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III - Diester/Möglich/Ruther/Zurbriggen

Red-light-regulated actuators for spatiotemporal control of opsin expression and modulation of cell-cell interactions within the prefrontal circuit during impulse control


1) Ilka Diester (PI; University of Freiburg), coworker:

2) Andreas Möglich (PI; University of Bayreuth), coworker:

3) Patrick Ruther (PI; University of Freiburg), coworker:

4) Matias Zurbriggen (PI; University of Düsseldorf), coworker:


The regulation of movements in response to internal and external cues represents one of the most sophisticated behavorial hallmarks of humans and animals. Electrophysiology has pinpointed the prefrontal cortex (PFC) as crucial in governing this behavorial response. Although optogenetic technology has helped in deciphering many aspects of the underlying intricate neural circuits in the PFC, at the same time this approach has been hampered by inadvertent co-stimulation of spatially overlapping cells and incoming axons emanating from cell bodies in neighboring brain areas. To overcome this significant bottleneck, we propose the development and implementation of optogenetic tools based on plant phytochrome photoreceptors for red-light-regulated gene expression and monitoring of anterograde communication between prefrontal projection and target cells. In this way, expression of rhodopsin-based optogenetic actuators can be restricted to target tissues of interest with much higher spatial and temporal accuracy than conventionally possible. To facilitate and diversify the optogenetic deployment of plant phytochrome-derived systems in vertebrates, we will use protein engineering to obtain variants that use as chromophore the widely occurring biliverdin as opposed to a plant-specific chromophore, and that respond to different colors across the visible spectrum. These novel tools will be embedded in gene-regulatory circuits in cell culture and in neurons of the rat PFC during impulse-control experiments. An optogenetically controlled anterograde tracing system will allow the precise functional mapping of projection patterns within and outgoing from the PFC. To afford simultaneous delivery of several light colors and electrical recordings from multiple sites, customized neural probes will be developed as part of this integrative collaborative project. As a team, we will thus provide and optimize genetically encoded light-regulated actuators and neural probes that in combination will serve to elucidate the neural circuitry underpinning movement control triggered by internal and external cues. Specifically, we will focus on the impact of the interaction between the prelimbic and infralimbic cortex as well as their projections to subcortical areas. Thereby, we hope to disentangle the prefrontal influence on the direct and indirect cortico-subcortical motor pathway.


Logic of interactions:

Ilka Diester: Identification of role prefrontal pathways with novel optogenetic tools; A. Möglich: Study and optimization of photoreceptors; P. Ruther: development of multisite optoelectronic probes with microfluidic channels for in vivo use, M. Zurbriggen: Development of optogenetic tools for in vivo control of neurons and cell-cell contacts.

Publications Diester, relevant for the proposal:

Ni J, Wunderle T, Lewis CM, Desimone R, Diester I, Fries P. (2016) Gamma-rhythmic Gain Modulation. Accepted at Neuron.

Fenno LE, Mattis J, Ramakrishnan C, Hyun M, Lee SY, He M, Tucciarone J, Selimbeyoglu A, Berndt A, Grosenick L, Zalocusky KA, Bernstein H, Swanson H, Perry C, Diester I, Boyce FM, Bass CE, Neve R, Huang ZJ, Deisseroth K (2014) Targeting cells with single vectors using multiple-feature Boolean logic. Nat Methods. 11(7): 763-72.

Wang J, Wagner F, Borton DA, Zhang J, Ozden I, Burwell RD, Nurmikko AV, van Wagenen R, Diester I, Deisseroth K (2012) Integrated Device for Combined Optical Neuromodulation and Electrical Recording for Chronic In Vivo Applications. Journal of Neural Engineering. 9(1):016001.

Gradinaru V, Zhang F, Ramakrishnan C, Mattis J, Prakash R, Diester I, Goshen I, Thompson KR, Deisseroth K (2010) Molecular, cellular, and genomic force multipliers for optogenetic control. Cell. 141(1): 154-65.

Publications Möglich, relevant for the proposal:

Gasser CF, Taiber S, Yeh C-M, Wittig CH, Hegemann P, Ryu S, Wunder F and Möglich A, “Engineering of a red-light-activated human cAMP/cGMP-specific phosphodiesterase”. Proceedings National Academy of Science USA (2014) 111(24), 8803-8808

Publications Ruther, relevant for the proposal:

Ruther P and Paul O, “New approaches for CMOS-based devices for large-scale neural recording”. Current Opinion in Neurobiology (2015) 32, 31-37

Gossler C, Bierbrauer C, Moser R, Kunzer M, Holc K, Pletschen W, Köhler K, Wagner J, Schwaerzle M, Ruther P, Paul O, Neef J, Keppeler D, Hoch G, Moser T and Schwarz UT, “GaN-based micro-LED arrays on flexible substrates for optical cochlear implants”. Journal of Physics D: Applied Physics (2014) Vol. 47, 205401

Seidl S, Herwik S, Torfs T, Neves HP, Paul O and Ruther P, “CMOS-Based High-Density Silicon Microprobe Arrays for Electronic Depth Control in Intracortical Neural Recording”. Journal of Microelectromechanical Systems (2011) vol. 20(11)

Spieth S, Brett O, Seidl K, Aarts AAA, Erismis MA, Herwik S, Trenkle F, Tätzner S, Auber J, Paul O, Neves HP, Puers R, Ruther P and Zengerle R, “A Floating 3D Silicon Microprobe Array for Neural Drug Delivery Compatible with Electrical Recording”. Journal of Micromechanical Microengineering (2011) vol. 21, 125001 (16pp)


Publications Zurbriggen, relevant for the proposal:

Beyer HM, Juillot S, Herbst K, Samodelov SL, Müller K, Schamel WW, Römer W, Schäfer E, Nagy F, Strähle U, Weber W and Zurbriggen MD, “Red light-regulated reversible nuclear localization of proteins in mammalian cells and zebra fish”. ACS Synthetic Biology (2015) 4(7). Cover Article Issue July 2015

Müller K, Engesser R, Timmer J, Zurbriggen MD and Weber W, “Orthogonal optogenetic triple-gene control in mammalian cells”. ACS Synthetic Biology (2014) 3(11), 796-8901

Müller K, Naumann S, Weber W and Zurbriggen MD, “Optogenetics for gene expression in mammalian cells”. Biological Chemistry (2014) 396(2), 145-152

Müller K, Zurbriggen MD and Weber W, “Control of gene expression using a red/far-red light-responsive bi-stable toggle switch”. Nature Protocols (2014) 9(3), 622-632

Müller K, Siegel D, Rodríguez Jahnke F, Gerrer K, Wend S, Decker EL, Reski R, Weber W and Zurbriggen MD, “A red light-controlled synthetic gene expression switch for plant systems“. Molecular BioSystems (2014) 10, 1679-1688