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

在整个生命过程中，大脑都被来自我们环境的不断变化的感觉轰炸着，它必须正确地理解这些感觉，以便我们能够以最好的方式对它们做出反应。因为我们的感官体验总是在变化，大脑必须不断地适应，以确保它能正确识别这些刺激。我们以这种方式适应的能力在很大程度上决定了我们的认知能力，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。在这项提议中，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。大脑的组成部分是神经细胞，也称为神经元，它们通过突触相互连接。信息是由神经元在大脑中编码的，神经元对感觉刺激的特定特征做出选择性反应，例如薄荷的气味或一段音乐中的特定音调。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，大脑并不是一成不变的，它会不断地调整其反应，以使我们的行为适应不断变化的环境。也许大脑设法适应的最重要的方式是通过调整特定神经元之间的连接强度来应对不断变化的感觉刺激，这一过程被称为突触可塑性。了解是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，我们的目标是研究大脑活动模式，这些模式控制着突触可塑性的过程，从而适应对感觉刺激的反应。突触的可塑性是由钙离子通过被称为NMDA受体的蛋白质穿过突触膜而触发的，当多个突触输入同时被激活时，NMDA受体被激活，在神经元的特定区域产生一个局部的活动热点。这一热点的产生对NMDA受体的激活量极为敏感。我们最近发现，神经递质乙酰胆碱在特定的行为状态下在大脑中释放，可以调节神经元的内在特性，从而对NMDA受体和突触可塑性的诱导提供潜在的精细控制。这就解释了一种常见的观察结果，即行为状态在决定我们是记住还是忘记事情方面发挥着重要作用。我们将通过实验来研究乙酰胆碱控制神经元对感觉刺激反应的适应性的机制，以找出乙酰胆碱如何调节NMDA受体激活的热点，从而诱导突触可塑性。为了做到这一点，我们将在神经元中填充当钙离子存在时会发出荧光的染料。我们还将通过记录神经元的电活动来测量突触是加强还是减弱。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。这项工作非常重要，因为它将带来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。功能失调的突触可塑性被认为是几种大脑疾病，如阿尔茨海默病和精神分裂症的神经元活动改变的基础。目前对阿尔茨海默氏症患者最常见和有效的治疗方法是模仿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衰弱疾病的了解，并可能有助于开发新的治疗方法。

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.