Dual-transmitter systems regulating arousal, attention, learning and memory

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HIGHLIGHTSAcetylcholine and GABA co-transmission may control cortical plasticity and learning.Histamine and GABA co-transmission are necessary for appropriate wakefulness.Orexin and glutamate co-transmission may function to stabilise wakefulness.Relaxin-3 and GABA co-transmission may influence stress-related arousal and behaviours.An array of neuromodulators, including monoamines and neuropeptides, regulate most behavioural and physiological traits. In the past decade, dramatic progress has been made in mapping neuromodulatory circuits, in analysing circuit dynamics, and interrogating circuit function using pharmacogenetic, optogenetic and imaging methods This review will focus on several distinct neural networks (acetylcholine/GABA/glutamate; histamine/GABA; orexin/glutamate; and relaxin-3/GABA) that originate from neural hubs that regulate wakefulness and related attentional and cognitive processes, and highlight approaches that have identified dual transmitter roles in these behavioural functions. Modulation of these different neural networks might be effective treatments of diseases related to arousal/sleep dysfunction and of cognitive dysfunction in psychiatric and neurodegenerative disorders.

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