Search

Parkinson's disease (PD) presents with a constellation of non-motor symptoms, notably increased anxiety, which are currently poorly treated and underrepresented in animal models of the disease. Human post-mortem studies report loss of catecholaminergic neurons in the pre-symptomatic phases of PD when anxiety symptoms emerge, and a large literature from rodent and human studies indicate that catecholamines are important mediators of anxiety via their modulatory effects on limbic regions such as the amygdala. On the basis of these observations, we hypothesized that anxiety in PD could result from an early loss of catecholaminergic inputs to the amygdala and/or other limbic structures. To interrogate this hypothesis, we bilaterally injected the neurotoxin 6-OHDA in the mouse basolateral amygdala (BL). This produced a restricted pattern of catecholaminergic (tyrosine-hydroxylase-labeled) denervation in the BL, intercalated cell masses and ventral hippocampus, but not the central amygdala or prefrontal cortex. We found that this circuit-specific lesion did not compromise performance on multiple measures of motor function (home cage, accelerating rotarod, beam balance, pole climbing), but did increase anxiety-like behavior in the elevated plus-maze and light-dark exploration tests. Fear behavior in the pavlovian cued conditioning and passive avoidance assays was, by contrast, unaffected; possibly due to preservation of catecholamine innervation of the central amygdala from the periaqueductal gray. These data provide some of the first evidence implicating loss of catecholaminergic neurotransmission in midbrain-amygdala circuits to increased anxiety-like behavior. Our findings offer an initial step towards identifying the neural substrates for pre-motor anxiety symptoms in PD.

Introduction: Excessive fear generalization has been associated with pathological anxiety, including posttraumatic stress disorder (PTSD). However, studies investigating the longitudinal relationship between generalization and the development of anxiety symptomatology are scarce. This study aims to test the predictive value of fear generalization for PTSD symptoms in a high-risk profession sample and to explore the relationship between generalization and neuroticism, which are both linked to PTSD., Method: Longitudinal data from a multi-wave study in 529 Dutch fire-fighters were used. Fear generalization, PTSD symptoms and neuroticism were assessed at baseline. PTSD symptoms were reevaluated at six, 12, 18, and 24 months. Generalization was assessed in a differential conditioning paradigm by measuring expectancies of an aversive outcome when presented with stimuli similar to previously conditioned stimuli., Results: Higher expectancy ratings towards stimuli most similar to safety signals predicted PTSD symptoms at follow-up after controlling for baseline PTSD symptoms, whereas higher expectancy ratings towards stimuli most similar to danger signals was associated with neuroticism. Neuroticism weakened the predictive power of fear generalization when considered simultaneously., Discussion: These findings suggest that heightened fear generalization is associated with the development of anxiety and trauma-related symptoms. Targeting problematic fear generalization may be a promising intervention approach., Competing Interests: Declaration of Competing Interest None., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

A central question in Pavlovian conditioning concerns the critical conditions that drive the acquisition and maintenance of the stimulus-outcome association. The spatial relationship between the conditioned (CS) and unconditioned (US) stimuli is considered to exert strong effects on learning. However, how spatial information modulates Pavlovian learning remains mostly unexplored in humans. Here, we test how the compatibility between the CS and the US location influences the acquisition, extinction, and recovery (following reinstatement) of Pavlovian conditioned threat. Participants (N = 20) completed a differential threat conditioning task in which visual CSs appeared on the same (compatible) or opposite (incompatible) hemispace as the US delivery (aversive shock to one hand), while their skin conductance response served as an index of learning. Results show that initial threat expectations were biased in favor of compatible CSs before conditioning. Nevertheless, this bias was revised during acquisition to reflect current stimulus-outcome contingencies. Computational modeling suggested that this effect occurred through a higher reliance on positive aversive prediction errors for incompatible CSs, thereby facilitating learning of their association with the US. Additionally, the conditioned response to incompatible CSs was associated with initially slower extinction and a greater recovery after threat reinstatement. These findings suggest that spatial information conveyed by stimuli and outcomes can be flexibly used to enact defensive responses to the current source of danger, highlighting the adaptive nature of Pavlovian learning., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background and Objectives: It is important to be able to learn which stimuli in our surroundings predict aversive outcomes. To maintain emotional well-being, it is similarly important to be able to learn which stimuli predict safety. The ability to discriminate between stimuli that predict danger and safety has been suggested to not only have an emotional component, but also a cognitive one. One such candidate mechanism is mnemonic discrimination (MD), the ability to differentiate between two memories that are similar but not identical. In the present study, we wanted to examine if MD performance helps to explain inter-individual differences in the ability to acquire a differentiated fear response during fear conditioning., Methods: Participants performed a task assessing MD ability, and then underwent a fear conditioning procedure. Fear responses were measured using skin conductance responses (SCRs)., Results: Results revealed no support for MD ability being associated with to which degree a differentiated fear response was acquired, or with the time needed to acquire such a response., Limitations: Our only outcome measurement was SCRs. Future studies need to include fear ratings, expectancy ratings and neural responses. Future studies also need to examine this using a stimulus material where the conditioned stimulus and the safety stimulus are more difficult to distinguish from each other., Conclusions: If MD ability has a role in inhibiting overgeneralization of fear learning, this does not seem to be driven by MD already during the initial learning., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Traumatic experiences, such as conditioned threat, are coded as enduring memories that are frequently subject to generalization, which is characterized by (re-) expression of fear in safe environments. However, the neurobiological mechanisms underlying threat generalization after a traumatic experience and the role of stress hormones in this process remain poorly understood., Methods: We examined the influence of glucocorticoid hormones on the strength and specificity of conditioned fear memory at the level of sparsely distributed dentate gyrus (DG) engram cells in male mice., Results: We found that elevating glucocorticoid hormones after fear conditioning induces a generalized contextual fear response. This was accompanied by a selective and persistent increase in the excitability and number of activated DG granule cells. Selective chemogenetic suppression of these sparse cells in the DG prevented glucocorticoid-induced fear generalization and restored contextual memory specificity, while leaving expression of auditory fear memory unaffected., Conclusions: These results implicate the sparse ensemble of DG engram cells as a critical cellular substrate underlying fear generalization induced by glucocorticoid stress hormones., (Copyright © 2021 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background and Objectives: Attention plays an important role in the treatment of anxiety. Increased attention to threat has been shown to yield improved treatment outcomes in anxious patients following exposure-based therapy. This study examined whether increasing attention to learned stimuli during fear extinction, an experimental analogue for exposure-based treatments, could improve extinction learning and its maintenance., Methods: Sixty-five healthy adults were randomized into experimental or control conditions. All completed a differential fear conditioning task. During extinction, a subtle attentional manipulation was implemented in the experimental group, designed to increase participants' attention to both threat and safety cues. Three days later, an extinction recall test was conducted using the original cues and two perceptually similar morphs., Results: Fear conditioning was achieved in both behavioral and psychophysiological measures. In addition, between-group differences emerged during extinction. The experimental group exhibited increased attention to stimuli and lower fear responses in physiological measure than the control group. Similarly, during extinction recall, the experimental group exhibited lower startle responses than the control group. Last, across groups, attending to the safety cue during extinction was associated with lower self-reported risk of the two generalization morphs displayed during extinction recall., Limitations: Skin conductance response (SCR) was not measured during extinction recall. Future research should include both SCR and additional generalization morphs so as to allow for the examination of more subtle individual differences., Conclusions: Results indicate that the attentional manipulation increased attention allocation to stimuli during extinction; this, in turn, affected fear-related physiological response., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Deficits in associative and Pavlovian learning are thought to lie at the center of anxiety-related disorders. However, the majority of studies have been carried out in adult populations. The aim of this review was to critically examine the behavioral and neuroimaging literature on Pavlovian learning in pediatric anxiety disorders. We conclude that although there is evidence for deficits in Pavlovian processes (e.g., heightened reactivity to safety cues in anxious samples), the extant literature suffers from key methodological and theoretical issues. We conclude with theoretical and methodological recommendations for future research in order to further elucidate the role of Pavlovian learning in the etiology, maintenance, and treatment of pediatric anxiety disorders., (Copyright © 2020 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Domain-specific cognitive training treatments for pediatric anxiety disorders rely on accurate and reliable identification of specific underlying deficits and biases in neurocognitive functions. Once identified, such biases can serve as specific targets for therapeutic intervention. Clinical translations typically reflect mechanized training protocols designed to rectify the identified biases. Here, we review and synthesize research on key neurocognitive processes that emerge as potential targets for specialized cognitive training interventions in pediatric anxiety disorders in the domains of attention, interpretation, error monitoring, working memory, and fear learning. For each domain, we describe the current status of target establishment (i.e., an association between pediatric anxiety and a specific neurocognitive process), and then review extant translational efforts regarding these targets and the evidence supporting their clinical utility in youths. We then localize each of the domains within the path leading to efficacious, evidence-supported treatments for pediatric anxiety, providing a roadmap for future research. The review indicates that specific cognitive targets in pediatric anxiety have been established in all the reviewed domains except for fear learning, where a clear target is yet to be elucidated. In contrast, evidence for clinical efficacy emerged only in the threat-related attention domain, with some preliminary findings in the domains of interpretation and working memory. The path to clinical translation in the domain of error monitoring is yet unclear. Implications and potential avenues for future research and translation are discussed., (Copyright © 2020 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Proteolysis as mediated by one of the major cellular protein degradation pathways, the ubiquitin-proteasome system (UPS), plays an essential role in learning and memory formation. However, the functional relevance of immunoproteasomes in the healthy brain and especially their impact on normal brain function including processes of learning and memory has not been investigated so far. In the present study, we analyzed the phenotypic effects of an impaired immunoproteasome formation using a β5i/LMP7-deficient mouse model in different behavioral paradigms focusing on locomotor activity, exploratory behavior, innate anxiety, startle response, prepulse inhibition, as well as fear and safety conditioning. Overall, our results demonstrate no strong effects of constitutive β5i/LMP7-deficiency on gross locomotor abilities and anxiety-related behavior in general. However, β5i/LMP7-deficient mice expressed more anxiety after mild stress and increased cued fear after fear conditioning. These findings indicate that the basal proper formation of immunoproteasomes and/or at least the expression of β5i/LMP7 in healthy mice seem to be involved in the regulation of anxiety and cued fear levels., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Background and Objectives: Anxiety in adolescence is characterised by disturbances in attentional processes and the overgeneralisation of fear, however, little is known about the combined and reciprocal effects of and between these factors on youth anxiety. The present study investigated whether attention (attention allocation and control) and fear generalisation processes together predict more variance on adolescent anxiety symptoms than each factor in isolation, and explored their interrelations., Methods: 197 adolescents completed a novel conditioning task, which paired balloon cues with mildly aversive or neutral outcomes. A spatial cueing task, and self-report measures of emotional attentional control and anxiety, were also completed., Results: Threat-avoidant attention allocation biases, impaired attention control, and exaggerated fear generalisation together predicted greater variance in anxiety symptoms (55.3%), than each set of fear and attention processes in isolation. Results also provided evidence of an interplay between these factors. Individual differences in threat-avoidant attention allocation biases predicted variability in the generalisation of fear, whilst the association between heightened anxiety and the overgeneralization of fear was moderated by poor attention control., Conclusions: This study provides unique evidence of the combined effects of attention and fear generalisation mechanisms in explaining youth anxiety, and interrelations between these factors. Importantly, results suggested that deficiencies in attention control may bring out anxiety-associated impairments in fear generalisation., Limitations: We relied on self-reported ratings of fear during generalization and also of attention control. Thus demand effects cannot be discounted. Reaction-time measures of attention focus are also indirect assessments of attention that may lack precision., (Copyright © 2018. Published by Elsevier Ltd.)

Fear conditioning and extinction is a construct integral to understanding trauma-, stress- and anxiety-related disorders. In the laboratory, associative learning paradigms that pair aversive with neutral stimuli are used as analogues to real-life fear learning. These studies use physiological indices, such as skin conductance, to sensitively measure rates and intensity of learning and extinction. In this review, we discuss some of the potential limitations in interpreting and analysing physiological data during the acquisition or extinction of conditioned fear. We argue that the utmost attention should be paid to the development of modelling approaches of physiological data in associative learning paradigms, by illustrating the lack of replicability and interpretability of results in current methods. We also show that statistical significance may be easily achieved in this paradigm without more stringent data and data analysis reporting requirements, leaving this particular field vulnerable to misleading conclusions. This review is written so that issues and potential solutions are accessible to researchers without mathematical training. We conclude the review with some suggestions that all laboratories should be able to implement, including visualising the full data set in publications and adopting modelling, or at least regression-based, approaches., (Copyright © 2018 Elsevier B.V. All rights reserved.)

A common challenge in fear conditioning studies is that a relatively large proportion of individuals fail to acquire a differential conditioned skin conductance response (SCR). Researchers have identified demographic factors associated with poorer fear learning and explored the use of different fear conditioning paradigms across various populations. However, few studies have strategically aimed to enhance acquisition by manipulating the unconditioned stimulus (UCS). In the current manuscript, we examined whether demographic factors predicted failure to condition (n = 274) and explored whether modifications to the UCS enhanced fear learning (n = 143). Results indicated that race, but not age, education, or gender, predicted failure to condition. Stepwise logistic regression demonstrated that race was the most influential of these predictors; African Americans were less likely to acquire a conditioned SCR, compared to non-African Americans. Also, use of a compound UCS (i.e., electric shock combined with a scream noise) led to nearly double the rate of acquisition of a conditioned SCR. Hence, use of a compound UCS may provide a way to reduce the number of excluded individuals in studies of fear-conditioned SCR and thereby improve the representativeness of research samples., (Copyright © 2018 Elsevier B.V. All rights reserved.)

In this review article, genetic variation associated with brain responses related to acute and chronic stress reactivity and fear learning in humans is presented as an important mechanism underlying posttraumatic stress disorder. We report that genes related to the regulation of the hypothalamic-pituitary-adrenal axis, as well as genes that modulate serotonergic, dopaminergic, and neuropeptidergic functions or plasticity, play a role in this context. The strong overlap of the genetic targets involved in stress and fear learning suggests that a dimensional and mechanistic model of the development of posttraumatic stress disorder based on these constructs is promising. Genome-wide genetic analyses on fear and stress mechanisms are scarce. So far, reliable replication is still lacking for most of the molecular genetic findings, and the proportion of explained variance is rather small. Further analysis of neurogenetic stress and fear learning needs to integrate data from animal and human studies., (Copyright © 2018 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Associative memory formation is essential for an animal's survival by ensuring adaptive behavioral responses in an ever-changing environment. This is particularly important under conditions of immediate threats such as in fear learning. One of the key brain regions involved in associative fear learning is the amygdala. The basolateral amygdala is the main entry site for sensory information to the amygdala complex, and local plasticity in excitatory basolateral amygdala principal neurons is considered to be crucial for learning of conditioned fear responses. However, activity and plasticity of excitatory circuits are tightly controlled by local inhibitory interneurons in a spatially and temporally defined manner. In this review, we provide an updated view on how distinct interneuron subtypes in the basolateral amygdala contribute to the acquisition and extinction of conditioned fear memories., (Copyright © 2017 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Fear extinction models have a key role in our understanding of anxiety disorders and their treatment with exposure therapy. Here, we tested whether individual differences in fear extinction learning and fear extinction recall in the laboratory were associated with the outcomes of an exposure therapy analog (ETA). Fifty adults with fear of spiders participated in a two-day fear-learning paradigm assessing fear extinction learning and fear extinction recall, and then underwent a brief ETA. Correlational analyses indicated that enhanced extinction learning was associated with better ETA outcome. Our results partially support the idea that individual differences in fear extinction learning may be associated with exposure therapy outcome, but suggest that further research in this area is needed., (Copyright © 2017 Elsevier B.V. All rights reserved.)

The value of common polymorphisms in guiding clinical psychiatry is limited by the complex polygenic architecture of psychiatric disorders. Common polymorphisms have too small an effect on risk for psychiatric disorders as defined by clinical phenomenology to guide clinical practice. To identify polymorphic effects that are large and reliable enough to serve as biomarkers requires detailed analysis of a polymorphism's biology across levels of complexity from molecule to cell to circuit and behavior. Emphasis on behavioral domains rather than clinical diagnosis, as proposed in the Research Domain Criteria framework, facilitates the use of mouse models that recapitulate human polymorphisms because effects on equivalent phenotypes can be translated across species and integrated across levels of analysis. A knockin mouse model of a common polymorphism in the brain-derived neurotrophic factor gene (BDNF) provides examples of how such a vertically integrated translational approach can identify robust genotype-phenotype relationships that have relevance to psychiatric practice., (Copyright © 2016 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

As a variant of the Pavlovian fear conditioning paradigm the conditional discrimination design allows for a detailed investigation of fear acquisition and fear inhibition. Measuring fear-potentiated startle responses, we investigated the influence of two genetic polymorphisms (5-HTTLPR and COMT Val(158)Met) on fear acquisition and fear inhibition which are considered to be critical mechanisms for the etiology and maintenance of anxiety disorders. 5-HTTLPR s-allele carriers showed a more stable potentiation of the startle response during fear acquisition. Homozygous COMT Met-allele carriers, which had demonstrated delayed extinction in previous investigations, show deficient fear inhibition in presence of a learned safety signal. Thus, our results provide further evidence that 5-HTTLPR and COMT Val(158)Met genotypes influence the vulnerability for the development of anxiety disorders via different mechanisms., (Copyright © 2014 Elsevier B.V. All rights reserved.)

The similarity between sickness behavior syndrome (SBS) in infection and autoimmune disorders and certain symptoms in major depressive disorder (MDD), and the high co-morbidity of autoimmune disorders and MDD, constitutes some of the major evidence for the immune-inflammation hypothesis of MDD. CD40 ligand-CD40 immune-activation is important in host response to infection and in development of autoimmunity. Mice given a single intra-peritoneal injection of CD40 agonist antibody (CD40AB) develop SBS for 2-3days characterized by weight loss and increased sleep, effects that are dependent on the cytokine, tumor necrosis factor (TNF). Here we report that CD40AB also induces behavioral effects that extend beyond acute SBS and co-occur with but are not mediated by kynurenine pathway activation and recovery. CD40AB led to decreased saccharin drinking (days 1-7) and decreased Pavlovian fear conditioning (days 5-6), and was without effect on physical fatigue (day 5). These behavioral effects co-occurred with increased plasma and brain levels of kynurenine and its metabolites (days 1-7/8). Co-injection of TNF blocker etanercept with CD40AB prevented each of SBS, reduced saccharin drinking, and kynurenine pathway activation in plasma and brain. Repeated oral administration of a selective indoleamine 2,3-dioxygenase (IDO) inhibitor blocked activation of the kynurenine pathway but was without effect on SBS and saccharin drinking. This study provides novel evidence that CD40-TNF activation induces deficits in saccharin drinking and Pavlovian fear learning and activates the kynurenine pathway, and that CD40-TNF activation of the kynurenine pathway is not necessary for induction of the acute or extended SBS effects., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Generalization of conditioned fear has been implicated in the maintenance and proliferation of fear in anxiety disorders. The role of cognitive processes in generalization of conditioning is an important yet understudied issue. Vervliet et al. (2010) tested generalization of fear to a visual stimulus of a particular color and shape paired with electric shock. Test stimuli shared either the color or shape of the CS+. Prior to conditioning, participants were instructed that either color or shape would be predictive of shock. Generalization was stronger to the stimulus containing the instructed feature, suggesting that instructions impacted generalization of fear. However, the result may also reflect the impact of instructions on attention and learning during the conditioning phase. In the present study, the instructional manipulation was given after the conditioning phase to control for any impact of instructions on learning. A similar result to that reported by Vervliet et al. was observed. On self-reported expectancy of shock, generalization was greater to the test stimulus that included the instructed stimulus feature. The same pattern was observed on skin conductance, although it did not reach statistical significance. The findings indicate that explicitly instructed information affected generalization of conditioned fear independently of any impact on learning, pointing to the role of cognitive processes in human fear generalization. They also support the utility of cognitive therapy approaches, which are employed after fear has already developed, in addressing clinical overgeneralization., (Copyright © 2015. Published by Elsevier Ltd.)