Anatomical analysis of cortical projections to the auditory midbrain

描述(由申请人提供)：听觉系统包括上行通路和下行通路，上行通路将信息从耳朵传输到更高层次以供感知，下行通路可以修改在上升通路的每个阶段如何处理该信息。听觉皮质是大量下行投射的来源，这些投射被认为在广泛的功能中发挥作用，包括在嘈杂环境中选择性注意和理解语言。关于潜在神经回路的问题阻碍了对这些功能的理解。目前的建议集中在最大的下行投射之一，从听觉皮质到中脑的下丘。一个目的是确定这些投射是否直接与使用神经递质GABA的中脑抑制回路进行突触接触。第二个目标是确定皮质投射是否与连接中脑两侧的大型连合通路直接突触接触(从而可能传播皮质效应)。这项研究将在豚鼠身上进行，这是一种对听觉功能的许多方面进行了充分研究的模型。这些实验将使用多标记解剖学技术，包括使用荧光神经元示踪剂标记特定的电路元件，以及使用免疫组织化学技术识别与这些元件相关的神经递质。该设计包括与光学显微镜和电子显微镜的协调研究，以允许直接识别突触，这是识别神经元电路的必要步骤。这一结果将为描述下行听觉通路及其与兴奋性和抑制性中脑回路的关系提供重要的一步。在GABA能回路和通往中脑的上升路径方面已经做了大量的工作；目前的提议应该有助于将下行系统整合到我们对中脑GABA能机制的看法中。这可能对与衰老或损伤相关的正常功能和功能障碍(如老年性耳聋或耳鸣)以及对人工耳蜗和脑干植入物的不断发展的设计和使用具有重要的意义。从培训的角度来看，拟议的实验涵盖了广泛的敏感解剖学技术，包括有效结合光学和电子显微镜的各种多重标记方法和策略。这项解剖学培训是为了补充申请人先前在神经生理学技术方面的广泛培训。将所有这些方法结合起来的能力将极大地扩大他未来能够解决的研究问题的范围。 公共卫生相关性：由于衰老、损伤或疾病导致的听觉功能障碍影响着许多人。我们开发治疗或假肢的能力在一定程度上依赖于识别神经回路和它们使用的神经递质。本提案将描述与广泛功能相关的听觉皮质和中脑之间回路的连接和神经递质。

DESCRIPTION (provided by applicant): The auditory system comprises ascending pathways that transmit information from the ear to higher levels for perception, and descending pathways that can modify how that information is processed at each stage of the ascending pathways. The auditory cortex is the source of massive descending projections that are considered to play a role in a wide range of functions, including selective attention and understanding speech in noisy environments. Progress in understanding these functions is hampered by questions regarding the underlying neural circuitry. The present proposal focuses on one of the largest descending projections, from auditory cortex to the inferior colliculus of the midbrain. One aim is to determine whether these projections make direct synaptic contact with midbrain inhibitory circuits that use the neurotransmitter GABA. A second aim is to determine whether the cortical projections make direct synaptic contact with the large commissural pathway that connects the two sides of the midbrain (and could thus spread the cortical effects). The study will be conducted in guinea pigs, a well-researched model for many aspects of auditory function. The experiments will use multilabeling anatomical techniques, including the use of fluorescent neuronal tracers for labeling specific circuit elements and immunohistochemical techniques for identifying the neurotransmitters associated with those elements. The design includes coordinated studies with both light and electron microscopes to allow for the direct identification of synapses, a necessary step for identifying neuronal circuits. The results will provide an important step in characterizing descending auditory pathways and their relationships to excitatory and inhibitory midbrain circuits. Considerable work has been done on GABAergic circuits and ascending pathways to the midbrain; the current proposal should help to integrate the descending systems into our view of GABAergic mechanisms in the midbrain. This may have important implications for normal function as well as dysfunction (such as presbycusis or tinnitus) associated with aging or injury and for the evolving design and use of cochlear implants and brainstem implants. From a training perspective, the proposed experiments cover a broad range of sensitive anatomical techniques, including a variety of multi-labeling methods and strategies for the effective combination of light and electron microscopy. This anatomical training is designed to complement the applicant's prior, extensive training in neurophysiological techniques. The ability to combine all these approaches will greatly expand the range of research questions that he will be able to address in the future. PUBLIC HEALTH RELEVANCE: Auditory dysfunction due to aging, damage or disease affects many people. Our ability to develop treatments or prosthetics relies in part on identifying the neuronal circuits and the neurotransmitters they use. The present proposal will characterize the connections and neurotransmitters of circuits between the auditory cortex and midbrain that are associated with a wide range of functions.