Imaging circuit structure and memories in a multifunctional network

描述(申请人提供)：人类的记忆是出了名的不准确。虽然新获得的记忆往往具有很高的有效性，但随着时间的推移，随后的经历可能会改变或降低它们，这种现象被称为“追溯干扰”。这不是简单的遗忘，而是后来的记忆对早期记忆的积极破坏。该项目的中心假设是，记忆之间的干扰自然是大脑以部分重叠的方式在神经网络中存储相关信息的方法造成的。在这个项目中，我们将研究两个存储在一起的记忆，这些记忆存储在一个实验上具有优势的海洋软体动物Tritonia diomedea的单一网络中。使用快速电压敏感染料的神经元群体的光学记录工具，尖锐电极的单个神经元的细胞内记录工具，以及动物记忆存储网络的真实网络模拟，我们将测试几个关于真实大脑中个体和多个记忆的解剖和功能组织的细胞水平假说。该项目将使用我们设计的一种新型混合显微镜，以促进传统的尖锐电极电生理学与大规模网络活动的光学记录的集成。我们的具体目标是：目标1。扩大我们对Tritonia记忆储存逃逸游泳网络的了解，包括新发现的一类“随意参与”的神经元的作用。在这里，我们将描述在我们的光学记录中发现的几个新的神经元，并测试一组关于网络功能的假设。目的2.映射第一记忆(敏感化)。虽然记忆已经在突触和分子水平上进行了深入的研究，但对其在神经系统中的解剖组织却知之甚少。编码单一记忆的细胞和突触变化分布如何？相对于记忆下的可塑性分布部位，信息的不同组成部分是如何组织的？我们将评估关于这些问题的相互竞争的假说，通过绘制出Tritonia大脑中敏化的记忆。目的3.映射第二记忆(习惯化)，并确定它如何部分地干扰和部分地与先前存在的记忆共存以进行敏化。根据行为学研究，习惯化似乎干扰了Tritonia中初始敏感化记忆的部分但不是全部成分。在这里，我们将绘制习惯化的记忆图谱，并试图确定它是否真的消除了先前的记忆，或者那个记忆是否在同一个神经网络中保持完好但隐藏着。该项目的长期目标是更好地了解大脑中记忆的网络组织，以及重叠存储如何影响记忆的准确性，目标是开发更好的治疗方法，用于治疗慢性焦虑、创伤后应激障碍和脑损伤后的记忆功能障碍。与公共健康相关：这个项目调查行为功能和记忆在大脑中以分布式、重叠的方式组织起来的程度。这一重要但鲜为人知的组织方案与各种现象有关，从受伤后大脑功能恢复的机制，到追溯干预，在这些现象中，后来的经历如此潜意识地改变了我们先前存在的记忆。我们开发了一种新的技术方法，用于在简单的模型准备中对大规模网络活动进行成像，从而使这项研究成为可能。

DESCRIPTION (provided by applicant): Human memory is notoriously inaccurate. Whereas newly acquired memories tend to have high validity, over time subsequent experiences can change or degrade them, a phenomenon termed "retroactive interference." This is not simple forgetting, but an active corruption of earlier memories by later ones. The central hypothesis of this project is that interference between memories results naturally from the brain's method of storing related information in partially overlapping fashion in neural networks. In this project we will study two memories that are stored together in a single network of the experimentally advantageous marine mollusk Tritonia diomedea. Using the tools of optical recording from neuronal populations with fast voltage-sensitive dyes, intracellular recording from individual neurons with sharp electrodes, and realistic network simulations of the animal's memory-storing network, we will test several cellular level hypotheses regarding the anatomical and functional organization of individual and multiple memories in a real brain. The project will utilize a new, hybrid microscope designed by us to facilitate the integration of conventional sharp electrode electrophysiology with large-scale optical recording of network activity. Our specific aims are: Aim 1. Expand our knowledge of Tritonia's memory-storing escape swim network, including the role of a newly-discovered class of "casually participating" neurons. Here we will characterize several new neurons discovered in our optical recordings, and test a set of hypotheses about network function. Aim 2. Map the first memory (sensitization). While memory has been intensively studied at the synaptic and molecular level, less is understood about its anatomical organization in nervous systems. How distributed are the cellular and synaptic changes encoding a single memory? How are the different components of information organized with respect to the distributed sites of plasticity underlying the memory? We will evaluate competing hypotheses regarding these issues by mapping out the memory for sensitization in the Tritonia brain. Aim 3. Map the second memory (habituation), and determine how it partially interferes with, and partially co-exists with the pre-existing memory for sensitization. Based on behavioral studies, habituation appears to interfere with some but not all components of an initial sensitization memory in Tritonia. Here we will map the memory for habituation as it develops, and will attempt to determine whether it does indeed erase the prior memory, or whether that memory persists, intact but hidden, in the same neural network. The long-term goal of this project is to better understand the network organization of memories in the brain, and how overlapping storage affects memory accuracy, with the goal of developing better treatments for conditions such as chronic anxiety, post-traumatic stress disorder, and memory dysfunction after brain injury. PUBLIC HEALTH RELEVANCE: This project investigates the degree to which behavioral functions and memories are organized in distributed, overlapping fashion in the brain. This important but poorly understood organizational scheme has relevance for phenomena ranging from mechanisms of recovery of brain function after injury, to retroactive interference, where later experiences so insidiously manage to alter our preexisting memories. This investigation is made possible by our development of a new technical approach for imaging large-scale network activity in a simple model preparation.