Cholinergic inputs to excitatory and inhibitory midbrain auditory circuits

描述（由申请人提供）：听觉系统包括将信息从耳朵传递到更高层次的感知的上升通路和可以修改每个听觉核如何处理信息的下降通路。从听觉皮层到中脑下丘的下行投影在广泛的听觉功能中发挥作用，包括选择性注意，可塑性和学习，以及在嘈杂环境中理解语言。最近的进展表明，胆碱能细胞（使用乙酰胆碱作为神经递质的神经元）在许多这些功能中起着重要作用。许多胆碱能效应是通过与下丘GABA能细胞（使用GABA作为神经递质的神经元）的相互作用介导的，但关于潜在神经回路的问题阻碍了进一步的理解。目前的建议侧重于胆碱能和下降系统之间的可能联系，最近发现的gaba能途径从下丘细胞到内侧膝状体的内侧分支。目的之一是通过下丘细胞的功能细分来确定这些细胞的位置。第二个和第三个目的是确定这些细胞是否接受胆碱能或听觉皮层输入。这项研究将在豚鼠身上进行，这是一个在听觉功能的许多方面都得到了充分研究的模型。实验将使用多标记解剖技术，包括荧光神经元示踪剂，用于标记特定的电路元件和免疫化学技术，用于识别与这些元件相关的神经递质。光学显微镜和电子显微镜的协同研究将允许直接识别突触，这是识别神经元回路的必要步骤。该结果将为描述兴奋性和抑制性中脑回路及其与上行和下行听觉通路的关系以及与胆碱能系统的关系提供重要的一步。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）以及耳蜗和脑干植入物的设计和使用具有重要意义。从训练的角度来看，所提出的实验涵盖了广泛的敏感解剖技术，包括各种多标记方法和有效结合光学和电子显微镜的策略。这种解剖训练的目的是扩大和多样化申请人之前有限的神经解剖技术训练。结合和分析多种解剖方法的能力将极大地扩展他将来能够解决的研究问题的范围。

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 auditory nucleus. Descending projections from auditory cortex to the inferior colliculus of the midbrain play a role in a wide range of auditory functions, including selective attention, plasticity and learning, and understanding speech in noisy environments. Recent progress indicates that cholinergic cells (neurons that use acetylcholine as a neurotransmitter) play an important role in many of these functions. Many of the cholinergic effects are mediated through interactions with GABAergic cells (neurons that use GABA as a neurotransmitter) in the inferior colliculus, but further understanding has been hindered by questions regarding the underlying neural circuitry. The present proposal focuses on possible connections between the cholinergic and descending systems to a recently discovered GABAergic pathway from cells of the inferior colliculus to the medial subdivision of the medial geniculate body. One aim is to identify the locations of these cells across the functional subdivisions of the inferior colliculus cells. The second and third aim determine whether these cells receive cholinergic or auditory cortical inputs. 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 fluorescent neuronal tracers for labeling specific circuit elements and immunochemical techniques for identifying the neurotransmitters associated with those elements. Coordinated studies with both light and electron microscopes will allow for the direct identification of synapses, a necessary step for identifying neuronal circuits. The results will provide an important step in characterizing excitatory and inhibitory midbrain circuits and their relationships to ascending and descending auditory pathways as well as their relationships to the cholinergic system. 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 expand and diversify the applicant's prior limited training in neuroanatomical techniques. The ability to combine and analyze multiple anatomical approaches will greatly expand the range of research questions that he will be able to address in the future.