INSPIRE · Interneuron subtype-specific control of hippocampal memory encoding and retrieval

The brain’s ability to encode novel experiences and to retrieve memories from partial cues is believed to be dependent on the unique circuitry of the hippocampal cornu ammonis 3 (CA3) region. Previous research has focused almost exclusively on the connectivity and function of excitatory pyramidal neurons in subregions of CA3. The contribution of inhibitory interneurons, key regulators of network dynamics, is largely unknown. Yet, dysfunction of parvalbumin-positive interneurons has been linked to memory impairment in psychiatric and neurodegenerative disorders, indicating their critical role for healthy cognition. This project will investigate how distinct parvalbumin-positive interneuron subtypes, basket cells (BCs) and axo-axonic cells (AACs), control CA3 computations and memory processing. Using an interdisciplinary approach, I will first employ in vitro whole-cell recordings to map synaptic input gradients of BCs and AACs along the proximodistal CA3 axis. Next, I will perform in vivo two-photon calcium imaging during a virtual reality-based behavioral task to monitor subtype-specific activity during spatial learning and recall. Finally, I will use holographic optogenetics to causally test, how individual interneurons control pyramidal cell dynamics and spatial memory representations. I hypothesize that BCs regulate activity of large pyramidal cell populations during memory formation, whereas AACs exert more selective control over subgroups of pyramidal neurons. By leveraging multiple advanced techniques and novel genetic tools, this project will provide causal evidence of how interneuron subtypes orchestrate memory computations. These findings could open new perspectives on treatment of inhibitory disruption in disorders such as schizophrenia and Alzheimer’s disease. This project will not only advance fundamental neuroscience but also lay the foundations for my independent research career at the interface of cellular, circuit, and behavioral neuroscience.