Mechanisms of cortical modulation of the auditory midbrain

听觉中脑皮质调节机制

• 批准号: BB/P003249/1
• 负责人: Adrian Rees
• 金额: $ 59.66万
• 依托单位: Newcastle University
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2017
• 资助国家: 英国
• 起止时间: 2017 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FP003249%2F1
• 关键词: Mechanisms; cortical; modulation; auditory; midbrain

Hearing is immensely important to us for communication, navigating our environment and appreciating music. What we hear is not simply determined by the sound waves that strike our ears. Rather our perception of incoming sounds depends on several additional factors including recently heard sounds that govern our expectations, signals from vision and other senses, and where our attention is directed. These mechanisms can aid our ability to understand sounds by providing contextual information or by 'tuning' our hearing. A decline in such systems with ageing may contribute to hearing difficulties (such as understanding speech in noisy environments) that often occur independently of any overall loss of sensitivity to sound.The auditory pathway consists of a series of brain centres which process sound-related information and feed it to the auditory cortex. The mechanisms by which recent sound experience and information from visual and other senses affect hearing are not clear. However, we know that the cortical regions where this information is represented send nerve fibre connections back to lower levels in the auditory pathway. The auditory centre that receives the most inputs from cortical regions is called the inferior colliculus. The inferior colliculus also receives converging inputs from lower parts of the auditory pathway, so it is a prime site at which to expect cortical modification to occur. Our overarching goal is to discover how the higher levels of the auditory system control lower centres in the auditory pathway. Specifically in this project using the rat as a model, we aim to discover how information from cortical regions influences the responses of inferior colliculus neurons to sounds. Although we know the inferior colliculus receives inputs from the cortex, we don't know the precise origin of these connections, what sorts of cells they contact in the inferior colliculus, or what neural signalling mechanisms they activate. We have three strategies to achieve this goal:First, we will discover the organisation of the connections between cortical regions and the inferior colliculus using tracer molecules that are picked up and transported by neurons as well as viruses which produce fluorescent proteins in the neurons. These methods allow us to see the neurons connecting different areas under the microscope. Importantly, we will do this along with mapping the auditory cortex with sounds to see how the projections relate to the different maps of sound frequency found there. We will also discover if there are inputs to the inferior colliculus from cortical regions concerned with vision or other senses.Second, we will use a method called 'optogenetics' to switch on and off the cortical neurons that project to the inferior colliculus using different colours of light delivered by a fine optical fibre. We will study how changing the activity of the cortical neurons affects the firing of nerve cells in the inferior colliculus in response to sounds played to the ears of an anaesthetised rat. Third, we aim to discover the mechanisms by which cortical neurons influence the inferior colliculus. Our pilot experiments show that the part of the inferior colliculus that receives most connections from the cortex has many neurons that produce a chemical neurotransmitter called nitric oxide. In other parts of the brain, nitric oxide interacts with a type of receptor for the neurotransmitter glutamate called the NMDA receptor. We think that an interaction of nitric oxide and NMDA receptors might be involved in the effects that cortical neurons have on the inferior colliculus. We will combine our recording and optogenetic methods with a technique that allows us to apply drugs to the inferior colliculus that block NMDA receptors and interfere with nitric oxide. These experiments will help us understand the important question of how the higher cortical centres influence processing earlier in the auditory pathway.

听觉对我们的沟通、导航环境和欣赏音乐非常重要。我们所听到的并不仅仅是由撞击我们耳朵的声波所决定的。相反，我们对传入声音的感知取决于几个额外的因素，包括最近听到的声音，这些声音决定了我们的期望，来自视觉和其他感官的信号，以及我们的注意力指向哪里。这些机制可以通过提供上下文信息或“调整”我们的听力来帮助我们理解声音的能力。随着年龄的增长，这些系统的衰退可能会导致听力困难（例如在嘈杂环境中理解语音），这些听力困难通常与对声音的敏感性的整体丧失无关。听觉通路由一系列大脑中心组成，这些中心处理与声音相关的信息并将其馈送到听觉皮层。最近的声音经验和来自视觉和其他感官的信息影响听觉的机制尚不清楚。然而，我们知道，代表这些信息的皮层区域将神经纤维连接发送回听觉通路中的较低水平。从皮层区域接收最多输入的听觉中心被称为下丘。下丘也接收来自听觉通路下部的汇聚输入，因此它是预期皮层修改发生的主要部位。我们的首要目标是发现听觉系统的高层次如何控制听觉通路中的低层次中心。特别是在这个项目中，使用大鼠作为模型，我们的目标是发现来自皮层区域的信息如何影响下丘神经元对声音的反应。虽然我们知道下丘接受来自皮层的输入，但我们不知道这些连接的确切来源，它们接触下丘中的哪种细胞，或者它们激活了什么神经信号机制。我们有三种策略来实现这一目标：首先，我们将发现皮质区域和下丘之间的连接组织，使用神经元拾取和运输的示踪分子以及在神经元中产生荧光蛋白的病毒。这些方法使我们能够在显微镜下看到连接不同区域的神经元。重要的是，我们将沿着绘制听觉皮层的声音映射图，以了解这些投射与那里发现的不同声音频率映射图之间的关系。我们还将发现是否有来自与视觉或其他感官有关的皮层区域的输入到下丘。第二，我们将使用一种称为“光遗传学”的方法，通过一根细光纤传递不同颜色的光，来打开和关闭投射到下丘的皮层神经元。我们将研究如何改变皮层神经元的活动影响放电的神经细胞在下丘的反应声音播放到麻醉大鼠的耳朵。第三，我们的目标是发现皮质神经元影响下丘的机制。我们的初步实验表明，下丘接受来自皮层的大部分连接的部分有许多神经元，这些神经元产生一种叫做一氧化氮的化学神经递质。在大脑的其他部分，一氧化氮与一种称为NMDA受体的神经递质谷氨酸受体相互作用。我们认为，一氧化氮和NMDA受体的相互作用可能参与了皮质神经元对下丘的影响。我们将联合收割机将我们的记录和光遗传学方法与一种技术相结合，这种技术允许我们将药物应用于下丘，阻断NMDA受体并干扰一氧化氮。这些实验将帮助我们理解高级皮层中心如何影响听觉通路中早期的处理这一重要问题。

项目成果

Multiple non-auditory cortical projections innervate the auditory midbrain

多个非听觉皮层投射支配听觉中脑

• 发表时间: 2019
• 作者: Olthof BMJ

Multiple non-auditory cortical regions innervate the auditory midbrain

多个非听觉皮层区域支配听觉中脑

• DOI: 10.1101/627232
• 发表时间: 2019
• 作者: Olthof B

Puncta of neuronal nitric oxide synthase (nNOS) mediate NMDA-receptor signalling in the auditory midbrain

神经元一氧化氮合酶 (nNOS) 的斑点介导听觉中脑中的 NMDA 受体信号传导

• 发表时间: 2019
• 作者: Olthof BMJ

Non-auditory projections to the inferior colliculus; a tracing study.

向下丘的非听觉投射；

• 发表时间: 2018
• 作者: Olthof BMJ

Non-auditory projections to the inferior colliculus

下丘的非听觉投射

• 发表时间: 2019
• 作者: Olthof BMJ