Extinction of cue-evoked food seeking recruits a GABAergic interneuron ensemble in the dorsal medial prefrontal cortex of mice

Animals must quickly adapt food-seeking strategies to locate nutrient sources in dynamically changing environments. Learned associations between food and environmental cues that predict its availability promote food-seeking behaviors. However, when such cues cease to predict food availability, animals undergo 'extinction' learning, resulting in the inhibition of food-seeking responses. Repeatedly activated sets of neurons, or 'neuronal ensembles', in the dorsal medial prefrontal cortex (dmPFC) are recruited following appetitive conditioning and undergo physiological adaptations thought to encode cue-reward associations. However, little is known about how the recruitment and intrinsic excitability of such dmPFC ensembles are modulated by extinction learning. Here, we used in vivo 2-Photon imaging in male Fos-GFP mice that express green fluorescent protein (GFP) in recently behaviorally-activated neurons to determine the recruitment of activated pyramidal and GABAergic interneuron mPFC ensembles during extinction. During extinction, we revealed a persistent activation of a subset of interneurons which emerged from a wider population of interneurons activated during the initial extinction session. This activation pattern was not observed in pyramidal cells, and extinction learning did not modulate the excitability properties of activated neurons. Moreover, extinction learning reduced the likelihood of reactivation of pyramidal cells activated during the initial extinction session. Our findings illuminate novel neuronal activation patterns in the dmPFC underlying extinction of food-seeking, and in particular, highlight an important role for interneuron ensembles in this inhibitory form of learning

From extinction learning to anxiety treatment: mind the gap

Laboratory models of extinction learning in animals and humans have the potential to illuminate methods for improving clinical treatment of fear-based clinical disorders. However, such translational research often neglects important differences between threat responses in animals and fear learning in humans, particularly as it relates to the treatment of clinical disorders. Specifically, the conscious experience of fear and anxiety, along with the capacity to deliberately engage top-down cognitive processes to modulate that experience, involves distinct brain circuitry and is measured and manipulated using different methods than typically used in laboratory research. This paper will identify how translational research that investigates methods of enhancing extinction learning can more effectively model such elements of human fear learning, and how doing so will enhance the relevance of this research to the treatment of fear-based psychological disorders.Published versio

Extinction learning as pretrauma vulnerability factor of posttraumatic stress:a replication study

BACKGROUND: Learning tasks have been used to predict why some, and not others, develop posttraumatic stress disorder (PTSD) after exposure to a traumatic event. There is some evidence from prospective studies in high risk profession samples that reduced extinction learning might represent a marker or even a vulnerability factor for PTSD development. OBJECTIVE: Since the evidence is scarce, the aim of this study was to perform a conceptual replication of an earlier prospective study, testing whether pretrauma extinction learning predicts later PTSD symptom severity. METHOD: A sample of 529 fire fighters performed a conditioning task at baseline and filled out questionnaires to assess PTSD symptom severity and neuroticism. At six and 12 months follow-up, exposure to stressful events and PTSD symptom severity were measured. RESULTS: Results indicate that previous findings were not replicated: although reduced extinction learning was associated with higher PTSD symptom severity at baseline, extinction learning did not predict PTSD symptom severity at follow-up. Only PTSD symptom severity at baseline and stressor severity predicted PTSD symptom severity at follow-up. CONCLUSIONS: Since earlier findings on the predictive value of pre-trauma extinction learning on PTSD symptom severity were not replicated, extinction learning might not be a general risk factor PTSD for all individuals. More prospective studies including multiple factors seem needed to unravel the complex relationships of these factors influencing PTSD development. HIGHLIGHTS: Reduced extinction learning correlated with higher PTSD symptom severity at baseline. Reduced extinction learning did not predict PTSD symptom severity at follow-up. The predictive effect of pre-trauma extinction learning on PTSD was not replicated

Multimodal evidence for delayed threat extinction learning in adolescence and young adulthood

Previous research in rodents and humans points to an evolutionarily conserved profle of blunted threat extinction learning during adolescence, underpinned by brain structures such as the amygdala and medial prefrontal cortex (mPFC). In this study, we examine age-related efects on the function and structural connectivity of this system in threat extinction learning in adolescence and young adulthood. Younger age was associated with greater amygdala activity and later engagement of the mPFC to learned threat cues as compared to safety cues. Furthermore, greater structural integrity of the uncinate fasciculus, a white matter tract that connects the amygdala and mPFC, mediated the relationship between age and mPFC engagement during extinction learning. These fndings suggest that age-related changes in the structure and function of amygdala-mPFC circuitry may underlie the protracted maturation of threat regulatory precesses

Neuroenhancement of exposure therapy in anxiety disorders

Although exposure-based treatments and anxiolytic medications are more effective than placebo for treating anxiety disorders, there is still considerable room for further improvement. Interestingly, combining these two modalities is usually not more effective than the monotherapies. Recent translational research has identified a number of novel approaches for treating anxiety disorders using agents that serve as neuroenhancers (also known as cognitive enhancers). Several of these agents have been studied to determine their efficacy at improving treatment outcome for patients with anxiety and other psychiatric disorders. In this review, we examine d-cycloserine, yohimbine, cortisol, catecholamines, oxytocin, modafinil, and nutrients such as caffeine and amino fatty acids as potential neuroenhancers. Of these agents, d-cycloserine shows the most promise as an effective neuroenhancer for extinction learning and exposure therapy. Yet, the optimal dosing and dose timing for drug administration remains uncertain. There is partial support for cortisol, catecholamines, yohimbine and oxytocin for improving extinction learning and exposure therapy. There is less evidence to indicate that modafinil and nutrients such as caffeine and amino fatty acids are effective neuroenhancers. More research is needed to determine their long term efficacy and clinical utility of these agents.R34 MH086668 - NIMH NIH HHS; R01 AT007257 - NCCIH NIH HHS; R21 MH101567 - NIMH NIH HHS; R34 MH099311 - NIMH NIH HHS; R21 MH102646 - NIMH NIH HHS; K23 MH100259 - NIMH NIH HHS; R01 MH099021 - NIMH NIH HH

Intolerance of uncertainty predicts fear extinction in amygdala-ventromedial prefrontal cortical circuitry

Background: Coordination of activity between the amygdala and ventromedial prefrontal cortex (vmPFC) is important for fear-extinction learning. Aberrant recruitment of this circuitry is associated with anxiety disorders. Here, we sought to determine if individual differences in future threat uncertainty sensitivity, a potential risk factor for anxiety disorders, underly compromised recruitment of fear extinction circuitry. Twenty-two healthy subjects completed a cued fear conditioning task with acquisition and extinction phases. During the task, pupil dilation, skin conductance response, and functional magnetic resonance imaging were acquired. We assessed the temporality of fear extinction learning by splitting the extinction phase into early and late extinction. Threat uncertainty sensitivity was measured using self-reported intolerance of uncertainty (IU). Results: During early extinction learning, we found low IU scores to be associated with larger skin conductance responses and right amygdala activity to learned threat vs. safety cues, whereas high IU scores were associated with no skin conductance discrimination and greater activity within the right amygdala to previously learned safety cues. In late extinction learning, low IU scores were associated with successful inhibition of previously learned threat, reflected in comparable skin conductance response and right amgydala activity to learned threat vs. safety cues, whilst high IU scores were associated with continued fear expression to learned threat, indexed by larger skin conductance and amygdala activity to threat vs. safety cues. In addition, high IU scores were associated with greater vmPFC activity to threat vs. safety cues in late extinction. Similar patterns of IU and extinction learning were found for pupil dilation. The results were specific for IU and did not generalize to self-reported trait anxiety. Conclusions: Overall, the neural and psychophysiological patterns observed here suggest high IU individuals to disproportionately generalize threat during times of uncertainty, which subsequently compromises fear extinction learning. More broadly, these findings highlight the potential of intolerance of uncertainty-based mechanisms to help understand pathological fear in anxiety disorders and inform potential treatment targets

A dopaminergic switch for fear to safety transitions

Overcoming aversive emotional memories requires neural systems that detect when fear responses are no longer appropriate. The midbrain ventral tegmental area (VTA) dopamine system has been implicated in reward and more broadly in signalling when a better than expected outcome has occurred. This suggests that it may be important in guiding fear to safety transitions. We report that when an expected aversive outcome does not occur, activity in midbrain dopamine neurons is necessary to extinguish behavioral fear responses and engage molecular signalling events in extinction learning circuits. Furthermore, a specific dopamine projection to the nucleus accumbens medial shell is partially responsible for this effect. By contrast, a separate dopamine projection to the medial prefrontal cortex opposes extinction learning. This demonstrates a novel function for the canonical VTA-dopamine reward system and reveals opposing behavioural roles for different dopamine neuron projections in fear extinction learning

A dopaminergic switch for fear to safety transitions

Overcoming aversive emotional memories requires neural systems that detect when fear responses are no longer appropriate so that they can be extinguished. The midbrain ventral tegmental area (VTA) dopamine system has been implicated in reward and more broadly in signaling when a better-than-expected outcome has occurred. This suggests that it may be important in guiding fear to safety transitions. We report that when an expected aversive outcome does not occur, activity in midbrain dopamine neurons is necessary to extinguish behavioral fear responses and engage molecular signaling events in extinction learning circuits. Furthermore, a specific dopamine projection to the nucleus accumbens medial shell is partially responsible for this effect. In contrast, a separate dopamine projection to the medial prefrontal cortex opposes extinction learning. This demonstrates a novel function for the canonical VTA-dopamine reward system and reveals opposing behavioral roles for different dopamine neuron projections in fear extinction learning

Enhancement of psychosocial treatment with D-cycloserine: models, moderators, and future directions

Advances in the understanding of the neurobiology of fear extinction have resulted in the development of d-cycloserine (DCS), a partial glutamatergic N-methyl-D-aspartate agonist, as an augmentation strategy for exposure treatment. We review a decade of research that has focused on the efficacy of DCS for augmenting the mechanisms (e.g., fear extinction) and outcome of exposure treatment across the anxiety disorders. Following a series of small-scale studies offering strong support for this clinical application, more recent larger-scale studies have yielded mixed results, with some showing weak or no effects. We discuss possible explanations for the mixed findings, pointing to both patient and session (i.e., learning experiences) characteristics as possible moderators of efficacy, and offer directions for future research in this area. We also review recent studies that have aimed to extend the work on DCS augmentation of exposure therapy for the anxiety disorders to DCS enhancement of learning-based interventions for addiction, anorexia nervosa, schizophrenia, and depression. Here, we attend to both DCS effects on facilitating therapeutic outcomes and additional therapeutic mechanisms beyond fear extinction (e.g., appetitive extinction, hippocampal-dependent learning).F31 MH103969 - NIMH NIH HHS; K24 DA030443 - NIDA NIH HHS; R34 MH099309 - NIMH NIH HHS; R34 MH086668 - NIMH NIH HHS; R21 MH102646 - NIMH NIH HHS; R34 MH099318 - NIMH NIH HH

Neural Plasticity of Extinction: Relations with Anxiety and Extinction Retention

ABSTRACT NEURAL PLASTICITY OF EXTINCTION LEARNING: RELATIONS WITH ANXIETY AND EXTINCTION RETENTION by Emily L. Belleau The University of Wisconsin-Milwaukee, 2016 Under the Supervision of Associate Professor Christine Larson Anxiety is a significant public health problem characterized by substantial psychological, physical, and economic burden. A key feature of anxiety is the inability to regulate fear. Aberrant extinction of conditioned fear is one prominent model of the etiology of anxiety disorders. Previous studies have shown that the neural circuitry underlying anxiety pathology overlaps with that mediating fear extinction learning. Recently, more precise pathways supporting the expression (CMA-aMCC) and inhibition (BLA-vmPFC) of conditioned fear have been identified, and dysfunction in these pathways has been linked with anxiety. However, this work has focused on examining these pathways at one point in time, outside of the context of learning, and no one has examined plastic changes in functional activity before and after extinction learning. In addition, no one has applied this inquiry to individual differences in anxiety and extinction retention. This gap in knowledge is a problem because deficits in extinction-induced neural plasticity may be a substantial contributing factor to sustained fear responses in anxiety. The aim of this project was to examine changes in the strength of CMA-aMCC and BLA-vmPFC pathways from before to after extinction learning and how this is related to anxiety and retention of extinction. In a more exploratory fashion, I investigated the degree to which extinction-related plasticity varies as a function of white matter integrity within these pathways. Our results indicated that extinction learning is associated with enhanced plasticity in fear inhibition circuits (BLA-vmPFC and CMA-vmPFC). Plasticity in these circuits appears to be intact in high anxious individuals. However, trait anxiety was positively associated with strengthened connectivity in a fear expression pathway (BLA-aMCC). Enhanced plasticity within a fear expression circuit likely contributes to fear inhibition problems, a core feature of anxiety problems