Adverse childhood experiences (ACEs) are a major risk factor for the development of multiple psychopathological conditions, but the mechanisms underlying this link are poorly understood. Associative learning encompasses key mechanisms through which individuals learn to link important environmental inputs to emotional and behavioral responses. ACEs may impact the normative maturation of associative learning processes, resulting in their enduring maladaptive expression manifesting in psychopathology. In this review, we lay out a systematic and methodological overview and integration of the available evidence of the proposed association between ACEs and threat and reward learning processes. We summarize results from a systematic literature search (following PRISMA guidelines) which yielded a total of 81 articles (threat: n=38, reward: n=43). Across the threat and reward learning fields, behaviorally, we observed a converging pattern of aberrant learning in individuals with a history of ACEs, independent of other sample characteristics, specific ACE types, and outcome measures. Specifically, blunted threat learning was reflected in reduced discrimination between threat and safety cues, primarily driven by diminished responding to conditioned threat cues. Furthermore, attenuated reward learning manifested in reduced accuracy and learning rate in tasks involving acquisition of reward contingencies. Importantly, this pattern emerged despite substantial heterogeneity in ACE assessment and operationalization across both fields. We conclude that blunted threat and reward learning may represent a mechanistic route by which ACEs may become physiologically and neurobiologically embedded and ultimately confer greater risk for psychopathology. In closing, we discuss potentially fruitful future directions for the research field, including methodological and ACE assessment considerations.

Apolipoprotein-E4 (ApoE4) is an important genetic risk factor for Alzheimer\'s disease. The development of targeted-replacement human ApoE knock-in mice facilitates research into mechanisms by which ApoE4 affects the brain. We performed meta-analyses and meta-regression analyses to examine differences in cognitive performance between ApoE4 and ApoE3 mice. We included 61 studies in which at least one of the following tests was assessed: Morris Water Maze (MWM), novel object location (NL), novel object recognition (NO) and Fear Conditioning (FC) test. ApoE4 vs. ApoE3 mice performed significantly worse on the MWM (several outcomes, 0.17 ≤ g ≤ 0.60), NO (exploration, g=0.33; index, g=0.44) and FC (contextual, g=0.49). ApoE4 vs. ApoE3 differences were not systematically related to sex or age. We conclude that ApoE4 knock-in mice in a non-AD condition show some, but limited cognitive deficits, regardless of sex and age. These effects suggest an intrinsic vulnerability in ApoE4 mice that may become more pronounced under additional brain load, as seen in neurodegenerative diseases.

BACKGROUND: We conducted a meta-analysis and qualitative review on the randomized controlled trials investigating the effects of transcranial direct current stimulation and transcranial magnetic stimulation on fear extinction and the return of fear in non-primate animals and humans.
METHODS: The meta-analysis was conducted by searching PubMed, Web of science, PsycINFO, and Cochrane Library and extracting fear response in the active and sham groups in the randomized controlled trials. The pooled effect size was quantified by Hedges\' g using a three-level meta-analytic model in R.
RESULTS: We identified 18 articles on the tDCS effect and 5 articles on the TMS effect, with 466 animal subjects and 621 human subjects. Our findings show that tDCS of the prefrontal cortex significantly inhibit fear retrieval in animal models (Hedges\' g = -0.50). In human studies, TMS targeting the dorsolateral/ventromedial prefrontal cortex has an inhibiting effect on the return of fear (Hedges\' g = -0.24).
CONCLUSIONS: The limited number of studies and the heterogeneous designs of the selected studies made cross-study and cross-species comparison difficult.
CONCLUSIONS: Our findings shed light on the optimal non-invasive brain stimulation protocols for targeting the neural circuitry of threat extinction in humans.

Dopamine, a catecholamine neurotransmitter, has historically been associated with the encoding of reward, whereas its role in aversion has received less attention. Here, we systematically gathered the vast evidence of the role of dopamine in the simplest forms of aversive learning: classical fear conditioning and extinction. In the past, crude methods were used to augment or inhibit dopamine to study its relationship with fear conditioning and extinction. More advanced techniques such as conditional genetic, chemogenic and optogenetic approaches now provide causal evidence for dopamine\'s role in these learning processes. Dopamine neurons encode conditioned stimuli during fear conditioning and extinction and convey the signal via activation of D1-4 receptor sites particularly in the amygdala, prefrontal cortex and striatum. The coordinated activation of dopamine receptors allows for the continuous formation, consolidation, retrieval and updating of fear and extinction memory in a dynamic and reciprocal manner. Based on the reviewed literature, we conclude that dopamine is crucial for the encoding of classical fear conditioning and extinction and contributes in a way that is comparable to its role in encoding reward.

BACKGROUND: Selective serotonin reuptake inhibitors (SSRIs) are considered first-line medication for anxiety-like disorders such as panic disorder, generalized anxiety disorder, and post-traumatic stress disorder. Fear learning plays an important role in the development and treatment of these disorders. Yet, the effect of SSRIs on fear learning are not well known.
OBJECTIVE: We aimed to systematically review the effect of six clinically effective SSRIs on acquisition, expression, and extinction of cued and contextual conditioned fear.
METHODS: We searched the Medline and Embase databases, which yielded 128 articles that met the inclusion criteria and reported on 9 human and 275 animal experiments.
RESULTS: Meta-analysis showed that SSRIs significantly reduced contextual fear expression and facilitated extinction learning to cue. Bayesian-regularized meta-regression further suggested that chronic treatment exerts a stronger anxiolytic effect on cued fear expression than acute treatment. Type of SSRI, species, disease-induction model, and type of anxiety test used did not seem to moderate the effect of SSRIs. The number of studies was relatively small, the level of heterogeneity was high, and publication bias has likely occurred which may have resulted in an overestimation of the overall effect sizes.
CONCLUSIONS: This review suggests that the efficacy of SSRIs may be related to their effects on contextual fear expression and extinction to cue, rather than fear acquisition. However, these effects of SSRIs may be due to a more general inhibition of fear-related emotions. Therefore, additional meta-analyses on the effects of SSRIs on unconditioned fear responses may provide further insight into the actions of SSRIs.

OBJECTIVE: Fear conditioning is an important aspect in the pathophysiology of anxiety disorders. The fear-potentiated startle test is based on classical fear conditioning and over the years, a broad range of drugs have been tested in this test. Synthesis of the available data may further our understanding of the neurotransmitter systems that are involved in the expression of conditioned fear.
METHODS: Following a comprehensive search in Medline and Embase, we included 68 research articles that reported on 103 drugs, covering 56 different drug classes. The systematic review was limited to studies using acute, systemic drug administration in naive animals.
RESULTS: Qualitative data synthesis showed that most clinically active anxiolytics, but not serotonin-reuptake inhibitors, reduced cued fear. Anxiogenic drugs increased fear potentiation in 35% of the experiments, reduced fear potentiation in 29% of the experiments, and were without effect in 29% of the experiments. Meta-analyses could be performed for five drug classes and showed that benzodiazepines, buspirone, 5-HT1A agonists, 5-HT1A antagonists, and mGluR2,3 agonists reduced cued conditioned fear. The non-cued baseline startle response, which may reflect contextual anxiety, was only significantly reduced by benzodiazepines and 5-HT1A antagonists. No associations were found between drug effects and methodological characteristics, except for strain.
CONCLUSIONS: The fear-potentiated startle test appears to have moderate to high predictive validity and may serve as a valuable tool for the development of novel anxiolytics. Given the limited available data, the generally low study quality and high heterogeneity additional studies are warranted to corroborate the findings of this review.

Some previous research has shown stronger acquisition and impaired extinction of fear conditioned to angry or fearful compared to happy or neutral face conditional stimuli (CS) - a difference attributed to biological \'preparedness\'. A systematic review and meta-analysis of fear conditioning studies comparing face CSs of differing expressions identified thirty studies, eighteen of which were eligible for meta-analysis. Skin conductance responses were larger to angry or fearful faces compared to happy or neutral faces during habituation, acquisition and extinction. Significant differences in differential conditioning between angry, fearful, neutral, and happy face CSs were also found, but differences were more prominent between angry and neutral faces compared to angry/fearful and happy faces. This is likely due to lower arousal elicited by neutral compared to happy faces, which may be more salient as CSs. The findings suggest there are small to moderate differences in differential conditioning when angry or fearful compared to happy or neutral faces are used as CSs. These findings have implications for fear conditioning study design and the preparedness theory.

The serotonergic system is involved in diverse cognitive functions including memory. Of particular importance to daily life are declarative memories that contain information about personal experiences, general facts, and events. Several psychiatric or neurological diseases, such as depression, attention-deficit-hyperactivity disorder (ADHD), and dementia, show alterations in serotonergic signalling and attendant memory disorders. Nevertheless, understanding serotonergic neurotransmission and its influence on memory remained a challenge until today. In this systematic review, we summarize recent psychopharmacological studies in animals and humans from a psychological memory perspective, in consideration of task-specific requirements. This approach has the advantage that comparisons between serotonin (5-HT)-related neurochemical mechanisms and manipulations are each addressing specific mnemonic circuits. We conclude that applications of the same 5-HT-related treatments can differentially affect unrelated tasks of declarative memories. Moreover, the analysis of specific mnemonic phases (e.g., encoding vs. consolidation) reveals opposing impacts of increased or decreased 5-HT tones, with low 5-HT supporting spatial encoding but impairing the consolidation of objects and verbal memories. Promising targets for protein synthesis-dependent consolidation enhancements include 5-HT4 receptor agonists and 5-HT6 receptor antagonists, with the latter being of special interest for the treatment of age-related decline. Further implications are pointed out as base for the development of novel therapeutic targets for memory impairment of neuropsychiatric disorders.

The use of pupillometry to track emotional learning processes in humans is generating an increasing interest. Here, we provide a first systematic review and meta-analysis on the value of pupil dilation as a marker of Pavlovian conditioning, focusing on the roles of UCS valence (aversive vs. appetitive), the time course across trials and response intervals within trials. Based on data from 39 independent samples (total n = 1303), our results revealed strong evidence for the overall validity of conditioned pupil responses, with a trend for larger effects in aversive (average g = 0.73) vs. appetitive conditioning (g = 0.39). Response differentiation increased over the course of acquisition. Substantial differentiation effects were found in both early and late response windows. Moderator analyses revealed a consistent influence of UCS modality on differential conditioning, while evidence for moderation by contingency instructions and length of acquisition phase was mixed. The results highlight pupil dilation as a sensitive and reliable index of Pavlovian conditioning across valence categories and stimulus modalities. Important implications regarding methodological considerations and research goals are discussed.

Sleep may contribute to the long-lasting consolidation and processing of emotional memories. Experimental fear conditioning and extinction paradigms model the development, maintenance, and treatment of anxiety disorders. The literature provides compelling evidence for the involvement of rapid eye movement (REM) sleep in the consolidation of such memories. This meta-analysis correlated polysomnographic sleep findings with psychophysiological reactivity to the danger (CS+) and safety stimuli (CS-), to clarify the specific role of sleep stages before and after fear conditioning, extinction learning and extinction recall. Overall, there was evidence that more pre-learning sleep stage two and less slow wave sleep was associated with higher psychophysiological reactivity to the safety stimulus during extinction learning. Preliminary evidence found here support the role of REM sleep during the post-extinction consolidation sleep phase in clinical populations with disrupted sleep, but not in healthy controls. Furthermore, the meta-regressions found that sex moderated the associations between sleep and psychophysiological reactivity throughout the paradigm providing evidence for diverging correlations in male and females. Specifically, increased post-extinction REM was associated with poorer extinction and safety recall in females while the opposite was found in males. These results have implications for future research in the role of sleep in emotional memory processing.