A comprehensive explanation of cholinergic neuromodulation is not yet possible, given the large number of behaviors, circuits, neuronal subtypes and cholinergic receptors in the brain. Despite that complexity, some unifying themes have emerged. The well-defined temporal association between firing of cholinergic projection neurons in the brain stem and the pause in firing of tonically active cholinergic interneurons in the striatum can facilitate the association of salient rewarding events with cues in the environment, contributing to reward prediction and promoting orienting behaviors toward potentially rewarding stimuli. This likely occurs through coordinated increases in glutamatergic drive that facilitate DA neuron burst firing, and decreases in response to subthreshold, tonic signals from DA terminals. Similarly, salient signals that require focused attention for correct performance of behavioral tasks, increase feed-forward activation of principal cortical neurons and decrease inhibition through specific classes of interneurons. The promotion of coordinated firing of adjacent axons and the promotion of rhythmic activity in structures such as the hippocampus when ACh is released and levels are high may provide an increase in the baseline excitability of neurons that are then
