Behavioral feedback and Neuronal Lifespan

行为反馈和神经元寿命

• 批准号: 7589586
• 负责人: CAROLYN Liv PYTTE
• 金额: $ 7.75万
• 依托单位: QUEENS COLLEGE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-15 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7589586
• 关键词: Adult; Age; Anterior; Area; Auditory; Behavior; Behavioral; Birds; Botox; Brain; Brain region; Brain-Derived Neurotrophic Factor; Caspase Inhibitor; Cell Death; Cell Nucleus; Cells; Cessation of life; Characteristics; Data; Feedback; Goals; Hippocampus (Brain); Human; Individual; Injury; Investigation; Label; Longevity; Measures; Medial; Mediating; Methods; Modeling; Motor Activity; Motor Pathways; Motor output; Muscle; Neurodegenerative Disorders; Neurons; Organism; Outcome; Paralysed; Pathway interactions; Population; Process; Production; Prosencephalon; Psychological reinforcement; Regulation; Replacement Therapy; Research; Research Design; Songbirds; Staging; Stem cells; Stroke; Study models; System; Testing; Testosterone; Therapeutic; Tissues; Transplantation; Trauma; Variant; Work; abstracting; adult neurogenesis; age group; age related; aged; auditory feedback; base; brain behavior; caspase-3; cohort; experience; immunocytochemistry; male; nerve stem cell; neurodevelopment; neuron loss; neuronal replacement; novel; olfactory bulb; programs; relating to nervous system; repaired; research study; response; sensory feedback; zebra finch

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.

描述（由申请人提供）：创伤，中风和神经退行性疾病后的神经替代疗法的开发沿两个主要方面聚焦：从外源干细胞衍生出受损的脑部区域的移植神经前体，并利用内源性神经元的产生来将细胞引导到目标区域。这两个程序的目的是将健康的神经组织引入通常不经历成人神经发生的区域。为了实现这一目标，了解成人神经元更新的自然调节将为治疗进步建立基础。此外，如果我们要靶向新的神经元融合到不同的大脑区域，我们也必须了解新近生成的神经元在海马和嗅球外的系统中的行为。 Avian Song System提供了一个强大的模型，用于研究整个大脑区域的成人神经元置换。在该系统中，新的神经元被纳入对歌曲产生必不可少的感觉运动核中，提供了一种高度可拖延的脑行为模型，在该模型中，研究成人神经发生与一系列相关的相关行为相关。拟议的研究的长期目标是了解生物体的行为，神经经验的行为之间的关系，以及在经历神经元更新的大脑区域中神经元寿命的调节。获得这种理解的最终目标是它在指定条件中的应用，这些条件鼓励和维持人脑中健康的神经元替代，以及为因疾病或损伤而导致神经元细胞死亡增加的个体开发治疗方法。该项目的具体目的是确定影响神经元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。但是，迄今为止，神经元经验是神经需求或特定大脑区域的使用或活动的代名词，并且体验质量的变化尚未被确定为神经元寿命的决定性。例如，产生的歌曲数量与歌曲电动通路中的新神经元的数量相关（Li等，2000）。相比之下，我们最近发现，异常的歌曲产生导致该途径中新神经元的数量急剧减少。这表明，不仅对电机输出的定量度量，而且行为反馈的质量也可能影响神经元更新。在拟议的工作中，我们将确定异常的歌曲制作和反馈是否会触发歌曲Motor Pathway中的神经元细胞死亡。通过使用肉毒杆菌毒素部分瘫痪声肌，使歌曲的产生扭曲。这样，在唱歌过程中收到的感官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评估不同年龄的神经元人群中的细胞死亡，以标记垂死的细胞，神经元特异性标记和细胞出生的标志物。不同年龄组神经元之间的不同反应将为随后研究可能发生反馈引起的神经元死亡的机制提供基础。