Behavioral feedback and Neuronal Lifespan

描述（由申请人提供）：用于创伤、中风和神经退行性疾病后脑修复的神经替代疗法的开发集中在沿着两个主要方面：将源自外源性干细胞的神经前体细胞移植到受损的脑区域，以及利用内源性神经元产生将迁移细胞引导到靶区域。这两个项目的目标都是将健康的神经组织引入到通常不经历成人神经发生的区域。为了实现这一目标，了解成人神经元周转的自然调节将为治疗进展奠定基础。此外，如果我们要将新的神经元整合到不同的大脑区域，那么我们还必须了解海马和嗅球以外系统中新产生的神经元的行为。鸟类的鸣唱系统为研究成年人大脑各区域的神经元替换提供了一个强大的模型。在这个系统中，新的神经元被纳入一个感觉运动核必不可少的歌曲生产，提供了一个高度听话的大脑行为模型，研究成人神经发生与丰富的一系列唱歌相关的行为。拟议研究的长期目标是了解生物体行为或神经体验与经历神经元更新的脑区域中神经元寿命的调节之间的关系。获得这种理解的最终目标是其在指定条件中的应用，这些条件鼓励和维持人类大脑中健康的神经元替代，以及在为由于疾病或损伤而增加神经元细胞死亡的个体开发治疗方法中的应用。该项目的具体目标是确定影响神经元细胞死亡的行为因素。已知神经元的经历会影响神经元的寿命。然而，到目前为止，神经元的经验已经与神经需求，或在特定的大脑区域的使用量或活动量同义，经验质量的变化尚未被确定为神经元寿命的决定因素。例如，产生的歌曲的量与歌曲运动通路中新神经元的数量相关（Li等人，2000年）。相比之下，我们最近发现异常的歌曲产生会导致该途径中新神经元的数量急剧减少。这表明不仅运动输出的定量测量，而且行为反馈的质量，可能会影响神经元的周转。在拟议的工作中，我们将确定是否异常的歌曲生产和反馈触发神经元细胞死亡的歌曲运动通路。用肉毒杆菌使声带肌肉部分麻痹，使歌曲的产生失真。以这种方式，在歌唱期间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标记垂死细胞，神经元特异性标记物和细胞出生日期标记物来评估不同年龄神经元队列中的细胞死亡。不同年龄组的神经元之间的不同反应将为后续研究反馈诱导的神经元死亡可能发生的机制提供基础。

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.