Mechanisms of cortical modulation of the auditory midbrain

听力对我们的交流、环境导航和欣赏音乐非常重要。我们听到的声音不仅仅是由进入我们耳朵的声波决定的。相反，我们对传入声音的感知取决于几个额外的因素，包括最近听到的控制我们期望的声音，来自视觉和其他感官的信号，以及我们的注意力被引导到哪里。这些机制可以通过提供上下文信息或“调节”我们的听力来帮助我们理解声音。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言语），而这些困难往往与声音敏感性的全面丧失无关。听觉通路由一系列处理声音相关信息并将其传递给听觉皮层的大脑中心组成。最近的声音经验和来自视觉和其他感官的信息影响听力的机制尚不清楚。然而，我们知道，大脑皮层中负责传递信息的区域会将神经纤维连接发送回听觉通路的较低层次。从皮层区域接收最多信息的听觉中枢被称为下丘。下丘也接收来自听觉通路下部的收敛输入，因此它是预期皮层修饰发生的主要部位。我们的首要目标是发现听觉系统的高级中枢是如何控制听觉通路中的低级中枢的。具体来说，在这个以大鼠为模型的项目中，我们的目标是发现来自皮质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收来自皮层的输入，但我们不知道这些连接的确切起源，不知道它们在下丘中与哪些细胞接触，也不知道它们激活了哪些神经信号机制。我们有三个策略来实现这一目标：首先，我们将使用由神经元吸收和运输的示踪分子以及在神经元中产生荧光蛋白的病毒来发现皮层区域和下丘之间的连接组织。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，我们将在用声音绘制听觉皮层图的同时，观察这些投影与在那里发现的不同声音频率图之间的关系。我们还将发现是否有来自与视觉或其他感官有关的皮质区域的输入到下丘。其次，我们将使用一种叫做“光遗传学”的方法，通过一根细光纤发出不同颜色的光，来打开和关闭投射到下丘的皮质神经元。我们将研究改变皮质神经元的活动如何影响下丘神经细胞对麻醉大鼠耳朵播放的声音的反应。第三，我们的目标是发现皮层神经元影响下丘的机制。我们的初步实验表明，下丘接收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。在大脑的其他部位，一氧化氮与一种叫做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层神经元对下丘的影响。我们将把我们的记录和光遗传学方法与一种技术结合起来，使我们能够将药物应用于下丘，阻断NMDA受体并干扰一氧化氮。这些实验将帮助我们理解一个重要的问题，即高级皮层中心如何影响听觉通路的早期处理。

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.