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水平以进行感知的上行通路，以及可以改变每个听觉核处理信息的方式的下行通路。从听觉皮层到中脑下丘的下行投射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音。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）在许多这些功能中发挥重要作用。许多胆碱能效应是通过与下丘中的GABA能细胞（使用GABA作为神经递质的神经元）相互作用介导的，但有关潜在神经回路的问题阻碍了进一步的理解。本建议的重点是胆碱能和下行系统之间的可能的连接，最近发现的GABA能通路从下丘细胞的内侧分内侧膝状体。目的之一是确定这些细胞在下丘细胞功能分区中的位置。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。该研究将在豚鼠中进行，豚鼠是听觉功能许多方面的一种经过充分研究的模型。实验将使用多标记解剖技术，包括用于标记特定电路元件的荧光神经元示踪剂和用于识别与这些元件相关的神经递质的免疫化学技术。光学显微镜和电子显微镜的协调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。结果将提供一个重要的一步，在表征兴奋性和抑制性中脑电路和它们的关系，上升和下降的听觉通路，以及它们的关系，胆碱能系统。这可能对正常功能以及与衰老或损伤相关的功能障碍（如老年性耳聋或耳鸣）以及耳蜗植入物和脑干植入物的不断发展的设计和使用具有重要意义。 从培训的角度来看，拟议的实验涵盖了广泛的敏感解剖技术，包括各种多标记方法和光学和电子显微镜的有效结合的策略。这种解剖学培训的目的是扩大和多样化的申请人在神经解剖学技术之前有限的培训。联合收割机和分析多种解剖方法的能力将大大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.