Functional role of adult neurogenesis in cognitive recovery from fetal alcohol

 描述（由申请人提供）：海马成体神经发生与海马依赖性学习和记忆之间的直接因果关系尚不清楚。FASD动物模型显示海马成体神经发生水平降低和海马依赖行为受损。暴露于运动单独或成功的环境复杂性增强成人神经发生的水平，并减轻行为缺陷对大脑依赖的任务，导致新生儿酒精暴露。本研究计划的长期目标是确定运动和/或环境诱导的新生成的神经元在FASD小鼠中表现出的海马依赖性任务的性能改善中的功能意义。初步数据表明，运动可以挽救产前酒精暴露引起的认知缺陷。初步数据显示，nestin-TK通过在神经祖细胞中表达病毒胸苷激酶，将运动动物的神经发生降低至久坐水平。本申请的目的是（1）开发更好的治疗方法，以帮助恢复因新生儿酒精暴露而丧失的认知功能;（2）了解健康和暴露于酒精大脑的齿状回中新生成的神经元的功能作用。这项研究的核心假设是，新的神经元是需要在FASD动物海马依赖行为的运动和/或环境诱导的救援赤字。其基本原理是，了解海马成体神经发生和海马行为缺陷之间的功能关系，可以为FASD患者制定特定的治疗干预措施提供基础。在第一个目标中，申请人将确定最成功的 在小鼠胎儿酒精模型中，来自运动和/或环境组合的干预用于增强成年神经发生和行为表现。接下来，申请人将通过Nestin TK转基因模型以及通过创新的转基因光遗传学模型直接测试由最成功的干预产生的新神经元的作用，其中新产生的神经元暂时失活然后重新激活。这项拟议中的研究意义重大，因为它将确定新产生的神经元在多大程度上有助于增强受损和健康大脑中的海马行为。这项研究具有创新性，因为它使用了尖端的无线光电技术，结合了一种新型的转基因小鼠品系，以暂时替代新的神经元。据我们所知，世界上没有其他地方可以制造这些独特的光电设备，这些设备的特点是安装在超薄生物相容性膜上的微型LED，可以实现无线微创光电功能。最终，该提案的结果有可能为美国FASD病例中改善认知表现的有效疗法的开发提供信息。

 DESCRIPTION (provided by applicant): A direct causal link between hippocampal adult neurogenesis and hippocampal dependent learning and memory remains unknown. Animal models of FASD show decreased levels of hippocampal adult neurogenesis and impaired hippocampal dependent behavior. Exposure to exercise alone or succeeded by environmental complexity enhances levels of adult neurogenesis and mitigates behavioral deficits on hippocampal-dependent tasks that result from neonatal alcohol exposure. The long-term goal of this research program is to determine the functional significance of exercise and/or environment induced newly generated neurons in the improved performance on hippocampal dependent tasks exhibited in FASD mice. Preliminary data indicate that exercise can rescue cognitive deficits induced by prenatal alcohol exposure. Pilot data show that nestin-TK reduces neurogenesis in exercising animals to sedentary levels through expression of a viral thymidine kinase in neural progenitor cells. The objective of this application is to (1) develop better treatments that would aid in the recovering of lost cognitive functioning due to neonatal alcohol exposure; (2) understand the functional role of newly generated neurons in the dentate gyrus of both the healthy and the neonatally exposed to alcohol brain. The central hypothesis for this research proposal is that new neurons are required for the exercise and/or environment-induced rescue deficits in hippocampal dependent behavior in FASD animals. The rationale is that understanding the functional relationship between hippocampal adult neurogenesis and hippocampal behavioral deficits can provide the foundation for developing specific therapeutic interventions for FASD patients. In the first aim, the applicant will determine the most successful intervention from combinations of exercise and/or environment for enhancing adult neurogenesis and behavioral performance in a mouse fetal alcohol model. Next, the applicant will directly test the role of new neurons, generated by the most successful intervention, through a Nestin TK transgenic model as well as through an innovative transgenic optogenetic model in which newly generated neurons are temporarily inactivated then reactivated. The proposed research is significant because it will determine the extent to which newly generated neurons contribute to enhanced hippocampal behavior in both the damaged and the healthy brain. The proposed research is innovative because it uses cutting-edge wireless optoeletronic technology combined with a novel transgenic mouse line to temporarily inactivate new neurons. To our knowledge, nowhere else in the world are they making these unique optoelectronic devices, that feature tiny LEDs mounted to an ultra thin biocompatible membrane that allows wireless minimally invasive optoelectronic capabilities. Ultimately, results from this proposal have the potential to inform development of effective therapies for improving cognitive performance in FASD cases in the United States.