Classical Fear Conditioning Research Articles

PACAP and the PAC1 Receptor in Post-Traumatic Stress Disorder

Post-traumatic stress disorder (PTSD) affects approximately 5–10% of all individuals and is more predominant in women (Breslau, 2001). Advances in treatment and prevention will require identifying biomarkers to aid early diagnosis and understanding the mechanisms underlying maladaptive responses to trauma. In a highly traumatized, urban civilian population, we have recently reported that women (but not men) that had been diagnosed with PTSD had higher blood PACAP (pituitary adenylate cyclase-activating polypeptide) levels (Ressler et al, 2011) (Figure 1a). The high PACAP levels were correlated with physiological measures of the acoustic startle reflex, which have previously also been associated with PTSD risk. In addition, to further understand the responsiveness of the PACAP system to emotionally relevant cues and ovarian hormones, we showed that mRNA levels of the receptor for PACAP–PAC1R, are increased in the extended amygdala of adult rodents following classical fear conditioning and as a function of estrogen exposure. These findings suggested that PACAP might be involved in the symptoms characteristic of women diagnosed with PTSD. Figure 1 Relationship between the pituitary adenylate cyclase-activating polypeptide (PACAP)–PAC1 receptor (PAC1R) system and post-traumatic stress disorder (PTSD). (a) Females, but not males with high plasma PACAP38 levels show more PTSD symptoms. (b) ... To further genetically probe this association, we analyzed the PACAP (Adcyap1) gene and its receptor-PAC1 (Adcyap1r1). Only the Adcyap1r1 SNP (rs2267735) was found to be associated with PTSD diagnosis in women (again not in males) (Figure 1b). Although note that this SNP association was not replicated in a less traumatized cohort (Chang et al., 2012). At the epigenetic level, we also found that differential methylation of the Adcyap1r1 gene was associated with PTSD symptoms (Figure 1c). Given the approximately 2 : 1 sex-bias in PTSD prevalence, we find it exciting that the Adcyap1r1 SNP is within a predicted estrogen response element (ERE). Furthermore, in a postmortem sample, we found that females had differential cortical expression of Adcyap1r1 mRNA levels as a function of their genotype. Notably, a recent follow-up study finds that the same genetic risk is associated with higher acoustic startle in traumatized boys and girls before puberty, suggesting that the estrogen effect may be age-dependent (Jovanovic et al, 2012). Looking to the future, the association between PTSD and the PACAP–PAC1 receptor system in traumatized populations warrants further investigation on several important levels. For example, longitudinal prospective studies are needed to ascertain whether peripheral PACAP levels would serve as a robust predictive biomarker of eventual PTSD diagnosis. The PACAP–PAC1 receptor system has been studied for its role in stress responsiveness (Vaudry et al, 2009; Stroth et al, 2011), and as such presents a convergence between the stress and learning components of PTSD that should be investigated further. The genetic observation of a predicted ERE supports other findings that hormonal mechanisms may underlie the sex-bias in PTSD prevalence (Ferree et al, 2011; Lebron-Milad and Milad, 2012), but replications of this finding are necessary. Finally, learning is accompanied by epigenetic modifications at key genetic loci (Zovkic and Sweatt, 2012), and probing the epigenetic signatures at the Adcyap1and Adcyap1r1 genes as a result of previous traumatic experience or hormonal condition presents fertile ground for empirical analysis (Figure 1). In summary, the relationship between PTSD and the PACAP–PAC1 receptor system affords us the opportunity to address PTSD from the perspectives of stress physiology, endocrinology, epigenetics, and predictive biomarkers using human samples and animal models—a truly multi-pronged attack that may be required for understanding complex neuropsychiatric disorders.

Acquired fears reflected in cortical sensory processing: A review of electrophysiological studies of human classical conditioning

The capacity to associate neutral stimuli with affective value is an important survival strategy that can be accomplished by cell assemblies obeying Hebbian learning principles. In the neuroscience laboratory, classical fear conditioning has been extensively used as a model to study learning-related changes in neural structure and function. Here, we review the effects of classical fear conditioning on electromagnetic brain activity in humans, focusing on how sensory systems adapt to changing fear-related contingencies. By considering spatiotemporal patterns of mass neuronal activity, we illustrate a range of cortical changes related to a retuning of neuronal sensitivity to amplify signals consistent with fear-associated stimuli at the cost of other sensory information. Putative mechanisms that may underlie fear-associated plasticity at the level of the sensory cortices are briefly considered, and several avenues for future work are outlined.

Behavioral Determination of Stimulus Pair Discrimination of Auditory Acoustic and Electrical Stimuli Using a Classical Conditioning and Heart-rate Approach

Acute animal preparations have been used in research prospectively investigating electrode designs and stimulation techniques for integration into neural auditory prostheses, such as auditory brainstem implants1-3 and auditory midbrain implants4,5. While acute experiments can give initial insight to the effectiveness of the implant, testing the chronically implanted and awake animals provides the advantage of examining the psychophysical properties of the sensations induced using implanted devices6,7.Several techniques such as reward-based operant conditioning6-8, conditioned avoidance9-11, or classical fear conditioning12 have been used to provide behavioral confirmation of detection of a relevant stimulus attribute. Selection of a technique involves balancing aspects including time efficiency (often poor in reward-based approaches), the ability to test a plurality of stimulus attributes simultaneously (limited in conditioned avoidance), and measure reliability of repeated stimuli (a potential constraint when physiological measures are employed).Here, a classical fear conditioning behavioral method is presented which may be used to simultaneously test both detection of a stimulus, and discrimination between two stimuli. Heart-rate is used as a measure of fear response, which reduces or eliminates the requirement for time-consuming video coding for freeze behaviour or other such measures (although such measures could be included to provide convergent evidence). Animals were conditioned using these techniques in three 2-hour conditioning sessions, each providing 48 stimulus trials. Subsequent 48-trial testing sessions were then used to test for detection of each stimulus in presented pairs, and test discrimination between the member stimuli of each pair. This behavioral method is presented in the context of its utilisation in auditory prosthetic research. The implantation of electrocardiogram telemetry devices is shown. Subsequent implantation of brain electrodes into the Cochlear Nucleus, guided by the monitoring of neural responses to acoustic stimuli, and the fixation of the electrode into place for chronic use is likewise shown.

Behavioral Determination of Stimulus Pair Discrimination of Auditory Acoustic and Electrical Stimuli Using a Classical Conditioning and Heart-rate Approach

Acute animal preparations have been used in research prospectively investigating electrode designs and stimulation techniques for integration into neural auditory prostheses, such as auditory brainstem implants1-3 and auditory midbrain implants4,5. While acute experiments can give initial insight to the effectiveness of the implant, testing the chronically implanted and awake animals provides the advantage of examining the psychophysical properties of the sensations induced using implanted devices6,7. Several techniques such as reward-based operant conditioning6-8, conditioned avoidance9-11, or classical fear conditioning12 have been used to provide behavioral confirmation of detection of a relevant stimulus attribute. Selection of a technique involves balancing aspects including time efficiency (often poor in reward-based approaches), the ability to test a plurality of stimulus attributes simultaneously (limited in conditioned avoidance), and measure reliability of repeated stimuli (a potential constraint when physiological measures are employed). Here, a classical fear conditioning behavioral method is presented which may be used to simultaneously test both detection of a stimulus, and discrimination between two stimuli. Heart-rate is used as a measure of fear response, which reduces or eliminates the requirement for time-consuming video coding for freeze behaviour or other such measures (although such measures could be included to provide convergent evidence). Animals were conditioned using these techniques in three 2-hour conditioning sessions, each providing 48 stimulus trials. Subsequent 48-trial testing sessions were then used to test for detection of each stimulus in presented pairs, and test discrimination between the member stimuli of each pair. This behavioral method is presented in the context of its utilisation in auditory prosthetic research. The implantation of electrocardiogram telemetry devices is shown. Subsequent implantation of brain electrodes into the Cochlear Nucleus, guided by the monitoring of neural responses to acoustic stimuli, and the fixation of the electrode into place for chronic use is likewise shown.

Nonconscious fear is quickly acquired but swiftly forgotten

The ability to learn which stimuli in the environment pose a threat is critical for adaptive functioning. Visual stimuli that are associated with threat when they are consciously perceived can evoke physiological [1] and neural [2] responses consistent with fear arousal even when they are later suppressed from awareness. It remains unclear, however, whether a specific new fear association can be acquired for stimuli that are never consciously seen [3], and whether such acquisition develops differently from conscious learning. It has recently been suggested [4] that, rather than simply affording a degraded version of conscious experience, processing of emotional stimuli without awareness may differ qualitatively from conscious perception, evoking different patterns of neural activity across the brain or differences in the time-course of behavioral and physiological responses. Here, we investigated nonconscious fear acquisition and how it may differ from conscious learning using classical fear conditioning, and found that conscious and unconscious fear acquisition both occur, but evolve differently over time.

Bimodal Control of Fear-Coping Strategies by CB1Cannabinoid Receptors

To maximize their chances of survival, animals need to rapidly and efficiently respond to aversive situations. These responses can be classified as active or passive and depend on the specific nature of threats, but also on individual fear coping styles. In this study, we show that the control of excitatory and inhibitory brain neurons by type-1 cannabinoid (CB₁) receptors is a key determinant of fear coping strategies in mice. In classical fear conditioning, a switch between initially predominant passive fear responses (freezing) and active behaviors (escape attempts and risk assessment) develops over time. Constitutive genetic deletion of CB₁ receptors in CB₁⁻/⁻ mice disrupted this pattern by favoring passive responses. This phenotype can be ascribed to endocannabinoid control of excitatory neurons, because it was reproduced in conditional mutant mice lacking CB₁ receptors from cortical glutamatergic neurons. CB₁ receptor deletion from GABAergic brain neurons led to the opposite phenotype, characterized by the predominance of active coping. The CB₁ receptor agonist Δ⁹-tetrahydrocannabinol exerted a biphasic control of fear coping strategies, with lower and higher doses favoring active and passive responses, respectively. Finally, viral re-expression of CB₁ receptors in the amygdala of CB₁⁻/⁻ mice restored the normal switch between the two coping strategies. These data strongly suggest that CB₁ receptor signaling bimodally controls the spontaneous adoption of active or passive coping strategies in individuals. This primary function of the endocannabinoid system in shaping individual behavioral traits should be considered when studying the mechanisms of physiological and pathological fear.

Expression pattern of the cannabinoid receptor genes in the frontal cortex of mood disorder patients and mice selectively bred for high and low fear

Although the endocannabinoid system (ECS) has been implicated in brain development and various psychiatric disorders, precise mechanisms of the ECS on mood and anxiety disorders remain unclear. Here, we have investigated developmental and disease-related expression pattern of the cannabinoid receptor 1 (CB1) and the cannabinoid receptor 2 (CB2) genes in the dorsolateral prefrontal cortex (PFC) of humans. Using mice selectively bred for high and low fear, we further investigated potential association between fear memory and the cannabinoid receptor expression in the brain. The CB1, not the CB2, mRNA levels in the PFC gradually decrease during postnatal development ranging in age from birth to 50 years (r2 > 0.6 & adj. p < 0.05). The CB1 levels in the PFC of major depression patients were higher when compared to the age-matched controls (adj. p < 0.05). In mice, the CB1, not the CB2, levels in the PFC were positively correlated with freezing behavior in classical fear conditioning (p < 0.05). These results suggest that the CB1 in the PFC may play a significant role in regulating mood and anxiety symptoms. Our study demonstrates the advantage of utilizing data from postmortem brain tissue and a mouse model of fear to enhance our understanding of the role of the cannabinoid receptors in mood and anxiety disorders.

Comparison of brain and blood gene expression in an animal model of negative symptoms in schizophrenia

To investigate the potential of white blood cells as probes for central processes we have measured gene expression in both the anterior cingulate cortex and white blood cells using a putative animal model of negative symptoms in schizophrenia. The model is based on the capability of ketamine to induce psychotic symptoms in healthy volunteers and to worsen such symptoms in schizophrenic patients. Classical fear conditioning is used to assess emotional processing and cognitive function in animals exposed to sub-chronic ketamine vs. controls. Gene expression was measured using a commercially sourced whole genome rat gene array. Data analyses were performed using ANOVA (Systat 11). In both anterior cingulate cortex and white blood cells a significant interaction between ketamine and fear conditioning could be observed. The outcome is largely supported by our subsequent metagene analysis. Moreover, the correlation between gene expression in brain and blood is about constant when no ketamine is present (r~0.4). With ketamine, however, the correlation becomes very low (r~0.2) when there is no fear, but it increases to ~0.6 when fear and ketamine are both present. Our results show that under normal conditions ketamine lowers gene expression in the brain, but this effect is completely reversed in combination with fear conditioning, indicating a stimulatory action. This paradoxical outcome indicates that extreme care must be taken when using gene expression data from white blood cells as marker for psychiatric disorders, especially when pharmacological and environmental interactions are at play.

Stress hormones are associated with the neuronal correlates of instructed fear conditioning

The effects of sex and stress hormones on classical fear conditioning have been subject of recent experimental studies. A correlation approach between basal cortisol concentrations and neuronal activation in fear-related structures seems to be a promising alternative approach in order to foster our understanding of how cortisol influences emotional learning. In this functional magnetic resonance imaging study, participants with varying sex hormone status (20 men, 15 women taking oral contraceptives, 15 women tested in the luteal phase) underwent an instructed fear conditioning protocol with geometrical figures as conditioned stimuli and an electrical stimulation as unconditioned stimulus. Salivary cortisol concentrations were measured and afterwards correlated with fear conditioned brain responses. Results revealed a positive correlation between basal cortisol levels and differential activation in the amygdala in men and OC women only. These results suggest that elevated endogenous cortisol levels are associated with enhanced fear anticipation depending on current sex hormone availability.

Conditioned Withdrawal in Goldfish: A Simple and Inexpensive Preparation for the Study of Classical Fear Conditioning in Vertebrates

Summary.-A preparation for the study of classical fear conditioning in vertebrates is described. Its unique features are that it is inexpensive and easy to construct and operate. The following classical conditioning phenomena are demonstrated using this preparation: excitatory conditioning, extinction, contextual conditioning, blocking, a conditioned inhibition discrimination, and latent inhibition.

Fear conditioning-related changes in cerebellar Purkinje cell activities in goldfish.

BackgroundFear conditioning-induced changes in cerebellar Purkinje cell responses to a conditioned stimulus have been reported in rabbits. It has been suggested that synaptic long-term potentiation and the resulting increases in firing rates of Purkinje cells are related to the acquisition of conditioned fear in mammals. However, Purkinje cell activities during acquisition of conditioned fear have not been analysed, and changes in Purkinje cell activities throughout the development of conditioned fear have not yet been investigated. In the present study, we tracked Purkinje cell activities throughout a fear conditioning procedure and aimed to elucidate further how cerebellar circuits function during the acquisition and expression of conditioned fear.MethodsActivities of single Purkinje cells in the corpus cerebelli were tracked throughout a classical fear conditioning procedure in goldfish. A delayed conditioning paradigm was used with cardiac deceleration as the conditioned response. Conditioning-related changes of Purkinje cell responses to a conditioned stimulus and unconditioned stimulus were examined.ResultsThe majority of Purkinje cells sampled responded to the conditioned stimulus by either increasing or decreasing their firing rates before training. Although there were various types of conditioning-related changes in Purkinje cells, more than half of the cells showed suppressed activities in response to the conditioned stimulus after acquisition of conditioned fear. Purkinje cells that showed unconditioned stimulus-coupled complex-spike firings also exhibited conditioning-related suppression of simple-spike responses to the conditioned stimulus. A small number of Purkinje cells showed increased excitatory responses in the acquisition sessions. We found that the magnitudes of changes in the firing frequencies of some Purkinje cells in response to the conditioned stimulus correlated with the magnitudes of the conditioned responses on a trial-to-trial basis.ConclusionsThese results demonstrate that Purkinje cells in the corpus cerebelli of goldfish show fear conditioning-related changes in response to a stimulus that had been emotionally neutral prior to conditioning. Unconditioned stimulus-induced climbing fibre inputs to the Purkinje cells may be involved in mediating these plastic changes.

Fear conditioning is disrupted by damage to the postsubiculum.

The hippocampus plays a central role in spatial and contextual learning and memory, however relatively little is known about the specific contributions of parahippocampal structures that interface with the hippocampus. The postsubiculum (PoSub) is reciprocally connected with a number of hippocampal, parahippocampal and subcortical structures that are involved in spatial learning and memory. In addition, behavioral data suggest that PoSub is needed for optimal performance during tests of spatial memory. Together, these data suggest that PoSub plays a prominent role in spatial navigation. Currently it is unknown whether the PoSub is needed for other forms of learning and memory that also require the formation of associations among multiple environmental stimuli. To address this gap in the literature we investigated the role of PoSub in Pavlovian fear conditioning. In Experiment 1 male rats received either lesions of PoSub or Sham surgery prior to training in a classical fear conditioning procedure. On the training day a tone was paired with foot shock three times. Conditioned fear to the training context was evaluated 24 hr later by placing rats back into theconditioning chamber without presenting any tones or shocks. Auditory fear was assessed on the third day by presenting the auditory stimulus in a novel environment (no shock). PoSub-lesioned rats exhibited impaired acquisition of the conditioned fear response as well as impaired expression of contextual and auditory fear conditioning. In Experiment 2, PoSub lesions were made 1 day after training to specifically assess the role of PoSub in fear memory. No deficits in the expression of contextual fear were observed, but freezing to the tone was significantly reduced in PoSub-lesioned rats compared to shams. Together, these results indicate that PoSub is necessary for normal acquisition of conditioned fear, and that PoSub contributes to the expression of auditory but not contextual fear memory.

Better fear conditioning is associated with reduced symptom severity in autism spectrum disorders

Evidence from behavioral and neuroimaging studies suggest that atypical amygdala function plays a critical role in the development of autism spectrum disorders (ASD). The handful of psychophysiological studies examining amygdala function in ASD using classical fear conditioning paradigms have yielded discordant results. We recorded skin conductance response (SCR) during a simple discrimination conditioning task in 30 children and adolescents (ages 8-18) diagnosed with high-functioning ASD and 30 age- and IQ-matched, typically developing controls. SCR response in the ASD group was uniquely and positively associated with social anxiety; and negatively correlated with autism symptom severity, in particular with social functioning. Fear conditioning studies have tremendous potential to aid understanding regarding the amygdale's role in the varied symptom profile of ASD. Our data demonstrate that such studies require careful attention to task-specific factors, including task complexity; and also to contributions of dimensional, within-group factors that contribute to ASD heterogeneity.

Cracking the almond (Commentary on Prévost et al.)

Recent advances in functional magnetic resonance imaging (fMRI) have provided an unprecedented peek into the activity of subareas of major anatomical structures in the healthy human brain. However, little is known about subregional activity in the human amygdala, a small, almondshaped corticoid structure in the medial temporal lobe that lacks clear MRI landmarks for compartmentalization of its dozen nuclei. Previous attempts to localize functions within the amygdala using standard fMRI either have relied on gross subdivisions, such as quadrants (Dolcos et al., 2004), or have estimated where the peak activation clusters lie (Davis et al., 2010), sometimes with the aid of probabilistic atlases (Amunts et al., 2005). In pages 134–145 of this volume, Prevost et al. (2011) use high-resolution fMRI to evaluate amygdalar subregional responses during reward and avoidance learning. Their paper makes several important methodological advances, including improved resolution using a tailored fMRI protocol, increased precision due to a region-of-interest-based alignment approach and lack of spatial smoothing, and better specification of behavioral correlates using computational modeling. The results indicate that the centromedial (CM) and basolateral (BLA) divisions make dissociable contributions to avoidance and reward learning, respectively, for coding action value at the time of choice and for evaluating estimation uncertainty of the cue. The CM further correlated with reward value of anticipatory state signals in the avoidance condition. However, a lateral region of the BLA correlated with reward prediction errors at the time of trial outcome during both learning conditions, albeit in adjacent sectors. These findings contribute to the broader literature regarding specialization of rewardand avoidance-based learning systems in the human brain and demonstrate the potential efficacy of high-resolution fMRI for investigating larger amygdalar subdivisions. Yet the findings show that reward and avoidance learning may not be neatly compartmentalized across subnuclear divisions in all aspects, and, curiously, neither region showed increased activation to putative aversive signals (loss of money) in the avoidance condition. Discrepancies between these observations and the clear role of both the BLA and the CM during classical fear conditioning remain to be resolved. Future studies could further validate anatomical localization by considering the known differences in relative connectivity of the CM and BLA with subcortical versus cortical association areas, respectively (Swanson & Petrovich, 1998), as demonstrated by Etkin et al. (2009) using functional connectivity analyses.

Ventrolateral prefrontal cortex is required for fear extinction in a modified delay conditioning paradigm in rats

Recent evidence has demonstrated that the ventromedial prefrontal cortex (vmPFC) is a critical site of the neural circuits underlying fear extinction memory. The ventrolateral prefrontal cortex (vlPFC) is not directly involved in extinction processes within the aversive domain. However, most of the current cumulated data on extinction is based on a classical delay fear conditioning paradigm in which the interval between the onset of the conditioned stimulus (CS) and the unconditioned stimulus (US) is consistent in a given protocol. In the present study, we developed a modified delay fear conditioning paradigm in which the temporal distribution of the footshock US during the duration of the tone CS is programmed to be pseudorandom. Here, we examined the effects of electrolytic vmPFC and vlPFC lesions made before training on conditioned fear response in the modified paradigm. The behavioral procedure involved four sessions with a 24-h interval: habituation, fear conditioning, extinction training, and extinction test. Percent freezing to tone was assessed as a measure of conditioned fear response. The results show that neither vmPFC nor vlPFC lesions affect acquisition or extinction of conditioned fear response during the fear conditioning and extinction training sessions, respectively. During the extinction test session, both vmPFC- and vlPFC-lesioned rats showed deficits in the recall of the between-session extinction memory. The deficits could not be attributed to altered nonspecific responses (footshock sensitivity, locomotor activity, and nonspecific freezing response). Furthermore, vlPFC lesions made before training had no effect on conditioned fear response in the classical fear conditioning paradigm. These data suggest a preserved role of the vmPFC in fear extinction and a selective involvement of the vlPFC in extinction process in certain fear conditioning tasks.

P02-58 - The antidepressant agomelatine reduces fear long term memory but not acquisition or short term expression of fear memories

Alterations in fear learning processes may be implicated in mood disorders. Fear learning has been investigated with Pavlovian classical fear conditioning paradigms, consisting of pairing a neutral conditioned stimulus (CS), such as a tone, with an aversive unconditioned stimulus (US), such as a footshock. Upon subsequent exposure, the CS is perceived as aversive and provokes a fear response.The novel antidepressant agomelatine acts as a melatonergic receptor agonist and a 5-HT2C receptor antagonist. Its antidepressant action was demonstrated in preclinical and clinical studies. Agomelatine has also anxiolytic properties. The aim of this study was to determine how acute agomelatine treatment might differentially alter fear circuits by using auditory fear conditioning in the rat.A single pre-training injection of agomelatine (40 mg/kg intraperitoneally) significantly reduced freezing to the fear arousing CS 24 hours after training but not during training or 3 hours after training. This pattern of results is consistent with an effect on the consolidation of the fear memory. A single pre-testing injection of agomelatine had no effect on conditioned fear expression.These effects of agomelatine should be considered in relation to its antidepressant action. Agomelatine achieved a reduction of fear conditioning in a single dose, while classical SSRIs only reduced fear conditioning after chronic treatment. This finding is consistent with clinical studies suggesting a faster onset of action of agomelatine than classical SSRI treatment.

Enhanced fear expression in a psychopathological mouse model of trait anxiety: pharmacological interventions.

The propensity to develop an anxiety disorder is thought to be determined by genetic and environmental factors. Here we investigated the relationship between a genetic predisposition to trait anxiety and experience-based learned fear in a psychopathological mouse model. Male CD-1 mice selectively bred for either high (HAB), or normal (NAB) anxiety-related behaviour on the elevated plus maze were subjected to classical fear conditioning. During conditioning both mouse lines showed increased fear responses as assessed by freezing behaviour. However, 24 h later, HAB mice displayed more pronounced conditioned responses to both a contextual or cued stimulus when compared with NAB mice. Interestingly, 6 h and already 1 h after fear conditioning, freezing levels were high in HAB mice but not in NAB mice. These results suggest that trait anxiety determines stronger fear memory and/or a weaker ability to inhibit fear responses in the HAB line. The enhanced fear response of HAB mice was attenuated by treatment with either the α2,3,5-subunit selective benzodiazepine partial agonist L-838,417, corticosterone or the selective neurokinin-1 receptor antagonist L-822,429. Overall, the HAB mouse line may represent an interesting model (i) for identifying biological factors underlying misguided conditioned fear responses and (ii) for studying novel anxiolytic pharmacotherapies for patients with fear-associated disorders, including post-traumatic stress disorder and phobias.

Test–Retest Reliability during Fear Acquisition and Fear Extinction in Humans

Classical fear conditioning and extinction has been used to understand the neurobiology of fear learning and its inhibition. The recall of an extinction memory involves the ventromedial prefrontal cortex and the amygdala, and patients with posttraumatic stress disorder (PTSD) have been shown to exhibit deficits in this process. Furthermore, extinction forms the basis of exposure therapies commonly used to treat PTSD patients. It is possible that effective pharmacological and/or psychological treatment regimens could influence the activity of these regions, and thereby increase the ability to retain an extinction memory. However, to test this, a fear conditioning and extinction paradigm must demonstrate within-subject reproducibility over time. We, therefore, sought to test the within-subject reliability of a previously used 2-day, classical fear conditioning and extinction paradigm. Eighteen healthy participants participated in a 2-day paradigm on three occasions, each separated by at least 12 weeks. Conditioning and extinction took place on Day 1, and extinction recall and fear renewal were evaluated on Day 2 on each of the three occasions. The conditioned stimulus was a visual cue and the unconditioned stimulus was a mild electric shock to the fingers. Skin conductance was recorded throughout the experiment to measure conditioned responses. We found that conditioning and extinction recall were not significantly different across time and were correlated within subjects. These data illustrate the reliability of this paradigm and its potential usefulness in evaluating the influence of a given treatment on the fear extinction network in longitudinal within-subject designs.

Hippocampal lesion effects on occasion setting by contextual and discrete stimuli

Three experiments examined the role of the dorsal hippocampus (dHIPP) in occasion setting with diffuse contextual and discrete light stimuli serving as occasion setters in classical fear conditioning with rats. Both sham-operated and dHIPP-lesioned animals readily learned a L→T+, T− serial feature-positive discrimination in which a light (L) “set the occasion” for reinforcement of a tone (T+). dHIPP-lesioned animals were deficient, however, in acquiring a similar discrimination in which different contexts (A and B) served as occasion setters, i.e., A(T+) and B(T−). The lesioned animals also failed to discriminate between a context in which a tone had been partially reinforced and a context in which no conditioning had taken place, whereas sham-operated animals froze more to the tone in the conditioned context than in the novel context. Collectively, the data indicate that the dorsal hippocampus is important in processing information about the signaling value of contextual, but not discrete, stimuli.

Strain differences of selective attention in mice: Effect of Kamin blocking on classical fear conditioning

Selective attention was assessed in mice using a classical fear conditioning procedure. Mice were trained by three regimens involving contextual and/or cued conditioning (classical fear conditioning). Most notably, C57BL/6J mice exhibited salient contextual blocking, whereas DBA/2J and ICR mice did not. This study provides a new method to assess the selective attention of mice and describes an animal model for certain human mental disorders, such as schizophrenia.