Acute Brain Injury, Mechanisms and Consequences

这是一份申请竞争续期RO1奖助金的申请书，该奖助金的资助期限为3年(11/1/98- 10/31/01)，支持旨在阐明兴奋性毒性和/或凋亡性细胞死亡机制的作用的研究(S 在与头部创伤和缺氧/缺血相关的发育性(围产期)脑损伤中。除了……之外 在赠款期间，针对这些目标，PI意外地发现，在 突触发育期一过性酒精中毒引发大量细胞凋亡 神经变性，从发育中的大鼠、小鼠或 豚鼠的大脑。我们的发现证明乙醇通过双重机制触发细胞凋亡--阻断 NMDA谷氨酸受体和GABAA受体的过度激活。我们认为我们的发现可以 有助于解释与人类胎儿相关的大脑质量减少和终生神经行为障碍 酒精综合征(FAS)。这一发现的意义被扩大了，因为有证据表明乙醇 神经毒性特性被许多其他药物所共有，这些药物要么阻断NMDA谷氨酸受体，要么 激活GABA^受体，其中许多药物是滥用药物和/或经常用于产科和 儿科医学。我们发现的一个重要特征是，在突触发生期间(前2周 大鼠和小鼠出生后，但人类出生后第三个月和第一个几年)神经元不同 人群对这些药物的凋亡诱导作用的反应有不同的时间模式。 因此，根据暴露的时间不同，神经元组的不同组合将被删除，这 这意味着这是一种神经发育机制，可以促进广泛的神经精神病学 骚乱。与这种解释一致的是，有证据表明，Fas的受害者不仅表现为童年 多动/注意力缺陷和学习障碍，但成人起病的精神病发病率较高 精神障碍，包括严重的抑郁障碍和精神病。这项相互竞争的更新提案的目的是 有三个方面，第一个是继续探索兴奋性毒性和凋亡机制在脑缺血中的作用 神经退行性变，第二和第三个是更全面地描述分子，神经病理和 我们已经发现的凋亡性神经退行性综合征的神经行为方面可以在 小鼠在突触发生过程中短暂接触乙醇而发育的大脑。

This is an application for competing renewal of an RO1 grant which was funded for 3 years (11/1/98 - 10/31/01) to support studies aimed at clarfying the role(s) of excitotoxic and/or apoptotic cell death mechanisms in developmental (perinatal) brain injury associated with head trauma and hypoxia/ischemia. In addition to addressing these aims during the grant period, the PI has made the unanticipated discovery that during the synaptogenesis period of development transient ethanol intoxication triggers a massive wave of apoptotic neurodegeneration, deleting millions of neurons from many different regions of the developing rat, mouse or guinea pig brain. Our findings document that ethanol triggers apoptosis by a dual mechanism - blockade of NMDA glutamate receptors and excessive activation of GABAA receptors. We propose that our findings can help explain the reduced brain mass and lifelong neurobehavioral disturbances associated with the human fetal alcohol syndrome (FAS). Significance of this discovery is broadened by accompanying evidence that ethanol's neurotoxic properties are shared by numerous other agents that either block NMDA glutamate receptors or activate GABA^ receptors, and many of these agents are drugs of abuse and/or are used regularly in obstetric and pediatric medicine. An important feature of our findings is that within the synaptogenesis period (first 2 weeks after birth for rats and mice, but third trimester and first several years after birth for humans) different neuronal populations have different temporal patterns for responding to the apoptosis-inducing effects of these drugs. Thus, depending on the timing of exposure, different combinations of neuronal groups will be deleted, which signifies that this is a neurodevelopmental mechanism that can contribute to a wide spectrum of neuropsychiatric disturbances. Consistent with this interpretation is evidence that victims of FAS manifest not only childhood hyperactivity/attention deficit and learning disorders, but have a high incidence of adult onset psychiatric disturbances, including major depressive disorder and psychosis. The aims of this competing renewal proposal are threefold, the first being to continue exploring the role of excitotoxic and apoptotic mechanisms in ischemic neurodegeneration, and the second and third being to more fully characterize molecular, neuropathological and neurobehavioral aspects of the apoptotic neurodegenerative syndrome we have found can be induced in the developing mouse brain by transient exposure to ethanol during synaptogenesis.