Sustained anxiety increases amygdala–dorsomedial prefrontal coupling: a mechanism for maintaining an anxious state in healthy adults

Background

Neuroimaging research has traditionally explored fear and anxiety in response to discrete threat cues (e.g., during fear conditioning). However, anxiety is a sustained aversive state that can persist in the absence of discrete threats. Little is known about mechanisms that maintain anxiety states over a prolonged period. Here, we used a robust translational paradigm (threat of shock) to induce sustained anxiety. Recent translational work has implicated an amygdala–prefrontal cortex (PFC) circuit in the maintenance of anxiety in rodents. To explore the functional homologues of this circuitry in humans, we used a novel paradigm to examine the impact of sustained anticipatory anxiety on amygdala–PFC intrinsic connectivity.

Methods

Task-independent fMRI data were collected in healthy participants during long-duration periods of shock anticipation and safety. We examined intrinsic functional connectivity.

Results

Our study involved 20 healthy participants. During sustained anxiety, amygdala activity was positively coupled with dorsomedial PFC (DMPFC) activity. High trait anxiety was associated with increased amygdala–DMPFC coupling. In addition, induced anxiety was associated with positive coupling between regions involved in defensive responding, and decreased coupling between regions involved in emotional control and the default mode network.

Limitations

Inferences regarding anxious pathology should be made with caution because this study was conducted in healthy participants.

Conclusion

Findings suggest that anticipatory anxiety increases intrinsic amygdala–DMPFC coupling and that the DMPFC may serve as a functional homologue for the rodent prefrontal regions by sustaining anxiety. Future research may use this defensive neural context to identify bio-markers of risk for anxious pathology and target these circuits for therapeutic intervention.     

Anticipation of peer evaluation in anxious adolescents: divergence in neural activation and maturation

Adolescence is the time of peak onset for many anxiety disorders, particularly Social Anxiety Disorder. Research using simulated social interactions consistently finds differential activation in several brain regions in anxious (vs non-anxious) youth, including amygdala, striatum and medial prefrontal cortex. However, few studies examined the anticipation of peer interactions, a key component in the etiology and maintenance of anxiety disorders. Youth completed the Chatroom Task while undergoing functional magnetic resonance imaging. Patterns of neural activation were assessed in anxious and non-anxious youth as they were cued to anticipate social feedback from peers. Anxious participants evidenced greater amygdala activation and rostral anterior cingulate (rACC)↔amygdala coupling than non-anxious participants during anticipation of feedback from peers they had previously rejected; anxious participants also evidenced less nucleus accumbens activation during anticipation of feedback from selected peers. Finally, anxiety interacted with age in rACC: in anxious participants, age was positively associated with activation to anticipated feedback from rejected peers and negatively for selected peers, whereas the opposite pattern emerged for non-anxious youth. Overall, anxious youth showed greater reactivity in anticipation of feedback from rejected peers and thus may ascribe greater salience to these potential interactions and increase the likelihood of avoidance behavior.     

Abnormal attention modulation of fear circuit function in pediatric generalized anxiety disorder

CONTEXT: Considerable work implicates abnormal neural activation and disrupted attention to facial-threat cues in adult anxiety disorders. However, in pediatric anxiety, no research has examined attention modulation of neural response to threat cues. OBJECTIVE: To determine whether attention modulates amygdala and cortical responses to facial-threat cues differentially in adolescents with generalized anxiety disorder and in healthy adolescents. DESIGN: Case-control study. SETTING: Government clinical research institute. PARTICIPANTS: Fifteen adolescents with generalized anxiety disorder and 20 controls. MAIN OUTCOME MEASURES: Blood oxygenation level-dependent signal as measured via functional magnetic resonance imaging. During imaging, participants completed a face-emotion rating task that systematically manipulated attention. RESULTS: While attending to their own subjective fear, patients, but not controls, showed greater activation to fearful faces than to happy faces in a distributed network including the amygdala, ventral prefrontal cortex, and anterior cingulate cortex (P<.05, small-volume corrected, for all). Right amygdala findings appeared particularly strong. Functional connectivity analyses demonstrated positive correlations among the amygdala, ventral prefrontal cortex, and anterior cingulate cortex. CONCLUSIONS: This is the first evidence in juveniles that generalized anxiety disorder-associated patterns of pathologic fear circuit activation are particularly evident during certain attention states. Specifically, fear circuit hyperactivation occurred in an attention state involving focus on subjectively experienced fear. These findings underscore the importance of attention and its interaction with emotion in shaping the function of the adolescent human fear circuit.     

Test–retest reliability of approach‐avoidance conflict decision‐making during functional magnetic resonance imaging in healthy adults

Neural and behavioral mechanisms during approach‐avoidance conflict decision‐making are relevant across various psychiatric disorders, particularly anxiety disorders. Studies using approach‐avoidance conflict paradigms in healthy adults have identified preliminary neural mechanisms, but findings must be replicated and demonstrated as reliable before further application. This study sought to replicate previous findings and examine test–retest reliability of behavioral (approach behavior, reaction time) and neural (regions of interest [ROIs]) responses during an approach‐avoidance conflict task conducted during functional magnetic resonance imaging (fMRI). Thirty healthy adults completed an approach‐avoidance conflict task during fMRI on two occasions (mean interval: 17 days; range: 11–32). Effects of task condition during three task phases (decision‐making, affective outcome and monetary reward) and intraclass correlation coefficients (ICCs) were calculated across time points. Results replicated that approach behavior was modulated by conflict during decision‐making. ROI activations were replicated such that dorsal anterior cingulate cortex (dACC) was modulated by conflict during decision‐making, and dACC, striatum, and anterior insula were modulated by valence during affective outcomes (p''s <.0083). Approach behavior during conflict demonstrated excellent reliability (ICCs ≥.77). Activation of dACC during conflict decision‐making and anterior insula during negative outcomes demonstrated fair reliability (ICCs = .51 and .54), and dACC and striatum activation demonstrated good reliability during negative outcomes (ICCs = .63 and .69). Two additional ROIs (amygdala, left dorsolateral prefrontal cortex) showed good reliability during negative outcomes (ICCs ≥.60). These results characterize several specific behavioral and neuroimaging responses that are replicable and sufficiently reliable during approach‐avoidance conflict decision‐making to support future utility.     

The human dimension: how the prefrontal cortex modulates the subcortical fear response

Numerous studies suggest that the amygdala is critical for the acquisition and expression of fear. Conditioned fear in animals has been considered a good model for human anxiety disorders, but animal models of anxiety have several limitations. Conditioned fear in animals can be directed to a specific stressor and is easily extinguished. Furthermore, animals do not seem to be able to develop the capacity to worry excessively about the future. While animal models are useful and can demonstrate psychiatric illnesses, they do not completely mimic the complex cognitive processes that occur in anxious humans. Thus, we hypothesize that human anxiety disorders are caused at least in part by differential activity in the prefrontal cortex, the brain region that most separates us from our nearest genetic neighbors. The human prefrontal cortex has not only been shown to be more developed than that of other mammals, but it also has unique morphology and gene expression. Neuroimaging studies repeatedly show abnormalities in the prefrontal cortex in anxious individuals. Thus, we suggest that the very same cortical complexity that allows us to produce a vibrant culture is also the seat of anxiety disorders. Interestingly, preclinical studies have shown that the prefrontal cortex inhibits the amygdala. There appears to be a distinction between two classes of anxiety disorders. Those disorders involving intense fear and panic--panic disorder, post-traumatic stress disorder, and phobias--seem to be characterized by an underactivity of the prefrontal cortex, thus disinhibiting the amygdala. Disorders such as generalized anxiety disorder and obsessive-compulsive disorder, which involve worry and rumination, on the other hand, seem to be characterized by an overactivity of the prefrontal cortex. Studies of prefrontal cortical function in psychiatric illness should be a fruitful method for identifying effective treatment approaches.     

Effective emotion regulation strategies improve fMRI and ECG markers of psychopathology in panic disorder: implications for psychological treatment action

Impairments in emotion regulation are thought to have a key role in the pathogenesis of anxiety disorders, but the neurobiological underpinnings contributing to vulnerability remain poorly understood. It has been a long-held view that exaggerated fear is linked to hyperresponsivity of limbic brain areas and impaired recruitment of prefrontal control. However, increasing evidence suggests that prefrontal–cortical networks are hyperactive during threat processing in anxiety disorders. This study directly explored limbic–prefrontal neural response, connectivity and heart-rate variability (HRV) in patients with a severe anxiety disorder during incidental versus intentional emotion regulation. During 3 Tesla functional magnetic resonance imaging, 18 participants with panic disorder and 18 healthy controls performed an emotion regulation task. They either viewed negative images naturally (Maintain), or they were instructed to intentionally downregulate negative affect using previously taught strategies of cognitive reappraisal (Reappraisal). Electrocardiograms were recorded throughout to provide a functional measure of regulation and emotional processing. Compared with controls, patients showed increased neural activation in limbic–prefrontal areas and reduced HRV during incidental emotion regulation (Maintain). During intentional regulation (Reappraisal), group differences were significantly attenuated. These findings emphasize patients'' ability to regulate negative affect if provided with adaptive strategies. They also bring prefrontal hyperactivation forward as a potential mechanism of psychopathology in anxiety disorders. Although these results challenge models proposing impaired allocation of prefrontal resources as a key characteristic of anxiety disorders, they are in line with more recent neurobiological frameworks suggesting that prefrontal hyperactivation might reflect increased utilisation of maladaptive regulation strategies quintessential for anxiety disorders.     

Fear responses to safety cues in anxious adolescents: Preliminary evidence for atypical age-associated trajectories of functional neural circuits

Adolescent anxiety is common and impairing and often persists into adulthood. There is growing evidence that adult anxiety is characterized by abnormal fear responses to threat and safety cues, along with perturbations in fear-related neural circuits. Although some of this work has been extended to adolescents, with promising results, it is not yet clear whether changes in these circuits across developmental age varies between anxious and non-anxious adolescents. Here we used fMRI to examine how age modulates neural responses as adolescents are exposed to threat and safety cues. Participants were 15 anxious and 11 non-anxious adolescents (age 12–17) who completed a fear conditioning paradigm. The paradigm incorporated a threat cue comprising a neutral face which was paired with a fearful, screaming face, a safety cue comprising a different neutral face, and a control stimulus. Across the whole sample, neural activation to the threat cue (relative to the control cue) correlated positively with age in a number of regions, including the dorsal anterior cingulate and bilateral dorsolateral prefrontal cortex (PFC). However, neural activation to the safety cue (relative to the control cue) was modulated differently by age in the two groups: a more positive association between activation and age was observed in the control group compared to the anxious group in various regions including medial and dorsolateral PFC, anterior insula, and amygdala. These findings suggest that maturation of the neural substrates of fear responses to safety cues may be perturbed in anxious adolescents, potentially contributing to the emergence and maintenance of anxiety disorders in adulthood.     

Emotional Context Sculpts Action Goal Representations in the Lateral Frontal Pole

Emotional states provide an ever-present source of contextual information that should inform behavioral goals. Despite the ubiquity of emotional signals in our environment, the neural mechanisms underlying their influence on goal-directed action remains unclear. Prior work suggests that the lateral frontal pole (FPl) is uniquely positioned to integrate affective information into cognitive control representations. We used pattern similarity analysis to examine the content of representations in FPl and interconnected mid-lateral prefrontal and amygdala circuitry. Healthy participants (n = 37; n = 21 females) were scanned while undergoing an event-related Affective Go/No-Go task, which requires goal-oriented action selection during emotional processing. We found that FPl contained conjunctive emotion–action goal representations that were related to successful cognitive control during emotional processing. These representations differed from conjunctive emotion–action goal representations found in the basolateral amygdala. While robust action goal representations were present in mid-lateral prefrontal cortex, they were not modulated by emotional valence. Finally, converging results from functional connectivity and multivoxel pattern analyses indicated that FPl emotional valence signals likely originated from interconnected subgenual anterior cingulate cortex (ACC) (BA25), which was in turn functionally coupled with the amygdala. Thus, our results identify a key pathway by which internal emotional states influence goal-directed behavior.SIGNIFICANCE STATEMENT Optimal functioning in everyday life requires behavioral regulation that flexibly adapts to dynamically changing emotional states. However, precisely how emotional states influence goal-directed action remains unclear. Unveiling the neural architecture that supports emotion–goal integration is critical for our understanding of disorders such as psychopathy, which is characterized by deficits in incorporating emotional cues into goals, as well as mood and anxiety disorders, which are characterized by impaired goal-based emotion regulation. Our study identifies a key circuit through which emotional states influence goal-directed behavior. This circuitry comprised the lateral frontal pole (FPl), which represented integrated emotion–goal information, as well as interconnected amygdala and subgenual ACC, which conveyed emotional signals to FPl.     

Central Amygdala Projections to Lateral Hypothalamus Mediate Avoidance Behavior in Rats

Persistent avoidance of stress-related stimuli following acute stress exposure predicts negative outcomes such as substance abuse and traumatic stress disorders. Previous work using a rat model showed that the central amygdala (CeA) plays an important role in avoidance of a predator odor stress-paired context. Here, we show that CeA projections to the lateral hypothalamus (LH) are preferentially activated in male rats that show avoidance of a predator odor-paired context (termed Avoider rats), that chemogenetic inhibition of CeA-LH projections attenuates avoidance in male Avoider rats, that chemogenetic stimulation of the CeA-LH circuit produces conditioned place avoidance (CPA) in otherwise naive male rats, and that avoidance behavior is associated with intrinsic properties of LH-projecting CeA cells. Collectively, these data show that CeA-LH projections are important for persistent avoidance of stress-related stimuli following acute stress exposure.SIGNIFICANCE STATEMENT This study in rats shows that a specific circuit in the brain [i.e., neurons that project from the central amygdala (CeA) to the lateral hypothalamus (LH)] mediates avoidance of stress-associated stimuli. In addition, this study shows that intrinsic physiological properties of cells in this brain circuit are associated with avoidance of stress-associated stimuli. Further characterization of the CeA-LH circuit may improve our understanding of the neural mechanisms underlying specific aspects of stress-related disorders in humans.     

Prior Cocaine Use Alters the Normal Evolution of Information Coding in Striatal Ensembles during Value-Guided Decision-Making

Substance use disorders (SUDs) are characterized by maladaptive behavior. The ability to properly adjust behavior according to changes in environmental contingencies necessitates the interlacing of existing memories with updated information. This can be achieved by assigning learning in different contexts to compartmentalized “states.” Though not often framed this way, the maladaptive behavior observed in individuals with SUDs may result from a failure to properly encode states because of drug-induced neural alterations. Previous studies found that the dorsomedial striatum (DMS) is important for behavioral flexibility and state encoding, suggesting the DMS may be an important substrate for these effects. Here, we recorded DMS neural activity in cocaine-experienced male rats during a decision-making task where blocks of trials represented distinct states to probe whether the encoding of state and state-related information is affected by prior drug exposure. We found that DMS medium spiny neurons (MSNs) and fast-spiking interneurons (FSIs) encoded such information and that prior cocaine experience disrupted the evolution of representations both within trials and across recording sessions. Specifically, DMS MSNs and FSIs from cocaine-experienced rats demonstrated higher classification accuracy of trial-specific rules, defined by response direction and value, compared with those drawn from sucrose-experienced rats, and these overly strengthened trial-type representations were related to slower switching behavior and reaction times. These data show that prior cocaine experience paradoxically increases the encoding of state-specific information and rules in the DMS and suggest a model in which abnormally specific and persistent representation of rules throughout trials in DMS slows value-based decision-making in well trained subjects.SIGNIFICANCE STATEMENT Substance use disorders (SUDs) may result from a failure to properly encode rules guiding situationally appropriate behavior. The dorsomedial striatum (DMS) is thought to be important for such behavioral flexibility and encoding that defines the situation or “state.” This suggests that the DMS may be an important substrate for the maladaptive behavior observed in SUDs. In the current study, we show that prior cocaine experience results in over-encoding of state-specific information and rules in the DMS, which may impair normal adaptive decision-making in the task, akin to what is observed in SUDs.     

Brain mechanisms of fear extinction: historical perspectives on the contribution of prefrontal cortex.

What brain regions are involved in regulating behavior when the emotional consequence of a stimulus changes from harmful to harmless? One way to address this question is to study the neural mechanisms underlying extinction of Pavlovian fear conditioning, an important form of emotional regulation that has direct relevance to the treatment of human fear and anxiety disorders. In fear extinction, the capacity of a conditioned stimulus to elicit fear is gradually reduced by repeatedly presenting it in the absence of any aversive consequence. In recent years there has been a dramatic increase in research on the brain mechanisms of fear extinction. One region that has received considerable attention as a component of the brain's extinction circuitry is the medial prefrontal cortex (mPFC). In the present article, we review the historical foundations of the modern notion that the mPFC plays a critical role in emotional regulation, a literature that was largely responsible for studies that explored the role of the mPFC in fear extinction. We also consider the role of the mPFC in a broader neural circuit for extinction that includes the amygdala and hippocampus.     

Placing prediction into the fear circuit

Pavlovian fear conditioning depends on synaptic plasticity at amygdala neurons. Here, we review recent electrophysiological, molecular and behavioral evidence suggesting the existence of a distributed neural circuitry regulating amygdala synaptic plasticity during fear learning. This circuitry, which involves projections from the midbrain periaqueductal gray region, can be linked to prediction error and expectation modulation of fear learning, as described by associative and computational learning models. It controls whether, and how much, fear learning occurs by signaling aversive events when they are unexpected. Functional neuroimaging and clinical studies indicate that this prediction circuit is recruited in humans during fear learning and contributes to exposure-based treatments for clinical anxiety. This aversive prediction error circuit might represent a conserved mechanism for regulating fear learning in mammals.     

Vigilance in the laboratory predicts avoidance in the real world: A dimensional analysis of neural,behavioral, and ecological momentary data in anxious youth

Vigilance and avoidance of threat are observed in anxious adults during laboratory tasks, and are posited to have real-world clinical relevance, but data are mixed in anxious youth. We propose that vigilance-avoidance patterns will become evident in anxious youth through a focus on individual differences and real-world strategic avoidance. Decreased functional connectivity between the amygdala and prefrontal cortex (PFC) could play a mechanistic role in this link. 78 clinically anxious youth completed a dot-probe task to assess vigilance to threat while undergoing fMRI. Real-world avoidance was assessed using Ecological Momentary Assessment (EMA) of self-reported suppression and distraction during negative life events. Vigilance toward threat was positively associated with EMA distraction and suppression. Functional connectivity between a right amygdala seed region and dorsomedial and right dorsolateral PFC regions was inversely related to EMA distraction. Dorsolateral PFC-amygdalar connectivity statistically mediated the relationship between attentional vigilance and real-world distraction. Findings suggest anxious youth showing attentional vigilance toward threat are more likely to use suppression and distraction to regulate negative emotions. Reduced PFC control over limbic reactivity is a possible neural substrate of this pattern. These findings lend ecological validity to laboratory vigilance assessments and suggest PFC-amygdalar connectivity is a neural mechanism bridging laboratory and naturalistic contexts.     

The psychobiology of anxiety

When the basic survival mechanism of fear goes awry, the result is often an anxiety disorder. The activation and modulation of the fear system in animals and humans has thus been an active subject of investigation. Neuroimaging studies have attempted to outline which areas of the brain are activated during anxiety-related phenomena; and the amygdala, known for its processing of emotions, has been considered the central relay point for the so-called fear circuit. The amygdala offers ‘upwind’ connections to the higher-order cognitive/psychological modifications of the cortex and subcortex, and ‘downwind’ connections to the physiological HPA neuroendocrine axis. Neurotransmitters assist in the communication and control along this fear circuit. Variations in anatomical activation and/or neurotransmitter action/sensitivity may be responsible for the different types of anxiety disorders, and these variations may partly result from genetic phenotypes and/or neuroendocrine stressors resulting from trauma. Further investigation of this fear system will hopefully lead to various entry points for therapeutic interventions, including medications that work with neurotransmitter systems and/or the HPA axis, as well as therapy that can address cortical fear activation by re-modulating behavioral contexts and psychological interpretations that cause anxiety.     

Maternal Acceptance Moderates Fear Ratings and Avoidance Behavior in Children

Avoidance is a hallmark feature of anxiety disorders, and avoidance-related impairment is often key to meeting diagnostic criteria. In children and adolescents with anxiety disorders, levels of avoidance vary considerably. Using a novel motion-tracking measure of avoidance behavior, we examined whether maternal acceptance, characterized by warm and accepting responses to child feelings and behaviors, moderates the association between fear of spiders and behavioral avoidance of spider stimuli in 103 clinically anxious children. As hypothesized, maternal acceptance significantly moderated children’s avoidance behavior. Child’s fear of spiders was significantly associated with behavioral avoidance when mothers were low in acceptance, as rated by either mothers or children. When mothers were high in acceptance, as rated by either mothers or children, child self-rated fear of spiders was not significantly associated with child avoidance. These are the first results to empirically demonstrate the moderating role of maternal acceptance in anxious children’s avoidance behavior.     

Neural substrates of classically conditioned fear-generalization in humans: a parametric fMRI study

Recent research on classical fear-conditioning in the anxiety disorders has identified overgeneralization of conditioned fear as an important conditioning correlate of anxiety pathology. Unfortunately, only one human neuroimaging study of classically conditioned fear generalization has been conducted, and the neural substrates of this clinically germane process remain largely unknown. The current generalization study employs a clinically validated generalization gradient paradigm, modified for the fMRI environment, to identify neural substrates of classically conditioned generalization that may function aberrantly in clinical anxiety. Stimuli include five rings of gradually increasing size with extreme sizes serving as cues of conditioned danger (CS+) and safety (CS−). The three intermediately sized rings serve as generalization stimuli (GSs) and create a continuum-of-size from CS+ to CS−. Results demonstrate ‘positive’ generalization gradients, reflected by declines in responding as the presented stimulus differentiates from CS+, in bilateral anterior insula, dorsomedial prefrontal cortex, and bilateral inferior parietal lobule. Conversely, ‘negative’ gradients, reflected by inclines in responding as the presented stimulus differentiates from CS+ were instantiated in bilateral ventral hippocampus, ventromedial prefrontal cortex and precuneus cortex. These results as well as those from connectivity analyses are discussed in relation to a working neurobiology of conditioned generalization centered on the hippocampus.     

A systematic review of the neural bases of psychotherapy for anxiety and related disorders

Brain imaging studies over two decades have delineated the neural circuitry of anxiety and related disorders, particularly regions involved in fear processing and in obsessive-compulsive symptoms. The neural circuitry of fear processing involves the amygdala, anterior cingulate, and insular cortex, while cortico-striatal-thalamic circuitry plays a key role in obsessive-compulsive disorder. More recently, neuroimaging studies have examined how psychotherapy for anxiety and related disorders impacts on these neural circuits. Here we conduct a systematic review of the findings of such work, which yielded 19 functional magnetic resonance imaging studies examining the neural bases of cognitive-behavioral therapy (CBT) in 509 patients with anxiety and related disorders. We conclude that, although each of these related disorders is mediated by somewhat different neural circuitry, CBT may act in a similar way to increase prefrontal control of subcortical structures. These findings are consistent with an emphasis in cognitive-affective neuroscience on the potential therapeutic value of enhancing emotional regulation in various psychiatric conditions.     

Neural systems underlying approach and avoidance in anxiety disorders

Approach-avoidance conflict is an important psychological concept that has been used extensively to better understand cognition and emotion. This review focuses on neural systems involved in approach, avoidance, and conflict decision making, and how these systems overlap with implicated neural substrates of anxiety disorders. In particular, the role of amygdala, insula, ventral striatal, and prefrontal regions are discussed with respect to approach and avoidance behaviors. Three specific hypotheses underlying the dysfunction in anxiety disorders are proposed, including: (i) over-representation of avoidance valuation related to limbic overactivation; (ii) under- or over-representation of approach valuation related to attenuated or exaggerated striatal activation respectively; and (iii) insufficient integration and arbitration of approach and avoidance valuations related to attenuated orbitofrontal cortex activation. These dysfunctions can be examined experimentally using versions of existing decision-making paradigms, but may also require new translational and innovative approaches to probe approach-avoidance conflict and related neural systems in anxiety disorders.     

Cell adhesion presence during adolescence controls the architecture of projection-defined prefrontal cortical neurons and reward-related action strategies later in life

Adolescent brain development is characterized by neuronal remodeling in the prefrontal cortex; relationships with behavior are largely undefined. Integrins are cell adhesion factors that link the extracellular matrix with intracellular actin cytoskeleton. We find that β1-integrin presence in the prelimbic prefrontal cortex (PL) during adolescence, but not adulthood, is necessary for mice to select actions based on reward likelihood and value. As such, adult mice that lacked β1-integrin during adolescence failed to modify response strategies when rewards lost value or failed to be delivered. This pattern suggests that β1-integrin-mediated neuronal development is necessary for PL function in adulthood. We next visualized adolescent PL neurons, including those receiving input from the basolateral amygdala (BLA) – thought to signal salience – and projecting to the dorsomedial striatum (DMS) – the striatal output by which the PL controls goal-seeking behavior. Firstly, we found that these projection-defined neurons had a distinct morphology relative to general layer V PL neurons. Secondly, β1-integrin loss triggered the overexpression of stubby-type dendritic spines at the expense of mature spines, including on projection-defined neurons. This phenotype was not observed when β1-integrins were silenced before or after adolescence. Altogether, our experiments localize β1-integrin-mediated cell adhesion within a developing di-synaptic circuit coordinating adaptive action     

Adolescent anxiety disorders and the developing brain: comparing neuroimaging findings in adolescents and adults

Adolescence is the peak period for the incidence of anxiety disorders. Recent findings have revealed the immaturity of neural networks underlying emotional regulation in this population. Brain vulnerability to anxiety in adolescence is related to the unsynchronised development of anxiety-relevant brain functional systems. However, our current knowledge on brain deficits in adolescent anxiety is mainly borrowed from studies on adults. Understanding adolescent-specific brain deficits is essential for developing biomarkers and brain-based therapies targeting adolescent anxiety. This article reviews and compares recent neuroimaging literature on anxiety-related brain structural and functional deficits between adolescent and adult populations, and proposes a model highlighting the differences between adolescence and adulthood in anxiety-related brain networks. This model emphasises that in adolescence the emotional control system tends to be hypoactivated, the fear conditioning system is immature, and the reward and stress response systems are hypersensitive. Furthermore, the striatum’s functional links to the amygdala and the prefrontal cortex are strengthened, while the link between the prefrontal cortex and the amygdala is weakened in adolescence. This model helps to explain why adolescents are vulnerable to anxiety disorders and provides insights into potential brain-based approaches to intervene in adolescent anxiety disorders.