REVIEW Cholinergic Circuitry of the Human Nucleus Basalis and Its Fate in Alzheimer’s Disease M.-Marsel Mesulam* Cognitive Neurology and Alzheimer’s Disease Center, Northwestern University Medical School, Chicago, Illinois 60611 ABSTRACT basomedial limbic structures may underlie its early and The nucleus basalis is located at the confluence of the high vulnerability to the tauopathy and neurofibrillary limbic and reticular activating systems. It receives degeneration of Alzheimer’s disease. The tauopathy in dopaminergic input from the ventral tegmental area/ Ch4 eventually leads to the degeneration of the cholin- substantia nigra, serotonergic input from the raphe ergic axons that it sends to the cerebral cortex. The nuclei, and noradrenergic input from the nucleus locus early involvement of Ch4 has a magnifying effect on coeruleus. Its cholinergic contingent, known as Ch4, Alzheimer’s pathology, because neurofibrillary degenera- provides the principal source of acetylcholine for the tion in a small number of neurons can perturb neuro- cerebral cortex and amygdala. More than half of pre- transmission in all cortical areas. Although the exact synaptic varicosities along its cholinergic axons make contribution of the Ch4 lesion to the cognitive changes traditional synaptic contacts with cortical neurons. Lim- of Alzheimer’s disease remains poorly understood, the bic and paralimbic cortices of the brain receive the cholinergic circuitry of the nucleus basalis is emerging heaviest cholinergic input from Ch4 and are also the as one of the most strategically positioned and behav- principal sources of reciprocal cortical projections back iorally consequential modulatory systems of the human to the nucleus basalis. This limbic affiliation explains cerebral cortex. J. Comp. Neurol. 521:4124–4144, the role of the nucleus basalis in modulating the impact 2013. and memorability of incoming sensory information. The anatomical continuity of the nucleus basalis with other VC 2013 Wiley Periodicals, Inc. INDEXING TERMS: cholinergic circuitry; nucleus basalis; Alzheimer’s disease The human cerebral cortex contains at least 20 bil- ond set includes noradrenergic axons from the nucleus lion neurons spread over 2.5 m2 of surface area (Pak- locus coeruleus, serotonergic axons from the midbrain kenberg and Gundersen, 1997; Tramo et al., 1995). raphe, dopaminergic axons from the ventral tegmental These neurons and the trillions of synaptic contacts area, and cholinergic axons from the nucleus basalis. through which they communicate are ultimately respon- Each of these extrathalamic projections arises from a sible for transforming simple sensations and muscle relatively small nucleus and becomes widely distributed twitches into experiences, memories, and actions. throughout the cortical mantle, where it influences Although most of the underlying detail remains to be properties such as the synaptic impact, valence, fidelity, clarified, it has become axiomatic that different parts of resonance, and perhaps even transcortical routing of the cerebral cortex display different functional special- the incoming information. The cholinergic component of izations and that these differences reflect regional var- iations of afferent and efferent connectivity. The afferent connections of each cortical area can be Grant sponsor: Javits Neuroscience Award from the National Insti- tute of Neurological Disorders and Stroke; Grant number: NS20285; divided into two interacting superclasses: a set of corti- Grant sponsor: Alzheimer’s Disease Center grant from the National cocortical and specific thalamocortical inputs that con- Institute on Aging; Grant number: AG05134. veys the factual content of incoming information (e.g., *CORRESPONDENCE TO: M.-Marsel Mesulam, MD, Cognitive Neurology and Alzheimer’s Disease Center, Northwestern University Medical School, auditory vs. visual, face vs. word, visceral vs. exterocep- 320 East Superior Street, Chicago, IL 60611. tive), and a set of extrathalamic and nonspecific tha- E-mail: [email protected] lamic inputs that modulates the collative properties of Received March 12, 2013; Revised May 11, 2013; Accepted June 28, 2013. these inputs. The extrathalamic contingent of this sec- DOI 10.1002/cne.23415 Published online July 13, 2013 in Wiley Online Library VC 2013 Wiley Periodicals, Inc. (wileyonlinelibrary.com) 4124 The Journal of Comparative Neurology | Research in Systems Neuroscience 521:4124–4144 (2013) Human cholinergic circuitry this extrathalamic subset is by far the most extensive and has been implicated in the modulation of an ever- expanding set of behavioral states, including attention, arousal, memory, learning, and sleep (Berger-Sweeney et al., 1994; Croxson et al., 2011; Karczmar, 1975, 2007; Krnjevic, 1981; Sarter et al., 2009; Thiel et al., 2002). This component of cortical innervation attracted a great deal of research attention, especially in the 1980s and 1990s, a period that witnessed the rise and fall of the cholinergic era in Alzheimer’s disease studies (AD; Mesulam, 2004). On the occasion of this special issue celebrating the contributions of Gary Van Hoesen to neuroanatomy, I thought it would be fitting to prepare a review of this pathway, based predominantly on neuroanatomical experiments that started in collaboration with Gary and that continued for more than 2 decades in my Boston and Chicago laboratories. A comprehensive coverage of Figure 1. Three coronal sections from a rhesus monkey with HRP the rich literature on cholinergic systems is beyond the injected into Brodmann areas 4 and 6. A: The cortical areas scope of this review, so notable limitations had to be within the injection site are blackened. Triangles represent nucleus basalis neurons. B: Camera lucida drawing from section imposed. First, the synopsis is heavily focused on the 2 in A. Open profiles represent AChE-rich perikarya, blackened work of a single laboratory. Second, it is heavily ones indicate double labeling of AChE-rich perikarya with retro- focused on the human brain. Results in the monkey are gradely transported HRP. The original version of this figure was reported only when analogous information is not avail- hand drawn in India ink by Gary Van Hoesen. ac, Anterior com- able for the human brain, and nonprimate species are missure; amg, amygdala; cgs, cingulate sulcus; gp, globus pal- mentioned only if relevant data are not available for the lidus; h, hypothalamus; ic, internal capsule; oc, optic chiasm; pu, putamen; rs, rhinal sulcus; spd, superior precentral dimple; Syl. f., monkey. Third, the review is heavily anatomical and pro- Sylvian fissure. From Mesulam and Van Hoesen (1976) with vides a cursory coverage of the immensely complicated permission. neurophysiology of cholinergic pathways. These impor- tant limitations notwithstanding, the facts that have been chosen for inclusion offer a unitary neuroanatomi- ported tracers in the early 1970s did, in fact, demon- cal overview of cortically projecting cholinergic path- strate monosynaptic projections from basal forebrain ways in the human brain and their response to AD. neurons to the cerebral cortex but without offering additional characterization of their transmitter charac- teristics (Divac, 1975; Kievit and Kuypers, 1975). The SEARCHING FOR THE SOURCE OF specific localization of cholinergic cell bodies that inner- CORTICAL CHOLINERGIC INNERVATION vate the cerebral cortex was made possible by the In the 1920s, Otto Loewi identified acetylcholine combined visualization of the hydrolytic enzyme acetyl- (ACh) as the cardioactive substance released by the cholinesterase (AChE) with retrogradely transported vagus nerve (Loewi, 1921). It took many years of addi- horseradish peroxidase (HRP; Fig. 1). Experiments tional work to establish that ACh was also a neurotrans- based on this methodology in the macaque monkey mitter of the central nervous system. Even 50 years showed that cortically injected HRP led to the retro- after Loewi’s discovery, the cholinergic innervation of grade labeling of AChE-rich basal forebrain neurons the cerebral cortex was poorly understood and even (Mesulam and Van Hoesen, 1976). In time, the sensitiv- questioned (Silver, 1974). During that period cases of ity of the HRP method was improved, and AChE histo- delirium in response to pilocarpine, amnesia in chemistry was replaced by immunolabeling with the response to scopolamine, and electroencephalographic synthetic enzyme of ACh, choline acetyltrasferase (EEG) slowing in response to atropine had strengthened (ChAT), for the more definitive identification of choliner- the belief in the presence of cortical cholinergic neuro- gic neurons (Mesulam et al., 1986). These develop- transmission just as histochemical observations in the ments helped to clarify the anatomical organization of rat and cat had started to point to the basal forebrain cortically projecting cholinergic pathways in the primate as its likely source (Jacobowitz and Palkovits, 1974; brain and to localize their neurons of origin within a Krnjevic and Silver, 1965). The advent of axonally trans- family of basal forebrain cell groups that came to be The Journal of Comparative Neurology | Research in Systems Neuroscience 4125 M.-M. Mesulam Figure 2. Choline acetyltransferase immunohistochemistry in the macaque monkey showing the Ch1–4 cell groups and anteromedial (am), anterolateral (al), intermediodorsal (id), intermedioventral (iv), and posterior (p) sectors of Ch4. Black dot-like profiles represent ChAT- positive neurons.