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Enduring behavioral changes upon stress exposure involve changes in gene expression sustained by epigenetic modifications in brain circuits, including the mesocorticolimbic pathway. Brahma (BRM) and Brahma Related Gene 1 (BRG1) are ATPase subunits of the SWI/SNF complexes involved in chromatin remodeling, a process essential to enduring plastic changes in gene expression. Here, we show that in mice, social defeat induces changes in BRG1 nuclear distribution. The inactivation of the Brg1/Smarca4 gene within dopamine-innervated regions or the constitutive inactivation of the Brm/Smarca2 gene leads to resilience to repeated social defeat and decreases the behavioral responses to cocaine without impacting midbrain dopamine neurons activity. Within striatal medium spiny neurons, Brg1 gene inactivation reduces the expression of stress- and cocaine-induced immediate early genes, increases levels of heterochromatin and at a global scale decreases chromatin accessibility. Altogether these data demonstrate the pivotal function of SWI/SNF complexes in behavioral and transcriptional adaptations to salient environmental challenges. Repeated exposure to social stressors in rodents results in behavioural changes. Here the authors show that behavioural adaptations to stress are associated with nuclear organization changes through SWI/SNF chromatin remodeler in specific neuronal populations of the mesolimbic system.

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.

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.

In humans, traumatic social experiences can contribute to psychiatric disorders 1 . It is suggested that social trauma impairs brain reward function such that social behaviour is no longer rewarding, leading to severe social avoidance 2 , 3 . In rodents, the chronic social defeat stress (CSDS) model has been used to understand the neurobiology underlying stress susceptibility versus resilience following social trauma, yet little is known regarding its impact on social reward 4 , 5 . Here we show that, following CSDS, a subset of male and female mice, termed susceptible (SUS), avoid social interaction with non-aggressive, same-sex juvenile C57BL/6J mice and do not develop context-dependent social reward following encounters with them. Non-social stressors have no effect on social reward in either sex. Next, using whole-brain Fos mapping, in vivo Ca 2+ imaging and whole-cell recordings, we identified a population of stress/threat-responsive lateral septum neurotensin (NT LS ) neurons that are activated by juvenile social interactions only in SUS mice, but not in resilient or unstressed control mice. Optogenetic or chemogenetic manipulation of NT LS neurons and their downstream connections modulates social interaction and social reward. Together, these data suggest that previously rewarding social targets are possibly perceived as social threats in SUS mice, resulting from hyperactive NT LS neurons that occlude social reward processing. The authors show that, in a chronic social defeat stress rodent model, a subset of male and female mice avoided social interaction with non-aggressive, same-sex juvenile mice and did not develop context-dependent social reward following these encounters.

Anxiety disorders are complex diseases, and often co-occur with depression. It is as yet unclear if a common neural circuit controls anxiety-related behaviors in both anxiety-alone and comorbid conditions. Here, utilizing the chronic social defeat stress (CSDS) paradigm that induces singular or combined anxiety- and depressive-like phenotypes in mice, we show that a ventral tegmental area (VTA) dopamine circuit projecting to the basolateral amygdala (BLA) selectively controls anxiety- but not depression-like behaviors. Using circuit-dissecting ex vivo electrophysiology and in vivo fiber photometry approaches, we establish that expression of anxiety-like, but not depressive-like, phenotypes are negatively correlated with VTA → BLA dopamine neuron activity. Further, our optogenetic studies demonstrate a causal link between such neuronal activity and anxiety-like behaviors. Overall, these data establish a functional role for VTA → BLA dopamine neurons in bi-directionally controlling anxiety-related behaviors not only in anxiety-alone, but also in anxiety-depressive comorbid conditions in mice. Anxiety and depression are highly comorbid, yet the distinct or shared neurobiological correlates of anxiety remain elusive. Here, Morel et al. define that the midbrain projection to the basolateral amygdala control anxiety but not depression.

Heightened aggression is characteristic of multiple neuropsychiatric disorders and can have various negative effects on patients, their families and the public. Recent studies in humans and animals have implicated brain reward circuits in aggression and suggest that, in subsets of aggressive individuals, domination of subordinate social targets is reinforcing. In this study, we showed that, in male mice, orexin neurons in the lateral hypothalamus activated a small population of glutamic acid decarboxylase 2 (GAD2)-expressing neurons in the lateral habenula (LHb) via orexin receptor 2 (OxR2) and that activation of these GAD2 neurons promoted male–male aggression and conditioned place preference for aggression-paired contexts. Moreover, LHb GAD2 neurons were inhibitory within the LHb and dampened the activity of the LHb as a whole. These results suggest that the orexin system is important for the regulation of inter-male aggressive behavior and provide the first functional evidence of a local inhibitory circuit within the LHb.Flanigan et al. show that activation of inhibitory neurons in the lateral habenula by the neuropeptide orexin (hypocretin) promotes both inter-male aggression and conditioned place preference for contexts associated with winning aggressive contests.

The dorsal raphe nucleus (DRN) is known to control aggressive behavior in mice. Here, we found that glutamatergic projections from the lateral habenula (LHb) to the DRN were activated in male mice that experienced pre-exposure to a rival male mouse (“social instigation”) resulting in heightened intermale aggression. Both chemogenetic and optogenetic suppression of the LHb-DRN projection blocked heightened aggression after social instigation in male mice. In contrast, inhibition of this pathway did not affect basal levels of aggressive behavior, suggesting that the activity of the LHb-DRN projection is not necessary for the expression of species-typical aggressive behavior, but required for the increase of aggressive behavior resulting from social instigation. Anatomical analysis showed that LHb neurons synapse on non-serotonergic DRN neurons that project to the ventral tegmental area (VTA), and optogenetic activation of the DRN-VTA projection increased aggressive behaviors. Our results demonstrate that the LHb glutamatergic inputs to the DRN promote aggressive arousal induced by social instigation, which contributes to aggressive behavior by activating VTA-projecting non-serotonergic DRN neurons as one of its potential targets. The dorsal raphe nucleus (DRN) is known to modulate aggressive behaviour in rodents. Here the authors show that glutamatergic projections from the lateral habenula to DRN modulate aggression between male mice.

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.

Those with diabetes mellitus are at high-risk of developing psychiatric disorders, especially mood disorders, yet the link between hyperglycemia and altered motivation has not been thoroughly explored. Here, we characterized value-based decision-making behavior of a streptozocin-induced diabetic mouse model on Restaurant Row, a naturalistic neuroeconomic foraging paradigm capable of behaviorally capturing multiple decision systems known to depend on dissociable neural circuits. Mice made self-paced choices on a daily limited time-budget, accepting or rejecting reward offers based on cost (delays cued by tone pitch) and subjective value (flavors), in a closed-economy system tested across months. We found streptozocin-treated mice disproportionately undervalued less-preferred flavors and inverted their meal-consumption patterns shifted toward a more costly strategy overprioritizing high-value rewards. These foraging behaviors were driven by impairments in multiple decision-making processes, including the ability to deliberate when engaged in conflict and cache the value of the passage of time as sunk costs. Surprisingly, diabetes-induced changes in motivation depended not only on the type of choice being made, but also on the salience of reward-scarcity in the environment. These findings suggest that complex relationships between metabolic dysfunction and dissociable valuation algorithms underlying unique cognitive heuristics and sensitivity to opportunity costs can disrupt distinct computational processes leading to comorbid psychiatric vulnerabilities. A neuroeconomic approach to characterize decision-making behavior reveals alterations in distinct valuation algorithms in a mouse model of diabetes, shedding light on the interaction between metabolic disorders, energy balance, and cognitive heuristics.