Abstract
Although the cholinergic system has long been implicated in the formation of memory, there had been no direct demonstration that activation of this system can actually induce specific behavioral memory. We have evaluated the "cholinergic-memory" hypothesis by pairing a tone with stimulation of the nucleus basalis (NB), which provides acetylcholine to the cerebral cortex. We found that such pairing induces behaviorally-validated auditory memory. NB-induced memory has the key features of natural memory: it is associative, highly-specific and rapidly induced. Moreover, the level of NB stimulation controls the amount of detail in memory about the tonal conditioned stimulus. While consistent with the hypothesis that properly-timed release of acetylcholine (ACh) during natural learning is sufficient to induce memory, pharmacological evidence has been lacking. This study asked whether scopolamine, a muscarinic antagonist, impairs or prevents the formation of NB-induced memory. Adult male rats were first tested for responses (disruption of ongoing respiration) to tones (1-15 kHz), constituting a pre-training behavioral frequency generalization gradient (BFGG). Then, they received a single session of 200 trials of a tone (8.00 kHz, 70 dB, 2 s) paired with electrical stimulation of the NB (100 Hz, 0.2 s). Immediately after training, they received either scopolamine (1.0 mg/kg, i.p.) or saline. Twenty-four hours later, they were tested for specific memory by obtaining post-training BFGGs. The saline group developed CS-specific memory, manifested by maximum increase in response specific to the CS frequency band. In contrast, the scopolamine group exhibited no such memory. These findings indicate that NB-induced specific associative behavioral memory requires the action of intrinsic acetylcholine at muscarinic receptors, and supports the hypothesis that natural memory formation engages the nucleus basalis and muscarinic receptors.