Revealing Single Molecules: From Nanophysiology to Dyshomeostasis of Neural Circuits

• Applicant: Professor Silvio-Olivier Rizzoli, Ph.D.
• Subject Area: Molecular Biology and Physiology of Neurons and Glial Cells
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 560920804

How neural circuits maintain the balance between stability and plasticity is one of the most intriguing questions in neuroscience. Neurons are composed of highly dynamic and heterogeneous proteins, making it challenging to determine how stable activity is preserved. Despite significant progress over the past decades, technological limitations, particularly in microscopy resolution, have hindered our ability to address this challenge fully. Most super-resolution imaging techniques are limited, for tissue implementations, to resolutions exceeding the size of individual proteins (~3–7 nm), thus preventing the accurate visualization of the topology of protein complexes. To bridge this gap, we propose to introduce ‘nanophysiology’, a transformative technology that enables the analysis of protein complex structures under functionally defined conditions. To better understand how protein complexes maintain brain homeostasis and how this balance is disrupted in brain disorders, we have developed an optics technique that achieves ~1 nm resolution with high labeling efficiency. Additionally, we established an experimental framework integrating multi-modal physiological data at multiple levels, including neural circuits, individual neurons, synapses, and organelles. To demonstrate the power of this approach, we will conduct a proof-of-concept study focusing on mitochondrial signaling and its role in maintaining homeostasis of neural circuits across different vigilance states. In our recent collaborative work, we identified neuronal mitochondria as key regulators of homeostasis in hippocampal circuits. By combining our technologies in imaging and physiology, we aim to address the following questions: (1) What mitochondrial mechanisms regulate firing rate homeostasis in hippocampal circuits across the sleep-wake cycle? (2) How do spike patterns and sleep-related neuromodulators influence the reorganization of the mitochondrial calcium uniporter complex in different sub-cellular neuronal compartments? (3) How does mitochondrial dysregulation contribute to hyperexcitability, sleep disturbances, and memory dysfunctions in Alzheimer’s disease (AD)? Our combined expertise and history of collaboration position us to answer these questions effectively. This work will provide the first comprehensive insights into how neural circuit stability is regulated across vigilance states, and will offer critical mechanistic insights into AD, a growing concern for aging populations. Beyond transforming the use of microscopy in biomedical research, this study will uncover fundamental principles of neural circuit stability at the molecular level, potentially revealing new therapeutic strategies for AD.

• DFG Programme: Research Grants
• International Connection: Israel
• Partner Organisation: The Israel Science Foundation
• Cooperation Partners: Professorin Dr. Inna Slutsky; Professorin Dr. Shani Stern