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最大限度地减少 由病理性神经元活动减少或增加引起的大脑功能，这是 各种各样的神经性疾病。有趣的是，在某些情况下，大脑进化了各种机制 部分纠正异常的神经功能。了解恢复大脑的适应机制 功能不仅提供了对正常大脑功能的洞察，而且还指导了未来 改善因疾病或损伤导致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，即使在神经元活动自然变化或受到干扰时也是如此。我们的初步证据是 鸣禽表明，参与歌曲产生的大脑回路显示出高水平的行为 无论是在短时间尺度还是在长时间尺度上的韧性。在短时间尺度上，前置电机的激发模式 直接参与歌曲产生的神经元每天都不同，尽管没有可测量的 歌曲中的变化多端。从长远来看，我们从基因上干扰了这些运动前神经元的活动。 这导致了歌曲的戏剧性中断。然而，被操纵的鸟类完全从 并能够在大约10天后制作出他们的原创歌曲。我们将在这些基础上继续努力 结果探索了确保大脑回路中行为弹性的神经机制 使用基因传递、光遗传学、体内功能成像、行为分析和 计算建模。

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.