Circuits for cortical control of hippocampal operations

In order to efficiently discover and optimally utilize resources of a dynamically changing environment, both humans and animals need to constantly monitor and evaluate the outcome of their actions and if necessary, update behaviour. Underscoring the importance of such abilities, disruptions in mechanisms supporting them contribute greatly to the most destructive symptoms of neurodevelopmental disorders, including schizophrenia. Conversely, our understanding of neuronal circuits underlying flexible adaptation of behavioural strategies is still limited. Therefore, in this project we seek better insights in the circuitry and the network operations that support the rapid switching between spatial (revisiting remembered reward locations) and non-spatial (cue-guided discovery of ever-changing reward locations) strategies of reward retrieval in mice. The hippocampal CA1 area is a key hub for goal-directed navigation receiving various inputs from cortical, thalamic and intra-hippocampal sources. During behavioural adaptation, we hypothesize profound adjustments occur in the ways how the CA1 integrates and combines information from different upstream areas. Indeed, in a previous study we identified an inhibitory cell type that controls cortical inputs to the distal dendrites of CA1 pyramidal cells (Sakalar et al., 2022, Science), and may therefore execute adjustments of local network operations. We also postulate that these adjustments of information transfer are orchestrated and initiated by top-down projections from prefrontal cortical areas, known to be indispensable for cognitive flexibility. To validate the above hypotheses, we will first design and implement a cue-response adjustment task in head fixed mice that requires the animals to promptly switch between applying a spatial memory guided strategy, and responding to a previously irrelevant cue, presented at variable locations. We will record the spiking activity of large neuronal populations in the prelimbic cortex together with neuronal oscillations and firing in the hippocampus during the cue response adjustment task to discover the emergence and temporal coordination of top-down control signals in the prefrontal cortex. Since direct axonal projection from the prelimbic cortex to the dorsal CA1 area is lacking, we will further investigate indirect pathways linking the two areas, using viral pathway tracing and electrophysiological and opto-tagging experiments in potential thalamic and cortical relay areas. Our experiments may help a better understanding of the network mechanism underlying fast behavioural adaptation during cognitive flexibility in rodents and may open the avenue to the identification of novel therapeutic strategies and targets in the treatment of neurodevelopmental disorders.