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This review summarizes the case for investing in adolescence as a period of rapid growth, learning, adaptation, and formational neurobiological development. Adolescence is a dynamic maturational period during which young lives can pivot rapidly—in both negative and positive directions. Scientific progress in understanding adolescent development provides actionable insights into windows of opportunity during which policies can have a positive impact on developmental trajectories relating to health, education, and social and economic success. Given current global changes and challenges that affect adolescents, there is a compelling need to leverage these advances in developmental science to inform strategic investments in adolescent health. Insights into windows of opportunity that will have strong positive impacts on the trajectories of health, education, social and economic success of adolescents are reviewed. Economic essence of adolescence Adolescence is a distinctive developmental period involving rapid growth, learning and neurobiological changes, with the potential for both positive and negative outcomes. This Perspective summarizes our current understanding of developmental processes that occur during adolescence, as well as the learning needed to develop the skills and self-regulatory capacity necessary for becoming independent and integrating into adult society. A more nuanced understanding of the distinctive features of adolescence, especially the enhanced social learning and exploration, may inform policy and interventions seeking to maximize windows of opportunity for shaping the future trajectories of the health, wellbeing and economic success of adolescents.

Dopamine is a critical modulator of both learning and motivation. This presents a problem: how can target cells know whether increased dopamine is a signal to learn or to move? It is often presumed that motivation involves slow (‘tonic’) dopamine changes, while fast (‘phasic’) dopamine fluctuations convey reward prediction errors for learning. Yet recent studies have shown that dopamine conveys motivational value and promotes movement even on subsecond timescales. Here I describe an alternative account of how dopamine regulates ongoing behavior. Dopamine release related to motivation is rapidly and locally sculpted by receptors on dopamine terminals, independently from dopamine cell firing. Target neurons abruptly switch between learning and performance modes, with striatal cholinergic interneurons providing one candidate switch mechanism. The behavioral impact of dopamine varies by subregion, but in each case dopamine provides a dynamic estimate of whether it is worth expending a limited internal resource, such as energy, attention, or time.

The locus coeruleus (LC), or ‘blue spot’, is a small nucleus located deep in the brainstem that provides the far-reaching noradrenergic neurotransmitter system of the brain. This phylogenetically conserved nucleus has proved relatively intractable to full characterization, despite more than 60 years of concerted efforts by investigators. Recently, an array of powerful new neuroscience tools have provided unprecedented access to this elusive nucleus, revealing new levels of organization and function. We are currently at the threshold of major discoveries regarding how this tiny brainstem structure exerts such varied and significant influences over brain function and behaviour. All LC neurons receive inputs related to autonomic arousal, but distinct subpopulations of those neurons can encode specific cognitive processes, presumably through more specific inputs from the forebrain areas. This ability, combined with specific patterns of innervation of target areas and heterogeneity in receptor distributions, suggests that activation of the LC has more specific influences on target networks than had initially been imagined.Major compelling questions about the functional role of the locus coeruleus nucleus that had been difficult to answer, given its remote location and diminutive size, have now become accessible via new neuroscience tools. In this Perspective, 14 investigators provide a historical context for recent discoveries and outline new vistas for investigation.

The amount of mental effort we invest in a task is influenced by the reward we can expect if we perform that task well. However, some of the rewards that have the greatest potential for driving these efforts are partly determined by factors beyond one’s control. In such cases, effort has more limited efficacy for obtaining rewards. According to the Expected Value of Control theory, people integrate information about the expected reward and efficacy of task performance to determine the expected value of control, and then adjust their control allocation (i.e., mental effort) accordingly. Here we test this theory’s key behavioral and neural predictions. We show that participants invest more cognitive control when this control is more rewarding and more efficacious, and that these incentive components separately modulate EEG signatures of incentive evaluation and proactive control allocation. Our findings support the prediction that people combine expectations of reward and efficacy to determine how much effort to invest. People only exert cognitive effort if they think the benefits outweigh the costs. Here, the authors show that people assess these benefits by considering expected rewards and how much their effort matters for obtaining those rewards, and then integrating these to determine how much effort to exert.

The dopamine projection from ventral tegmental area (VTA) to nucleus accumbens (NAc) is critical for motivation to work for rewards and reward-driven learning. How dopamine supports both functions is unclear. Dopamine cell spiking can encode prediction errors, which are vital learning signals in computational theories of adaptive behaviour. By contrast, dopamine release ramps up as animals approach rewards, mirroring reward expectation. This mismatch might reflect differences in behavioural tasks, slower changes in dopamine cell spiking or spike-independent modulation of dopamine release. Here we compare spiking of identified VTA dopamine cells with NAc dopamine release in the same decision-making task. Cues that indicate an upcoming reward increased both spiking and release. However, NAc core dopamine release also covaried with dynamically evolving reward expectations, without corresponding changes in VTA dopamine cell spiking. Our results suggest a fundamental difference in how dopamine release is regulated to achieve distinct functions: broadcast burst signals promote learning, whereas local control drives motivation. The dopamine projection from midbrain dopamine cells to the nucleus accumbens is essential for normal motivation, yet motivation-related changes in nucleus accumbens dopamine release occur independently of dopamine cell firing.

Compulsion is a cardinal symptom of drug addiction (severe substance use disorder). However, compulsion is observed in only a small proportion of individuals who repeatedly seek and use addictive substances. Here, we integrate accounts of the neuropharmacological mechanisms that underlie the transition to compulsion with overarching learning theories, to outline how compulsion develops in addiction. Importantly, we emphasize the conceptual distinctions between compulsive drug-seeking behaviour and compulsive drug-taking behaviour (that is, use). In the latter, an individual cannot stop using a drug despite major negative consequences, possibly reflecting an imbalance in frontostriatal circuits that encode reward and aversion. By contrast, an individual may compulsively seek drugs (that is, persist in seeking drugs despite the negative consequences of doing so) when the neural systems that underlie habitual behaviour dominate goal-directed behavioural systems, and when executive control over this maladaptive behaviour is diminished. This distinction between different aspects of addiction may help to identify its neural substrates and new treatment strategies.Compulsion is a key symptom of drug addiction. In this Review, Lüscher, Robbins and Everitt integrate the neural and psychological mechanisms that underlie the transition to compulsion within a learning theory framework, highlighting the distinctions between compulsive drug taking and compulsive drug seeking.

Motivated behaviors are critically dependent upon arousal but little is known about the neuronal mechanisms that coordinate motivational processes with sleep–wake regulation. The authors demonstrate that VTA dopaminergic neurons, which are central regulators of motivational processes, bidirectionally regulate sleep–wake states and sleep-related nesting behavior. Dopaminergic ventral tegmental area (VTA) neurons are critically involved in a variety of behaviors that rely on heightened arousal, but whether they directly and causally control the generation and maintenance of wakefulness is unknown. We recorded calcium activity using fiber photometry in freely behaving mice and found arousal-state-dependent alterations in VTA dopaminergic neurons. We used chemogenetic and optogenetic manipulations together with polysomnographic recordings to demonstrate that VTA dopaminergic neurons are necessary for arousal and that their inhibition suppresses wakefulness, even in the face of ethologically relevant salient stimuli. Nevertheless, before inducing sleep, inhibition of VTA dopaminergic neurons promoted goal-directed and sleep-related nesting behavior. Optogenetic stimulation, in contrast, initiated and maintained wakefulness and suppressed sleep and sleep-related nesting behavior. We further found that different projections of VTA dopaminergic neurons differentially modulate arousal. Collectively, our findings uncover a fundamental role for VTA dopaminergic circuitry in the maintenance of the awake state and ethologically relevant sleep-related behaviors.

Exercise exerts a wide range of beneficial effects for healthy physiology 1 . However, the mechanisms regulating an individual’s motivation to engage in physical activity remain incompletely understood. An important factor stimulating the engagement in both competitive and recreational exercise is the motivating pleasure derived from prolonged physical activity, which is triggered by exercise-induced neurochemical changes in the brain. Here, we report on the discovery of a gut–brain connection in mice that enhances exercise performance by augmenting dopamine signalling during physical activity. We find that microbiome-dependent production of endocannabinoid metabolites in the gut stimulates the activity of TRPV1-expressing sensory neurons and thereby elevates dopamine levels in the ventral striatum during exercise. Stimulation of this pathway improves running performance, whereas microbiome depletion, peripheral endocannabinoid receptor inhibition, ablation of spinal afferent neurons or dopamine blockade abrogate exercise capacity. These findings indicate that the rewarding properties of exercise are influenced by gut-derived interoceptive circuits and provide a microbiome-dependent explanation for interindividual variability in exercise performance. Our study also suggests that interoceptomimetic molecules that stimulate the transmission of gut-derived signals to the brain may enhance the motivation for exercise. It is demonstrated that the brain circuitry involved in regulating the motivation for physical activity is not strictly central nervous system autonomous but is shaped by peripheral influences that originate in the intestinal microbial community.

Research on defensive behaviour in mammals has in recent years focused on elicited reactions; however, organisms also make active choices when responding to danger. We propose a hierarchical taxonomy of defensive behaviour on the basis of known psychological processes. Included are three categories of reactions (reflexes, fixed reactions and habits) and three categories of goal-directed actions (direct action-outcome behaviours and actions based on implicit or explicit forecasting of outcomes). We then use this taxonomy to guide a summary of findings regarding the underlying neural circuits.

The rhesus macaque is an important model species in several branches of science, including neuroscience, psychology, ethology, and medicine. The utility of the macaque model would be greatly enhanced by the ability to precisely measure behavior in freely moving conditions. Existing approaches do not provide sufficient tracking. Here, we describe OpenMonkeyStudio, a deep learning-based markerless motion capture system for estimating 3D pose in freely moving macaques in large unconstrained environments. Our system makes use of 62 machine vision cameras that encircle an open 2.45 m × 2.45 m × 2.75 m enclosure. The resulting multiview image streams allow for data augmentation via 3D-reconstruction of annotated images to train a robust view-invariant deep neural network. This view invariance represents an important advance over previous markerless 2D tracking approaches, and allows fully automatic pose inference on unconstrained natural motion. We show that OpenMonkeyStudio can be used to accurately recognize actions and track social interactions. The rhesus macaque is an important model species in several branches of science, but the utility of this model would be enhanced by the ability to measure behaviour throughout pose. Here, the authors describe a deep learning-based markerless motion capture system for estimating 3D pose in freely moving macaques.