Memory trace formation at and beyond individual synapses in the intact brain
完整大脑中单个突触内外的记忆痕迹形成
基本信息
- 批准号:BB/Y003926/1
- 负责人:
- 金额:$ 90.67万
- 依托单位:
- 依托单位国家:英国
- 项目类别:Research Grant
- 财政年份:2024
- 资助国家:英国
- 起止时间:2024 至 无数据
- 项目状态:未结题
- 来源:
- 关键词:
项目摘要
The principle of memory trace formation formulated by Donal Hebb refers to the strengthening of functional neuronal connections upon coincidence of informative inputs. This principle has found its empirical validation in the long-term potentiation (LTP) of synaptic transmission, an elemental model of synaptic memory. However, our understanding of its cellular mechanisms remains limited, mainly because attempts to relate LTP to a memory trace in the intact brain have never achieved resolution of individual synapses. Published evidence suggests that the increase in neuronal responses representing LTP could arise form either increased postsynaptic current or from increased probability of presynaptic neurotransmitter release (synaptic fidelity), or both. The present project will take advantage of the recent emergence of genetically encoded indicators (GEIs), which we have shown could provide robust monitoring of neurotransmitter release from individual synaptic connections. Our pilot data and other studies also indicate that the excitatory neurotransmitter glutamate could escape the active synaptic connection reaching its receptors at micron distances from its synaptic release site. Because synapses in the brain are less than a micron apart, this suggests a significant volume-transmitted component of excitatory transmission, challenging the principle of wired, one-to-one connectivity in neuronal networks. Whether memory formation involves changes in synaptic fidelity, whether the volume-transmitted excitatory signal is significant in the intact brain, and what could be its neurocomputational implications - these questions are fundamental for our understanding of the memory machinery. Addressing them has been a key motive for the present proposal. Our overall aim is therefore to understand the dynamics of synaptic fidelity and the extent and role of extrasynaptic excitatory signalling during memory trace formation in the brain. Built on our in-house established innovative methods and our preliminary results, this aim breaks down into several specific objectives. - To determine population dynamics of synaptic release probability during LTP induction in organised brain tissue and the key underlying mechanisms. - To establish the dynamics of synaptic fidelity at thalamocortical synapses during a sensory stimulation induced LTP in vivo. - To evaluate the extent and plasticity-associated changes in the extrasynaptic actions of glutamate at excitatory cortical synapses in vivo. - To understand physiological significance and network implications of the documented extrasynaptic glutamate escape. We will achieve these objectives by combining single-cell electrophysiology with high-resolution, high-speed multiplexed two-photon excitation imaging of cell-targeted GEIs. Control tests in ex vivo preparations will help us to optimise experiments in vivo in which we will monitor function of individual identified thalamocortical synapses in our tested paradigm of whisker stimulation. We will use our established high-end computer models to evaluate the significance of our observations for brain network activity. The established experimental protocols and pilot data that we have accumulated to date should ensure technical feasibility of the proposed research strategy.
多纳尔·赫布(Donal Hebb)阐述的记忆痕迹形成原理是指信息输入的同时,功能性神经元连接的加强。这一原理在突触传递的长时程增强(LTP)中得到了经验验证,这是突触记忆的基本模型。然而,我们对其细胞机制的理解仍然有限,主要是因为将LTP与完整大脑中的记忆痕迹联系起来的尝试从未实现单个突触的解析。已发表的证据表明,代表LTP的神经元反应的增加可能是由于突触后电流增加或突触前神经递质释放(突触保真度)的可能性增加,或两者兼而有之。本项目将利用最近出现的遗传编码指标(GEI),我们已经证明,它可以提供强大的监测神经递质释放从个人突触连接。我们的试点数据和其他研究还表明,兴奋性神经递质谷氨酸可以逃脱活跃的突触连接,到达距离其突触释放位点微米距离的受体。由于大脑中的突触相距不到一微米,这表明兴奋性传递中有一个重要的体积传递成分,挑战了神经元网络中有线的一对一连接的原则。记忆的形成是否涉及突触保真度的变化,体积传递的兴奋性信号在完整的大脑中是否重要,以及它的神经计算含义是什么-这些问题对于我们理解记忆机制至关重要。解决这些问题是本提案的一个主要动机。因此,我们的总体目标是了解突触保真度的动态和突触外兴奋性信号在大脑记忆痕迹形成过程中的程度和作用。基于我们内部建立的创新方法和我们的初步成果,这一目标分为几个具体目标。- 确定在有组织的脑组织中LTP诱导过程中突触释放概率的群体动力学和关键的潜在机制。- 建立感觉刺激诱发的长时程增强(LTP)过程中丘脑皮层突触保真度的动态变化。- 评价谷氨酸在体内兴奋性皮层突触的突触外作用的程度和可塑性相关变化。- 了解记录的突触外谷氨酸逃逸的生理意义和网络意义。我们将通过将单细胞电生理学与细胞靶向GEI的高分辨率、高速多路复用双光子激发成像相结合来实现这些目标。在离体制剂的控制测试将帮助我们优化体内实验,我们将在我们测试的晶须刺激范例中监测个体识别的丘脑皮质突触的功能。我们将使用我们建立的高端计算机模型来评估我们观察到的大脑网络活动的重要性。我们迄今积累的既定实验方案和试点数据应确保拟议研究战略的技术可行性。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Dmitri Rusakov其他文献
Tornado-FLIM acquisition for monitoring single-synapse presynaptic calcium dynamics in a mouse model of a migraine
- DOI:
10.1016/j.ibror.2019.07.1533 - 发表时间:
2019-09-01 - 期刊:
- 影响因子:
- 作者:
Olga Tyurikova;Elizabeth Nicholson;Dimitri Michael Kullmann;Dmitri Rusakov;Kirill Volynski - 通讯作者:
Kirill Volynski
AMPA receptor-mediated presynaptic inhibition at cerebellar GABAergic synapses : a characterization of molecular mechanisms.
AMPA 受体介导的小脑 GABA 突触突触前抑制:分子机制的表征。
- DOI:
- 发表时间:
2004 - 期刊:
- 影响因子:0
- 作者:
Shin'Ichiro Satake;Fumihito Saitow;Dmitri Rusakov;Shiro Konishi - 通讯作者:
Shiro Konishi
Dmitri Rusakov的其他文献
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{{ truncateString('Dmitri Rusakov', 18)}}的其他基金
A 3Rs platform for glial research: From animal to human to in-silico models
神经胶质研究的 3R 平台:从动物到人类再到计算机模型
- 批准号:
NC/X001067/1 - 财政年份:2022
- 资助金额:
$ 90.67万 - 项目类别:
Research Grant
Targeting Kir4.1 To Control Brain Excitability And Seizures
以 Kir4.1 为目标来控制大脑兴奋性和癫痫发作
- 批准号:
MR/W019752/1 - 财政年份:2022
- 资助金额:
$ 90.67万 - 项目类别:
Research Grant
Targeted drug delivery to neurons and glia using light- and field-sensitive microcapsules
使用光和场敏感微胶囊将靶向药物递送至神经元和神经胶质细胞
- 批准号:
BB/J001473/1 - 财政年份:2012
- 资助金额:
$ 90.67万 - 项目类别:
Research Grant
Modulation of neurotransmitter release by cannabinoid receptors at individual cortical synapses
大麻素受体对单个皮质突触神经递质释放的调节
- 批准号:
G0900613/1 - 财政年份:2009
- 资助金额:
$ 90.67万 - 项目类别:
Research Grant
Nano-diffusion in the brain: mechanisms and implications examined with time-resolved fluorescence anisotropy imaging
大脑中的纳米扩散:通过时间分辨荧光各向异性成像检查的机制和影响
- 批准号:
G0802216/1 - 财政年份:2009
- 资助金额:
$ 90.67万 - 项目类别:
Research Grant
Probing presynaptic receptor function with two-photon uncaging, Ca2+ imaging and photobleaching
通过双光子解笼、Ca2 成像和光漂白探测突触前受体功能
- 批准号:
G0600368/1 - 财政年份:2007
- 资助金额:
$ 90.67万 - 项目类别:
Research Grant
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