Cholinergic Modulation of Cortical Microcircuits Is Layer-Specific: Evidence from Rodent, Monkey and Human Brain

Abstract

Acetylcholine (ACh) signaling shapes neuronal circuit development and underlies specific aspects of cognitive functions and behaviors, including attention, learning, memory and motivation. During behavior, activation of muscarinic and nicotinic acetylcholine receptors (mAChRs and nAChRs) by ACh alters the activation state of neurons, and neuronal circuits most likely process information differently with elevated levels of ACh. In several brain regions, ACh has been shown to alter synaptic strength as well. By changing the rules for synaptic plasticity, ACh can have prolonged effects on and rearrange connectivity between neurons that outlasts its presence. From recent discoveries in the mouse, rat, monkey and human brain, a picture emerges in which the basal forebrain (BF) cholinergic system targets the neocortex with much more spatial and temporal detail than previously considered. Fast cholinergic synapses acting on a millisecond time scale are abundant in the mammalian cerebral cortex, and provide BF cholinergic neurons with the possibility to rapidly alter information flow in cortical microcircuits. Finally, recent studies have outlined novel mechanisms of how cholinergic projections from the BF affect synaptic strength in several brain areas of the rodent brain, with behavioral consequences. This review highlights these exciting developments and discusses how these findings translate to human brain circuitries.

Regulation of cholinergic basal forebrain development, connectivity, and function by neurotrophin receptors

“…cBF neurons have axonal collaterals within all layers of a cortical column, but the modulation is layer specific, and can also vary according to cortical area and species. Examples are provided below and in Table 1 (for recent more comprehensive reviews, see references [105,106]). There is emerging evidence that cBF neurotransmission is particularly important for layer 1 interneurons which express nicotinic and muscarinic acetylcholine receptors (nAchRs and mAchRs, respectively [107,108]).…”

Cholinergic modulation of spatial learning, memory and navigation

“…Second, while there is generally little support for nicotinic postsynaptic effects on pyramidal neurons, as a notable exception, layer 6 pyramidal neurons express the relatively rare α5‐subunit together with β2 in heteromeric nicotinic receptors leading to nicotinic postsynaptic potentials and regulating short‐term plasticity. (Hay, Lambolez, & Tricoire, ; Hedrick & Waters, ; Verhoog et al., ) For detailed description on the distribution and differential impact of cholinergic receptors in the hippocampus and neocortex, see (Dannenberg, Young, & Hasselmo, ; Obermayer, Verhoog, Luchicchi, & Mansvelder, ).…”

Prefrontal cortical ChAT-VIP interneurons provide local excitation by cholinergic synaptic transmission and control attention

“…These interneurons could form a local source of ACh in the neocortex, but despite molecular, morphological and physiological characterizations, technical limitations thus far prevented a direct demonstration of whether ChAT-VIP interneurons release ACh or GABA or both. Moreover, BF cholinergic neurons that project to the neocortex have been shown to form direct point-to-point synapses with several types of neurons in different layers, thereby modulating their activity on a millisecond time scale 20–23 . Activation of ChAT-VIP interneurons can slowly alter local activity of glutamatergic inputs to L2/3 pyramidal neurons 17 , but it is unknown whether ChAT-VIP interneurons do this via direct cholinergic synaptic transmission, or whether they modulate local neuronal activity more diffusely.…”