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Neural adaptation to sensory stimuli by regulation of dendritic spikes and synaptic plasticity.

通过调节树突尖峰和突触可塑性来适应感觉刺激。

基本信息

批准号：
BB/R002177/1
负责人：
Jack Mellor
金额：
$ 112.86万
依托单位：
University of Bristol
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2018
资助国家：
英国
起止时间：
2018 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=BB%2FR002177%2F1
关键词：
Neural adaptation sensory stimuli regulation

项目摘要

Throughout life the brain is bombarded with ever-changing sensations from our environment that it must understand correctly so that we can respond to them in the best way possible. Because our sensory experiences are always changing, the brain must constantly adapt to ensure it can identify these stimuli correctly. Our ability to adapt in this manner determines a large part of our cognitive capabilities and disruptions to this process occur in diseases such as schizophrenia and Alzheimer's disease. In this proposal, we aim to uncover and define ways in which the brain manages to maintain this adaptability.The building blocks of the brain are nerves cells, also called neurons, which are connected to each other by synapses. Information is encoded within the brain by neurons responding selectively to specific features of sensory stimulation, for example the smell of peppermint or a particular tone in a piece of music. Neurons are able to do this because they receive and integrate specific synaptic inputs that guide their responses. However, the brain is not static and constantly adapts its responses in order to adapt our behaviour to the changing environment. Perhaps the most important waythe brain manages to adapt is by adjusting the strength of connections between particular neurons in response to changing sensory stimuli, a process termed synaptic plasticity. Understanding what regulates synaptic plasticity and subsequent behavioural adaptation is an important research goal. In this BBSRC project, we aim to investigate the brain activity patterns that control the processes enabling synaptic plasticity and therefore adaptation of responses to sensory stimulation. Synaptic plasticity is triggered by the influx of calcium ions across the synaptic membrane through proteins called NMDA receptors which are activated when multiple synaptic inputs are activated simultaneously creating a localized "hotspot" of activity in a specific region of the neuron. The creation of this hotspot is extremely sensitive to the amount of NMDA receptor activation. We have recently found that the neurotransmitter acetylcholine, which is released in the brain during specific behavioural states, can regulate the intrinsic properties of neurons and thus provide a potentially exquisite control of NMDA receptors and induction of synaptic plasticity. This suggests an explanation for the common observation that behavioural states play a major role in determining whether we remember things, or forget them. We are going to investigate the mechanisms by which acetylcholine controls adaptation of neuronal responses to sensory stimulation by performing experiments to find out how acetylcholine regulates the hotspots of NMDA receptor activation and therefore the induction of synaptic plasticity. To do this we will fill neurons with dyes that fluoresce when calcium ions are present. We will also measure whether a synapse has strengthened or weakened by recording electrical activity from the neurons. These techniques will enable us to visualize hotspots of synaptic activity and the process of synaptic plasticity. This work is important because it will lead to a wealth of new information about synaptic plasticity and its role in adapting neuronal responses. Dysfunctional synaptic plasticity is thought to underlie the altered neuronal activity in several brain diseases, such as Alzheimer's disease and schizophrenia. The most common and effective treatment currently available for Alzheimer's patients are drugs that mimic or enhance the actions of acetylcholine. Therefore, the mechanisms that we will study in this research will add to our knowledge about these debilitating diseases, and may contribute to developing novel therapies.

在整个生命过程中，大脑受到来自我们环境的不断变化的感觉的轰炸，它必须正确理解，以便我们能够以最好的方式对它们做出反应。由于我们的感官体验总是在变化，大脑必须不断适应，以确保它能够正确识别这些刺激。我们以这种方式适应的能力决定了我们认知能力的很大一部分，而这一过程的中断发生在精神分裂症和阿尔茨海默病等疾病中。在这个提议中，我们的目标是揭示和定义大脑设法保持这种适应性的方式。大脑的构建模块是神经细胞，也称为神经元，它们通过突触相互连接。大脑中的神经元对感官刺激的特定特征（例如薄荷的气味或一段音乐中的特定音调）做出选择性反应，从而对信息进行编码。神经元之所以能够做到这一点，是因为它们接收并整合了指导其反应的特定突触输入。然而，大脑并不是静止的，它会不断调整自己的反应，以使我们的行为适应不断变化的环境。也许大脑适应变化的最重要方式是通过调整特定神经元之间的连接强度来响应变化的感官刺激，这一过程被称为突触可塑性。了解什么调节突触可塑性和随后的行为适应是一个重要的研究目标。在这个BBSRC项目中，我们的目标是调查大脑活动模式，控制过程，使突触可塑性，从而适应对感官刺激的反应。突触可塑性是由钙离子通过称为NMDA受体的蛋白质穿过突触膜的流入触发的，当多个突触输入被同时激活时，NMDA受体被激活，从而在神经元的特定区域中产生局部活动“热点”。该热点的产生对NMDA受体激活的量极其敏感。我们最近发现，神经递质乙酰胆碱，这是在特定的行为状态下释放在大脑中，可以调节神经元的内在特性，从而提供了一个潜在的精细控制NMDA受体和诱导突触可塑性。这就解释了一个常见的观察结果，即行为状态在决定我们是记住还是忘记事情方面起着重要作用。我们将通过实验研究乙酰胆碱如何调节NMDA受体激活的热点，从而诱导突触可塑性，从而研究乙酰胆碱控制神经元对感觉刺激的反应适应的机制。为了做到这一点，我们将用染料填充神经元，当钙离子存在时，这些染料会发出荧光。我们还将通过记录神经元的电活动来测量突触是增强还是减弱。这些技术将使我们能够可视化突触活动的热点和突触可塑性的过程。这项工作很重要，因为它将导致大量关于突触可塑性及其在适应神经元反应中的作用的新信息。突触可塑性功能障碍被认为是几种脑部疾病（如阿尔茨海默病和精神分裂症）中神经元活动改变的基础。目前对阿尔茨海默病患者最常见和有效的治疗方法是模拟或增强乙酰胆碱作用的药物。因此，我们将在这项研究中研究的机制将增加我们对这些使人衰弱的疾病的了解，并可能有助于开发新的治疗方法。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Acetylcholine prioritises direct synaptic inputs from entorhinal cortex to CA1 by differential modulation of feedforward inhibitory circuits

乙酰胆碱通过前馈抑制电路的差分调制优先考虑从内嗅皮层到 CA1 的直接突触输入

DOI：
10.1101/2020.01.20.912873
发表时间：
2020
期刊：
影响因子：
0
作者：
Palacios-Filardo J
通讯作者：
Palacios-Filardo J

Acetylcholine Boosts Dendritic NMDA Spikes in a CA3 Pyramidal Neuron Model.

DOI：
10.1016/j.neuroscience.2021.11.014
发表时间：
2022-05-01
期刊：
Neuroscience
影响因子：
3.3
作者：
Humphries R;Mellor JR;O'Donnell C
通讯作者：
O'Donnell C

Neuromodulation of hippocampal long-term synaptic plasticity.

DOI：
10.1016/j.conb.2018.08.009
发表时间：
2019-03
期刊：
Current opinion in neurobiology
影响因子：
5.7
作者：
Palacios-Filardo J;Mellor JR
通讯作者：
Mellor JR

Convergent Metabotropic Signaling Pathways Inhibit SK Channels to Promote Synaptic Plasticity in the Hippocampus.

DOI：
10.1523/jneurosci.1160-18.2018
发表时间：
2018-10-24
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
0
作者：
Tigaret CM;Chamberlain SEL;Sadowski JHLP;Hall J;Ashby MC;Mellor JR
通讯作者：
Mellor JR

Acetylcholine prioritises direct synaptic inputs from entorhinal cortex to CA1 by differential modulation of feedforward inhibitory circuits.

DOI：
10.1038/s41467-021-25280-5
发表时间：
2021-09-16
期刊：
Nature communications
影响因子：
16.6
作者：
Palacios-Filardo J;Udakis M;Brown GA;Tehan BG;Congreve MS;Nathan PJ;Brown AJH;Mellor JR
通讯作者：
Mellor JR