Grey matter embedding of the cholinergic system

Acetylcholine is an important neurotransmitter for neurodevelopment and brain functioning. Historically, measuring cholinergic effects in living brains required invasive and irradiating procedures, severely limiting our understanding of this system in health and disease. Here, we developed a non-invasive magnetic resonance imaging-based approach to evaluate how cholinergic synapses shape the brains macroanatomical architecture in exploration (n=1113) and replication cohorts (n=587) of healthy adults. Spatial colocalization of presynaptic acetylcholine transporters emphasized a cholinergic basis of grey matter coupling between basal forebrain and its corticopetal projection targets amygdala, insula and cingulate cortices. Unexpectedly, covarying grey matter regions mimicked the density topographies of M1-muscarinic and 4{beta}2-nicotinic receptors beyond predominant target regions and highlighted effect of the brains overall cholinergic neuronal populations. The results establish the basis for non-invasive assessments of cholinergic contributions to neurodegenerative and psychiatric pathologies, and pave the way for neuroimaging-guided pharmacological indications of muscarinic antipsychotics, nicotinic anti-addiction and cholinergic anti-dementia drugs. SummaryCholinergic neurons (Ch1-4) in basal forebrain are the predominant source of acetylcholine in neocortex, amygdala and hippocampus1, 2. While previous studies suggested that grey matter alterations in basal forebrain indicate cholinergic deficits in neurodegenerative and psychiatric pathologies3-11, the molecular basis and correspondence with synaptic cholinergic markers remained poorly understood. In this study, we performed structural covariance and spatial colocalization analyses to understand (1) grey matter coupling with Ch1-4 projection targets and (2) the extent to which this is explained by the synaptic density topography of vesicular acetylcholine transporters, 4{beta}2-nicotinic and M1-muscarinic receptors. Our results confirm basal forebrain grey matter as reliable, sensitive indicator for brain-wide cholinergic innervation but contradict the specificity for corticofugal and fornix projections deriving from Ch1-4 subpopulations. Instead, the topography of coupled grey matter maps the overall landscape of the human cholinergic system2, 12 including the human-enriched but often-disregarded subputaminal nucleus13, brain stem cholinergic projections, muscarinic-driven striatal interneuron locations and nicotinic-driven neocortical effects. We introduce single-participant receptor-specific cholinergic indices for each of above molecular targets. Applied to patients with affected brain health, these indices could help understand the role of acetylcholines molecular targets in neuropsychiatric pathologies and complement pharmacological treatment decisions for drugs against dementia, psychosis and addiction.