HYMNS · Hypothalamic Modulation of Neocortical States

The neocortex is densely innervated by neuromodulatory systems that act through the release of hormones, neuropeptides, and neurotransmitters such as histamine (HA), acetylcholine (ACh), noradrenaline (NA), dopamine (DA), and serotonin (5-HT), which modulate cortical function by diffusely targeting neurons and synapses in neural microcircuits. These neuromodulators regulate shifts between behavioral states such as sleep and wakefulness, or distraction and attention by controlling rhythmic network activity. It is thought that neuromodulators regulate rhythmic activity by controlling the intrinsic characteristics of neuronal networks across different organizational levels – dendritic properties, cellular physiology, synaptic plasticity, and microcircuit dynamics. Recent work has demonstrated that high-frequency “gamma” oscillations (30-80 Hz), which crucially subserve cognitive processes such as attention, learning and memory, are associated with an increase in HA levels in subcortical regions. Altered levels of HA in the neocortex and dysfunction of its receptors have been implicated in the onset of Alzheimer’s and Parkinson’s disease – pathologies whose economic cost to Europe has been estimated at about € 200 billion per year. Despite the importance of HA in brain function and dysfunction, the mechanisms through which it controls neuronal, synaptic, dendritic, and microcircuit activity in the neocortex are unknown. Therefore, the objective of the HYMNS project is to employ an innovative combination of experiments and computational modelling to provide a unifying view of the mechanisms by which HA enables rhythmic microcircuit activity by controlling different organizational levels in the neocortex. The novel methods established in HYMNS will be useful not only for studies of HA but also for future investigations of other neuromodulators.