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Light-controllable tools provide powerful means to manipulate and interrogate brain function with relatively low invasiveness and high spatiotemporal precision. Although optogenetic approaches permit neuronal excitation or inhibition at the network level, other technologies, such as optopharmacology (also known as photopharmacology) have emerged that provide molecular-level control by endowing light sensitivity to endogenous biomolecules. In this Review, we discuss the challenges and opportunities of photocontrolling native neuronal signalling pathways, focusing on ion channels and neurotransmitter receptors. We describe existing strategies for rendering receptors and channels light sensitive and provide an overview of the neuroscientific insights gained from such approaches. At the crossroads of chemistry, protein engineering and neuroscience, optopharmacology offers great potential for understanding the molecular basis of brain function and behaviour, with promises for future therapeutics.

This review discusses recent advances in optogenetic pharmacology, discussing its potential to manipulate endogenous neuronal signaling proteins. These approaches include caged agonists and antagonists and reversibly photoswitchable ligands. The optical neuroscience revolution is transforming how we study neural circuits. By providing a precise way to manipulate endogenous neuronal signaling proteins, it also has the potential to transform our understanding of molecular neuroscience. Recent advances in chemical biology have produced light-sensitive compounds that photoregulate a wide variety of proteins underlying signaling between and within neurons. Chemical tools for optopharmacology include caged agonists and antagonists and reversibly photoswitchable ligands. These reagents act on voltage-gated ion channels and neurotransmitter receptors, enabling control of neuronal signaling with a high degree of spatial and temporal precision. By covalently attaching photoswitch molecules to genetically tagged proteins, the newly emerging methodology of optogenetic pharmacology allows biochemically precise control in targeted subsets of neurons. Now that the tools for manipulating endogenous neuronal signaling proteins are available, they can be implemented in vivo to enhance our understanding of the molecular bases of brain function and dysfunctions.

Long-term exposure to nicotine alters brain circuits and induces profound changes in decision-making strategies, affecting behaviors both related and unrelated to drug seeking and consumption. Using an intracranial self-stimulation reward-based foraging task, we investigated in mice the impact of chronic nicotine on midbrain dopamine neuron activity and its consequence on the trade-off between exploitation and exploration. Model-based and archetypal analysis revealed substantial inter-individual variability in decision-making strategies, with mice passively exposed to nicotine shifting toward a more exploitative profile compared to non-exposed animals. We then mimicked the effect of chronic nicotine on the tonic activity of dopamine neurons using optogenetics, and found that photo-stimulated mice adopted a behavioral phenotype similar to that of mice exposed to chronic nicotine. Our results reveal a key role of tonic midbrain dopamine in the exploration/exploitation trade-off and highlight a potential mechanism by which nicotine affects the exploration/exploitation balance and decision-making. Chronic nicotine exposure impacts various components of decision-making processes, such as exploratory behaviors. Here, the authors identify the cellular mechanism and show that chronic nicotine exposure increases the tonic activity of VTA dopaminergic neurons and reduces exploration in mice.

Nicotine intake is likely to result from a balance between the rewarding and aversive properties of the drug, yet the individual differences in neural activity that control aversion to nicotine and their adaptation during the addiction process remain largely unknown. Using a two-bottle choice experiment, we observed considerable heterogeneity in nicotine-drinking profiles in isogenic adult male mice, with about half of the mice persisting in nicotine consumption even at high concentrations, whereas the other half stopped consuming. We found that nicotine intake was negatively correlated with nicotine-evoked currents in the interpeduncular nucleus (IPN), and that prolonged exposure to nicotine, by weakening this response, decreased aversion to the drug, and hence boosted consumption. Lastly, using knock-out mice and local gene re-expression, we identified β4-containing nicotinic acetylcholine receptors of IPN neurons as molecular and cellular correlates of nicotine aversion. Collectively, our results identify the IPN as a substrate for individual variabilities and adaptations in nicotine consumption.

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.

Phasic variations in dopamine levels are interpreted as a teaching signal reinforcing rewarded behaviors. However, behavior also depends on the motivational, neuromodulatory effect of phasic dopamine. In this study, we reveal a neurodynamical principle that unifies these roles in a recurrent network-based decision architecture embodied through an action-perception loop with the task space, the MAGNet model. Dopamine optogenetic conditioning in mice was accounted for by an embodied network model in which attractors encode internal goals. Dopamine-dependent synaptic plasticity created “latent” attractors, to which dynamics converged, but only locally. Attractor basins were widened by dopamine-modulated synaptic excitability, rendering goals accessible globally, i.e. from distal positions. We validated these predictions optogenetically in mice: dopamine neuromodulation suddenly and specifically attracted animals toward rewarded locations, without off-target motor effects. We thus propose that motivational dopamine reveals dopamine-built attractors representing potential goals in a behavioral landscape. The reason why manipulating dopamine (DA) activity can affect both action latency, action direction, and movement vigor, but only in certain animal states and behavioral settings is not fully understood. Here, the authors propose that DA signaling builds and reveals latent attractors representing potential goals. They validate their model predictions: activation of dopamine neurons exerts context- and state-dependent effects on mouse movements.

Glutamate is the major excitatory neurotransmitter in the brain, and photochemical release of glutamate (or uncaging) is a chemical technique widely used by biologists to interrogate its physiology. A basic prerequisite of these optical probes is bio-inertness before photolysis. However, all caged glutamates are known to have strong antagonism toward receptors of γ-aminobutyric acid, the major inhibitory transmitter. We have developed a caged glutamate probe that is inert toward these receptors at concentrations that are effective for photolysis with violet light. Pharmacological tests in vitro revealed that attachment of a fifth-generation (G5) dendrimer (i.e., cloaking) to the widely used 4-methoxy-7-nitro-indolinyl(MNI)-Glu probe prevented such off-target effects while not changing the photochemical properties of MNI-Glu significantly. G5-MNI-Glu was used with optofluidic delivery to stimulate dopamine neurons of the ventral tegmental area of freely moving mice in a conditioned placepreference protocol so as to mediate Pavlovian conditioning.

Nicotine activates ventral tegmental area (VTA) dopaminergic (DA) neurons projecting to the nucleus accumbens (NAc) to drive its reinforcing effects. Simultaneously, nicotine inhibits those projecting to the amygdala (Amg) to mediate anxiety-like behavior through a process that remains unknown. Here, we show that in male mice, NAc- and Amg-projecting DA neurons respond with similar polarities to ethanol and nicotine, suggesting a shared network-based mechanism underlying the inhibitory effect of these otherwise pharmacologically-distinct drugs. Selective activation of NAc-projecting DA neurons, using genetic or optogenetic strategies, produced inhibition of Amg-projecting DA neurons, through a GABAergic feedback loop. Furthermore, optogenetically silencing this feedback loop prevented nicotine from inducing both inhibition of DA neurons and anxiety-like behavior. Therefore, nicotine-induced inhibition of the VTA-Amg DA pathway results from a VTA-NAc inhibitory feedback loop, mediating anxiety-like behavior. Drugs of abuse exert both motivational and emotional effects. Here, the authors show that nicotine and ethanol activate a VTA–NAc loop that inhibits dopamine neurons projecting to the amygdala, thereby inducing anxiety-like behavior and linking the reward and emotional circuits.

How nicotine acts on developing neurocircuitry in adolescence to promote later addiction vulnerability remains largely unknown, but may hold the key for informing more effective intervention efforts. We found transient nicotine exposure in early adolescent (PND 21-28) male mice was sufficient to produce a marked vulnerability to nicotine in adulthood (PND 60 + ), associated with disrupted functional connectivity in dopaminergic circuits. These mice showed persistent adolescent-like behavioral and physiological responses to nicotine, suggesting that nicotine exposure in adolescence prolongs an immature, imbalanced state in the function of these circuits. Chemogenetically resetting the balance between the underlying dopamine circuits unmasked the mature behavioral response to acute nicotine in adolescent-exposed mice. Together, our results suggest that the perseverance of a developmental imbalance between dopamine pathways may alter vulnerability profiles for later dopamine-dependent psychopathologies. How nicotine impacts the adolescent development of neural circuitry is not fully understood. Here authors show that early adolescent nicotine exposure in male mice blocked the maturation of nicotine-evoked dopamine signaling, causing an immature, vulnerable behavioral response in adult mice. Restoring their adult-like nicotine-evoked signaling unmasks a mature behavioral response in male mice.

Advances in synthetic chemistry, structural biology, molecular modelling and molecular cloning have enabled the systematic functional manipulation of transmembrane proteins. By combining genetically manipulated proteins with light-sensitive ligands, innately ‘blind’ neurobiological receptors can be converted into photoreceptors, which allows them to be photoregulated with high spatiotemporal precision. Here, we present the optochemical control of neuronal nicotinic acetylcholine receptors (nAChRs) with photoswitchable tethered agonists and antagonists. Using structure-based design, we produced heteromeric α3β4 and α4β2 nAChRs that can be activated or inhibited with deep-violet light, but respond normally to acetylcholine in the dark. The generation of these engineered receptors should facilitate investigation of the physiological and pathological functions of neuronal nAChRs and open a general pathway to photosensitizing pentameric ligand-gated ion channels. Light-sensitive ligands can be used to regulate neurobiological receptors with high spatiotemporal precision. Here, the optochemical control of neuronal nicotinic acetylcholine receptors, using both photoswitchable tethered agonists and antagonists, is described. These rationally designed hybrid photoreceptors will facilitate the investigation of the physiological and pathological functions of nicotinic receptors in the brain.