Encoding precise movements in the rodent brain

我们的生存取决于我们如何很好地适应不断变化的环境，通过学习过程改变我们的行为。这种学习被编码在大脑中，作为神经电路执行的计算的变化，进而驱动行为。大脑的这一非凡特性丰富了我们的行为模式，并定义了我们的身份。然而，关于学习是如何在大脑中编码的，还有很多需要了解。哪些算法决定了哪些突触、神经元和回路会因触发刺激而改变？这种变化是如何储存的，这又如何导致行为学习呢？ 为了回答这些问题，我们研究了一种相对简单和定义明确的行为--小脑依赖的小鼠运动学习。小脑神经回路被很好地绘制，小脑支持学习精确和校准的运动，这可以在动物模型中以高精度测量。由于小脑细胞结构相对简单，在运动学习过程中感觉输入和运动输出之间的转换可以直接与行为结果联系在一起。 我的研究项目的长期目标是确定记忆是如何在突触、细胞和电路水平上编码的。这项研究计划(短期目标)旨在使用一种简单而精确的眼球运动学习形式来确定学习在突触和小脑细胞中诱导了什么变化。具体目标有三个： 1.确定前庭-眼反射(VOR)学习的突触和细胞底物 2.确定VOR学习的结构特征。 3.揭示短期记忆是如何转化为长期记忆的 我们将利用电生理学、行为分析和形态分析的组合来确定VOR学习是如何在小脑中编码的。我们的主要关注点是浦肯野细胞，之前的结果表明它是记忆存储的场所。利用膜片钳记录，我们将测试在浦肯野细胞上学习兴奋性和抑制性突触会引起什么变化。这一分析将得到浦肯野细胞突触形状和密度变化的形态分析的补充。此外，我们还将检验这一假设，即随着时间的推移，学习诱导的可塑性变化的位置从浦肯野细胞转移到输出脑干核团。 这项研究计划将对复杂的计算创造一个新的理解水平，这些计算管理着学习过程中神经电路的适应。此外，拟议的研究将为受训者提供一个很好的培训机会，让他们使用尖端的神经生理学技术来识别学习行为的突触和回路基础。

Our survival depends on how well we adapt to changing conditions by modifying our behavior through a process of learning. Such learning is encoded in the brain, as changes in the computations performed by neural circuits, which in turn drives the behavior. This remarkable property of the brain enriches our behavioral repertoire and defines our identity. However, much remains to be understood about how learning is encoded in the brain. What algorithms determine which synapses, neurons, and circuits will change in response to triggering stimuli? How is such change stored, and how does this result in behavioral learning? We study a relatively simple and well-defined behavior, cerebellum-dependent motor learning in mice, in order to answer these questions. Cerebellar neuronal circuitry is well-mapped, and the cerebellum supports the learning of precise and well-calibrated movements, which can be measured with a high degree of precision in animal models. Because of the relative simplicity of cerebellar cytoarchitecture, the transformations that occur between sensory input and motor output during motor learning can be directly linked to a behavioral outcome. The long-term goals of my research program are to identify how memories are encoded, at the synaptic, cellular and circuit levels. This research proposal (short-term goals) aims to use a simple and precise form of oculomotor learning to determine what changes learning induces at synapses and cells in the cerebellum. There are three specific aims: 1. To identify the synaptic and cellular substrates of vestibulo-ocular reflex (VOR) learning 2. To determine the structural signatures of VOR learning. 3. To uncover how short-term memories are converted into long-term memories We will utilize a combination of electrophysiology, behavioral analysis and morphological analysis to identify how VOR learning is encoded within the cerebellum. Our primary focus is on the Purkinje cell, which previous results suggest is the site of memory storage. Using patch-clamp recordings, we will test what changes are induced by learning at excitatory and inhibitory synapses onto Purkinje cells. This analysis will be complemented by morphological analysis of changes in shape and density of synapses onto Purkinje cells. Furthermore, we will also test the hypothesis that, over time, the site of learning-induced plastic changes moves away from Purkinje cells to the output brainstem nuclei. This research program will create a new level of understanding of the complex computations that govern the adaptation of neural circuits during learning. Moreover, the proposed research will provide an excellent training opportunity for trainees to use cutting-edge neurophysiological techniques to identify the synaptic and circuit basis of learned behavior.