Evolution in Neuromodulation-The Differential Roles of Acetylcholine in Higher Order Association vs. Primary Visual Cortices

Abstract

This review contrasts the neuromodulatory influences of acetylcholine (ACh) on the relatively conserved primary visual cortex (V1), compared to the newly evolved dorsolateral prefrontal association cortex (dlPFC). ACh is critical both for proper circuit development and organization, and for optimal functioning of mature systems in both cortical regions. ACh acts through both nicotinic and muscarinic receptors, which show very different expression profiles in V1 vs. dlPFC, and differing effects on neuronal firing. Cholinergic effects mediate attentional influences in V1, enhancing representation of incoming sensory stimuli. In dlPFC ACh plays a permissive role for network communication. ACh receptor expression and ACh actions in higher visual areas have an intermediate profile between V1 and dlPFC. This changing role of ACh modulation across association cortices may help to illuminate the particular susceptibility of PFC in cognitive disorders, and provide therapeutic targets to strengthen cognition.

Keywords: V1; acetylcholine; cholinergic; muscarinic; neuromodulation; nicotinic; prefrontal cortex.

Figure 1

Cholinergic nuclei and cortical cholinergic projections as detailed in (Mesulam et al., ,; Luiten et al., 1987). (A) The left shows the 8 different cholinergic nuclei in primate brain, referred to as Ch1-8 (see text), and the right image shows the corresponding 6 cholinergic nuclei in rat brain. The 4 nuclei comprising the basal forebrain are Ch1-4. (B) The left shows the specific cortical projection patterns of the four distinct subsections of the Ch4 nucleus corresponding to the Nucleus Baysalis of Meynert (see text), based on those reported by Mesulam et al. (1983a). Ch4 anteromedial primarily projects to the midprincipalis, medial frontal pole, subcallosal gyrus, cingulate, dorsomedial motor cortex, and medal parietal cortex (areas 5 and 7). The anterolateral subsection projects to lateral area 12, frontal operculum, ventral S1, ventral posterior parietal cortex and the amygdala. The intermediate Ch4 region was further divided by Mesulam et al. (1983a) into a dorsal and ventral portion, which are combined here. The combined intermediate region innervates the ventrolateral orbital cortex, insula, periarcuate, posterior principalis, inferior parietal lobule, peristriate visual cortex, inferior temporal cortex, and parahippocampal regions. The posterior Ch4 subsection projects to the auditory association cortex and temporal pole. The right section shows the cortical projections in rodent arising from Ch4, based primarily on those reported by Luiten et al. (1987). In rodent these projections show a gradient pattern with considerable overlap between subsections. The anterior division projects to infralimbic, prelimbic, anterior cingulate, agranular insula, orbitofrontal in some animals, olfactory tubercle, piriform cortex, entorhinal cortex, occipital cortex in some animals, and motor and somatosensory cortex in some animals. This subsection appears to be a transition area between the intermediate region and the HDB (not pictured) which overlaps with all anterior Ch4 projections except amygdala, which HDB does not innervate. The intermediate Ch4 subsection innervates medial and lateral precentral cortex, motor cortex, somatosensory cortex in some animals, agranular insula, and perirhinal regions. The posterior section projects to motor, lateral precentral cortex, somatosensory cortex, temporal cortex, perirhinal cortex, and agranular insula and occipital cortex in some animals. In rodent, all Ch4 subdivisions strongly innervate amygdala. As this review focuses on cholinergic actions in different cortical areas and across species, these cortical projections are of key relevance.

Figure 2

Distribution of cholinergic receptors across cortical regions in primate and their physiological functions. Studies in primate have shown unique patterns of receptor expression for both nicotinic and muscarinic cholinergic receptors between cortical areas. (A) In V1 muscarinic receptors are expressed by GABAergic cells (M1 and M2) or presynaptically (M2), and nicotinic β2-containing receptors are predominantly expressed presynaptically on thalamocortical terminals. Nicotinic α7 receptors are also expressed in V1 but their precise localization is still unclear. (B) In area MT, M1 receptors are expressed by both GABAergic cells and the majority of excitatory pyramidal cells. (C) In layer III of dlPFC, NMDAR-NR2B are found within the PSD of glutamate spine synapses. Muscarinic receptors are found within or near the PSD on spines (M1) or presynaptically on presumed ACh terminals (M2). Nicotinic α7 receptors are also found within or near the PSD on spines in primate layer III dlPFC. The specific distribution pattern of α4β2 receptors in primate PFC is unknown. (D) The effect of nicotinic receptor activation in monkey and tree shrew V1, based on data from Disney et al. (2007) and Bhattacharyya et al. (2012), showing that activation of nicotinic receptors significantly increases gain response in layer IV, but not in other layers. (E) Data from dlPFC based on Yang et al. (2013) showing that nicotinic α7 receptor stimulation enhances Delay cell persistent firing at optimal doses. See text for more details.