Cell type specific genetic tools for circuit analysis

The analysis of neural circuits or the molecular machinery of neural computation relies on genetic access to individual cells or cell types, or distinct access to two potential synaptic partners.

Several efforts have recently been made to develop genetic tools that allow this degree of specificity. Starting in the Clandinin lab at Stanford University, USA, we (Gohl, Silies et al. 2011) have developed a genetic toolkit, the InSITE system, that can be used to refine and repurpose expression patterns.
To this end, we have generated ~2000 InSITE Gal4 driver lines that can be genetically replaced in vivo with components of e.g. the splitGal4 system for genetic intersections, or components of other binary expression for distinct genetic access to different cell types. The toolkit as well as the full Gal4 driver collections are publicly available.

We are also continuing to develop tools for more specific manipulations of subcellular circuit elements.
A causal understanding of the brain requires manipulating neural activity. Current manipulations such as activating or inhibiting neural activity are performed down to single cell type level. However, neural circuits are inter-connected networks - single cell-types can simultaneously receive input from, and, feed into different pathways through distinct synaptic partners. One great example of this is the well-studied Drosophila optic lobe where connectivity is extensively mapped through Electron Microscopy reconstructions.

This neural organization suggests that individual neurons can contribute differentially to neural computations and instead of an individual neuron or cell type, one should rather consider the specific connection between two cell types a computationally relevant unit. Thus, understanding the fundamentals of neural computations requires tools to manipulate neural activity with synaptic resolution.



We are currently developing STAB (Synapse Targeted Activity Block), that will disrupt synaptic function in a way that is contingent on both the pre- and the postsynaptic site. The STAB strategy is based on disruption of synaptic communication via proteolytic cleavage of an essential synaptic protein. This tool will serve to understand how single circuit components are used between different processing streams and what are their influence on circuit output and even on behavior. Due to its versatility, our genetic tool can also be applied to answer many longstanding questions in Drosophila circuit analysis.