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

Abstract

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.

Keywords: Acetylcholine; Arousal and attention; GABA; Glutamate; Histamine; Hypocretin; Learning and memory; Orexin; Relaxin-3.

Figure 1. Dual neurotransmitter neural hubs regulating arousal, attention, learning and memory

(A) Basal forebrain (BF) cholinergic projections. Known sites of co-transmission are labelled by dual colour. (B) Histaminergic projections from the tuberomammillary nucleus (TMN). (C) Orexin projections from the lateral hypothalamus (LH). (D) Relaxin-3 projections from the nucleus incertus (NI). Known interactions between these systems are marked by dashed outlines.

Figure 2. Co-release vs co-transmission of acetylcholine and GABA

ACh and GABA may be released from: (A) the same vesicles, (B) separate vesicles in the same terminals, or (C) separate terminals of cholinergic neurons.