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In the present study, an attempt was made to replicate results found about the influence of valence on prioritisation and decay in iconic memory. Hereby, the evaluative conditioning effect was used to induce valence for formerly neutral stimuli. The effect is gained by pairing neutral stimuli with either positive, negative, or neutral images in a conditioning phase. Afterwards, the conditioned stimuli acted as targets in an iconic memory test. In the iconic memory test, targets were presented together with seven other stimuli on a circular placement on the screen for a short time. A cue delayed by either 17, 68, 221, 493, or 1003 ms pointed at the target to be reported. Participants rated the targets before and after the conditioning phase. In addition, the affective and neutral images used in the pairing procedure were rated at the end of the experiment. While no significant change in rating could be observed for the conditioned targets, a significant effect of conditioned valence was still present in the response times and the accuracy of the iconic memory test. Participants reacted the quickest in response to a cue for positively conditioned targets compared to neutral or negatively conditioned targets. Accuracy was highest for positively conditioned targets and was lowest for negatively conditioned targets. Unlike in prior studies, slower decay of information in iconic memory for negative targets was not revealed. Further research should be conducted to identify reasons for this inconsistency., (© 2024. The Author(s).)

Even in healthy populations, conditioned pain modulation (CPM) magnitude varies. This may be accounted for by (non-)modifiable factors, including physical activity (PA). Yet, little research has thoroughly examined PA and its relation with CPM magnitude in a representative sample. Therefore, the present study investigated the predictive effect of PA on CPM magnitude in 105 healthy adults. PA was assessed during 7 consecutive days by self-report using the International Physical Activity Questionnaire and by monitor-based accelerometry. CPM was examined using a heterotopic noxious-conditioning stimulation protocol during which the effect of a hot water-conditioning stimulus on pressure pain thresholds was evaluated. Comparative, correlation, and hierarchical linear regression analyses were performed. Report-based walking predicts 4.8% of variance in pain-modulatory capacity, moderate PA predicts 10.2% of variance in pain-modulatory capacity, and report-based time spent on total PA predicts 7.0% of variance in pain-modulatory capacity. More metabolic equivalent-minutes/week spent on total PA, including walking and moderate PA, is associated with greater pain-modulatory capacity. The findings of this study add to the limited evidence on the predictive effect of PA on CPM. It urges to consider PA a confounding factor when examining CPM. The current study provides evidence that a physically active lifestyle benefits endogenous pain modulation in healthy adults. Given its potential, walking and moderate-intensity PA might be achievable treatment strategies for pain patients known to have impaired CPM. PERSPECTIVE: The results of this article show that a physically active lifestyle, including larger amounts of walking and moderate activity, predicts greater pain-modulatory capacity. TRIAL REGISTRATION: This study has not been preregistered., (Copyright © 2024 United States Association for the Study of Pain, Inc. Published by Elsevier Inc. All rights reserved.)

Objective: The transient receptor potential cation channel, subfamily V (vanilloid), member 1 (TRPV1) mediates pain perception to thermal and chemical stimuli in peripheral neurons. The cannabinoid receptor type 1 (CB 1 ), on the other hand, promotes analgesia in both the periphery and the brain. TRPV1 and CB 1 have also been implicated in learned fear, which involves the association of a previously neutral stimulus with an aversive event. In this review, we elaborate on the interplay between CB 1 receptors and TRPV1 channels in learned fear processing., Methods: We conducted a PubMed search for a narrative review on endocannabinoid and endovanilloid mechanisms on fear conditioning., Results: TRPV1 and CB 1 receptors are activated by a common endogenous agonist, arachidonoyl ethanolamide (anandamide), Moreover, they are expressed in common neuroanatomical structures and recruit converging cellular pathways, acting in concert to modulate fear learning. However, evidence suggests that TRPV1 exerts a facilitatory role, whereas CB 1 restrains fear responses., Conclusion: TRPV1 and CB 1 seem to mediate protective and aversive roles of anandamide, respectively. However, more research is needed to achieve a better understanding of how these receptors interact to modulate fear learning.

Hyperglycemia and high adiposity are risk factors for pain in diabetes. To clarify these links with pain, the effects of a glucose load on sensory detection, pain sensitivity, conditioned pain modulation (primary aims), and autonomic and endothelial functions (secondary aims) were examined in 64 pain-free participants: 22 with normal adiposity (determined by dual-energy X-ray absorptiometry), 29 with high adiposity, and 13 with combined high adiposity and elevated glycated hemoglobin (HbA1c; including prediabetes and type 2 diabetes). Participants ingested either 37.5 g glucose or 200 mg sucralose (taste-matched) in the first session and crossed over to the other substance in the second session 1 month later. At baseline, painful temple cooling (the conditioning stimulus) inhibited pressure- and heat-pain in the ipsilateral arm (the test stimuli) immediately after cooling ceased (partial η 2 's > .32). Glucose ingestion weakened pressure-pain inhibition irrespective of HbA1c levels (partial η 2 = .11). However, a larger reduction in pressure-pain inhibition after ingesting glucose was associated with a higher waist/hip ratio (r = .31), suggesting a role of central obesity. Heat-pain inhibition was absent at baseline in unmedicated participants with elevated HbA1c, and these participants reported more occlusion-induced pain after ingesting glucose (partial η 2 's > .17). Glucose ingestion interfered with parasympathetic activity in all participants (partial η 2 = .11) but did not affect endothelial function (measured by reactive hyperemia) or alter other sensations (eg, feet vibration detection). The disruptive effect of hyperglycemia on conditioned pain modulation increases in line with central obesity, which might facilitate pain in diabetes. PERSPECTIVE: Ingesting 37.5 g glucose (approximately 350 mL soft drink) interfered with pain modulation in pain-free adults with normal adiposity or with combined high adiposity and HbA1c levels. The interference was stronger alongside increasing central obesity, suggesting that controlling blood glucose and body fat mass might help preserve pain modulation., (Copyright © 2024 United States Association for the Study of Pain, Inc. Published by Elsevier Inc. All rights reserved.)

Conditioned pain modulation and exercise-induced hypoalgesia reflect inhibitory pain controls emanating from the brain. The aim of this study was to compare the extent of pain inhibition from exercise-induced hypoalgesia (isometric wall squat), conditioned pain modulation (cold-water immersion), and their combination (wall squat followed by cold water in fixed order) in healthy pain-free adults. Sixty-one participants (median age 21 years) completed 3 sessions (wall-squat, cold-water, and combined) in random order. Sessions were separated by at least a week. In each session, pressure-pain thresholds, single-pinprick-pain ratings, and pinprick-temporal summation of pain (the fifth minus the first) were obtained at quadriceps, forearms, and forehead, before and after wall squat and/or cold water. Each intervention inhibited pain to pressure (partial η 2 = .26) and single pinprick (partial η 2 = .16) to a similar extent; however, pressure-pain inhibition was negligible in the forehead. After adjusting for age and sex, single-pinprick-pain inhibition in the forehead induced by wall squat was associated with that induced by cold water (adjusted R 2 = .15; P = .007), and stronger pain inhibition was predicted by a higher thigh-pain rating to wall squat (adjusted R 2 = .10; P = .027). Neither intervention affected pinprick-temporal summation of pain. Together, the findings suggest that pain-inhibitory effects of exercise-induced hypoalgesia and conditioned pain modulation may overlap when exercise is at least moderately painful (6/10 intensity). Pressure pain in body regions remote from the exercised or conditioned sites may be weakly modulated. PERSPECTIVE: The current findings suggest that pain-inhibitory effects induced by painful wall squat and by cold-water immersion may overlap. The magnitude of pain inhibition in the forehead remote from the exercised thigh or the conditioned foot appears smaller, which could be examined further in future research., (Copyright © 2024 United States Association for the Study of Pain, Inc. Published by Elsevier Inc. All rights reserved.)

Growing evidence supports dopamine's role in aversive states, yet systematic reviews focusing on dopamine receptors in defensive behaviors are lacking. This study presents a systematic review of the literature examining the influence of drugs acting on dopamine D2-like receptors on unconditioned and conditioned fear in rodents. The review reveals a predominant use of adult male rats in the studies, with limited inclusion of female rodents. Commonly employed tests include the elevated plus maze and auditory-cued fear conditioning. The findings indicate that systemic administration of D2-like drugs has a notable impact on both innate and learned aversive states. Generally, antagonists tend to increase unconditioned fear, while agonists decrease it. Moreover, both agonists and antagonists typically reduce conditioned fear. These effects are attributed to the involvement of distinct neural circuits in these states. The observed increase in unconditioned fear induced by D2-like antagonists aligns with dopamine's role in suppressing midbrain-mediated responses. Conversely, the reduction in conditioned fear is likely a result of blocking dopamine activity in the mesolimbic pathway. The study highlights the need for future research to delve into sex differences, explore alternative testing paradigms, and identify specific neural substrates. Such investigations have the potential to advance our understanding of the neurobiology of aversive states and enhance the therapeutic application of dopaminergic agents., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2023. Published by Elsevier Inc.)

A growing literature has sought to include mental imagery in fear conditioning studies. Imaginal extinction and imagery rescripting are mental imagery-based interventions that reduce conditioned fear. In the current study, we reviewed the recent findings on the efficacy of imaginal extinction and imagery rescripting as interventions to attenuate conditioned fear responses among healthy individuals. In accordance with the PRISMA guidelines, we conducted a literature search in four databases, PubMed, Scopus, Science Direct, and Web of Science to find published original empirical articles involving imagery-based interventions using a fear conditioning paradigm. The inclusion criteria were (i) use of an imagery-based intervention (either imaginal extinction or imagery rescripting), and (ii) use of a differential fear conditioning paradigm. 13 original articles reporting 15 experimental studies were included in the review. The review revealed that imagery-based interventions are effective in reducing conditioned fear. Although studies have shown that imaginal extinction and standard extinction have comparable effects in fear extinction, many studies have not been conducted to confirm the findings, or explore the underlying mechanisms. We also found the need for a standardized intervention protocol to enhance experimental control in intervention-based fear conditioning studies., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Inducing fear memory extinction by re-presenting a conditioned stimulus (CS) is the foundation of exposure therapy for post-traumatic stress disorder (PTSD). Investigating differences in the ability of different CS presentation patterns to induce extinction learning is crucial for improving this type of therapy. Using a trace fear conditioning paradigm in mice, we demonstrate that spaced presentation of the CS facilitated the extinction of a strong fear memory to a greater extent than continuous CS presentation. These results lay the groundwork for developing more effective exposure therapy techniques for PTSD., Competing Interests: Declaration of competing interest The authors declare that there are no conflicts of interest regarding the publication of this manuscript., (Copyright © 2024. Published by Elsevier Inc.)

Stress exposure can lead to post-traumatic stress disorder (PTSD) in male and female rats. Social-Single Prolonged Stress (SPS) protocol has been considered a potential PTSD model. This study aimed to pharmacologically validate the Social-SPS as a PTSD model in male and female rats. Male and female Wistar rats (60-day-old) were exposed to Social-SPS protocol and treated with fluoxetine (10 mg/Kg) or saline solution intraperitoneally 24 h before euthanasia. Two cohorts of animals were used; for cohort 1, male and female rats were still undisturbed until day 7 post-Social-SPS exposure, underwent locomotor and conditioned fear behaviors, and were euthanized on day 9. Animals of cohort 2 were subjected to the same protocol but were re-exposed to contextual fear behavior on day 14. Results showed that fluoxetine-treated rats gained less body weight than control and Social-SPS in both sexes. Social-SPS effectively increased the freezing time in male and female rats on day eight but not on day fourteen. Fluoxetine blocked the increase of freezing in male and female rats on day 8. Different mechanisms for fear behavior were observed in males, such as Social-SPS increased levels of glucocorticoid receptors and Beclin-1 in the amygdala. Social-SPS was shown to increase the levels of NMDA2A, GluR-1, PSD-95, and CAMKII in the amygdala of female rats. No alterations were observed in the amygdala of rats on day fourteen. The study revealed that Social-SPS is a potential PTSD protocol applicable to both male and female rats., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Oxytocin is a peptide released into brain regions associated with the processing of aversive memory and threat responses. Given the expression of oxytocin receptors across this vigilance surveillance system of the brain, we investigated whether pharmacological antagonism of the receptor would impact contextual aversive conditioning and memory. Adult male rats were conditioned to form an aversive contextual memory. The effects of peripheral administration of either the competitive antagonist Atosiban or noncompetitive antagonist L-368,899 were compared to saline controls. Oxytocin receptor antagonism treatment did not significantly impact the consolidation of aversive contextual memory in any of the groups. We conclude that peripheral antagonism of oxytocin signalling did not impact the formation of aversive memory., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Central to the navigation of an ever-changing environment is the ability to form positive associations with places and conspecifics. The functions of location and social conditioned preferences are often studied independently, limiting our understanding of their interplay. Furthermore, a de-emphasis on natural functions of conditioned preferences has led to neurobiological interpretations separated from ecological context. By adopting a naturalistic and ethological perspective, we uncover complexities underlying the expression of conditioned preferences. Development of conditioned preferences is a combination of motivation, reward, associative learning, and context, including for social and spatial environments. Both social- and location-dependent reward-responsive behaviors and their conditioning rely on internal state-gating mechanisms that include neuroendocrine and hormone systems such as opioids, dopamine, testosterone, estradiol, and oxytocin. Such reinforced behavior emerges from mechanisms integrating past experience and current social and environmental conditions. Moreover, social context, environmental stimuli, and internal state gate and modulate motivation and learning via associative reward, shaping the conditioning process. We highlight research incorporating these concepts, focusing on the integration of social neuroendocrine mechanisms and behavioral conditioning. We explore three paradigms: 1) conditioned place preference, 2) conditioned social preference, and 3) social conditioned place preference. We highlight nonclassical species to emphasize the naturalistic applications of these conditioned preferences. To fully appreciate the complex integration of spatial and social information, future research must identify neural networks where endocrine systems exert influence on such behaviors. Such research promises to provide valuable insights into conditioned preferences within a broader naturalistic context., Competing Interests: Declaration of competing interest None., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Research on myofascial temporomandibular disorder (mTMD) has often focused on potential dysfunction in endogenous pain modulation. However, studies on the specific inhibitory and facilitatory components of endogenous pain modulation using conditioned pain modulation (CPM) and temporal summation of second pain (TSSP) have shown mixed results. This study aimed to 1) examine whether women with mTMD demonstrated efficient CPM compared to controls; 2) explore the association between independent measures of CPM and TSSP in women with mTMD relative to controls; and 3) determine whether resulting modulatory profiles differentially predicted pain intensity among cases. All participants were recruited from dental clinics. Cases were women who met the research diagnostic criteria for mTMD. Controls did not have facial pain on exam and were selected to be sociodemographically similar to cases. CPM and TSSP were assessed via independent psychophysical protocols. CPM was examined in linear mixed models predicting pain thresholds adjusted for age and stratified by TSSP. Mean CPM was estimated at a 2.2 (SD = 2.8) degree increase in pain thresholds (P ≤ .001), similar in cases and controls (P = .67). CPM was less efficient in cases with enhanced TSSP (P = .031), but not in controls. Although the double-pronociceptive profile of both low CPM and high TSSP trended higher among cases than controls, it did not predict higher levels of pain intensity among cases. This study does not support deficient inhibitory endogenous pain modulation in mTMD, but results suggest that inhibitory and facilitatory pain modulation should be examined concomitantly in the study of endogenous pain modulation. PERSPECTIVE: This manuscript presents a novel examination of inhibitory modulation by the level of facilitatory modulation in mTMD. The findings and approach may prove useful for mechanistic researchers studying endogenous pain modulation and clinical researchers seeking to jointly examine conditioned pain modulation and temporal summation in future research on chronic pain., (Copyright © 2024 United States Association for the Study of Pain, Inc. All rights reserved.)

Renewal is a 'return of fear' manipulation in human fear conditioning to investigate learning processes underlying anxiety and trauma. Even though renewal paradigms are widely used, no study has compared the strength of different renewal paradigms. We conduct a systematic review (N = 80) and meta-analysis (N = 23) of human fear conditioning studies assessing renewal. Our analysis shows that the classic ABA design is the most effective paradigm, compared to ABC and ABBA designs. We present evidence that conducting extinction in multiple contexts and increasing the similarity between acquisition and extinction contexts reduce renewal. Furthermore, we show that additional cues can be used as safety and 'protection from extinction' cues. The review shows that alcohol weakens the extinction process and that older adults appear less sensitive to context changes and thus show less renewal. The large variability in approaches to study renewal in humans suggests that standardisation of fear conditioning procedures across laboratories would be of great benefit to the field., Competing Interests: Conflict of interest The authors have no conflicts of interest to declare., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The presence of a companion can reduce fear, but the neural mechanisms underlying this social buffering of fear are incompletely known. We studied social buffering of fear in male and female, and its encoding in the amygdala of male, auditory fear-conditioned rats. Pharmacological, opto,- and/or chemogenetic interventions showed that oxytocin signaling from hypothalamus-to-central amygdala projections underlied fear reduction acutely with a companion and social buffering retention 24 h later without a companion. Single-unit recordings with optetrodes in the central amygdala revealed fear-encoding neurons (showing increased conditioned stimulus-responses after fear conditioning) inhibited by social buffering and blue light-stimulated oxytocinergic hypothalamic projections. Other central amygdala neurons showed baseline activity enhanced by blue light and companion exposure, with increased conditioned stimulus responses that persisted without the companion. Social buffering of fear thus switches the conditioned stimulus from encoding "fear" to "safety" by oxytocin-mediated recruitment of a distinct group of central amygdala "buffer neurons"., (© 2024. The Author(s).)

Several authors assume that evaluative conditioning (EC) relies on high-level propositional thinking. In contrast, the dual-process perspective proposes two processing pathways, one associative and the other propositional, contributing to EC. Dual-process theorists argue that attitudinal ambiguity resulting from these two pathways' conflicting evaluations demonstrate the involvement of both automatic and controlled processes in EC. Previously, we suggested that amplitude variations of error-related negativity and error-positivity, two well-researched event-related potentials of performance monitoring, allow for the detection of attitudinal ambiguity at the neural level. The present study utilises self-reported evaluation, categorisation performance, and neural correlates of performance monitoring to explore associative-propositional ambiguity during social attitude formation. Our results show that compared to associative-propositional harmony, attitudinal ambiguity correlates with more neutral subjective evaluations, longer response times, increased error commission, and diminished error-related negativity amplitudes. While our findings align with dual-process models, we aim to offer a propositional interpretation. We discuss dual-process theories in the context of evolutionary psychology, suggesting that associative processes may only represent a small piece of the EC puzzle.

During Drosophila aversive olfactory conditioning, aversive shock information needs to be transmitted to the mushroom bodies (MBs) to associate with odor information. We report that aversive information is transmitted by ensheathing glia (EG) that surround the MBs. Shock induces vesicular exocytosis of glutamate from EG. Blocking exocytosis impairs aversive learning, whereas activation of EG can replace aversive stimuli during conditioning. Glutamate released from EG binds to N -methyl-d-aspartate receptors in the MBs, but because of Mg 2+ block, Ca 2+ influx occurs only when flies are simultaneously exposed to an odor. Vesicular exocytosis from EG also induces shock-associated dopamine release, which plays a role in preventing formation of inappropriate associations. These results demonstrate that vesicular glutamate released from EG transmits negative valence information required for associative learning.

Inaccessibility of stored memory in ensemble cells through the forgetting process causes animals to be unable to respond to natural recalling cues. While accumulating evidence has demonstrated that reactivating memory-stored cells can switch cells from an inaccessible state to an accessible form and lead to recall of previously learned information, the underlying cellular and molecular mechanisms remain elusive. The current study used Drosophila as a model to demonstrate that the memory of one-trial aversive olfactory conditioning, although inaccessible within a few hours after learning, is stored in KCαβ and retrievable after mild retraining. One-trial aversive conditioning triggers protein synthesis to form a long-lasting cellular memory trace, approximately 20 days, via creb in KCαβ, and a transient cellular memory trace, approximately one day, via orb in MBON-α3. PPL1-α3 negatively regulates forgotten one-trial conditioning memory retrieval. The current study demonstrated that KCαβ, PPL1-α3, and MBON-α3 collaboratively regulate the formation of forgotten one-cycle aversive conditioning memory formation and retrieval., (© 2023. The Author(s).)

Extinction learning is tremendously adaptive as it allows an animal to adjust their behavior in a changing environment. Yet, extinction is not without limitations and fear often reemerges over time (i.e. spontaneous recovery). Relative to adults, adolescent rodents and humans are particularly prone to spontaneous recovery following extinction. In this study, we aimed to address whether combining methods of fear regulation (extinction and conditioned inhibition) can facilitate extinction retention. Early adolescent (29 days old, n = 81) and adult (70 days old, n = 80) mice underwent extinction with or without a safety cue present. Safety cue presentations were systematically varied to overlap with or alternate with fear cue presentations. We found that initial safety learning was faster in adolescent mice. In addition, intermixing safety cues into extinction reduced spontaneous recovery during a test two weeks later. The decrease in spontaneous recovery relative to a standard extinction protocol was greater in adolescents than adults. Together, our findings provide initial evidence that safety learning may be inherently stronger during adolescence. These results inform the parameters by which conditioned safety and extinction learning may be merged to augment the inhibition of fear. While methods to enhance fear regulation are valuable for any age, the potential to do so during adolescence is particularly striking., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Social buffering is a phenomenon in which the stress response of an individual can be reduced by the presence of another individual. However, little is known about the effect of social buffering on aversive after memory extinction, especially when animals are tested alone afterwards. The aim of this study was to verify the social buffering effect in rats during the extinction session of the contextual fear conditioning model and the fear response when animals are tested alone in the following day. Animals were divided into subjects and associates, with the subjects undergoing the fear conditioning protocol and the associates paired with the subjects during the fear extinction session. Across five different experiments, we tested moderate and high intensity contextual fear conditioning protocols, as well four variations of pairs: (i) two conditioned subjects, (ii) a conditioned subject and a non-conditioned associate, (iii) a conditioned subject and an associate who observed the conditioning of the partner and (iv) two conditioned subjects, with one treated with diazepam. The social buffering effect was found efficient to reduce the fear memory expression during the fear extinction session. In the moderate intensity protocol, the reduction in freezing time occurred only in subjects accompanied by non-conditioned associates and observer associates. In the high intensity protocol, the social buffering effect occurred in subjects accompanied by either conditioned or non-conditioned associates, although the effect was more evident in the presence of non-conditioned subjects. Treatment of the conditioned associates with diazepam did not improve the social buffering effect. Moreover, social buffering effects were not correlated with self-grooming or prosocial behaviors, which indicates that the presence of another animal might decrease freezing by promotion of exploratory activity. Finally, the social buffering effect was not observed in the extinction test, either because the extinction was too effective in the moderate intensity protocol or because the extinction was equally ineffective in the high intensity protocol. Our results suggest that social buffering does not improve fear extinction consolidation., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Inhibitory associative learning counters the effects of excitatory learning, whether appetitively or aversively motivated. Moreover, the affective responses accompanying the inhibitory associations are of opponent valence to the excitatory conditioned responses. Inhibitors for negative aversive outcomes (e.g. shock) signal safety, while inhibitors for appetitive outcomes (e.g. food reward) elicit frustration and/or disappointment. This raises the question as to whether studies using appetitive and aversive conditioning procedures should demonstrate the same neural substrates for inhibitory learning. We review the neural substrates of appetitive and aversive inhibitory learning as measured in different procedural variants and in the context of the underpinning excitatory conditioning on which it depends. The mesocorticolimbic dopamine pathways, retrosplenial cortex and hippocampus are consistently implicated in inhibitory learning. Further neural substrates identified in some procedural variants may be related to the specific motivation of the learning task and modalities of the learning cues. Finally, we consider the translational implications of our understanding of the neural substrates of inhibitory learning, for obesity and addictions as well as for anxiety disorders., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

While persistence of fear memories is essential for survival, a failure to inhibit fear in response to harmless stimuli is a feature of anxiety disorders. Extinction training only temporarily suppresses fear memory recovery in adults, but it is highly effective in juvenile rodents. Maturation of GABAergic circuits, in particular of parvalbumin-positive (PV + ) cells, restricts plasticity in the adult brain, thus reducing PV + cell maturation could promote the suppression of fear memories following extinction training in adults. Epigenetic modifications such as histone acetylation control gene accessibility for transcription and help couple synaptic activity to changes in gene expression. Histone deacetylase 2 (Hdac2), in particular, restrains both structural and functional synaptic plasticity. However, whether and how Hdac2 controls the maturation of postnatal PV + cells is not well understood. Here, we show that PV + - cell specific Hdac2 deletion limits spontaneous fear memory recovery in adult mice, while enhancing PV + cell bouton remodeling and reducing perineuronal net aggregation around PV + cells in prefrontal cortex and basolateral amygdala. Prefrontal cortex PV + cells lacking Hdac2, show reduced expression of Acan, a critical perineuronal net component, which is rescued by Hdac2 re-expression. Pharmacological inhibition of Hdac2 before extinction training is sufficient to reduce both spontaneous fear memory recovery and Acan expression in wild-type adult mice, while these effects are occluded in PV + -cell specific Hdac2 conditional knockout mice. Finally, a brief knock-down of Acan expression mediated by intravenous siRNA delivery before extinction training but after fear memory acquisition is sufficient to reduce spontaneous fear recovery in wild-type mice. Altogether, these data suggest that controlled manipulation of PV + cells by targeting Hdac2 activity, or the expression of its downstream effector Acan, promotes the long-term efficacy of extinction training in adults., (© 2023. The Author(s).)

Fear and anxiety are crucial for adaptive responding in life-threatening situations. Whereas fear is a phasic response to an acute threat accompanied by selective attention, anxiety is characterized by a sustained feeling of apprehension and hypervigilance during situations of potential threat. In the current literature, fear and anxiety are usually considered mutually exclusive, with partially separated neural underpinnings. However, there is accumulating evidence that challenges this distinction between fear and anxiety, and simultaneous activation of fear and anxiety networks has been reported. Therefore, the current study experimentally tested potential interactions between fear and anxiety. Fifty-two healthy participants completed a differential fear conditioning paradigm followed by a test phase in which the conditioned stimuli were presented in front of threatening or neutral contextual images. To capture defense system activation, we recorded subjective (threat, US-expectancy), physiological (skin conductance, heart rate) and visuocortical (steady-state visual evoked potentials) responses to the conditioned stimuli as a function of contextual threat. Results demonstrated successful fear conditioning in all measures. In addition, threat and US-expectancy ratings, cardiac deceleration, and visuocortical activity were enhanced for fear cues presented in threatening compared with neutral contexts. These results are in line with an additive or interactive rather than an exclusive model of fear and anxiety, indicating facilitated defensive behavior to imminent danger in situations of potential threat., (© 2022 The Authors. Psychophysiology published by Wiley Periodicals LLC on behalf of Society for Psychophysiological Research.)

Abstract: Persistent pain despite satisfactory disease treatment is frequent in rheumatoid arthritis (RA) and spondyloarthritis (Spa) and may result from specific changes in central pain processing. We assessed these mechanisms further by systematically comparing thermal pain thresholds and conditioned pain modulation (CPM) between patients with active RA or Spa and healthy controls. We included 50 patients with RA and 50 patients with Spa and 100 age-matched and sex-matched controls. Heat and cold pain thresholds (HPT-CPT) were measured on the dominant forearm, and CPM was assessed by applying conditioning stimuli (immersion in a cold-water bath) to one foot and the nondominant hand in 2 successive randomized sequences. Descending pain modulation was assessed as the difference in HPTs (in °C) before and after conditioning. Larger HPT differences (ie, a larger CPM effect) reflected more efficient descending inhibition. Potential associations between changes in CPM and clinical data, including disease activity, pain intensity, and psychological and functional variables, were systematically assessed. Heat pain threshold and cold pain threshold were similar in patients and controls. The mean CPM effect was significantly weaker in patients than that in controls for conditioning applied to either the foot (0.25°C ±2.57 vs 2.79°C ±2.31; P < 0.001) or the nondominant hand (0.57°C ±2.74 vs 2.68°C ±2.12; P < 0.001). The smaller CPM effect in patients was correlated with average pain intensity, but not with disease activity or other clinical characteristics, suggesting a significant pathophysiological role for changes in endogenous pain modulation in the mechanisms of chronic pain associated with inflammatory rheumatism., (Copyright © 2022 International Association for the Study of Pain.)

Here we review the effects of immune activation primarily via lipopolysaccharide (LPS), a cell wall component of Gram-negative bacteria, on hippocampal and non-hippocampal-dependent learning and memory. Rodent studies have found that LPS alters both the acquisition and consolidation of aversive learning and memory, such as those evoking evolutionarily adaptive responses like fear and disgust. The inhibitory effects of LPS on the acquisition and consolidation of contextual fear memory are discussed. LPS-induced alterations in the acquisition of taste and place-related conditioned disgust memory within bottle preference tasks and taste reactivity tests (taste-related), in addition to conditioned context avoidance tasks and the anticipatory nausea paradigm (place-related), are highlighted. Further, conditioned disgust memory consolidation may also be influenced by LPS-induced effects. Growing evidence suggests a central role of immune activation, especially pro-inflammatory cytokine activity, in eliciting the effects described here. Understanding how infection-induced immune activation alters learning and memory is increasingly important as bacterial and viral infections are found to present a risk of learning and memory impairment., Competing Interests: Conflict of interest The authors declare that they have no conflict of interest., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Conditioned pain modulation (CPM) and offset analgesia quantify impairment of endogenous pain modulation, but magnitude and reliability vary broadly between studies, indicating influencing factors that are not currently controlled for. The aim of this study was to quantify magnitude and retest reliability of CPM and offset analgesia in healthy participants, while investigating the influence of sex and sex hormone levels., Methods: Sixty-two participants (30 female) completed the study. We tested CPM (heat-cold paradigm) and offset analgesia on 6 days within two menstrual cycles (tests were performed in each phase of two subsequent menstrual cycles, with similar time points for men)., Results: Median offset effect was -29.4% in female and - 22.5% in male participants (as change from initial stimulus). Median early CPM effects were - 16.7% for women versus -13.3% for men. Reliability (intra-class correlation coefficient [ICC]) was similar between the main measures, offset effect (female: 0.48, male: 0.47) and early CPM effect (female: 0.49, male: 0.43). There was significant variance between individual experimental parameters within protocols but not between sexes or menstrual phases. While oestradiol and progesterone did not correlate with the magnitude of effect within sexes, we found that testosterone levels explained an estimated 5%-10% of variance within individual responses in all sexes., Conclusions: Our results show that the reliability of both CPM effect and offset analgesia was independent of sex and menstrual cycle phase. The magnitude of CPM and offset effects was weakly influenced by sex and testosterone levels, indicating an area for future research, rather than clinical significance., Significance: This study investigated CPM and offset analgesia in parallel, across sexes and during two menstrual cycles while assessing the impact of sex hormones. Reliability seems to depend on experimental parameters rather than participant characteristics, while the magnitude of effect could be weakly linked to sex hormones and sex., (© 2022 The Authors. European Journal of Pain published by John Wiley & Sons Ltd on behalf of European Pain Federation - EFIC ®.)

Fear extinction allows for adaptive control of learned fear responses but often fails, resulting in a renewal or spontaneous recovery of the extinguished fear, i.e., forgetting of the extinction memory readily occurs. Using an activity-dependent neuronal labeling strategy, we demonstrate that engram neurons for fear extinction memory are dynamically positioned in the medial prefrontal cortex (mPFC), basolateral amygdala (BLA), and ventral hippocampus (vHPC), which constitute an engram construct in the term of directional engram synaptic connectivity from the BLA or vHPC to mPFC, but not that in the opposite direction, for retrieval of extinction memory. Fear renewal or spontaneous recovery switches the extinction engram construct from an accessible to inaccessible state, whereas additional extinction learning or optogenetic induction of long-term potentiation restores the directional engram connectivity and prevents the return of fear. Thus, the plasticity of engram construct underlies forgetting of extinction memory., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Conditioned pain modulation (CPM), a psychophysical measure in which 1 pain stimulus (conditioning stimulus) is used to inhibit another pain stimulus (test stimulus), is an important indicator of endogenous pain inhibition in adults, but is understudied in children. Preliminary evidence suggests that CPM effects are present in healthy children and are more robust in adolescents. However, developmental differences in younger children are not well documented and few studies control for potential distraction effects of the conditioning stimulus (CS). Participants were 54 healthy children aged 6 to 12 years. After a baseline pressure pain threshold (PPT) test, participants underwent 2 conditioning trials in which PPT was assessed while they placed their left hand in a water bath maintained at either 12 °C (painful CS) or 22 °C (nonpainful sham CS) in counterbalanced order. Results revealed a significant CPM effect. PPT values were significantly higher relative to baseline during the painful CS trial; PPT during the nonpainful CS trial did not differ from baseline. There were no significant age differences in magnitude of CPM effect. The results indicate that children as young as 6 years of age demonstrate CPM, suggesting that descending inhibitory pathways may be better developed in young children than previously thought. PERSPECTIVE: This study was successful in producing inhibitory CPM effects in physically healthy children while controlling for sensory distraction. The findings provide strong evidence that the obtained CPM responses cannot be attributed to sensory distraction or other nonspecific effects. Future studies could utilize CPM paradigms to study various aspects of pediatric endogenous pain inhibition, in order to better predict pain responses and improve interventions., (Copyright © 2022 United States Association for the Study of Pain, Inc. Published by Elsevier Inc. All rights reserved.)

Objectives: Conditioned pain modulation (CPM) is a psychophysical parameter that is used to reflect the efficacy of endogenous pain inhibition. CPM reliability is important for research and potential clinical applications. The aim of this systematic review and meta-analysis was to evaluate the reliability of CPM tests in healthy individuals and chronic pain patients., Methods: We searched three databases for peer-reviewed studies published from inception to October 2020: EMBASE, Web of Science and NCBI. Risk of bias and the quality of the included studies were assessed. A meta-analysis with a random effects model was conducted to estimate intraclass correlation coefficients (ICCs)., Results: Meta-analysis was performed on 25 papers that examined healthy participants ( k =21) or chronic pain patients ( k =4). The highest CPM intra-session reliability was with pressure as test stimulus (TS) and ischemic pressure (IP) or cold pressor test (CPT) as conditioning stimulus (CS) in healthy individuals (ICC 0.64, 95% CI 0.45-0.77), and pressure as TS with CPT as CS in patients (ICC 0.77, 95% CI 0.70-0.82). The highest inter-session ICC was with IP as TS and IP or CPT as CS (ICC 0.51, 95% CI 0.42-0.59) in healthy subjects. The only data available in patients for inter-session reliability were with pressure as TS and CPT as CS (ICC 0.44, 95% CI 0.11-0.69). Quality ranged from very good to excellent using the QACMRR checklist. The majority of the studies (24 out of 25) scored inadequate in Kappa coefficient reporting item of the COSMIN-ROB checklist., Conclusions: Pressure and CPT were the TS and CS most consistently associated with good to excellent intra-session reliability in healthy volunteers and chronic pain patients. The inter-session reliability was fair or less for all modalities, both in healthy volunteers and chronic pain patients., (© 2022 Walter de Gruyter GmbH, Berlin/Boston.)

Of all frontocortical subregions, the anterior cingulate cortex (ACC) has perhaps the most overlapping theories of function. 1-3 Recording studies in rats, humans, and other primates have reported diverse neural responses that support many theories, 4-12 yet nearly all these studies have in common tasks in which one event reliably predicts another. This leaves open the possibility that ACC represents associative pairing of events, independent of their overt biological significance. Sensory preconditioning 13 provides an opportunity to test this. In the first phase, preconditioning, value-neutral sensory stimuli are paired (A→B). To test whether this was learned, subjects are given standard conditioning during which one of the previously neutral sensory cues is paired with a biologically meaningful outcome (B→outcome). During the final probe test, the neutral cue which was never paired with a biologically meaningful outcome is presented alone (A→) and will elicit a conditional response, suggesting that subjects had learned the associative structure during preconditioning and use that knowledge to infer presentation of the biologically relevant outcome (A→B→outcome). Inference-based responding demonstrates a fundamental property of model-based reasoning 14 , 15 and requires learning of the associations between neutral stimuli before rewards are introduced. 16-19 ACC neurons developed firing patterns that reflected the learning of sensory associations during preconditioning, even though no rewards were present. The strength of these correlates predicted rats' ability to later mobilize and use that associative information during the probe test. These results demonstrate that clear biological significance is not necessary to produce correlates of learning in ACC., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021. Published by Elsevier Inc.)

Fear extinction (FExt) is used to treat patients with posttraumatic stress disorder (PTSD). However, fear related to traumatic events can be persistent and return even after successful extinction. The neurochemical control of extinction seems to be performed by several neurotransmitters, including dopamine (DA), through D1 and D2 receptors. Recently, we showed that intranasally applied DA (IN-DA) facilitated the FExt, but the mechanisms by which it promoted this effect are still unknown. This study focused on investigating whether these effects are mediated by the action of DA on D2-like receptors since these receptors seem to be related to neurochemical and molecular changes underlying extinction. Also, we investigated whether IN-DA treatment would affect conditioned fear-induced antinociception (Fear-IA). Rats treated with IN-DA (1 mg/kg) twenty-five minutes after sulpiride (SUL; 40 mg/kg, i.p., D2-antagonist) were subjected to the extinction of contextual fear. IN-DA applied before the extinction session induced the FExt and prevented Fear-IA. These effects were impaired by pre-treatment with SUL, suggesting that the IN-DA effects are mediated by DA on D2-like receptors. SUL per se also facilitated the FExt but did not affect Fear-IA. These data suggest IN-DA as a promising pharmacological tool to supplement the psychotherapy of patients suffering from PTSD., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Sensory preconditioning protocols can be used to assess how the brain integrates memories that share common features. In these protocols, animals are first exposed to pairings of two relatively innocuous stimuli, S2 and S1 (stage 1), and then to pairings of one of these stimuli, S1, with an event of motivational significance (stage 2). Following this training, test presentations of S2 elicit responses appropriate to the motivationally significant event, and these responses are taken to indicate formation of distinct S2-S1 and S1-event memories that are integrated in some way to generate that responding. This paper reviews studies of sensory preconditioning in rats, mice, rabbits and people to determine whether S2-S1 and S1-event memories are integrated through a chaining process at the time of their retrieval (i.e., test presentations of S2 trigger retrieval of S1, and thereby, responses appropriate to the event); or "online" at the time of memory formation (i.e., in stage 2, S1 activates a representation of S2 such that both stimuli associate with the motivationally significant event). It finds that the type of integration is determined by the manner in which stimuli are presented in preconditioning as well as their familiarity. When the stimuli in preconditioning are presented repeatedly and/or serially (i.e., one after the other), the S2-S1 and S1-event memories are chained at the time of retrieval/testing. In contrast, when the stimuli in preconditioning are relatively novel and/or presented simultaneously, the S2-S1 and S1-event memories are integrated online. These statements are related to prior claims regarding the circumstances that promote different types of memory integration and, more generally, mechanisms of information processing in the mammalian brain., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Treatment resistance of anxiety-related disorders often arises from an inappropriate fear expression, impairment in fear extinction, and spontaneous return of fear. Stress exposure is considered a high risk factor for neuropsychiatric disorders, but understanding of the long-term consequences of stress is limited, particularly when it comes to treatment outcome. Therefore, studying the consequences of acute stress would provide critical information on the role of stress in psychopathology. In the present study, we investigated the effect of acute immobilization stress on anxiety-like behavior and on conditioned fear memory. Our results demonstrate that prior stress exposure had no effect on anxiety-related behavior, fear acquisition, as well as fear extinction compared to non-stressed controls, but resulted in significantly higher rates of freezing during recall of extinction, indicating a consolidation failure. Further, immunohistochemical analysis of the expression of the immediate early gene c-Fos after recall of extinction revealed increased neuronal activity in the posterior paraventricular nucleus of the thalamus (PVT) in previously stressed animals compared to non-stressed controls. These results indicate, firstly, that acute stress affects long-term fear memory even after successful extinction training, and secondly, a strong involvement of the PVT in maladaptive fear responses induced by prior stress. Thus, stress-induced changes in PVT neuronal activity might be of importance for the pathophysiology of stress-sensitive anxiety-related psychiatric disorders, since exposure to an earlier acute stressor could counteract the success of therapy., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Animals respond to threatening situations by exhibiting a number of defensive behaviors, including avoidance, freezing, and risk assessment. An animal model with an ethological approach offers a deeper insight into the biological mechanisms underlying threat responses. This paper describes a methodology to measure defensive behaviors toward both innate and learned aversive stimuli in rats. Animals were individually exposed to predator odor in an inescapable chamber to elicit a measurable, sustained, defensive state. The experimental design involved placing a rat in a familiar chamber for 10 min followed by exposure to cat odor for another 10 min in the same context. The next day, the rats were re-exposed for 10 min to the same context chamber where cat odor exposure occurred. Sessions were video-recorded and defensive behaviors were assessed on both days. The behavioral test was coupled with reversible functional inactivation and c-Fos immunohistochemistry techniques to determine the role of the interoceptive cortex in threat responses. Rats exposed to cat odor on the first day and re-exposed to the context chamber on the second day displayed higher levels of defensive behaviors, and that cat odor elicited a robust increase in the neural activity of the interoceptive cortex. Moreover, muscimol inactivation of the interoceptive cortex reduced the expression of defensive behaviors in response to cat odor and impaired contextual threat memory. These results show that this behavioral assay is a useful tool for studying neural mechanisms of defensive behaviors and may offer insight into mechanisms that mediate fear in humans and its related disorders.

Odor perception can both evoke emotional states and be shaped by emotional or hedonic states. The amygdala complex plays an important role in recognition of, and response to, hedonically valenced stimuli, and has strong, reciprocal connectivity with the primary olfactory (piriform) cortex. Here, we used differential odor-threat conditioning in rats to test the role of basolateral amygdala (BLA) input to the piriform cortex in acquisition and expression of learned olfactory threat responses. Using local field potential recordings, we demonstrated that functional connectivity (high gamma band coherence) between the BLA and posterior piriform cortex (pPCX) is enhanced after differential threat conditioning. Optogenetic suppression of activity within the BLA prevents learned threat acquisition, as do lesions of the pPCX prior to threat conditioning (without inducing anosmia), suggesting that both regions are critical for acquisition of learned odor threat responses. However, optogenetic BLA suppression during testing did not impair threat response to the CS+ , but did induce generalization to the CS-. A similar loss of stimulus control and threat generalization was induced by selective optogenetic suppression of BLA input to pPCX. These results suggest an important role for amygdala-sensory cortical connectivity in shaping responses to threatening stimuli., (© 2021. The Author(s).)

Besides their clinical application, chronic misuse of opioids has often been associated to drug addiction due to their addictive properties, underlying neuroadaptations of AMPA glutamate-receptor-dependent synaptic plasticity. Topiramate (TPM), an AMPAR antagonist, has been used to treat psychostimulants addiction, despite its harmful effects on memory. This study aimed to evaluate the effects of a novel topiramate nanosystem on molecular changes related to morphine reinstatement. Rats were previously exposed to morphine in conditioned place preference (CPP) paradigm and treated with topiramate-chitosan nanoparticles (TPM-CS-NP) or non-encapsulated topiramate in solution (S-TPM) during CPP extinction; following memory performance evaluation, they were re-exposed to morphine reinstatement. While morphine-CPP extinction was comparable among all experimental groups, TPM-CS-NP treatment prevented morphine reinstatement, preserving memory performance, which was impaired by both morphine-conditioning and S-TPM treatment. In the NAc, morphine increased D1R, D2R, D3R, DAT, GluA1 and MOR immunoreactivity. It also increased D1R, DAT, GluA1 and MOR in the dorsal hippocampus. TPM-CS-NP treatment decreased D1R, D3R and GluA1 and increased DAT in the NAc, decreasing GluA1 and increasing D2 and DAT in the dorsal hippocampus. Taken together, we may infer that TPM-CS-NP treatment was able to prevent the morphine reinstatement without memory impairment. Therefore, TPM-CS-NP may be considered an innovative therapeutic tool due to its property to prevent opioid reinstatement because it acts modifying both dopaminergic and glutamatergic neurotransmission, which are commonly related to morphine addiction., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Living in mix-species aggregations provides animals with substantive anti-predator, foraging and locomotory advantages while simultaneously exposing them to costs, including increased competition and pathogen exposure. Given each species possess unique morphology, competitive ability, parasite vulnerability and predator defences, we can surmise that each species in mixed groups will experience a unique set of trade-offs. In addition to this unique balance, each species must also contend with anthropogenic changes, a relatively new, and rapidly increasing phenomenon, that adds further complexity to any system. This complex balance of biotic and abiotic factors is on full display in the exceptionally diverse, yet anthropogenically degraded, Great Barrier Reef of Australia. One such example within this intricate ecosystem is the inability of some damselfish to utilize their own chemical alarm cues within degraded habitats, leaving them exposed to increased predation risk. These cues, which are released when the skin is damaged, warn nearby individuals of increased predation risk and act as a crucial associative learning tool. Normally, a single exposure of alarm cues paired with an unknown predator odour facilitates learning of that new odour as dangerous. Here, we show that Ambon damselfish, Pomacentrus amboinensis, a species with impaired alarm responses in degraded habitats, failed to learn a novel predator odour as risky when associated with chemical alarm cues. However, in the same degraded habitats, the same species learned to recognize a novel predator as risky when the predator odour was paired with alarm cues of the closely related, and co-occurring, whitetail damselfish, Pomacentrus chrysurus. The importance of this learning opportunity was underscored in a survival experiment which demonstrated that fish in degraded habitats trained with heterospecific alarm cues, had higher survival than those we tried to train with conspecific alarm cues. From these data, we conclude that redundancy in learning mechanisms among prey guild members may lead to increased stability in rapidly changing environments., (© 2021. The Author(s).)

Adaptive behaviour is under the potent control of environmental cues. Such cues can acquire value by virtue of their associations with outcomes of motivational significance, be they appetitive or aversive. There are at least two ways through which an environmental cue can acquire value, through first-order and higher-order conditioning. In first-order conditioning, a neutral cue is directly paired with an outcome of motivational significance. In higher-order conditioning, a cue is indirectly associated with motivational events via a directly conditioned first-order stimulus. The present article reviews some of the associations that support learning in first- and higher-order conditioning, as well as the role of the BLA and the molecular mechanisms involved in these two types of learning., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Exploring the neural circuits of the extinction of conditioned fear is critical to advance our understanding of fear- and anxiety-related disorders. The field has focused on examining the role of various regions of the medial prefrontal cortex, insular cortex, hippocampus, and amygdala in conditioned fear and its extinction. The contribution of this 'fear network' to the conscious awareness of fear has recently been questioned. And as such, there is a need to examine higher/multiple cortical systems that might contribute to the conscious feeling of fear and anxiety. Herein, we studied functional connectivity patterns across the entire brain to examine the contribution of multiple networks to the acquisition of fear extinction learning and its retrieval. We conducted trial-by-trial analyses on data from 137 healthy participants who underwent a two-day fear conditioning and extinction paradigm in a functional magnetic resonance imaging (fMRI) scanner. We found that functional connectivity across a broad range of brain regions, many of which are part of the default mode, frontoparietal, and ventral attention networks, increased from early to late extinction learning only to a conditioned cue. The increased connectivity during extinction learning predicted the magnitude of extinction memory tested 24 h later. Together, these findings provide evidence supporting recent studies implicating distributed brain regions in learning, consolidation and expression of fear extinction memory in the human brain., Competing Interests: Declaration of Competing Interest The authors declare no competing interests., (Copyright © 2021. Published by Elsevier Inc.)

We studied the influence of combined preconditioning (compound pQ-4 and moderate hypoxia) on morphometrical parameters of neuronal populations in hippocampal fields CA1 and CA3 in rats after bilateral ligation of the common carotid artery. Preconditioning produced a neuroprotective effect, improved survival of pyramidal neurons in the early and delayed periods of modeled ischemia, prevented the formation of necrotic and apoptotic neurons and hyperactivation of microglia, and protected endotheliocytes. The positive influence of preconditioning factors on the morphometric parameters of the brain under ischemic conditions agrees with the results of behavioral tests (open field and elevated plus maze) that demonstrated increased locomotor activity and exploratory behavior of animals., (© 2021. Springer Science+Business Media, LLC, part of Springer Nature.)

N6-methyladenosine (m6A) is the most prevalent internal modification found in mRNAs and lncRNA and plays a vital role in posttranscriptional regulation in mammals. m6A is abundant in the nervous system, where it modulates neuronal development and hippocampus-dependent learning and memory. However, the roles of RNAs m6A modification and its related enzymes in cocaine reward are still not fully understood. In this study, we found that the fat mass and obesity-associated gene (FTO) demethylase, but not methyltransferase-like 3 (METTL3) and 14 (METTL14), was downregulated in the hippocampus following cocaine-induced conditioned place preference (CPP), and the level of m6A is notably higher in the hippocampus of cocaine CPP training mice. Using methylated m6A RNA immunoprecipitation sequencing (MeRIP-m6A-seq), we identified a total of 6516 m6A peaks within 4460 mRNAs, and 3083 m6A peaks within 850 lncRNAs were significantly dysregulated. Intriguingly, the altered m6A peaks within mRNAs and lncRNAs were enriched in synapse maturation and localization processes. Our study uncovers a critical role for an m6A epitranscriptomic dysregulation and downregulation of FTO expression in the hippocampus following cocaine-induced CPP., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Expectation can shape the perception of pain within a fraction of time, but little is known about how perceived expectation unfolds over time and modulates pain perception. Here, we combine magnetoencephalography (MEG) and machine learning approaches to track the neural dynamics of expectations of pain in healthy participants with both sexes. We found that the expectation of pain, as conditioned by facial cues, can be decoded from MEG as early as 150 ms and up to 1100 ms after cue onset, but decoding expectation elicited by unconsciously perceived cues requires more time and decays faster compared to consciously perceived ones. Also, results from temporal generalization suggest that neural dynamics of decoding cue-based expectation were predominately sustained during cue presentation but transient after cue presentation. Finally, although decoding expectation elicited by consciously perceived cues were based on a series of time-restricted brain regions during cue presentation, decoding relied on the medial prefrontal cortex and anterior cingulate cortex after cue presentation for both consciously and unconsciously perceived cues. These findings reveal the conscious and unconscious processing of expectation during pain anticipation and may shed light on enhancing clinical care by demonstrating the impact of expectation cues., Competing Interests: Declaration of Competing Interest All authors declare no conflicts of interest., (Copyright © 2021. Published by Elsevier Inc.)

Associative learning allows animals to adapt their behavior in response to environmental cues. For example, sensory cues associated with food availability can trigger overconsumption even in sated animals. However, the neural mechanisms mediating cue-driven non-homeostatic feeding are poorly understood. To study this, we recently developed a behavioral task in which contextual cues increase feeding even in sated mice. Here, we show that an insular cortex to central amygdala circuit is necessary for conditioned overconsumption, but not for homeostatic feeding. This projection is marked by a population of glutamatergic nitric oxide synthase-1 (Nos1)-expressing neurons, which are specifically active during feeding bouts. Finally, we show that activation of insular cortex Nos1 neurons suppresses satiety signals in the central amygdala. The data, thus, indicate that the insular cortex provides top-down control of homeostatic circuits to promote overconsumption in response to learned cues., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 Elsevier Inc. All rights reserved.)

The brain mechanisms underlying conditioned aversion learning in birds were studied using experimental model in young chicks. The learning consisted of a conditioning stimulus presentation followed by a delayed sickness-inducing treatment reinforcement. Intraventricular administration of an NMDA receptor antagonist MK-801, a protein synthesis inhibitor anisomycin, or an inhibitor of glycoprotein fucosylation 2-deoxygalactose just before presentation of the conditioning stimulus prevented aversion learning. Injections of the same chemicals before reinforcement did not affect learning. The obtained results show that the investigated mechanisms underlying aversion learning were critical at the early stage of memory formation. Later processes of association of the conditioning stimulus with the reinforcement appear to be independent of the NMDA receptors and protein synthesis/glycosylation, or alternatively to be located in other brain areas., (© 2021. Springer Science+Business Media, LLC, part of Springer Nature.)

Gut microbiota influence numerous aspects of host biology, including brain structure and function. Growing evidence implicates gut microbiota in aversive conditioning and anxiety-related behaviors, but research has focused almost exclusively on males. To investigate whether effects of gut dysbiosis on aversive learning and memory differ by sex, adult female and male C57BL/6N mice were orally administered a moderate dose of nonabsorbable antimicrobial medications (ATMs: neomycin, bacitracin, and pimaricin) or a control over 10 days. Changes in gut microbiome composition were analyzed by 16S rRNA sequencing. Open field behavior, cued aversive learning, context recall, and cued recall were assessed. Following behavioral testing, the morphology of basolateral amygdala (BLA) principal neuron dendrites and spines was characterized. Results revealed that ATMs induced gut dysbiosis in both sexes, with stronger effects in females. ATMs also exerted sex-specific effects on behavior and neuroanatomy. Males were more susceptible than females to microbial modulation of locomotor activity and anxiety-like behavior. Females were more susceptible than males to ATM-induced impairments in aversive learning and cued recall. Context recall remained intact, as did dendritic structure of BLA principal neurons. However, ATMs exerted a sex-specific effect on spine density. A second experiment was conducted to isolate the effects of gut perturbation to cued recall. Extinction was also examined. Results revealed no effect of ATMs on cued recall or extinction, suggesting that gut dysbiosis preferentially impacts aversive learning. These data shed new light on how gut microbiota interact with sex to influence aversive conditioning, open field behavior, and BLA dendritic spine architecture., (© 2021 Wiley Periodicals LLC.)

Rationale: The co-occurrence of alcohol consumption and sexual activity is associated with increased risk for sexual assault, sexually transmitted disease, and unplanned pregnancy among young adult women with alcohol use disorder (AUD). There is considerable previous work demonstrating neural reactivity to alcohol cues in AUD. Because alcohol consumption and sexual behavior are both rewarding and tend to co-occur, sexual cues may produce similar neural reactivity in women with AUD, possibly indicating a shared mechanism underlying reactivity to both types of cues. Alternatively, reactivity to alcohol versus sexual cues may be distinct, suggesting domain-specific mechanisms., Objectives: We investigated whether the decision vulnerabilities in AUD women regarding sexual activity were related to differences in brain activation compared to control women., Methods: Women with (n = 15) and without (n = 16) AUD completed a hypothetical decision-making task during fMRI that presented low- or high-risk scenarios involving visual sexual, appetitive, and neutral cues., Results: Results showed that sexual cues were more often endorsed by women with AUD compared to controls and elicited differential brain activation patterns in frontal, visual, and reward regions. During high-risk decisions, women with AUD failed to downregulate activation, causing hyperactivation compared to controls., Conclusions: Visual sexual cues produced reactivity like that previously demonstrated for alcohol cues, suggesting a shared or domain-general mechanism for alcohol and sexual cue reactivity in women with AUD. Riskier sexual decisions in women with AUD may be a consequence of repeatedly pairing alcohol use and sexual activity, a characteristic behavior of this population.

Fear generalization is a symptom of anxiety-related disorders, including acute stress disorder and post-traumatic stress disorder. Using a contextual fear conditioning paradigm, we found that mice exposed to a similar neutral context but not a different neutral context soon after training showed fear generalization immediately after contextual fear memory consolidation (i.e., 6 h after training). This fear generalization was reflected by a change not only in the total amount but also the pattern of freezing between conditioned and generalized contexts. These results provide insight into the factors that influence fear generalization and can facilitate future studies investigating the underlying pathophysiological mechanisms of anxiety-related disorders., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Memories of adverse events can be maladaptive when they lead to exaggerated fear, as observed in post-traumatic stress disorder (PTSD). Fear conditioning and fear sensitization are learning processes thought to play a role in fear-related disorders, and only few animal studies have evaluated the relationship between the associative and non-associative fear memory components on the development and maintenance of PTSD-like behavioral changes. Here we assessed the effects of a single dose of propranolol (10 mg/kg) or saline after fear memory retrieval on the long-term behavioral responses induced by severe stress in male rats. Animals were submitted to contextual fear conditioning (delayed shock group) or not (non-shock group) and underwent fear memory retrieval followed by propranolol or saline administration two weeks later. Rats were then evaluated in different behavioral tests to assess the expression of the conditioned fear response, anxiety-like and exploratory behaviors, and fear response after the presentation of unknown acoustic stimulus. Post-retrieval propranolol did not disrupt the subsequent expression of neither conditioned fear response nor the exploratory deficit and fear sensitization response, indicating that propranolol failed to mitigate long-term behavioral changes induced by severe stress in rats., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Rats display a rich social behavioral repertoire. An important component of this repertoire is the emission of whistle-like calls in the ultrasonic range, so-called ultrasonic vocalizations (USV). Long low-frequency 22-kHz USV occur in aversive situations, including aggressive interactions, predator exposure, and electric shocks during fear conditioning. They are believed to reflect a negative affective state akin to anxiety and fear. A prominent theory suggests that 22-kHz USV function as alarm calls to warn conspecifics. Serotonin (5-hydroxytryptamine, 5-HT) is strongly implicated in the regulation of affective states, particularly anxiety and fear. A key component of the system is the 5-HT transporter (5-HTT, also known as SERT), regulating 5-HT availability in the synaptic cleft. In the present experiment, we studied the effects of SERT deficiency on overt fear-related behavior and alarm 22-kHz USV during fear conditioning in male and female rats. While overt fear-related behavior was not affected by SERT deficiency and sex, the emission of alarm 22-kHz USV was clearly reduced in homozygous SERT -/- but not heterozygous SERT +/- mutants, as compared to their wildtype SERT +/+ littermate controls. Genotype effects were particularly prominent in females. Females in general emitted fewer alarm 22-kHz USV than males. This supports the view that 22-kHz USV are, at least partly, independently regulated from anxiety or fear and as socially mediated alarm calls do not simply express a negative affective state. Reduced 22-kHz USV emission in rats lacking SERT might be due to social deficits in the use of 22-kHz USV as a socio-affective signal to warn conspecifics about threats., (Copyright © 2020 Elsevier Inc. All rights reserved.)