DEVELOPMENT OF A 3-DIMENSIONAL ATLAS OF THE GERBIL BRAIN

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 GA Johnson为他们的提议写了一封支持信： 我们向国家耳聋和其他沟通障碍研究所提交了R01拨款申请。该项目是我们三个具体目标的组成部分，具体目标如下： 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，听觉丘脑是中枢神经系统中最不被了解的听觉结构。哺乳动物感觉系统的一个基本组织原则是，刺激的特征从感受器表面系统地映射到感觉皮质。在听觉系统中，在听觉中脑(下丘)和听觉皮质之间，刺激的表现形式发生了显著的变化。其中最明显的一种是下丘中央核(ICC)中单一的正音表达向听觉皮质中多个正音区域的重组。两个普遍的假说表明这是如何发生的：1)在听觉丘脑中维持单一的强直表现，随后在听觉皮质中的强直区域倍增，或2)在丘脑中创建多个强直区域，并维持或阐述皮质投射的这种增加。目前，所感知的理解似乎是面积的倍增是皮层而不是丘脑的特征，也就是说，假设1更受欢迎(例如，Winer和Schliner，2005)。然而，我们实验室的最新结果(以及其他实验室的一些结果)支持假设2。Fitzpatrick实验室的研究表明，长胡子的蝙蝠听觉丘脑包含多个紧张性有组织的区域，类似于皮质模式。丘脑水平的这种复杂性源于重新混合来自ICC的纯音输出。Cant实验室对沙土鼠的研究表明，至少有两条在地形上有组织的通路出现在下丘的中央核，并终止于内侧膝状核腹侧分裂的不同部分(Cant和Benson，2006,2007)。基于这些结果，指导这一建议的假设是，听觉丘脑包含多个由ICC的复杂输入支持的紧张区。为了解决这一假设，我们建议将生理标测技术与成像和脑对齐技术相结合，并对ICC、听觉丘脑和听觉皮质之间的联系进行解剖标测。了解前脑听觉通路中听觉表征的变化对于语音处理器的设计以及为不能使用人工耳蜗者或耳鸣等顽固性疾病的聋人选择直接脑刺激目标具有重要意义。 具体目的1.定位听觉丘脑的生理反应特性。沙土鼠的内侧膝状核将以高分辨率进行生理标测。沙土鼠下丘的组织结构遵循典型的哺乳动物的计划，中央核包含似乎是刺激的单一调性表示。已知在该物种的皮质中存在多个强直区(Budinger等人，2000年)。我们的假设是，听觉丘脑也包含多个纯音表征。预计每个代表将在试听中发挥不同的职能作用。所有数据将被映射到在特定目标3中开发的基于磁共振成像的三维地图集。 具体目的2.使用示踪方法确定丘脑多个张力组织区域的神经解剖学基础。我们的假设是，正是ICC输出的复杂性导致丘脑产生多个紧张性区域，然后这种复杂性在向皮质水平的投射中保持或放大。为了解决这一假设，我们将在用于生理测绘的相同动物中进行解剖跟踪研究，并在特定目标3中开发的基于MRI的脑图谱中结合跨动物的信息。 具体目的3.利用磁共振成像和脑定位技术建立沙土鼠中脑和丘脑的三维图谱，用于绘制生理和神经解剖学数据。由于其复杂的内部组织结构，听觉丘脑对标测提出了特殊的挑战。事实上，我们的工作假设是，内侧膝状核的腹侧分裂比目前所了解的要复杂得多。为了令人信服地证明这种复杂性，我们建议使用高分辨率(80微米体素大小)沙土鼠大脑的MRI成像来创建一个三维大脑重建，其中所有的生理和解剖数据都可以绘制出来。

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.