the self-tuning brain: cellular and circuit mechanisms of behavioral resilience

摘要 临床神经科学的一个主要目标是开发有效的治疗方法来预防或尽量减少神经元的损失。 由神经元活动的病理性减少或增加引起的脑功能，这是神经元活动的标志 多种神经系统疾病。有趣的是，在某些情况下，大脑已经进化出一些机制 部分纠正异常的神经元功能。了解恢复大脑的适应性机制 功能不仅可以深入了解正常大脑的功能，还可以指导未来 改善因疾病或损伤引起的脑功能丧失的方法。我们建议开始一项研究 研究大脑维持恒定行为的细胞和电路机制的程序 输出，即使神经元活动自然变化或受到干扰。我们的初步证据 鸣禽表明，参与歌曲产生的大脑回路表现出高水平的行为能力 短期和长期的弹性。在短时间尺度上，前电机的放电模式 直接参与歌曲产生的神经元每天都在变化，尽管没有可测量的 歌曲的变化性。在很长的时间尺度上，我们从基因上扰乱了这些前运动神经元的活动 这导致了歌曲的戏剧性破坏。然而，经过操控的鸟类已完全康复 大约10天后就能够制作出他们的原创歌曲。我们将以此为基础 结果探索了确保参与某项活动的大脑回路中的行为弹性的神经元机制 使用基因传递、光遗传学、体内功能成像、行为分析和 计算模型。

ABSTRACT A major goal in clinical neuroscience is to develop efficient treatments to prevent or minimize the loss of brain function caused by pathological decreases or increases of neuronal activity, which are hallmarks of a wide variety of neurological disorders. Interestingly, in some instances, the brain has evolved mechanisms to partially correct abnormal neuronal function. Understanding the adaptive mechanisms that restore brain function would not only provide insight into the functioning of the normal brain but also guide future approaches to ameliorate loss of brain function caused by disease or injury. We propose to start a research program to investigate the cellular and circuit mechanisms by which the brain maintains constant behavioral output, even when neuronal activity is naturally variable or it is perturbed. Our preliminary evidence with songbirds indicate that the brain circuits involved in song production demonstrate a high level of behavioral resilience both at short and long timescales. At the short timescale the patterns of firing of premotor neurons directly involved in song production vary from day to day, although there is no measurable variability in the song. At the long timescale, we genetically perturbed the activity of these premotor neurons and this caused a dramatic disruption of song. However, manipulated birds fully recovered from the perturbation, and were able to produce their original song after around 10 days. We will build on these results to explore the neuronal mechanisms that ensure behavioral resilience in a brain circuit involved in a complex behavior using gene delivery, optogenetics, in vivo functional imaging, behavioral analysis, and computational modelling.