Cholinergic circuits in cognitive flexibility

Cognitive flexibility, the ability to adjust behavior in response to new and unexpected conditions in the environment, is essential for adaptation to new challenges and survival. The cholinergic system is an important modulator of this complex behavior however, the exact cholinergic circuits involved in this modulation and the precise influence of acetylcholine (ACh) in the process is still not fully understood. Here we review the role of different cholinergic circuits in cognitive flexibility. Strong evidence indicates that cholinergic interneurons (CINs) from the dorsomedial striatum are essential for facilitating the establishment of a new selected strategy; an effect that seems to depend mainly on activation of muscarinic receptors. Cholinergic neurons from the nucleus basalis magnocellularis (nBM), which project to the prefrontal cortex, seem to modulate the initial inhibition of a previously learned strategy, however, this concept is still controversial. Additionally, some studies suggest that basal forebrain cholinergic neurons projecting to the hippocampus, basolateral amygdala, and posterior parietal cortex may also participate on the modulation of cognitive flexibility. We highlight the fact that when investigating effects of ACh on behavioral flexibility, or any other behavior, one has to keep in mind two important particularities of the cholinergic system: (1) Many cholinergic neurons in the brain co-release glutamate or GABA with ACh. Methodologies that rely on neuronal silencing or ablation lead to simultaneous elimination of both neurotransmitters, making interpretation of results complex. (2) The cholinergic gene locus has a unique organization, with the vesicular acetylcholine transporter (VAChT) gene present within the intron between the first and second exons of the choline acetyltransferase (ChAT) gene. Thus, behavioral studies using transgenic animals generated with ChAT bacterial artificial chromosome (BAC) clones should be considered carefully, taking into consideration that these mice may overexpress VAChT and therefore, present a hypercholinergic tone that can be a confounder in behavioral studies.