Connectomics of cholinergic circuits: Structural strategies and functional principles across species

Subcortical cholinergic systems are essential neuromodulatory architectures that support attention, arousal, learning, and internal state regulation across vertebrate species, particularly in mammals, where these systems are best characterized.Among these, the basal forebrain (BF) cholinergic system plays a central role, projecting broadly to the cortex, including dense innervation of prefrontal regions involved in executive control. Mapping the connectomics of these circuits, including their projection patterns, structural motifs, and integration within large-scale networks, is critical for understanding how cholinergic modulation shapes brain function in both health and disease. Evidence highlights the early vulnerability of BF cholinergic neurons in neurodegenerative conditions such as Alzheimer’s disease (AD), and related disorders. In AD, selective degeneration of cholinergic projections to the cortex may disrupt local neuronal computation in cholinoceptive areas well before gross cortical atrophy becomes detectable.Beyond disease-related degeneration, the structural rules governing these circuits, including cross-species variation, projection specificity, and connectivity principles, remain incompletely defined. Cross-species comparisons of brain structure and function are particularly valuable for studying evolutionarily conserved neuromodulatory systems such as the cholinergic network. Across mammals, birds, and other vertebrates, basal forebrain cholinergic neurons exhibit both conserved circuit motifs and species-specific expansions that reflect differences in cortical complexity and cognitive demand.These comparative perspectives are being transformed by novel methodologies: viral tracing, single-cell transcriptomics, large-scale connectomics, and whole-brain clearing approaches (e.g., CLARITY, iDISCO) enable high-resolution circuit reconstruction. Meanwhile, ultra-high-field 7 Tesla MRI, receptor-specific PET imaging, and multimodal computational modeling now permit direct translational mapping of these systems in the human brain. Together, these tools make it possible to bridge molecular, circuit-level, and systems neuroscience across species and scales.This Topic welcomes studies that use anatomical, molecular, imaging, and physiological methods to chart subcortical cholinergic organization in model systems and humans. Special interest is given to work that links structural disruption with functional impairment across disease models. We particularly encourage cross-species and translational perspectives, including comparative mapping in rodents, non-human primates, and other species that inform our understanding of the human cholinergic system.Contributions may focus on comparative neuroanatomy, in vivo imaging, molecular profiling, computational modeling, or disease-related degeneration. Integrative studies that link structure to function, especially those bridging circuit-mapping studies in animal models with non-invasive approaches in humans, such as 7 Tesla fMRI, PET imaging, or computational modeling, are particularly welcome.By combining anatomical precision with functional interpretation, this Research Topic aims to provide a timely, mechanistically grounded view of how cholinergic circuits shape, and are shaped by, brain-wide network dynamics. Topic editors: Laszlo Zaborszky, James Mac Shine, Balazs Hangya Source: https://www.frontiersin.org/research-topics/76537/connectomics-of-cholinergic-circuits-structural-strategies-and-functional-principles-across-species