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，以防止或最大限度地减少神经元的损失。 由神经元活动的病理性减少或增加引起的脑功能，这是一个 各种神经系统疾病有趣的是，在某些情况下，大脑已经进化出了 来部分纠正异常的神经元功能了解恢复大脑的适应机制 功能不仅可以深入了解正常大脑的功能，还可以指导未来的研究。 改善由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 一个研究大脑维持恒定行为的细胞和电路机制的项目 输出，即使当神经元活动是自然可变的或它是扰动。我们的初步证据 鸣禽的研究表明，与鸣叫有关的大脑回路表现出高水平的行为反应， 在短期和长期时间尺度上的弹性。在短时间尺度上，前运动神经元的放电模式 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 歌曲中的变化。在较长的时间尺度上，我们从遗传学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中断。然而，被操纵的鸟类完全从 他们的歌曲在大约10天后就能制作出来。我们将在此基础上 结果探索神经元机制，确保行为弹性的大脑回路参与了一个 使用基因递送、光遗传学、体内功能成像、行为分析和 计算机建模

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.