Ca 2+ Plateau Potentials Reflect Cross-Theta Cortico-Hippocampal Input Dynamics and Acetylcholine for Rapid Formation of Efficient Place-Cell Code

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Summary A central tenet of Systems Neuroscience lies in an understanding of memory and behavior through learning rules, but synaptic plasticity has rarely been shown to create functional single-neuron code in a causal and biophysically rooted manner. Behavioral Time-Scale Synaptic Plasticity (BTSP), identified in vivo , holds a great potential for explaining instantaneous hippocampal selectivity emergence by long-term potentiation (LTP), yet the cellular and endogenous mechanisms are unknown, impeding broader conceptualization of this novel rule for its algorithmic, systems-level and theoretical implications. Here, we addressed this gap by in-vivo , ex-vivo , in-silico and computational approaches to seek neurophysiologically inspired protocols for synaptically evoking Ca 2+ plateau potentials and inducing potentiation in the CA1. We found induction of BTSP-LTP is best explained by a theta-oscillation-paced, gradually developed cellular state being supported with precisely timed weak ramping inputs. Remarkably, the previously presumed one-shot LTP for in-vivo place-field formation is possible under the influence of muscarinic activation. Through modeling, the notion of acetylcholine-gated BTSP gave rise to a computational advantage for low-interference continual learning. We further demonstrated that biophysics of Transient Receptor Potential (TRPM) and NMDA receptor (NMDAR) channels powerfully shapes the cross-theta dynamics underlying BTSP. These results which cover pre-, post-synaptic and neuromodulatory factors and their timing suggest fundamental principles for graded plateau potentials and hippocampal LTP induction. Overall, our work dissects cellular mechanisms potentially important for a prominent in-vivo hippocampal plasticity phenomenon, and offers a biological basis for framing BTSP as an input-dynamics-aware, neuromodulation-tuned synaptic algorithm.

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