Behavioral feedback and Neuronal Lifespan

描述(申请人提供)：针对创伤、中风和神经退行性疾病后的脑修复的神经替代疗法的开发主要集中在两个主要方面：将来自外源干细胞的神经前体移植到受损的大脑区域，以及利用内源性神经元产生的物质将迁移细胞引导到靶区。这两个项目的目标都是将健康的神经组织引入正常情况下不会进行成人神经再生的区域。为了达到这一目标，了解成年神经元周转的自然调节将为治疗的进步奠定基础。此外，如果我们要将新神经元整合到不同的大脑区域，那么了解海马体和嗅球以外系统中新生成的神经元的行为也是至关重要的。鸟鸣系统为研究跨脑区域的成年神经元替换提供了一个强大的模型。在这个系统中，新的神经元被结合到一个对歌曲产生至关重要的感觉运动核团中，提供了一个高度可处理的大脑行为模型，在这个模型中，可以研究与丰富的歌唱相关行为相关的成人神经发生。这项拟议研究的长期目标是了解有机体的行为或神经经验与经历神经元更替的大脑区域中神经元寿命调节之间的关系。获得这一理解的最终目标是将其应用于指定条件，以鼓励和维持人脑中健康的神经元替换，以及开发治疗因疾病或损伤而增加神经细胞死亡的个人。该项目的具体目标是确定影响神经细胞死亡的行为因素。众所周知，神经元经验会影响神经元的寿命。然而，到目前为止，神经元体验一直是神经需求的同义词，也就是特定大脑区域的使用量或活动量，体验质量的差异尚未被确定为神经元寿命的决定因素。例如，歌曲产生的数量与歌曲运动通路中新神经元的数量相关(Li等人，2000年)。相反，我们最近发现，异常的歌曲产生导致这一途径中新神经元的数量急剧减少。这表明，不仅是运动输出的量化指标，而且行为反馈的质量也可能影响神经元的更替。在这项拟议的工作中，我们将确定异常的歌曲产生和反馈是否会触发歌曲运动通路中的神经细胞死亡。通过使用肉毒杆菌毒素使声带肌肉部分瘫痪，歌曲的产生被扭曲。通过这种方式，在歌唱过程中接收到的感觉反馈与预期的感觉反馈不匹配。然后，我们将使用免疫细胞化学来标记死亡细胞、神经元特异性标记物和细胞生日标记物，来评估不同年龄神经元队列中的细胞死亡。不同年龄组神经元之间的不同反应将为后续研究反馈诱导神经元死亡的机制提供基础。

DESCRIPTION (provided by applicant): The development of neural replacement therapies for brain repair after trauma, stroke, and neurodegenerative disease is focused along two main fronts: transplanting neural precursors derived from exogenous stem cells into damaged brain regions, and harnessing endogenous neuron production to direct migrating cells to target areas. The goal of both programs is to introduce healthy neural tissue to regions which do not normally undergo adult neurogenesis. Toward this aim, understanding the natural regulation of adult neuronal turnover will establish the basis for therapeutic advancement. In addition, it is critical that we also understand the behavior of newly generated neurons in systems outside of the hippocampus and olfactory bulb if we are to target new neuron incorporation into diverse brain regions. The avian song system provides a powerful model for studying adult neuron replacement across brain regions. In this system, new neurons are incorporated into a sensorimotor nucleus essential for song production, providing a highly tractable brain-behavior model in which to study adult neurogenesis in association with a rich array of singing related behaviors. The long term objective of the proposed research is to understand the relationship between behavior of the organism, or neural experience, and the regulation of neuronal lifespan in brain regions that undergo neuronal turnover. The ultimate goal of gaining this understanding is its application in designating conditions which encourage and maintain healthy neuronal replacement in the human brain as well as in developing treatments for individuals with increased neuron cell death due to illness or injury. The specific aim of this project is to identify behavioral factors that impact neuron cell death. Neuronal experience is known to influence neuron lifespan. However, to date, neuronal experience has been synonymous with neural demand, or the amount of use or activity in a particular brain region, and variations in the quality of the experience has not yet been identified as a determinant of neuronal lifespan. For instance, the amount of song produced is correlated with the number of new neurons in the song motor pathway (Li et al., 2000). In contrast, we have recently discovered that aberrant song production results in a dramatic decrease in the number of new neuron in this pathway. This suggests that not only a quantitative measure of motor output, but also the quality of behavioral feedback, may influence neuronal turnover. In the proposed work, we will determine whether aberrant song production and feedback triggers neuron cell death in the song motor pathway. Song production is distorted by partially paralyzing the vocal muscles using botox. In this way, sensory feedback that is received during singing is mismatched to the expected sensory feedback. We will then assess cell death in cohorts of neurons of different ages using immunocytochemistry to label dying cells, neuron-specific markers, and markers of cell birthdate. Different responses among neurons of different age groups will provide the basis for subsequent investigation of the mechanisms by which feedback-induced neuron death may occur.