Abstract
Cholinergic modulation of prefrontal cortex is essential for attention. In essence, it focuses the mind on relevant, transient stimuli in support of goal-directed behavior. The excitation of prefrontal layer VI neurons through nicotinic acetylcholine receptors optimizes local and top-down control of attention. Layer VI of prefrontal cortex is the origin of a dense feedback projection to the thalamus and is one of only a handful of brain regions that express the α5 nicotinic receptor subunit, encoded by the gene chrna5. This accessory nicotinic receptor subunit alters the properties of high-affinity nicotinic receptors in layer VI pyramidal neurons in both development and adulthood. Studies investigating the consequences of genetic deletion of α5, as well as other disruptions to nicotinic receptors, find attention deficits together with altered cholinergic excitation of layer VI neurons and aberrant neuronal morphology. Nicotinic receptors in prefrontal layer VI neurons play an essential role in focusing attention under challenging circumstances. In this regard, they do not act in isolation, but rather in concert with cholinergic receptors in other parts of prefrontal circuitry. This review urges an intensification of focus on the cellular mechanisms and plasticity of prefrontal attention circuitry. Disruptions in attention are one of the greatest contributing factors to disease burden in psychiatric and neurological disorders, and enhancing attention may require different approaches in the normal and disordered prefrontal cortex.
Highlights
Non-specific lesions of the cholinergic neurons of the basal forebrain first suggested a more specific involvement of acetylcholine in attention [11,12,13,14,15,16], and it subsequently became clear that cholinergic projections to the prefrontal cortex are especially important in this regard [17, 18]
The importance of cholinergic modulation of prefrontal cortex can be seen in the detrimental effects for attention of specific lesions to its cholinergic projections
The development of choline-sensitive microelectrodes, which offer greater temporal resolution than microdialysis probes, has further revealed that acetylcholine release in the prefrontal cortex increases rapidly and transiently—on the timescale of seconds to minutes— during the performance of attention tasks [29] where, as we will emphasize in this review, it can exert profound effects on corticothalamic neurons via the nicotinic acetylcholine receptors [36,37,38]
Summary
The importance of prefrontal cholinergic modulation was further suggested by microdialysis studies showing robust acetylcholine efflux within the prefrontal cortex during the performance of attention tasks [30,31,32], which reflects both attentional effort [33, 34] and behavioral context [35]. The excitatory nicotinic responses of layer VI pyramidal neurons are directly mediated by postsynaptic somatodendritic receptors since currents are resistant to blockade of synaptic transmission by the Na+ channel antagonist tetrodotoxin and to pharmacological inhibition of ionotropic and metabotropic glutamate receptors [36] These nicotinic currents are suppressed by the α4β2* competitive antagonist DHβE, insensitive to the α7 antagonist MLA and potentiated by the α5 allosteric modulator galanthamine [36, 88]. Most convincing is the demonstration that nicotinic excitation of layer VI pyramidal cells is substantially reduced in mice in which the α5 subunit has been genetically deleted (α5−/−) [37] Together, these findings highlight that the relatively rare α5 subunit plays an important role in mediating optimal cholinergic excitation of layer VI neurons of the prefrontal cortex, where it is densely expressed and incorporated into α4β2* nicotinic receptors
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