Functionally, anxiety serves to increase vigilance towards aversive stimuli and improve the ability to detect and avoid danger. We have recently shown, for instance, that anxiety increases the ability to a) detect and b) instigate defensive responses towards aversive and not appetitive face stimuli in healthy individuals. This is arguably the key adaptive function of anxiety, yet the neural circuitry underlying this valence-specific effect is unknown. In the present translational study, we sought evidence for the proposition that dorsomedial regions of the prefrontal (DMPFC) and cingulate cortex constitute the human homologue of the rodent prelimbic and are thus associated with increased amygdala responding during this adaptive threat bias in anxiety. To this end, we applied a novel functional connectivity analysis to healthy subjects (N=20) identifying the emotion of fearful and happy faces in an fMRI scanner under anxious (threat of unpredictable foot shock) and non-anxious (safe) conditions. We showed that anxiety significantly increased positive DMPFC-amygdala connectivity during the processing of fearful faces. This effect was a) valence-specific (it was not seen for happy faces), b) paralleled by faster behavioral response to fearful faces, and c) correlated positively with trait anxiety. As such we provide the first experimental support for an anxiety-mediated, valence-specific, DMPFC-amygdala aversive amplification mechanism in healthy humans. This may be homologous to the rodent prelimbic-amygdala circuit and may, given the relationship with trait anxiety, underlie vulnerability to anxiety disorders. This study thus pinpoints a key neural mechanism in adaptive anxiety and highlights its potential link to maladaptive anxiety.

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From job interviews to the heat of battle, it is evident that people think and learn differently when stressed. In fact, learning under stress may have long-term consequences; stress facilitates aversive conditioning and associations learned during extreme stress may result in debilitating emotional responses in posttraumatic stress disorder. The mechanisms underpinning such stress-related associations, however, are unknown. Computational neuroscience has successfully characterized several mechanisms critical for associative learning under normative conditions. One such mechanism, the detection of a mismatch between expected and observed outcomes within the ventral striatum (i.e., "prediction errors"), is thought to be a critical precursor to the formation of new stimulusoutcome associations. An untested possibility, therefore, is that stress may affect learning via modulation of this mechanism. Here we combine a translational model of stress with a cognitive neuroimaging paradigm to demonstrate that stress significantly increases ventral striatum aversive (but not appetitive) prediction error signal. This provides a unique account of the propensity to form threat-related associations under stress with direct implications for our understanding of both normal stress and stress-related disorders.threat of shock | punishment | anxiety | face perception L earning to associate cues with threat is adaptive because it allows future threat to be predicted and avoided (1). However, such associative learning also may lead to haunting and debilitating memories; the smell of stir-fry may evoke painful intrusive memories in Vietnam veterans. How aversive information is integrated to guide adaptive or maladaptive behavior, however, is not well understood. Here, we report that stress increases a key learning mechanism: the neural detection of a mismatch between an expected and observed aversive outcome within the ventral striatum, commonly referred to as the aversive prediction error (PE) signal (1, 2).Neurocomputational and neuroeconomic accounts of cognition posit that stimulus-outcome associations during conditioning are formed via temporal difference learning (1, 3, 4), in which learning depends upon comparing expectation to what is currently happening. New associations, it is argued, are driven by a difference between predicted and actual outcomes (i.e., "prediction errors"), with greater mismatch between expected and actual outcomes evoking greater PE, resulting in greater predictive learning. This mismatch gives rise to phasic dopamine release in the ventral striatum (1, 3-5) for both appetitive and aversive stimuli (1, 2, 6, 7). Little is known, however, about how PE processing might be affected by an organism's emotional state. Stress, for instance, is well known to facilitate aversive conditioning in both humans and animals (8, 9), raising the possibility that aversive PEs also might be increased by stress. This hypothesis, however, is untested. Therefore, here we used a translational stress induction method in healt...

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