Molekulare Regulierung neuronaler Netzwerke zum Stabilisieren von Langzeitgedächtnis in adulten und alternden Mäusen
Zusammenfassung der Projektergebnisse
The mammalian brain is capable to form and store episodic memories, that link events, objects and context. Often, those memories lose detail over time. On a neuronal level, subsets of neurons in the hippocampus and neocortical anterior cingulate cortex (ACC) form a representation of the learned experience. The change from very detailed to gist-like memory is thought to be due to a change in hippocampal to neocortical neuronal representation. In this project, we investigated the role of feed-forward inhibition through parvalbumin-positive interneurons in the hippocampal subregion CA3 in the maintenance of neuronal representation. We successfully combined a viral manipulation that mimics a learning-induced increase in feedforward inhibition from dentate gyrus to CA3 (DG-CA3 FFI) with longitudinal calcium imaging in excitatory neurons in hippocampal CA1 and neocortical ACC. Our findings reveal a role for DG- CA3 FFI in forming and maintaining context-specific neuronal representation in both CA1 and ACC resulting in improved long-term memory. On a neuronal level, we found a decay of neuronal representation in CA1 and a loss of specificity in ACC ensembles over time in control mice further supporting recent studies. Increased DG-CA3 FFI prior to learning prevented the decay in CA1 and ACC ensembles over time. On a behavioral level, these mice showed improved long-term memory. Thus, we were able to demonstrate that DG-CA3 FFI dictates evolution of neuronal ensembles in CA1 and ACC during memory consolidation. Furthermore, our findings suggest a teacher-like function of hippocampal CA1 in re-organization of cortical representation over time. Overall, our findings extend the knowledge of hippocampal interneurons towards a role of CA3, and not only CA1, PV interneurons in memory consolidation. It is plausible that connectivity reengineering strategies such as that used in this study harbor potential to enhance memory consolidation in aging and in mouse models of Alzheimer’s disease.
