Brenda Milner Award 2022


Dr. Marta Orlando (@Charité projects A01/A02) is awarded the Brenda Milner Award 2022 for her contributions to dedicated basic research projects focusing on synaptic plasticity in the hippocampal mossy fiber system.

Dr. Orlando’s experimental work and theoretical analysis of the data for her current project exemplify her outstanding ability to pursue challenging scientific questions. Notably, work on structural plasticity is demanding and requires excellent technical skills. These skills were recognized recently in a competitive process, where she was awarded a NeuroCure Research Fellowship for her excellent project proposal to understand the ultrastructural correlates of presynaptic plasticity. Marta’s sincere and deep interest in scientific problems and questions is coupled with an equally impressive work ethic. Outside of the lab, she has been a driving force in local initiatives supporting career development for postdocs, and in co-organizing annual neuroscience competitions for high school students in Berlin and internationally.

Research on structural plasticity was recently published (PLoS Biol. 19(6):e3001149, 2021) with Dr. Orlando as first author and conducting all the electron microscopy (EM) experiments. A second project defined according to her skills focuses on detection and localization of vesicles in EM images, with a last authorship currently in second revision. Briefly:

Structural plasticity: Synaptic plasticity is a cellular model for learning and memory. However, the expression mechanisms underlying presynaptic forms of plasticity are not well understood. Here, we investigate functional and structural correlates of presynaptic potentiation at large hippocampal mossy fiber boutons induced by the adenylyl cyclase activator forskolin. We performed 2-photon imaging of the genetically encoded glutamate sensor iGlu that revealed an increase in the surface area used for glutamate release at potentiated terminals. Time-gated stimulated emission depletion microscopy revealed no change in the coupling distance between P/Q-type calcium channels and release sites mapped by Munc13-1 cluster position. Finally, by high-pressure freezing and transmission electron microscopy analysis, we found a fast remodeling of synaptic ultrastructure at potentiated boutons: Synaptic vesicles dispersed in the terminal and accumulated at the active zones, while active zone density and synaptic complexity increased. We suggest that these rapid and early structural rearrangements might enable long-term increase in synaptic strength.

Automated detection and localization of vesicles in electron microscopy images: Information transfer and integration in the brain occurs at chemical synapses and is mediated by the fusion of synaptic vesicles filled with neurotransmitter. Synaptic vesicle dynamic spatial organization regulates synaptic transmission as well as synaptic plasticity. Because of their small size, synaptic vesicles require electron microscopy for their imaging, and their analysis is conducted manually. The manual annotation and segmentation of the hundreds to thousands of synaptic vesicles, is highly time consuming and limits the throughput of data collection. To overcome this limitation, we built an algorithm, mainly relying on convolutional neural networks, capable of automatically detecting and localizing synaptic vesicles in electron micrographs. The algorithm was trained on murine synapses, but we show that it works well on synapses from different species, ranging from zebrafish to human, and from different preparations. As output, we provide the vesicles count and coordinates, the nearest neighbor distance, and the estimate of the vesicles area. We also provide a graphical user interface (GUI) to guide users through image analysis, result visualization and manual proof-reading. The application of our algorithm is especially recommended for images produced by transmission electron microscopy. Since this type of imaging is used routinely to investigate presynaptic terminals, our solution will likely be of interest for numerous research groups.

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Dr. Marta Orlando
Charité-Universitätsmedizin Berlin

NeuroCure Research Fellow

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