Mechanisms of cortical modulation of the auditory midbrain

听觉对于我们的交流、环境导航和欣赏音乐都是极其重要的。我们所听到的并不是简单地由击中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，包括最近听到的支配我们预期的声音，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背景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，这类系统的衰退可能会导致听力障碍(如在嘈杂环境中理解语音)，这种听力障碍通常与对声音失去任何整体敏感性无关。听觉通路由一系列大脑中心组成，这些中枢处理与声音有关的信息，并将其馈送到听觉皮质。最近来自视觉和其他感官的声音经验和信息影响听力的机制尚不清楚。然而，我们知道，代表这些信息的皮质区域将神经纤维连接发送回听觉通路中的较低水平。从大脑皮层接收最多信息的听觉中枢称为下丘。下丘也接受来自听觉通路下部的汇聚输入，因此它是期待皮质改变发生的主要部位。我们的首要目标是发现较高水平的听觉系统如何控制听觉通路中较低的中枢。具体地说，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受皮质的输入，但我们不知道这些联系的确切来源，它们在下丘接触的是什么细胞，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：第一，我们将使用神经元以及在神经元中产生荧光蛋白的病毒拾取和运输的示踪分子来发现皮质区域和下丘之间的连接的组织。这些方法让我们可以在显微镜下看到连接不同区域的神经元。重要的是，我们将在绘制听觉皮质与声音的地图的同时进行这项工作，以了解这些投影与那里发现的不同声音频率地图之间的关系。我们还将发现下丘是否有来自与视觉或其他感官有关的皮质区域的输入。第二，我们将使用一种名为“光遗传学”的方法来打开和关闭投射到下丘的皮质神经元，该方法使用一根细光纤发射的不同颜色的光。我们将研究改变皮层神经元的活动如何影响下丘神经细胞的放电，以回应麻醉大鼠耳朵听到的声音。第三，我们的目标是发现皮质神经元影响下丘的机制。我们的先导实验表明，下丘从大脑皮层接受连接最多的部分有许多神经元，产生一种名为一氧化氮的化学神经递质。在大脑的其他部位，一氧化氮与一种名为NMDA受体的神经递质谷氨酸受体相互作用。我们认为，皮质神经元对下丘的影响可能与一氧化氮和NMDA受体的相互作用有关。我们将把我们的记录和光遗传学方法与一项允许我们向下丘应用药物的技术相结合，该药物可以阻断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，即高级皮质中心如何影响听觉通路早期的处理。

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.