Group Leader

Sven Truckenbrodt

Molecular brain mapping

Sven Truckenbrodt

All human culture, from society to science, engineering and art, is the product of our brains. And yet, the brain — the biological hardware of cognition — remains enigmatic. To generate new hypotheses about how it works, we need brain maps with an ever-increasing abundance of information.

We are generating this abundance of information in our datasets by applying the new paradigm of molecular connectomics. Molecular connectomics combines synaptic resolution circuit mapping with access to the extensive toolboxes of molecular biology to enable multimodal readouts of molecular information:

  • In expansion microscopy, we use hydrogels to expand biological tissue by more than 1,000-fold in volume. This separates biological features — increasing resolution — and allows us to map brains at synaptic resolution on conventional light microscopes.
  • Light microscopy unlocks the toolboxes of molecular biology, from immunostainings of synaptic markers to RNA cell-typing, viral barcoding of neurons, etc.
  • We combine these tools in multimodal multiplexing to read out dozens of targets and different biomolecules within the same brain map.

Our goal is to understand animal behaviour at the molecular level of the biological hardware that gives rise to the computational capabilities of our remarkable brains.

Four display items outline what constitutes “molecular connectomics.” First, expansion microscopy is represented by a photo of a mouse brain slice before and after expansion. Second, morphological readouts are represented by a microscopy image of neurons with pan-protein labelling. Third, molecular tools are represented by a compound microscopy image of neuronal barcodes. Fourth, molecular readouts are represented by a microscopy image of neuronal barcodes with pre- and post-synaptic markers. Finally, a 3D rendering of a reconstruction of barcoded neurons with synaptic markers acts as a representation of how these modules combine.
Contributions from E11 Bio, Crick (Rodriques), MIT (Boyden), and Max Planck (Kornfeld).

Data credits: E11 Bio: Sung-Yun (Rosa) Park, Arlo Sheridan, William Patton, Julia Lyudchik, Erin Jarvis, Jun Axup, Stephanie Chan, Hugo Damstra, Clarence Magno, Aashir Meeran, Jules Michalska, Michelle Wu, Kathleen Leeper, Sven Truckenbrodt, Johan Winnubst, Andrew Payne. Crick Institute: Samuel Rodriques, Sung-Yun (Rosa) Park. MIT: Ed Boyden, Bobae An, Daniel Leible. MPI: Jörgen Kornfeld, Franz Rieger. 3D rendering: Tyler Sloan.

Selected Publications

Combinatorial protein barcodes enable self-correcting neuron tracing with nanoscale molecular contextPark SY, Sheridan A, An B, Jarvis E, Lyudchik J, Patton W, Axup JY, Chan SW, Damstra HGJ, Leible D, Leung KS, Magno CA, Meeran A, Michalska JM, Rieger F, Wang C, Wu M, Church GM, Funke J, Huffman T, Leeper KGC, Truckenbrodt S, Winnubst J, Kornfeld JMR, Boyden ES, Rodriques SG, Payne ACbioRxiv: (2025) preprint
Expansion Microscopy: Super-Resolution Imaging with HydrogelsTruckenbrodt SAnalytical Chemistry 95(1): 3-32 (2023)
A practical guide to optimization in X10 expansion microscopyTruckenbrodt S, Sommer C, Rizzoli SO, Danzl JGNature Protocols 14(3): 832-863 (2019)
X10 expansion microscopy enables 25‐nm resolution on conventional microscopesTruckenbrodt S, Maidorn M, Crzan D, Wildhagen H, Kabatas S, Rizzoli SOEMBO reports 19(9): (2018)