DEVELOPMENT OF A 3-DIMENSIONAL ATLAS OF THE GERBIL BRAIN

该子项目是利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得主要资金， 因此可以在其他CRISP条目中表示。列出的机构是 中心，不一定是研究者的机构。 GA约翰逊写了一封信支持他们的建议： 我们向国家耳聋和其他交流障碍研究所提交了R 01资助申请。该项目是我们三个具体目标的组成部分，具体如下： 我们提出了三个具体的目标，旨在解决听觉丘脑的功能组织，在中枢神经系统中的听觉结构了解最少。哺乳动物感觉系统的一个基本组织原则是，刺激的特征从受体表面系统地映射到感觉皮层。 在听觉系统中，听觉中脑（下丘）和听觉皮层之间会发生刺激表征的显著变化。其中最明显的是从一个单一的tonotopic代表下丘中央核（ICc）的听觉皮层的多个tonotopic区的重组。两个一般性的假设表明这是如何发生的：1）在听觉丘脑中维持单一的音调定位表征，随后在听觉皮层中增加音调定位区域，或者2）在丘脑中创建多个音调定位区域，并在皮层投射中维持或阐述这种增加。目前，人们的理解似乎是，区域的倍增是皮质而不是丘脑的特征，即，假设1是有利的（例如，Winer和Schreiner，2005年）。然而，我们实验室最近的结果（以及其他实验室的一些结果）支持假设2。菲茨帕特里克实验室的研究表明，胡子蝙蝠的听觉丘脑包含多个音调组织区域，类似于皮层模式。丘脑水平上的这种复杂性来自于对来自ICc的音调分布输出的重新混合。Cant实验室对沙鼠的研究表明，至少有两条地形组织的通路起源于下丘中央核，并终止于内侧膝状体核腹侧部的不同部分（Cant和Benson，2006，2007）。基于这些结果，指导这一建议的假设是，听觉丘脑包含多个tonotopic地区的复杂输入的ICc的支持。为了解决这一假设，我们建议结合联合收割机的生理映射技术与成像和大脑对齐技术，也解剖映射的ICc之间的连接，听觉丘脑和听觉皮层。理解在前脑听觉通路中听觉表征发生的转换对于语音处理器的设计以及对于不能使用人工耳蜗的耳聋患者或诸如耳鸣的难治性疾病中选择直接脑刺激的目标将是重要的。 具体目标1。绘制听觉丘脑的生理反应特性。将在沙鼠的内侧膝状体核生理映射在高分辨率。沙鼠下丘的组织结构遵循典型的哺乳动物计划，中央核包含似乎是刺激的单一tonotopic表示。已知在该物种的皮层中存在多个音调定位区域（Budinger等人，2000年）。我们的假设是，听觉丘脑也包含多个tonotopic代表。每个代表将在试镜中发挥不同的职能作用。所有数据将被映射到特定目标3中开发的三维MRI图谱中。 具体目标2。利用追踪方法确定丘脑内多个音调组织区域的神经解剖学基础。我们的假设是，这是复杂的输出从ICc导致创建多个tonotopic领域的丘脑，这种复杂性，然后保持或放大的预测皮质水平。为了解决这一假设，我们将在用于生理标测的相同动物中进行解剖追踪研究，并将动物之间的信息联合收割机结合到Specific Aim 3中开发的基于MRI的脑图谱中。 具体目标3。利用磁共振成像和脑排列技术建立沙鼠中脑和丘脑的三维图谱，可用于绘制生理和神经解剖数据。听觉丘脑由于其复杂的内部组织结构，对映射提出了特殊的挑战。事实上，我们的工作假设是，内侧膝状体核的腹侧分裂比目前理解的要复杂得多。为了提供一个令人信服的证明，这种复杂性，我们建议使用高分辨率（80微米体素大小）的沙鼠大脑MRI成像创建一个三维的大脑重建，其中所有的生理和解剖数据可以绘制。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. GA Johnson wrote a letter of support for their proposal: We submitted an R01 grant application to the National Institute on Deafness and Other Communication Disorders. The project is an integral part of our three specific aims as follow: We propose three specific aims that are designed to address the functional organization of the auditory thalamus, the least understood of the auditory structures in the central nervous system. A fundamental organizing principle of mammalian sensory systems is that features of the stimulus are mapped systematically from the receptor surface to the sensory cortex. In the auditory system, striking transformations in the representations of the stimulus occur between the auditory midbrain (inferior colliculus) and the auditory cortex. One of the most obvious is a reorganization from a single tonotopic representation in the central nucleus of the inferior colliculus (ICc) to multiple tonotopic areas in the auditory cortex. Two general hypotheses suggest how this occurs: 1) There is maintenance of a single tonotopic representation in the auditory thalamus with subsequent multiplication of tonotopic areas in the auditory cortex, or 2) There is a creation of multiple tonotopic areas in the thalamus and maintenance or elaboration of this increase in the cortical projections. Presently, the perceived understanding seems to be that the multiplication of areas is a cortical rather than a thalamic feature, i.e., hypothesis 1 is favored (e.g., Winer and Schreiner, 2005). However, recent results from our laboratories (as well as some results from other laboratories) favor hypothesis 2. Studies in the Fitzpatrick laboratory demonstrated that the mustached bat auditory thalamus contains multiple tonotopically organized areas, similar to the cortical pattern. This complexity at the thalamic level arises from remixing the tonotopic outputs from the ICc. Studies in the gerbil in the Cant laboratory demonstrated at least two topographically organized pathways arising in the central nucleus of the inferior colliculus and terminating in different parts of the ventral division of the medial geniculate nucleus (Cant and Benson, 2006, 2007). Based on these results, the hypothesis guiding this proposal is that the auditory thalamus contains multiple tonotopic areas supported by complex inputs from the ICc. To address this hypothesis, we propose to combine physiological mapping techniques with both imaging and brain alignment techniques and also anatomical mapping of connections between the ICc, auditory thalamus and auditory cortex. Understanding the transformations that occur in auditory representations in the forebrain auditory pathways will be important for designs of speech processors and for selecting targets for direct brain stimulation in deaf patients who cannot use a cochlear prosthesis or in intractable disorders such as tinnitus. Specific Aim 1. To map physiological response properties in the auditory thalamus. The medial geniculate nucleus will be physiologically mapped at high resolution in the gerbil. The organization of the inferior colliculus in the gerbil follows the typical mammalian plan with the central nucleus containing what appears to be a single tonotopic representation of the stimulus. Multiple tonotopic areas are know to exist in the cortex of this species (Budinger et al., 2000). Our hypothesis is that the auditory thalamus also contains multiple tonotopic representations. Each representation would be expected to play a different functional role in audition. All data will be mapped into the three-dimensional MRI-based atlas developed in Specific Aim 3. Specific Aim 2. To use tracing methods to determine the neuroanatomical basis for multiple tonotopically organized areas in the thalamus. Our hypothesis is that it is complexity in the outputs from the ICc leads to creation of multiple tonotopic areas in the thalamus, and that this complexity is then maintained or amplified in projections to the cortical level. To address this hypothesis, we will perform anatomical tracing studies in the same animals used for physiological mapping, and combine the information across animals in the MRI-based brain atlas developed in Specific Aim 3. Specific Aim 3. To use magnetic resonance imaging and brain alignment techniques to develop a three-dimensional atlas of the gerbil midbrain and thalamus that can be used for mapping the physiological and neuroanatomical data. The auditory thalamus presents a special challenge for mapping due to its complex internal organization. Indeed, our working hypothesis is that the ventral division of the medial geniculate nucleus is considerably more complex than currently understood. To provide a convincing demonstration of this complexity, we propose to use high-resolution (80 um voxel size) MRI imaging of the gerbil brain to create a three-dimensional brain reconstruction in which all physiological and anatomical data can be plotted.