脑发育中的作用。在进行拟议的研究计划时，申请人将在对其职业发展至关重要的几个领域接受培训，包括免疫组织化学，药代动力学，电子显微镜，体视学，基因敲除小鼠和条件性基因敲除小鼠的使用，放射免疫测定以及病毒载体的维护和使用。 公共卫生相关性：目前，大量胎儿/新生儿暴露于GC用于围产期医学治疗或在与围产期应激相关的内源性释放期间。已知这两种情况都会产生永久性的行为缺陷，但对这种情况如何发生知之甚少。因此，这项研究可能会提供关键的见解暴露于GC对围产期健康的影响。

DESCRIPTION (provided by applicant): There is considerable evidence that perinatal glucocorticoid (GC) exposure, either from the administration of drugs or during periods of extreme perinatal stress, can produce neurodevelopmental deficits leading to permanent neuropsychlatric disorders. In our preliminary results, we have found that acute injections of GCs and exposure to neonatal stress can both produce an identical pattern of neural progenitor cell (NFC) apoptotic degeneration in the developing rodent cerebellum. Therefore, delineating the underlying mechanisms for this toxicity has the potential to provide important information for perinatal healthcare and basic mechanisms of neuredevelopment. While the cerebellum has traditionally been associated with neuromotor function, recent research has established that it plays a critical role in cognitive and affective behaviors. Therefore, this research may also suggest a role for GC induced cerebellar dysfunction in a variety of neuropsychlatric conditions. Consistent with this idea, prematurely born infants exposed to GCs have been found to develop cognitive and neuromotor deficits when compared to a saline control group. Of equal importance, exposure to perinatal stress has been associated with cognitive and affective dysfunction and has been implicated in a variety of neuropsychlatric conditions. In Aim 1, the applicant will test the potential safener drug lithium for its ability to protect against GC induced NPC apoptosis and its long term effects in the cerebellum. In Aim 2, the applicant will determine whether a perinatal stress paradigm associated with increased corticosterone release can produce apoptosis in cerebellar NPCs acutely and produce long term reductions in cerebellar granule cells. Finally, in Aim 3, the applicant will make use of the Cre/lox recombination system to selectively knockout GC receptors in the NPCs of the cerebellum in order to determine their role in this toxicity and cerebellar development. While conducting the proposed research plan the applicant will become trained in several areas critical for his career development including immunohistochemistry, pharmacokinetics, electron microscopy, stereology, the use of both knockout mice and conditional knockout mice, radioimmunoassay, and viral vector maintenance and use. PUBLIC HEALTH RELEVANCE: Currently, a large number of fetuses/neonates are exposed to GCs for either perinatal medical treatment or during the endogenous release associated with perinatal stress. Both of these conditions are known to produce permanent behavioral deficits yet little is known about how this occurs. Therefore, this research may provide key insights on the effects of exposure to GCs on perinatal health.