Short-Term Memory and Cholinergic Gate Keeper

초록

Short-term memory, the ability to temporarily retain external information, is associated with persistent neuronal activity in the prefrontal cortex (PFC). Reciprocal excitation between the mediodorsal thalamus (MD) and PFC has been proposed as a key mechanism supporting this persistent activity. However, the exact neural circuit mechanisms underlying short-term memory remain poorly understood. Notably, thalamocortical synapses are known to exhibit strong short-term depression. Consistent with this, our ex vivo and in vivo electrophysiological recordings under anesthesia revealed that high-frequency firing in MD—mimicking activity during short-term memory—fails to reliably evoke action potentials in PFC neurons. In this study, we demonstrate that acetylcholine functions as a switch for the cortico-thalamocortical activity loop. Specifically, we show that the fidelity of thalamocortical transmission during high-frequency activity is significantly enhanced by muscarinic acetylcholine receptor (mAChR) agonist, both in vitro and in vivo. This enhancement is mediated by increased intrinsic excitability of PFC neurons. Conversely, blocking mAChRs with atropine, a competitive antagonist, impaired performance in a short-term memory task. Using high-density electrode recordings during behavior, we identified three distinct neuronal populations in the medial PFC (mPFC): neurons active only during the cue period, neurons with sustained activity from the late cue period through the delay, and neurons with biphasic activity—showing activation both during the cue and again at the end of the delay and into the response period. These populations likely serve different functional roles: encoding external cues, maintaining information across the delay, and integrating cue encoding with motor planning or retrieval, respectively. Importantly, we found that direction-selectivity of mPFC neuron activity increased during the delay period in correct trials, both at the single-cell and population level. In contrast, this selectivity was significantly reduced in error trials and in trials with mAChR blockade. Together, our findings demonstrate that muscarinic receptor activation is essential for maintaining the cortico-thalamo-cortical activity loop and for sustaining task-relevant, cue-dependent activity patterns in the PFC that underlie successful short-term memory performance.