Any attempt to understand the function of the nervous system relies on the ability to target and manipulate specific cell types. Mouse genetics has provided impressive tools to achieve this goal but the cost, complexity, time, and obligate restriction to use in mice have meant that our understanding in other species has lagged behind.  This has prompted both my laboratory and others to develop new tools for accessing specific cell types across species. An ancillary benefit of BICCN (Brain Initiative- Cell consensus network) has been the rapid expansion in transcriptomic, chromatin accessibility (i.e. ATAC-seq) and encode data (e.g. H3K27ac) for particular cell types.  The Fishell laboratory has made considerable efforts to collect detailed information for the breadth of cortical interneuron subtypes (Dimidschstein et al., Nature Neurosci. 2017; Vormstein-Schneider et al., Nature Neurosci, 2020) to assemble a growing armamentarium of enhancers that allow for the targeting of specific interneuron types.   To complement and expand these efforts, we have developed a viral tool kit (VTK) that leverages recombinant driver lines to optimize the selective targeting and manipulation of cell types (Pouchelon et al., Cell Reports Methods, 2022).  Using both virus-based and hybrid genetic-viral approaches we have been able to create a breadth of reagents that allow for the targeting of various interneuron types.  As we continue to explore cell-specific enhancer space and pioneer the use of intersectional strategies, we hope to help transform the communities access to the CNS across mammalian species, including primates and humans.

Figure 1 - Enhancer-mediated targeting of PV interneurons across mammalian species

Figure 2 - Optimization of a viral toolkit (VTK) for direct and combinatorial transgene expression

Figure 3 - Macque PV interneuron labeled using an rAAV with the E2-enhancer

Selected References

Pouchelon G, Vergara J, McMahon J, Gorissen BL, Lin JD, Vormstein-Schneider D, Niehaus JL, Burbridge TJ, Wester JC, Sherer M, Fernandez-Otero M, Allaway KC, Pelkey K, Chittajallu R, McBain CJ, Fan M, Nasse JS, Wildenberg GA, Fishell G, Dimidschstein J. A versatile viral toolkit for functional discovery in the nervous system. Cell Rep Methods. 2022 May 26;2(6):100225. PMID: 35784651; PMCID: PMC9243523. [pdf]

Vormstein-Schneider D, Lin J, Pelkey K, Chittajallu R, Guo B, Garcia MA, Allaway K, Sakopoulos S, Schneider G, Stevenson O, Vergara J, Sharma J, Zhang Q, Franken T, Smith J, Ibrahim L, Mastro K, Sabri E, Huang, S, Favuzzi E, Burbridge T, Xu Q, Guo L, Vogel I, Sanchez V, Saldi G, Yuan X, Zaghloul K, Devinsky O, Sabatini B, Batista-Brito R, Reynolds J, Feng G, Fu Z, Chris McBain C, Fishell G, Dimidschstein J. Viral manipulation of functionally distinct neurons from mice to humans. bioRxiv preprint doi: https://doi.org/10.1101/808170. this version posted January 29, 2020. [pdf]

Dimidschstein J, Chen Q, Tremblay R, Rogers SL, Saldi GA, Guo L, Xu Q, Liu R, Lu C, Chu J, Avery MC, Rashid MS, Baek M, Jacob AL, Smith GB, Wilson DE, Kosche G, Kruglikov I, Rusielewicz T, Kotak VC, Mowery TM, Anderson SA, Callaway EM, Dasen JS, Fitzpatrick D, Fossati V, Long MA, Noggle S, Reynolds JH, Sanes DH, Rudy B, Feng G, Fishell G. Corrigendum: A viral strategy for targeting and manipulating interneurons across vertebrate species. Nat Neurosci. 2017 Jun 27;20(7):1033. doi: 10.1038/nn0717-1033c. [pdf]