Synaptic mechanisms of temporal pattern separation

项目摘要 模式分离是大脑区分相似或重叠的过程 外部世界的特征。这种基本计算是由多层电路执行的，包括 齿状回、小脑皮质和昆虫蘑菇体--它们扩展和多样化神经 表示。实现了“空间”的多样性（即对给定刺激作出反应的神经元的身份）。 稀疏和非结构化的突触连接，但我们目前缺乏对突触 产生时间分集以支持时间模式分离。这一差距是由于两个基本挑战：（1） 测量到给定神经元的多个突触输入的动力学特性，以及（2）因果地扰动那些 同时监测下游神经元和行为。 在这里，我们提出克服这些挑战，通过研究突触机制的时间 在一个易于处理的实验系统中的模式分离：果蝇的蘑菇体。我们有 开发了新的方法来快速表征多个突触输入的短期可塑性动力学， 单个神经元，以及扰乱这些动力学的遗传策略。这使得系统 研究突触如何随着时间的推移产生多样性，以分离感觉中的细微时间差异。 输入。在目标1中，我们将确定蘑菇体神经元群体如何使用时间多样性来 扩展他们的感官编码能力。在目标2中，我们将联合收割机结合双光子光遗传学刺激和全基因组。 细胞电生理学检查突触输入的短期可塑性特性的组织 到蘑菇体。在目标3中，我们将实验性地操纵蘑菇体的短期塑性 输入突触来研究它们在联想学习中的作用。总之，这些研究将揭示突触和 蘑菇体中时间模式分离的细胞机制。 尽管苍蝇和哺乳动物之间存在差异，但模式分离的基本逻辑是 在无脊椎动物和脊椎动物的神经回路中非常保守。这些相似之处表明， 在果蝇中的发现将与其他疾病中的时间模式分离机制有关。 动物更深入地了解短期突触可塑性如何实现更高阶的 计算有可能改变我们对时间在学习和记忆中的作用的理解， 这可能会改善记忆相关疾病的治疗方法。

PROJECT SUMMARY Pattern separation is the process by which the brain distinguishes between similar or overlapping features of the external world. This fundamental computation is performed by multilayered circuits – including the dentate gyrus, cerebellar cortex, and insect mushroom body – that expand and diversify neural representations. Diversity in “space” (i.e. the identities of neurons responding to a given stimulus) is achieved by sparse and unstructured synaptic connectivity, but we currently lack an understanding of how synapses generate diversity in time to support temporal pattern separation. This gap is due to two basic challenges: (1) measuring dynamical properties of multiple synaptic inputs to a given neuron and (2) causally perturbing those properties while monitoring downstream neurons and behavior. Here we propose to overcome these challenges, by investigating synaptic mechanisms of temporal pattern separation in a tractable experimental system: the mushroom body of the fruit fly, Drosophila. We have developed new methods to rapidly characterize the short-term plasticity dynamics of multiple synaptic inputs to a single neuron, as well as genetic strategies to perturb these dynamics. This enables a systematic examination of how synapses generate diversity over time to separate fine temporal differences in sensory inputs. In Aim 1, we will determine how populations of mushroom body neurons use temporal diversity to expand their sensory coding capacity. In Aim 2, we will combine 2-photon optogenetic stimulation with whole- cell electrophysiology to examine the organization of short-term plasticity properties across the synaptic inputs to the mushroom body. In Aim 3, we will experimentally manipulate short-term plasticity at mushroom body input synapses to study their role in associative learning. Together, these studies will reveal synaptic and cellular mechanisms for temporal pattern separation in the mushroom body. Although there are differences between flies and mammals, the basic logic of pattern separation is strikingly conserved between circuits of invertebrates and vertebrates. These similarities suggest that discoveries made in the fruit fly will be relevant to the mechanisms of temporal pattern separation in other animals. A more thorough understanding of how short-term synaptic plasticity implements higher-order computations has the potential to transform our understanding of the role of timing in learning and memory, which could lead to improved treatments for memory-related disorders.