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Rudolph, Stephanie

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Rudolph

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Stephanie

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Rudolph, Stephanie
Author's Publications: search.filters.isAuthorOfPublication.1e5a0994-a679-454c-a200-ed4c6f19cf4b

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    Bidirectional Perisomatic Inhibitory Plasticity of a Fos Neuronal Network
    (Springer Science and Business Media LLC, 2020-12-09) Yap, Ee-Lynn; Pettit, Noah L.; Davis, Christopher; Nagy, M. Aurel; Harmin, David; Golden, Emily; Dagliyan, Onur; Lin, Cindy; Rudolph, Stephanie; Sharma, Nikhil; Griffith, Eric C.; Harvey, Christopher D.; Greenberg, Michael
    Behavioral experiences activate the Fos transcription factor (TF) in sparse populations of neurons that are critical for encoding and recalling specific events1-3. However, there is limited understanding of the mechanisms by which experience drives circuit reorganization to establish a network of Fos-activated cells. It is also unknown if Fos is required in this process beyond serving as a marker of recent neural activity and, if so, which of its many gene targets underlie circuit reorganization. Here we demonstrate that when mice engage in spatial exploration of novel environments, perisomatic inhibition of Fos-expressing hippocampal CA1 pyramidal neurons by parvalbumin (PV)-interneurons (INs) is enhanced, while perisomatic inhibition by cholecystokinin (CCK)-INs is weakened. This bidirectional modulation of inhibition is abolished when the function of the Fos TF complex is disrupted. Single-cell RNA-sequencing, ribosome-associated mRNA profiling, and chromatin analyses, combined with electrophysiology, reveal that Fos activates the transcription of Scg2 (secretogranin II), a gene that encodes multiple distinct neuropeptides, to coordinate these changes in inhibition. As PV- and CCK-INs mediate distinct features of pyramidal cell activity4-6, the Scg2-dependent reorganization of inhibitory synaptic input might be predicted to affect network function in vivo. Consistent with this prediction, hippocampal gamma rhythms and pyramidal cell coupling to CA1 theta are significantly altered with loss of Scg2. These findings reveal an instructive role for Fos and Scg2 in establishing a network of Fos-activated neurons via the rewiring of local inhibition to form a selectively modulated state. The opposing plasticity mechanisms on distinct inhibitory pathways may support the consolidation of memories over time.
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    Detection and manipulation of live antigen-expressing cells using conditionally stable nanobodies
    (eLife Sciences Publications, Ltd, 2016) Tang, Jonathan CY; Drokhlyansky, Eugene; Etemad, Behzad; Rudolph, Stephanie; Guo, Ella; Wang, Sui; Ellis, Emily G; Li, Jonathan; Cepko, Constance
    The ability to detect and/or manipulate specific cell populations based upon the presence of intracellular protein epitopes would enable many types of studies and applications. Protein binders such as nanobodies (Nbs) can target untagged proteins (antigens) in the intracellular environment. However, genetically expressed protein binders are stable regardless of antigen expression, complicating their use for applications that require cell-specificity. Here, we created a conditional system in which the stability of an Nb depends upon an antigen of interest. We identified Nb framework mutations that can be used to rapidly create destabilized Nbs. Fusion of destabilized Nbs to various proteins enabled applications in living cells, such as optogenetic control of neural activity in specific cell types in the mouse brain, and detection of HIV-infected human cells by flow cytometry. These approaches are generalizable to other protein binders, and enable the rapid generation of single-polypeptide sensors and effectors active in cells expressing specific intracellular epitopes. DOI: http://dx.doi.org/10.7554/eLife.15312.001
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    Cell Type-Specific Manipulation with GFP-Dependent Cre Recombinase
    (2016) Tang, Jonathan C Y; Rudolph, Stephanie; Dhande, Onkar S; Abraira, Victoria E; Choi, Seungwon; Lapan, Sylvain; Drew, Iain R; Drokhlyansky, Eugene; Huberman, Andrew D; Regehr, Wade; Cepko, Constance
    Summary There are many transgenic GFP reporter lines that allow visualization of specific populations of cells. Using such lines for functional studies requires a method that transforms GFP into a molecule that enables genetic manipulation. Here we report the creation of a method that exploits GFP for gene manipulation, Cre Recombinase Dependent on GFP (CRE-DOG), a split component system that uses GFP and its derivatives to directly induce Cre/loxP recombination. Using plasmid electroporation and AAV viral vectors, we delivered CRE-DOG to multiple GFP mouse lines, leading to effective recombination selectively in GFP-labeled cells. Further, CRE-DOG enabled optogenetic control of these neurons. Beyond providing a new set of tools for manipulation of gene expression selectively in GFP+ cells, we demonstrate that GFP can be used to reconstitute the activity of a protein not known to have a modular structure, suggesting that this strategy might be applicable to a wide range of proteins.