DEVELOPMENT OF A 3-DIMENSIONAL ATLAS OF THE GERBIL BRAIN

Duke University, Durham NC

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Abstract

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.