Is There a Canonical Cortical Circuit for the Cholinergic System? Anatomical Differences Across Common Model Systems

Abstract

Acetylcholine (ACh) is believed to act as a neuromodulator in cortical circuits that support cognition, specifically in processes including learning, memory consolidation, vigilance, arousal and attention. The cholinergic modulation of cortical processes is studied in many model systems including rodents, cats and primates. Further, these studies are performed in cortical areas ranging from the primary visual cortex to the prefrontal cortex and using diverse methodologies. The results of these studies have been combined into singular models of function—a practice based on an implicit assumption that the various model systems are equivalent and interchangeable. However, comparative anatomy both within and across species reveals important differences in the structure of the cholinergic system. Here, we will review anatomical data including innervation patterns, receptor expression, synthesis and release compared across species and cortical area with a focus on rodents and primates. We argue that these data suggest no canonical cortical model system exists for the cholinergic system. Further, we will argue that as a result, care must be taken both in combining data from studies across cortical areas and species, and in choosing the best model systems to improve our understanding and support of human health.

Structure and function of dual‐source cholinergic modulation in early vision

“…In rodents, only a small percentage of basal forebrain neurons are cholinergic (~5%; (Gritti et al, ; Gritti, Mainville, Mancia, & Jones, )). This contrasts greatly with human and nonhuman primates in which, for example, at least 90% of neurons in the nucleus basalis are cholinergic (Mesulam et al, ; Raghanti et al, ; reviewed by Coppola & Disney ()).…”

“…The tasks that are commonly used in rodents to assay cholinergic effects on “attention” would generally be considered vigilance tasks by the community of researchers who study selective attention in the visual system of human and nonhuman primates. When added to the profound species differences between the cholinergic systems of rodents and primates (discussed briefly above and reviewed by Coppola & Disney, ), it is not at all clear that it is possible, or even appropriate, to attempt to merge the vast literature on cholinergic modulation of vigilance and task‐demand with the similarly vast literature on the mechanisms of visual attention in primates (Desimone & Duncan, ; Egeth & Yantis, ; Herrero et al, ; Moore, ; Moore & Zirnsak, ; Reynolds & Chelazzi, ; Treue, ). We will briefly address the evidence for ACh playing a role in attention, or attentive‐like behaviors in primates.…”

Translational implications of the anatomical nonequivalence of functionally equivalent cholinergic circuit motifs

“…From the perspective of using biological research to improve human health, a problem with these efforts is that we have known since the late 1980s that in the basal forebrain of both human and nonhuman primates, that large population of noncholinergic projection neurons likely does not exist (27)(28)(29)(30); reviewed by ref. 31). This is a fascinating species difference because, in general, subcortical nuclei, including the basal forebrain, have not scaled along with the expansion of cortex; they have hyposcaled.…”

“…]), there are differences in basal forebrain composition (discussed above and reviewed by ref. 31), in the pattern of cholinergic innervation of the primary visual cortex (50), and in receptor expression in the visual thalamus (51,52), the afferent pathway from the thalamus to the primary cortex (33,37), and within the intrinsic circuitry of V1 (44).…”

Most calbindin‐immunoreactive neurons, but few calretinin‐immunoreactive neurons, express the m1 acetylcholine receptor in the middle temporal visual area of the macaque monkey

“…This is one of many possible scales on which the modulatory compartmentalization of cortex exists—some are finer grained (such as laminar differences in acetylcholinesterase expression) and others will be coarser (such as differences between frontal and occipital cortices in overall innervation density). Regardless of the scale, a nuanced understanding of the structural determinants of cholinergic function and how they differ both between and within species (Coppola & Disney, ) will be essential if we are to understand when and how neuromodulators contribute to the dynamical control of cortical state.…”