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Among symptoms of post-traumatic stress disorders (PTSD), flashbacks, fear memory extinction deficits and chronic pain are the most cited. This innovative model, focusing on morphine withdrawal symptoms persistence in the context of a conditioned stress, may be valuable to evaluate new behavioral and pharmacological strategies of the PTSD - addiction comorbidity. [Extracted from the article]

Highlights: [•] ABA-renewal is not observed in infant rats when using standard contexts (without explicit odors). [•] The ABA-renewal procedure was effective in reinstating the extinguished CR when contexts (A and B) included an explicit odor. [•] This is the first evidence of renewal of an extinguished fear conditioning response in the infant rat. [Copyright &y& Elsevier]

Highlights: [•] We used an imaging genetics approach during fear conditioning in healthy people. [•] Risk variant for alcoholism in GRIN2A affects amygdala activity during conditioning. [•] Risk variant for alcoholism in GRIN2A affects insula activity during conditioning. [•] These reduced responses may represent an intermediate phenotype for alcoholism. [ABSTRACT FROM AUTHOR]

Drugs that modulate serotonin (5-HT) synaptic concentrations impact neurogenesis and hippocampal (HPC)-dependent learning. The primary objective is to determine the extent to which psilocybin (PSOP) modulates neurogenesis and thereby affects acquisition and extinction of HPC-dependent trace fear conditioning. PSOP, the 5-HT agonist 25I-NBMeO and the 5-HT antagonist ketanserin were administered via an acute intraperitoneal injection to mice. Trace fear conditioning was measured as the amount of time spent immobile in the presence of the conditioned stimulus (CS, auditory tone), trace (silent interval) and post-trace interval over 10 trials. Extinction was determined by the number of trials required to resume mobility during CS, trace and post-trace when the shock was not delivered. Neurogenesis was determined by unbiased counts of cells in the dentate gyrus of the HPC birth-dated with BrdU co-expressing a neuronal marker. Mice treated with a range of doses of PSOP acquired a robust conditioned fear response. Mice injected with low doses of PSOP extinguished cued fear conditioning significantly more rapidly than high-dose PSOP or saline-treated mice. Injection of PSOP, 25I-NBMeO or ketanserin resulted in significant dose-dependent decreases in number of newborn neurons in hippocampus. At the low doses of PSOP that enhanced extinction, neurogenesis was not decreased, but rather tended toward an increase. Extinction of 'fear conditioning' may be mediated by actions of the drugs at sites other than hippocampus such as the amygdala, which is known to mediate the perception of fear. Another caveat is that PSOP is not purely selective for 5-HT receptors. PSOP facilitates extinction of the classically conditioned fear response, and this, and similar agents, should be explored as potential treatments for post-traumatic stress disorder and related conditions. [ABSTRACT FROM AUTHOR]

Common and persistent fears may emerge through learning mechanisms such as fear conditioning and generalisation. Although there have been extensive studies of these learning processes in healthy but also psychiatric samples, many of the tasks used to produce conditioning and assess generalisation either use painful and aversive stimuli as the unconditioned stimuli (UCS), or suffer from poor belongingness between the conditioned stimuli and the UCS. Here, we present novel data from a paradigm designed to examine fear conditioning and generalisation in healthy individuals. Two female faces served as conditioned threat cue (CS+) and conditioned safety cue (CS−) respectively. The CS+ was paired repeatedly with a fearful, screaming face (unconditioned stimulus). Generalisation included intermediate faces which varied in their similarity to the CS+ and CS−. We measured eyeblink startle reflex and self-reported ratings. Acquired fear of the CS+ generalised to intermediate stimuli in proportion to their perceptual similarity to the CS+. Our findings demonstrate how fears of new individuals may develop based on resemblance to others with whom an individual has had negative experiences. The paradigm offers new opportunities for probing the role of generalisation in the emergence of common and persistent fears. [ABSTRACT FROM PUBLISHER]

Memories can be unreliable. We created a false memory in mice by optogenetically manipulating memory engram-bearing cells in the hippocampus. Dentate gyrus (DG) or CA1 neurons activated by exposure to a particular context were labeled with channelrhodopsin-2. These neurons were later optically reactivated during fear conditioning in a different context. The DG experimental group showed increased freezing in the original context, in which a foot shock was never delivered. The recall of this false memory was context-specific, activated similar downstream regions engaged during natural fear memory recall, and was also capable of driving an active fear response. Our data demonstrate that it is possible to generate an internally represented and behaviorally expressed fear memory via artificial means. [ABSTRACT FROM AUTHOR]

Highlights: [•] Microinjection of GRP at the IL cortex elicits GRP release at the BLA. [•] Co-administration of a GRP receptor antagonist (RC-3095) blocks this effect. [•] A functional pathway utilizing GRP between the IL cortex and the BLA is proposed. [ABSTRACT FROM AUTHOR]

Highlights: [•] C57BL/6 mice acquired conditioned fear and subsequent fear extinction that were retained weeks later. [•] During retention testing, dendritic spines and intersections were measured in basolateral amygdala neurons. [•] Fear conditioning increased spines and intersections and fear extinction reversed these effects. [ABSTRACT FROM AUTHOR]

Highlights: [•] Preexposure parameters influence the CPFE similarly in adult and juvenile rats. [•] Enhanced preexposure does not alter impairment of the CPFE by neonatal alcohol. [•] Neonatal alcohol impairs spatial cognition by disrupting cholinergic function. [ABSTRACT FROM AUTHOR]

Three experiments used an ABA renewal paradigm to study deepening of response loss produced by extinction of reinstated or ABC renewed fear responses. In Experiment 1, rats were trained with two stimuli, Si and S2, in context A and extinguished to S1 in context B and S2 in context C, shocked in B but not in C, and subjected to additional extinction of S1 in B and S2 in C. Rats froze less to S1 than S2 when subsequently tested in A. In Experiments 2 and 3, following training of S1 and S2 in A, one group received extinction of S1 in B and S2 in C followed by extinction of S1 in C and S2 in B. This group froze less to S1 in A or to S2 in a novel context, D, than a group always extinguished to Si in B and S2 in C or a group extinguished to both S1 and S2 in B and C. These results show that additional extinction of a conditioned stimulus (conditional stimulus [CS]) exhibiting either reinstatement or ABC renewal renders that CS resistant to ABA renewal. They are consistent with theories that allow a role for context in extinction learning and that use error-correction mechanisms to update this learning. [ABSTRACT FROM AUTHOR]

Highlights: [•] Extensive review on mPFC functions in conditioned fear behavior. [•] Contribution of mPFC neuronal elements and circuits in fear behavior. [•] Detailed neuronal and cellular mechanisms involved in the regulation of fear memory. [•] Neuronal rate and temporal encoding of fear responses in the mPFC. [•] Optogenetic strategies to causally relate mPFC circuits and fear behavior. [ABSTRACT FROM AUTHOR]

Background: Like fear conditioning, the acquisition phase of extinction involves new learning that is mediated by the amygdala. During extinction training, the conditioned stimulus is repeatedly presented in the absence of the unconditioned stimulus, and the expression of previously learned fear gradually becomes suppressed. Our previous study revealed that chronic treatment with a selective serotonin reuptake inhibitor (SSRI) impairs the acquisition of auditory fear conditioning. To gain further insight into how SSRIs affect fear learning, we tested the effects of chronic SSRI treatment on the acquisition of extinction. Methods: Rats were treated chronically (22 days) or subchronically (9 days) with the SSRI citalopram (10 mg/kg/day) before extinction training. The results were compared with those after chronic and subchronic treatment with tianeptine (10 mg/kg/day), an antidepressant with a different method of action. The expression of the NR2B subunit of the N-methyl-D-aspartate receptor in the amygdala was examined after behavioral testing. Results: Chronic but not subchronic administration of citalopram impaired the acquisition of extinction and downregulated the NR2B subunit of the N-methyl-D-aspartate receptor in the lateral and basal nuclei of the amygdala. Similar behavioral and molecular changes were found with tianeptine treatment. Conclusions: These results provide further evidence that chronic antidepressant treatment can impair amygdala-dependent learning. Our findings are consistent with a role for glutamatergic neurotransmission in the final common pathway of antidepressant treatment. [ABSTRACT FROM AUTHOR]

Background: Fearful experiences can produce long-lasting and debilitating memories. Extinction of conditioned fear requires consolidation of new memories that compete with fearful associations. In human subjects, as well as rats, posttraining stimulation of the vagus nerve enhances memory consolidation. Subjects with posttraumatic stress disorder show impaired extinction of conditioned fear. The objective of this study was to determine whether vagus nerve stimulation (VNS) can enhance the consolidation of extinction of conditioned fear. Methods: Male Sprague-Dawley rats were trained on an auditory fear conditioning task followed by 1 to 10 days of extinction training. Treatment with vagus nerve or sham stimulation was administered concurrently with exposure to the fear conditioned stimulus. Another group was given VNS and extinction training but the VNS was not paired with exposure to conditioned cues. Retention of fear conditioning was tested 24 hours after each treatment. Results: Vagus nerve stimulation paired with exposure to conditioned cues enhanced the extinction of conditioned fear. After a single extinction trial, rats given VNS stimulation demonstrated a significantly lower level of freezing, compared with that of sham control rats. When extinction trials were extended to 10 days, paired VNS accelerated extinction of the conditioned response. Conclusions: Extinction paired with VNS is more rapid than extinction paired with sham stimulation. As it is currently approved by the Federal Food and Drug Administration for depression and seizure prevention, VNS is a readily available and promising adjunct to exposure therapy for the treatment of severe anxiety disorders. [ABSTRACT FROM AUTHOR]

Introduction: Studies suggest that sleep plays a role in traumatic memories and that treatment of sleep disorders may help alleviate symptoms of posttraumatic stress disorder. Fear-conditioning paradigms in rodents are used to investigate causal mechanisms of fear acquisition and the relationship between sleep and posttraumatic behaviors. We developed a novel conditioning stimulus (CS) that evoked fear and was subsequently used to study re-exposure to the CS during sleep. Methods: Experiment 1 assessed physiological responses to a conditioned stimulus (mild transient hypercapnia, mtHC; 3.0% CO2; n = 17)+footshock for the purpose of establishing a novel CS in male FVB/J mice. Responses to the novel CS were compared to tone+footshock (n = 18) and control groups of tone alone (n = 17) and mild transient hypercapnia alone (n = 10). A second proof of principle experiment re-exposed animals during sleep to mild transient hypercapnia or air (control) to study sleep processes related to the CS. Results: Footshock elicited a response of acute tachycardia (30–40 bpm) and increased plasma epinephrine. When tone predicted footshock it elicited mild hypertension (1–2 mmHg) and a three-fold increase in plasma epinephrine. When mtHC predicted footshock it also induced mild hypertension, but additionally elicited a conditioned bradycardia and a smaller increase in plasma epinephrine. The overall mean 24 hour sleep–wake profile was unaffected immediately after fear conditioning. Discussion: Our study demonstrates the efficacy of mtHC as a conditioning stimulus that is perceptible but innocuous (relative to tone) and applicable during sleep. This novel model will allow future studies to explore sleep-dependent mechanisms underlying maladaptive fear responses, as well as elucidate the moderators of the relationship between fear responses and sleep. [ABSTRACT FROM AUTHOR]

Abstract: Background and objectives: Human fear conditioning is widely regarded as one of the prime paradigms for the study of fear and anxiety disorders. We provide an evaluation of a commonly used subjective measure in the human fear conditioning paradigm, namely the US-expectancy measurement. Methods: We assess the validity of US-expectancy with respect to conditions of pathological fear and anxiety using four established criteria for scrutiny of a laboratory test or model (i.e., face validity, diagnostic validity, predictive validity, construct validity). Results: Arguably, there is sufficient evidence for the face validity, diagnostic validity, predictive validity and construct validity of the US-expectancy measure. Limitations: Presumed limitations of the US-expectancy measure, including its susceptibility to experimental demand and memory bias, are discussed. Conclusions: The US-expectancy measure is a valuable measurement method that can be effectively used in research that aims to enhance our understanding of fear and anxiety disorders. [Copyright &y& Elsevier]

Heart physiology is a highly useful indicator for measuring not only physical states, but also emotional changes in animals. Yet changes of heart rate variability during fear conditioning have not been systematically studied in mice. Here, we investigated changes in heart rate and heart rate variability in both short-term and long-term contextual and cued fear conditioning. We found that while fear conditioning could increase heart rate, the most significant change was the reduction in heart rate variability which could be further divided into two distinct stages: a highly rhythmic phase (stage-I) and a more variable phase (stage-II). We showed that the time duration of the stage-I rhythmic phase were sensitive enough to reflect the transition from short-term to long-term fear memories. Moreover, it could also detect fear extinction effect during the repeated tone recall. These results suggest that heart rate variability is a valuable physiological indicator for sensitively measuring the consolidation and expression of fear memories in mice. [ABSTRACT FROM AUTHOR]

Abstract: There are still uncertainties about the role of the hippocampus (HPC) in memory consolidation. One theory, systems consolidation, states that the HPC is required for the initial storage of certain memories that subsequently become established in non-HPC networks through a lengthy process, involving an interaction with the HPC. A similar process may underlie the ability of multiple, distributed learning episodes of contextual fear conditioning to create a HPC-independent context fear memory, in a memory task that does not undergo systems consolidation with the mere passage of time [5]. The current study examined whether post-learning HPC activity is necessary to establish these HPC-independent context memories through distributed learning episodes. Rats received either three or six context conditioning sessions over the course of three days. The HPC-dependence of context memories was assessed using multisite, temporary inactivation of the HPC using ropivacaine during retention testing. We established that six conditioning sessions, but not three, created a memory that could be retrieved while the HPC was inactive. To directly test our hypothesis, HPC was inactivated after half of the six context-shock pairings in an independent group of rats. The rats were then tested for retention of context fear in the absence of HPC activity. Post-learning inactivation of the HPC did not affect the establishment of a HPC-independent context memory. These results favor the idea that at least one memory system outside the HPC can acquire context memories independently. [Copyright &y& Elsevier]

Abstract: Group III metabotropic glutamate receptors (mGluRs), which are generally located presynaptically, modulate synaptic transmission by regulating neurotransmitter release. Previously we showed enhanced amygdala-dependent cued fear conditioning in mGluR4−/− mice 24 h following training involving two tone-shock pairings. In this study, we assessed the effects of modulating mGluR4 signaling on acquisition and extinction of conditioned fear. mGluR4−/− and wild-type female and male mice received 10 tone-shock pairings during training. Compared to wild-type mice, mGluR4−/− mice showed enhanced acquisition and extinction of cued fear. Next, we assessed whether acute pharmacological stimulation of mGluR4 with the specific orthosteric mGluR4 agonist LSP1-2111 also affects acquisition and extinction of cued fear. Consistent with the enhanced acquisition of cued fear in mGluR4−/−, LSP1-2111, at 2.5 and 5 mg/kg, inhibited acquisition of cued fear conditioning in wild-type male mice. The drug''s effect on extinction was less clear and only a subtle effect was seen at 5 mg/kg. Finally, analysis of microarray data of amygdala tissues from mGluR4−/− versus wild-type and from wild-type mice treated with a mGluR4 agonist versus saline revealed a significant overlap in pattern of gene expression. Together, these data support a role for mGluR4 signaling in acquisition of fear learning and memory. This article is part of a Special Issue entitled ‘Metabotropic Glutamate Receptors’. [Copyright &y& Elsevier]

Abstract: Positive emotional states have been reported to modify human resilience to fear and anxiety, but few animal models are available to elucidate underlying mechanisms. In the current study, we examined whether 2 weeks of tickling, which is considered to evoke positive emotions, alters conditioned fear and hormonal reactions in Fischer rats. We conditioned rats to fear an auditory tone which was initially paired with a mild foot-shock (0.2mA), and retention test was conducted 48h and 96h after conditioning. During these tests, we found that prior tickling treatment significantly diminished fear-induced freezing. To examine the effects of tickling on sympatho-adrenal and hypothalamic-pituitary-adrenal responses associated with conditioned fear, we measured plasma catecholamine and corticosterone levels in the retention test 96h after conditioning. The plasma catecholamine concentration of non-tickled rats was higher than basal levels, whereas tickled rats showed significantly reduced concentrations of both plasma adrenaline and noradrenaline. No significant differences in plasma corticosterone levels were observed between tickled and non-tickled rats. These results suggest that repeated exposure to tickling can modulate fear-related behavior and sympatho-adrenal stress responses. [Copyright &y& Elsevier]

The putative endogenous imidazoline binding site ligand harmane enhances neuronal activation in response to psychological stress and alters behaviour in animal models of anxiety and antidepressant efficacy. However, the neurobiological mechanisms underlying harmane’s psychotropic effects are poorly understood. We investigated the effects of intraperitoneal injection of harmane (2.5 and 10 mg/kg) on fear-conditioned behaviour, hypothalamo-pituitary-adrenal axis activity, and monoaminergic activity within specific fear-associated areas of the rat brain. Harmane had no significant effect on the duration of contextually induced freezing or 22 kHz ultrasonic vocalisations and did not alter the contextually induced suppression of motor activity, including rearing. Harmane reduced the duration of rearing and tended to increase freezing in non-fear-conditioned controls, suggesting potential sedative effects. Harmane increased plasma ACTH and corticosterone concentrations, and serotonin (in hypothalamus, amygdaloid cortex, prefrontal cortex and hippocampus) and noradrenaline (prefrontal cortex) content, irrespective of fear-conditioning. Furthermore, harmane reduced dopamine and serotonin turnover in the PFC and hypothalamus, and serotonin turnover in the amygdaloid cortex in both fear-conditioned and non-fear-conditioned rats. In contrast, harmane increased dopamine and noradrenaline content and reduced dopamine turnover in the amygdala of fear-conditioned rats only, suggesting differential effects on catecholaminergic transmission in the presence and absence of fear. The precise mechanism(s) mediating these effects of harmane remain to be determined but may involve its inhibitory action on monoamine oxidases. These findings support a role for harmane as a neuromodulator, altering behaviour, brain neurochemistry and neuroendocrine function. [ABSTRACT FROM AUTHOR]

Fear extinction can be defined as the weakening of the expression of a conditioned response (CR) by extended experience of nonreinforcement. Conceptually, two distinct models have been invoked to account for extinction. R. A. Rescorla and A. R. Wagner (1972, A theory of Pavlovian conditioning: Variations in the effectiveness of reinforcement and nonreinforcement, in A. H. B. W. F. Prokasy (Ed.), Classical conditioning: II. Current research and theory, pp. 64-99, New York, NY, Appleton-Century-Crofts) postulated that the number of exposure trials is the primary determinant of CR decrement, whereas C. R. Gallistel and J. Gibbon (2000, Time, rate, and conditioning, Psychological Review, Vol. 107, pp. 289-344) proposed that the decisive event is the cumulated exposure time to the nonreinforced conditioned stimulus (CS) elapsed after the last CS reinforcement. We evaluated these two accounts in a human differential fear conditioning study in which CR was measured with the fear-potentiated startle response. Cumulated duration of nonreinforcement fails to explain our findings, whereas the number of trials appeared critical. In fact, many CS trials with a duration shorter than the acquisition CS duration facilitated within-session extinction, but this effect did not predict the recovery of fear. [ABSTRACT FROM AUTHOR]

Abstract: We investigated the relationship between deficits in fear memory induced by sleep deprivation and pCREB expression in the basal and central nuclei of the amygdala. Sleep deprivation reduced pCREB expression in the central nucleus compared to control or sleep recovered groups, and in the basal nucleus only compared to sleep recovered group. Moreover, 24h of sleep recovery prior to training prevented changes in both pCREB expression and performance. [Copyright &y& Elsevier]

Abstract: Background: Women are twice as likely as men to develop Posttraumatic Stress Disorder (PTSD). Abnormal acquisition of conditioned fear has been suggested as a mechanism for the development of PTSD. While some studies of healthy humans suggest that women are either no different or express less conditioned fear responses during conditioning relative to men, differences in the acquisition of conditioned fear between men and women diagnosed with PTSD has not been examined. Methods: Thirty-one participants (18 men; 13 women) with full or subsyndromal PTSD completed a fear conditioning task. Participants were shown computer-generated colored circles that were paired (CS+) or unpaired (CS−) with an aversive electrical stimulus and skin conductance levels were assessed throughout the task. Results: Repeated measures ANOVA indicated a significant sex by stimulus interaction during acquisition. Women had greater differential conditioned skin conductance responses (CS + trials compared to CS− trials) than did men, suggesting greater acquisition of conditioned fear in women with PTSD. Conclusions: In contrast to studies of healthy individuals, we found enhanced acquisition of conditioned fear in women with PTSD. Greater fear conditioning in women may either be a pre-existing vulnerability trait or an acquired phenomenon that emerges in a sex-dependent manner after the development of PTSD. Characterizing the underlying mechanisms of these differences is needed to clarify sex-related differences in the pathophysiology of PTSD. [Copyright &y& Elsevier]

Abstract: The present study investigated interoceptive fear conditioning (IFC) to an interoceptive and exteroceptive conditional stimulus (CS) with a severe respiratory load applied for 30s as the unconditional stimulus (US). CSs were another, weak respiratory load in the intero-IFC study (N =74), and a neutral picture in the extero-IFC study (N =42). CSs preceded the US in the paired groups, whereas the unpaired groups received the same number of unpaired CSs and USs. We measured startle blink EMG, self-reported fear and respiration. In the intero-IFC study, the CS-load was associated with larger startle blinks and a smaller decrease in respiratory rate and tidal volume in the paired compared to the unpaired group. In the extero-IFC study, the CS-picture evoked an increase in tidal volume and self-reported fear only in the paired group. In addition, startle potentiation during the CS-picture was greater for the paired than for the unpaired group. [Copyright &y& Elsevier]

Abstract: Fear conditioning is one of the prime paradigms of behavioural neuroscience and a source of tremendous insight in the fundamentals of learning and memory and the psychology and neurobiology of emotion. It is also widely regarded as a model for the pathogenesis of anxiety disorders in a diathesis-stress model of psychopathology. Starting from the apparent paradox between the adaptive nature of fear conditioning and the dysfunctional nature of pathological anxiety, we present a critique of the human fear conditioning paradigm as an experimental model for psychopathology. We discuss the potential benefits of expanding the human fear conditioning paradigm by (1) including action tendencies as an important index of fear and (2) paying more attention to “weak” (i.e., ambiguous) rather than “strong” fear learning situations (Lissek et al., 2006), such as contained in selective learning procedures. We present preliminary data that illustrate these ideas and discuss the importance of response systems divergence in understanding individual differences in vulnerability for the development of pathological anxiety. [Copyright &y& Elsevier]

Abstract: A differential fear conditioning paradigm was used with 107 healthy undergraduate participants to evaluate the effect of conditioned stimulus (CS) temporal properties on fear acquisition and extinction. Two minute duration CSs were used for Day 1 fear acquisition. Participants were randomized to receive either 1, 2, or 4min CS durations during Day 2 extinction. Extinction re-test was examined on Day 3 using the original acquisition CS duration (2min). Findings indicated that participants who were aware of the CS+/unconditioned stimulus (US) contingency (n =52) develop a temporal expectation about when the unconditioned stimulus will be delivered. Although the shorter duration CS resulted in greater fear reduction during extinction, cessation of fear responding at re-test was the same for CS extinction durations ranging from half the CS acquisition duration to twice the CS acquisition duration. Thus, extinction performance did not predict extinction at re-test, which could have important implications for optimizing exposure therapy for anxiety disorders. [Copyright &y& Elsevier]

Abstract: Two experiments are described that explore the effects of verbal information and direct conditioning in the acquisition and extinction of fear responses. Participants were given verbal threat information about novel animals before conditioning trials in which the animals were presented alongside an aversive outcome (Experiment 1), or positive information about the animals before extinction trials (Experiment 2). Fear was measured using self-reported fear beliefs, expectancy of the unconditioned stimulus (US) and event-related brain potential (ERP). The results showed a direct effect of verbal information on acquisition (Experiment 1) and extinction (Experiment 2). There was a P2 peak latency shift at acquisition (Experiment 1) and P1 mean amplitude response at extinction (Experiment 2) based on the interaction between verbal information and US-contingency. However, the P2 response showed little evidence for an enhanced conditioned response (CR) when verbal threat information and direct conditioning combined: earlier P2 responses were found for all animals that had been associated with either threat information or the aversive US. Additionally, increase in P1 mean amplitude response (Experiment 2) seemed to stem from the conflict between verbal information and contingency information, rather than the predicted decrease in response where positive information and extinction training were combined. Future studies are suggested that might explore whether attention/arousal modulate the P1 response as a result of such expectation violations. [Copyright &y& Elsevier]

Abstract: We investigated whether resting brain metabolism can be used to predict autonomic and neuronal responses during fear conditioning in 20 healthy humans. Regional cerebral metabolic rate for glucose was measured via positron emission tomography at rest. During conditioning, autonomic responses were measured via skin conductance, and blood oxygen level dependent signal was measured via functional magnetic resonance imaging. Resting dorsal anterior cingulate metabolism positively predicted differentially conditioned skin conductance responses. Midbrain and insula resting metabolism negatively predicted midbrain and insula functional reactivity, while dorsal anterior cingulate resting metabolism positively predicted midbrain functional reactivity. We conclude that resting metabolism in limbic areas can predict some aspects of psychophysiological and neuronal reactivity during fear learning. [Copyright &y& Elsevier]

Abstract: Recent studies on fear generalization have demonstrated that fear-potentiated startle and skin conductance responses to a conditioned stimulus (CS) generalize to similar stimuli, with the strength of the fear response linked to perceptual similarity to the CS. The aim of the present study was to extend this work by examining neural correlates of fear generalization. An initial experiment (N =8) revealed that insula reactivity tracks the conditioned fear gradient. We then replicated this effect in a larger independent sample (N =25). Activation in the insula, anterior cingulate, right supplementary motor cortex and caudate increased reactivity as generalization stimuli (GS) were more similar to the CS, consistent with participants’ overall ratings of perceived shock likelihood and pupillary response to each stimulus. [Copyright &y& Elsevier]

Animal models of posttraumatic stress disorder (PTSD) are based on fear conditioning where innocuous cues elicit reactions that originally occur to traumatic events--a core feature of PTSD. Another core feature is hyperarousal--exaggerated reactions to stressful events. One limitation of animal models of PTSD is that group effects do not model the sporadic incidence of PTSD. We developed an animal model of PTSD in which rabbit nictitating membrane responses become exaggerated as a function of classical conditioning to a tone conditioned stimulus (CS) paired with a shock unconditioned stimulus (US). Exaggerated responses to the US are a form of hyperarousal termed conditioning-specific reflex modification (CRM) and occur in the absence of the CS. Inspecting data across several experiments, we determined 25% of our rabbits exhibit strong CRM despite all subjects having high levels of condition-ing. To determine how prone rabbits were to CRM (susceptibility) or how resistant (resilience), we examined data from 135 rabbits analyzing for factors during CS-US pairings and during US prescreening that would predict CRM. We found the magnitude of CRM was correlated with the onset latency and area of conditioned responding during CS-US pairings and with the peak latency of a response during US pretesting. In an animal model of PTSD that more accurately reflects clinical prevalence, we can begin to predict susceptibility not only during responding to a stressful conditioning situation but also during a screening process before the stressful situation takes place. The results suggest relatively innocuous testing may help detect PTSD after trauma and screen for it before trauma occurs. [ABSTRACT FROM AUTHOR]

Absence of memory or verbal recall for symptom acquisition in fear and trauma exposure, as well as absence of successful coping behavior for life events, is associated with a number of diagnoses, including traumatic brain injury, posttraumatic stress disorder, pain, and anxiety. The difficulty with diagnosis and treatment planning based on the absence of recall, memory, and successful coping behavior is threefold: (1) these assessments do not distinguish between disruption of behavior and lack of capacity, (2) the absence of verbal recall and memory complicates cognitive-based treatment, and (3) a confounding issue is the same absent behavior can be observed at different times and contexts. While memory of the specific details of the initial traumatic event(s) may not be available to verbal report, the existence of time- and context-dependent relationships for the initial as well as subsequent experiences is arguable. The absence of memory or lack of verbal recall does not rule out measurable physiological bodily responses for the initial trauma(s), nor does it help to establish the effects of subsequent experiences for symptom expression. Also, the absence of memory must include the prospect of fear-based learning that does not require or involve the cortex. It is posited that the literatures of fear conditioning and learned nonuse provide complementary illustrations of how the time and context of the initial trauma(s) and subsequent experiences affect behavior, which is not dependent on the effected individual being able to provide a memory-based verbal report. The replicated clinical application demonstrates that, without scientific demonstration, neither neuroanatomy nor verbal report can be assumed sufficient to predict overt behavior or physiologic responses. For example, while commonly assumed to be predictively so, autonomic nervous system innervation is insufficient to define the unique stimulus- and context-dependent physiological responses of an individual. By recording simultaneous physiological responses to the controlled presentation of a context-dependent stimulus, the unique relationships of physiology and overt behaviors for the individual can be demonstrated. Using this process also allows more complex virtual reality or other in vivo stimulus assessments to be incorporated for the development of individually tailored assessments and therapeutic plans. Thus, with or without memory or verbal recall, the use of multiple time- and context-specific simultaneous physiological measures and overt behavior can guide clinical effort as well as serve to objectively assess the ongoing treatment and its outcome. [ABSTRACT FROM AUTHOR]

Background. Enhanced acquisition and delayed extinction of fear conditioning are viewed as major determinants of anxiety disorders, which are often characterized by a dysfunctional hypothalamic-pituitary-adrenal (HPA) axis. Method. In this study we employed cued fear conditioning in two independent samples of healthy subjects (sample 1: n = 60, sample 2: n = 52). Two graphical shapes served as conditioned stimuli and painful electrical stimulation as the unconditioned stimulus. In addition, guided by findings from published animal studies on HPA axis-related genes in fear conditioning, we examined variants of the glucocorticoid receptor and corticotropin-releasing hormone receptor 1 genes. Results. Variation in these genes showed enhanced amygdala activation during the acquisition and reduced prefrontal activation during the extinction of fear as well as altered amygdala-prefrontal connectivity. Conclusions. This is the first demonstration of the involvement of genes related to the HPA axis in human fear conditioning. [ABSTRACT FROM AUTHOR]

Abstract: Many personality theories link specific traits to the sensitivities of the neural systems that control approach and avoidance. But there is no consensus on the nature of these systems. Here we combine recent advances in economics and neuroscience to provide a more solid foundation for a neuroscience of approach/avoidance personality. We propose a two-stage integration of valuation (loss/gain) sensitivities with motivational (approach/avoidance/conflict) sensitivities. Our key conclusions are: (1) that valuation of appetitive and aversive events (e.g. gain and loss as studied by behavioural economists) is an independent perceptual input stage – with the economic phenomenon of loss aversion resulting from greater negative valuation sensitivity compared to positive valuation sensitivity; (2) that valuation of an appetitive stimulus then interacts with a contingency of presentation or omission to generate a motivational ‘attractor’ or ‘repulsor’, respectively (vice versa for an aversive stimulus); (3) the resultant behavioural tendencies to approach or avoid have distinct sensitivities to those of the valuation systems; (4) while attractors and repulsors can reinforce new responses they also, more usually, elicit innate or previously conditioned responses and so the perception/valuation–motivation/action complex is best characterised as acting as a ‘reinforcer’ not a ‘reinforcement’; and (5) approach–avoidance conflict must be viewed as activating a third motivation system that is distinct from the basic approach and avoidance systems. We provide examples of methods of assessing each of the constructs within approach–avoidance theories and of linking these constructs to personality measures. We sketch a preliminary five-element reinforcer sensitivity theory (RST-5) as a first step in the integration of existing specific approach–avoidance theories into a coherent neuroscience of personality. [Copyright &y& Elsevier]

Recent advances in the field of fear learning have demonstrated that a single reminder exposure prior to extinction training can prevent the return of extinguished fear by disrupting the process of reconsolidation. These findings have however proven hard to replicate in humans. Given the significant implications of preventing the return of fear, the purpose of the present study was to further study the prerequisites for the putative effects of disrupting reconsolidation. In two experiments, we assessed whether extinction training initiated within the reconsolidation time window could abolish the return of fear using fear-relevant (experiment 1) or fear-irrelevant (experiment 2) conditioned stimuli (CS). In both experiments, participants went through conditioning, extinction and reinstatement testing on three consecutive days, with one of two reinforced CS being reactivated 10 minutes prior to extinction. We found that a single reminder exposure prior to extinction training did not prevent the return of extinguished fear responding using either fear-relevant or fear-irrelevant CSs. Our findings point to the need to further study the specific parameters that enable disruption of reconsolidation. [ABSTRACT FROM AUTHOR]

The only evidence-based behavioral treatment for anxiety and stress-related disorders involves desensitization techniques that rely on principles of extinction learning. However, 40% of patients do not respond to this treatment. Efforts have focused on individual differences in treatment response, but have not examined when, during development, such treatments may be most effective. We examined fear-extinction learning across development in mice and humans. Parallel behavioral studies revealed attenuated extinction learning during adolescence. Probing neural circuitry in mice revealed altered synaptic plasticity of prefrontal cortical regions implicated in suppression of fear responses across development. The results suggest a lack of synaptic plasticity in the prefrontal regions, during adolescence, is associated with blunted regulation of fear extinction. These findings provide insight into optimizing treatment outcomes for when, during development, exposure therapies may be most effective. [ABSTRACT FROM AUTHOR]

A series of experiments used rats to compare and contrast the effects of subjecting an already extinguished target conditioned stimulus (CS) to additional extinction in compound with either another extinguished or a nonextinguished CS. Exposure to either compound restored responding and their extinction deepened the loss of fear responses (freezing) to the target relative to a CS given equivalent extinction in isolation. This deepening was greater to the target extinguished in compound with the nonextinguished than with the extinguished CS. Summation tests showed that the target suppressed responding to an excitor or an excitatory context when it had been extinguished in compound with a nonextinguished but not with an extinguished CS. The results were interpreted to mean that additional extinction in compound with another extinguished CS resulted in the target acquiring the additional inhibition required to more fully oppose its original excitation. In contrast, additional extinction in compound with a nonextinguished CS resulted in the target acquiring not only the additional inhibition required to oppose its original excitation but also that of the nonextinguished CS, thereby converting the target into a net inhibitor. [ABSTRACT FROM AUTHOR]

Abstract: Fear extinction can be viewed as an inhibitory learning process. This is supported by post-extinction phenomena demonstrating the return of fear, such as reinstatement. Recent work has questioned this account, claiming that extinction initiated immediately after fear acquisition can abolish the return of fear. In the current study, participants were fear conditioned to four different conditioned stimuli (CS) and underwent extinction either immediately or after a 24h delay. During extinction, we manipulated CS contingency awareness by presenting two of the CSs (one CS+, one CS−) under non-masked conditions and the other two CSs under masked conditions. Compared to delayed extinction, immediate extinction of non-masked CSs promoted less extinction of fear-potentiated startle and shock expectancy ratings and less reinstatement of fear-potentiated startle without affecting shock expectancy ratings. Critically, future research should clarify how the differences between immediate and delayed extinction in within-session extinction modulate the recovery of fear. [Copyright &y& Elsevier]

Previously, zebrafish were shown to respond to the presence of a live predator, the sight of a live predator, moving computer images of a predator, and images of different moving objects in a context and stimulus specific manner. For example, zebrafish showed a robust antipredatory reaction towards a sympatric predator, the Indian leaf fish (Nandus nandus) but not towards an allopatric predator or sympatric or allopatric harmless fish species. In a subsequent study, however, we found zebrafish not to show avoidance in response to the image of another sympatric predator, Xenentodon cancila. The results implied that zebrafish may possess genetic predispositions that allow them to effectively evade at least certain sympatric predators without any prior exposure to them. However, it is not known whether zebrafish can respond to other sympatric predators with antipredatory reactions without any prior exposure to such predators. It is also not known whether such responses may be dependent upon, or idiosyncratic to, predator species. To answer these questions, we examined the effect of computer animated (moving) images of five different predator species all sympatric with zebrafish (Nandus nandus, Channa maculata, Xenentodon cancila, Mystus bleekeri, Chitala chitala) and of two abstract shapes (star and rectangle, also animated) on zebrafish behaviour. The results confirmed that the sight of N. nandus is an aversive stimulus and that the image of X. cancila is not. However, the results also revealed that images of three other species (C. maculata, M. bleekeri, C. chitala) and that of a rectangle induce even more robust aversive reactions than what is elicited by N. nandus. At this point we do not know what features of the images may be perceived as aversive by zebrafish or whether the observed behavioural responses would be adaptive or effective in nature. Nevertheless, we argue that image-presentation based fear paradigms will be useful in future translational research. We also conclude that it may be premature to decide whether zebrafish can recognize their sympatric predators. [ABSTRACT FROM AUTHOR]

Abstract: In this study, we investigated whether two brain regions, the bed nucleus of the stria terminalis (BNST) and the basolateral amygdala (BLA), affected male rats’ (Rattus norvigicus) ability to innately discriminate between a predator odor (cat urine) and female rat urine. Muscimol, a GABAa receptor agonist, was bilaterally microinjected into either the BNST or BLA of rats through implanted stainless-steel guide cannulas to temporarily inactivate these brain nuclei. The behavioral responses of the treated rats to female rat urine and cat urine were then tested in an experimental arena. Compared to a saline infusion control, the injection of muscimol into the BNST strongly reversed the innate aversion of rats to cat urine but the injection of muscimol into the BLA had no effect. Furthermore, intra-BNST infusion of muscimol caused rats to be equally attracted to urine from cats and female rats but intra-BLA infusion did not stop rats manifesting fear on exposure to cat urine and exploratory behavior on exposure to female rat urine. We conclude that the BNST plays a more crucial role in modulating innate fear responses in rats than the BLA. [Copyright &y& Elsevier]

Abstract: The hippocampus plays a critical role in contextual fear conditioning. Population activity in the hippocampal CA1 encoding the surrounding environment is thought to be responsible for retrieval of contextual fear memory. However, the characteristics of CA1 neuronal ensemble activity during retrieval of contextual fear memory remain unclear. Here, we examined CA1 ensemble activity during contextual fear memory expression in male C57Bl/6J mice, using Arc cellular compartment analysis of temporal activity by fluorescence in situ hybridization. The “Shock” group was conditioned with a footshock in two separate chambers, whereas the “No shock” group was not exposed to shocks in the chamber. Animals were then re-exposed to either the same chamber twice or two different conditioning chambers. In the No shock group, exposure to the same chamber twice activated a more significantly overlapping neuronal population than exposure to two different chambers. In the Shock group, exposure to the same conditioning chamber twice activated a similarly overlapping neuronal population as exposure to two different chambers, with overlap smaller than in nonshocked mice exposed to the same chamber twice. Thus, population activity in the hippocampal CA1 encoding the surrounding environment is detected during spatial exploration, but absent during contextual fear memory expression. Even the variable ensemble activity of CA1 may contribute to retrieval of contextual fear memory. [Copyright &y& Elsevier]

People seem to differ in their conditionability, that is, the ease by which fear associations (neutral stimulus-unconditioned stimulus [CS-us] contingencies) are learned. Recently, the level of trait worry has been proposed as a predictor of heightened conditionability. The current research aimed to (a) further investigate this influence of individual differences in trait worry on the strength of fear acquisition, (b) explore whether this association could be explained by trait anxiety, and (c) assess possible underlying mechanisms of this relationship. In a nonclinical sample, the amount of trait worry predicted heightened conditionability in a differential fear conditioning paradigm, both in fear ratings and in performance on a secondary probe reaction time task.A significant correlation was observed for general conditioning to the CS+ and also for differential conditioning (taking into account excitatory and inhibitory responding) in Experiment l.These associations could not be fully explained by trait anxiety. US inflation and strengthening of the CS-US contingency through rehearsal are discussed as possible underlying mechanisms. [ABSTRACT FROM AUTHOR]

Abstract: The learning of new information and recall of that information presumably involves modification of and access to shared circuitry in the brain. However, learning and recall may involve the activation of distinct parts of that circuitry, according to the quite distinct functional differences between these two processes. Previously we examined neuronal activation following learning of context fear conditioning. Using the Fos-Tau-LacZ (FTL) transgenic mouse to label activated neurons, we identified a number of distinct populations of neurons in amygdala and hypothalamus which showed learning specific activation. These populations of neurons showed much less activation following recall. Here we ask what populations of neurons might be specifically activated following recall. We trained mice in context fear conditioning, and then looked at FTL activation following recall of context fear. We identified a number of populations of neurons which showed recall specific activation in nucleus accumbens shell, the anterio-medial bed nucleus of stria terminalis, the anterior commissural nucleus and the periventricular hypothalamic nucleus. These were all different populations of neurons compared with those activated following context fear learning. These different functional activation patterns occurring between learning and recall may reflect the different brain functions occurring between these two memory related processes. [Copyright &y& Elsevier]

Abstract: The deleterious effects of paradoxical sleep deprivation on memory processes are well documented. However, non-selective sleep deprivation occurs more commonly in modern society and thus represents a better translational model. We have recently reported that acute total sleep deprivation (TSD) for 6h immediately before testing impaired performance of male mice in the plus-maze discriminative avoidance task (PM-DAT) and in the passive avoidance task (PAT). In order to extend these findings to females, we examined the effect of (pre-test) TSD on the retrieval of different memory tasks in both male and female mice. Animals were tested using 3 distinct memory models: 1) conditioning fear context (CFC), 2) PAT and 3) PM-DAT. In all experiments, animals were totally sleep-deprived by the gentle interference method for 6h immediately before being tested. In the CFC task and the PAT, TSD induced memory impairment regardless of sex. In PM-DAT, the memory impairing effects of TSD were greater in females. Collectively, our results confirm the impairing effect of TSD on emotional memory retrieval and demonstrate that it can be higher in female mice depending on the memory task evaluated. [Copyright &y& Elsevier]

Recent epidemiological studies demonstrate that obesity is related to a high incidence of cognitive impairment. In the present study, cognitive behaviours in diet-induced obese (DIO) mice fed 60% high-fat diet for 16 weeks were compared with those in mice fed a control diet (CD) in fear-conditioning tests including both contextual and cued elements that preferentially depend on the hippocampus and amygdala, respectively. Furthermore, brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) content in the brain areas was examined in both CD and DIO mice. In fear-conditioning tests, the freezing percentages of both contextual fear and cued fear responses in DIO mice were significantly lower than in CD mice. BDNF content in the cerebral cortex and hippocampus of DIO mice was significantly lower than that in CD mice. Its receptor, full-length TrkB, in the amygdala of DIO mice was significantly decreased compared to that in CD mice, although not in the cerebral cortex, hippocampus and hypothalamus. By contrast, NT-3 content in the hippocampus, amygdala and hypothalamus of DIO mice was significantly higher than that in CD mice. Its receptor, full-length TrkC, was not significantly different between CD and DIO mice. The present study demonstrates that DIO mice show impairment of both hippocampus-dependent contextual and amygdala-dependent cued responses in the fear-conditioning tests, as well as an imbalance in the interaction between the BDNF and NT-3 systems in the cerebral cortex, hippocampus and amygdala related to cognition and fear. [ABSTRACT FROM AUTHOR]

Abstract: Research on the inhibition of learned fear currently relies almost exclusively on one specific procedure, namely extinction of the conditioned stimulus (CS). Importantly, however, learned fear responses can be reduced by a number of other procedures, including habituation of the unconditioned stimulus (US). We recently demonstrated that reductions in learned fear following US habituation, like CS extinction, were subject to both renewal and reinstatement (). The present study further investigates the associative and non-associative processes shared between habituation and extinction. Given that habituation is typically context-independent (), in the present study we directly compared renewal and reinstatement of both a conditioned response (CR; freezing) and an unconditioned response (UR; startle) following habituation. It was found that the reduction in conditioned freezing resulting from habituation was context specific (i.e., a change in context led to a renewal of the conditioned fear response; Experiment 1) and was attenuated when a pre-test shock was given (i.e., reinstatement of conditioned fear was observed; Experiment 2). In contrast, habituation of an unconditioned response elicited by the US (i.e., a startle response) was unaffected by either a change in test context or administration of a pre-test shock. This dissociation in the effects of habituation on learned and unlearned responses is discussed in relation to theories of fear extinction. [Copyright &y& Elsevier]

Abstract: Anxiety disorders, characterized by anxiety and fearfulness, are found to be able to cause abnormal emotional responses’ associated with memories of negative events, which implicate pressure on society with an increasingly large burden. Better treatment has been of concern to the community. Venlafaxine (VEN), a nonclassical antidepressant agent, is applied in the treatment of social phobia, major depression (MD) and general anxiety disorder (GAD) and, to a certain extent, posttraumatic stress disorder (PTSD), which improves working memory and spatial memory as well as ameliorates emotion by affecting specified brain regions. In this study, we committed to seek a new way for using VEN on treatment of anxiety disorders. To investigate the effect of VEN on extinction of auditory-cue conditioned fear, conditioned rats received a treatment with VEN before extinction training and tests for freezing level of within-session and between-session extinction. To investigate the effect of VEN on reinstatement, all conditioned rats received a treatment with VEN over a period for 21 days. After a rest for 7 days, two tests for freezing level were conducted. We found that: (1) VEN (40mg/kg) treatment at 30min prior to extinction training significantly facilitated the between-session extinction, but not the within-session extinction; (2) chronic administration with VEN (40mg/kg) prevented the return of extinguished auditory-cue fear. These data elucidate the critical role of VEN in auditory-cue fear memory, suggesting that VEN may be an ideal choice for the exposure-based drug treatment and maintenance treatment in patients with GAD, SAD and PTSD. [Copyright &y& Elsevier]

Abstract: Conditioned fear is supported by a distributed network that prominently includes lateral and central amygdaloid nuclei. The role of corticomedial amygdaloid nuclei, including the medial nucleus (MeA), in fear acquisition or expression is not well understood. The present study demonstrates that pre-training excitotoxic lesions directed at the MeA disrupted both fear-potentiated startle (FPS) and conditioned freezing behavior elicited by re-exposure to a discrete olfactory cue. In contrast, such lesions had no effect on baseline startle reactivity or contextual FPS. These findings suggest that the MeA plays an obligatory role in either the acquisition or expression of olfactory conditioned fear, not limited by form of behavioral expression, but is not necessary for contextual conditioned fear. [Copyright &y& Elsevier]

Abstract: Auditory P50 suppression, which is assessed using a paired auditory stimuli (S1 and S2) paradigm to record the P50 mid-latency evoked potential, is assumed to reflect sensory gating. Recently, P50 suppression deficits were observed in patients with anxiety disorders, including panic disorder, post-traumatic stress disorder and obsessive–compulsive disorder, as we previously reported. The processes of fear conditioning are thought to play a role in the pathophysiology of anxiety disorders. In addition, we found that the P50 sensory gating mechanism might be physiologically associated with fear conditioning and extinction in a simple human fear-conditioning paradigm that involved a light signal as a conditioned stimulus (CS+). Our objective was to investigate the different patterns of P50 suppression in a discrimination fear-conditioning paradigm with both a CS+ (danger signal) and a CS− (safety signal). Twenty healthy volunteers were recruited. We measured the auditory P50 suppression in the control (baseline) phase, in the fear-acquisition phase, and in the fear-extinction phase using a discrimination fear-conditioning paradigm. Two-way (CSs vs. phase) Analysis of variance with repeated measures demonstrated a significant interaction between the two factors. Post-hoc LSD analysis indicated that the P50 S2/S1 ratio in the CS+ acquisition phase was significantly higher than that in the CS− acquisition phase. These results suggest that the auditory P50 sensory gating might differ according to the cognition of the properties (potentially dangerous or safe) of the perceived signal. [Copyright &y& Elsevier]

Abstract: Recent research investigating Pavlovian fear conditioning and fear extinction has elucidated the neurocircuitry involved in acquisition and inhibition of fear responses. Modulatory factors that may underlie individual differences in fear acquisition and inhibition, however, are not well understood. Testosterone is known to affect anxiety-like behavior and cognitive processing. In this study, we hypothesized that castration would increase anxiety and reduce memory for contextual fear conditioning in an age-dependent manner. In addition, castration would reduce the rate of extinction to context, as high levels of testosterone correlate with reduced PTSD-like symptoms. We compared behaviors in male mice that were castrated at one of two different time points, either before puberty (at 4weeks) or after puberty (at 10weeks) to sham-operated control mice. The behaviors investigated included: anxiety, cued and contextual fear conditioning, and extinction of the fear memory. An interaction of hormone status and age and a significant effect of age were measured in the elevated plus maze, a measure of anxiety. Castration caused a significant reduction of contextual fear memory, but no effect on cued fear memory. There was no significant effect of castration on extinction. Interestingly, a significant effect of age of the mouse at the time of testing was observed on extinction. These results suggest that endogenous androgens during puberty are important for anxiety and fear memory formation. In addition, these results define a late post-adolescent developmental time point for changes in anxiety and fear extinction. [Copyright &y& Elsevier]