The mossy fiber synapse - imprinting a memory trace in CA3
Final Report Abstract
Memories about unique events or ‘episodes’ in our life build the individual narrative that shapes our personality. Such memories have impact on our wellbeing, and can promote both self-esteem, but also be the source of psychological trauma and ignite psychiatric diseases. While the importance of episodic memories is undoubted, their representations in the brain remain mostly elusive. The hippocampus is a brain area that plays a crucial role in storing new experiences as episodic memories. In our current work, we explore the mechanisms by which hippocampal neurons, particularly in the CA3 area, form mnemonic representations of experiences and which role their synaptic inputs from the dentate gyrus and entorhinal cortex play in this process. We performed high-density electrophysiological recordings of extracellular action potentials from large numbers of neurons simultaneously in the entorhinal cortex, dentate gyrus, and CA3 and studied how they form neuronal ensembles representing distinct mnemonic entities during explorative behaviors. We furthermore investigated the re-activation of such neuronal assemblies during sleep after an initial learning session and are currently evaluating the relationship between these neuronal activity patterns and successful memory retention. In a separate line of studies, we addressed the relationship between entorhinal and hippocampal representations of the same environment using calcium imaging of entorhinal cortex axons and cell bodies of hippocampal neurons in head-fixed mice foraging in animated sceneries in a virtual environment. We observed that during exploration the entorhinal cortex provides the hippocampus with a rich input stream representing the relevant variables of the virtual world, such as the current location or the behavioral context. However, these representations have a high level of variance and are unreliable on short timescales. Our computational analyses indicate that hippocampal principal cells filter out these stochastic irregularities creating a reliable output that may allow the brain to read out memory-relevant information rapidly from a finite ensemble of neurons. The function of hippocampal principal cell circuits is controlled by inhibitory interneurons. We previously found a differential response of hippocampal principal cells to novel environments, with a strong activation of episode-specific representations in CA3 and a concomitant decrease in activation of dentate gyrus granule cells representing invariable, schema-like features of the environment. Using calcium imaging of genetically identified interneuron subtypes, we were able to show that distinct circuits comprising somatostatinand parvalbumin expressing interneurons govern the response to novelty in their respective hippocampal subfields. This knowledge may potentially open future avenues to alter the degree by which preexisting knowledge is integrated into newly formed memories, a process thought to be altered and disrupted in psychiatric conditions such as schizophrenia. While we are still in the process of analyzing the results of our electrophysiological experiments, we have compiled our calcium imaging studies. We furthermore published a highly cited review on the function of the dentate gyrus in mnemonic operations and will continue to close gaps in the knowledge about such operations in the future. We hope thereby to foster an understanding of hippocampal memory operations to find biological targets for therapies leveraging memory processes.
Publications
- (2020) Dentate gyrus circuits for encoding, retrieval and discrimination of episodic memories. Nat Rev Neurosci. 21:153–168
Hainmueller T, Bartos M
(See online at https://doi.org/10.1038/s41583-019-0260-z) - (2021) Subfield-Specific Interneuron Circuits Govern the Hippocampal Response to Novelty. SSRN Journal
Hainmueller T, Huang L-W, Bartos M
(See online at https://doi.org/10.2139/ssrn.3796495) - (2021) The hippocampus converts dynamic entorhinal inputs into stable spatial maps. Neuron 109:3135-3148.e7
Cholvin T, Hainmueller T, Bartos M
(See online at https://doi.org/10.1016/j.neuron.2021.09.019)
