Role of the Entorhinal Cortical Delta Oscillations in Systems Consolidation - Project Summary / Abstract Memory consolidation, a crucial step in memory formation that creates long-lasting engrams in the neocortex using labile memory created during waking, is severely impaired in Alzheimer’s disease. Memory consolidation occurs via two levels: Cellular consolidation, which stores new information via strengthening synapses in the hippocampus within hours of learning, and systems consolidation, which creates long-term memory in the neocortex via large-scale communication between the hippocampus and the neocortex. It has been shown that this large-scale communication is mediated by oscillatory activities in the hippocampus known as sharp-wave ripples (SPW-Rs), which are coordinated by slow oscillations and sleep spindles in the neocortex. The entorhinal cortex has extensive connections with the hippocampus and is the earliest region impacted by the pathogenesis of Alzheimer’s disease even before the hippocampus or neocortex are affected. Yet, there is a fundamental gap in understanding the role of entorhinal cortical oscillations in systems consolidation. Our published and pilot data provide compelling evidence that delta oscillations generated by temporoammonic (TA) pathway neurons, which project from the entorhinal cortical layer III to the hippocampal output area CA1, play a crucial role in the formation of long-term explicit memory. However, neither the circuit mechanism underlying the role of the entorhinal cortex in memory consolidation nor the role of the TA pathway in systems consolidation is yet known. The proposed studies will examine the role of delta oscillations of the TA pathway (“TA delta”) in mediating cortical feedback on the hippocampus during systems consolidation using cell-type specific optical recordings, electrophysiology, monosynaptic tracing, optogenetics, chemogenetics, and rodent behavioral testing. The proposal focuses on the following three questions: (1) Does TA delta modulate hippocampal SPW-Rs? (2) How is TA delta modulated by neocortical inputs from the anterior cingulate cortex? (3) Does TA delta play a crucial role in integrating new information with the cortically consolidated remote memory? Completion of these studies will elucidate the key mechanism underlying cortical communication to the hippocampus mediated by TA delta during systems consolidation, which would unravel a new mechanism underlying the impairment of memory consolidation shown in Alzheimer’s disease.
