All-optical interrogation of hippocampal circuits in head-restrained and freely-moving mice

• Applicant: Dr. Johannes Vierock
• Subject Area: Experimental and Theoretical Network Neuroscience ; Biophysics
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 569127795

GABAergic hub neurons represent a critical and sparse neuronal subtype that bridges developmental neurobiology and integrative neuroscience. First characterized by the Cossart lab over 15 years ago, these neurons have emerged as fundamental components of cortical circuit formation and function, with a remarkable ability to persist from early development through adulthood. The widespread presence of hub neurons across different cortical regions and species suggests a profound role in neural circuit organization. However, their precise functional mechanisms have remained challenging to investigate due to significant technical limitations in long-term neural manipulation, particularly in freely behaving animal models. This interdisciplinary research project brings together experts from physics, biophysics, and neuroscience to advance 2P and 3P optogenetic technology and comprehensively explore hub neurons in the CA1region of the mouse hippocampus. The investigation will examine hub neuron function from two primary perspectives: their role during early postnatal development and their involvement in hippocampus dependent behavioral paradigms. The research team proposes two fundamental hypotheses. During developmental stages, hub neurons are believed to facilitate the internalization of hippocampal dynamics by enhancing local connectivity, particularly through GABAergic innervation. In adult neural circuits, these neurons are hypothesized to play a critical role in organizing internally-driven CA1 neural dynamics. To address these hypotheses, the project requires an impressive array of cutting-edge technological strategies. These include the combination of advanced optical microscopy techniques with a new generation of tailored optogenetic actuators, that together will pioneer in vivo 3-photon optogenetics with holographic illumination, and a holographic photostimulation and imaging in freely moving mice using next generation two-photon fiberscopes. The research leverages the complementary expertise of the Cossart, Emiliani, and Vierock labs, building upon a robust foundation of previous investigations into interneuron dynamics and two-photon optogenetics. By integrating leading optogenetic tool development, extensive experience in systems neuroscience research, and innovative technological approaches to circuit manipulation, the project aims to provide unprecedented insights into the complex functional landscape of hippocampal hub neurons. Ultimately, this research aims to establish an advanced set of optical and molecular tools to push the frontiers of circuit analysis with optogenetics and to revolutionize our understanding of neural circuit development and function, offering a deeper insight into how specialized neurons contribute to brain organization and behavior.

• DFG Programme: Research Grants
• International Connection: France
• Cooperation Partners: Professorin Rosa Cossart, Ph.D.; Professorin Dr. Valentina Emiliani