The use of transgenic tools to selectively label and detect individual neuronal populations and modulate gene expression in those cells to manipulate activity can have significant impact in neuroplasticity research. In recent years a number of molecular tools have been developed to study neural circuitry and plasticity at exquisite detail and control. However, application of these tools in different neuronal cell types and circuits at cellular and subcellular level has been limited, in particular because of the time and effort needed to develop each individual transgenic animal. This issue has been partially addressed by putting in great effort into the development of cell type specific Cre-driver lines. However, there have still been hurdles to overcome in creating the necessary numbers of Cre responsive transgenic lines that can express the molecular tools at sufficiently strong levels for imaging and for functional manipulation in a cell type specific, subcellularly targeted manner for use by academic researchers. To attempt to address this issue, we propose to systematically target a set of genomic loci that will convey strong ubiquitous expression or selective pre and post-synaptic specific targeting of genes in inhibitory and excitatory neurons respectively, to develop a Cre-responder platform in these genomic loci to which any existing or newly developed molecular tools can be easily inserted. We are committed to use this program to provide diverse transgenic mice to the academic community that will exploit many of the new tools and probes to study neural networks and in particular study neuronal plasticity as it relates to behavior and physiology. The Allen Institute has a high throughput ISH platform and capability of high resolution image acquisition and data-basing. By combining these innovative technologies with the transgenic lines to be developed, we will be able to increase the utility of the transgenic mice as an approach to study neuroplasticity by making such experimental animals freely available for the neuroscience community.
Neuroplasticity is a fundamental process underlying brain development and brain's ability to acquire knowledge and skills, as well as a component of many brain disorders. Genetic tools have been widely used in every area of plasticity research. Our proposed research will provide to the neuroscience community a transgenic platform to incorporate state-of-the-art probes and tools for monitoring and manipulating plasticity at cellular and subcellular levels. Use of these genetic tools by the neuroscience community will have major impact on the further understanding of the roles of plasticity plays in brain function and diseases, leading to ways in treating diseases and improving public health.
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|Zariwala, Hatim A; Borghuis, Bart G; Hoogland, Tycho M et al. (2012) A Cre-dependent GCaMP3 reporter mouse for neuronal imaging in vivo. J Neurosci 32:3131-41|
|Madisen, Linda; Mao, Tianyi; Koch, Henner et al. (2012) A toolbox of Cre-dependent optogenetic transgenic mice for light-induced activation and silencing. Nat Neurosci 15:793-802|
|Zeng, Hongkui; Madisen, Linda (2012) Mouse transgenic approaches in optogenetics. Prog Brain Res 196:193-213|