In the central nervous system, ACh has a variety of effects as a neuromodulator upon plasticity, arousal and reward. ACh has an important role in the enhancement of sensory perceptions when we wake up and sustained attention.
Damage to the cholinergic system in the brain has been suggested to play a role in the memory deficits associated with Alzheimer's disease.
Acetylcholine and the associated neurons form a neurotransmitter system, the cholinergic system from the brainstem and basal forebrain that projects axons to mainly areas of the brain. In the brainstem it originates from the Pedunculopontine nucleus and dorsolateral tegmental nuclei collectively known as the mesopontine tegmentum area or pontomesencephalotegmental complex. In the basal forebrain, it originates from the basal optic nucleus of Meynert and medial septal nucleus,:
* The pontomesencephalotegmental complex acts mainly on M1 receptors in the brainstem, deep cerebellar nuclei, pontine nuclei, locus ceruleus, raphe nucleus, lateral reticular nucleus and inferior olive. It also projects to the thalamus, tectum, basal ganglia and basal forebrain
* Basal optic nucleus of Meynert acts mainly on M1 receptors in the neocortex.
* Medial septal nucleus acts mainly on M1 receptors in the hippocampus and neocortex.
In addition, ACh acts as an important "internal" transmitter in the striatum, which is part of the basal ganglia. It is released by a large set of interneurons with smooth dendrites, known as tonically active neurons or TANs.
ACh is involved with synaptic plasticity, specifically in learning and short-term memory.
Acetylcholine has been shown to enhance the amplitude of synaptic potentials following long-term potentiation in many regions, including the dentate gyrus, CA1, piriform cortex, and neocortex. This effect most likely occurs either through enhancing currents through NMDA receptors or indirectly by suppressing adaptation. The suppression of adaptation has been shown in brain slices of regions CA1, cingulate cortex, and piriform cortex, as well as in vivo in cat somatosensory and motor cortex by decreasing the conductance of voltage-dependent M currents and Ca2+-dependent K+ currents.
Acetylcholine also has other effects on neurons. One effect is to cause a slow depolarization by blocking a tonically-active K+ current, which increases neuronal excitability. Another upon postsynaptic M4-muscarinic ACH receptors is to open inward-rectifier potassium ion channel (Kir) and cause inhibition.
These two effects happen upon neurons in different neuron layers. For instance, the excitation effect acts on intrinsic and associational fibers in layer Ib of piriform cortex, but has no effect on afferent fibers in layer Ia. Similar laminar selectivity has been shown in dentate gyrus and region CA1 of the hippocampus.
In the cerebral cortex, ACH inhibits layer 4 medium spiny neurons, the main targets of thalamocortical inputs while excitating of pyramidal cells in layers 2/3 and layer 5. This filters out weak sensory inputs in layer 4 and amplifies inputs that reach the layers 2/3 and layer L5 excitatory microcircuits. As a result, these layer-specific effects of ACH might function to improve the signal noise ratio of cortical processing.
Another theory interprets acetylcholine neuromodulation in the neocortex as modulating the estimate of expected uncertainty, acting counter to norepinephrine (NE) signals for unexpected uncertainty. Both modulations would then decrease synaptic transition strength, but ACh would then be needed to counter the effects of NE in learning, a signal understood to be 'noisy'.