Neuromodulation of neocortical microcircuits is one of the most fascinating
and mysterious aspects of brain physiology. Despite over a century of research,
the neuroscientific community has yet to uncover the fundamental
biological 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 neurons
and synapses, and modulates neural microcircuits to bring about a
reconfiguration of global network states. ACh is known to support cognitive
processes such as learning and memory, and is involved in the regulation
of arousal, attention and sensory processing. While the effects of ACh in
the neocortex have been characterized extensively, integrated knowledge of
its mechanisms of action is lacking. Furthermore, the ways in which ACh
is released from en-passant axons originating in subcortical nuclei are still
debatable. Simulation-based paradigms play an important role in testing
scientific hypotheses, and provide a useful framework to integrate what is
already known and systematically explore previously uncharted territory.
Importantly, data-driven computational approaches highlight gaps in current
knowledge and guide experimental research. To this end, I developed a
multi-scale model of cholinergic innervation of rodent somatosensory cortex
comprising two distinct sets of ascending projections implementing either
synaptic (ST) or volumetric transmission (VT). The model enables the projection
types to be combined in arbitrary proportions, thus permitting investigations
of the relative contributions of these two transmission modalities.
Using our ACh model, we find that the two modes of cholinergic release act
in concert and have powerful desynchronizing effects on microcircuit activity.
Furthermore we show that this modeling framework can be extended
to other neuromodulators, such as dopamine and serotonin, with minimal
constraining data. In summary, our results suggest a more nuanced view of
neuromodulation in which multiple modes of transmitter release - ST vs VT
- are required to produce synergistic functional effects.