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Memory reconsolidation interventions offer an exciting alternative to exposure treatment because they may target fear memories directly, thereby preventing relapse. A previous reconsolidation intervention for spider fear abruptly reduced avoidance behaviour, whereas changes in self-reported fear followed later. In this pre-registered placebo-controlled study, we first aimed to conceptually replicate these effects in spider phobia. Second, we investigated whether re-encountering the phobic cue after the reconsolidation intervention is necessary for changes in self-reported fear to occur. Third, we tested whether the window to trigger such changes is time limited. Individuals with spider phobia ( N  = 69) were randomized into three groups and underwent a memory reactivation procedure with a tarantula, followed immediately by propranolol (reconsolidation intervention) or placebo. One reconsolidation intervention group and the placebo group re-encountered spiders two days after treatment in behavioural approach tasks, whereas another reconsolidation intervention group re-encountered spiders after four weeks. Changes in spider avoidance behaviour and self-reported fear were followed for one year. In the short term, the reconsolidation intervention was not more effective than placebo: both conditions benefited from the intervention. In the long term, the reconsolidation intervention was more effective than placebo, but only when the phobic stimulus was re-encountered within days after treatment. Specifically, we found less tarantula avoidance behaviour and self-reported fear over the course of one year when spiders were re-encountered two days after the reconsolidation intervention, but not when the behavioural test was conducted four weeks after the intervention. These findings challenge the idea that a reconsolidation-inspired intervention alone is sufficient to treat clinical fears: Experiencing the behavioural change during the re-encounter within days after the reconsolidation window has closed seems crucial to observe a lasting fear reduction.

Background A dearth of laboratory tests to study actual human approach-avoidance behavior has complicated translational research on anxiety. The elevated plus-maze (EPM) is the gold standard to assess approach-avoidance behavior in rodents. Methods Here, we translated the EPM to humans using mixed reality through a combination of virtual and real-world elements. In two validation studies, we observed participants’ anxiety on a behavioral, physiological, and subjective level. Results Participants reported higher anxiety on open arms, avoided open arms, and showed an activation of endogenous stress systems. Participants’ with high anxiety exhibited higher avoidance. Moreover, open arm avoidance was moderately predicted by participants’ acrophobia and sensation seeking, with opposing influences. In a randomized, double blind, placebo controlled experiment, GABAergic stimulation decreased avoidance of open arms while alpha-2-adrenergic antagonism increased avoidance. Conclusion These findings demonstrate cross-species validity of open arm avoidance as a translational measure of anxiety. We thus introduce the first ecologically valid assay to track actual human approach-avoidance behavior under laboratory conditions.

The basolateral amygdala (BLA) plays essential roles in behaviors motivated by stimuli with either positive or negative valence, but how it processes motivationally opposing information and participates in establishing valence-specific behaviors remains unclear. Here, by targeting Fezf2 -expressing neurons in the BLA, we identify and characterize two functionally distinct classes in behaving mice, the negative-valence neurons and positive-valence neurons, which innately represent aversive and rewarding stimuli, respectively, and through learning acquire predictive responses that are essential for punishment avoidance or reward seeking. Notably, these two classes of neurons receive inputs from separate sets of sensory and limbic areas, and convey punishment and reward information through projections to the nucleus accumbens and olfactory tubercle, respectively, to drive negative and positive reinforcement. Thus, valence-specific BLA neurons are wired with distinctive input–output structures, forming a circuit framework that supports the roles of the BLA in encoding, learning and executing valence-specific motivated behaviors. Zhang et al. report that the BLA contains ‘hardwired’ positive-valence and negative-valence neurons, which each express Fezf2 but have distinct connectivity. These neurons separately drive learning and expression of avoidance or approach behavior.

Avoidance learning encompasses the acquisition of behaviours that enable individuals to evade or withdraw from potentially harmful stimuli, prior to their occurrence. Maladaptive avoidance is a crucial feature of anxiety and trauma-related disorders. In biological and clinical settings, avoidance behaviours usually involve uninstructed, idiosyncratic and complex motor actions. However, there is a lack of laboratory paradigms that allow investigating how such actions are acquired. To fill this gap, we developed a wireless virtual reality platform to investigate avoidance learning in naturalistic settings, with an uncomfortable sound as unconditioned stimulus (US), a physically plausible avoidance action, and allowing for unconstrained movements. This platform, the CogLearn Toolkit for Unity, is publicly available and allows conducting various types of learning experiments with simple text files as input. We validated this platform in an exploration-confirmation approach with five independent experiments. Overall, participants showed successful acquisition of avoidance behaviour in all experiments. In three exploration experiments, we refined the paradigm and identified mean distance from US location during conditioned stimulus (CS) presentation (before US occurs) as a sensitive measure of avoidance. Two confirmation experiments revealed stronger avoidance for CS+ than CS- during avoidance learning, whether or not this phase was preceded by Pavlovian acquisition. Furthermore, we demonstrated reduced avoidance during extinction with instruction to approach CS, but persistent residual avoidance during this phase. We found evidence of reinstatement in one of two confirmation experiments. Overall, our study provides robust evidence supporting the efficacy of our paradigm in studying avoidance learning in conditions of high ecological relevance.

Punishment involves learning about the relationship between behavior and its adverse consequences. Punishment is fundamental to reinforcement learning, decision-making and choice, and is disrupted in psychiatric disorders such as addiction, depression, and psychopathy. However, little is known about the brain mechanisms of punishment and much of what is known is derived from study of superficially similar, but fundamentally distinct, forms of aversive learning such as fear conditioning and avoidance learning. Here we outline the unique conditions that support punishment, the contents of its learning, and its behavioral consequences. We consider evidence implicating GABA and monoamine neurotransmitter systems, as well as corticostriatal, amygdala, and dopamine circuits in punishment. We show how maladaptive punishment processes are implicated in addictions, impulse control disorders, psychopathy, anxiety, and depression and argue that a better understanding of the cellular, circuit, and cognitive mechanisms of punishment will make important contributions to next generation therapeutic approaches.

Social animals detect the affective states of conspecifics and utilize this information to orchestrate social interactions. In a social affective preference text in which experimental adult male rats could interact with either naive or stressed conspecifics, the experimental rats either approached or avoided the stressed conspecific, depending upon the age of the conspecific. Specifically, experimental rats approached stressed juveniles but avoided stressed adults. Inhibition of insular cortex, which is implicated in social cognition, and blockade of insular oxytocin receptors disrupted the social affective behaviors. Oxytocin application increased intrinsic excitability and synaptic efficacy in acute insular cortex slices, and insular oxytocin administration recapitulated the behaviors observed toward stressed conspecifics. Network analysis of c-Fos immunoreactivity in 29 regions identified functional connectivity between insular cortex, prefrontal cortex, amygdala and the social decision-making network. These results implicate insular cortex as a key component in the circuit underlying age-dependent social responses to stressed conspecifics.

The most successful obesity therapeutics, glucagon-like peptide-1 receptor (GLP1R) agonists, cause aversive responses such as nausea and vomiting 1 , 2 , effects that may contribute to their efficacy. Here, we investigated the brain circuits that link satiety to aversion, and unexpectedly discovered that the neural circuits mediating these effects are functionally separable. Systematic investigation across drug-accessible GLP1R populations revealed that only hindbrain neurons are required for the efficacy of GLP1-based obesity drugs. In vivo two-photon imaging of hindbrain GLP1R neurons demonstrated that most neurons are tuned to either nutritive or aversive stimuli, but not both. Furthermore, simultaneous imaging of hindbrain subregions indicated that area postrema (AP) GLP1R neurons are broadly responsive, whereas nucleus of the solitary tract (NTS) GLP1R neurons are biased towards nutritive stimuli. Strikingly, separate manipulation of these populations demonstrated that activation of NTS GLP1R neurons triggers satiety in the absence of aversion, whereas activation of AP GLP1R neurons triggers strong aversion with food intake reduction. Anatomical and behavioural analyses revealed that NTS GLP1R and AP GLP1R neurons send projections to different downstream brain regions to drive satiety and aversion, respectively. Importantly, GLP1R agonists reduce food intake even when the aversion pathway is inhibited. Overall, these findings highlight NTS GLP1R neurons as a population that could be selectively targeted to promote weight loss while avoiding the adverse side effects that limit treatment adherence. The neural circuits in the hindbrain that link satiety and aversion are shown to be separate, raising the possibility of developing obesity drugs without the common side effects of nausea and vomiting.

Emotional learning and memory are functionally and dysfunctionally regulated by the neuromodulatory state of the brain. While the role of excitatory and inhibitory neural circuits mediating emotional learning and its control have been the focus of much research, we are only now beginning to understand the more diffuse role of neuromodulation in these processes. Recent experimental studies of the acetylcholine, noradrenaline and dopamine systems in fear learning and extinction of fear responding provide surprising answers to key questions in neuromodulation. One area of research has revealed how modular organization, coupled with context-dependent coding modes, allows for flexible brain-wide or targeted neuromodulation. Other work has shown how these neuromodulators act in downstream targets to enhance signal-to-noise ratios and gain, as well as to bind distributed circuits through neuronal oscillations. These studies elucidate how different neuromodulatory systems regulate aversive emotional processing and reveal fundamental principles of neuromodulatory function.

Ventral tegmental area (VTA) dopamine neurons have important roles in adaptive and pathological brain functions related to reward and motivation. However, it is unknown whether subpopulations of VTA dopamine neurons participate in distinct circuits that encode different motivational signatures, and whether inputs to the VTA differentially modulate such circuits. Here we show that, because of differences in synaptic connectivity, activation of inputs to the VTA from the laterodorsal tegmentum and the lateral habenula elicit reward and aversion in mice, respectively. Laterodorsal tegmentum neurons preferentially synapse on dopamine neurons projecting to the nucleus accumbens lateral shell, whereas lateral habenula neurons synapse primarily on dopamine neurons projecting to the medial prefrontal cortex as well as on GABAergic (γ-aminobutyric-acid-containing) neurons in the rostromedial tegmental nucleus. These results establish that distinct VTA circuits generate reward and aversion, and thereby provide a new framework for understanding the circuit basis of adaptive and pathological motivated behaviours. Through the use of a combination of state-of-the-art techniques, different populations of ventral tegmental area dopamine neurons in the mouse are shown to form separate circuits with distinct connectivity: neurons receiving input from the laterodorsal tegmentum and lateral habenula are found to mediate reward and aversion, respectively. Control of reward and aversion by midbrain neurons Dopamine neurons in the ventral tegmental area (VTA) are perhaps best known for their reward-related activity, but they can also signal aversion. Here, the authors show that different populations of VTA neurons form separate circuits with distinct connectivity for reward and aversion. Using a combination of state-of-the-art functional anatomical techniques, they find that neurons receiving input from the laterodorsal tegmentum and lateral habenula mediate reward and aversion, respectively.

The ability of the taste system to identify a tastant (what it tastes like) enables animals to recognize and discriminate between the different basic taste qualities 1 , 2 . The valence of a tastant (whether it is appetitive or aversive) specifies its hedonic value and elicits the execution of selective behaviours. Here we examine how sweet and bitter are afforded valence versus identity in mice. We show that neurons in the sweet-responsive and bitter-responsive cortex project to topographically distinct areas of the amygdala, with strong segregation of neural projections conveying appetitive versus aversive taste signals. By manipulating selective taste inputs to the amygdala, we show that it is possible to impose positive or negative valence on a neutral water stimulus, and even to reverse the hedonic value of a sweet or bitter tastant. Remarkably, mice with silenced neurons in the amygdala no longer exhibit behaviour that reflects the valence associated with direct stimulation of the taste cortex, or with delivery of sweet and bitter chemicals. Nonetheless, these mice can still identify and discriminate between tastants, just as wild-type controls do. These results help to explain how the taste system generates stereotypic and predetermined attractive and aversive taste behaviours, and support the existence of distinct neural substrates for the discrimination of taste identity and the assignment of valence. The identity and hedonic value of tastes are encoded in distinct neural substrates; in mice, the amygdala is necessary and sufficient to drive valence-specific behaviours in response to bitter or sweet taste stimuli, and the cortex can independently represent taste identity.