Catherine A. Hartley

Changing Fear: The Neurocircuitry of Emotion Regulation

The ability to alter emotional responses as circumstances change is a critical component of normal adaptive behavior and is often impaired in psychological disorders. In this review, we discuss four emotional regulation techniques that have been investigated as means to control fear: extinction, cognitive regulation, active coping, and reconsolidation. For each technique, we review what is known about the underlying neural systems, combining findings from animal models and human neuroscience. The current evidence suggests that these different means of regulating fear depend on both overlapping and distinct components of a fear circuitry.

Anxiety and Decision-Making

Although the everyday decision-making of clinically anxious individuals is clearly influenced by their excessive fear and worry, the relationship between anxiety and decision-making remains relatively unexplored in neuroeconomic studies. In this review, we attempt to explore the role of anxiety in decision-making with a neuroeconomic approach. We first review the neural systems mediating fear and anxiety, which overlap with a network of brain regions implicated in studies of economic decision-making. We then discuss the potential influence of cognitive biases associated with anxiety upon economic choice, focusing on a set of decision-making biases involving choice in the face of potential aversive outcomes. We propose that the neural circuitry supporting fear learning and regulation may mediate the influence of anxiety upon choice and suggest that techniques for altering fear and anxiety may also change decisions.

FAAH genetic variation enhances fronto-amygdala function in mouse and human

Cross-species studies enable rapid translational discovery and produce the broadest impact when both mechanism and phenotype are consistent across organisms. We developed a knock-in mouse that biologically recapitulates a common human mutation in the gene for fatty acid amide hydrolase (FAAH) (C385A; rs324420), the primary catabolic enzyme for the endocannabinoid anandamide. This common polymorphism impacts the expression and activity of FAAH, thereby increasing anandamide levels. Here, we show that the genetic knock-in mouse and human variant allele carriers exhibit parallel alterations in biochemisty, neurocircuitry, and behavior. Specifically, there is reduced FAAH expression associated with the variant allele that selectively enhances fronto-amygdala connectivity and fear extinction learning, and decreases anxiety-like behaviors. These results suggest a gain-of-function in fear regulation and may indicate for whom and for what anxiety symptoms FAAH inhibitors or exposure-based therapies will be most efficacious, bridging an important translational gap between the mouse and human.

Serotonin transporter polyadenylation polymorphism modulates the retention of fear extinction memory

Growing evidence suggests serotonins role in anxiety and depression is mediated by its effects on learned fear associations. Pharmacological and genetic manipulations of serotonin signaling in mice alter the retention of fear extinction learning, which is inversely associated with anxious temperament in mice and humans. Here, we test whether genetic variation in serotonin signaling in the form of a common human serotonin transporter polyadenylation polymorphism (STPP/rs3813034) is associated with spontaneous fear recovery after extinction. We show that the risk allele of this polymorphism is associated with impaired retention of fear extinction memory and heightened anxiety and depressive symptoms. These STPP associations in humans mirror the phenotypic effects of serotonin transporter knockout in mice, highlighting the STPP as a potential genetic locus underlying interindividual differences in serotonin transporter function in humans. Furthermore, we show that the serotonin transporter polyadenylation profile associated with the STPP risk allele is altered through the chronic administration of fluoxetine, a treatment that also facilitates retention of extinction learning. The propensity to form persistent fear associations due to poor extinction recall may be an intermediate phenotype mediating the effects of genetic variation in serotonergic function on anxiety and depression. The consistency and specificity of these data across species provide robust support for this hypothesis and suggest that the little-studied STPP may be an important risk factor for mood and anxiety disorders in humans.

Fear and Anxiety from Principle to Practice: Implications for When to Treat Youth with Anxiety Disorders

To the Editor: Anxiety disorders are the most common psychiatric conditions, affecting as many as 1 in 10 individuals. The diagnosis of anxiety disorders peak during adolescence, a period characterized by pronounced changes in the ability to regulate emotional thoughts and behavior. These changes occur in parallel with development of frontolimbic circuitry captured by the “imbalance model” of adolescence (Figure 1A). Clarifying the nature of neurobehavioral changes during this developmental phase may provide important insight into both the etiology and treatment of anxiety disorders. Figure 1 Fear extinction learning and improvement of anxiety by age. (A) Representative illustration of frontolimbic circuitry, highlighting the earlier developing limbic areas (red) and later developing prefrontal cortex (green) suggested by the imbalance model ...

The neuroscience of adolescent decision-making

Adolescence is a phase of lifespan associated with greater independence, and thus greater demands to make self-guided decisions in the face of risks, uncertainty, and varying proximal and distal outcomes. A new wave of developmental research takes a neuroeconomic approach to specify what decision processes are changing during adolescence, along what trajectory they are changing, and what neurodevelopmental processes support these changes. Evidence is mounting to suggest that multiple decision processes are tuned differently in adolescents and adults including reward reactivity, uncertainty-tolerance, delay discounting, and experiential assessments of value and risk. Unique interactions between prefrontal cortical, striatal, and salience processing systems during adolescence both constrain and amplify various component processes of mature decision-making.

From Creatures of Habit to Goal-Directed Learners: Tracking the Developmental Emergence of Model-Based Reinforcement Learning

Theoretical models distinguish two decision-making strategies that have been formalized in reinforcement-learning theory. A model-based strategy leverages a cognitive model of potential actions and their consequences to make goal-directed choices, whereas a model-free strategy evaluates actions based solely on their reward history. Research in adults has begun to elucidate the psychological mechanisms and neural substrates underlying these learning processes and factors that influence their relative recruitment. However, the developmental trajectory of these evaluative strategies has not been well characterized. In this study, children, adolescents, and adults performed a sequential reinforcement-learning task that enabled estimation of model-based and model-free contributions to choice. Whereas a model-free strategy was apparent in choice behavior across all age groups, a model-based strategy was absent in children, became evident in adolescents, and strengthened in adults. These results suggest that recruitment of model-based valuation systems represents a critical cognitive component underlying the gradual maturation of goal-directed behavior.

Sensitive Periods in Affective Development: Nonlinear Maturation of Fear Learning

At specific maturational stages, neural circuits enter sensitive periods of heightened plasticity, during which the development of both brain and behavior are highly receptive to particular experiential information. A relatively advanced understanding of the regulatory mechanisms governing the initiation, closure, and reinstatement of sensitive period plasticity has emerged from extensive research examining the development of the visual system. In this article, we discuss a large body of work characterizing the pronounced nonlinear changes in fear learning and extinction that occur from childhood through adulthood, and their underlying neural substrates. We draw upon the model of sensitive period regulation within the visual system, and present burgeoning evidence suggesting that parallel mechanisms may regulate the qualitative changes in fear learning across development.

Experiential reward learning outweighs instruction prior to adulthood

Throughout our lives, we face the important task of distinguishing rewarding actions from those that are best avoided. Importantly, there are multiple means by which we acquire this information. Through trial and error, we use experiential feedback to evaluate our actions. We also learn which actions are advantageous through explicit instruction from others. Here, we examined whether the influence of these two forms of learning on choice changes across development by placing instruction and experience in competition in a probabilistic-learning task. Whereas inaccurate instruction markedly biased adults’ estimations of a stimulus’s value, children and adolescents were better able to objectively estimate stimulus values through experience. Instructional control of learning is thought to recruit prefrontal–striatal brain circuitry, which continues to mature into adulthood. Our behavioral data suggest that this protracted neurocognitive maturation may cause the motivated actions of children and adolescents to be less influenced by explicit instruction than are those of adults. This absence of a confirmation bias in children and adolescents represents a paradoxical developmental advantage of youth over adults in the unbiased evaluation of actions through positive and negative experience.

Stressor controllability modulates fear extinction in humans

Traumatic events are proposed to play a role in the development of anxiety disorders, however not all individuals exposed to extreme stress experience a pathological increase in fear. Recent studies in animal models suggest that the degree to which one is able to control an aversive experience is a critical factor determining its behavioral consequences. In this study, we examined whether stressor controllability modulates subsequent conditioned fear expression in humans. Participants were randomly assigned to an escapable stressor condition, a yoked inescapable stressor condition, or a control condition involving no stress exposure. One week later, all participants underwent fear conditioning, fear extinction, and a test of extinction retrieval the following day. Participants exposed to inescapable stress showed impaired fear extinction learning and increased fear expression the following day. In contrast, escapable stress improved fear extinction and prevented the spontaneous recovery of fear. Consistent with the bidirectional controllability effects previously reported in animal models, these results suggest that ones degree of control over aversive experiences may be an important factor influencing the development of psychological resilience or vulnerability in humans.