Neuromodulation of neocortical microcircuitry: a multi-scale framework to model the effects of cholinergic release

Neuromodulation of neocortical microcircuits is one of the most fascinatingand mysterious aspects of brain physiology. Despite over a century of research,the neuroscientific community has yet to uncover the fundamentalbiological organizing principles underlying neuromodulatory release. Phylogenetically,Acetylcholine (ACh) is perhaps the oldest neuromodulator,and one of the most well-studied. ACh regulates the physiology of neuronsand synapses, and modulates neural microcircuits to bring about areconfiguration of global network states. ACh is known to support cognitiveprocesses such as learning and memory, and is involved in the regulationof arousal, attention and sensory processing. While the effects of ACh inthe neocortex have been characterized extensively, integrated knowledge ofits mechanisms of action is lacking. Furthermore, the ways in which AChis released from en-passant axons originating in subcortical nuclei are stilldebatable. Simulation-based paradigms play an important role in testingscientific hypotheses, and provide a useful framework to integrate what isalready known and systematically explore previously uncharted territory.Importantly, data-driven computational approaches highlight gaps in currentknowledge and guide experimental research. To this end, I developed amulti-scale model of cholinergic innervation of rodent somatosensory cortexcomprising two distinct sets of ascending projections implementing eithersynaptic (ST) or volumetric transmission (VT). The model enables the projectiontypes to be combined in arbitrary proportions, thus permitting investigationsof the relative contributions of these two transmission modalities.Using our ACh model, we find that the two modes of cholinergic release actin concert and have powerful desynchronizing effects on microcircuit activity.Furthermore we show that this modeling framework can be extendedto other neuromodulators, such as dopamine and serotonin, with minimalconstraining data. In summary, our results suggest a more nuanced view ofneuromodulation in which multiple modes of transmitter release - ST vs VT- are required to produce synergistic functional effects.