Journal Article

Manipulating midbrain dopamine neurons and reward-related behaviors with light-controllable nicotinic acetylcholine receptors

Naudé, Jérémie, Kramer, Richard H, Mondoloni, Sarah, Lemoine, Damien, Mourot, Alexandre, Pons, Stéphanie, Trauner, Dirk, Durand-de Cuttoli, Romain, Maskos, Uwe, Nguyen, Claire, Marti, Fabio, d'Izarny-Gargas, Thibaut, Faure, Philippe

2018

Overview

Dopamine (DA) neurons of the ventral tegmental area (VTA) integrate cholinergic inputs to regulate key functions such as motivation and goal-directed behaviors. Yet the temporal dynamic range and mechanism of action of acetylcholine (ACh) on the modulation of VTA circuits and reward-related behaviors are not known. Here, we used a chemical-genetic approach for rapid and precise optical manipulation of nicotinic neurotransmission in VTA neurons in living mice. We provide direct evidence that the ACh tone fine-tunes the firing properties of VTA DA neurons through β2-containing (β2*) nicotinic ACh receptors (nAChRs). Furthermore, locally photo-antagonizing these receptors in the VTA was sufficient to reversibly switch nicotine reinforcement on and off. By enabling control of nicotinic transmission in targeted brain circuits, this technology will help unravel the various physiological functions of nAChRs and may assist in the design of novel therapies relevant to neuropsychiatric disorders. Acetylcholine is one of the most abundant chemicals in the brain, with key roles in learning, memory and attention. Neurons throughout the brain use acetylcholine to exchange messages. Acetylcholine binds to two different classes of receptors on neurons: nicotinic and muscarinic. As the name suggests, nicotinic receptors also respond to nicotine, the main addictive substance in tobacco, while muscarinic receptors respond to muscarine, present in certain poisonous mushrooms. Nicotinic and muscarinic receptors each consist of many different subtypes. But standard pharmacology techniques cannot discriminate between the effects of acetylcholine binding to these different subtypes. Likewise, they cannot distinguish between acetylcholine binding to the same receptor subtype on different neurons. Durand-de Cuttoli, Mondoloni et al. have now developed a new nanotechnology that uses light to target specific acetylcholine receptor subtypes in freely moving mice. The technology was tested in a brain region called the VTA, which is part of the brain’s reward system. Experiments showed that when acetylcholine binds to a specific subtype of nicotinic receptors on VTA neurons – called β2-containing receptors – it makes the neurons release the brain's reward signal, dopamine. Switching these receptors on and off changed how the mice responded to nicotine. With the receptors switched on, mice preferred locations associated with nicotine. Switching the receptors off removed this preference. Nicotine may thus be addictive in part because it triggers VTA neurons to release dopamine via its actions on β2-containing nicotinic receptors. This new technology will help reveal the mechanisms of action of acetylcholine and nicotine. Blocking the effects of nicotine at a specific time and place in the mouse brain may uncover the receptors and brain regions that drive nicotine consumption. Smoking remains a major cause of preventable death worldwide. This new approach could help us develop strategies to prevent or treat addiction.

• Publisher: eLife Science Publications, Ltd,eLife Sciences Publications Ltd,eLife Sciences Publication,eLife Sciences Publications, Ltd
• Subject: acetylcholine / Acetylcholine receptors (nicotinic) / Action Potentials - drug effects / Action Potentials - physiology / Action Potentials - radiation effects / Addiction / Addictions / Animals / Brain / Cardiotonic agents / Cell Line / Circuits / Dopamine / Dopamine receptors / Dopaminergic Neurons - drug effects / Dopaminergic Neurons - metabolism / Dopaminergic Neurons - radiation effects / Life Sciences / Ligands / Light / Mental disorders / Mesencephalon / Mesencephalon - cytology / Mice, Inbred C57BL / Motivation / Mushrooms / Nanotechnology / Nervous system agents / Nervous system diseases / Neurons / Neuroscience / Neurosciences / Neurotransmission / Nicotine / Nicotine - pharmacology / Novels / optogenetics / Pharmacology / Phenols (Class of compounds) / photopharmacology / Receptor mechanisms / Receptors, Nicotinic - metabolism / Reinforcement / Reward / Signal Transduction - radiation effects / Technology / Ventral Tegmental Area - drug effects / Ventral Tegmental Area - metabolism / Ventral Tegmental Area - radiation effects / Ventral tegmentum