The definition of a neuromodulator is flexible but has evolved to describe any kind of neurotransmission that is not directly excitatory (mediated through ionotropic glutamate receptors) or inhibitory (mediated through ionotropic GABA receptors) (Ito and Schuman, 2008; Siggins, 1979). Neuromodulation can be thought of as a change in the state of a neuron, or group of neurons, that alters its response to subsequent stimulation. A number of models have been proposed to explain the actions of ACh in the central nervous system (CNS). For example, ACh has been suggested to be critical for the response to uncertainty, such that an increase in cholinergic tone predicts the unreliability of predictive cues in a known context, and improves the signal-to-noise ratio in a learning environment (Yu and Dayan, 2005). Another model has suggested that ACh reinforces neuronal loops and cortical dynamics during learning by enhancing the influence of feed-forward afferent inputs to the cortex carrying sensory information and decreasing excitatory feedback activity mediating retrieval (Hasselmo, 2006). ACh can also alter firing of neurons on a rapid time scale, as in fear-conditioning, when
