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Sample records for classical fear conditioning

  1. Involvement of the cerebellum in classical fear conditioning in goldfish.

    PubMed

    Yoshida, Masayuki; Okamura, Izumi; Uematsu, Kazumasa

    2004-08-12

    To investigate the emotional role of the cerebellum of fish, we conducted experiments examining effects of cerebellar manipulations on fear-related classical heart rate conditioning in goldfish. We performed total ablation of the corpus cerebelli to examine the effect of irreversible effects. We also performed localized cooling of the corpus cerebelli, in place of the ablation, for reversible inactivation of the cerebellar function. Both the cardiac arousal response to the first presentation of the conditioned stimulus and the cardiac reflex to the aversive unconditioned stimulus were not impaired by the ablation or cooling of the corpus cerebelli. On the other hand, inactivation of cerebellar function severely impaired the acquisition of a conditioned cardiac response in the fear-related conditioning. In addition, localized cooling of the corpus cerebelli reversibly suppressed the expression of established conditioned response. We suggest that the cerebellum of fish is not only being a motor coordination center but also is involved in emotional learning.

  2. Conditioned withdrawal in goldfish: a simple and inexpensive preparation for the study of classical fear conditioning in vertebrates.

    PubMed

    Barela, Peter B

    2012-02-01

    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.

  3. Differential Transcriptional Response to Nonassociative and Associative Components of Classical Fear Conditioning in the Amygdala and Hippocampus

    ERIC Educational Resources Information Center

    Isiegas, Carolina; Stein, Joel; Hellman, Kevin; Hannenhalli, Sridhar; Abel, Ted; Keeley, Michael B.; Wood, Marcelo A.

    2006-01-01

    Classical fear conditioning requires the recognition of conditioned stimuli (CS) and the association of the CS with an aversive stimulus. We used Affymetrix oligonucleotide microarrays to characterize changes in gene expression compared to naive mice in both the amygdala and the hippocampus 30 min after classical fear conditioning and 30 min after…

  4. Conditioned fear in adult rats is facilitated by the prior acquisition of a classically conditioned motor response

    PubMed Central

    Lindquist, Derick H.; Mahoney, Luke P.; Steinmetz, Joseph E.

    2010-01-01

    Early in eyeblink classical conditioning, amygdala-dependent fear responding is reported to facilitate acquisition of the cerebellar-dependent eyeblink conditioned response (CR), in accord with the two-process model of conditioning (Konorski, 1967). In the current study, we predicted that the conditioned fear (e.g., freezing) observed during eyeblink conditioning may become autonomous of the eyeblink CR and amenable to further associative modification. Conditioned freezing was assessed during and following Pavlovian fear conditioning in Long-Evans rats that had or had not undergone eight prior sessions of eyeblink conditioning. The amplitude and frequency of the tone conditioned stimulus (CS) was held constant across both forms of conditioning. Following fear conditioning in Experiment 1, freezing to the tone CS, but not the context, was facilitated in rats that previously experienced CS-unconditioned stimulus (US) paired eyeblink conditioning. In Experiment 2, freezing immediately following each fear conditioning trial was enhanced in rats subjected to the antecedent eyeblink conditioning, indicating a faster acquisition rate. Finally, in Experiment 3, faster acquisition was seen only in those rats fear conditioned in the same context used for the prior eyeblink conditioning. Taken together, the data indicate that the conditioned fear associated with the context and CS as a result of eyeblink conditioning can be built upon or strengthened during subsequent learning. PMID:20493273

  5. Updated meta-analysis of classical fear conditioning in the anxiety disorders.

    PubMed

    Duits, Puck; Cath, Danielle C; Lissek, Shmuel; Hox, Joop J; Hamm, Alfons O; Engelhard, Iris M; van den Hout, Marcel A; Baas, Joke M P

    2015-04-01

    The aim of the current study was twofold: (1) to systematically examine differences in fear conditioning between anxiety patients and healthy controls using meta-analytic methods, and (2) to examine the extent to which study characteristics may account for the variability in findings across studies. Forty-four studies (published between 1920 and 2013) with data on 963 anxiety disordered patients and 1,222 control subjects were obtained through PubMed and PsycINFO, as well as from a previous meta-analysis on fear conditioning (Lissek et al.). Results demonstrated robustly increased fear responses to conditioned safety cues (CS-) in anxiety patients compared to controls during acquisition. This effect may represent an impaired ability to inhibit fear in the presence of safety cues (CS-) and/or may signify an increased tendency in anxiety disordered patients to generalize fear responses to safe stimuli resembling the conditioned danger cue (CS+). In contrast, during extinction, patients show stronger fear responses to the CS+ and a trend toward increased discrimination learning (differentiation between the CS+ and CS-) compared to controls, indicating delayed and/or reduced extinction of fear in anxiety patients. Finally, none of the included study characteristics, such as the type of fear measure (subjective vs. psychophysiological index of fear), could account significantly for the variance in effect sizes across studies. Further research is needed to investigate the predictive value of fear extinction on treatment outcome, as extinction processes are thought to underlie the beneficial effects of exposure treatment in anxiety disorders.

  6. Emotional stress evoked by classical fear conditioning induces yawning behavior in rats.

    PubMed

    Kubota, Natsuko; Amemiya, Seiichiro; Yanagita, Shinya; Nishijima, Takeshi; Kita, Ichiro

    2014-04-30

    Yawning is often observed not only in a state of boredom or drowsiness but also in stressful emotional situations, suggesting that yawning is an emotional behavior. However, the neural mechanisms for yawning during stressful emotional situations have not been fully determined, though previous studies have suggested that both parvocellular oxytocin (OT) and corticotropin-releasing factor (CRF) neurons in the hypothalamic paraventricular nucleus (PVN) are responsible for induction of yawning. Thus, using ethological observations and c-Fos immunohistochemistry, we examined whether emotional stress evoked by classical fear conditioning is involved in induction of yawning behavior in freely moving rats. Emotional stress induced yawning behavior that was accompanied by anxiety-related behavior, and caused neuronal activation of the central nucleus of the amygdala (CeA), as well as increases in activity of both OT and CRF neurons in the PVN. These results suggest that emotional stress may induce yawning behavior, in which the neuronal activation of the CeA may have a key role.

  7. Serotonin in fear conditioning processes.

    PubMed

    Bauer, Elizabeth P

    2015-01-15

    This review describes the latest developments in our understanding of how the serotonergic system modulates Pavlovian fear conditioning, fear expression and fear extinction. These different phases of classical fear conditioning involve coordinated interactions between the extended amygdala, hippocampus and prefrontal cortices. Here, I first define the different stages of learning involved in cued and context fear conditioning and describe the neural circuits underlying these processes. The serotonergic system can be manipulated by administering serotonin receptor agonists and antagonists, as well as selective serotonin reuptake inhibitors (SSRIs), and these can have significant effects on emotional learning and memory. Moreover, variations in serotonergic genes can influence fear conditioning and extinction processes, and can underlie differential responses to pharmacological manipulations. This research has considerable translational significance as imbalances in the serotonergic system have been linked to anxiety and depression, while abnormalities in the mechanisms of conditioned fear contribute to anxiety disorders.

  8. Classical conditioning of autonomic fear responses is independent of contingency awareness.

    PubMed

    Schultz, Douglas H; Helmstetter, Fred J

    2010-10-01

    The role of contingency awareness in classical conditioning experiments using human subjects is currently under debate. This study took a novel approach to manipulating contingency awareness in a differential Pavlovian conditioning paradigm. Complex sine wave gratings were used as visual conditional stimuli (CS). By manipulating the fundamental spatial frequency of the displays, we were able to construct pairs of stimuli that varied in discriminability. One group of subjects was given an "easy" discrimination, and another was exposed to a "difficult" CS+ and CS-. A 3rd group was exposed to a stimulus that was paired with the unconditional stimulus (UCS) 50% of the time and served as a control. Skin conductance response (SCR) and continuous UCS expectancy data were measured concurrently throughout the experiment. Differential UCS expectancy was found only in the easy discrimination group. Differential SCRs were found in the easy discrimination group as well as in the difficult discrimination group, but not in the 50% contingency control. The difficult discrimination group did not exhibit differential UCS expectancy but did show clear differential SCR. These observations support a dual process interpretation of classical conditioning whereby conditioning on an implicit level can occur without explicit knowledge about the contingencies. The role of contingency awareness in classical conditioning experiments using human subjects is currently under debate. This study took a novel approach to manipulating contingency awareness in a differential Pavlovian conditioning paradigm. Complex sine wave gratings were used as visual conditional stimuli (CS). By manipulating the fundamental spatial frequency of the displays, we were able to construct pairs of stimuli that varied in discriminability. One group of subjects was given an "easy" discrimination, and another was exposed to a "difficult" CS+ and CS-. A 3rd group was exposed to a stimulus that was paired with the

  9. The involvement of ventral tegmental area cholinergic muscarinic receptors in classically conditioned fear expression as measured with fear-potentiated startle.

    PubMed

    Greba, Q; Munro, L J; Kokkinidis, L

    2000-07-01

    Accumulating evidence suggests that dopamine (DA) neurons in the ventral tegmental area (VTA) contribute to the complex amygdala-based neurocircuitry that mediates fear-motivated behaviors. Because of acetylcholine's (ACh) role in DA neuronal activation, the involvement of VTA cholinergic muscarinic receptors in Pavlovian conditioned fear responding was evaluated in the present study. Fear-potentiated startle was used to assess the effects of intraVTA infused methylscopolamine on conditioned fear performance in laboratory rats. Application of this nonspecific muscarinic receptor antagonist to VTA neurons was observed to inhibit the ability of a conditioned stimulus (CS) previously paired with footshock to enhance the amplitude of the acoustic startle reflex. Doses of methylscopolamine that blocked conditioned fear expression did not alter baseline sensorimotor responding. These results identify ACh neurotransmission in the VTA as a potential excitatory mechanism underlying the fear-arousing properties of threatening environmental stimuli.

  10. Limbic system development underlies the emergence of classical fear conditioning during the third and fourth weeks of life in the rat.

    PubMed

    Deal, Alex L; Erickson, Kristen J; Shiers, Stephanie I; Burman, Michael A

    2016-04-01

    Classical fear conditioning creates an association between an aversive stimulus and a neutral stimulus. Although the requisite neural circuitry is well understood in mature organisms, the development of these circuits is less well studied. The current experiments examine the ontogeny of fear conditioning and relate it to neuronal activation assessed through immediate early gene (IEG) expression in the amygdala, hippocampus, perirhinal cortex, and hypothalamus of periweanling rats. Rat pups were fear conditioned, or not, during the third or fourth weeks of life. Neuronal activation was assessed by quantifying expression of FBJ osteosarcoma oncogene (FOS) using immunohistochemistry (IHC) in Experiment 1. Fos and early growth response gene-1 (EGR1) expression was assessed using qRT-PCR in Experiment 2. Behavioral data confirm that both auditory and contextual fear continue to emerge between PD 17 and 24. The IEG expression data are highly consistent with these behavioral results. IHC results demonstrate significantly more FOS protein expression in the basal amygdala of fear-conditioned PD 23 subjects compared to control subjects, but no significant difference at PD 17. qRT-PCR results suggest specific activation of the amygdala only in older subjects during auditory fear expression. A similar effect of age and conditioning status was also observed in the perirhinal cortex during both contextual and auditory fear expression. Overall, the development of fear conditioning occurring between the third and fourth weeks of life appears to be at least partly attributable to changes in activation of the amygdala and perirhinal cortex during fear conditioning or expression. (PsycINFO Database Record PMID:26820587

  11. Limbic system development underlies the emergence of classical fear conditioning during the 3rd and 4th weeks of life in the rat

    PubMed Central

    Deal, Alex L.; Erickson, Kristen J.; Shiers, Stephanie I.; Burman, Michael A.

    2016-01-01

    Classical fear conditioning creates an association between an aversive stimulus and a neutral stimulus. Although the requisite neural circuitry is well understood in mature organisms, the development of these circuits is less well studied. The current experiments examine the ontogeny of fear conditioning and relate it to neuronal activation assessed through immediate early gene (IEG) expression in the amygdala, hippocampus, perirhinal cortex, and hypothalamus of periweanling rats. Rat pups were fear conditioned, or not, during the 3rd or 4th weeks of life. Neuronal activation was assessed by quantifying expression of FBJ osteosarcoma oncogene (FOS) using immunohistochemistry (IHC) in Experiment 1. Fos and early growth response gene-1 (EGR1) expression was assessed using qRT-PCR in Experiment 2. Behavioral data confirm that both auditory and contextual fear continue to emerge between PD 17 and 24. The IEG expression data are highly consistent with these behavioral results. IHC results demonstrate significantly more FOS protein expression in the basal amygdala of fear conditioned PD 23 subjects compared to control subjects, but no significant difference at PD 17. qRT-PCR results suggest specific activation of the amygdala only in older subjects during auditory fear expression. A similar effect of age and conditioning status was also observed in the perirhinal cortex during both contextual and auditory fear expression. Overall, the development of fear conditioning occurring between the 3rd and 4th weeks of life appears to be at least partly attributable to changes in activation of the amygdala and perirhinal cortex during fear conditioning or expression. PMID:26820587

  12. Limbic system development underlies the emergence of classical fear conditioning during the third and fourth weeks of life in the rat.

    PubMed

    Deal, Alex L; Erickson, Kristen J; Shiers, Stephanie I; Burman, Michael A

    2016-04-01

    Classical fear conditioning creates an association between an aversive stimulus and a neutral stimulus. Although the requisite neural circuitry is well understood in mature organisms, the development of these circuits is less well studied. The current experiments examine the ontogeny of fear conditioning and relate it to neuronal activation assessed through immediate early gene (IEG) expression in the amygdala, hippocampus, perirhinal cortex, and hypothalamus of periweanling rats. Rat pups were fear conditioned, or not, during the third or fourth weeks of life. Neuronal activation was assessed by quantifying expression of FBJ osteosarcoma oncogene (FOS) using immunohistochemistry (IHC) in Experiment 1. Fos and early growth response gene-1 (EGR1) expression was assessed using qRT-PCR in Experiment 2. Behavioral data confirm that both auditory and contextual fear continue to emerge between PD 17 and 24. The IEG expression data are highly consistent with these behavioral results. IHC results demonstrate significantly more FOS protein expression in the basal amygdala of fear-conditioned PD 23 subjects compared to control subjects, but no significant difference at PD 17. qRT-PCR results suggest specific activation of the amygdala only in older subjects during auditory fear expression. A similar effect of age and conditioning status was also observed in the perirhinal cortex during both contextual and auditory fear expression. Overall, the development of fear conditioning occurring between the third and fourth weeks of life appears to be at least partly attributable to changes in activation of the amygdala and perirhinal cortex during fear conditioning or expression. (PsycINFO Database Record

  13. N-methyl-D-aspartate receptor antagonist MK-801 impairs learning but not memory fixation or expression of classical fear conditioning in goldfish (Carassius auratus).

    PubMed

    Xu, X; Davis, R E

    1992-04-01

    The amnestic effects of the noncompetitive antagonist MK-801 on visually mediated, classic fear conditioning in goldfish (Carassius auratus) was examined in 5 experiments. MK-801 was administered 30 min before the training session on Day 1 to look for anterograde amnestic effects, immediately after training to look for retrograde amnestic effects, and before the training or test session, or both, to look for state-dependence effects. The results showed that MK-801 produced anterograde amnesia at doses that did not produce retrograde amnesia or state dependency and did not impair the expression of conditioned or unconditioned branchial suppression responses (BSRs) to the conditioned stimulus. The results indicate that MK-801 disrupts the mechanism of learning of the conditioned stimulus-unconditioned stimulus relation. Evidence is also presented that the learning processes that are disrupted by MK-801 occur during the initial stage of BSR conditioning.

  14. Brief fear preexposure facilitates subsequent fear conditioning.

    PubMed

    Iwasaki, Satoshi; Sakaguchi, Tetsuya; Ikegaya, Yuji

    2015-06-01

    Post-traumatic stress disorder (PTSD) is an anxiety disorder that occurs following an unexpected exposure to a severe psychological event. A history of a brief trauma is reported to affect a risk for future PTSD development; however, little is known about the mechanisms by which a previous trauma exposure drives the sensitivity to a late-coming trauma. Using a mouse PTSD model, we found that a prior foot shock enhances contextual fear conditioning. This shock-induced facilitation of fear conditioning (i.e., priming effect) persisted for 7 days and was prevented by MK801, an N-methyl-D-aspartate receptor antagonist. Other types of trauma, such as forced swimming or tail pinch, did not induce a priming effect on fear conditioning. Thus, a trauma is unlikely generalized to modify the sensitivity to other traumatic experiences. The behavioral procedure employed in this study may be a useful tool to elucidate the etiology of PTSD.

  15. Extinction in human fear conditioning.

    PubMed

    Hermans, Dirk; Craske, Michelle G; Mineka, Susan; Lovibond, Peter F

    2006-08-15

    Although most extinction research is conducted in animal laboratories, the study of extinction learning in human fear conditioning has gained increasing attention over the last decade. The most important findings from human fear extinction are reviewed in this article. Specifically, we review experimental investigations of the impact of conditioned inhibitors, conditioned exciters, context renewal, and reinstatement on fear extinction in human samples. We discuss data from laboratory studies of the extinction of aversively conditioned stimuli, as well as results from experimental clinical work with fearful or anxious individuals. We present directions for future research, in particular the need for further investigation of differences between animal and human conditioning outcomes, and research examining the role of both automatic and higher-order cognitive processes in human conditioning and extinction.

  16. Trace fear conditioning in mice.

    PubMed

    Lugo, Joaquin N; Smith, Gregory D; Holley, Andrew J

    2014-03-20

    In this experiment we present a technique to measure learning and memory. In the trace fear conditioning protocol presented here there are five pairings between a neutral stimulus and an unconditioned stimulus. There is a 20 sec trace period that separates each conditioning trial. On the following day freezing is measured during presentation of the conditioned stimulus (CS) and trace period. On the third day there is an 8 min test to measure contextual memory. The representative results are from mice that were presented with the aversive unconditioned stimulus (shock) compared to mice that received the tone presentations without the unconditioned stimulus. Trace fear conditioning has been successfully used to detect subtle learning and memory deficits and enhancements in mice that are not found with other fear conditioning methods. This type of fear conditioning is believed to be dependent upon connections between the medial prefrontal cortex and the hippocampus. One current controversy is whether this method is believed to be amygdala-independent. Therefore, other fear conditioning testing is needed to examine amygdala-dependent learning and memory effects, such as through the delay fear conditioning.

  17. Posterior insular cortex is necessary for conditioned inhibition of fear.

    PubMed

    Foilb, Allison R; Flyer-Adams, Johanna G; Maier, Steven F; Christianson, John P

    2016-10-01

    Veridical detection of safety versus danger is critical to survival. Learned signals for safety inhibit fear, and so when presented, reduce fear responses produced by danger signals. This phenomenon is termed conditioned inhibition of fear. Here, we report that CS+/CS- fear discrimination conditioning over 5 days in rats leads the CS- to become a conditioned inhibitor of fear, as measured by the classic tests of conditioned inhibition: summation and retardation of subsequent fear acquisition. We then show that NMDA-receptor antagonist AP5 injected to posterior insular cortex (IC) before training completely prevented the acquisition of a conditioned fear inhibitor, while intra-AP5 to anterior and medial IC had no effect. To determine if the IC contributes to the recall of learned fear inhibition, injections of the GABAA agonist muscimol were made to posterior IC before a summation test. This resulted in fear inhibition per se, which obscured inference to the effect of IC inactivation with recall of the safety cue. Control experiments sought to determine if the role of the IC in conditioned inhibition learning could be reduced to simpler fear discrimination function, but fear discrimination and recall were unaffected by AP5 or muscimol, respectively, in the posterior IC. These data implicate a role of posterior IC in the learning of conditioned fear inhibitors. PMID:27523750

  18. Monetary effects on fear conditioning.

    PubMed

    Qu, Chen; Zhang, Aiyi; Chen, Qishan

    2013-04-01

    Previous research has found that the loss of money as a negative secondary reinforcer was as effective as a primary reinforcer during fear conditioning. The purpose of the present study was to explore the effect of monetary gain as a positive secondary reinforcer in fear conditioning. Participants were assigned to a high-reward group or low-reward group. Three kinds of squares prompting non-compensation shock, compensation shock, and no shock were presented. Skin conductance responses (SCRs) and self-ratings were recorded. The results revealed that (a) both SCRs and self-ratings in the compensation shock condition were lower than in the non-compensation shock condition, suggesting that money might block the learning stage of fear conditioning; and (b) a higher ratio of fear reduction was present in self-rating when compared to SCRs, suggesting that people might overstate the utility of money, subjectively. Monetary effects, the effects of different amounts of money, and the differences between subjective and physiological levels are discussed.

  19. Worrying affects associative fear learning: a startle fear conditioning study.

    PubMed

    Gazendam, Femke J; Kindt, Merel

    2012-01-01

    A valuable experimental model for the pathogenesis of anxiety disorders is that they originate from a learned association between an intrinsically non-aversive event (Conditioned Stimulus, CS) and an anticipated disaster (Unconditioned Stimulus, UCS). Most anxiety disorders, however, do not evolve from a traumatic experience. Insights from neuroscience show that memory can be modified post-learning, which may elucidate how pathological fear can develop after relatively mild aversive events. Worrying--a process frequently observed in anxiety disorders--is a potential candidate to strengthen the formation of fear memory after learning. Here we tested in a discriminative fear conditioning procedure whether worry strengthens associative fear memory. Participants were randomly assigned to either a Worry (n = 23) or Control condition (n = 25). After fear acquisition, the participants in the Worry condition processed six worrisome questions regarding the personal aversive consequences of an electric stimulus (UCS), whereas the Control condition received difficult but neutral questions. Subsequently, extinction, reinstatement and re-extinction of fear were tested. Conditioned responding was measured by fear-potentiated startle (FPS), skin conductance (SCR) and UCS expectancy ratings. Our main results demonstrate that worrying resulted in increased fear responses (FPS) to both the feared stimulus (CS(+)) and the originally safe stimulus (CS(-)), whereas FPS remained unchanged in the Control condition. In addition, worrying impaired both extinction and re-extinction learning of UCS expectancy. The implication of our findings is that they show how worry may contribute to the development of anxiety disorders by affecting associative fear learning.

  20. Human serotonin transporter availability predicts fear conditioning.

    PubMed

    Åhs, Fredrik; Frick, Andreas; Furmark, Tomas; Fredrikson, Mats

    2015-12-01

    Serotonin facilitates fear learning in animals. We therefore predicted that individual differences in the capacity to regulate serotonergic transmission in the human neural fear circuit would be inversely related to fear conditioning. The capacity to regulate serotonergic transmission was indexed by serotonin transporter availability measured with [(11)C]-DASB positron emission tomography. Results indicate that lower serotonin transporter availability in the amygdala, insula and dorsal anterior cingulate cortex predicts enhanced conditioned autonomic fear responses. Our finding supports serotonergic modulation of fear conditioning in humans and may aid in understanding susceptibility for developing anxiety conditions such as post-traumatic stress disorder. PMID:25498766

  1. Human serotonin transporter availability predicts fear conditioning.

    PubMed

    Åhs, Fredrik; Frick, Andreas; Furmark, Tomas; Fredrikson, Mats

    2015-12-01

    Serotonin facilitates fear learning in animals. We therefore predicted that individual differences in the capacity to regulate serotonergic transmission in the human neural fear circuit would be inversely related to fear conditioning. The capacity to regulate serotonergic transmission was indexed by serotonin transporter availability measured with [(11)C]-DASB positron emission tomography. Results indicate that lower serotonin transporter availability in the amygdala, insula and dorsal anterior cingulate cortex predicts enhanced conditioned autonomic fear responses. Our finding supports serotonergic modulation of fear conditioning in humans and may aid in understanding susceptibility for developing anxiety conditions such as post-traumatic stress disorder.

  2. Conditioned fear modulates visual selection.

    PubMed

    Mulckhuyse, Manon; Crombez, Geert; Van der Stigchel, Stefan

    2013-06-01

    Eye movements reflect the dynamic interplay between top-down- and bottom-up-driven processes. For example, when we voluntarily move our eyes across the visual field, salient visual stimuli in the environment may capture our attention, our eyes, or modulate the trajectory of an eye movement. Previous research has shown that the behavioral relevance of a salient stimulus modulates these processes. This study investigated whether a stimulus signaling an aversive event modulates saccadic behavior. Using a differential fear-conditioning procedure, we presented a threatening (conditional stimulus: CS+) and a nonthreatening stimulus distractor (CS-) during an oculomotor selection task. The results show that short-latency saccades deviated more strongly toward the CS+ than toward the CS- distractor, whereas long-latency saccades deviated more strongly away from the CS+ than from the CS- distractor. Moreover, the CS+ distractor captured the eyes more often than the CS- distractor. Together, these results demonstrate that conditioned fear has a direct and immediate influence on visual selection. The findings are interpreted in terms of a neurobiological model of emotional visual processing. PMID:23356561

  3. Fear conditioning to subliminal fear relevant and non fear relevant stimuli.

    PubMed

    Lipp, Ottmar V; Kempnich, Clare; Jee, Sang Hoon; Arnold, Derek H

    2014-01-01

    A growing body of evidence suggests that conscious visual awareness is not a prerequisite for human fear learning. For instance, humans can learn to be fearful of subliminal fear relevant images--images depicting stimuli thought to have been fear relevant in our evolutionary context, such as snakes, spiders, and angry human faces. Such stimuli could have a privileged status in relation to manipulations used to suppress usually salient images from awareness, possibly due to the existence of a designated sub-cortical 'fear module'. Here we assess this proposition, and find it wanting. We use binocular masking to suppress awareness of images of snakes and wallabies (particularly cute, non-threatening marsupials). We find that subliminal presentations of both classes of image can induce differential fear conditioning. These data show that learning, as indexed by fear conditioning, is neither contingent on conscious visual awareness nor on subliminal conditional stimuli being fear relevant.

  4. Fear conditioning to subliminal fear relevant and non fear relevant stimuli.

    PubMed

    Lipp, Ottmar V; Kempnich, Clare; Jee, Sang Hoon; Arnold, Derek H

    2014-01-01

    A growing body of evidence suggests that conscious visual awareness is not a prerequisite for human fear learning. For instance, humans can learn to be fearful of subliminal fear relevant images--images depicting stimuli thought to have been fear relevant in our evolutionary context, such as snakes, spiders, and angry human faces. Such stimuli could have a privileged status in relation to manipulations used to suppress usually salient images from awareness, possibly due to the existence of a designated sub-cortical 'fear module'. Here we assess this proposition, and find it wanting. We use binocular masking to suppress awareness of images of snakes and wallabies (particularly cute, non-threatening marsupials). We find that subliminal presentations of both classes of image can induce differential fear conditioning. These data show that learning, as indexed by fear conditioning, is neither contingent on conscious visual awareness nor on subliminal conditional stimuli being fear relevant. PMID:25198514

  5. Distinct Contributions of Median Raphe Nucleus to Contextual Fear Conditioning and Fear-Potentiated Startle

    PubMed Central

    Silva, R. C. B.; Cruz, A. P. M.; Avanzi, V.; Landeira-Fernandez, J.; Brandão, M. L.

    2002-01-01

    Ascending 5-HT projections from the median raphe nucleus (MRN), probably to the hippocampus, are implicated in the acquisition of contextual fear (background stimuli), as assessed by freezing behavior. Foreground cues like light, used as a conditioned stimulus (CS) in classical fear conditioning, also cause freezing through thalamic transmission to the amygdala. As the MRN projects to the hippocampus and amygdala, the role of this raphe nucleus in fear conditioning to explicit cues remains to be explained. Here we analyzed the behavior of rats with MRN electrolytic lesions in a contextual conditioning situation and in a fear-potentiated startle procedure. The animals received MRN electrolytic lesions either before or on the day after two consecutive training sessions in which they were submitted to 10 conditioning trials, each in an experimental chamber (same context) where they. received foot-shocks (0.6 mA, 1 sec) paired to a 4-sec light CS. Seven to ten days later, the animals were submitted to testing sessions for assessing conditioned fear when they were placed for five shocks, and the duration of contextual freezing was recorded. The animals were then submitted to a fear-potentiated startle in response to a 4-sec light-CS, followed by white noise (100 dB, 50 ms). Control rats (sham) tested in the same context showed more freezing than did rats with pre- or post-training MRN lesions. Startle was clearly potentiated in the presence of light CS in the sham-lesioned animals. Whereas pretraining lesions reduced both freezing and fear-potentiated startle, the post-training lesions reduced only freezing to context, without changing the fear-potentiated startle. In a second experiment, neurotoxic lesions of the MRN with local injections of N-methyl-D-aspartate or the activation of 5-HT1A somatodendritic auto-receptors of the MRN by microinjections of the 5-HT1A receptor agonist 8-hydroxy- 2-(di-n-propylamino)tetralin (8-OH-DPAT) before the training sessions also

  6. Adrenergic Transmission Facilitates Extinction of Conditional Fear in Mice

    ERIC Educational Resources Information Center

    Barad, Mark; Cain, Christopher K.; Blouin, Ashley M.

    2004-01-01

    Extinction of classically conditioned fear, like its acquisition, is active learning, but little is known about its molecular mechanisms. We recently reported that temporal massing of conditional stimulus (CS) presentations improves extinction memory acquisition, and suggested that temporal spacing was less effective because individual CS…

  7. Prefrontal neuronal circuits of contextual fear conditioning.

    PubMed

    Rozeske, R R; Valerio, S; Chaudun, F; Herry, C

    2015-01-01

    Over the past years, numerous studies have provided a clear understanding of the neuronal circuits and mechanisms involved in the formation, expression and extinction phases of conditioned cued fear memories. Yet, despite a strong clinical interest, a detailed understanding of these memory phases for contextual fear memories is still missing. Besides the well-known role of the hippocampus in encoding contextual fear behavior, growing evidence indicates that specific regions of the medial prefrontal cortex differentially regulate contextual fear acquisition and storage in both animals and humans that ultimately leads to expression of contextual fear memories. In this review, we provide a detailed description of the recent literature on the role of distinct prefrontal subregions in contextual fear behavior and provide a working model of the neuronal circuits involved in the acquisition, expression and generalization of contextual fear memories. PMID:25287656

  8. Fear Conditioning is Disrupted by Damage to the Postsubiculum

    PubMed Central

    Robinson, Siobhan; Bucci, David J.

    2011-01-01

    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 the conditioning 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. PMID:22076971

  9. Odors eliciting fear: a conditioning approach to Idiopathic Environmental Intolerances.

    PubMed

    Leer, Arne; Smeets, Monique A M; Bulsing, Patricia J; van den Hout, Marcel A

    2011-06-01

    Patients suffering from Idiopathic Environmental Intolerances (IEI) report health symptoms, referable to multiple organ systems, which are triggered by harmless odors and therefore medically unexplainable. In line with previous research that predominantly points towards psychological explanations, the present study tests the hypothesis that IEI symptoms result from learning via classical conditioning of odors to fear. A differential conditioning paradigm was employed. Hedonically different odors were compared on ease of fear acquisition. Conditioned stimuli (CSs) were Dimethyl Sulfide (unpleasant) and peach (pleasant). The unconditioned stimulus (US) was an electrical shock. During acquisition one odor (CS+) was followed by shock, while the other odor (CS-) was not. Next, fear extinction was tested by presenting both CS+ and CS- without US. Electrodermal response, odor evaluation, and sniffing behavior were monitored. Results showed successful fear conditioning irrespective of hedonic character as evidenced by electrodermal response. Acquired fear did not extinguish. There was no evidence of evaluative conditioning taking place, as CS evaluation did not change during fear acquisition. Early avoidance of the CS+, as deduced from odor inhalation measures, was demonstrated, but did not sustain during the entire acquisition phase. This study suggests that a fear conditioning account of IEI is only partially satisfactory.

  10. Fear conditioning is disrupted by damage to the postsubiculum.

    PubMed

    Robinson, Siobhan; Bucci, David J

    2012-06-01

    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.

  11. Teaching and Demonstrating Classical Conditioning.

    ERIC Educational Resources Information Center

    Sparrow, John; Fernald, Peter

    1989-01-01

    Discusses classroom demonstrations of classical conditioning and notes tendencies to misrepresent Pavlov's procedures. Describes the design and construction of the conditioner that is used for demonstrating classical conditioning. Relates how students experience conditioning, generalization, extinction, discrimination, and spontaneous recovery.…

  12. Mesolimbic dopaminergic pathways in fear conditioning.

    PubMed

    Pezze, Marie A; Feldon, Joram

    2004-12-01

    One of the most common paradigms used to study the biological basis of emotion, as well as of learning and memory, is Pavlovian fear conditioning. In the acquisition phase of a fear conditioning experiment, an emotionally neutral conditioned stimulus (CS)--which can either be a discrete stimulus, such as a tone, or a contextual stimulus, such as a specific environment--is paired with an aversive unconditioned stimulus (US), for example a foot shock. As a result, the CS elicits conditioned fear responses when subsequently presented alone during the expression phase of the experiment. While considerable work has been done in relating specific circuits of the brain to fear conditioning, less is known about its regulation by neuromodulators; the understanding of which would be of therapeutic relevance for fear related diseases such as phobia, panic attacks, post traumatic stress disorder, obsessive compulsive disorder, or generalized anxiety disorder. Dopamine is one of the neuromodulators most potently acting on the mechanisms underlying states of fear and anxiety. Recently, a growing body of evidence has suggested that dopaminergic mechanisms are significant for different aspects of affective memory, namely its formation, expression, retrieval, and extinction. The aim of this review is to clarify the complex actions of dopamine in fear conditioning with respect to the wide-spread distribution of dopaminergic innervation over structures constituting the fear related circuitry. A particular effort is made to understand how dopamine in the amygdala, medial prefrontal cortex and nucleus accumbens--target structures of the mesolimbic dopamine system originating from the ventral tegmental area--could relate to different aspects of fear conditioning.

  13. A Complete Reanalysis of Horner's Classic "Fear of Success" Study.

    ERIC Educational Resources Information Center

    Brandt, David A.; Kline, Kay H.

    The well-known study on fear of success (FOS) by Horner (1968) asserted that women low in FOS do better on achievement-oriented tasks under competitive conditions, while women high in the motive do better when the situation is non-competitive. This paper critically reviews the methodology of this study and concludes that the statistical test…

  14. Social Modeling of Conditioned Fear in Mice by Non-fearful Conspecifics

    PubMed Central

    Guzman, Yomayra F.; Tronson, Natalie C.; Guedea, Anita; Huh, Kyu Hwan; Gao, Can; Radulovic, Jelena

    2009-01-01

    Social interactions with conspecifics markedly alter the neuroendocrine, behavioral and emotional responses to stressful events. Some of these effects involve observational learning and result in lasting changes of fear-motivated behavior. While most evidence reveals increased fearfulness after observation of fearful demonstrators (models) in a number of species, a few reports from human and non-human primates indicate that observational learning can also attenuate some forms of fear. In the present study, we set out to determine the effects of social modeling and observational learning on fear conditioning in the mouse. Observers were pre-exposed to a novel context in the presence of fearful (F group) or non-fearful (NF group) demonstrators. Mice of the F group acquired control levels of conditioned fear. On the other hand, mice of the NF group exhibited profound and persistent reduction of fear. The decrease of fear in NF observers was most likely due to context-specific impairments of fear conditioning, as revealed by selective effects on long- but not short-term contextual fear memory, and normal fear conditioning in response to a novel context or cue. The effect was lasting, but constrained by the shock intensity. Attenuation of fear conditioning resulting from interactions with non-fearful conspecifics was largely, but not entirely, mediated by vicarious learning. These findings identify an important social buffering process serving to prevent a lasting induction of fear in response to isolated, moderately intense stressful events. PMID:19428631

  15. Language conditioning, emotional instructions, and cognitions in conditioned responses to fear-relevant and fear-irrelevant stimuli.

    PubMed

    Eifert, G H; Schermelleh, K

    1985-06-01

    This study compared the effects of experimentally induced self-verbalizations (SV) on conditioned responses to fear-relevant (snakes) and fear-irrelevant (rabbits) stimuli. To extend the analysis of "preparedness theory" beyond its former reliance on physiological measures of fear, subjective and behavioral measures were also included. Using aversive tones (UCS) and slides of snakes or rabbits (CS), fear was classically conditioned in 44 volunteers. In 20 subsequent language conditioning trials without aversive tones, the same slides were paired with verbalizations referring either to positive features of the animals (stimulus-referent SV) or to approach behavior (response-referent SV). Skin conductance responses to fear-relevant stimuli were more readily acquired, of higher magnitude, and more resistant to extinction. Extinction was differentially affected by the two types of SV. Snakes were consistently evaluated more negatively than rabbits and approached less in a behavior test. Results are discussed in relation to preparedness theory and interpreted within Staats' social-behavioral learning paradigm.

  16. Contextual fear conditioning induces differential alternative splicing.

    PubMed

    Poplawski, Shane G; Peixoto, Lucia; Porcari, Giulia S; Wimmer, Mathieu E; McNally, Anna G; Mizuno, Keiko; Giese, K Peter; Chatterjee, Snehajyoti; Koberstein, John N; Risso, Davide; Speed, Terence P; Abel, Ted

    2016-10-01

    The process of memory consolidation requires transcription and translation to form long-term memories. Significant effort has been dedicated to understanding changes in hippocampal gene expression after contextual fear conditioning. However, alternative splicing by differential transcript regulation during this time period has received less attention. Here, we use RNA-seq to determine exon-level changes in expression after contextual fear conditioning and retrieval. Our work reveals that a short variant of Homer1, Ania-3, is regulated by contextual fear conditioning. The ribosome biogenesis regulator Las1l, small nucleolar RNA Snord14e, and the RNA-binding protein Rbm3 also change specific transcript usage after fear conditioning. The changes in Ania-3 and Las1l are specific to either the new context or the context-shock association, while the changes in Rbm3 occur after context or shock only. Our analysis revealed novel transcript regulation of previously undetected changes after learning, revealing the importance of high throughput sequencing approaches in the study of gene expression changes after learning. PMID:27451143

  17. Fear conditioned responses and PTSD symptoms in children: Sex differences in fear-related symptoms.

    PubMed

    Gamwell, Kaitlyn; Nylocks, Maria; Cross, Dorthie; Bradley, Bekh; Norrholm, Seth D; Jovanovic, Tanja

    2015-11-01

    Fear conditioning studies in adults have found that posttraumatic stress disorder (PTSD) is associated with heightened fear responses and impaired discrimination. The objective of the current study was to examine the association between PTSD symptoms and fear conditioned responses in children from a highly traumatized urban population. Children between 8 and 13 years old participated in a fear conditioning study in addition to providing information about their trauma history and PTSD symptoms. Results showed that females showed less discrimination between danger and safety signals during conditioning compared to age-matched males. In boys, intrusive symptoms were predictive of fear responses, even after controlling for trauma exposure. However, in girls, conditioned fear to the danger cue was predictive of self-blame and fear of repeated trauma. This study suggests there are early sex differences in the patterns of fear conditioning and that these sex differences may translate to differential risk for trauma-related psychopathology.

  18. Contextual and auditory fear conditioning continue to emerge during the periweaning period in rats.

    PubMed

    Burman, Michael A; Erickson, Kristen J; Deal, Alex L; Jacobson, Rose E

    2014-01-01

    Anxiety disorders often emerge during childhood. Rodent models using classical fear conditioning have shown that different types of fear depend upon different neural structures and may emerge at different stages of development. For example, some work has suggested that contextual fear conditioning generally emerges later in development (postnatal day 23-24) than explicitly cued fear conditioning (postnatal day 15-17) in rats. This has been attributed to an inability of younger subjects to form a representation of the context due to an immature hippocampus. However, evidence that contextual fear can be observed in postnatal day 17 subjects and that cued fear conditioning continues to emerge past this age raises questions about the nature of this deficit. The current studies examine this question using both the context pre-exposure facilitation effect for immediate single-shock contextual fear conditioning and traditional cued fear conditioning using Sprague-Dawley rats. The data suggest that both cued and contextual fear conditioning are continuing to develop between PD 17 and 24, consistent with development occurring the in essential fear conditioning circuit.

  19. Conditioned Fear Acquisition and Generalization in Generalized Anxiety Disorder.

    PubMed

    Tinoco-González, Daniella; Fullana, Miquel Angel; Torrents-Rodas, David; Bonillo, Albert; Vervliet, Bram; Blasco, María Jesús; Farré, Magí; Torrubia, Rafael

    2015-09-01

    Abnormal fear conditioning processes (including fear acquisition and conditioned fear-generalization) have been implicated in the pathogenesis of anxiety disorders. Previous research has shown that individuals with panic disorder present enhanced conditioned fear-generalization in comparison to healthy controls. Enhanced conditioned fear-generalization could also characterize generalized anxiety disorder (GAD), but research so far is inconclusive. An important confounding factor in previous research is comorbidity. The present study examined conditioned fear-acquisition and fear-generalization in 28 patients with GAD and 30 healthy controls using a recently developed fear acquisition and generalization paradigm assessing fear-potentiated startle and online expectancies of the unconditioned stimulus. Analyses focused on GAD patients without comorbidity but included also patients with comorbid anxiety disorders. Patients and controls did not differ as regards fear acquisition. However, contrary to our hypothesis, both groups did not differ either in most indexes of conditioned fear-generalization. Moreover, dimensional measures of GAD symptoms were not correlated with conditioned fear-generalization indexes. Comorbidity did not have a significant impact on the results. Our data suggest that conditioned fear-generalization is not enhanced in GAD. Results are discussed with special attention to the possible effects of comorbidity on fear learning abnormalities.

  20. Conditioned Fear Extinction and Reinstatement in a Human Fear-Potentiated Startle Paradigm

    ERIC Educational Resources Information Center

    Norrholm, Seth D.; Jovanovic, Tanja; Vervliet, Bram; Myers, Karyn M.; Davis, Michael; Rothbaum, Barbara O.; Duncan, Erica J.

    2006-01-01

    The purpose of this study was to analyze fear extinction and reinstatement in humans using fear-potentiated startle. Participants were fear conditioned using a simple discrimination procedure with colored lights as the conditioned stimuli (CSs) and an airblast to the throat as the unconditioned stimulus (US). Participants were extinguished 24 h…

  1. Sex differences in learning processes of classical and operant conditioning.

    PubMed

    Dalla, Christina; Shors, Tracey J

    2009-05-25

    Males and females learn and remember differently at different times in their lives. These differences occur in most species, from invertebrates to humans. We review here sex differences as they occur in laboratory rodent species. We focus on classical and operant conditioning paradigms, including classical eyeblink conditioning, fear-conditioning, active avoidance and conditioned taste aversion. Sex differences have been reported during acquisition, retention and extinction in most of these paradigms. In general, females perform better than males in the classical eyeblink conditioning, in fear-potentiated startle and in most operant conditioning tasks, such as the active avoidance test. However, in the classical fear-conditioning paradigm, in certain lever-pressing paradigms and in the conditioned taste aversion, males outperform females or are more resistant to extinction. Most sex differences in conditioning are dependent on organizational effects of gonadal hormones during early development of the brain, in addition to modulation by activational effects during puberty and adulthood. Critically, sex differences in performance account for some of the reported effects on learning and these are discussed throughout the review. Because so many mental disorders are more prevalent in one sex than the other, it is important to consider sex differences in learning when applying animal models of learning for these disorders. Finally, we discuss how sex differences in learning continue to alter the brain throughout the lifespan. Thus, sex differences in learning are not only mediated by sex differences in the brain, but also contribute to them.

  2. Differential roles of the dorsal and ventral hippocampus in predator odor contextual fear conditioning.

    PubMed

    Wang, Melissa E; Fraize, Nicolas P; Yin, Linda; Yuan, Robin K; Petsagourakis, Despina; Wann, Ellen G; Muzzio, Isabel A

    2013-06-01

    The study of fear memory is important for understanding various anxiety disorders in which patients experience persistent recollections of traumatic events. These memories often involve associations of contextual cues with aversive events; consequently, Pavlovian classical conditioning is commonly used to study contextual fear learning. The use of predator odor as a fearful stimulus in contextual fear conditioning has become increasingly important as an animal model of anxiety disorders. Innate fear responses to predator odors are well characterized and reliable; however, attempts to use these odors as unconditioned stimuli in fear conditioning paradigms have proven inconsistent. Here we characterize a contextual fear conditioning paradigm using coyote urine as the unconditioned stimulus. We found that contextual conditioning induced by exposure to coyote urine produces long-term freezing, a stereotypic response to fear observed in mice. This paradigm is context-specific and parallels shock-induced contextual conditioning in that it is responsive to extinction training and manipulations of predator odor intensity. Region-specific lesions of the dorsal and ventral hippocampus indicate that both areas are independently required for the long-term expression of learned fear. These results in conjunction with c-fos immunostaining data suggest that while both the dorsal and ventral hippocampus are required for forming a contextual representation, the ventral region also modulates defensive behaviors associated with predators. This study provides information about the individual contributions of the dorsal and ventral hippocampus to ethologically relevant fear learning.

  3. [Mechanisms for regulation of fear conditioning and memory].

    PubMed

    Kida, Satoshi

    2014-11-01

    Pavlovian fear conditioning is a model of fear learning and memory. The mechanisms regulating fear conditioning and memory have been investigated in humans and rodents. In this paradigm, animals learn and memorize an association between a conditioned stimulus (CS), such as context, and an unconditioned stimulus (US), such as an electrical footshock that induces fear. Fear memory generated though fear conditioning is stabilized via a memory consolidation process. Moreover, recent studies have shown the existence of memory processes that control fear memory following the retrieval of consolidated memory. Indeed, when fear memory is retrieved by re-exposure to the CS, the retrieved memory is re-stabilized via the reconsolidation process. On the other hand, the retrieval of fear memory by prolonged re-exposure to the CS also leads to fear memory extinction, new inhibitory learning against the fear memory, in which animals learn that they do not need to respond to the CS. Importantly, the reinforcement of fear memory after retrieval (i.e., re-experience such as flashbacks or nightmares) has been thought to be associated with the development of emotional disorders such as post-traumatic stress disorder (PTSD). In this review, I summarize recent progress in studies on the mechanism of fear conditioning and memory consolidation, reconsolidation and extinction, and furthermore, introduce our recent establishment of a mouse PTSD model that shows enhancement of fear memory after retrieval.

  4. [Mechanisms for regulation of fear conditioning and memory].

    PubMed

    Kida, Satoshi

    2014-11-01

    Pavlovian fear conditioning is a model of fear learning and memory. The mechanisms regulating fear conditioning and memory have been investigated in humans and rodents. In this paradigm, animals learn and memorize an association between a conditioned stimulus (CS), such as context, and an unconditioned stimulus (US), such as an electrical footshock that induces fear. Fear memory generated though fear conditioning is stabilized via a memory consolidation process. Moreover, recent studies have shown the existence of memory processes that control fear memory following the retrieval of consolidated memory. Indeed, when fear memory is retrieved by re-exposure to the CS, the retrieved memory is re-stabilized via the reconsolidation process. On the other hand, the retrieval of fear memory by prolonged re-exposure to the CS also leads to fear memory extinction, new inhibitory learning against the fear memory, in which animals learn that they do not need to respond to the CS. Importantly, the reinforcement of fear memory after retrieval (i.e., re-experience such as flashbacks or nightmares) has been thought to be associated with the development of emotional disorders such as post-traumatic stress disorder (PTSD). In this review, I summarize recent progress in studies on the mechanism of fear conditioning and memory consolidation, reconsolidation and extinction, and furthermore, introduce our recent establishment of a mouse PTSD model that shows enhancement of fear memory after retrieval. PMID:25536762

  5. Generalization of Conditioned Fear along a Dimension of Increasing Fear Intensity

    ERIC Educational Resources Information Center

    Dunsmoor, Joseph E.; Mitroff, Stephen R.; LaBar, Kevin S.

    2009-01-01

    The present study investigated the extent to which fear generalization in humans is determined by the amount of fear intensity in nonconditioned stimuli relative to a perceptually similar conditioned stimulus. Stimuli consisted of graded emotionally expressive faces of the same identity morphed between neutral and fearful endpoints. Two…

  6. Hippocampal Structural Plasticity Accompanies the Resulting Contextual Fear Memory Following Stress and Fear Conditioning

    ERIC Educational Resources Information Center

    Giachero, Marcelo; Calfa, Gaston D.; Molina, Victor A.

    2013-01-01

    The present research investigated the resulting contextual fear memory and structural plasticity changes in the dorsal hippocampus (DH) following stress and fear conditioning. This combination enhanced fear retention and increased the number of total and mature dendritic spines in DH. Intra-basolateral amygdala (BLA) infusion of midazolam prior to…

  7. The conditions that promote fear learning: prediction error and Pavlovian fear conditioning.

    PubMed

    Li, Susan Shi Yuan; McNally, Gavan P

    2014-02-01

    A key insight of associative learning theory is that learning depends on the actions of prediction error: a discrepancy between the actual and expected outcomes of a conditioning trial. When positive, such error causes increments in associative strength and, when negative, such error causes decrements in associative strength. Prediction error can act directly on fear learning by determining the effectiveness of the aversive unconditioned stimulus or indirectly by determining the effectiveness, or associability, of the conditioned stimulus. Evidence from a variety of experimental preparations in human and non-human animals suggest that discrete neural circuits code for these actions of prediction error during fear learning. Here we review the circuits and brain regions contributing to the neural coding of prediction error during fear learning and highlight areas of research (safety learning, extinction, and reconsolidation) that may profit from this approach to understanding learning.

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

    PubMed

    Merz, Christian Josef; Stark, Rudolf; Vaitl, Dieter; Tabbert, Katharina; Wolf, Oliver Tobias

    2013-01-01

    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.

  9. Asymmetrical Stimulus Generalization following Differential Fear Conditioning

    PubMed Central

    Bang, Sun Jung; Allen, Timothy A.; Jones, Lauren K.; Boguszewski, Pawel; Brown, Thomas H.

    2008-01-01

    Rodent ultrasonic vocalizations (USVs) are ethologically critical social signals. Rats emit 22 kHz USVs and 50 kHz USVs, respectively, in conjunction with negative and positive affective states. Little is known about what controls emotional reactivity to these social signals. Using male Sprague-Dawley rats, we examined unconditional and conditional freezing behavior in response to the following auditory stimuli: three 22 kHz USVs, a discontinuous tone whose frequency and on-off pattern matched one of the USVs, a continuous tone with the same or lower frequencies, a 4 kHz discontinuous tone with an on-off pattern matched to one of the USVs, and a 50 kHz USV. There were no differences among these stimuli in terms of the unconditional elicitation of freezing behavior. Thus, the stimuli were equally neutral before conditioning. During differential fear conditioning, one of these stimuli (the CS+) always co-terminated with a footshock unconditional stimulus (US) and another stimulus (the CS−) was explicitly unpaired with the US. There were no significant differences among these cues in CS+-elicited freezing behavior. Thus, the stimuli were equally salient or effective as cues in supporting fear conditioning. When the CS+ was a 22 kHz USV or a similar stimulus, rats discriminated based on the principal frequency and/or the temporal pattern of the stimulus. However, when these same stimuli served as the CS−, discrimination failed due to generalization from the CS+. Thus, the stimuli differed markedly in the specificity of conditioning. This strikingly asymmetrical stimulus generalization is a novel bias in discrimination. PMID:18434217

  10. Predicting aversive events and terminating fear in the mouse anterior cingulate cortex during trace fear conditioning.

    PubMed

    Steenland, Hendrik W; Li, Xiang-Yao; Zhuo, Min

    2012-01-18

    A variety of studies have implicated the anterior cingulate cortex (ACC) in fear, including permanent storage of fear memory. Recent pharmacological and genetic studies indicate that early synaptic plasticity in the ACC may also contribute to certain forms of fear memory at early time points. However, no study has directly examined the possible changes in neuronal activity of ACC neurons in freely behaving mice during early learning. In the present study, we examined the neural responses of the ACC during trace fear conditioning. We found that ACC putative pyramidal and nonpyramidal neurons were involved in the termination of fear behavior ("un-freezing"), and the spike activity of these neurons was reduced during freezing. Some of the neurons were also found to acquire un-freezing locked activity and change their tuning. The results implicate the ACC neurons in fear learning and controlling the abolition of fear behavior. We also show that the ACC is important for making cue-related fear memory associations in the trace fear paradigm as measured with tone-evoked potentials and single-unit activity. Collectively, our findings indicate that the ACC is involved in predicting future aversive events and terminating fear during trace fear. PMID:22262906

  11. No effect of trait anxiety on differential fear conditioning or fear generalization.

    PubMed

    Torrents-Rodas, David; Fullana, Miquel A; Bonillo, Albert; Caseras, Xavier; Andión, Oscar; Torrubia, Rafael

    2013-02-01

    Previous studies have shown that individuals with anxiety disorders exhibit deficits in fear inhibition and excessive generalization of fear, but little data exist on individuals at risk from these disorders. The present study examined the role of trait anxiety in the acquisition and generalization of fear in 126 healthy participants selected on the basis of their trait-anxiety scores. Measures of conditioning included fear-potentiated startle, skin conductance response and online risk ratings for the unconditioned stimulus. Contrary to our hypotheses, trait anxiety did not have any effect either on the acquisition or the generalization of fear. Our results suggest that these fear conditioning processes are not impaired in individuals at risk from anxiety. PMID:23131617

  12. Versatility of fear-potentiated startle paradigms for assessing human conditioned fear extinction and return of fear.

    PubMed

    Norrholm, Seth D; Anderson, Kemp M; Olin, Ilana W; Jovanovic, Tanja; Kwon, Cliffe; Warren, Victor T; McCarthy, Alexander; Bosshardt, Lauren; Sabree, Justin; Duncan, Erica J; Rothbaum, Barbara O; Bradley, Bekh

    2011-01-01

    Fear conditioning methodologies have often been employed as testable models for assessing learned fear responses in individuals with anxiety disorders such as post-traumatic stress disorder (PTSD) and specific phobia. One frequently used paradigm is measurement of the acoustic startle reflex under conditions that mimic anxiogenic and fear-related conditions. For example, fear-potentiated startle is the relative increase in the frequency or magnitude of the acoustic startle reflex in the presence of a previously neutral cue (e.g., colored shape; termed the conditioned stimulus or CS+) that has been repeatedly paired with an aversive unconditioned stimulus (e.g., airblast to the larynx). Our group has recently used fear-potentiated startle paradigms to demonstrate impaired fear extinction in civilian and combat populations with PTSD. In the current study, we examined the use of either auditory or visual CSs in a fear extinction protocol that we have validated and applied to human clinical conditions. This represents an important translational bridge in that numerous animal studies of fear extinction, upon which much of the human work is based, have employed the use of auditory CSs as opposed to visual CSs. Participants in both the auditory and visual groups displayed robust fear-potentiated startle to the CS+, clear discrimination between the reinforced CS+ and non-reinforced CS-, significant extinction to the previously reinforced CS+, and marked spontaneous recovery. We discuss the current results as they relate to future investigations of PTSD-related impairments in fear processing in populations with diverse medical and psychiatric histories.

  13. Plastic Synaptic Networks of the Amygdala for the Acquisition, Expression, and Extinction of Conditioned Fear

    PubMed Central

    Pape, Hans-Christian; Pare, Denis

    2009-01-01

    The last ten years have witnessed a surge of interest for the mechanisms underlying the acquisition and extinction of classically conditioned fear responses. In part, this results from the realization that abnormalities in fear learning mechanisms likely participate to the development and/or maintenance of human anxiety disorders. The simplicity and robustness of this learning paradigm, coupled to the fact that the underlying circuitry is evolutionarily well conserved makes it an ideal model to study the basic biology of memory and identify genetic factors and neuronal systems that regulate the normal and pathological expressions of learned fear. Critical advances have been made in determining how modified neuronal functions upon fear acquisition become stabilized during fear memory consolidation and how these processes are controlled in the course of fear memory extinction. With these advances, came the realization that activity in remote neuronal networks must be coordinated for these events to take place. In this paper, we review these mechanisms of coordinated network activity and the molecular cascades leading to enduring fear memory, and allowing for their extinction. We will focus on Pavlovian fear conditioning as a model and the amygdala as a key component for the acquisition and extinction of fear responses. PMID:20393190

  14. Thalamocortical interactions underlying visual fear conditioning in humans.

    PubMed

    Lithari, Chrysa; Moratti, Stephan; Weisz, Nathan

    2015-11-01

    Despite a strong focus on the role of the amygdala in fear conditioning, recent works point to a more distributed network supporting fear conditioning. We aimed to elucidate interactions between subcortical and cortical regions in fear conditioning in humans. To do this, we used two fearful faces as conditioned stimuli (CS) and an electrical stimulation at the left hand, paired with one of the CS, as unconditioned stimulus (US). The luminance of the CS was rhythmically modulated leading to "entrainment" of brain oscillations at a predefined modulation frequency. Steady-state responses (SSR) were recorded by MEG. In addition to occipital regions, spectral analysis of SSR revealed increased power during fear conditioning particularly for thalamus and cerebellum contralateral to the upcoming US. Using thalamus and amygdala as seed-regions, directed functional connectivity was calculated to capture the modulation of interactions that underlie fear conditioning. Importantly, this analysis showed that the thalamus drives the fusiform area during fear conditioning, while amygdala captures the more general effect of fearful faces perception. This study confirms ideas from the animal literature, and demonstrates for the first time the central role of the thalamus in fear conditioning in humans.

  15. Faster acquisition of conditioned fear to fear-relevant than to nonfear-relevant conditional stimuli.

    PubMed

    Ho, Yiling; Lipp, Ottmar V

    2014-08-01

    Prepared learning theory posits that prepared associations are acquired rapidly and resist extinction. Although it has been shown repeatedly that prepared associations resist extinction, there is currently little evidence to support the proposal of faster acquisition. The current study provides such evidence using a within-subjects conditioning procedure with a 50% reinforcement schedule. Participants were presented with pictures of four animals, two fear-relevant (snake, spider) and two nonfear-relevant (fish, bird), one of each paired with an unpleasant electrotactile stimulus on 50% of the trials during acquisition. Differential electrodermal responding was observed within the first two blocks of acquisition for fear-relevant but not for nonfear-relevant conditional stimuli, confirming the prediction that prepared associations are acquired faster than nonprepared associations.

  16. Faster acquisition of conditioned fear to fear-relevant than to nonfear-relevant conditional stimuli.

    PubMed

    Ho, Yiling; Lipp, Ottmar V

    2014-08-01

    Prepared learning theory posits that prepared associations are acquired rapidly and resist extinction. Although it has been shown repeatedly that prepared associations resist extinction, there is currently little evidence to support the proposal of faster acquisition. The current study provides such evidence using a within-subjects conditioning procedure with a 50% reinforcement schedule. Participants were presented with pictures of four animals, two fear-relevant (snake, spider) and two nonfear-relevant (fish, bird), one of each paired with an unpleasant electrotactile stimulus on 50% of the trials during acquisition. Differential electrodermal responding was observed within the first two blocks of acquisition for fear-relevant but not for nonfear-relevant conditional stimuli, confirming the prediction that prepared associations are acquired faster than nonprepared associations. PMID:24725116

  17. Rapid amygdala responses during trace fear conditioning without awareness.

    PubMed

    Balderston, Nicholas L; Schultz, Douglas H; Baillet, Sylvain; Helmstetter, Fred J

    2014-01-01

    The role of consciousness in learning has been debated for nearly 50 years. Recent studies suggest that conscious awareness is needed to bridge the gap when learning about two events that are separated in time, as is true for trace fear conditioning. This has been repeatedly shown and seems to apply to other forms of classical conditioning as well. In contrast to these findings, we show that individuals can learn to associate a face with the later occurrence of a shock, even if they are unable to perceive the face. We used a novel application of magnetoencephalography (MEG) to non-invasively record neural activity from the amygdala, which is known to be important for fear learning. We demonstrate rapid (∼ 170-200 ms) amygdala responses during the stimulus free period between the face and the shock. These results suggest that unperceived faces can serve as signals for impending threat, and that rapid, automatic activation of the amygdala contributes to this process. In addition, we describe a methodology that can be applied in the future to study neural activity with MEG in other subcortical structures.

  18. [Specific features of fear conditioning expression in active and passive rabbits].

    PubMed

    2013-11-01

    The active and passive rabbits selected previously on the basis of their behavior in open field and light-dark test, were subjected to fear conditioning using pairing light (4 s) with footshocks (10 Hz, 0.5 s). Heart rate and respiration rate were measured during the classical fear conditioning. Heart rate and respiration rate decreased in response to light before footshock in case of passive-defensive reaction. There were no heart rate and respiration rate reduction in the course of the active defensive reaction. In active rabbits, as compared to passive ones, the frequency of active locomotors reactions and heart rate were higher, the decrease of respiration rate to light was observed at later stages of training, and the detected bradycardia was not stable. Thus, based upon vegetative characteristics, the active rabbits had lower level of fear than passive ones. The active or passive behavioral strategies of animals were preserved during fear conditioning.

  19. Developmental aspects of fear: Comparing the acquisition and generalization of conditioned fear in children and adults

    PubMed Central

    Schiele, Miriam A.; Reinhard, Julia; Reif, Andreas; Domschke, Katharina; Romanos, Marcel; Deckert, Jürgen

    2016-01-01

    ABSTRACT Most research on human fear conditioning and its generalization has focused on adults whereas only little is known about these processes in children. Direct comparisons between child and adult populations are needed to determine developmental risk markers of fear and anxiety. We compared 267 children and 285 adults in a differential fear conditioning paradigm and generalization test. Skin conductance responses (SCR) and ratings of valence and arousal were obtained to indicate fear learning. Both groups displayed robust and similar differential conditioning on subjective and physiological levels. However, children showed heightened fear generalization compared to adults as indexed by higher arousal ratings and SCR to the generalization stimuli. Results indicate overgeneralization of conditioned fear as a developmental correlate of fear learning. The developmental change from a shallow to a steeper generalization gradient is likely related to the maturation of brain structures that modulate efficient discrimination between danger and (ambiguous) safety cues. © 2016 The Authors. Developmental Psychobiology Published by Wiley Periodicals, Inc. Dev Psychobiol 58: 471–481, 2016. PMID:26798984

  20. Nonassociative learning processes determine expression and extinction of conditioned fear in mice.

    PubMed

    Kamprath, Kornelia; Wotjak, Carsten T

    2004-01-01

    Freezing to a tone following auditory fear conditioning is commonly considered as a measure of the strength of the tone-shock association. The decrease in freezing on repeated nonreinforced tone presentation following conditioning, in turn, is attributed to the formation of an inhibitory association between tone and shock that leads to a suppression of the expression of fear. This study challenges these concepts for auditory fear conditioning in mice. We show that acquisition of conditioned fear by a few tone-shock pairings is accompanied by a nonassociative sensitization process. As a consequence, the freezing response of conditioned mice seems to be determined by both associative and nonassociative memory components. Our data suggest that the intensity of freezing as a function of footshock intensity is primarily determined by the nonassociative component, whereas the associative component is more or less categorical. We next demonstrate that the decrease in freezing on repeated nonreinforced tone presentation following conditioning shows fundamental properties of habituation. Thus, it might be regarded as a habituation-like process, which abolishes the influence of sensitization on the freezing response to the tone without affecting the expression of the associative memory component. Taken together, this study merges the dual-process theory of habituation with the concept of classical fear conditioning and demonstrates that sensitization and habituation as two nonassociative learning processes may critically determine the expression of conditioned fear in mice.

  1. Attraction under Aversive Conditions: Misattributions or Fear-Reduction?

    ERIC Educational Resources Information Center

    Miller, Rowland S.

    Interpersonal attraction appears to increase under aversive conditions. Two distinct theories suggest that attraction results from either misattribution or fear reduction. To investigate the effects of misattribution and fear reduction on attraction, 36 male college students were ostensibly exposed to an electromagnetic field while an attractive…

  2. Classical Conditioning: Eliciting the Right Response.

    ERIC Educational Resources Information Center

    Tauber, Robert T.

    1990-01-01

    Classical conditioning is responsible for students' positive and negative feelings, whether directed toward subject matter, peers, teachers, or education in general. This article explains how educators can use classical conditioning principles (such as reinforcement, extinction, and paired stimuli) to create an anxiety-free learning environment.…

  3. Sex, stress, and fear: individual differences in conditioned learning.

    PubMed

    Zorawski, Michael; Cook, Craig A; Kuhn, Cynthia M; LaBar, Kevin S

    2005-06-01

    It has long been recognized that humans vary in their conditionability, yet the factors that contribute to individual variation in emotional learning remain to be delineated. The goal of the present study was to investigate the relationship among sex, stress hormones, and fear conditioning in humans. Forty-five healthy adults (22 females) underwent differential delay conditioning, using fear-relevant conditioned stimuli and a shock unconditioned stimulus. Salivary cortisol samples were taken at baseline and after acquisition training and a 24-h-delayed retention test. The results showed that acquisition of conditioning significantly correlated with postacquisition cortisol levels in males, but not in females. This sex-specific relationship was found despite similar overall levels of conditioning, unconditioned responding, and cortisol. There was no effect of postacquisition cortisol on consolidation of fear learning in either sex. These findings have implications for the understanding of individual differences in fear acquisition and risk factors for the development of affective disorders.

  4. Effects of sleep on memory for conditioned fear and fear extinction

    PubMed Central

    Pace-Schott, Edward F.; Germain, Anne; Milad, Mohammed R.

    2015-01-01

    Learning and memory for extinction of conditioned fear is a basic mammalian mechanism for regulating negative emotion. Sleep promotes both the consolidation of memory and the regulation of emotion. Sleep can influence consolidation and modification of memories associated with both fear and its extinction. After brief overviews of the behavior and neural circuitry associated with fear conditioning, extinction learning and extinction memory in the rodent and human, interactions of sleep with these processes will be examined. Animal and human studies suggest that sleep can serve to consolidate both fear and extinction memory. In humans, sleep also promotes generalization of extinction memory. Time-of-day effects on extinction learning and generalization are also seen. REM may be a sleep stage of particular importance for the consolidation of both fear and extinction memory as evidenced by selective REM deprivation experiments. REM sleep is accompanied by selective activation of the same limbic structures implicated in the learning and memory of fear and extinction. Preliminary evidence also suggests extinction learning can take place during slow wave sleep. Study of low-level processes such as conditioning, extinction and habituation may allow sleep effects on emotional memory to be identified and inform study of sleep’s effects on more complex, emotionally salient declarative memories. Anxiety disorders are marked by impairments of both sleep and extinction memory. Improving sleep quality may ameliorate anxiety disorders by strengthening naturally acquired extinction. Strategically timed sleep may be used to enhance treatment of anxiety by strengthening therapeutic extinction learned via exposure therapy. PMID:25894546

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

    PubMed Central

    2012-01-01

    Background Fear 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. Methods Activities 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. Results The 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

  6. Social transmission of Pavlovian fear: fear-conditioning by-proxy in related female rats.

    PubMed

    Jones, Carolyn E; Riha, Penny D; Gore, Andrea C; Monfils, Marie-H

    2014-05-01

    Pairing a previously neutral conditioned stimulus (CS; e.g., a tone) to an aversive unconditioned stimulus (US; e.g., a foot-shock) leads to associative learning such that the tone alone will elicit a conditioned response (e.g., freezing). Individuals can also acquire fear from a social context, such as through observing the fear expression of a conspecific. In the current study, we examined the influence of kinship/familiarity on social transmission of fear in female rats. Rats were housed in triads with either sisters or non-related females. One rat from each cage was fear conditioned to a tone CS+ shock US. On day two, the conditioned rat was returned to the chamber accompanied by one of her cage mates. Both rats were allowed to behave freely, while the tone was played in the absence of the foot-shock. The previously untrained rat is referred to as the fear-conditioned by-proxy (FCbP) animal, as she would freeze based on observations of her cage-mate's response rather than due to direct personal experience with the foot-shock. The third rat served as a cage-mate control. The third day, long-term memory tests to the CS were performed. Consistent with our previous application of this paradigm in male rats (Bruchey et al. in Behav Brain Res 214(1):80-84, 2010), our results revealed that social interactions between the fear conditioned and FCbP rats on day two contribute to freezing displayed by the FCbP rats on day three. In this experiment, prosocial behavior occurring at the termination of the cue on day two was significantly greater between sisters than their non-sister counterparts, and this behavior resulted in increased freezing on day three. Our results suggest that familiarity and/or kinship influences the social transmission of fear in female rats.

  7. Stress differentially affects fear conditioning in men and women.

    PubMed

    Merz, Christian Josef; Wolf, Oliver Tobias; Schweckendiek, Jan; Klucken, Tim; Vaitl, Dieter; Stark, Rudolf

    2013-11-01

    Stress and fear conditioning processes are both important vulnerability factors in the development of psychiatric disorders. In behavioral studies considerable sex differences in fear learning have been observed after increases of the stress hormone cortisol. But neuroimaging experiments, which give insights into the neurobiological correlates of stress × sex interactions in fear conditioning, are lacking so far. In the current functional magnetic resonance imaging (fMRI) study, we tested whether a psychosocial stressor (Trier Social Stress Test) compared to a control condition influenced subsequent fear conditioning in 48 men and 48 women taking oral contraceptives (OCs). One of two pictures of a geometrical figure was always paired (conditioned stimulus, CS+) or never paired (CS-) with an electrical stimulation (unconditioned stimulus). BOLD responses as well as skin conductance responses were assessed. Sex-independently, stress enhanced the CS+/CS- differentiation in the hippocampus in early acquisition but attenuated conditioned responses in the medial frontal cortex in late acquisition. In early acquisition, stress reduced the CS+/CS- differentiation in the nucleus accumbens in men, but enhanced it in OC women. In late acquisition, the same pattern (reduction in men, enhancement in OC women) was found in the amygdala as well as in the anterior cingulate. Thus, psychosocial stress impaired the neuronal correlates of fear learning and expression in men, but facilitated them in OC women. A sex-specific modulation of fear conditioning after stress might contribute to the divergent prevalence of men and women in developing psychiatric disorders.

  8. Controlled cortical impact before or after fear conditioning does not affect fear extinction in mice

    PubMed Central

    Sierra-Mercado, Demetrio; McAllister, Lauren M.; Lee, Christopher C.H.; Milad, Mohammed R.; Eskandar, Emad N.; Whalen, Michael J.

    2015-01-01

    Post-traumatic stress disorder (PTSD) is characterized in part by impaired extinction of conditioned fear. Traumatic brain injury (TBI) is thought to be a risk factor for development of PTSD. We tested the hypothesis that controlled cortical impact (CCI) would impair extinction of fear learned by Pavlovian conditioning, in mice. To mimic the scenarios in which TBI occurs prior to or after exposure to an aversive event, severe CCI was delivered to the left parietal cortex at one of two time points: (1) Prior to fear conditioning, or (2) after conditioning. Delay auditory conditioning was achieved by pairing a tone with a foot shock in “context A”. Extinction training involved the presentation of tones in a different context (context B) in the absence of foot shock. Test for extinction memory was achieved by presentation of additional tones alone in context B over the following two days. In pre- or post-injury paradigms, CCI did not influence fear learning and extinction. Furthermore, CCI did not affect locomotor activity or elevated plus maze testing. Our results demonstrate that, within the time frame studied, CCI does not impair the acquisition and expression of conditioned fear or extinction memory. PMID:25721797

  9. Controlled cortical impact before or after fear conditioning does not affect fear extinction in mice.

    PubMed

    Sierra-Mercado, Demetrio; McAllister, Lauren M; Lee, Christopher C H; Milad, Mohammed R; Eskandar, Emad N; Whalen, Michael J

    2015-05-01

    Post-traumatic stress disorder (PTSD) is characterized in part by impaired extinction of conditioned fear. Traumatic brain injury (TBI) is thought to be a risk factor for development of PTSD. We tested the hypothesis that controlled cortical impact (CCI) would impair extinction of fear learned by Pavlovian conditioning, in mice. To mimic the scenarios in which TBI occurs prior to or after exposure to an aversive event, severe CCI was delivered to the left parietal cortex at one of two time points: (1) Prior to fear conditioning, or (2) after conditioning. Delay auditory conditioning was achieved by pairing a tone with a foot shock in "context A". Extinction training involved the presentation of tones in a different context (context B) in the absence of foot shock. Test for extinction memory was achieved by presentation of additional tones alone in context B over the following two days. In pre- or post-injury paradigms, CCI did not influence fear learning and extinction. Furthermore, CCI did not affect locomotor activity or elevated plus maze testing. Our results demonstrate that, within the time frame studied, CCI does not impair the acquisition and expression of conditioned fear or extinction memory.

  10. Psychopaths Show Enhanced Amygdala Activation during Fear Conditioning

    PubMed Central

    Schultz, Douglas H.; Balderston, Nicholas L.; Baskin-Sommers, Arielle R.; Larson, Christine L.; Helmstetter, Fred J.

    2016-01-01

    Psychopathy is a personality disorder characterized by emotional deficits and a failure to inhibit impulsive behavior and is often subdivided into “primary” and “secondary” psychopathic subtypes. The maladaptive behavior related to primary psychopathy is thought to reflect constitutional “fearlessness,” while the problematic behavior related to secondary psychopathy is motivated by other factors. The fearlessness observed in psychopathy has often been interpreted as reflecting a fundamental deficit in amygdala function, and previous studies have provided support for a low-fear model of psychopathy. However, many of these studies fail to use appropriate screening procedures, use liberal inclusion criteria, or have used unconventional approaches to assay amygdala function. We measured brain activity with BOLD imaging in primary and secondary psychopaths and non-psychopathic control subjects during Pavlovian fear conditioning. In contrast to the low-fear model, we observed normal fear expression in primary psychopaths. Psychopaths also displayed greater differential BOLD activity in the amygdala relative to matched controls. Inverse patterns of activity were observed in the anterior cingulate cortex (ACC) for primary versus secondary psychopaths. Primary psychopaths exhibited a pattern of activity in the dorsal and ventral ACC consistent with enhanced fear expression, while secondary psychopaths exhibited a pattern of activity in these regions consistent with fear inhibition. These results contradict the low-fear model of psychopathy and suggest that the low fear observed for psychopaths in previous studies may be specific to secondary psychopaths. PMID:27014154

  11. Psychopaths Show Enhanced Amygdala Activation during Fear Conditioning.

    PubMed

    Schultz, Douglas H; Balderston, Nicholas L; Baskin-Sommers, Arielle R; Larson, Christine L; Helmstetter, Fred J

    2016-01-01

    Psychopathy is a personality disorder characterized by emotional deficits and a failure to inhibit impulsive behavior and is often subdivided into "primary" and "secondary" psychopathic subtypes. The maladaptive behavior related to primary psychopathy is thought to reflect constitutional "fearlessness," while the problematic behavior related to secondary psychopathy is motivated by other factors. The fearlessness observed in psychopathy has often been interpreted as reflecting a fundamental deficit in amygdala function, and previous studies have provided support for a low-fear model of psychopathy. However, many of these studies fail to use appropriate screening procedures, use liberal inclusion criteria, or have used unconventional approaches to assay amygdala function. We measured brain activity with BOLD imaging in primary and secondary psychopaths and non-psychopathic control subjects during Pavlovian fear conditioning. In contrast to the low-fear model, we observed normal fear expression in primary psychopaths. Psychopaths also displayed greater differential BOLD activity in the amygdala relative to matched controls. Inverse patterns of activity were observed in the anterior cingulate cortex (ACC) for primary versus secondary psychopaths. Primary psychopaths exhibited a pattern of activity in the dorsal and ventral ACC consistent with enhanced fear expression, while secondary psychopaths exhibited a pattern of activity in these regions consistent with fear inhibition. These results contradict the low-fear model of psychopathy and suggest that the low fear observed for psychopaths in previous studies may be specific to secondary psychopaths.

  12. Psychopaths Show Enhanced Amygdala Activation during Fear Conditioning.

    PubMed

    Schultz, Douglas H; Balderston, Nicholas L; Baskin-Sommers, Arielle R; Larson, Christine L; Helmstetter, Fred J

    2016-01-01

    Psychopathy is a personality disorder characterized by emotional deficits and a failure to inhibit impulsive behavior and is often subdivided into "primary" and "secondary" psychopathic subtypes. The maladaptive behavior related to primary psychopathy is thought to reflect constitutional "fearlessness," while the problematic behavior related to secondary psychopathy is motivated by other factors. The fearlessness observed in psychopathy has often been interpreted as reflecting a fundamental deficit in amygdala function, and previous studies have provided support for a low-fear model of psychopathy. However, many of these studies fail to use appropriate screening procedures, use liberal inclusion criteria, or have used unconventional approaches to assay amygdala function. We measured brain activity with BOLD imaging in primary and secondary psychopaths and non-psychopathic control subjects during Pavlovian fear conditioning. In contrast to the low-fear model, we observed normal fear expression in primary psychopaths. Psychopaths also displayed greater differential BOLD activity in the amygdala relative to matched controls. Inverse patterns of activity were observed in the anterior cingulate cortex (ACC) for primary versus secondary psychopaths. Primary psychopaths exhibited a pattern of activity in the dorsal and ventral ACC consistent with enhanced fear expression, while secondary psychopaths exhibited a pattern of activity in these regions consistent with fear inhibition. These results contradict the low-fear model of psychopathy and suggest that the low fear observed for psychopaths in previous studies may be specific to secondary psychopaths. PMID:27014154

  13. Adrenal-dependent diurnal modulation of conditioned fear extinction learning.

    PubMed

    Woodruff, Elizabeth R; Greenwood, Benjamin N; Chun, Lauren E; Fardi, Sara; Hinds, Laura R; Spencer, Robert L

    2015-06-01

    Post traumatic stress disorder (PTSD) is associated with altered conditioned fear extinction expression and impaired circadian function including dysregulation of glucocorticoid hormone secretion. We examined in adult male rats the relationship between conditioned fear extinction learning, circadian phase, and endogenous glucocorticoids (CORT). Rats maintained on a 12h light:dark cycle were trained and tested across 3 separate daily sessions (conditioned fear acquisition and 2 extinction sessions) that were administered during either the rats' active or inactive circadian phase. In an initial experiment we found that rats at both circadian phases acquired and extinguished auditory cue conditioned fear to a similar degree in the first extinction session. However, rats trained and tested at zeitgeber time-16 (ZT16) (active phase) showed enhanced extinction memory expression during the second extinction session compared to rats trained and tested at ZT4 (inactive phase). In a follow-up experiment, adrenalectomized (ADX) or sham surgery rats were similarly trained and tested across 3 separate daily sessions at either ZT4 or ZT16. ADX had no effect on conditioned fear acquisition or conditioned fear memory. Sham ADX rats trained and tested at ZT16 exhibited better extinction learning across the two extinction sessions compared to all other groups of rats. These results indicate that conditioned fear extinction learning is modulated by time of day, and this diurnal modulation requires the presence of adrenal hormones. These results support an important role of CORT-dependent circadian processes in regulating conditioned fear extinction learning, which may be capitalized upon to optimize effective treatment of PTSD.

  14. The Role of Contingency in Classical Conditioning.

    ERIC Educational Resources Information Center

    Papini, Mauricio R.; Bitterman, M. E.

    1990-01-01

    Early experiments suggesting that classical conditioning depends on the contingency between conditioned stimulus (CS) and the unconditioned stimulus (US) are reconsidered along with later evidence that shows conditioning of the CS and its context in random training. CS-US contingency is neither necessary nor sufficient for conditioning. (SLD)

  15. Discriminative fear conditioning to context expressed by multiple measures of fear in the rat.

    PubMed

    Antoniadis, E A; McDonald, R J

    1999-05-01

    There has been a renewed interest in the neural basis of fear conditioning to context. These current approaches are accompanied by some limitations including the use of short testing windows, non-discriminative paradigms, and unitary fear response assessment. In an attempt to circumvent these limitations, a discriminative context procedure assessing multiple response measures of fear was used in the present study. Conditioning consisted of three training sessions and each session consisted of 2 days. On day one, the animals were placed in the paired context and received three foot shocks. On the other day, they were placed in the unpaired chamber in the absence of any aversive event. Animals were tested after each training session and the response measures of fear recorded included: preference, freezing, heart rate, ultrasonic vocalizations, defecation, body temperature, urination and locomotion. The results suggest that behavioral, as well as physiological changes evoked by fearful stimuli become associated with the context in which the aversive event occurred. In general these findings also suggest that there are different learning parameters for the measures of fear examined in this paradigm.

  16. Repeated valproate treatment facilitates fear extinction under specific stimulus conditions.

    PubMed

    Heinrichs, Stephen C; Leite-Morris, Kimberly A; Rasmusson, Ann M; Kaplan, Gary B

    2013-09-27

    Single dose treatment with histone deacetylase inhibitor (HDACi) agents has been shown to enhance extinction learning in rodent models under certain conditions. The present novel studies were designed to examine the effects of repeated HDACi treatment, with valproate or sodium butyrate, on the extinction of conditioned fear. In Experiments 1 and 2, short duration CS exposure (30s) in combination with vehicle administration progressively attenuated conditioned fear responses over 40 or more sessions. This effective extinction training was not augmented by HDACi treatments. In Experiment 3, we used a long duration CS exposure (120 s) to weaken extinction training. With these extinction parameters, repeated valproate treatment substantially facilitated the acquisition and retention of fear extinction. Results of this study extend previous work suggesting that HDACi's have utility in augmenting the efficiency of fear extinction, although their apparent benefits are critically dependent upon specific parameters of extinction training.

  17. Sound tuning of amygdala plasticity in auditory fear conditioning.

    PubMed

    Park, Sungmo; Lee, Junuk; Park, Kyungjoon; Kim, Jeongyeon; Song, Beomjong; Hong, Ingie; Kim, Jieun; Lee, Sukwon; Choi, Sukwoo

    2016-01-01

    Various auditory tones have been used as conditioned stimuli (CS) for fear conditioning, but researchers have largely neglected the effect that different types of auditory tones may have on fear memory processing. Here, we report that at lateral amygdala (LA) synapses (a storage site for fear memory), conditioning with different types of auditory CSs (2.8 kHz tone, white noise, FM tone) recruits distinct forms of long-term potentiation (LTP) and inserts calcium permeable AMPA receptor (CP-AMPAR) for variable periods. White noise or FM tone conditioning produced brief insertion (<6 hr after conditioning) of CP-AMPARs, whereas 2.8 kHz tone conditioning induced more persistent insertion (≥6 hr). Consistently, conditioned fear to 2.8 kHz tone but not to white noise or FM tones was erased by reconsolidation-update (which depends on the insertion of CP-AMPARs at LA synapses) when it was performed 6 hr after conditioning. Our data suggest that conditioning with different auditory CSs recruits distinct forms of LA synaptic plasticity, resulting in more malleable fear memory to some tones than to others. PMID:27488731

  18. Sound tuning of amygdala plasticity in auditory fear conditioning

    PubMed Central

    Park, Sungmo; Lee, Junuk; Park, Kyungjoon; Kim, Jeongyeon; Song, Beomjong; Hong, Ingie; Kim, Jieun; Lee, Sukwon; Choi, Sukwoo

    2016-01-01

    Various auditory tones have been used as conditioned stimuli (CS) for fear conditioning, but researchers have largely neglected the effect that different types of auditory tones may have on fear memory processing. Here, we report that at lateral amygdala (LA) synapses (a storage site for fear memory), conditioning with different types of auditory CSs (2.8 kHz tone, white noise, FM tone) recruits distinct forms of long-term potentiation (LTP) and inserts calcium permeable AMPA receptor (CP-AMPAR) for variable periods. White noise or FM tone conditioning produced brief insertion (<6 hr after conditioning) of CP-AMPARs, whereas 2.8 kHz tone conditioning induced more persistent insertion (≥6 hr). Consistently, conditioned fear to 2.8 kHz tone but not to white noise or FM tones was erased by reconsolidation-update (which depends on the insertion of CP-AMPARs at LA synapses) when it was performed 6 hr after conditioning. Our data suggest that conditioning with different auditory CSs recruits distinct forms of LA synaptic plasticity, resulting in more malleable fear memory to some tones than to others. PMID:27488731

  19. Effects of psilocybin on hippocampal neurogenesis and extinction of trace fear conditioning.

    PubMed

    Catlow, Briony J; Song, Shijie; Paredes, Daniel A; Kirstein, Cheryl L; Sanchez-Ramos, Juan

    2013-08-01

    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-HT2A agonist 25I-NBMeO and the 5-HT2A/C 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-HT2A 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. PMID:23727882

  20. Effects of psilocybin on hippocampal neurogenesis and extinction of trace fear conditioning.

    PubMed

    Catlow, Briony J; Song, Shijie; Paredes, Daniel A; Kirstein, Cheryl L; Sanchez-Ramos, Juan

    2013-08-01

    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-HT2A agonist 25I-NBMeO and the 5-HT2A/C 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-HT2A 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.

  1. An Appetitive Conditioned Stimulus Enhances Fear Acquisition and Impairs Fear Extinction

    ERIC Educational Resources Information Center

    Leung, Hiu T.; Holmes, Nathan M.; Westbrook, R. Frederick

    2016-01-01

    Four experiments used between- and within-subject designs to examine appetitive-aversive interactions in rats. Experiments 1 and 2 examined the effect of an excitatory appetitive conditioned stimulus (CS) on acquisition and extinction of conditioned fear. In Experiment 1, a CS shocked in a compound with an appetitive excitor (i.e., a stimulus…

  2. Increased tone-offset response in the lateral nucleus of the amygdala underlies trace fear conditioning.

    PubMed

    Kim, Namsoo; Kong, Mi-Seon; Jo, Kyeong Im; Kim, Eun Joo; Choi, June-Seek

    2015-12-01

    Accumulating evidence suggests that the lateral nucleus of the amygdala (LA) stores associative memory in the form of enhanced neural response to the sensory input following classical fear conditioning in which the conditioned stimulus (CS) and the unconditioned stimulus (US) are presented in a temporally continuous manner. However, little is known about the role of the LA in trace fear conditioning where the CS and the US are separated by a temporal gap. Single-unit recordings of LA neurons before and after trace fear conditioning revealed that the short-latency activity to the CS offset, but not that to the onset, increased significantly and accompanied the conditioned fear response. The increased short-latency activity was evident in two aspects: the number of offset-responsive neurons was increased and the latency of the neuronal response to the CS offset was shortened. On the contrary, changes in the firing rate to either the onset or the offset were negligible following unpaired presentations of the CS and US. In sum, our results suggest that increased synaptic efficacy in the CS offset pathway in the LA might underlie the association between temporally distant stimuli in trace fear conditioning.

  3. Cerebellar vermis contributes to the extinction of conditioned fear.

    PubMed

    Utz, A; Thürling, M; Ernst, T M; Hermann, A; Stark, R; Wolf, O T; Timmann, D; Merz, C J

    2015-09-14

    The cerebellum is known to contribute to the acquisition and retention of conditioned motor and emotional responses. Eyeblink conditioning and fear conditioning have been studied in greatest detail. Whereas a considerable number of studies have shown that the cerebellum is also involved in extinction of conditioned eyeblink responses, the likely contribution of the cerebellum to extinction of conditioned fear responses has largely been ignored. In the present study, we analyzed functional brain imaging data (fMRI) of previous work investigating extinction of conditioned fear in 32 young and healthy men, in which event-related fMRI analysis did not include the cerebellum. This dataset was analyzed using a spatial normalization method optimized for the cerebellum. During fear acquisition, an unpleasant electric shock (unconditioned stimulus; US) was paired with one of two pictures of geometrical figures (conditioned stimulus; CS+), while the other picture (CS-) was never paired with the US. During extinction, CS+ and CS- were presented without the US. During the acquisition phase, the fMRI signal related to the CS+ was significantly higher in hemispheric lobule VI in early compared to late acquisition (p<.05, permutation corrected). During the extinction phase, the fMRI signal related to the contrast CS+>CS- was significantly higher within the anterior vermis in early compared to late extinction (p<.05, permutation corrected). The present data show that the cerebellum is not only associated with the acquisition but also with the extinction of conditioned fear.

  4. Cerebellar vermis contributes to the extinction of conditioned fear.

    PubMed

    Utz, A; Thürling, M; Ernst, T M; Hermann, A; Stark, R; Wolf, O T; Timmann, D; Merz, C J

    2015-09-14

    The cerebellum is known to contribute to the acquisition and retention of conditioned motor and emotional responses. Eyeblink conditioning and fear conditioning have been studied in greatest detail. Whereas a considerable number of studies have shown that the cerebellum is also involved in extinction of conditioned eyeblink responses, the likely contribution of the cerebellum to extinction of conditioned fear responses has largely been ignored. In the present study, we analyzed functional brain imaging data (fMRI) of previous work investigating extinction of conditioned fear in 32 young and healthy men, in which event-related fMRI analysis did not include the cerebellum. This dataset was analyzed using a spatial normalization method optimized for the cerebellum. During fear acquisition, an unpleasant electric shock (unconditioned stimulus; US) was paired with one of two pictures of geometrical figures (conditioned stimulus; CS+), while the other picture (CS-) was never paired with the US. During extinction, CS+ and CS- were presented without the US. During the acquisition phase, the fMRI signal related to the CS+ was significantly higher in hemispheric lobule VI in early compared to late acquisition (p<.05, permutation corrected). During the extinction phase, the fMRI signal related to the contrast CS+>CS- was significantly higher within the anterior vermis in early compared to late extinction (p<.05, permutation corrected). The present data show that the cerebellum is not only associated with the acquisition but also with the extinction of conditioned fear. PMID:26219987

  5. Updating versus Exposure to Prevent Consolidation of Conditioned Fear.

    PubMed

    Pile, Victoria; Barnhofer, Thorsten; Wild, Jennifer

    2015-01-01

    Targeting the consolidation of fear memories following trauma may offer a promising method for preventing the development of flashbacks and other unwanted re-experiencing symptoms that characterise Posttraumatic Stress Disorder (PTSD). Research has demonstrated that performing visuo-spatial tasks after analogue trauma can block the consolidation of fear memory and reduce the frequency of flashbacks. However, no research has yet used verbal techniques to alter memories during the consolidation window. This is surprising given that the most effective treatments for PTSD are verbally-based with exposure therapy and trauma-focused cognitive behavioural therapy gaining the most evidence of efficacy. Psychological therapies aim to reduce the conditioned fear response, which is in keeping with the preliminary finding that an increased propensity for fear conditioning may be a vulnerability factor for PTSD. Our research had two aims. We investigated the degree to which individual differences in fear conditioning predict the development of PTSD symptoms. We also compared the preventative effects of two clinically informed psychological techniques administered during the consolidation window: exposure to the trauma memory and updating the meaning of the trauma. 115 healthy participants underwent a fear conditioning paradigm in which traumatic film stimuli (unconditioned stimuli) were paired with neutral stimuli (conditioned stimuli). Participants were randomly allocated to an updating, exposure or control group to compare the effects on the conditioned fear response and on PTSD symptomatology. The results showed that stronger conditioned responses at acquisition significantly predicted the development of PTSD symptoms. The updating group, who verbally devalued the unconditioned stimulus within the consolidation window, experienced significantly lower levels of PTSD symptoms during follow-up than the exposure and control groups. These findings are consistent with clinical

  6. Characterization of fear conditioning and fear extinction by analysis of electrodermal activity.

    PubMed

    Faghih, Rose T; Stokes, Patrick A; Marin, Marie-France; Zsido, Rachel G; Zorowitz, Sam; Rosenbaum, Blake L; Huijin Song; Milad, Mohammed R; Dougherty, Darin D; Eskandar, Emad N; Widge, Alik S; Brown, Emery N; Barbieri, Riccardo

    2015-08-01

    Electrodermal activity (EDA) is a measure of physical arousal, which is frequently measured during psychophysical tasks relevant for anxiety disorders. Recently, specific protocols and procedures have been devised in order to examine the neural mechanisms of fear conditioning and extinction. EDA reflects important responses associated with stimuli specifically administrated during these procedures. Although several previous studies have demonstrated the reproducibility of measures estimated from EDA, a mathematical framework associated with the stimulus-response experiments in question and, at the same time, including the underlying emotional state of the subject during fear conditioning and/or extinction experiments is not well studied. We here propose an ordinary differential equation model based on sudomotor nerve activity, and estimate the fear eliciting stimulus using a compressed sensing algorithm. Our results show that we are able to recover the underlying stimulus (visual cue or mild electrical shock). Moreover, relating the time-delay in the estimated stimulation to the visual cue during extinction period shows that fear level decreases as visual cues are presented without shock, suggesting that this feature might be used to estimate the fear state. These findings indicate that a mathematical model based on electrodermal responses might be critical in defining a low-dimensional representation of essential cognitive features in order to describe dynamic behavioral states.

  7. Categories, Concepts, and Conditioning: How Humans Generalize Fear

    PubMed Central

    Dunsmoor, Joseph E.; Murphy, Gregory L.

    2015-01-01

    During the past century, Pavlovian conditioning has served as the predominant experimental paradigm and theoretical framework to understand how humans learn to fear and avoid real or perceived dangers. Animal models for translational research offer insight into basic behavioral and neurophysiological factors mediating the acquisition, expression, inhibition, and generalization of fear. However, it is important to consider the limits of traditional animal models when applied to humans. Here, we focus on the question of how humans generalize fear. We propose that to understand fear generalization in humans requires taking into account research on higher-level cognition such as category-based induction, inferential reasoning, and representation of conceptual knowledge. Doing so will open the door for productive avenues of new research. PMID:25577706

  8. Categories, concepts, and conditioning: how humans generalize fear.

    PubMed

    Dunsmoor, Joseph E; Murphy, Gregory L

    2015-02-01

    During the past century, Pavlovian conditioning has served as the predominant experimental paradigm and theoretical framework to understand how humans learn to fear and avoid real or perceived dangers. Animal models for translational research offer insight into basic behavioral and neurophysiological factors mediating the acquisition, expression, inhibition, and generalization of fear. However, it is important to consider the limits of traditional animal models when applied to humans. Here, we focus on the question of how humans generalize fear. We propose that to understand fear generalization in humans requires taking into account research on higher-level cognition such as category-based induction, inferential reasoning, and representation of conceptual knowledge. Doing so will open the door for productive avenues of new research.

  9. Appetitive-aversive interactions in Pavlovian fear conditioning.

    PubMed

    Nasser, Helen M; McNally, Gavan P

    2012-06-01

    The existence of value coding and salience coding neurons in the mammalian brain, including in habenula and ventral tegmental area, has sparked considerable interest in the interactions that occur between Pavlovian appetitive and aversive conditioning. Here we studied these appetitive-aversive interactions at the behavioral level by assessing the learning that occurs when a Pavlovian appetitive conditioned stimulus (conditional stimulus, CS) serves as a CS for shock in Pavlovian fear conditioning. A Pavlovian appetitive CS was retarded in the rate at which it could be transformed into a fear CS (counterconditioning), but the presence of the appetitive CS augmented fear learning to a concurrently presented neutral CS (superconditioning). Retardation of fear learning was not alleviated by manipulations designed to restore the associability of the appetitive CS before fear conditioning but was alleviated by manipulations designed to increase the aversive quality of the shock unconditioned stimulus (US). These findings are consistent with opponent interactions between the appetitive and aversive motivational systems and provide a behavioral approach for assessing the neural correlates of these appetitive-aversive interactions.

  10. Effects of sleep on memory for conditioned fear and fear extinction.

    PubMed

    Pace-Schott, Edward F; Germain, Anne; Milad, Mohammed R

    2015-07-01

    Learning and memory for extinction of conditioned fear is a basic mammalian mechanism for regulating negative emotion. Sleep promotes both the consolidation of memory and the regulation of emotion. Sleep can influence consolidation and modification of memories associated with both fear and its extinction. After brief overviews of the behavior and neural circuitry associated with fear conditioning, extinction learning, and extinction memory in the rodent and human, interactions of sleep with these processes will be examined. Animal and human studies suggest that sleep can serve to consolidate both fear and extinction memory. In humans, sleep also promotes generalization of extinction memory. Time-of-day effects on extinction learning and generalization are also seen. Rapid eye movement (REM) may be a sleep stage of particular importance for the consolidation of both fear and extinction memory as evidenced by selective REM deprivation experiments. REM sleep is accompanied by selective activation of the same limbic structures implicated in the learning and memory of fear and extinction. Preliminary evidence also suggests extinction learning can take place during slow wave sleep. Study of low-level processes such as conditioning, extinction, and habituation may allow sleep effects on emotional memory to be identified and inform study of sleep's effects on more complex, emotionally salient declarative memories. Anxiety disorders are marked by impairments of both sleep and extinction memory. Improving sleep quality may ameliorate anxiety disorders by strengthening naturally acquired extinction. Strategically timed sleep may be used to enhance treatment of anxiety by strengthening therapeutic extinction learned via exposure therapy. (PsycINFO Database Record

  11. Topiramate diminishes fear memory consolidation and extinguishes conditioned fear in rats

    PubMed Central

    do Prado-Lima, Pedro Antônio Schmidt; Perrenoud, Myriam Fortes; Kristensen, Christian Haag; Cammarota, Martin; Izquierdo, Ivan

    2011-01-01

    Background Topiramate has been recognized as a drug that can induce memory and cognitive impairment. Using the one-trial inhibitory avoidance task, we sought to verify the effect of topiramate on consolidation and extinction of aversive memory. Our hypothesis was that topiramate inhibits the consolidation and enhances the extinction of this fear memory. Methods In experiment 1, which occured immediately or 3 hours after training, topiramate was administered to rats, and consolidation of memory was verified 18 days after the conditioning session. In experiment 2, which occured 18–22 days after the training session, rats were submitted to the extinction protocol. Rats received topiramate 14 days before or during the extinction protocol. Results Topiramate blocked fear memory retention (p < 0.01) and enhanced fear memory extinction (p < 0.001) only when administered during the extinction protocol. Limitations This experimental design did not allow us to determine whether topiramate also blocked the reconsolidation of fear memory. Conclusion Topiramate diminishes fear memory consolidation and promotes extinction of inhibitory avoidance memory. PMID:21392483

  12. Neural signatures of human fear conditioning: an updated and extended meta-analysis of fMRI studies.

    PubMed

    Fullana, M A; Harrison, B J; Soriano-Mas, C; Vervliet, B; Cardoner, N; Àvila-Parcet, A; Radua, J

    2016-04-01

    Classical Pavlovian fear conditioning remains the most widely employed experimental model of fear and anxiety, and continues to inform contemporary pathophysiological accounts of clinical anxiety disorders. Despite its widespread application in human and animal studies, the neurobiological basis of fear conditioning remains only partially understood. Here we provide a comprehensive meta-analysis of human fear-conditioning studies carried out with functional magnetic resonance imaging (fMRI), yielding a pooled sample of 677 participants from 27 independent studies. As a distinguishing feature of this meta-analysis, original statistical brain maps were obtained from the authors of 13 of these studies. Our primary analyses demonstrate that human fear conditioning is associated with a consistent and robust pattern of neural activation across a hypothesized genuine network of brain regions resembling existing anatomical descriptions of the 'central autonomic-interoceptive network'. This finding is discussed with a particular emphasis on the neural substrates of conscious fear processing. Our associated meta-analysis of functional deactivations-a scarcely addressed dynamic in fMRI fear-conditioning studies-also suggests the existence of a coordinated brain response potentially underlying the 'safety signal' (that is, non-threat) processing. We attempt to provide an integrated summary on these findings with the view that they may inform ongoing studies of fear-conditioning processes both in healthy and clinical populations, as investigated with neuroimaging and other experimental approaches.

  13. Voluntary exercise during extinction of auditory fear conditioning reduces the relapse of fear associated with potentiated activity of striatal direct pathway neurons.

    PubMed

    Mika, Agnieszka; Bouchet, Courtney A; Bunker, Preston; Hellwinkel, Justin E; Spence, Katie G; Day, Heidi E W; Campeau, Serge; Fleshner, Monika; Greenwood, Benjamin N

    2015-11-01

    Relapse of previously extinguished fear presents a significant, pervasive obstacle to the successful long-term treatment of anxiety and trauma-related disorders. Thus, identification of a novel means to enhance fear extinction to stand the passage of time and generalize across contexts is of the utmost importance. Acute bouts of exercise can be used as inexpensive, noninvasive treatment strategies to reduce anxiety, and have been shown to enhance memory for extinction when performed in close temporal proximity to the extinction session. However, it is unclear whether acute exercise can be used to prevent relapse of fear, and the neural mechanisms underlying this potential effect are unknown. The current study therefore examined whether acute exercise during extinction of auditory fear can protect against the later relapse of fear. Male F344 rats lacking an extended history of wheel running were conditioned to fear a tone CS and subsequently extinguished within either a freely mobile running wheel, a locked wheel, or a control context lacking a wheel. Rats exposed to fear extinction within a freely mobile wheel ran during fear extinction, and demonstrated reduced fear as well as attenuated corticosterone levels during re-exposure to the extinguished CS during the relapse test in a novel context 1week later. Examination of cfos mRNA patterns elicited by re-exposure to the extinguished CS during the relapse test revealed that acute exercise during extinction decreased activation of brain circuits classically involved in driving fear expression and interestingly, increased activity within neurons of the direct striatal pathway involved in reward signaling. These data suggest that exercise during extinction reduces relapse through a mechanism involving the direct pathway of the striatum. It is suggested that a positive affective state could become associated with the CS during exercise during extinction, thus resulting in a relapse-resistant extinction memory. PMID

  14. Voluntary exercise during extinction of auditory fear conditioning reduces the relapse of fear associated with potentiated activity of striatal direct pathway neurons.

    PubMed

    Mika, Agnieszka; Bouchet, Courtney A; Bunker, Preston; Hellwinkel, Justin E; Spence, Katie G; Day, Heidi E W; Campeau, Serge; Fleshner, Monika; Greenwood, Benjamin N

    2015-11-01

    Relapse of previously extinguished fear presents a significant, pervasive obstacle to the successful long-term treatment of anxiety and trauma-related disorders. Thus, identification of a novel means to enhance fear extinction to stand the passage of time and generalize across contexts is of the utmost importance. Acute bouts of exercise can be used as inexpensive, noninvasive treatment strategies to reduce anxiety, and have been shown to enhance memory for extinction when performed in close temporal proximity to the extinction session. However, it is unclear whether acute exercise can be used to prevent relapse of fear, and the neural mechanisms underlying this potential effect are unknown. The current study therefore examined whether acute exercise during extinction of auditory fear can protect against the later relapse of fear. Male F344 rats lacking an extended history of wheel running were conditioned to fear a tone CS and subsequently extinguished within either a freely mobile running wheel, a locked wheel, or a control context lacking a wheel. Rats exposed to fear extinction within a freely mobile wheel ran during fear extinction, and demonstrated reduced fear as well as attenuated corticosterone levels during re-exposure to the extinguished CS during the relapse test in a novel context 1week later. Examination of cfos mRNA patterns elicited by re-exposure to the extinguished CS during the relapse test revealed that acute exercise during extinction decreased activation of brain circuits classically involved in driving fear expression and interestingly, increased activity within neurons of the direct striatal pathway involved in reward signaling. These data suggest that exercise during extinction reduces relapse through a mechanism involving the direct pathway of the striatum. It is suggested that a positive affective state could become associated with the CS during exercise during extinction, thus resulting in a relapse-resistant extinction memory.

  15. Enhanced Generalization of Auditory Conditioned Fear in Juvenile Mice

    ERIC Educational Resources Information Center

    Ito, Wataru; Pan, Bing-Xing; Yang, Chao; Thakur, Siddarth; Morozov, Alexei

    2009-01-01

    Increased emotionality is a characteristic of human adolescence, but its animal models are limited. Here we report that generalization of auditory conditioned fear between a conditional stimulus (CS+) and a novel auditory stimulus is stronger in 4-5-wk-old mice (juveniles) than in their 9-10-wk-old counterparts (adults), whereas nonassociative…

  16. Sex Differences in Response to an Observational Fear Conditioning Procedure

    ERIC Educational Resources Information Center

    Kelly, Megan M.; Forsyth, John P.

    2007-01-01

    The present study evaluated sex differences in observational fear conditioning using modeled ''mock'' panic attacks as an unconditioned stimulus (UCS). Fifty-nine carefully prescreened healthy undergraduate participants (30 women) underwent 3 consecutive differential conditioning phases: habituation, acquisition, and extinction. It was expected…

  17. Generalization of Extinguished Skin Conductance Responding in Human Fear Conditioning

    ERIC Educational Resources Information Center

    Vervliet, Bram; Vansteenwegen, Debora; Eelen, Paul

    2004-01-01

    In a human fear conditioning paradigm using the skin conductance response (SCR), participants were assigned to two groups. Following identical acquisition, group ABA (n = 16) was extinguished to a generalization stimulus (GS), whereas group AAB (n = 20) was extinguished to the conditioned stimulus (CS). At test, presenting the CS in group ABA…

  18. Contextual fear conditioning differs for infant, adolescent, and adult rats.

    PubMed

    Esmorís-Arranz, Francisco J; Méndez, Cástor; Spear, Norman E

    2008-07-01

    Contextual fear conditioning was tested in infant, adolescent, and adult rats in terms of Pavlovian-conditioned suppression. When a discrete auditory-conditioned stimulus (CS) was paired with footshock (unconditioned stimulus, US) within the largely olfactory context, infants and adolescents conditioned to the context with substantial effectiveness, but adult rats did not. When unpaired presentations of the CS and US occurred within the context, contextual fear conditioning was strong for adults, weak for infants, but about as strong for adolescents as when pairings of CS and US occurred in the context. Nonreinforced presentations of either the CS or context markedly reduced contextual fear conditioning in infants, but, in adolescents, CS extinction had no effect on contextual fear conditioning, although context extinction significantly reduced it. Neither CS extinction nor context extinction affected responding to the CS-context compound in infants, suggesting striking discrimination between the compound and its components. Female adolescents showed the same lack of effect of component extinction on response to the compound as infants, but CS extinction reduced responding to the compound in adolescent males, a sex difference seen also in adults. Theoretical implications are discussed for the development of perceptual-cognitive processing and hippocampus role.

  19. Teens that fear screams: A comparison of fear conditioning, extinction, and reinstatement in adolescents and adults.

    PubMed

    Den, Miriam Liora; Graham, Bronwyn M; Newall, Carol; Richardson, Rick

    2015-11-01

    This study investigated differences between adolescents and adults on fear conditioning, extinction, and reinstatement (i.e., the recovery of conditioned fear following re-exposure to the unconditioned stimulus [US] post-extinction). Participants underwent differential conditioning (i.e., the Screaming Lady) where one neutral face (CS+) was followed by the same face expressing fear and a loud scream (US) while another neutral face (CS-) remained neutral. Extinction involved non-reinforced presentations of both CSs, after which participants were reinstated (2xUSs) or not. On two self-report measures, both ages showed conditioning, good extinction learning and retention, and reinstatement-induced relapse. However, only adolescents showed conditioning, extinction, and reinstatement on the eye tracking measure; relapse on this measure could not be assessed in adults given they did not show initial conditioning. Lastly, higher levels of depression predicted stronger conditioning and weaker extinction in adolescents only. These findings are discussed in terms of their implications for adolescent anxiety disorders.

  20. Fear conditioning induced by interpersonal conflicts in healthy individuals.

    PubMed

    Tada, Mitsuhiro; Uchida, Hiroyuki; Maeda, Takaki; Konishi, Mika; Umeda, Satoshi; Terasawa, Yuri; Nakajima, Shinichiro; Mimura, Masaru; Miyazaki, Tomoyuki; Takahashi, Takuya

    2015-01-01

    Psychophysiological markers have been focused to investigate the psychopathology of psychiatric disorders and personality subtypes. In order to understand neurobiological mechanisms underlying these conditions, fear-conditioning model has been widely used. However, simple aversive stimuli are too simplistic to understand mechanisms because most patients with psychiatric disorders are affected by social stressors. The objective of this study was to test the feasibility of a newly-designed conditioning experiment using a stimulus to cause interpersonal conflicts and examine associations between personality traits and response to that stimulus. Twenty-nine healthy individuals underwent the fear conditioning and extinction experiments in response to three types of stimuli: a simple aversive sound, disgusting pictures, and pictures of an actors' face with unpleasant verbal messages that were designed to cause interpersonal conflicts. Conditioned response was quantified by the skin conductance response (SCR). Correlations between the SCR changes, and personality traits measured by the Zanarini Rating Scale for Borderline Personality Disorder (ZAN-BPD) and Revised NEO Personality Inventory were explored. The interpersonal conflict stimulus resulted in successful conditioning, which was subsequently extinguished, in a similar manner as the other two stimuli. Moreover, a greater degree of conditioned response to the interpersonal conflict stimulus correlated with a higher ZAN-BPD total score. Fear conditioning and extinction can be successfully achieved, using interpersonal conflicts as a stimulus. Given that conditioned fear caused by the interpersonal conflicts is likely associated with borderline personality traits, this paradigm could contribute to further understanding of underlying mechanisms of interpersonal fear implicated in borderline personality disorder.

  1. Contextual fear conditioning in humans using feature-identical contexts.

    PubMed

    Baeuchl, Christian; Meyer, Patric; Hoppstädter, Michael; Diener, Carsten; Flor, Herta

    2015-05-01

    Contextual fear conditioning studies in animals and humans found an involvement of the hippocampus and amygdala during fear learning. To exclude a focus on elements of the context we employed a paradigm, which uses two feature-identical contexts that only differ in the arrangement of the features and requires configural processing. We employed functional magnetic resonance imaging to determine the role of the hippocampus and neocortical areas during the acquisition of contextual fear in humans. For contextual fear acquisition, we paired one context (CS+) with an aversive electrical stimulus, whereas the other (CS-) was never followed by aversive stimulation. Blood oxygen level dependent activation to the CS+ was present in the insula, inferior frontal gyrus, inferior parietal lobule, superior medial gyrus and caudate nucleus. Furthermore, the amygdala and hippocampus were involved in a time-dependent manner. Psychophysiological interaction analyses revealed functional connectivity of a more posterior hippocampal seed region with the anterior hippocampus, posterior cingulate cortex and superior parietal lobule. The anterior hippocampus was functionally coupled with the amygdala and postcentral gyrus. This study complements previous findings in contextual fear conditioning in humans and provides a paradigm which might be useful for studying patients with hippocampal impairment. PMID:25792231

  2. Priority in the Classical Conditioning of Children.

    ERIC Educational Resources Information Center

    Windholz, George; Lamal, P. A.

    1986-01-01

    Contrary to widely held belief, Watons and Rayner's (1920) experiment with Little Albert is not first reported case of classical conditioning of a child. Their work was preceded by that of Bogen and of Krasnogorskii. Mateer's work either preceded or coincided with Watons and Rayner's. This article clarifies chronology of these early studies of…

  3. Stimulus Configuration, Classical Conditioning, and Hippocampal Function.

    ERIC Educational Resources Information Center

    Schmajuk, Nestor A.; DiCarlo, James J.

    1991-01-01

    The participation of the hippocampus in classical conditioning is described in terms of a multilayer network portraying stimulus configuration. A model of hippocampal function is presented, and computer simulations are used to study neural activity in the various brain areas mapped according to the model. (SLD)

  4. Attitudes of Children Established by Classical Conditioning.

    ERIC Educational Resources Information Center

    Barnabei, Fred; And Others

    This study examined the attitudes of children established by classical conditioning. Subjects were 4th graders (26 males and 31 females). Each child was randomly assigned to either an experimental or a control group. A posttest-only design was used with positive and negative word associations presented to the experimental group, and neutral word…

  5. Learning to fear suffocation: a new paradigm for interoceptive fear conditioning.

    PubMed

    Pappens, Meike; Smets, Elyn; Vansteenwegen, Debora; Van Den Bergh, Omer; Van Diest, Ilse

    2012-06-01

    The present study aimed to establish a new interoceptive fear conditioning paradigm. The conditioned stimulus (CS) was a flow resistor that slightly obstructs breathing; the unconditional stimulus (US) was a breathing occlusion. The paired group (N = 21) received 6 acquisition trials with paired CS-US presentations. The unpaired group (N = 19) received 6 trials of unpaired CS-US presentations. In the extinction phase, both groups were administered 6 CS-only trials. Measurements included startle eyeblink response, electrodermal responses, and self-reported US expectancy. In the paired group, startle blink responses were larger during CS compared to intertrial interval during acquisition and extinction. Electrodermal and US expectancies were larger for the paired than for the unpaired group during acquisition, but not during extinction. The present paradigm successfully established interoceptive fear conditioning with panic-relevant stimuli.

  6. Ethnic Differences in Physiological Responses to Fear Conditioned Stimuli

    PubMed Central

    Martínez, Karen G.; Franco-Chaves, José A.; Milad, Mohammed R.; Quirk, Gregory J.

    2014-01-01

    The idea that emotional expression varies with ethnicity is based largely on questionnaires and behavioral observations rather than physiological measures. We therefore compared the skin conductance responses (SCR) of Hispanic (Puerto Rican) and White non-Hispanic subjects in a fear conditioning and fear extinction task. Subjects were recruited from two sites: San Juan, Puerto Rico (PR), and Boston, Massachusetts (MA), using identical methods. A total of 78 healthy subjects (39 from PR, 39 from MA) were divided by sex and matched for age and educational level. Females from the two sites did not differ in their SCRs during any experimental phase of fear conditioning (habituation, conditioning, or extinction). In contrast, PR males responded significantly to the conditioned stimulus than MA males or PR females. Subtracting ethnic differences observed during the habituation phase (prior to conditioning) eliminated differences from subsequent phases, suggesting that PR males are elevated in their response to novelty rather than fear learning. Our findings suggest that, in addition to sex differences, there are ethnic differences in physiological responses to novel stimuli at least in males, which could be relevant for the assessment and treatment of anxiety disorders. PMID:25501365

  7. Secondary extinction in Pavlovian fear conditioning.

    PubMed

    Vurbic, Drina; Bouton, Mark E

    2011-09-01

    Pavlov (1927/1960) reported that following the conditioning of several stimuli, extinction of one conditioned stimulus (CS) attenuated responding to others that had not undergone direct extinction. However, this secondary extinction effect has not been widely replicated in the contemporary literature. In three conditioned suppression experiments with rats, we further explored the phenomenon. In Experiment 1, we asked whether secondary extinction is more likely to occur with target CSs that have themselves undergone some prior extinction. A robust secondary extinction effect was obtained with a nonextinguished target CS. Experiment 2 showed that extinction of one CS was sufficient to reduce renewal of a second CS when it was tested in a neutral (nonextinction) context. In Experiment 3, secondary extinction was observed in groups that initially received intermixed conditioning trials with the target and nontarget CSs, but not in groups that received conditioning of the two CSs in separate sessions. The results are consistent with the hypothesis that CSs must be associated with a common temporal context during conditioning for secondary extinction to occur.

  8. High-dose corticosterone after fear conditioning selectively suppresses fear renewal by reducing anxiety-like response.

    PubMed

    Wang, Hongbo; Xing, Xiaoli; Liang, Jing; Bai, Yunjing; Lui, Zhengkui; Zheng, Xigeng

    2014-09-01

    Exposure therapy is widely used to treat anxiety disorders, including posttraumatic stress disorder (PTSD). However, preventing the return of fear is still a major challenge after this behavioral treatment. An increasing number of studies suggest that high-dose glucocorticoid treatment immediately after trauma can alleviate the symptoms of PTSD in humans. Unknown is whether high-dose glucocorticoid treatment following fear conditioning suppresses the return of fear. In the present study, a typical fear renewal paradigm (AAB) was used, in which the fear response to an auditory cue can be restored in a novel context (context B) when both training and extinction occur in the same context (context A). We trained rats for auditory fear conditioning and administered corticosterone (CORT; 5 and 25mg/kg, i.p.) or vehicle with different delays (1 and 24h). Forty-eight hours after drug injection, extinction was conducted with no drug in the training context, followed by a test of tone-induced freezing behavior in the same (AAA) or a shifted (AAB) context. Both immediate and delayed administration of high-dose CORT after fear conditioning reduced fear renewal. To examine the anxiolytic effect of CORT, independent rats were trained for cued or contextual fear conditioning, followed by an injection of CORT (5 and 25mg/kg, i.p.) or vehicle at a 1 or 24h delay. One week later, anxiety-like behavior was assessed in the elevated plus maze (EPM) before and after fear expression. We found that high-dose CORT decreased anxiety-like behavior without changing tone- or context-induced freezing. These findings indicate that a single high-dose CORT administration given after fear conditioning may selectively suppress fear renewal by reducing anxiety-like behavior and not by altering the consolidation, retrieval, or extinction of fear memory.

  9. Prediction of "fear" acquisition in healthy control participants in a de novo fear-conditioning paradigm.

    PubMed

    Otto, Michael W; Leyro, Teresa M; Christian, Kelly; Deveney, Christen M; Reese, Hannah; Pollack, Mark H; Orr, Scott P

    2007-01-01

    Studies using fear-conditioning paradigms have found that anxiety patients are more conditionable than individuals without these disorders, but these effects have been demonstrated inconsistently. It is unclear whether these findings have etiological significance or whether enhanced conditionability is linked only to certain anxiety characteristics. To further examine these issues, the authors assessed the predictive significance of relevant subsyndromal characteristics in 72 healthy adults, including measures of worry, avoidance, anxious mood, depressed mood, and fears of anxiety symptoms (anxiety sensitivity), as well as the dimensions of Neuroticism and Extraversion. Of these variables, the authors found that the combination of higher levels of subsyndromal worry and lower levels of behavioral avoidance predicted heightened conditionability, raising questions about the etiological significance of these variables in the acquisition or maintenance of anxiety disorders. In contrast, the authors found that anxiety sensitivity was more linked to individual differences in orienting response than differences in conditioning per se. PMID:17179530

  10. Potentiation and Overshadowing in Pavlovian Fear Conditioning

    PubMed Central

    Urcelay, Gonzalo P.; Miller, Ralph R.

    2009-01-01

    The present experiments addressed a fundamental discrepancy in the Pavlovian conditioning literature concerning responding to a target cue following compound reinforced training with another cue of higher salience. Experiment 1 identified one determinant of whether the target cue will be overshadowed or potentiated by the more salient cue, namely contiguity between compound CS termination and US presentation. Overshadowing and potentiation were observed with delay and trace procedures, respectively. Experiments 2-3 contrasted elemental and configural explanations of potentiation. Both experiments supported a configural account. Experiments 3 and 4, by manipulating prior learning experiences to bias subjects to encode the same compound elementally or configurally, demonstrated decreased potentiation and overshadowing, respectively. Overall, these experiments demonstrate potentiation with non-taste stimuli and identify one variable that determines whether overshadowing or potentiation will occur. Moreover, they show that prior experiences can determine how a compound is encoded and are compatible with the idea of flexible encoding as a principle of information processing. PMID:19594280

  11. Adolescent traumatic stress experience results in less robust conditioned fear and post-extinction fear cue responses in adult rats.

    PubMed

    Moore, Nicole L T; Gauchan, Sangeeta; Genovese, Raymond F

    2014-05-01

    Early exposure to a traumatic event may produce lasting effects throughout the lifespan. Traumatic stress during adolescence may deliver a distinct developmental insult compared with more-often studied neonatal or juvenile traumatic stress paradigms. The present study describes the lasting effects of adolescent traumatic stress upon adulthood fear conditioning. Adolescent rats were exposed to a traumatic stressor (underwater trauma, UWT), then underwent fear conditioning during adulthood. Fear extinction was tested over five conditioned suppression extinction sessions three weeks later. The efficacies of two potential extinction-enhancing compounds, endocannabinoid reuptake inhibitor AM404 (10mg/kg) and M1 muscarinic positive allosteric modulator BQCA (10mg/kg), were also assessed. Finally, post-extinction fear responses were examined using a fear cue (light) as a prepulse stimulus. Rats traumatically stressed during adolescence showed blunted conditioned suppression on day 1 of extinction training, and AM404 reversed this effect. Post-extinction startle testing showed that fear conditioning eliminates prepulse inhibition to the light cue. Startle potentiation was observed only in rats without adolescent UWT exposure. AM404 and BQCA both ameliorated this startle potentiation, while BQCA increased startle in the UWT group. These results suggest that exposure to a traumatic stressor during adolescence alters developmental outcomes related to stress response and fear extinction compared to rats without adolescent traumatic stress exposure, blunting the adulthood fear response and reducing residual post-extinction fear expression. Efficacy of pharmacological interventions may also vary as a factor of developmental traumatic stress exposure.

  12. Coantagonism of Glutamate Receptors and Nicotinic Acetylcholinergic Receptors Disrupts Fear Conditioning and Latent Inhibition of Fear Conditioning

    ERIC Educational Resources Information Center

    Gould, Thomas J.; Lewis, Michael C.

    2005-01-01

    The present study investigated the hypothesis that both nicotinic acetylcholinergic receptors (nAChRs) and glutamate receptors ([alpha]-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptors (AMPARs) and N-methyl-D-aspartate glutamate receptors (NMDARs)) are involved in fear conditioning, and may modulate similar processes. The effects of the…

  13. Dual functions of perirhinal cortex in fear conditioning.

    PubMed

    Kent, Brianne A; Brown, Thomas H

    2012-10-01

    The present review examines the role of perirhinal cortex (PRC) in Pavlovian fear conditioning. The focus is on rats, partly because so much is known, behaviorally and neurobiologically, about fear conditioning in these animals. In addition, the neuroanatomy and neurophysiology of rat PRC have been described in considerable detail at the cellular and systems levels. The evidence suggests that PRC can serve at least two types of mnemonic functions in Pavlovian fear conditioning. The first function, termed "stimulus unitization," refers to the ability to treat two or more separate items or stimulus elements as a single entity. Supporting evidence for this perceptual function comes from studies of context conditioning as well as delay conditioning to discontinuous auditory cues. In a delay paradigm, the conditional stimulus (CS) and unconditional stimulus (US) overlap temporally and co-terminate. The second PRC function entails a type of "transient memory." Supporting evidence comes from studies of trace cue conditioning, where there is a temporal gap or trace interval between the CS offset and the US onset. For learning to occur, there must be a transient CS representation during the trace interval. We advance a novel neurophysiological mechanism for this transient representation. These two hypothesized functions of PRC are consistent with inferences based on non-aversive forms of learning.

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

    PubMed

    South, Mikle; Larson, Michael J; White, Sarah E; Dana, Julianne; Crowley, Michael J

    2011-12-01

    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.

  15. Conditioned stimulus determinants of conditioned response form in Pavlovian fear conditioning.

    PubMed

    Kim, S D; Rivers, S; Bevins, R A; Ayres, J J

    1996-01-01

    Four experiments using barpress conditioned suppression in rats found that tone evoked more freezing (immobility) than did light. Still, tone and light appeared to have similar conditioned value as assessed by suppression in Experiments 1, 2, and 3, and by blocking, second-order conditioning, and overconditioning assays in Experiments 1, 2, and 3, respectively. Experiment 4 arranged for tone to evoke less suppression than light but more freezing. Results suggest that in fear conditioning, the nature of the conditioned stimulus affects the form of conditioned responding (strong vs. weak freezing). This conclusion extends one drawn by P. C. Holland (1977) on the basis of his work in appetitive conditioning.

  16. A model of amygdala-hippocampal-prefrontal interaction in fear conditioning and extinction in animals

    PubMed Central

    Moustafa, Ahmed A.; Gilbertson, Mark W.; Orr, Scott P.; Herzallah, Mohammad M.; Servatius, Richard. J.; Myers, Catherine E.

    2012-01-01

    Empirical research has shown that the amygdala, hippocampus, and ventromedial prefrontal cortex (vmPFC) are involved in fear conditioning. However, the functional contribution of each brain area and the nature of their interactions are not clearly understood. Here, we extend existing neural network models of the functional roles of the hippocampus in classical conditioning to include interactions with the amygdala and prefrontal cortex. We apply the model to fear conditioning, in which animals learn physiological (e.g. heart rate) and behavioral (e.g. freezing) responses to stimuli that have been paired with a highly aversive event (e.g. electrical shock). The key feature of our model is that learning of these conditioned responses in the central nucleus of the amygdala is modulated by two separate processes, one from basolateral amygdala and signaling a positive prediction error, and one from the vmPFC, via the intercalated cells of the amygdala, and signaling a negative prediction error. In addition, we propose that hippocampal input to both vmPFC and basolateral amygdala is essential for contextual modulation of fear acquisition and extinction. The model is sufficient to account for a body of data from various animal fear conditioning paradigms, including acquisition, extinction, reacquisition, and context specificity effects. Consistent with studies on lesioned animals, our model shows that damage to the vmPFC impairs extinction, while damage to the hippocampus impairs extinction in a different context (e.g., a different conditioning chamber from that used in initial training in animal experiments). We also discuss model limitations and predictions, including the effects of number of training trials on fear conditioning. PMID:23164732

  17. A model of amygdala-hippocampal-prefrontal interaction in fear conditioning and extinction in animals.

    PubMed

    Moustafa, Ahmed A; Gilbertson, Mark W; Orr, Scott P; Herzallah, Mohammad M; Servatius, Richard J; Myers, Catherine E

    2013-02-01

    Empirical research has shown that the amygdala, hippocampus, and ventromedial prefrontal cortex (vmPFC) are involved in fear conditioning. However, the functional contribution of each brain area and the nature of their interactions are not clearly understood. Here, we extend existing neural network models of the functional roles of the hippocampus in classical conditioning to include interactions with the amygdala and prefrontal cortex. We apply the model to fear conditioning, in which animals learn physiological (e.g. heart rate) and behavioral (e.g. freezing) responses to stimuli that have been paired with a highly aversive event (e.g. electrical shock). The key feature of our model is that learning of these conditioned responses in the central nucleus of the amygdala is modulated by two separate processes, one from basolateral amygdala and signaling a positive prediction error, and one from the vmPFC, via the intercalated cells of the amygdala, and signaling a negative prediction error. In addition, we propose that hippocampal input to both vmPFC and basolateral amygdala is essential for contextual modulation of fear acquisition and extinction. The model is sufficient to account for a body of data from various animal fear conditioning paradigms, including acquisition, extinction, reacquisition, and context specificity effects. Consistent with studies on lesioned animals, our model shows that damage to the vmPFC impairs extinction, while damage to the hippocampus impairs extinction in a different context (e.g., a different conditioning chamber from that used in initial training in animal experiments). We also discuss model limitations and predictions, including the effects of number of training trials on fear conditioning.

  18. Fear Memory.

    PubMed

    Izquierdo, Ivan; Furini, Cristiane R G; Myskiw, Jociane C

    2016-04-01

    Fear memory is the best-studied form of memory. It was thoroughly investigated in the past 60 years mostly using two classical conditioning procedures (contextual fear conditioning and fear conditioning to a tone) and one instrumental procedure (one-trial inhibitory avoidance). Fear memory is formed in the hippocampus (contextual conditioning and inhibitory avoidance), in the basolateral amygdala (inhibitory avoidance), and in the lateral amygdala (conditioning to a tone). The circuitry involves, in addition, the pre- and infralimbic ventromedial prefrontal cortex, the central amygdala subnuclei, and the dentate gyrus. Fear learning models, notably inhibitory avoidance, have also been very useful for the analysis of the biochemical mechanisms of memory consolidation as a whole. These studies have capitalized on in vitro observations on long-term potentiation and other kinds of plasticity. The effect of a very large number of drugs on fear learning has been intensively studied, often as a prelude to the investigation of effects on anxiety. The extinction of fear learning involves to an extent a reversal of the flow of information in the mentioned structures and is used in the therapy of posttraumatic stress disorder and fear memories in general. PMID:26983799

  19. Fear Memory.

    PubMed

    Izquierdo, Ivan; Furini, Cristiane R G; Myskiw, Jociane C

    2016-04-01

    Fear memory is the best-studied form of memory. It was thoroughly investigated in the past 60 years mostly using two classical conditioning procedures (contextual fear conditioning and fear conditioning to a tone) and one instrumental procedure (one-trial inhibitory avoidance). Fear memory is formed in the hippocampus (contextual conditioning and inhibitory avoidance), in the basolateral amygdala (inhibitory avoidance), and in the lateral amygdala (conditioning to a tone). The circuitry involves, in addition, the pre- and infralimbic ventromedial prefrontal cortex, the central amygdala subnuclei, and the dentate gyrus. Fear learning models, notably inhibitory avoidance, have also been very useful for the analysis of the biochemical mechanisms of memory consolidation as a whole. These studies have capitalized on in vitro observations on long-term potentiation and other kinds of plasticity. The effect of a very large number of drugs on fear learning has been intensively studied, often as a prelude to the investigation of effects on anxiety. The extinction of fear learning involves to an extent a reversal of the flow of information in the mentioned structures and is used in the therapy of posttraumatic stress disorder and fear memories in general.

  20. FAAH inhibitor OL-135 disrupts contextual, but not auditory, fear conditioning in rats.

    PubMed

    Burman, Michael A; Szolusha, Kerribeth; Bind, Rebecca; Kerney, Kristen; Boger, Dale L; Bilsky, Edward J

    2016-07-15

    Anxiety disorders are among the most prevalent psychological disorders, have significant negative impacts on quality of life and the healthcare system, and yet effective treatments remain elusive. Manipulating the endocannabinoid system has demonstrated potential for treating anxiety, although the side effects of direct manipulations of cannabinoid receptors keeps them from widespread clinical use. Disrupting the degradation enzyme fatty acid amide hydrolase (FAAH) enhances endogenous signaling and may produce similar efficacy without the side effects. The current experiments examine the effects of low (5.6mg/kg) or moderate (10.0mg/kg) doses of OL-135, a FAAH inhibitor, on the acquisition and consolidation of classical fear conditioning, a common model of trauma-induced anxiety. The acquisition of contextual, but not auditory, fear conditioning was disrupted by both doses of OL-135. Shock reactivity was not affected. Due to the additional neural circuitry required for contextual, but not auditory, fear conditioning, these data suggest that endocannabinoid signaling outside the amygdala may be critical for a subset of fearful memories. PMID:27083303

  1. FAAH inhibitor OL-135 disrupts contextual, but not auditory, fear conditioning in rats.

    PubMed

    Burman, Michael A; Szolusha, Kerribeth; Bind, Rebecca; Kerney, Kristen; Boger, Dale L; Bilsky, Edward J

    2016-07-15

    Anxiety disorders are among the most prevalent psychological disorders, have significant negative impacts on quality of life and the healthcare system, and yet effective treatments remain elusive. Manipulating the endocannabinoid system has demonstrated potential for treating anxiety, although the side effects of direct manipulations of cannabinoid receptors keeps them from widespread clinical use. Disrupting the degradation enzyme fatty acid amide hydrolase (FAAH) enhances endogenous signaling and may produce similar efficacy without the side effects. The current experiments examine the effects of low (5.6mg/kg) or moderate (10.0mg/kg) doses of OL-135, a FAAH inhibitor, on the acquisition and consolidation of classical fear conditioning, a common model of trauma-induced anxiety. The acquisition of contextual, but not auditory, fear conditioning was disrupted by both doses of OL-135. Shock reactivity was not affected. Due to the additional neural circuitry required for contextual, but not auditory, fear conditioning, these data suggest that endocannabinoid signaling outside the amygdala may be critical for a subset of fearful memories.

  2. Eyeblink classical conditioning in the preweanling lamb.

    PubMed

    Johnson, Timothy B; Stanton, Mark E; Goodlett, Charles R; Cudd, Timothy A

    2008-06-01

    Classical conditioning of eyeblink responses has been one of the most important models for studying the neurobiology of learning, with many comparative, ontogenetic, and clinical applications. The current study reports the development of procedures to conduct eyeblink conditioning in preweanling lambs and demonstrates successful conditioning using these procedures. These methods will permit application of eyeblink conditioning procedures in the analysis of functional correlates of cerebellar damage in a sheep model of fetal alcohol spectrum disorders, which has significant advantages over more common laboratory rodent models. Because sheep have been widely used for studies of pathogenesis and mechanisms of injury with many different prenatal or perinatal physiological insults, eyeblink conditioning can provide a well-studied method to assess postnatal behavioral outcomes, which heretofore have not typically been pursued with ovine models of developmental insults.

  3. Bidirectional synaptic plasticity in intercalated amygdala neurons and the extinction of conditioned fear responses.

    PubMed

    Royer, S; Paré, D

    2002-01-01

    Classical fear conditioning is believed to result from potentiation of conditioned synaptic inputs in the basolateral amygdala. That is, the conditioned stimulus would excite more neurons in the central nucleus and, via their projections to the brainstem and hypothalamus, evoke fear responses. However, much data suggests that extinction of fear responses does not depend on the reversal of these changes but on a parallel NMDA-dependent learning that competes with the first one. Because they control impulse traffic from the basolateral amygdala to the central nucleus, GABAergic neurons of the intercalated cell masses are ideally located to implement this second learning. Consistent with this hypothesis, the present study shows that low- and high-frequency stimulation of basolateral afferents respectively induce long-term depression (LTD) and potentiation (LTP) of responses in intercalated cells. Moreover, induction of LTP and LTD is prevented by application of an NMDA antagonist. To determine how these activity-dependent changes are expressed, we tested whether LTD and LTP induction are associated with modifications in paired-pulse facilitation, an index of transmitter release probability. Only LTP induction was associated with a change in paired-pulse facilitation. Depotentiation of previously potentiated synapses did not revert the modification in paired pulse facilitation, suggesting that LTP is associated with presynaptic alterations, but that LTD and depotentiation depend on postsynaptic changes. Taken together, our results suggest that basolateral synapses onto intercalated neurons can express NMDA-dependent LTP and LTD, consistent with the possibility that intercalated neurons are a critical locus of plasticity for the extinction of conditioned fear responses. Ultimately, these plastic events may prevent conditioned amygdala responses from exciting neurons of the central nucleus, and thus from evoking conditioned fear responses.

  4. Demand Characteristics in Classical Verbal Conditioning and Attitude Conditioning Studies.

    ERIC Educational Resources Information Center

    McGinley, Hugh

    This paper is a draft for the American Psychological Association Symposium on the conditioning of verbal behavior and attitudes. The author presents the results of several studies he conducted in the classical conditioning of meaning and attitude. These studies attempt to control the measurement effects created by extraneous variables operating on…

  5. The amygdala is critical for trace, delay, and contextual fear conditioning.

    PubMed

    Kochli, Daniel E; Thompson, Elaine C; Fricke, Elizabeth A; Postle, Abagail F; Quinn, Jennifer J

    2015-02-01

    Numerous investigations have definitively shown amygdalar involvement in delay and contextual fear conditioning. However, much less is known about amygdala contributions to trace fear conditioning, and what little evidence exists is conflicting as noted in previous studies. This discrepancy may result from selective targeting of individual nuclei within the amygdala. The present experiments further examine the contributions of amygdalar subnuclei to trace, delay, and contextual fear conditioning. Rats were trained using a 10-trial trace, delay, or unpaired fear conditioning procedure. Pretraining lesions targeting the entire basolateral amygdala (BLA) resulted in a deficit in trace, delay, and contextual fear conditioning. Immediate post-training infusions of the protein synthesis inhibitor, cycloheximide, targeting the basal nucleus of the amygdala (BA) attenuated trace and contextual fear memory expression, but had no effect on delay fear conditioning. However, infusions targeting the lateral nucleus of the amygdala (LA) immediately following conditioning attenuated contextual fear memory expression, but had no effect on delay or trace fear conditioning. In follow-up experiments, rats were trained using a three-trial delay conditioning procedure. Immediate post-training infusions targeting the LA produced deficits in both delay tone and context fear, while infusions targeting the BA produced deficits in context but not delay tone fear. These data fully support a role for the BLA in trace, delay, and contextual fear memories. Specifically, these data suggest that the BA may be more critical for trace fear conditioning, whereas the LA may be more critical for delay fear memories.

  6. VOLUNTARY WHEEL RUNNING ENHANCES CONTEXTUAL BUT NOT TRACE FEAR CONDITIONING

    PubMed Central

    Kohman, Rachel A.; Clark, Peter J.; DeYoung, Erin K.; Bhattacharya, Tushar K.; Venghaus, Christine E.; Rhodes, Justin S.

    2011-01-01

    Exercise improves performance on a number of hippocampus involved cognitive tasks including contextual fear conditioning, but whether exercise enhances contextual fear when the retention interval is longer than 1 day is not known. Also unknown is whether exercise improves trace conditioning, a task that requires the hippocampus to bridge the time interval between stimuli. Hence, 4-month-old male C57BL/6J mice were housed with or without running wheels. To assess whether hippocampal neurogenesis was associated with behavioral outcomes, during the initial ten days, mice received Bromodeoxyuridine to label dividing cells. After 30 days, one group of mice was trained in a contextual fear conditioning task. Freezing to context was assessed 1, 7, or 21 days post-training. A separate group was trained on a trace procedure, in which a tone and footshock were separated by a 15, 30, or 45 sec interval. Freezing to the tone was measured 24 hrs later in a novel environment, and freezing to training context was measured 48 hrs later. Running enhanced freezing to context when the retention interval was 1, but not 7 or 21 days. Running had no effect on trace conditioning even though runners displayed enhanced freezing to the training context 48 hrs later. Wheel running increased survival of new neurons in the hippocampus. Collectively, findings indicate that wheel running enhances cognitive performance on some tasks but not others and that enhanced neurogenesis is not always associated with improved performance on hippocampus tasks, one example of which is trace conditioning. PMID:21896289

  7. Voluntary exercise improves both learning and consolidation of cued conditioned fear in C57 mice.

    PubMed

    Falls, William A; Fox, James H; MacAulay, Christina M

    2010-03-01

    Exercise is associated with improved cognitive function in humans as well as improved learning across a range of tasks in rodents. Although these studies provide a strong link between exercise and learning, to date studies have largely focused on tasks that principally involve the hippocampus. However, exercise has been shown to produce alterations in other brain areas suggesting that the cognitive enhancing effects of exercise may be more general. Therefore we set out to examine the effects of voluntary exercise on cued Pavlovian fear conditioning, a form of learning that is critically dependent on the amygdala. In Experiment 1 we showed that mice given 2 weeks of access to a running wheel prior to tone and foot shock fear conditioning showed enhanced conditioned fear as measured by fear-potentiated startle. This effect was not the result of altered shock reactivity nor was it to due to reduced baseline startle amplitude in exercising mice. In subsequent experiments we sought to examine whether the enhanced cued conditioned fear was the result of an improvement in learning, consolidation or retrieval of conditioned fear. In separate groups of mice, two weeks of access to a running wheel was begun either prior to fear conditioning, immediately after fear conditioning (consolidation period) or 2 weeks after fear conditioning. Compared to sedentary mice, mice that exercised either prior to fear conditioning, or immediately after fear conditioning, showed enhanced cued conditioned fear. Fear conditioning was not enhanced in mice that began exercising 2 weeks after fear conditioning. Taken together these results suggest that voluntary exercise improves the learning and consolidation of cued conditioned fear but does not improve the retrieval or performance of conditioned fear. Because a great deal is known about the neural circuit for cued conditioned fear, it is now possible to examine the cellular, molecular and pharmacological changes associated with exercise in

  8. Evaluating the TD model of classical conditioning.

    PubMed

    Ludvig, Elliot A; Sutton, Richard S; Kehoe, E James

    2012-09-01

    The temporal-difference (TD) algorithm from reinforcement learning provides a simple method for incrementally learning predictions of upcoming events. Applied to classical conditioning, TD models suppose that animals learn a real-time prediction of the unconditioned stimulus (US) on the basis of all available conditioned stimuli (CSs). In the TD model, similar to other error-correction models, learning is driven by prediction errors--the difference between the change in US prediction and the actual US. With the TD model, however, learning occurs continuously from moment to moment and is not artificially constrained to occur in trials. Accordingly, a key feature of any TD model is the assumption about the representation of a CS on a moment-to-moment basis. Here, we evaluate the performance of the TD model with a heretofore unexplored range of classical conditioning tasks. To do so, we consider three stimulus representations that vary in their degree of temporal generalization and evaluate how the representation influences the performance of the TD model on these conditioning tasks.

  9. Acceleration of visually cued conditioned fear through the auditory pathway.

    PubMed

    Newton, Jessica R; Ellsworth, Charlene; Miyakawa, Tsuyoshi; Tonegawa, Susumu; Sur, Mriganka

    2004-09-01

    Defensive responses elicited by sensory experiences are critical for survival. Mice acquire a conditioned fear response rapidly to an auditory cue but slowly to a visual cue, a difference in learned behavior that is likely to be mediated by direct projections to the lateral amygdala from the auditory thalamus but mainly indirect ones from the visual thalamus. Here, we show that acquisition of visually cued conditioned fear is accelerated in 'rewired' mice that have retinal projections routed to the auditory thalamus. Visual stimuli induce expression of the immediate early gene Fos (also known as c-fos) in the auditory thalamus and the lateral amygdala in rewired mice, similar to the way auditory stimuli do in control mice. Thus, the rewired auditory pathway conveys visual information and mediates rapid activity-dependent plasticity in central structures that influence learned behavior.

  10. Interoceptive fear conditioning and panic disorder: the role of conditioned stimulus-unconditioned stimulus predictability.

    PubMed

    Acheson, Dean T; Forsyth, John P; Moses, Erica

    2012-03-01

    Interoceptive fear conditioning is at the core of contemporary behavioral accounts of panic disorder. Yet, to date only one study has attempted to evaluate interoceptive fear conditioning in humans (see Acheson, Forsyth, Prenoveau, & Bouton, 2007). That study used brief (physiologically inert) and longer-duration (panicogenic) inhalations of 20% CO(2)-enriched air as an interoceptive conditioned (CS) and unconditioned (US) stimulus and evaluated fear learning in three conditions: CS only, CS-US paired, and CS-US unpaired. Results showed fear conditioning in the paired condition, and fearful responding and resistance to extinction in an unpaired condition. The authors speculated that such effects may be due to difficulty discriminating between the CS and the US. The aims of the present study are to (a) replicate and expand this line of work using an improved methodology, and (b) clarify the role of CS-US discrimination difficulties in either potentiating or depotentiating fear learning. Healthy participants (N=104) were randomly assigned to one of four conditions: (a) CS only, (b) contingent CS-US pairings, (c) unpaired CS and US presentations, or (d) an unpaired "discrimination" contingency, which included an exteroceptive discrimination cue concurrently with CS onset. Electrodermal and self-report ratings served as indices of conditioned responding. Consistent with expectation, the paired contingency and unpaired contingencies yielded elevated fearful responding to the CS alone. Moreover, adding a discrimination cue to the unpaired contingency effectively attenuated fearful responding. Overall, findings are consistent with modern learning theory accounts of panic and highlight the role of interoceptive conditioning and unpredictability in the etiology of panic disorder.

  11. Interoceptive fear conditioning and panic disorder: the role of conditioned stimulus-unconditioned stimulus predictability.

    PubMed

    Acheson, Dean T; Forsyth, John P; Moses, Erica

    2012-03-01

    Interoceptive fear conditioning is at the core of contemporary behavioral accounts of panic disorder. Yet, to date only one study has attempted to evaluate interoceptive fear conditioning in humans (see Acheson, Forsyth, Prenoveau, & Bouton, 2007). That study used brief (physiologically inert) and longer-duration (panicogenic) inhalations of 20% CO(2)-enriched air as an interoceptive conditioned (CS) and unconditioned (US) stimulus and evaluated fear learning in three conditions: CS only, CS-US paired, and CS-US unpaired. Results showed fear conditioning in the paired condition, and fearful responding and resistance to extinction in an unpaired condition. The authors speculated that such effects may be due to difficulty discriminating between the CS and the US. The aims of the present study are to (a) replicate and expand this line of work using an improved methodology, and (b) clarify the role of CS-US discrimination difficulties in either potentiating or depotentiating fear learning. Healthy participants (N=104) were randomly assigned to one of four conditions: (a) CS only, (b) contingent CS-US pairings, (c) unpaired CS and US presentations, or (d) an unpaired "discrimination" contingency, which included an exteroceptive discrimination cue concurrently with CS onset. Electrodermal and self-report ratings served as indices of conditioned responding. Consistent with expectation, the paired contingency and unpaired contingencies yielded elevated fearful responding to the CS alone. Moreover, adding a discrimination cue to the unpaired contingency effectively attenuated fearful responding. Overall, findings are consistent with modern learning theory accounts of panic and highlight the role of interoceptive conditioning and unpredictability in the etiology of panic disorder. PMID:22304889

  12. A role for midline and intralaminar thalamus in the associative blocking of Pavlovian fear conditioning.

    PubMed

    Sengupta, Auntora; McNally, Gavan P

    2014-01-01

    Fear learning occurs in response to positive prediction error, when the expected outcome of a conditioning trial exceeds that predicted by the conditioned stimuli present. This role for error in Pavlovian association formation is best exemplified by the phenomenon of associative blocking, whereby prior fear conditioning of conditioned stimulus (CS) A is able to prevent learning to CSB when they are conditioned in compound. The midline and intralaminar thalamic nuclei (MIT) are well-placed to contribute to fear prediction error because they receive extensive projections from the midbrain periaqueductal gray-which has a key role in fear prediction error-and project extensively to prefrontal cortex and amygdala. Here we used an associative blocking design to study the role of MIT in fear learning. In Stage I rats were trained to fear CSA via pairings with shock. In Stage II rats received compound fear conditioning of CSAB paired with shock. On test, rats that received Stage I training expressed less fear to CSB relative to control rats that did not receive this training. Microinjection of bupivacaine into MIT prior to Stage II training had no effect on the expression of fear during Stage II and had no effect on fear learning in controls, but prevented associative blocking and so enabled fear learning to CSB. These results show an important role for MIT in predictive fear learning and are discussed with reference to previous findings implicating the midline and posterior intralaminar thalamus in fear learning and fear responding.

  13. Opioid receptors regulate the extinction of Pavlovian fear conditioning.

    PubMed

    McNally, Gavan P; Westbrook, R Frederick

    2003-12-01

    Rats received a single pairing of an auditory conditioned stimulus (CS) with a footshock unconditioned stimulus (US). The fear (freezing) that had accrued to the CS was then extinguished. Injection of naloxone prior to this extinction significantly impaired the development of extinction. This impairment was mediated by opioid receptors in the brain and was not observed when naloxone was injected after extinction training. Finally, an injection of naloxone on test failed to reinstate extinguished responding that had already accrued to the CS. These experiments show that opioid receptors regulate the development, but not the expression, of fear extinction and are discussed with reference to the roles of opioid receptors in US processing, memory, and appetitive motivation.

  14. Muscarinic receptors in amygdala control trace fear conditioning.

    PubMed

    Baysinger, Amber N; Kent, Brianne A; Brown, Thomas H

    2012-01-01

    Intelligent behavior requires transient memory, which entails the ability to retain information over short time periods. A newly-emerging hypothesis posits that endogenous persistent firing (EPF) is the neurophysiological foundation for aspects or types of transient memory. EPF is enabled by the activation of muscarinic acetylcholine receptors (mAChRs) and is triggered by suprathreshold stimulation. EPF occurs in several brain regions, including the lateral amygdala (LA). The present study examined the role of amygdalar mAChRs in trace fear conditioning, a paradigm that requires transient memory. If mAChR-dependent EPF selectively supports transient memory, then blocking amygdalar mAChRs should impair trace conditioning, while sparing delay and context conditioning, which presumably do not rely upon transient memory. To test the EPF hypothesis, LA was bilaterally infused, prior to trace or delay conditioning, with either a mAChR antagonist (scopolamine) or saline. Computerized video analysis quantified the amount of freezing elicited by the cue and by the training context. Scopolamine infusion profoundly reduced freezing in the trace conditioning group but had no significant effect on delay or context conditioning. This pattern of results was uniquely anticipated by the EPF hypothesis. The present findings are discussed in terms of a systems-level theory of how EPF in LA and several other brain regions might help support trace fear conditioning.

  15. Sexually divergent expression of active and passive conditioned fear responses in rats.

    PubMed

    Gruene, Tina M; Flick, Katelyn; Stefano, Alexis; Shea, Stephen D; Shansky, Rebecca M

    2015-01-01

    Traditional rodent models of Pavlovian fear conditioning assess the strength of learning by quantifying freezing responses. However, sole reliance on this measure includes the de facto assumption that any locomotor activity reflects an absence of fear. Consequently, alternative expressions of associative learning are rarely considered. Here we identify a novel, active fear response ('darting') that occurs primarily in female rats. In females, darting exhibits the characteristics of a learned fear behavior, appearing during the CS period as conditioning proceeds and disappearing from the CS period during extinction. This finding motivates a reinterpretation of rodent fear conditioning studies, particularly in females, and it suggests that conditioned fear behavior is more diverse than previously appreciated. Moreover, rats that darted during initial fear conditioning exhibited lower freezing during the second day of extinction testing, suggesting that females employ distinct and adaptive fear response strategies that improve long-term outcomes. PMID:26568307

  16. Sexually divergent expression of active and passive conditioned fear responses in rats.

    PubMed

    Gruene, Tina M; Flick, Katelyn; Stefano, Alexis; Shea, Stephen D; Shansky, Rebecca M

    2015-11-14

    Traditional rodent models of Pavlovian fear conditioning assess the strength of learning by quantifying freezing responses. However, sole reliance on this measure includes the de facto assumption that any locomotor activity reflects an absence of fear. Consequently, alternative expressions of associative learning are rarely considered. Here we identify a novel, active fear response ('darting') that occurs primarily in female rats. In females, darting exhibits the characteristics of a learned fear behavior, appearing during the CS period as conditioning proceeds and disappearing from the CS period during extinction. This finding motivates a reinterpretation of rodent fear conditioning studies, particularly in females, and it suggests that conditioned fear behavior is more diverse than previously appreciated. Moreover, rats that darted during initial fear conditioning exhibited lower freezing during the second day of extinction testing, suggesting that females employ distinct and adaptive fear response strategies that improve long-term outcomes.

  17. Necessary and sufficient factors in classical conditioning.

    PubMed

    Damianopoulos, E N

    1982-01-01

    The issue of necessary and sufficient factors (pairing-contiguity vs. contingency-correlation) in classical (Pavlovian) excitatory conditioning is examined: first, in terms of definitional (logical) and manipulational requirements of "necessary" and "sufficient"; second, in terms of Boolean logic test models indicating experimental and control manipulations in tests of pairing and contingency as necessary and sufficient factors; and, third, by a selective review of reference experiments showing appropriate experimental and control manipulations of pairing and contingency indicated in the Boolean logic test models. Results of examination show pairing-contiguity as the sole necessary and sufficient factor for excitatory conditioning, while contingency-correlation is conceptualized as a modulating factor controlling minimal-maximal effects of pairing-contiguity. Reservations and diagnostic experiments are indicated to assess effects of uncontrolled conditioned stimulus--unconditioned stimulus (--CS--US) probability characteristics (e.g., p (CS--US)/p (--CS--US) in truly random (TR) schedule manipulations). Similar analysis of conditioned inhibition reveals insufficient evidence to support a choice among current alternatives.

  18. On the resistance to extinction of fear conditioned to angry faces.

    PubMed

    Rowles, Monique E; Lipp, Ottmar V; Mallan, Kimberley M

    2012-03-01

    The present study investigated whether, like fear conditioned to pictures of snakes and spiders, fear conditioned to angry faces resists extinction even after verbal instruction and removal of the shock electrode. Participants were trained in a differential Pavlovian fear conditioning procedure with angry face or happy face conditional stimuli (CSs). Prior to extinction, half the participants in each group were informed that no more unconditional stimuli would be presented and the shock electrode was removed. In the absence of this manipulation, participants showed resistance to extinction after training with angry face CSs, but not after training with happy face CSs. Instructed extinction and electrode removal abolished fear conditioning regardless of the emotion expressed by the CS faces. This finding suggests that fear conditioned to angry faces, like fear conditioned to racial out-group faces, is more malleable than fear conditioned to snakes and spiders. PMID:22091639

  19. An "egr-1" ("zif268") Antisense Oligodeoxynucleotide Infused into the Amygdala Disrupts Fear Conditioning

    ERIC Educational Resources Information Center

    Donley, Melanie P.; Rosen, Jeffrey B.; Malkani, Seema; Wallace, Karin J.

    2004-01-01

    Studies of gene expression following fear conditioning have demonstrated that the inducible transcription factor, "egr-1," is increased in the lateral nucleus of the amygdala shortly following fear conditioning. These studies suggest that "egr-1" and its protein product Egr-1 in the amygdala are important for learning and memory of fear. To…

  20. Modafinil and memory: effects of modafinil on Morris water maze learning and Pavlovian fear conditioning.

    PubMed

    Shuman, Tristan; Wood, Suzanne C; Anagnostaras, Stephan G

    2009-04-01

    Modafinil has been shown to promote wakefulness and some studies suggest the drug can improve cognitive function. Because of many similarities, the mechanism of action may be comparable to classical psychostimulants, although the exact mechanisms of modafinil's actions in wakefulness and cognitive enhancement are unknown. The current study aims to further examine the effects of modafinil as a cognitive enhancer on hippocampus-dependent memory in mice. A high dose of modafinil (75 mg/kg ip) given before training improved acquisition on a Morris water maze. When given only before testing, modafinil did not affect water maze performance. We also examined modafinil (0.075 to 75 mg/kg) on Pavlovian fear conditioning. A low dose of pretraining modafinil (0.75 mg/kg) enhanced memory of contextual fear conditioning (tested off-drug 1 week later) whereas a high dose (75 mg/kg) disrupted memory. Pretraining modafinil did not affect cued conditioning at any dose tested, and immediate posttraining modafinil had no effect on either cued or contextual fear. These results suggest that modafinil's effects of memory are more selective than amphetamine or cocaine and specific to hippocampus-dependent memory.

  1. Object-location training elicits an overlapping but temporally distinct transcriptional profile from contextual fear conditioning.

    PubMed

    Poplawski, Shane G; Schoch, Hannah; Wimmer, Mathieu E; Hawk, Joshua D; Walsh, Jennifer L; Giese, Karl P; Abel, Ted

    2014-12-01

    Hippocampus-dependent learning is known to induce changes in gene expression, but information on gene expression differences between different learning paradigms that require the hippocampus is limited. The bulk of studies investigating RNA expression after learning use the contextual fear conditioning task, which couples a novel environment with a footshock. Although contextual fear conditioning has been useful in discovering gene targets, gene expression after spatial memory tasks has received less attention. In this study, we used the object-location memory task and studied gene expression at two time points after learning in a high-throughput manner using a microfluidic qPCR approach. We found that expression of the classic immediate-early genes changes after object-location training in a fashion similar to that observed after contextual fear conditioning. However, the temporal dynamics of gene expression are different between the two tasks, with object-location memory producing gene expression changes that last at least 2 hours. Our findings indicate that different training paradigms may give rise to distinct temporal dynamics of gene expression after learning. PMID:25242102

  2. Object-location training elicits an overlapping but temporally distinct transcriptional profile from contextual fear conditioning.

    PubMed

    Poplawski, Shane G; Schoch, Hannah; Wimmer, Mathieu E; Hawk, Joshua D; Walsh, Jennifer L; Giese, Karl P; Abel, Ted

    2014-12-01

    Hippocampus-dependent learning is known to induce changes in gene expression, but information on gene expression differences between different learning paradigms that require the hippocampus is limited. The bulk of studies investigating RNA expression after learning use the contextual fear conditioning task, which couples a novel environment with a footshock. Although contextual fear conditioning has been useful in discovering gene targets, gene expression after spatial memory tasks has received less attention. In this study, we used the object-location memory task and studied gene expression at two time points after learning in a high-throughput manner using a microfluidic qPCR approach. We found that expression of the classic immediate-early genes changes after object-location training in a fashion similar to that observed after contextual fear conditioning. However, the temporal dynamics of gene expression are different between the two tasks, with object-location memory producing gene expression changes that last at least 2 hours. Our findings indicate that different training paradigms may give rise to distinct temporal dynamics of gene expression after learning.

  3. Fear but not fright: re-evaluating traumatic experience attenuates anxiety-like behaviors after fear conditioning.

    PubMed

    Costanzi, Marco; Saraulli, Daniele; Cannas, Sara; D'Alessandro, Francesca; Florenzano, Fulvio; Rossi-Arnaud, Clelia; Cestari, Vincenzo

    2014-01-01

    Fear allows organisms to cope with dangerous situations and remembering these situations has an adaptive role preserving individuals from injury and death. However, recalling traumatic memories can induce re-experiencing the trauma, thus resulting in a maladaptive fear. A failure to properly regulate fear responses has been associated with anxiety disorders, like Posttraumatic Stress Disorder (PTSD). Thus, re-establishing the capability to regulate fear has an important role for its adaptive and clinical relevance. Strategies aimed at erasing fear memories have been proposed, although there are limits about their efficiency in treating anxiety disorders. To re-establish fear regulation, here we propose a new approach, based on the re-evaluation of the aversive value of traumatic experience. Mice were submitted to a contextual-fear-conditioning paradigm in which a neutral context was paired with an intense electric footshock. Three weeks after acquisition, conditioned mice were treated with a less intense footshock (pain threshold). The effectiveness of this procedure in reducing fear expression was assessed in terms of behavioral outcomes related to PTSD (e.g., hyper-reactivity to a neutral tone, anxiety levels in a plus maze task, social avoidance, and learning deficits in a spatial water maze) and of amygdala activity by evaluating c-fos expression. Furthermore, a possible role of lateral orbitofrontal cortex (lOFC) in mediating the behavioral effects induced by the re-evaluation procedure was investigated. We observed that this treatment: (i) significantly mitigates the abnormal behavioral outcomes induced by trauma; (ii) persistently attenuates fear expression without erasing contextual memory; (iii) prevents fear reinstatement; (iv) reduces amygdala activity; and (v) requires an intact lOFC to be effective. These results suggest that an effective strategy to treat pathological anxiety should address cognitive re-evaluation of the traumatic experience mediated

  4. The contextual brain: implications for fear conditioning, extinction and psychopathology

    PubMed Central

    Maren, Stephen; Phan, K. Luan; Liberzon, Israel

    2016-01-01

    Contexts surround and imbue meaning to events; they are essential for recollecting the past, interpreting the present and anticipating the future. Indeed, the brain’s capacity to contextualize information permits enormous cognitive and behavioural flexibility. Studies of Pavlovian fear conditioning and extinction in rodents and humans suggest that a neural circuit including the hippocampus, amygdala and medial prefrontal cortex is involved in the learning and memory processes that enable context-dependent behaviour. Dysfunction in this network may be involved in several forms of psychopathology, including post-traumatic stress disorder, schizophrenia and substance abuse disorders. PMID:23635870

  5. Early Extinction after Fear Conditioning Yields a Context-Independent and Short-Term Suppression of Conditional Freezing in Rats

    ERIC Educational Resources Information Center

    Chang, Chun-hui; Maren, Stephen

    2009-01-01

    Extinction of Pavlovian fear conditioning in rats is a useful model for therapeutic interventions in humans with anxiety disorders. Recently, we found that delivering extinction trials soon (15 min) after fear conditioning yields a short-term suppression of fear, but little long-term extinction. Here, we explored the possible mechanisms underlying…

  6. Neurophysiological theory of kamin blocking in fear conditioning.

    PubMed

    Padlubnaya, Diana B; Parekh, Nirav H; Brown, Thomas H

    2006-04-01

    Kamin blocking in fear conditioning is thought to reflect diminished processing of the unconditional stimulus (US) in the presence of a conditional stimulus (CS-super(+)) that was previously paired with this US. According to Fanselow's (1998) hypothesis, the CS-super(+) drives output from the amygdala that ultimately produces analgesia by causing opiate release onto afferent pain circuits. This hypothesis was explored quantitatively through neurophysiological simulations. The results suggest that opiate-mediated, negative-feedback control of US processing is too slow for efficient blocking of cue conditioning. The reason is that conditioning-produced synaptic modifications can be induced before the opiate-mediated inhibition has any substantial effect on US processing. The results suggest the existence of an additional, faster-acting, inhibitory neurotransmitter in the blocking circuit.

  7. Retrospective reversal of extinction of conditioned fear by instruction.

    PubMed

    Zeng, Qing; Jia, Yanlei; Wang, Yuanjun; Zhang, Junhua; Liu, Chuyi; Zheng, Xifu

    2015-09-01

    In the present study, we examined the impact of verbal instruction during extinction of human fear-conditioning. We extended the study of Raes, De Houwer, Verschuere, and De Raedt (2011) by controlling for context conditioning and recording unconditioned stimulus expectancy online in a within-subject design. We informed participants of an alternative reason for the absence of the aversive unconditioned stimulus after extinction had been carried out, to see if such instruction could induce retrospective protection from extinction. The results demonstrated that both the expectancy of an aversive outcome and conditioned skin conductance were significantly increased for the conditioned stimulus targeted by the instruction. Thus extinction was reversed by the concurrent presence of an alternative cause for the absence of the unconditioned stimulus.

  8. Comparison of timing and classical conditioning.

    PubMed

    Holder, M D; Roberts, S

    1985-04-01

    Four experiments with rats investigated if the timing of a stimulus (sound) correlated with the strength of a conditioned response (CR) to the stimulus. The timing (effective duration) of the stimulus was measured using the peak procedure, similar to a discrete-trials fixed-interval procedure. The rats were trained so that their response rate reached a maximum about 40 s or 60 s after the onset of a light; the time of the maximum measured from the start of the light (peak time) was the measure of timing. On some trials, the light was preceded by a short (5 s) or long (20 s or 30 s) interval of sound. We assumed that the difference in peak time after long and short sounds reflected the timing of the sound--if the sound was timed, the longer sound would produce a lower peak time; if the sound was not timed, the two durations of sound would produce the same peak time. The CR was lever-pressing during the sound. The sound was treated in various ways: presented alone (Experiments 1, 3, and 4), followed by food (Experiments 1, 3, and 4), preceded by food (Experiment 3), and followed by food after 20 s (Experiment 4). Treatments that produced no timing of sound produced no CR, and treatments that increased (or diseased) timing also increased (or decreased) the CR. The results suggest that there is overlap between the mechanisms that produce time discrimination and the mechanisms that produce classical conditioning.

  9. Pavlovian fear conditioning as a behavioral assay for hippocampus and amygdala function: cautions and caveats.

    PubMed

    Maren, Stephen

    2008-10-01

    Pavlovian fear conditioning has become an important model for investigating the neural substrates of learning and memory in rats, mice and humans. The hippocampus and amygdala are widely believed to be essential for fear conditioning to contexts and discrete cues, respectively. Indeed, this parsing of function within the fear circuit has been used to leverage fear conditioning as a behavioral assay of hippocampal and amygdala function, particularly in transgenic mouse models. Recent work, however, blurs the anatomical segregation of cue and context conditioning and challenges the necessity for the hippocampus and amygdala in fear learning. Moreover, nonassociative factors may influence the performance of fear responses under a variety of conditions. Caution must therefore be exercised when using fear conditioning as a behavioral assay for hippocampal- and amygdala-dependent learning.

  10. Pavlovian fear conditioning as a behavioral assay for hippocampus and amygdala function: cautions and caveats.

    PubMed

    Maren, Stephen

    2008-10-01

    Pavlovian fear conditioning has become an important model for investigating the neural substrates of learning and memory in rats, mice and humans. The hippocampus and amygdala are widely believed to be essential for fear conditioning to contexts and discrete cues, respectively. Indeed, this parsing of function within the fear circuit has been used to leverage fear conditioning as a behavioral assay of hippocampal and amygdala function, particularly in transgenic mouse models. Recent work, however, blurs the anatomical segregation of cue and context conditioning and challenges the necessity for the hippocampus and amygdala in fear learning. Moreover, nonassociative factors may influence the performance of fear responses under a variety of conditions. Caution must therefore be exercised when using fear conditioning as a behavioral assay for hippocampal- and amygdala-dependent learning. PMID:18973583

  11. Mindfulness-Based Stress Reduction, Fear Conditioning, and The Uncinate Fasciculus: A Pilot Study.

    PubMed

    Hölzel, Britta K; Brunsch, Vincent; Gard, Tim; Greve, Douglas N; Koch, Kathrin; Sorg, Christian; Lazar, Sara W; Milad, Mohammed R

    2016-01-01

    Mindfulness has been suggested to impact emotional learning, but research on these processes is scarce. The classical fear conditioning/extinction/extinction retention paradigm is a well-known method for assessing emotional learning. The present study tested the impact of mindfulness training on fear conditioning and extinction memory and further investigated whether changes in white matter fiber tracts might support such changes. The uncinate fasciculus (UNC) was of particular interest in the context of emotional learning. In this pilot study, 46 healthy participants were quasi-randomized to a Mindfulness-Based Stress Reduction (MBSR, N = 23) or waitlist control (N = 23) group and underwent a two-day fear conditioning, extinction learning, and extinction memory protocol before and after the course or control period. Skin conductance response (SCR) data served to measure the physiological response during conditioning and extinction memory phases. Diffusion tensor imaging (DTI) data were analyzed with probabilistic tractography and analyzed for changes of fractional anisotropy in the UNC. During conditioning, participants were able to maintain a differential response to conditioned vs. not conditioned stimuli following the MBSR course (i.e., higher sensitivity to the conditioned stimuli), while controls dropped the response. Extinction memory results were not interpretable due to baseline differences. MBSR participants showed a significant increase in fractional anisotropy in the UNC, while controls did not (group by time interaction missed significance). Pre-post changes in UNC were correlated with changes in the response to the conditioned stimuli. The findings suggest effects of mindfulness practice on the maintenance of sensitivity of emotional responses and suggest underlying neural plasticity. (ClinicalTrials.gov, Identifier NCT01320969, https://clinicaltrials.gov/ct2/show/NCT01320969). PMID:27378875

  12. Mindfulness-Based Stress Reduction, Fear Conditioning, and The Uncinate Fasciculus: A Pilot Study.

    PubMed

    Hölzel, Britta K; Brunsch, Vincent; Gard, Tim; Greve, Douglas N; Koch, Kathrin; Sorg, Christian; Lazar, Sara W; Milad, Mohammed R

    2016-01-01

    Mindfulness has been suggested to impact emotional learning, but research on these processes is scarce. The classical fear conditioning/extinction/extinction retention paradigm is a well-known method for assessing emotional learning. The present study tested the impact of mindfulness training on fear conditioning and extinction memory and further investigated whether changes in white matter fiber tracts might support such changes. The uncinate fasciculus (UNC) was of particular interest in the context of emotional learning. In this pilot study, 46 healthy participants were quasi-randomized to a Mindfulness-Based Stress Reduction (MBSR, N = 23) or waitlist control (N = 23) group and underwent a two-day fear conditioning, extinction learning, and extinction memory protocol before and after the course or control period. Skin conductance response (SCR) data served to measure the physiological response during conditioning and extinction memory phases. Diffusion tensor imaging (DTI) data were analyzed with probabilistic tractography and analyzed for changes of fractional anisotropy in the UNC. During conditioning, participants were able to maintain a differential response to conditioned vs. not conditioned stimuli following the MBSR course (i.e., higher sensitivity to the conditioned stimuli), while controls dropped the response. Extinction memory results were not interpretable due to baseline differences. MBSR participants showed a significant increase in fractional anisotropy in the UNC, while controls did not (group by time interaction missed significance). Pre-post changes in UNC were correlated with changes in the response to the conditioned stimuli. The findings suggest effects of mindfulness practice on the maintenance of sensitivity of emotional responses and suggest underlying neural plasticity. (ClinicalTrials.gov, Identifier NCT01320969, https://clinicaltrials.gov/ct2/show/NCT01320969).

  13. Mindfulness-Based Stress Reduction, Fear Conditioning, and The Uncinate Fasciculus: A Pilot Study

    PubMed Central

    Hölzel, Britta K.; Brunsch, Vincent; Gard, Tim; Greve, Douglas N.; Koch, Kathrin; Sorg, Christian; Lazar, Sara W.; Milad, Mohammed R.

    2016-01-01

    Mindfulness has been suggested to impact emotional learning, but research on these processes is scarce. The classical fear conditioning/extinction/extinction retention paradigm is a well-known method for assessing emotional learning. The present study tested the impact of mindfulness training on fear conditioning and extinction memory and further investigated whether changes in white matter fiber tracts might support such changes. The uncinate fasciculus (UNC) was of particular interest in the context of emotional learning. In this pilot study, 46 healthy participants were quasi-randomized to a Mindfulness-Based Stress Reduction (MBSR, N = 23) or waitlist control (N = 23) group and underwent a two-day fear conditioning, extinction learning, and extinction memory protocol before and after the course or control period. Skin conductance response (SCR) data served to measure the physiological response during conditioning and extinction memory phases. Diffusion tensor imaging (DTI) data were analyzed with probabilistic tractography and analyzed for changes of fractional anisotropy in the UNC. During conditioning, participants were able to maintain a differential response to conditioned vs. not conditioned stimuli following the MBSR course (i.e., higher sensitivity to the conditioned stimuli), while controls dropped the response. Extinction memory results were not interpretable due to baseline differences. MBSR participants showed a significant increase in fractional anisotropy in the UNC, while controls did not (group by time interaction missed significance). Pre-post changes in UNC were correlated with changes in the response to the conditioned stimuli. The findings suggest effects of mindfulness practice on the maintenance of sensitivity of emotional responses and suggest underlying neural plasticity. (ClinicalTrials.gov, Identifier NCT01320969, https://clinicaltrials.gov/ct2/show/NCT01320969). PMID:27378875

  14. Acute and chronic effects of selective serotonin reuptake inhibitor treatment on fear conditioning: implications for underlying fear circuits.

    PubMed

    Burghardt, N S; Bauer, E P

    2013-09-01

    Selective serotonin reuptake inhibitors (SSRIs) are widely used for the treatment of a spectrum of anxiety disorders, yet paradoxically they may increase symptoms of anxiety when treatment is first initiated. Despite extensive research over the past 30 years focused on SSRI treatment, the precise mechanisms by which SSRIs exert these opposing acute and chronic effects on anxiety remain unknown. By testing the behavioral effects of SSRI treatment on Pavlovian fear conditioning, a well characterized model of emotional learning, we have the opportunity to identify how SSRIs affect the functioning of specific brain regions, including the amygdala, bed nucleus of the stria terminalis (BNST) and hippocampus. In this review, we first define different stages of learning involved in cued and context fear conditioning and describe the neural circuits underlying these processes. We examine the results of numerous rodent studies investigating how acute SSRI treatment modulates fear learning and relate these effects to the known functions of serotonin in specific brain regions. With these findings, we propose a model by which acute SSRI administration, by altering neural activity in the extended amygdala and hippocampus, enhances both acquisition and expression of cued fear conditioning, but impairs the expression of contextual fear conditioning. Finally, we review the literature examining the effects of chronic SSRI treatment on fear conditioning in rodents and describe how downregulation of N-methyl-d-aspartate (NMDA) receptors in the amygdala and hippocampus may mediate the impairments in fear learning and memory that are reported. While long-term SSRI treatment effectively reduces symptoms of anxiety, their disruptive effects on fear learning should be kept in mind when combining chronic SSRI treatment and learning-based therapies, such as cognitive behavioral therapy.

  15. Reconsolidation in a human fear conditioning study: a test of extinction as updating mechanism.

    PubMed

    Kindt, Merel; Soeter, Marieke

    2013-01-01

    Disrupting reconsolidation seems to be a promising approach to dampen the expression of fear memory. Recently, we demonstrated that disrupting reconsolidation by a pharmacological manipulation specifically targeted the emotional expression of memory (i.e., startle response). Here we test in a human differential fear-conditioning paradigm with fear-relevant stimuli whether the spacing of a single unreinforced retrieval trial relative to extinction learning allows for "rewriting" the original fear association, thereby preventing the return of fear. In contrast to previous findings reported by Schiller et al. (2010), who used a single-method for indexing fear (skin conductance response) and fear-irrelevant stimuli, we found that extinction learning within the reconsolidation window did not prevent the recovery of fear on multiple indices of conditioned responding (startle response, skin conductance response and US-expectancy). These conflicting results ask for further critical testing given the potential impact on the field of emotional memory and its application to clinical practice.

  16. Learning-induced changes in mPFC-BLA connections after fear conditioning, extinction, and reinstatement of fear.

    PubMed

    Vouimba, Rose-Marie; Maroun, Mouna

    2011-10-01

    The neural circuit linking the medial prefrontal cortex (mPFC) and the basolateral amygdala (BLA) has crucial roles in both the acquisition and the extinction of fear. However, the mechanism by which this circuit encodes fear and extinction remains unknown. In this study, we monitored changes in the magnitude of evoked field potentials (EFPs) in the mPFC-BLA and BLA-mPFC pathways following auditory fear conditioning and extinction, in freely moving rats. We report that extinction of fear is mediated by depression of the EFPs in the mPFC-BLA and by potentiation in the reciprocal pathway of BLA-mPFC. Interestingly, reinstatement of fear was associated with recovery of freezing and with reversal of the changes in EFPs that were observed following extinction in both pathways. The findings indicate that the mPFC-BLA circuit expresses differential changes following fear and extinction and point to dynamic and plastic changes underlying fear, extinction, and reinstatement. Manipulations targeting these different types of plasticity could constitute a therapeutic tool for the treatment of anxiety disorders. PMID:21750582

  17. Thwarting the Renewal (Relapse) of Conditioned Fear with the Explicitly Unpaired Procedure: Possible Interpretations and Implications for Treating Human Fears and Phobias

    ERIC Educational Resources Information Center

    Thomas, Brian L.; Longo, Craig L.; Ayres, John J. B.

    2005-01-01

    In three experiments using the barpress conditioned suppression task with albino rats, we studied the renewal (relapse) of conditioned fear in an ABA fear-renewal paradigm. We found that explicitly unpaired (EU) deliveries of conditioned stimuli (CSs) and unconditioned stimuli (USs) in Context B thwarted fear renewal in Context A. Evidence…

  18. Role of conceptual knowledge in learning and retention of conditioned fear.

    PubMed

    Dunsmoor, Joseph E; Martin, Alex; LaBar, Kevin S

    2012-02-01

    Associating sensory cues with aversive outcomes is a relatively basic process shared across species. Yet higher-order cognitive processes likely contribute to associative fear learning in many circumstances, especially in humans. Here we ask whether fears can be acquired based on conceptual knowledge of object categories, and whether such concept-based fear conditioning leads to enhanced memory representations for conditioned objects. Participants were presented with a heterogeneous collection of images of animals and tools. Objects from one category were reinforced by an electrical shock, whereas the other category was never reinforced. Results confirmed concept-based fear learning through subjective report of shock expectancy, heightened skin conductance responses, and enhanced 24h recognition memory for items from the conditioned category. These results provide novel evidence that conditioned fear can generalize through knowledge of object concepts, and sheds light on the persistent nature of fear memories and category-based fear responses symptomatic of some anxiety disorders.

  19. Striatal dopamine D1 receptor is essential for contextual fear conditioning.

    PubMed

    Ikegami, Masaru; Uemura, Takeshi; Kishioka, Ayumi; Sakimura, Kenji; Mishina, Masayoshi

    2014-02-05

    Fear memory is critical for animals to trigger behavioural adaptive responses to potentially threatening stimuli, while too much or inappropriate fear may cause psychiatric problems. Numerous studies have shown that the amygdala, hippocampus and medial prefrontal cortex play important roles in Pavlovian fear conditioning. Recently, we showed that striatal neurons are required for the formation of the auditory fear memory when the unconditioned stimulus is weak. Here, we found that selective ablation of striatal neurons strongly diminished contextual fear conditioning irrespective of the intensity of footshock. Furthermore, contextual fear conditioning was strongly reduced in striatum-specific dopamine D1 receptor knockout mice. On the other hand, striatum-specific dopamine D2 receptor knockout mice showed freezing responses comparable to those of control mice. These results suggest that striatal D1 receptor is essential for contextual fear conditioning.

  20. Effects of Neonatal Amygdala Lesions on Fear Learning, Conditioned Inhibition, and Extinction in Adult Macaques

    PubMed Central

    Kazama, Andy M.; Heuer, Eric; Davis, Michael; Bachevalier, Jocelyne

    2013-01-01

    Fear conditioning studies have demonstrated the critical role played by the amygdala in emotion processing. Although all lesion studies until now investigated the effect of adult-onset damage on fear conditioning, the current study assessed fear-learning abilities, as measured by fear-potentiated startle, in adult monkeys that had received neonatal neurotoxic amygdala damage or sham-operations. After fear acquisition, their abilities to learn and use a safety cue to modulate their fear to the conditioned cue, and, finally, to extinguish their response to the fear conditioned cue were measured with the AX+/BX− Paradigm. Neonatal amygdala damage retarded, but did not completely abolish, the acquisition of a learned fear. After acquisition of the fear signal, four of the six animals with neonatal amygdala lesions discriminated between the fear and safety cues and were also able to use the safety signal to reduce the potentiated-startle response and to extinguish the fear response when the air-blast was absent. In conclusion, the present results support the critical contribution of the amygdala during the early phases of fear conditioning that leads to quick, robust responses to potentially threatening stimuli, a highly adaptive process across all species and likely to be present in early infancy. The neonatal amygdala lesions also indicated the presence of amygdala-independent alternate pathways that are capable to support fear learning in the absence of a functional amygdala. This parallel processing of fear responses within these alternate pathways was also sufficient to support the ability to flexibly modulate the magnitude of the fear responses. PMID:22642884

  1. Effects of neonatal amygdala lesions on fear learning, conditioned inhibition, and extinction in adult macaques.

    PubMed

    Kazama, Andy M; Heuer, Eric; Davis, Michael; Bachevalier, Jocelyne

    2012-06-01

    Fear conditioning studies have demonstrated the critical role played by the amygdala in emotion processing. Although all lesion studies until now investigated the effect of adult-onset damage on fear conditioning, the current study assessed fear-learning abilities, as measured by fear-potentiated startle, in adult monkeys that had received neonatal neurotoxic amygdala damage or sham-operations. After fear acquisition, their abilities to learn and use a safety cue to modulate their fear to the conditioned cue, and, finally, to extinguish their response to the fear conditioned cue were measured with the AX+/BX- Paradigm. Neonatal amygdala damage retarded, but did not completely abolish, the acquisition of a learned fear. After acquisition of the fear signal, four of the six animals with neonatal amygdala lesions discriminated between the fear and safety cues and were also able to use the safety signal to reduce the potentiated-startle response and to extinguish the fear response when the air-blast was absent. In conclusion, the present results support the critical contribution of the amygdala during the early phases of fear conditioning that leads to quick, robust responses to potentially threatening stimuli, a highly adaptive process across all species and likely to be present in early infancy. The neonatal amygdala lesions also indicated the presence of amygdala-independent alternate pathways that are capable to support fear learning in the absence of a functional amygdala. This parallel processing of fear responses within these alternate pathways was also sufficient to support the ability to flexibly modulate the magnitude of the fear responses.

  2. Opioid regulation of Pavlovian overshadowing in fear conditioning.

    PubMed

    Zelikowsky, Moriel; Fanselow, Michael S

    2010-08-01

    In Pavlovian overshadowing, a stimulus that predicts a biologically important event reduces conditioning to another, equally predictive stimulus. We tested the effects of an opioid antagonist and dopamine agonist on the ability of a salient white noise to overshadow a less salient light. Rats were conditioned to fear a light or a noise-light compound using a mild footshock. Compound-conditioned rats trained under the saline vehicle revealed significant overshadowing of the light by the noise. This overshadowing effect was significantly attenuated in rats trained under the opioid antagonist naltrexone, consistent with an opioid-mediated negative feedback model of conditioning. In line with predictions made by negative feedback-type models, we failed to obtain overshadowing with few trials, suggesting that the processes underlying conditioning during initial trials do not contribute to the opioid-dependent Pavlovian overshadowing obtained in our preparation. Lastly, we compared the involvement of dopamine-mediated and opioid-mediated processes in overshadowing by conditioning rats under the partial dopamine D1 receptor agonist SKF 38393 or the opioid antagonist naltrexone. Both naltrexone and SKF 38393 were found to attenuate overshadowing; however, the behavioral profiles produced by each pharmacological manipulation were distinct. Collectively, these studies demonstrate an important role for both opioid- and dopamine-mediated processes in multiple-trial overshadowing.

  3. Neuropeptide S reduces fear and avoidance of con-specifics induced by social fear conditioning and social defeat, respectively.

    PubMed

    Zoicas, Iulia; Menon, Rohit; Neumann, Inga D

    2016-09-01

    Neuropeptide S (NPS) has anxiolytic effects and facilitates extinction of cued fear in rodents. Here, we investigated whether NPS reverses social fear and social avoidance induced by social fear conditioning (SFC) and acute social defeat (SD), respectively, in male CD1 mice. Our results revealed that intracerebroventricular NPS (icv; 10 and 50 nmol/2 μl) reversed fear of unknown con-specifics induced by SFC and dose-dependently reduced avoidance of known aggressive con-specifics induced by SD. While 50 nmol of NPS completely reversed social avoidance and reinstated social preference, 10 nmol of NPS reduced social avoidance, but did not completely reinstate social preference in socially-defeated mice. Further, a lower dose (1 nmol/2 μl) of NPS facilitated the within-session extinction of cued fear, while a higher dose (10 nmol/2 μl) reduced the expression of cued fear. We could also confirm the anxiolytic effects of NPS (1, 10 and 50 nmol/2 μl) on the elevated plus-maze (EPM), which were not accompanied by alterations in locomotor activity either on the EPM or in the home cage. Finally, we could show that icv infusion of the NPS receptor 1 antagonist D-Cys((t)Bu)(5)-NPS (10 nmol/2 μl) did not alter SFC-induced social fear, general anxiety and locomotor activity. Taken together, our study extends the potent anxiolytic profile of NPS to a social context by demonstrating the reduction of social fear and social avoidance, thus providing the framework for studies investigating the involvement of the NPS system in the regulation of different types of social behaviour.

  4. Double dissociation of amygdala and hippocampal contributions to trace and delay fear conditioning.

    PubMed

    Raybuck, Jonathan D; Lattal, K Matthew

    2011-01-19

    A key finding in studies of the neurobiology of learning memory is that the amygdala is critically involved in Pavlovian fear conditioning. This is well established in delay-cued and contextual fear conditioning; however, surprisingly little is known of the role of the amygdala in trace conditioning. Trace fear conditioning, in which the CS and US are separated in time by a trace interval, requires the hippocampus and prefrontal cortex. It is possible that recruitment of cortical structures by trace conditioning alters the role of the amygdala compared to delay fear conditioning, where the CS and US overlap. To investigate this, we inactivated the amygdala of male C57BL/6 mice with GABA (A) agonist muscimol prior to 2-pairing trace or delay fear conditioning. Amygdala inactivation produced deficits in contextual and delay conditioning, but had no effect on trace conditioning. As controls, we demonstrate that dorsal hippocampal inactivation produced deficits in trace and contextual, but not delay fear conditioning. Further, pre- and post-training amygdala inactivation disrupted the contextual but the not cued component of trace conditioning, as did muscimol infusion prior to 1- or 4-pairing trace conditioning. These findings demonstrate that insertion of a temporal gap between the CS and US can generate amygdala-independent fear conditioning. We discuss the implications of this surprising finding for current models of the neural circuitry involved in fear conditioning.

  5. Fear of losing money? Aversive conditioning with secondary reinforcers.

    PubMed

    Delgado, M R; Labouliere, C D; Phelps, E A

    2006-12-01

    Money is a secondary reinforcer that acquires its value through social communication and interaction. In everyday human behavior and laboratory studies, money has been shown to influence appetitive or reward learning. It is unclear, however, if money has a similar impact on aversive learning. The goal of this study was to investigate the efficacy of money in aversive learning, comparing it with primary reinforcers that are traditionally used in fear conditioning paradigms. A series of experiments were conducted in which participants initially played a gambling game that led to a monetary gain. They were then presented with an aversive conditioning paradigm, with either shock (primary reinforcer) or loss of money (secondary reinforcer) as the unconditioned stimulus. Skin conductance responses and subjective ratings indicated that potential monetary loss modulated the conditioned response. Depending on the presentation context, the secondary reinforcer was as effective as the primary reinforcer during aversive conditioning. These results suggest that stimuli that acquire reinforcing properties through social communication and interaction, such as money, can effectively influence aversive learning.

  6. Effects of Recent Exposure to a Conditioned Stimulus on Extinction of Pavlovian Fear Conditioning

    ERIC Educational Resources Information Center

    Chan, Wan Yee Macy; Leung, Hiu T.; Westbrook, R. Frederick; McNally, Gavan P.

    2010-01-01

    In six experiments we studied the effects of a single re-exposure to a conditioned stimulus (CS; "retrieval trial") prior to extinction training (extinction-reconsolidation boundary) on the development of and recovery from fear extinction. A single retrieval trial prior to extinction training significantly augmented the renewal and reinstatement…

  7. The conditioning and extinction of fear in youths: what's sex got to do with it?

    PubMed

    Chauret, Mélissa; La Buissonnière-Ariza, Valérie; Lamoureux Tremblay, Vickie; Suffren, Sabrina; Servonnet, Alice; Pine, Daniel S; Maheu, Françoise S

    2014-07-01

    Adult work shows differences in emotional processing influenced by sexes of both the viewer and expresser of facial expressions. We investigated this in 120 healthy youths (57 boys; 10-17 years old) randomly assigned to fear conditioning and extinction tasks using either neutral male or female faces as the conditioned threat and safety cues, and a fearful face paired with a shrieking scream as the unconditioned stimulus. Fear ratings and skin conductance responses (SCRs) were assessed. Male faces triggered increased fear ratings in all participants during conditioning and extinction. Greater differential SCRs were observed in boys viewing male faces and in girls viewing female faces during conditioning. During extinction, differential SCR findings remained significant in boys viewing male faces. Our findings demonstrate how sex of participant and sex of target interact to shape fear responses in youths, and how the type of measure may lead to distinct profiles of fear responses.

  8. Olfactory Fear Conditioning Induces Field Potential Potentiation in Rat Olfactory Cortex and Amygdala

    ERIC Educational Resources Information Center

    Messaoudi, Belkacem; Granjon, Lionel; Mouly, Anne-Marie; Sevelinges, Yannick; Gervais, Remi

    2004-01-01

    The widely used Pavlovian fear-conditioning paradigms used for studying the neurobiology of learning and memory have mainly used auditory cues as conditioned stimuli (CS). The present work assessed the neural network involved in olfactory fear conditioning, using olfactory bulb stimulation-induced field potential signal (EFP) as a marker of…

  9. Eye Movements Index Implicit Memory Expression in Fear Conditioning

    PubMed Central

    Hopkins, Lauren S.; Schultz, Douglas H.; Hannula, Deborah E.; Helmstetter, Fred J.

    2015-01-01

    The role of contingency awareness in simple associative learning experiments with human participants is currently debated. Since prior work suggests that eye movements can index mnemonic processes that occur without awareness, we used eye tracking to better understand the role of awareness in learning aversive Pavlovian conditioning. A complex real-world scene containing four embedded household items was presented to participants while skin conductance, eye movements, and pupil size were recorded. One item embedded in the scene served as the conditional stimulus (CS). One exemplar of that item (e.g. a white pot) was paired with shock 100 percent of the time (CS+) while a second exemplar (e.g. a gray pot) was never paired with shock (CS-). The remaining items were paired with shock on half of the trials. Participants rated their expectation of receiving a shock during each trial, and these expectancy ratings were used to identify when (i.e. on what trial) each participant became aware of the programmed contingencies. Disproportionate viewing of the CS was found both before and after explicit contingency awareness, and patterns of viewing distinguished the CS+ from the CS-. These observations are consistent with “dual process” models of fear conditioning, as they indicate that learning can be expressed in patterns of viewing prior to explicit contingency awareness. PMID:26562298

  10. Eye Movements Index Implicit Memory Expression in Fear Conditioning.

    PubMed

    Hopkins, Lauren S; Schultz, Douglas H; Hannula, Deborah E; Helmstetter, Fred J

    2015-01-01

    The role of contingency awareness in simple associative learning experiments with human participants is currently debated. Since prior work suggests that eye movements can index mnemonic processes that occur without awareness, we used eye tracking to better understand the role of awareness in learning aversive Pavlovian conditioning. A complex real-world scene containing four embedded household items was presented to participants while skin conductance, eye movements, and pupil size were recorded. One item embedded in the scene served as the conditional stimulus (CS). One exemplar of that item (e.g. a white pot) was paired with shock 100 percent of the time (CS+) while a second exemplar (e.g. a gray pot) was never paired with shock (CS-). The remaining items were paired with shock on half of the trials. Participants rated their expectation of receiving a shock during each trial, and these expectancy ratings were used to identify when (i.e. on what trial) each participant became aware of the programmed contingencies. Disproportionate viewing of the CS was found both before and after explicit contingency awareness, and patterns of viewing distinguished the CS+ from the CS-. These observations are consistent with "dual process" models of fear conditioning, as they indicate that learning can be expressed in patterns of viewing prior to explicit contingency awareness.

  11. Fear conditioning and extinction across development: evidence from human studies and animal models.

    PubMed

    Shechner, Tomer; Hong, Melanie; Britton, Jennifer C; Pine, Daniel S; Fox, Nathan A

    2014-07-01

    The ability to differentiate danger and safety through associative processes emerges early in life. Understanding the mechanisms underlying associative learning of threat and safety can clarify the processes that shape development of normative fears and pathological anxiety. Considerable research has used fear conditioning and extinction paradigms to delineate underlying mechanisms in animals and human adults; however, little is known about these mechanisms in children and adolescents. The current paper summarizes the empirical data on the development of fear conditioning and extinction. It reviews methodological considerations and future directions for research on fear conditioning and extinction in pediatric populations.

  12. Adversity-induced relapse of fear: neural mechanisms and implications for relapse prevention from a study on experimentally induced return-of-fear following fear conditioning and extinction.

    PubMed

    Scharfenort, R; Menz, M; Lonsdorf, T B

    2016-01-01

    The efficacy of current treatments for anxiety disorders is limited by high relapse rates. Relapse of anxiety disorders and addiction can be triggered by exposure to life adversity, but the underlying mechanisms remain unexplored. Seventy-six healthy adults were a priori selected for the presence or absence of adverse experiences during childhood (CA) and recent past (RA; that is, past 12 months). Participants underwent fear conditioning (day 1) and fear extinction and experimental return-of-fear (ROF) induction through reinstatement (a model for adversity-induced relapse; day 2). Ratings, autonomic (skin conductance response) and neuronal activation measures (functional magnetic resonance imaging (fMRI)) were acquired. Individuals exposed to RA showed a generalized (that is, not CS- specific) fear recall and ROF, whereas unexposed individuals showed differential (that is, CS+ specific) fear recall and ROF on an autonomic level despite no group differences during fear acquisition and extinction learning. These group differences in ROF were accompanied by corresponding activation differences in brain areas known to be involved in fear processing and differentiability/generalization of ROF (that is, hippocampus). In addition, dimensional measures of RA, CA and lifetime adversity were negatively correlated with differential skin conductance responses (SCRs) during ROF and hippocampal activation. As discriminating signals of danger and safety, as well as a tendency for overgeneralization, are core features in clinically anxious populations, these deficits may specifically contribute to relapse risk following exposure to adversity, in particular to recent adversity. Hence, our results may provide first and novel insights into the possible mechanisms mediating enhanced relapse risk following exposure to (recent) adversity, which may guide the development of effective pre- and intervention programs. PMID:27434492

  13. Conditioned fear associated phenotypes as robust, translational indices of trauma-, stressor-, and anxiety-related behaviors.

    PubMed

    Briscione, Maria Anne; Jovanovic, Tanja; Norrholm, Seth Davin

    2014-01-01

    Post-traumatic stress disorder (PTSD) is a heterogeneous disorder that affects individuals exposed to trauma (e.g., combat, interpersonal violence, and natural disasters). It is characterized by hyperarousal, intrusive reminders of the trauma, avoidance of trauma-related cues, and negative cognition and mood. This heterogeneity indicates the presence of multiple neurobiological mechanisms underlying the development and maintenance of PTSD. Fear conditioning is a robust, translational experimental paradigm that can be employed to elucidate these mechanisms by allowing for the study of fear-related dimensions of PTSD (e.g., fear extinction, fear inhibition, and generalization of fear) across multiple units of analysis. Fear conditioning experiments have identified varying trajectories of the dimensions described, highlighting exciting new avenues of targeted, focused study. Additionally, fear conditioning studies provide a translational platform to develop novel interventions. The current review highlights the versatility of fear conditioning paradigms, the implications for pharmacological and non-pharmacological treatments, the robustness of these paradigms to span an array of neuroscientific measures (e.g., genetic studies), and finally the need to understand the boundary conditions under which these paradigms are effective. Further understanding these paradigms will ultimately allow for optimization of fear conditioning paradigms, a necessary step towards the advancement of PTSD treatment methods.

  14. Conditioned Fear Associated Phenotypes as Robust, Translational Indices of Trauma-, Stressor-, and Anxiety-Related Behaviors

    PubMed Central

    Briscione, Maria Anne; Jovanovic, Tanja; Norrholm, Seth Davin

    2014-01-01

    Post-traumatic stress disorder (PTSD) is a heterogeneous disorder that affects individuals exposed to trauma (e.g., combat, interpersonal violence, and natural disasters). It is characterized by hyperarousal, intrusive reminders of the trauma, avoidance of trauma-related cues, and negative cognition and mood. This heterogeneity indicates the presence of multiple neurobiological mechanisms underlying the development and maintenance of PTSD. Fear conditioning is a robust, translational experimental paradigm that can be employed to elucidate these mechanisms by allowing for the study of fear-related dimensions of PTSD (e.g., fear extinction, fear inhibition, and generalization of fear) across multiple units of analysis. Fear conditioning experiments have identified varying trajectories of the dimensions described, highlighting exciting new avenues of targeted, focused study. Additionally, fear conditioning studies provide a translational platform to develop novel interventions. The current review highlights the versatility of fear conditioning paradigms, the implications for pharmacological and non-pharmacological treatments, the robustness of these paradigms to span an array of neuroscientific measures (e.g., genetic studies), and finally the need to understand the boundary conditions under which these paradigms are effective. Further understanding these paradigms will ultimately allow for optimization of fear conditioning paradigms, a necessary step towards the advancement of PTSD treatment methods. PMID:25101010

  15. Reinstatement of an extinguished fear conditioned response in infant rats.

    PubMed

    Revillo, Damian A; Trebucq, Gastón; Paglini, Maria G; Arias, Carlos

    2016-01-01

    Although it is currently accepted that the extinction effect reflects new context-dependent learning, this is not so clear during infancy, because some studies did not find recovery of the extinguished conditioned response (CR) in rodents during this ontogenetic stage. However, recent studies have shown the return of an extinguished CR in infant rats. The present study analyzes the possibility of recovering an extinguished CR with a reinstatement procedure in a fear conditioning paradigm, on PD17 (Experiments 1-4) and on PD24 (Experiment 5), while exploring the role of the olfactory content of the context upon the reinstatement effect during the preweanling period. Preweanling rats expressed a previously extinguished CR after a single experience with an unsignaled US. Furthermore, this result was only found when subjects were trained and tested in contexts that included an explicit odor, but not in standard experimental cages. Finally, Experiment 5 demonstrated the reinstatement effect on PD24 in a standard context. These results support the notion that extinction during infancy has the same characteristics as those described for extinction that occurs in adulthood. Instead of postulating a different mechanism for extinction during infancy, we propose that it may be more accurate to view the problem in terms of the variables that may differentially modulate the extinction effect according to the stages of ontogeny. PMID:26670181

  16. Revealing context-specific conditioned fear memories with full immersion virtual reality.

    PubMed

    Huff, Nicole C; Hernandez, Jose Alba; Fecteau, Matthew E; Zielinski, David J; Brady, Rachael; Labar, Kevin S

    2011-01-01

    The extinction of conditioned fear is known to be context-specific and is often considered more contextually bound than the fear memory itself (Bouton, 2004). Yet, recent findings in rodents have challenged the notion that contextual fear retention is initially generalized. The context-specificity of a cued fear memory to the learning context has not been addressed in the human literature largely due to limitations in methodology. Here we adapt a novel technology to test the context-specificity of cued fear conditioning using full immersion 3-D virtual reality (VR). During acquisition training, healthy participants navigated through virtual environments containing dynamic snake and spider conditioned stimuli (CSs), one of which was paired with electrical wrist stimulation. During a 24-h delayed retention test, one group returned to the same context as acquisition training whereas another group experienced the CSs in a novel context. Unconditioned stimulus expectancy ratings were assayed on-line during fear acquisition as an index of contingency awareness. Skin conductance responses time-locked to CS onset were the dependent measure of cued fear, and skin conductance levels during the interstimulus interval were an index of context fear. Findings indicate that early in acquisition training, participants express contingency awareness as well as differential contextual fear, whereas differential cued fear emerged later in acquisition. During the retention test, differential cued fear retention was enhanced in the group who returned to the same context as acquisition training relative to the context shift group. The results extend recent rodent work to illustrate differences in cued and context fear acquisition and the contextual specificity of recent fear memories. Findings support the use of full immersion VR as a novel tool in cognitive neuroscience to bridge rodent models of contextual phenomena underlying human clinical disorders.

  17. Revealing Context-Specific Conditioned Fear Memories with Full Immersion Virtual Reality

    PubMed Central

    Huff, Nicole C.; Hernandez, Jose Alba; Fecteau, Matthew E.; Zielinski, David J.; Brady, Rachael; LaBar, Kevin S.

    2011-01-01

    The extinction of conditioned fear is known to be context-specific and is often considered more contextually bound than the fear memory itself (Bouton, 2004). Yet, recent findings in rodents have challenged the notion that contextual fear retention is initially generalized. The context-specificity of a cued fear memory to the learning context has not been addressed in the human literature largely due to limitations in methodology. Here we adapt a novel technology to test the context-specificity of cued fear conditioning using full immersion 3-D virtual reality (VR). During acquisition training, healthy participants navigated through virtual environments containing dynamic snake and spider conditioned stimuli (CSs), one of which was paired with electrical wrist stimulation. During a 24-h delayed retention test, one group returned to the same context as acquisition training whereas another group experienced the CSs in a novel context. Unconditioned stimulus expectancy ratings were assayed on-line during fear acquisition as an index of contingency awareness. Skin conductance responses time-locked to CS onset were the dependent measure of cued fear, and skin conductance levels during the interstimulus interval were an index of context fear. Findings indicate that early in acquisition training, participants express contingency awareness as well as differential contextual fear, whereas differential cued fear emerged later in acquisition. During the retention test, differential cued fear retention was enhanced in the group who returned to the same context as acquisition training relative to the context shift group. The results extend recent rodent work to illustrate differences in cued and context fear acquisition and the contextual specificity of recent fear memories. Findings support the use of full immersion VR as a novel tool in cognitive neuroscience to bridge rodent models of contextual phenomena underlying human clinical disorders. PMID:22069384

  18. Dissociated Roles for the Lateral and Medial Septum in Elemental and Contextual Fear Conditioning

    ERIC Educational Resources Information Center

    Calandreau, Ludovic; Jaffard, Robert; Desmedt, Aline

    2007-01-01

    Extensive evidence indicates that the septum plays a predominant role in fear learning, yet the direction of this control is still a matter of debate. Increasing data suggest that the medial (MS) and lateral septum (LS) would be differentially required in fear conditioning depending on whether a discrete conditional stimulus (CS) predicts, or not,…

  19. Antagonism of Lateral Amygdala Alpha1-Adrenergic Receptors Facilitates Fear Conditioning and Long-Term Potentiation

    ERIC Educational Resources Information Center

    Lazzaro, Stephanie C.; Hou, Mian; Cunha, Catarina; LeDoux, Joseph E.; Cain, Christopher K.

    2010-01-01

    Norepinephrine receptors have been studied in emotion, memory, and attention. However, the role of alpha1-adrenergic receptors in fear conditioning, a major model of emotional learning, is poorly understood. We examined the effect of terazosin, an alpha1-adrenergic receptor antagonist, on cued fear conditioning. Systemic or intra-lateral amygdala…

  20. Effects of Stress and Sex on Acquisition and Consolidation of Human Fear Conditioning

    ERIC Educational Resources Information Center

    Kuhn, Cynthia M.; LaBar, Kevin S.; Zorawski, Michael; Blanding, Nineequa Q.

    2006-01-01

    We examined the relationship between stress hormone (cortisol) release and acquisition and consolidation of conditioned fear learning in healthy adults. Participants underwent acquisition of differential fear conditioning, and consolidation was assessed in a 24-h delayed extinction test. The acquisition phase was immediately followed by an 11-min…

  1. A Discrete Population of Neurons in the Lateral Amygdala Is Specifically Activated by Contextual Fear Conditioning

    ERIC Educational Resources Information Center

    Wilson, Yvette M.; Murphy, Mark

    2009-01-01

    There is no clear identification of the neurons involved in fear conditioning in the amygdala. To search for these neurons, we have used a genetic approach, the "fos-tau-lacZ" (FTL) mouse, to map functionally activated expression in neurons following contextual fear conditioning. We have identified a discrete population of neurons in the lateral…

  2. The Amygdala Is Critical for Trace, Delay, and Contextual Fear Conditioning

    ERIC Educational Resources Information Center

    Kochli, Daniel E.; Thompson, Elaine C.; Fricke, Elizabeth A.; Postle, Abagail F.; Quinn, Jennifer J.

    2015-01-01

    Numerous investigations have definitively shown amygdalar involvement in delay and contextual fear conditioning. However, much less is known about amygdala contributions to trace fear conditioning, and what little evidence exists is conflicting as noted in previous studies. This discrepancy may result from selective targeting of individual nuclei…

  3. Brain morphology correlates of interindividual differences in conditioned fear acquisition and extinction learning.

    PubMed

    Winkelmann, Tobias; Grimm, Oliver; Pohlack, Sebastian T; Nees, Frauke; Cacciaglia, Raffaele; Dinu-Biringer, Ramona; Steiger, Frauke; Wicking, Manon; Ruttorf, Michaela; Schad, Lothar R; Flor, Herta

    2016-05-01

    The neural circuits underlying fear learning have been intensively investigated in pavlovian fear conditioning paradigms across species. These studies established a predominant role for the amygdala in fear acquisition, while the ventromedial prefrontal cortex (vmPFC) has been shown to be important in the extinction of conditioned fear. However, studies on morphological correlates of fear learning could not consistently confirm an association with these structures. The objective of the present study was to investigate if interindividual differences in morphology of the amygdala and the vmPFC are related to differences in fear acquisition and extinction learning in humans. We performed structural magnetic resonance imaging in 68 healthy participants who underwent a differential cued fear conditioning paradigm. Volumes of subcortical structures as well as cortical thickness were computed by the semi-automated segmentation software Freesurfer. Stronger acquisition of fear as indexed by skin conductance responses was associated with larger right amygdala volume, while the degree of extinction learning was positively correlated with cortical thickness of the right vmPFC. Both findings could be conceptually replicated in an independent sample of 53 subjects. The data complement our understanding of the role of human brain morphology in the mechanisms of the acquisition and extinction of conditioned fear. PMID:25716297

  4. Postural responses explored through classical conditioning.

    PubMed

    Campbell, A D; Dakin, C J; Carpenter, M G

    2009-12-15

    The purpose of the study was to determine whether the central nervous system (CNS) requires the sensory feedback generated by balance perturbations in order to trigger postural responses (PRs). In Experiment 1, twenty-one participants experienced toes-up support-surface tilts in two blocks. Control blocks involved unexpected balance perturbations whereas an auditory tone cued the onset of balance perturbations in Conditioning blocks. A single Cue-Only trial followed each block (Cue-Only(Control) and Cue-Only(Conditioning) trials) in the absence of balance perturbations. Cue-Only(Conditioning) trials were used to determine whether postural perturbations were required in order to trigger PRs. Counter-balancing the order of Control and Conditioning blocks allowed Cue-Only(Control) trials to examine both the audio-spinal/acoustic startle effects of the auditory cue and the carryover effects of the initial conditioning procedure. In Experiment 2, six participants first experienced five consecutive Tone-Only trials that were followed by twenty-five conditioning trials. After conditioning, five Tone-Only trials were again presented consecutively to first elicit and then extinguish the conditioned PRs. Surface electromyography (EMG) recorded muscle activity in soleus (SOL), tibialis anterior (TA) and rectus femoris (RF). EMG onset latencies and amplitudes were calculated together with the onset latency, peak and time-to-peak of shank angular accelerations. Results indicated that an auditory cue could be conditioned to initiate PRs in multiple muscles without balance-relevant sensory triggers generated by balance perturbations. Postural synergies involving excitation of TA and RF and inhibition of SOL were observed following the Cue-Only(Conditioning) trials that resulted in shank angular accelerations in the direction required to counter the expected toes-up tilt. Postural synergies were triggered in response to the auditory cue even 15 min post-conditioning. Furthermore

  5. Sexually divergent expression of active and passive conditioned fear responses in rats

    PubMed Central

    Gruene, Tina M; Flick, Katelyn; Stefano, Alexis; Shea, Stephen D; Shansky, Rebecca M

    2015-01-01

    Traditional rodent models of Pavlovian fear conditioning assess the strength of learning by quantifying freezing responses. However, sole reliance on this measure includes the de facto assumption that any locomotor activity reflects an absence of fear. Consequently, alternative expressions of associative learning are rarely considered. Here we identify a novel, active fear response (‘darting’) that occurs primarily in female rats. In females, darting exhibits the characteristics of a learned fear behavior, appearing during the CS period as conditioning proceeds and disappearing from the CS period during extinction. This finding motivates a reinterpretation of rodent fear conditioning studies, particularly in females, and it suggests that conditioned fear behavior is more diverse than previously appreciated. Moreover, rats that darted during initial fear conditioning exhibited lower freezing during the second day of extinction testing, suggesting that females employ distinct and adaptive fear response strategies that improve long-term outcomes. DOI: http://dx.doi.org/10.7554/eLife.11352.001 PMID:26568307

  6. Cerebellar Secretin Modulates Eyeblink Classical Conditioning

    ERIC Educational Resources Information Center

    Fuchs, Jason R.; Robinson, Gain M.; Dean, Aaron M.; Schoenberg, Heidi E.; Williams, Michael R.; Morielli, Anthony D.; Green, John T.

    2014-01-01

    We have previously shown that intracerebellar infusion of the neuropeptide secretin enhances the acquisition phase of eyeblink conditioning (EBC). Here, we sought to test whether endogenous secretin also regulates EBC and to test whether the effect of exogenous and endogenous secretin is specific to acquisition. In Experiment 1, rats received…

  7. Eyeblink Classical Conditioning and Post-Traumatic Stress Disorder – A Model Systems Approach

    PubMed Central

    Schreurs, Bernard G.; Burhans, Lauren B.

    2015-01-01

    Not everyone exposed to trauma suffers flashbacks, bad dreams, numbing, fear, anxiety, sleeplessness, hyper-vigilance, hyperarousal, or an inability to cope, but those who do may suffer from post-traumatic stress disorder (PTSD). PTSD is a major physical and mental health problem for military personnel and civilians exposed to trauma. There is still debate about the incidence and prevalence of PTSD especially among the military, but for those who are diagnosed, behavioral therapy and drug treatment strategies have proven to be less than effective. A number of these treatment strategies are based on rodent fear conditioning research and are capable of treating only some of the symptoms because the extinction of fear does not deal with the various forms of hyper-vigilance and hyperarousal experienced by people with PTSD. To help address this problem, we have developed a preclinical eyeblink classical conditioning model of PTSD in which conditioning and hyperarousal can both be extinguished. We review this model and discuss findings showing that unpaired stimulus presentations can be effective in reducing levels of conditioning and hyperarousal even when unconditioned stimulus intensity is reduced to the point where it is barely capable of eliciting a response. These procedures have direct implications for the treatment of PTSD and could be implemented in a virtual reality environment. PMID:25904874

  8. Factors Regulating the Effects of Hippocampal Inactivation on Renewal of Conditional Fear after Extinction

    ERIC Educational Resources Information Center

    Corcoran, Kevin A.; Maren, Stephen

    2004-01-01

    After extinction of fear to a Pavlovian conditional stimulus (CS), contextual stimuli come to regulate the expression of fear to that CS. There is growing evidence that the context dependence of memory retrieval after extinction involves the hippocampus. In the present experiment, we examine whether hippocampal involvement in memory retrieval…

  9. Electrolytic Lesions of the Dorsal Hippocampus Disrupt Renewal of Conditional Fear after Extinction

    ERIC Educational Resources Information Center

    Ji, Jinzhao; Maren, Stephen

    2005-01-01

    There is a growing body of evidence that the hippocampus is critical for context-dependent memory retrieval. In the present study, we used Pavlovian fear conditioning in rats to examine the role of the dorsal hippocampus (DH) in the context-specific expression of fear memory after extinction (i.e., renewal). Pre-training electrolytic lesions of…

  10. Brain Region-Specific Activity Patterns after Recent or Remote Memory Retrieval of Auditory Conditioned Fear

    ERIC Educational Resources Information Center

    Kwon, Jeong-Tae; Jhang, Jinho; Kim, Hyung-Su; Lee, Sujin; Han, Jin-Hee

    2012-01-01

    Memory is thought to be sparsely encoded throughout multiple brain regions forming unique memory trace. Although evidence has established that the amygdala is a key brain site for memory storage and retrieval of auditory conditioned fear memory, it remains elusive whether the auditory brain regions may be involved in fear memory storage or…

  11. Individual Differences in the Expression of Conditioned Fear Are Associated with Endogenous Fibroblast Growth Factor 2

    ERIC Educational Resources Information Center

    Graham, Bronwyn M.; Richardson, Rick

    2016-01-01

    These experiments examined the relationship between the neurotrophic factor fibroblast growth factor 2 (FGF2) and individual differences in the expression of conditioned fear. Experiments 1 and 2 demonstrated that rats naturally expressing low levels of contextual or cued fear have higher levels of hippocampal FGF2 relative to rats that express…

  12. Systemic Blockade of D2-Like Dopamine Receptors Facilitates Extinction of Conditioned Fear in Mice

    ERIC Educational Resources Information Center

    Ponnusamy, Ravikumar; Nissim, Helen A.; Barad, Mark

    2005-01-01

    Extinction of conditioned fear in animals is the explicit model of behavior therapy for human anxiety disorders, including panic disorder, obsessive-compulsive disorder, and post-traumatic stress disorder. Based on previous data indicating that fear extinction in rats is blocked by quinpirole, an agonist of dopamine D2 receptors, we hypothesized…

  13. Fear generalization in humans: impact of feature learning on conditioning and extinction.

    PubMed

    Vervliet, Bram; Geens, Maarten

    2014-09-01

    Little is known about the role of discrete stimulus features in the regulation of fear. This study examined the effects of feature learning on the acquisition and extinction of fear conditioning. Human participants were fear conditioned to a yellow triangle (CS+) using an electrical shock. We manipulated feature learning through differential conditioning. The nonconditioned control stimulus (CS-) was a red triangle in one group (Color-Relevant), but a yellow circle in the other group (Shape-Relevant). Next, two generalization stimuli were tested that shared the shape- or color-feature with the CS+ (a blue triangle and a yellow square). Online shock-expectancy ratings and skin conductance responding showed that the CS- determined the pattern of fear generalization: the same-color stimulus elicited more fear in Group Color-Relevant, versus the same-shape stimulus in group Shape-Relevant. Furthermore, extinguishing these two generalization stimuli had no detectable effect on fear of the CS+. These results show that fear generalization is influenced by feature learning through differential conditioning, and that exposures to different features of a stimulus are not sufficient to extinguish fear of that stimulus as a whole.

  14. The Role of the Medial Prefrontal Cortex in the Conditioning and Extinction of Fear

    PubMed Central

    Giustino, Thomas F.; Maren, Stephen

    2015-01-01

    Once acquired, a fearful memory can persist for a lifetime. Although learned fear can be extinguished, extinction memories are fragile. The resilience of fear memories to extinction may contribute to the maintenance of disorders of fear and anxiety, including post-traumatic stress disorder (PTSD). As such, considerable effort has been placed on understanding the neural circuitry underlying the acquisition, expression, and extinction of emotional memories in rodent models as well as in humans. A triad of brain regions, including the prefrontal cortex, hippocampus, and amygdala, form an essential brain circuit involved in fear conditioning and extinction. Within this circuit, the prefrontal cortex is thought to exert top-down control over subcortical structures to regulate appropriate behavioral responses. Importantly, a division of labor has been proposed in which the prelimbic (PL) and infralimbic (IL) subdivisions of the medial prefrontal cortex (mPFC) regulate the expression and suppression of fear in rodents, respectively. Here, we critically review the anatomical and physiological evidence that has led to this proposed dichotomy of function within mPFC. We propose that under some conditions, the PL and IL act in concert, exhibiting similar patterns of neural activity in response to aversive conditioned stimuli and during the expression or inhibition of conditioned fear. This may stem from common synaptic inputs, parallel downstream outputs, or cortico-cortical interactions. Despite this functional covariation, these mPFC subdivisions may still be coding for largely opposing behavioral outcomes, with PL biased towards fear expression and IL towards suppression. PMID:26617500

  15. Impairments in Fear Conditioning in Mice Lacking the nNOS Gene

    ERIC Educational Resources Information Center

    Kelley, Jonathan B.; Balda, Mara A.; Anderson, Karen L.; Itzhak, Yossef

    2009-01-01

    The fear conditioning paradigm is used to investigate the roles of various genes, neurotransmitters, and substrates in the formation of fear learning related to contextual and auditory cues. In the brain, nitric oxide (NO) produced by neuronal nitric oxide synthase (nNOS) functions as a retrograde neuronal messenger that facilitates synaptic…

  16. Exposure to Novelty Weakens Conditioned Fear in Long-Evans Rats

    ERIC Educational Resources Information Center

    Anderson, Matthew J.; Burpee, Tara E.; Wall, Matthew J.; McGraw, Justin J.

    2013-01-01

    The present study sought to determine whether post-training exposure to a novel or familiar object, encountered in either the location of the original fear conditioning (black compartment of a passive avoidance {PA} chamber) or in a neutral setting (open field where initial object training had occurred) would prove capable of reducing fear at…

  17. Cerebellar cortical inhibition and classical eyeblink conditioning.

    PubMed

    Bao, Shaowen; Chen, Lu; Kim, Jeansok J; Thompson, Richard F

    2002-02-01

    The cerebellum is considered a brain structure in which memories for learned motor responses (e.g., conditioned eyeblink responses) are stored. Within the cerebellum, however, the relative importance of the cortex and the deep nuclei in motor learning/memory is not entirely clear. In this study, we show that the cerebellar cortex exerts both basal and stimulus-activated inhibition to the deep nuclei. Sequential application of a gamma-aminobutyric acid type A receptor (GABA(A)R) agonist and a noncompetitive GABA(A)R antagonist allows selective blockade of stimulus-activated inhibition. By using the same sequential agonist and antagonist methods in behaving animals, we demonstrate that the conditioned response (CR) expression and timing are completely dissociable and involve different inhibitory inputs; although the basal inhibition modulates CR expression, the conditioned stimulus-activated inhibition is required for the proper timing of the CR. In addition, complete blockade of cerebellar deep nuclear GABA(A)Rs prevents CR acquisition. Together, these results suggest that different aspects of the memories for eyeblink CRs are encoded in the cerebellar cortex and the cerebellar deep nuclei.

  18. Factors governing single-trial contextual fear conditioning in the weanling rat.

    PubMed

    Burman, M A; Murawski, N J; Schiffino, F L; Rosen, J B; Stanton, M E

    2009-10-01

    Although contextual fear conditioning emerges later in development than explicit-cue fear conditioning, little is known about the stimulus parameters and biological substrates required at early ages. The authors adapted methods for investigating hippocampus function in adult rodents to identify determinants of contextual fear conditioning in developing rats. Experiment 1 examined the duration of exposure required by weanling rats at postnatal day (PND) 23 to demonstrate contextual fear conditioning. This experiment demonstrated that 30 s of context exposure is sufficient to support conditioning. Furthermore, preexposure enhanced conditioning to an immediate footshock, the context preexposure facilitation effect (CPFE), but had no effect on contextual conditioning to a delayed shock. Experiment 2 demonstrated that N-methyl-D-aspartate (NMDA) receptor inactivation during preexposure impairs contextual learning at PND 23. Thus, the conjuctive representations underlying the CPFE are NMDA-dependent as early as PND23 in the rat. PMID:19824781

  19. The premise of equipotentiality in human classical conditioning: conditioned electrodermal responses to potentially phobic stimuli.

    PubMed

    Ohman, A; Fredrikson, M; Hugdahl, K; Rimmö, P A

    1976-12-01

    The premise of equipotentiality, which has been widely adhered to among learning theorists, states that the laws of learning should not vary with the use of particular stimuli, responses, or reinforcements. This premise has recently been challenged by some data originating within the learning tradition itself, for example, studies on the effects of verbal stimuli in eye-lid conditioning. More importantly, however, the premise of equipotentiality is incompatible with data from experiments carried out within a biological-ethological framework. The results of such studies indicate that a given species is prepared to associate certain stimuli, responses, and reinforcers but not others. In an attempt to examine the validity of this premise in human classical conditioning, we investigated the effect of pictures of potentially phobic objects as conditioned stimuli (CSs) for electrodermal responses, since it has been suggested that phobias may be instances of biologically prepared learning. Three experiments are reported, all of them involving a long interstimulus interval differential conditioning paradigm with different pictures as CSs and electric shock as the unconditioned stimulus (UCS). In Experiment 1 we established that different pictures are differentially effective as CSs. A groupconditioned to potentially phobic stimuli, snakes or spiders, showed greater resistance to extinction than a group conditioned to fear-irrelevant pictorial stimuli, that is, flowers or mushrooms. A third group conditioned to "representative laboratory stimuli," circles or triangles, fell in between thses two groups. Experuce similar effects to those observed with phobic and fear-irrelevant stimuli in Experiment 1. In Experiment 3 superior resistance to extinction for phobic stimuli was demonstrated when the UCS was an electric shock, but not when it was a tone to which the subject produced reaction times. Thus, the effect appears specific for aversive UCSs, and CS-UCS "belongingness" has

  20. Different brain networks underlying the acquisition and expression of contextual fear conditioning: a metabolic mapping study.

    PubMed

    González-Pardo, H; Conejo, N M; Lana, G; Arias, J L

    2012-01-27

    The specific brain regions and circuits involved in the acquisition and expression of contextual fear conditioning are still a matter of debate. To address this issue, regional changes in brain metabolic capacity were mapped during the acquisition and expression of contextual fear conditioning using cytochrome oxidase (CO) quantitative histochemistry. In comparison with a group briefly exposed to a conditioning chamber, rats that received a series of randomly presented footshocks in the same conditioning chamber (fear acquisition group) showed increased CO activity in anxiety-related brain regions like the ventral periaqueductal gray, the ventral hippocampus, the lateral habenula, the mammillary bodies, and the laterodorsal thalamic nucleus. Another group received randomly presented footshocks, and it was re-exposed to the same conditioning chamber one week later (fear expression group). The conditioned group had significantly higher CO activity as compared with the matched control group in the following brain regions: the ventral periaqueductal gray, the central and lateral nuclei of the amygdala, and the bed nucleus of the stria terminalis. In addition, analysis of functional brain networks using interregional CO activity correlations revealed different patterns of functional connectivity between fear acquisition and fear expression groups. In particular, a network comprising the ventral hippocampus and amygdala nuclei was found in the fear acquisition group, whereas a closed reciprocal dorsal hippocampal network was detected in the fear expression group. These results suggest that contextual fear acquisition and expression differ as regards to the brain networks involved, although they share common brain regions involved in fear, anxiety, and defensive behavior. PMID:22173014

  1. Human fear conditioning conducted in full immersion 3-dimensional virtual reality.

    PubMed

    Huff, Nicole C; Zeilinski, David J; Fecteau, Matthew E; Brady, Rachael; LaBar, Kevin S

    2010-01-01

    Fear conditioning is a widely used paradigm in non-human animal research to investigate the neural mechanisms underlying fear and anxiety. A major challenge in conducting conditioning studies in humans is the ability to strongly manipulate or simulate the environmental contexts that are associated with conditioned emotional behaviors. In this regard, virtual reality (VR) technology is a promising tool. Yet, adapting this technology to meet experimental constraints requires special accommodations. Here we address the methodological issues involved when conducting fear conditioning in a fully immersive 6-sided VR environment and present fear conditioning data. In the real world, traumatic events occur in complex environments that are made up of many cues, engaging all of our sensory modalities. For example, cues that form the environmental configuration include not only visual elements, but aural, olfactory, and even tactile. In rodent studies of fear conditioning animals are fully immersed in a context that is rich with novel visual, tactile and olfactory cues. However, standard laboratory tests of fear conditioning in humans are typically conducted in a nondescript room in front of a flat or 2D computer screen and do not replicate the complexity of real world experiences. On the other hand, a major limitation of clinical studies aimed at reducing (extinguishing) fear and preventing relapse in anxiety disorders is that treatment occurs after participants have acquired a fear in an uncontrolled and largely unknown context. Thus the experimenters are left without information about the duration of exposure, the true nature of the stimulus, and associated background cues in the environment. In the absence of this information it can be difficult to truly extinguish a fear that is both cue and context-dependent. Virtual reality environments address these issues by providing the complexity of the real world, and at the same time allowing experimenters to constrain fear

  2. The roles of Eph receptors in contextual fear conditioning memory formation.

    PubMed

    Dines, Monica; Grinberg, Svetlana; Vassiliev, Maria; Ram, Alon; Tamir, Tal; Lamprecht, Raphael

    2015-10-01

    Eph receptors regulate glutamate receptors functions, neuronal morphology and synaptic plasticity, cellular events believed to be involved in memory formation. In this study we aim to explore the roles of Eph receptors in learning and memory. Toward that end, we examined the roles of EphB2 and EphA4 receptors, key regulators of synaptic functions, in fear conditioning memory formation. We show that mice lacking EphB2 (EphB2(-/-)) are impaired in short- and long-term contextual fear conditioning memory. Mice that express a carboxy-terminally truncated form of EphB2 that lacks forward signaling, instead of the full EphB2, are impaired in long-term, but not short-term, contextual fear conditioning memory. Long-term contextual fear conditioning memory is attenuated in CaMKII-cre;EphA4(lx/-) mice where EphA4 is removed from all pyramidal neurons of the forebrain. Mutant mice with targeted kinase-dead EphA4 (EphA4(KD)) exhibit intact long-term contextual fear conditioning memory showing that EphA4 kinase-mediated forward signaling is not needed for contextual fear memory formation. The ability to form long-term conditioned taste aversion (CTA) memory is not impaired in the EphB2(-/-) and CaMKII-cre;EphA4(lx/-) mice. We conclude that EphB2 forward signaling is required for long-term contextual fear conditioning memory formation. In contrast, EphB2 mediates short-term contextual fear conditioning memory formation in a forward signaling-independent manner. EphA4 mediates long-term contextual fear conditioning memory formation in a kinase-independent manner. PMID:26165136

  3. The roles of Eph receptors in contextual fear conditioning memory formation.

    PubMed

    Dines, Monica; Grinberg, Svetlana; Vassiliev, Maria; Ram, Alon; Tamir, Tal; Lamprecht, Raphael

    2015-10-01

    Eph receptors regulate glutamate receptors functions, neuronal morphology and synaptic plasticity, cellular events believed to be involved in memory formation. In this study we aim to explore the roles of Eph receptors in learning and memory. Toward that end, we examined the roles of EphB2 and EphA4 receptors, key regulators of synaptic functions, in fear conditioning memory formation. We show that mice lacking EphB2 (EphB2(-/-)) are impaired in short- and long-term contextual fear conditioning memory. Mice that express a carboxy-terminally truncated form of EphB2 that lacks forward signaling, instead of the full EphB2, are impaired in long-term, but not short-term, contextual fear conditioning memory. Long-term contextual fear conditioning memory is attenuated in CaMKII-cre;EphA4(lx/-) mice where EphA4 is removed from all pyramidal neurons of the forebrain. Mutant mice with targeted kinase-dead EphA4 (EphA4(KD)) exhibit intact long-term contextual fear conditioning memory showing that EphA4 kinase-mediated forward signaling is not needed for contextual fear memory formation. The ability to form long-term conditioned taste aversion (CTA) memory is not impaired in the EphB2(-/-) and CaMKII-cre;EphA4(lx/-) mice. We conclude that EphB2 forward signaling is required for long-term contextual fear conditioning memory formation. In contrast, EphB2 mediates short-term contextual fear conditioning memory formation in a forward signaling-independent manner. EphA4 mediates long-term contextual fear conditioning memory formation in a kinase-independent manner.

  4. Temporary inhibition of dorsal or ventral hippocampus by muscimol: distinct effects on measures of innate anxiety on the elevated plus maze, but similar disruption of contextual fear conditioning.

    PubMed

    Zhang, Wei-Ning; Bast, Tobias; Xu, Yan; Feldon, Joram

    2014-04-01

    Studies in rats, involving hippocampal lesions and hippocampal drug infusions, have implicated the hippocampus in the modulation of anxiety-related behaviors and conditioned fear. The ventral hippocampus is considered to be more important for anxiety- and fear-related behaviors than the dorsal hippocampus. In the present study, we compared the role of dorsal and ventral hippocampus in innate anxiety and classical fear conditioning in Wistar rats, examining the effects of temporary pharmacological inhibition by the GABA-A agonist muscimol (0.5 ug/0.5 ul/side) in the elevated plus maze and on fear conditioning to a tone and the conditioning context. In the elevated plus maze, dorsal and ventral hippocampal muscimol caused distinct behavioral changes. The effects of ventral hippocampal muscimol were consistent with suppression of locomotion, possibly accompanied by anxiolytic effects, whereas the pattern of changes caused by dorsal hippocampal muscimol was consistent with anxiogenic effects. In contrast, dorsal and ventral hippocampal muscimol caused similar effects in the fear conditioning experiments, disrupting contextual, but not tone, fear conditioning.

  5. Dual role of dopamine D(2)-like receptors in the mediation of conditioned and unconditioned fear.

    PubMed

    Brandão, Marcus Lira; de Oliveira, Amanda Ribeiro; Muthuraju, Sangu; Colombo, Ana Caroline; Saito, Viviane Mitsuko; Talbot, Teddy

    2015-11-14

    A reduction of dopamine release or D2 receptor blockade in the terminal fields of the mesolimbic system, particularly the amygdala, clearly reduces conditioned fear. Similar D2 receptor antagonism in the neural substrates of fear in the midbrain tectum attenuates the processing of unconditioned aversive information. However, the implications of the interplay between opposing actions of dopamine in the rostral and caudal segments of the dopaminergic system are still unclear. Previous studies from this laboratory have reported the effects of dopaminergic drugs on behavior in rats in the elevated plus maze, auditory-evoked potentials (AEPs) recorded from the midbrain tectum, fear-potentiated startle, and conditioned freezing. These findings led to an interesting framework on the functional roles of dopamine in both anxiety and fear states. Dopamine D2 receptor inhibition in the terminal fields of the mesolimbic dopamine system generally causes anxiolytic-like effects, whereas the activity of midbrain substrates of unconditioned fear are enhanced by D2 receptor antagonists, suggesting that D2 receptor-mediated mechanisms play opposing roles in fear/anxiety processes, depending on the brain region under study. Dopamine appears to mediate conditioned fear by acting at rostral levels of the brain and regulate unconditioned fear at the midbrain level, likely by reducing the sensorimotor gating of aversive events.

  6. The Impact of Instructions on Generalization of Conditioned Fear in Humans.

    PubMed

    Ahmed, Ola; Lovibond, Peter F

    2015-09-01

    Generalization of conditioned fear has been implicated in the maintenance and proliferation of fear in anxiety disorders. The role of cognitive processes in generalization of conditioning is an important yet understudied issue. Vervliet et al. (2010) tested generalization of fear to a visual stimulus of a particular color and shape paired with electric shock. Test stimuli shared either the color or shape of the CS+. Prior to conditioning, participants were instructed that either color or shape would be predictive of shock. Generalization was stronger to the stimulus containing the instructed feature, suggesting that instructions impacted generalization of fear. However, the result may also reflect the impact of instructions on attention and learning during the conditioning phase. In the present study, the instructional manipulation was given after the conditioning phase to control for any impact of instructions on learning. A similar result to that reported by Vervliet et al. was observed. On self-reported expectancy of shock, generalization was greater to the test stimulus that included the instructed stimulus feature. The same pattern was observed on skin conductance, although it did not reach statistical significance. The findings indicate that explicitly instructed information affected generalization of conditioned fear independently of any impact on learning, pointing to the role of cognitive processes in human fear generalization. They also support the utility of cognitive therapy approaches, which are employed after fear has already developed, in addressing clinical overgeneralization. PMID:26459840

  7. The Impact of Instructions on Generalization of Conditioned Fear in Humans.

    PubMed

    Ahmed, Ola; Lovibond, Peter F

    2015-09-01

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

  8. Making Classical Conditioning Understandable through a Demonstration Technique.

    ERIC Educational Resources Information Center

    Gibb, Gerald D.

    1983-01-01

    One lemon, an assortment of other fruits and vegetables, a tennis ball, and a Galvanic Skin Response meter are needed to implement this approach to teaching about classical conditioning in introductory psychology courses. (RM)

  9. Social fear conditioning as an animal model of social anxiety disorder.

    PubMed

    Toth, Iulia; Neumann, Inga D; Slattery, David A

    2013-01-01

    Social fear and avoidance of social situations represent the main behavioral symptoms of social anxiety disorder (SAD), a disorder that is poorly elucidated and has rather unsatisfactory therapeutic options. Therefore, animal models are needed to study the underlying etiology of the disorder and possible novel treatment approaches. However, the current paradigms modeling SAD-like symptoms in rodents are not specific, as they induce numerous other behavioral deficits in addition to social fear and avoidance. Here, we describe the protocol for the social fear conditioning paradigm, an animal model of SAD that specifically induces social fear of unfamiliar con-specifics without potentially confounding alterations in other behavioral measures. Theoretical and practical considerations for performing the social fear conditioning paradigm in both rats and mice, as well as for the analysis and interpretation of the obtained data, are described in detail.

  10. An organization of visual and auditory fear conditioning in the lateral amygdala.

    PubMed

    Bergstrom, Hadley C; Johnson, Luke R

    2014-12-01

    Pavlovian fear conditioning is an evolutionary conserved and extensively studied form of associative learning and memory. In mammals, the lateral amygdala (LA) is an essential locus for Pavlovian fear learning and memory. Despite significant progress unraveling the cellular mechanisms responsible for fear conditioning, very little is known about the anatomical organization of neurons encoding fear conditioning in the LA. One key question is how fear conditioning to different sensory stimuli is organized in LA neuronal ensembles. Here we show that Pavlovian fear conditioning, formed through either the auditory or visual sensory modality, activates a similar density of LA neurons expressing a learning-induced phosphorylated extracellular signal-regulated kinase (p-ERK1/2). While the size of the neuron population specific to either memory was similar, the anatomical distribution differed. Several discrete sites in the LA contained a small but significant number of p-ERK1/2-expressing neurons specific to either sensory modality. The sites were anatomically localized to different levels of the longitudinal plane and were independent of both memory strength and the relative size of the activated neuronal population, suggesting some portion of the memory trace for auditory and visually cued fear conditioning is allocated differently in the LA. Presenting the visual stimulus by itself did not activate the same p-ERK1/2 neuron density or pattern, confirming the novelty of light alone cannot account for the specific pattern of activated neurons after visual fear conditioning. Together, these findings reveal an anatomical distribution of visual and auditory fear conditioning at the level of neuronal ensembles in the LA.

  11. Amygdala upregulation of NCAM polysialylation induced by auditory fear conditioning is not required for memory formation, but plays a role in fear extinction.

    PubMed

    Markram, Kamila; Lopez Fernandez, Miguel Angel; Abrous, Djoher Nora; Sandi, Carmen

    2007-05-01

    There is much interest to understand the mechanisms leading to the establishment, maintenance, and extinction of fear memories. The amygdala has been critically involved in the processing of fear memories and a number of molecular changes have been implicated in this brain region in relation to fear learning. Although neural cell adhesion molecules (NCAMs) have been hypothesized to play a role, information available about their contribution to fear memories is scarce. We investigate here whether polysialylated NCAM (PSA-NCAM) contributes to auditory fear conditioning in the amygdala. First, PSA-NCAM expression was evaluated in different amygdala nuclei after auditory fear conditioning at two different shock intensities. Results showed that PSA-NCAM expression was increased 24 h post-training only in animals subjected to the highest shock intensity (1mA). Second, PSA-NCAM was cleaved in the basolateral amygdaloid complex through micro-infusions of the enzyme endoneuraminidase N, and the consequences of such treatment were investigated on the acquisition, consolidation, remote memory expression, and extinction of conditioned fear memories. Intra-amygdaloid cleavage of PSA-NCAM did not affect acquisition, consolidation or expression of remote fear memories. However, intra-amygdaloid PSA-NCAM cleavage enhanced fear extinction processes. These results suggest that upregulation of PSA-NCAM is a correlate of fear conditioning that is not necessary for the establishment of fear memory in the amygdala, but participates in mechanisms precluding fear extinction. These findings point out PSA-NCAM as a potential target for the treatment of psychopathologies that involve impairment in fear extinction.

  12. Body temperature as a conditional response measure for pavlovian fear conditioning.

    PubMed

    Godsil, B P; Quinn, J J; Fanselow, M S

    2000-01-01

    On six days rats were exposed to each of two contexts. They received an electric shock in one context and nothing in the other. Rats were tested later in each environment without shock. The rats froze and defecated more often in the shock-paired environment; they also exhibited a significantly larger elevation in rectal temperature in that environment. The rats discriminated between each context, and we suggest that the elevation in temperature is the consequence of associative learning. Thus, body temperature can be used as a conditional response measure in Pavlovian fear conditioning experiments that use footshock as the unconditional stimulus.

  13. Cerebellar secretin modulates eyeblink classical conditioning.

    PubMed

    Fuchs, Jason R; Robinson, Gain M; Dean, Aaron M; Schoenberg, Heidi E; Williams, Michael R; Morielli, Anthony D; Green, John T

    2014-12-01

    We have previously shown that intracerebellar infusion of the neuropeptide secretin enhances the acquisition phase of eyeblink conditioning (EBC). Here, we sought to test whether endogenous secretin also regulates EBC and to test whether the effect of exogenous and endogenous secretin is specific to acquisition. In Experiment 1, rats received intracerebellar infusions of the secretin receptor antagonist 5-27 secretin or vehicle into the lobulus simplex of cerebellar cortex immediately prior to sessions 1-3 of acquisition. Antagonist-infused rats showed a reduction in the percentage of eyeblink CRs compared with vehicle-infused rats. In Experiment 2, rats received intracerebellar infusions of secretin or vehicle immediately prior to sessions 1-2 of extinction. Secretin did not significantly affect extinction performance. In Experiment 3, rats received intracerebellar infusions of 5-27 secretin or vehicle immediately prior to sessions 1-2 of extinction. The secretin antagonist did not significantly affect extinction performance. Together, our current and previous results indicate that both exogenous and endogenous cerebellar secretin modulate acquisition, but not extinction, of EBC. We have previously shown that (1) secretin reduces surface expression of the voltage-gated potassium channel α-subunit Kv1.2 in cerebellar cortex and (2) intracerebellar infusions of a Kv1.2 blocker enhance EBC acquisition, much like secretin. Kv1.2 is almost exclusively expressed in cerebellar cortex at basket cell-Purkinje cell pinceaus and Purkinje cell dendrites; we propose that EBC-induced secretin release from PCs modulates EBC acquisition by reducing surface expression of Kv1.2 at one or both of these sites.

  14. Cerebellar secretin modulates eyeblink classical conditioning

    PubMed Central

    Fuchs, Jason R.; Robinson, Gain M.; Dean, Aaron M.; Schoenberg, Heidi E.; Williams, Michael R.; Morielli, Anthony D.

    2014-01-01

    We have previously shown that intracerebellar infusion of the neuropeptide secretin enhances the acquisition phase of eyeblink conditioning (EBC). Here, we sought to test whether endogenous secretin also regulates EBC and to test whether the effect of exogenous and endogenous secretin is specific to acquisition. In Experiment 1, rats received intracerebellar infusions of the secretin receptor antagonist 5-27 secretin or vehicle into the lobulus simplex of cerebellar cortex immediately prior to sessions 1–3 of acquisition. Antagonist-infused rats showed a reduction in the percentage of eyeblink CRs compared with vehicle-infused rats. In Experiment 2, rats received intracerebellar infusions of secretin or vehicle immediately prior to sessions 1–2 of extinction. Secretin did not significantly affect extinction performance. In Experiment 3, rats received intracerebellar infusions of 5-27 secretin or vehicle immediately prior to sessions 1–2 of extinction. The secretin antagonist did not significantly affect extinction performance. Together, our current and previous results indicate that both exogenous and endogenous cerebellar secretin modulate acquisition, but not extinction, of EBC. We have previously shown that (1) secretin reduces surface expression of the voltage-gated potassium channel α-subunit Kv1.2 in cerebellar cortex and (2) intracerebellar infusions of a Kv1.2 blocker enhance EBC acquisition, much like secretin. Kv1.2 is almost exclusively expressed in cerebellar cortex at basket cell–Purkinje cell pinceaus and Purkinje cell dendrites; we propose that EBC-induced secretin release from PCs modulates EBC acquisition by reducing surface expression of Kv1.2 at one or both of these sites. PMID:25403455

  15. Tone conditioning potentiates rather than overshadows context fear in adult animals following adolescent ethanol exposure.

    PubMed

    Broadwater, Margaret A; Spear, Linda P

    2014-07-01

    We have shown that adults exposed to ethanol during adolescence exhibit a deficit in the retention of context fear, reminiscent of that normally seen in preweanling rats. However, preweanlings have been reported to exhibit a potentiation of context fear when they are conditioned in the presence of a tone. Therefore, this study examined context retention 24 hr after tone or context conditioning in male Sprague-Dawley rats exposed intragastrically to 4 g/kg ethanol or water every 48 hr (total of 11 exposures) during adolescence [Postnatal day (P) 28-48] or adulthood (P70-90). Approximately 3 weeks following exposure, retention of fear to the context in animals exposed to ethanol during adolescence was attenuated after context conditioning, but enhanced after tone conditioning. Comparable adult ethanol exposure groups showed typical overshadowing of context fear retention after tone conditioning. These data suggest that adolescent ethanol exposure may induce an immature pattern of cognitive processing.

  16. Delayed Extinction Attenuates Conditioned Fear Renewal and Spontaneous Recovery in Humans

    PubMed Central

    Huff, Nicole C.; Hernandez, Jose Alba; Blanding, Nineequa Q.; LaBar, Kevin S.

    2009-01-01

    This study investigated whether the retention interval after an aversive learning experience influences the return of fear after extinction training. After fear conditioning, participants underwent extinction training either 5 min or 1 day later and in either the same room (same context) or a different room (context shift). The next day, conditioned fear was tested in the original room. When extinction took place immediately, fear renewal was robust and prolonged for context-shift participants, and spontaneous recovery was observed in the same-context participants. Delayed extinction, by contrast, yielded a brief form of fear renewal that reextinguished within the testing session for context-shift participants, and there was no spontaneous recovery in the same-context participants. The authors conclude that the passage of time allows for memory consolidation processes to promote the formation of distinct yet flexible emotional memory traces that confer an ability to recall extinction, even in an alternate context, and minimize the return of fear. Furthermore, immediate extinction can yield spontaneous recovery and prolong fear renewal. These findings have potential implications for ameliorating fear relapse in anxiety disorders. PMID:19634943

  17. Resting heart rate variability is associated with inhibition of conditioned fear.

    PubMed

    Wendt, Julia; Neubert, Jörg; Koenig, Julian; Thayer, Julian F; Hamm, Alfons O

    2015-09-01

    Startle blink as well as skin conductance responses (SCR) are widely used indices of learning processes associated with fear conditioning and extinction. During safety learning, the amygdala is under top-down inhibitory control by the prefrontal cortex (PFC). The capacity of the PFC to exert inhibitory control over subcortical brain structures may be indexed by resting state vagally mediated heart rate variability (HRV). The present study investigated the association of resting HRV with startle blink and SCR during conditioned fear inhibition and extinction. Participants first learned to discriminate a threat cue (A) signaling an aversive unconditioned stimulus from a safety signal (B), which were each presented together with a third stimulus X (AX+/BX-). Then, both the threat and safety signal were presented together (AB) to test whether the presence of the learned safety signal inhibits the fear response to the danger signal. Finally, AX was presented without reinforcement (AX-) to investigate fear extinction. Higher HRV was associated with pronounced fear inhibition and fear extinction. Resting HRV levels were associated with fear extinction as indexed by startle blink potentiation but not SCR, which presumably reflect more cognitive aspects of learning. Resting HRV may reflect the capacity of the prefrontal cortex to inhibit subcortical fear responses in the presence of safety or when former threat cues are presented in the absence of threat.

  18. Classical-Conditioning Demonstrations for Elementary and Advanced Courses.

    ERIC Educational Resources Information Center

    Abramson, Charles I.; And Others

    1996-01-01

    Describes two new exercises in classical conditioning that use earthworms and houseflies. The animals are available year-round and pose no risk to the students or instructor. The conditioned stimuli are odorants. These elicit a conditioned response of contraction in worms or proboscis extension in flies. (MJP)

  19. Identification of plasticity-associated genes regulated by Pavlovian fear conditioning in the lateral amygdala.

    PubMed

    Ploski, Jonathan E; Park, Kevin W; Ping, Junli; Monsey, Melissa S; Schafe, Glenn E

    2010-02-01

    Most recent studies aimed at defining the cellular and molecular mechanisms of Pavlovian fear conditioning have focused on protein kinase signaling pathways and the transcription factor cAMP-response element binding protein (CREB) that promote fear memory consolidation in the lateral nucleus of the amygdala (LA). Despite this progress, there still remains a paucity of information regarding the genes downstream of CREB that are required for long-term fear memory formation in the LA. We have adopted a strategy of using microarray technology to initially identify genes induced within the dentate gyrus following in vivo long-term potentiation (LTP) followed by analysis of whether these same genes are also regulated by fear conditioning within the LA. In the present study, we first identified 34 plasticity-associated genes that are induced within 30 min following LTP induction utilizing a combination of DNA microarray, qRT-PCR, and in situ hybridization. To determine whether these genes are also induced in the LA following Pavlovian fear conditioning, we next exposed rats to an auditory fear conditioning protocol or to control conditions that do not support fear learning followed by qRT-PCR on mRNA from microdissected LA samples. Finally, we asked whether identified genes induced by fear learning in the LA are downstream of the extracellular-regulated kinase/mitogen-activated protein kinase signaling cascade. Collectively, our findings reveal a comprehensive list of genes that represent the first wave of transcription following both LTP induction and fear conditioning that largely belong to a class of genes referred to as 'neuronal activity dependent genes' that are likely calcium, extracellular-regulated kinase/mitogen-activated protein kinase, and CREB-dependent.

  20. Electrolytic lesion of the nucleus incertus retards extinction of auditory conditioned fear.

    PubMed

    Pereira, C W; Santos, F N; Sánchez-Pérez, A M; Otero-García, M; Marchioro, M; Ma, S; Gundlach, A L; Olucha-Bordonau, F E

    2013-06-15

    Fear memory circuits in the brain function to allow animals and humans to recognize putative sources of danger and adopt an appropriate behavioral response; and research on animal models of fear have helped reveal the anatomical and neurochemical nature of these circuits. The nucleus (n.) incertus in the dorsal pontine tegmentum provides a strong GABAergic projection to forebrain 'fear centers' and is strongly activated by neurogenic stressors. In this study in adult male rats, we examined the effect of electrolytic lesions of n. incertus on different stages of the fear conditioning-extinction process and correlated the outcomes with anatomical data on the distribution of n. incertus-derived nerve fibers in areas implicated in fear circuits. In a contextual auditory fear conditioning paradigm, we compared freezing behavior in control (naïve) rats (n=23) and rats with sham- or electrolytic lesions of n. incertus (n=13/group). The effectiveness and extent of the lesions was assessed post-mortem using immunohistochemical markers for n. incertus neurons-calretinin and relaxin-3. There were no differences between the three experimental groups in the habituation, acquisition, or context conditioning phases; but n. incertus lesioned rats displayed a markedly slower, 'delayed' extinction of conditioned freezing responses compared to sham-lesion and control rats, but no differences in retrieval of extinguished fear. These and earlier findings suggest that n. incertus-related circuits normally promote extinction through inhibitory projections to the amygdala, which is involved in acquisition of extinction memories.

  1. Fear conditioning enhances gamma oscillations and their entrainment of neurons representing the conditioned stimulus

    PubMed Central

    Headley, Drew B.; Weinberger, Norman M.

    2013-01-01

    Learning alters the responses of neurons in the neocortex, typically strengthening their encoding of behaviorally relevant stimuli. These enhancements are extensively studied in the auditory cortex by characterizing changes in firing rates and evoked potentials. However, synchronous activity is also important for the processing of stimuli, especially the relationship between gamma oscillations in the local field potential and spiking. We investigated whether tone/shock fear conditioning in rats, a task known to alter responses in auditory cortex, also modified the relationship between gamma and unit activity. A boost in gamma oscillations developed, especially at sites tuned near the tone, and strengthened across multiple conditioning sessions. Unit activity became increasingly phase-locked to gamma, with sites tuned near the tone developing enhanced phase-locking during the tone, while those tuned away maintained a tendency to decrease their phase-locking. Enhancements in the coordination of spiking between sites tuned near the tone developed within the first conditioning session, and remained throughout the rest of training. Enhanced cross-covariances in unit activity were strongest for subjects that exhibited robust conditioned fear. These results illustrate that changes in sensory cortex during associative learning extend to the coordination of neurons encoding the relevant stimulus, with implications for how it is processed downstream. PMID:23536084

  2. Contingency spaces and measures in classical and instrumental conditioning.

    PubMed

    Gibbon, J; Berryman, R; Thompson, R L

    1974-05-01

    The contingency between conditional and unconditional stimuli in classical conditioning paradigms, and between responses and consequences in instrumental conditioning paradigms, is analyzed. The results are represented in two- and three-dimensional spaces in which points correspond to procedures, or procedures and outcomes. Traditional statistical and psychological measures of association are applied to data in classical conditioning. Root mean square contingency, Ø, is proposed as a measure of contingency characterizing classical conditioning effects at asymptote. In instrumental training procedures, traditional measures of association are inappropriate, since one degree of freedom-response probability-is yielded to the subject. Further analysis of instrumental contingencies yields a surprising result. The well established "Matching Law" in free-operant concurrent schedules subsumes the "Probability Matching" finding of mathematical learning theory, and both are equivalent to zero contingency between responses and consequences.

  3. Neural correlates of appetitive-aversive interactions in Pavlovian fear conditioning.

    PubMed

    Nasser, Helen M; McNally, Gavan P

    2013-03-19

    We used Pavlovian counterconditioning in rats to identify the neural mechanisms for appetitive-aversive motivational interactions. In Stage I, rats were trained on conditioned stimulus (CS)-food (unconditioned stimulus [US]) pairings. In Stage II, this appetitive CS was transformed into a fear CS via pairings with footshock. The development of fear responses was retarded in rats that had received Stage I appetitive training. This counterconditioning was associated with increased levels of phosphorylated mitogen activated protein kinase immunoreactivity (pMAPK-IR) in several brain regions, including midline thalamus, rostral agranular insular cortex (RAIC), lateral amygdala, and nucleus accumbens core and shell, but decreased expression in the ventrolateral quadrant of the midbrain periaqueductal gray. These brain regions showing differential pMAPK-IR have previously been identified as part of the fear prediction error circuit. We then examined the causal role of RAIC MAPK in fear learning and showed that Stage II fear learning was prevented by RAIC infusions of the MEK inhibitor PD098059 (0.5 µg/hemisphere). Taken together, these results show that there are opponent interactions between the appetitive and aversive motivational systems during fear learning and that the transformation of a reward CS into a fear CS is linked to heightened activity in the fear prediction error circuit.

  4. Selection for contextual fear conditioning affects anxiety-like behaviors and gene expression.

    PubMed

    Ponder, C A; Kliethermes, C L; Drew, M R; Muller, J; Das, K; Risbrough, V B; Crabbe, J C; Gilliam, T Conrad; Palmer, A A

    2007-11-01

    Conditioned fear and anxiety-like behaviors have many similarities at the neuroanatomical and pharmacological levels, but their genetic relationship is less well defined. We used short-term selection for contextual fear conditioning (FC) to produce outbred mouse lines with robust genetic differences in FC. The high and low selected lines showed differences in fear learning that were stable across various training parameters and were not secondary to differences in sensitivity to the unconditioned stimulus (foot shock). They also showed a divergence in fear potentiated startle, indicating that differences induced by selection generalized to another measure of fear learning. However, there were no differences in performance in a Pavlovian approach conditioning task or the Morris water maze, indicating no change in general learning ability. The high fear learning line showed greater anxiety-like behavior in the open field and zero maze, confirming a genetic relationship between FC and anxiety-like behavior. Gene expression analysis of the amygdala and hippocampus identified genes that were differentially expressed between the two lines. Quantitative trait locus (QTL) analysis identified several chromosomal regions that may underlie the behavioral response to selection; cis-acting expression QTL were identified in some of these regions, possibly identifying genes that underlie these behavioral QTL. These studies support the validity of a broad genetic construct that includes both learned fear and anxiety and provides a basis for further studies aimed at gene identification.

  5. Involvement of the dopaminergic system in the consolidation of fear conditioning in hippocampal CA3 subregion.

    PubMed

    Wen, Jia-Ling; Xue, Li; Wang, Run-Hua; Chen, Zi-Xiang; Shi, Yan-Wei; Zhao, Hu

    2015-02-01

    The hippocampus, the primary brain structure related to learning and memory, receives sparse but comprehensive dopamine innervations and contains dopamine D1 and D2 receptors. Systematic hippocampal dopaminergic dysfunction can cause deficits in spatial working memory and impair consolidation of contextual fear memories. CA3 is involved in the rapid acquisition of new memories and has extensive nerve fibre connections with other brain structures such as CA1, the amygdala, and the medial prefrontal cortex (mPFC). A bidirectional fibrous connection between CA3 and the amygdala reflects the importance of CA3 in fear conditioning. The present study evaluated the effects of a 6-OHDA lesion in CA3 on the acquisition and expression of conditioned fear. The results showed CA3 involvement in the expression but not the acquisition of conditioned fear. Injection of SCH23390 and quinpirole into the bilateral CA3 attenuated a conditioned fear-related freezing response, whereas SKF38393 and sulpiride were not associated with this effect. The present study found that a 6-OHDA lesion in CA3 up-regulated the expression of GluR1 in BLA and down-regulated NR2B in CA1 and the basolateral amygdala (BLA). Our data suggest that dopamine depletion in hippocampal subdivision CA3 may not be necessary for the acquisition of conditioned fear, but the expression of conditioned fear is likely dependent on the integrity of mesohippocampal dopaminergic connections. It is probable that both D1 and D2 dopaminergic receptors modulate the expression of conditioned fear. Changes in the expression of NR2B and GluR1 indicate that CA3 may modulate the activities of other brain structures. PMID:25446753

  6. The Role of Nucleus Accumbens Shell in Learning about Neutral versus Excitatory Stimuli during Pavlovian Fear Conditioning

    ERIC Educational Resources Information Center

    Bradfield, Laura A.; McNally, Gavan P.

    2010-01-01

    We studied the role of nucleus accumbens shell (AcbSh) in Pavlovian fear conditioning. Rats were trained to fear conditioned stimulus A (CSA) in Stage I, which was then presented in compound with a neutral stimulus and paired with shock in Stage II. AcbSh lesions had no effect on fear-learning to CSA in Stage I, but selectively prevented learning…

  7. Transfer from a Classically Conditioned to an Instrumentally Learned Response.

    ERIC Educational Resources Information Center

    Whitman, Thomas L.; Taub, Susan Ilene

    The present experiments investigated the effects of several classical conditioning manipulations on the performance of young children in an instrumental discrimination learning situation. Two predictions from general conditioning-extinction theory were tested: (1) acquisition of an instrumental response to a stimulus for a positive reinforcer in a…

  8. CLASSICAL CONDITIONING AND PAIN: CONDITIONED ANALGESIA AND HYPERALGESIA

    PubMed Central

    Miguez, Gonzalo; Laborda, Mario A.; Miller, Ralph R.

    2013-01-01

    This article reviews situations in which stimuli produce an increase or a decrease in nociceptive responses through basic associative processes and provides an associative account of such changes. Specifically, the literature suggests that cues associated with stress can produce conditioned analgesia or conditioned hyperalgesia, depending on the properties of the conditioned stimulus (e.g., contextual cues and audiovisual cues vs. gustatory and olfactory cues, respectively) and the proprieties of the unconditioned stimulus (e.g., appetitive, aversive, or analgesic, respectively). When such cues are associated with reducers of exogenous pain (e.g., opiates), they typically increase sensitivity to pain. Overall, the evidence concerning conditioned stress-induced analgesia, conditioned hyperalagesia, conditioned tolerance to morphine, and conditioned reduction of morphine analgesia suggests that selective associations between stimuli underlie changes in pain sensitivity. PMID:24269884

  9. Classical conditioning and pain: conditioned analgesia and hyperalgesia.

    PubMed

    Miguez, Gonzalo; Laborda, Mario A; Miller, Ralph R

    2014-01-01

    This article reviews situations in which stimuli produce an increase or a decrease in nociceptive responses through basic associative processes and provides an associative account of such changes. Specifically, the literature suggests that cues associated with stress can produce conditioned analgesia or conditioned hyperalgesia, depending on the properties of the conditioned stimulus (e.g., contextual cues and audiovisual cues vs. gustatory and olfactory cues, respectively) and the proprieties of the unconditioned stimulus (e.g., appetitive, aversive, or analgesic, respectively). When such cues are associated with reducers of exogenous pain (e.g., opiates), they typically increase sensitivity to pain. Overall, the evidence concerning conditioned stress-induced analgesia, conditioned hyperalagesia, conditioned tolerance to morphine, and conditioned reduction of morphine analgesia suggests that selective associations between stimuli underlie changes in pain sensitivity.

  10. Identification of functional circuitry between retrosplenial and postrhinal cortices during fear conditioning.

    PubMed

    Robinson, Siobhan; Poorman, Caroline E; Marder, Thomas J; Bucci, David J

    2012-08-29

    The retrosplenial cortex (RSP) and postrhinal cortex (POR) are heavily interconnected with medial temporal lobe structures involved in learning and memory. Previous studies indicate that RSP and POR are necessary for contextual fear conditioning, but it remains unclear whether these regions contribute individually or instead work together as a functional circuit to modulate learning and/or memory. In Experiment 1, learning-related neuronal activity was assessed in RSP from home cage, shock-only, context-only, or fear-conditioned rats using real-time PCR and immunohistochemical methods to quantify immediate-early gene expression. A significant increase in activity-regulated cytoskeleton-associated protein (Arc) mRNA and Arc and c-Fos protein expression was detected in RSP from fear-conditioned rats compared with all other groups. In Experiment 2, retrograde tracing combined with immunohistochemistry revealed that, compared with controls, a significant proportion of cells projecting from RSP to POR were immunopositive for c-Fos in fear-conditioned rats. These results demonstrate that neurons projecting from RSP to POR are indeed active during fear conditioning. In Experiment 3, a functional disconnection paradigm was used to further examine the interaction between RSP and POR during fear conditioning. Compared with controls, rats with unilateral lesions of RSP and POR on opposite sides of the brain exhibited impaired contextual fear memory, whereas rats with unilateral lesions in the same hemisphere displayed intermediate levels of freezing compared with controls and rats with contralateral lesions. Collectively, these results are the first to show that RSP and POR function as a cortical network necessary for contextual fear learning and memory.

  11. Identification of Functional Circuitry Between Retrosplenial and Postrhinal Cortices During Fear Conditioning

    PubMed Central

    Robinson, Siobhan; Poorman, Caroline E.; Marder, Thomas J.; Bucci, David J.

    2012-01-01

    The retrosplenial (RSP) and postrhinal (POR) cortices are heavily interconnected with medial temporal lobe structures involved in learning and memory. Previous studies indicate that RSP and POR are necessary for contextual fear conditioning, but it remains unclear whether these regions contribute individually or instead work together as a functional circuit to modulate learning and/or memory. In Experiment 1, learning-related neuronal activity was assessed in RSP from home-cage, shock-only, context-only or fear conditioned rats using real-time PCR and immunohistochemical methods to quantify immediate early gene expression. A significant increase in Arc (activity regulated cytoskeleton-associated protein) mRNA and Arc and c-Fos protein expression was detected in RSP from fear conditioned rats compared to all other groups. In Experiment 2, retrograde tracing combined with immunohistochemistry revealed that compared to controls, a significant proportion of cells projecting from RSP to POR were immunopositive for c-Fos in fear conditioned rats. These results demonstrate that neurons projecting from RSP to POR are indeed active during fear conditioning. In Experiment 3, a functional disconnection paradigm was used to further examine the interaction between RSP and POR during fear conditioning. Compared to controls, rats with unilateral lesions of RSP and POR on opposite sides of the brain exhibited impaired contextual fear memory whereas rats with unilateral lesions in the same hemisphere displayed intermediate levels of freezing compared to controls and rats with contralateral lesions. Collectively these results are the first to show that RSP and POR function as a cortical network necessary for contextual fear learning and memory. PMID:22933791

  12. Plasticity of inhibitory synaptic network interactions in the lateral amygdala upon fear conditioning in mice.

    PubMed

    Szinyei, Csaba; Narayanan, Rajeevan T; Pape, Hans-Christian

    2007-02-01

    After fear conditioning, plastic changes of excitatory synaptic transmission occur in the amygdala. Fear-related memory also involves the GABAergic system, although no influence on inhibitory synaptic transmission is known. In the present study we assessed the influence of Pavlovian fear conditioning on the plasticity of GABAergic synaptic interactions in the lateral amygdala (LA) in brain slices prepared from fear-conditioned, pseudo-trained and naïve adult mice. Theta-burst tetanization of thalamic afferent inputs to the LA evoked an input-specific potentiation of inhibitory postsynaptic responses in projection neurons; the cortical input was unaffected. Philanthotoxin (10 microM), an antagonist of Ca2+-permeable AMPA receptors, disabled this plastic phenomenon. Surgical isolation of the LA, extracellular application of a GABA(B) receptor antagonist (CGP 55845A, 10 microM) or an NMDA receptor antagonist (APV, 50 microM), or intracellular application of BAPTA (10 mM), did not influence the plasticity. The plasticity also showed as a potentiation of monosynaptic excitatory responses in putative GABAergic interneurons. Pavlovian fear conditioning, but not pseudo-conditioning, resulted in a significant reduction in this potentiation that was evident 24 h after training. Two weeks after training, the potentiation returned to control levels. In conclusion, a reduction in potentiation of inhibitory synaptic interactions occurs in the LA and may contribute to a shift in synaptic balance towards excitatory signal flow during the processes of fear-memory acquisition or consolidation.

  13. Computational search for hypotheses concerning the endocannabinoid contribution to the extinction of fear conditioning.

    PubMed

    Anastasio, Thomas J

    2013-01-01

    Fear conditioning, in which a cue is conditioned to elicit a fear response, and extinction, in which a previously conditioned cue no longer elicits a fear response, depend on neural plasticity occurring within the amygdala. Projection neurons in the basolateral amygdala (BLA) learn to respond to the cue during fear conditioning, and they mediate fear responding by transferring cue signals to the output stage of the amygdala. Some BLA projection neurons retain their cue responses after extinction. Recent work shows that activation of the endocannabinoid system is necessary for extinction, and it leads to long-term depression (LTD) of the GABAergic synapses that inhibitory interneurons make onto BLA projection neurons. Such GABAergic LTD would enhance the responses of the BLA projection neurons that mediate fear responding, so it would seem to oppose, rather than promote, extinction. To address this paradox, a computational analysis of two well-known conceptual models of amygdaloid plasticity was undertaken. The analysis employed exhaustive state-space search conducted within a declarative programming environment. The analysis reveals that GABAergic LTD actually increases the number of synaptic strength configurations that achieve extinction while preserving the cue responses of some BLA projection neurons in both models. The results suggest that GABAergic LTD helps the amygdala retain cue memory during extinction even as the amygdala learns to suppress the previously conditioned response. The analysis also reveals which features of both models are essential for their ability to achieve extinction with some cue memory preservation, and suggests experimental tests of those features.

  14. Fear conditioning suppresses large-conductance calcium-activated potassium channels in lateral amygdala neurons.

    PubMed

    Sun, P; Zhang, Q; Zhang, Y; Wang, F; Wang, L; Yamamoto, R; Sugai, T; Kato, N

    2015-01-01

    It was previously shown that depression-like behavior is accompanied with suppression of the large-conductance calcium activated potassium (BK) channel in cingulate cortex pyramidal cells. To test whether BK channels are also involved in fear conditioning, we studied neuronal properties of amygdala principal cells in fear conditioned mice. After behavior, we made brain slices containing the amygdala, the structure critically relevant to fear memory. The resting membrane potential in lateral amygdala (LA) neurons obtained from fear conditioned mice (FC group) was more depolarized than in neurons from naïve controls. The frequencies of spikes evoked by current injections were higher in neurons from FC mice, demonstrating that excitability of LA neurons was elevated by fear conditioning. The depolarization in neurons from FC mice was shown to depend on BK channels by using the BK channel blocker charybdotoxin. Suppression of BK channels in LA neurons from the FC group was further confirmed on the basis of the spike width, since BK channels affect the descending phase of spikes. Spikes were broader in the FC group than those in the naïve control in a manner dependent on BK channels. Consistently, quantitative real-time PCR revealed a decreased expression of BK channel mRNA. The present findings suggest that emotional disorder manifested in the forms of fear conditioning is accompanied with BK channel suppression in the amygdala, the brain structure critical to this emotional disorder.

  15. Computational search for hypotheses concerning the endocannabinoid contribution to the extinction of fear conditioning

    PubMed Central

    Anastasio, Thomas J.

    2013-01-01

    Fear conditioning, in which a cue is conditioned to elicit a fear response, and extinction, in which a previously conditioned cue no longer elicits a fear response, depend on neural plasticity occurring within the amygdala. Projection neurons in the basolateral amygdala (BLA) learn to respond to the cue during fear conditioning, and they mediate fear responding by transferring cue signals to the output stage of the amygdala. Some BLA projection neurons retain their cue responses after extinction. Recent work shows that activation of the endocannabinoid system is necessary for extinction, and it leads to long-term depression (LTD) of the GABAergic synapses that inhibitory interneurons make onto BLA projection neurons. Such GABAergic LTD would enhance the responses of the BLA projection neurons that mediate fear responding, so it would seem to oppose, rather than promote, extinction. To address this paradox, a computational analysis of two well-known conceptual models of amygdaloid plasticity was undertaken. The analysis employed exhaustive state-space search conducted within a declarative programming environment. The analysis reveals that GABAergic LTD actually increases the number of synaptic strength configurations that achieve extinction while preserving the cue responses of some BLA projection neurons in both models. The results suggest that GABAergic LTD helps the amygdala retain cue memory during extinction even as the amygdala learns to suppress the previously conditioned response. The analysis also reveals which features of both models are essential for their ability to achieve extinction with some cue memory preservation, and suggests experimental tests of those features. PMID:23761759

  16. De novo fear conditioning across diagnostic groups in the affective disorders: evidence for learning impairments.

    PubMed

    Otto, Michael W; Moshier, Samantha J; Kinner, Dina G; Simon, Naomi M; Pollack, Mark H; Orr, Scott P

    2014-09-01

    De novo fear conditioning paradigms have served as a model for how clinical anxiety may be acquired and maintained. To further examine variable findings in the acquisition and extinction of fear responses between clinical and nonclinical samples, we assessed de novo fear conditioning outcomes in outpatients with either anxiety disorders or depression and healthy subjects recruited from the community. Overall, we found evidence for attenuated fear conditioning, as measured by skin conductance, among the patient sample, with significantly lower fear acquisition among patients with depression and posttraumatic stress disorder. These acquisition deficits were evident in both the simple (considering the CS+only) and differential (evaluating the CS+in relation to the CS-) paradigms. Examination of extinction outcomes were hampered by the low numbers of patients who achieved adequate conditioning, but the available data indicated slower extinction among the patient, primarily panic disorder, sample. Results are interpreted in the context of the cognitive deficits that are common to the anxiety and mood disorders, with attention to a range of potential factors, including mood comorbidity, higher-and lower-order cognitive processes and deficits, and medication use, that may modulate outcomes in fear conditioning studies, and, potentially, in exposure-based cognitive behavioral therapy.

  17. Expatriates’ Multiple Fears, from Terrorism to Working Conditions: Development of a Model

    PubMed Central

    Giorgi, Gabriele; Montani, Francesco; Fiz-Perez, Javier; Arcangeli, Giulio; Mucci, Nicola

    2016-01-01

    Companies’ internationalization appears to be fundamental in the current globalized and competitive environment and seems important not only for organizational success, but also for societal development and sustainability. On one hand, global business increases the demand for managers for international assignment. On the other hand, emergent fears, such as terrorism, seem to be developing around the world, enhancing the risk of expatriates’ potential health problems. The purpose of this paper is to examine the relationships between the emergent concept of fear of expatriation with further workplace fears (economic crisis and dangerous working conditions) and with mental health problems. The study uses a quantitative design. Self-reported data were collected from 265 Italian expatriate workers assigned to both Italian and worldwide projects. Structural equation model analyses showed that fear of expatriation mediates the relationship of mental health with fear of economic crisis and with perceived dangerous working conditions. As expected, in addition to fear, worries of expatriation are also related to further fears. Although, the study is based on self-reports and the cross-sectional study design limits the possibility of making causal inferences, the new constructs introduced add to previous research. PMID:27790173

  18. Cerebellum lesion impairs eyeblink-like classical conditioning in goldfish.

    PubMed

    Gómez, A; Durán, E; Salas, C; Rodríguez, F

    2010-03-10

    The cerebellum of mammals is an essential component of the neural circuitry underlying classical conditioning of eyeblink and other discrete responses. Although the neuroanatomical organization of the cerebellum is notably well conserved in vertebrates, little is actually known about the cerebellar learning functions in nonmammal vertebrate groups. In this work we studied whether the cerebellum of teleost fish plays a critical role in the classical conditioning of a motor response. In Experiment 1, we classically conditioned goldfish in a procedure analogous to the eyeblink conditioning paradigm commonly used in mammals. Goldfish were able to learn to express an eyeblink-like conditioned response to a predictive light (conditioned stimulus) that was paired with a mild electric shock (unconditioned stimulus). The application of unpaired and extinction control procedures demonstrated that also in teleosts the learning of this motor response depends on associative rules. In Experiment 2 we studied whether classical conditioning of this response is critically dependent on the cerebellum and independent of telencephalic structures as occurs in mammals. Cerebellum lesion prevented the acquisition of the eyeblink-like conditioned response whereas telencephalon ablation did not impair the learning of this response. No deficit was observed following lesions in the performance of the unconditioned response or in the percentage of spontaneous responses. These results suggest that cerebellum ablation in goldfish affects a critical component of the circuitry necessary for the acquisition of the conditioned response but does not interfere with the ability of the animal to perform the response itself. The striking similarity in the role of cerebellum in classical conditioning of a motor response between teleost fish and mammals suggests that this learning function of the cerebellum could be a primitive feature of the vertebrate brain that has been conserved through evolution.

  19. Cerebellum: essential involvement in the classically conditioned eyelid response.

    PubMed

    McCormick, D A; Thompson, R F

    1984-01-20

    Classical conditioning of the eyelid response in the rabbit was used to investigate the neuronal structures mediating basic associative learning of discrete, adaptive responses. Lesions of the ipsilateral dentate-interpositus nuclei, but not of the cerebellar cortex, abolished the learned eyeblink response. Recordings from these nuclei have revealed neuronal responses related to the learning of the response. Stimulating these recording sites produced the eyelid response. The dentate-interpositus nuclei were concluded to be critically involved in the learning and production of classically conditioned responses.

  20. Modulation of cannabinoid signaling by amygdala α2-adrenergic system in fear conditioning.

    PubMed

    Nasehi, Mohammad; Zamanparvar, Majid; Ebrahimi-Ghiri, Mohaddeseh; Zarrindast, Mohammad-Reza

    2016-03-01

    The noradrenergic system plays a critical role in the modulation of emotional state, primarily related to anxiety, arousal, and stress. Growing evidence suggests that the endocannabinoid system mediates stress responses and emotional homeostasis, in part, by targeting noradrenergic circuits. In addition, there is an interaction between the cannabinoid and noradrenergic system that has significant functional and behavioral implications. Considering the importance of these systems in forming memories for fearful events, we have investigated the involvement of basolateral amygdala (BLA) α2-adrenoceptors on ACPA (as selective cannabinoid CB1 agonist)-induced inhibition of the acquisition of contextual and auditory conditioned fear. A contextual and auditory fear conditioning apparatus for assess fear memory in adult male NMRI mice was used. Pre-training, intraperitoneal administration of ACPA decreased the percentage freezing time in contextual (at doses of 0.05 and 0.1mg/kg) and auditory (at dose of 0.1 mg/kg) in the fear conditioning task, indicating memory acquisition deficit. The same result was observed with intra-BLA microinjection of clonidine (0.001-0.5 μg/mouse, for both memories), as α2-adrenoceptor agonist and yohimbine (at doses of 0.005 and 0.05 for contextual and at dose of 0.05 μg/mouse for auditory fear memory), as α2-adrenoceptor antagonist. In addition, intra-BLA microinjection of clonidine (0.0005 μg/mouse) did not alter ACPA response in both conditions, while the same dose of yohimbine potentiated ACPA response at the lower dose on contextual fear memory. It is concluded that BLA α2-adrenergic receptors may be involved in context- but not tone-dependent fear memory impairment induced by activation of CB1 receptors.

  1. Extinction instead of incubation following classical aversive conditioning in dogs.

    PubMed

    Kimmel, H D; Kearns, W D; Anderson, D E

    1992-01-01

    Two dogs received a single paired classical conditioning trial, with tone CS and 12 mA shock US. Both dogs then showed a conditioned blood pressure increase in response to the nonreinforced CS, which extinguished with additional nonreinforced presentations. The CR showed spontaneous recovery four days later, but reextinguished with additional nonreinforced presentations. The results were interpreted as not supporting Eysenck's theory of "incubation" following one-trial aversive conditioning.

  2. Effects of recent exposure to a conditioned stimulus on extinction of Pavlovian fear conditioning.

    PubMed

    Chan, Wan Yee Macy; Leung, Hiu T; Westbrook, R Frederick; McNally, Gavan P

    2010-10-01

    In six experiments we studied the effects of a single re-exposure to a conditioned stimulus (CS; "retrieval trial") prior to extinction training (extinction-reconsolidation boundary) on the development of and recovery from fear extinction. A single retrieval trial prior to extinction training significantly augmented the renewal and reinstatement of extinguished responding. Augmentation of recovery was not observed if the retrieval and extinction training occurred in different contexts. These results contrast with those reported in earlier papers by Monfils and coworkers in rats and by Schiller and coworkers in humans. We suggest that these contrasting results could depend on the contrasting influences of either: (1) occasion-setting contextual associations vs. direct context-CS associations formed as a consequence of the retrieval trial or (2) discrimination vs. generalization between the circumstances of conditioning and extinction.

  3. Trait anxiety and perceptual load as determinants of emotion processing in a fear conditioning paradigm.

    PubMed

    Fox, Elaine; Yates, Alan; Ashwin, Chris

    2012-04-01

    The impact of trait anxiety and perceptual load on selective attention was examined in a fear conditioning paradigm. A fear-conditioned angry face (CS+), an unconditioned angry face (CS-), or an unconditioned face with a neutral or happy expression were used in distractor interference and attentional probe tasks. In Experiments 1 and 2, participants classified centrally presented letters under two conditions of perceptual load. When perceptual load was high, distractors had no effect on selective attention, even with aversive conditioning. However, when perceptual load was low, strong response interference effects for CS+ face distractors were found for low trait-anxious participants. Across both experiments, this enhanced distractor interference reversed to strong facilitation effects for those reporting high trait anxiety. Thus, high trait-anxious participants were faster, rather than slower, when ignoring CS+ distractors. Using an attentional probe task in Experiment 3, it was found that fear conditioning resulted in strong attentional avoidance in a high trait-anxious group, which contrasted with enhanced vigilance in a low trait-anxious group. These results demonstrate that the impact of fear conditioning on attention is modulated by individual variation in trait anxiety when perceptual load is low. Fear conditioning elicits an avoidance of threat-relevant stimuli in high trait-anxious participants.

  4. Role of classical conditioning in learning gastrointestinal symptoms.

    PubMed

    Stockhorst, Ursula; Enck, Paul; Klosterhalfen, Sibylle

    2007-07-01

    Nausea and/or vomiting are aversive gastrointestinal (GI) symptoms. Nausea and vomiting manifest unconditionally after a nauseogenic experience. However, there is correlative, quasiexperimental and experimental evidence that nausea and vomiting can also be learned via classical (Pavlovian) conditioning and might occur in anticipation of the nauseogenic event. Classical conditioning of nausea can develop with chemotherapy in cancer patients. Initially, nausea and vomiting occur during and after the administration of cytotoxic drugs (post-treatment nausea and vomiting) as unconditioned responses (UR). In addition, 20%-30% of cancer patients receiving chemotherapy report these side effects, despite antiemetic medication, when being re-exposed to the stimuli that usually signal the chemotherapy session and its drug infusion. These symptoms are called anticipatory nausea (AN) and/or anticipatory vomiting (ANV) and are explained by classical conditioning. Moreover, there is recent evidence for the assumption that post-chemotherapy nausea is at least partly influenced by learning. After summarizing the relevant assumptions of the conditioning model, revealing that a context can become a conditioned stimulus (CS), the present paper summarizes data that nausea and/or vomiting is acquired by classical conditioning and, consequently, may be alleviated by conditioning techniques. Our own research has focussed on two aspects and is emphasized here. First, a conditioned nausea model was established in healthy humans using body rotation as the nausea-inducing treatment. The validity of this motion-sickness model to examine conditioning mechanisms in the acquisition and alleviation of conditioned nausea and associated endocrine and immunological responses is summarized. Results from the rotation-induced motion sickness model showed that gender is an important moderator variable to be considered in further studies. This paper concludes with a review of the application of the

  5. Allocation of cognitive processing capacity during human autonomic classical conditioning.

    PubMed

    Dawson, M E; Schell, A M; Beers, J R; Kelly, A

    1982-09-01

    In each of two experiments, allocation of cognitive processing capacity was measured in college-student subjects during autonomic discrimination classical conditioning. A 7.0-sec delay paradigm was used to establish classically conditioned responses to a reinforced visual conditioned stimulus (CS+). Electrodermal responses were the primary measures of autonomic classical conditioning. Allocation of processing capacity was measured by monitoring performance on a secondary reaction-time (RT) task. The auditory secondary-task RT signal was presented before, and 300, 500, 3500, 6500, and 7500 msec following CS onset. The RT signal was also presented following properly and improperly cued shock unconditioned stimuli (UCSs). Significant discrimination classical conditioning was obtained in both experiments. Comparison with control subjects who did not receive the RT signals indicated that the presence of the RT signals did not interfere with the development of classical conditioning. Four principal findings were obtained with the secondary-task RT measure. First, RTs to signals presented during CS+ were consistently slower than RTs to signals presented during CS-. This finding indicates that greater capacity allocation occurred during CS+ than CS- and is consistent with recent cognitive interpretations of classical conditioning. Second, the largest capacity allocation (i.e., slowing of RTs) occurred 300 msec following CS+ onset. This finding is consistent with the notion that subjects are actively processing the signal properties of the CS+ at 300 msec following CS+ onset. Third, presentation of the UCS when improperly cued (following CS-) significantly increased capacity allocation, whereas presentation of the same UCS when properly cued (following CS+) did not affect capacity allocation. These findings indicate that subjects were actively prepared for the UCS following CS+ but not following CS- and that a surprising UCS elicits greater capacity allocation than does an

  6. The Development of Skin Conductance Fear Conditioning in Children from Ages 3 to 8 Years

    ERIC Educational Resources Information Center

    Gao, Yu; Raine, Adrian; Venables, Peter H.; Dawson, Michael E.; Mednick, Sarnoff A.

    2010-01-01

    Although fear conditioning is an important psychological construct implicated in behavioral and emotional problems, little is known about how it develops in early childhood. Using a differential, partial reinforcement conditioning paradigm, this longitudinal study assessed skin conductance conditioned responses in 200 children at ages 3, 4, 5, 6,…

  7. P50 suppression in human discrimination fear conditioning paradigm using danger and safety signals.

    PubMed

    Kurayama, Taichi; Matsuzawa, Daisuke; Komiya, Zen; Nakazawa, Ken; Yoshida, Susumu; Shimizu, Eiji

    2012-04-01

    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.

  8. From Pavlov to PTSD: the extinction of conditioned fear in rodents, humans, and anxiety disorders.

    PubMed

    VanElzakker, Michael B; Dahlgren, M Kathryn; Davis, F Caroline; Dubois, Stacey; Shin, Lisa M

    2014-09-01

    Nearly 100 years ago, Ivan Pavlov demonstrated that dogs could learn to use a neutral cue to predict a biologically relevant event: after repeated predictive pairings, Pavlov's dogs were conditioned to anticipate food at the sound of a bell, which caused them to salivate. Like sustenance, danger is biologically relevant, and neutral cues can take on great salience when they predict a threat to survival. In anxiety disorders such as posttraumatic stress disorder (PTSD), this type of conditioned fear fails to extinguish, and reminders of traumatic events can cause pathological conditioned fear responses for decades after danger has passed. In this review, we use fear conditioning and extinction studies to draw a direct line from Pavlov to PTSD and other anxiety disorders. We explain how rodent studies have informed neuroimaging studies of healthy humans and humans with PTSD. We describe several genes that have been linked to both PTSD and fear conditioning and extinction and explain how abnormalities in fear conditioning or extinction may reflect a general biomarker of anxiety disorders. Finally, we explore drug and neuromodulation treatments that may enhance therapeutic extinction in anxiety disorders.

  9. From Pavlov to PTSD: The extinction of conditioned fear in rodents, humans, and in anxiety disorders

    PubMed Central

    VanElzakker, Michael B.; Dahlgren, M. Kathryn; Davis, F. Caroline; Dubois, Stacey; Shin, Lisa M.

    2014-01-01

    Nearly 100 years ago, Ivan Pavlov demonstrated that dogs could learn to use a neutral cue to predict a biologically relevant event: after repeated predictive pairings, Pavlov's dogs were conditioned to anticipate food at the sound of a bell, which caused them to salivate. Like sustenance, danger is biologically relevant, and neutral cues can take on great salience when they predict a threat to survival. In anxiety disorders such as posttraumatic stress disorder (PTSD), this type of conditioned fear fails to extinguish, and reminders of traumatic events can cause pathological conditioned fear responses for decades after danger has passed. In this review, we use fear conditioning and extinction studies to draw a direct line from Pavlov to PTSD and other anxiety disorders. We explain how rodent studies have informed neuroimaging studies of healthy humans and humans with PTSD. We describe several genes that have been linked to both PTSD and fear conditioning and extinction and explain how abnormalities in fear conditioning or extinction may reflect a general biomarker of anxiety disorders. Finally, we explore drug and neuromodulation treatments that may enhance therapeutic extinction in anxiety disorders. PMID:24321650

  10. From Pavlov to PTSD: the extinction of conditioned fear in rodents, humans, and anxiety disorders.

    PubMed

    VanElzakker, Michael B; Dahlgren, M Kathryn; Davis, F Caroline; Dubois, Stacey; Shin, Lisa M

    2014-09-01

    Nearly 100 years ago, Ivan Pavlov demonstrated that dogs could learn to use a neutral cue to predict a biologically relevant event: after repeated predictive pairings, Pavlov's dogs were conditioned to anticipate food at the sound of a bell, which caused them to salivate. Like sustenance, danger is biologically relevant, and neutral cues can take on great salience when they predict a threat to survival. In anxiety disorders such as posttraumatic stress disorder (PTSD), this type of conditioned fear fails to extinguish, and reminders of traumatic events can cause pathological conditioned fear responses for decades after danger has passed. In this review, we use fear conditioning and extinction studies to draw a direct line from Pavlov to PTSD and other anxiety disorders. We explain how rodent studies have informed neuroimaging studies of healthy humans and humans with PTSD. We describe several genes that have been linked to both PTSD and fear conditioning and extinction and explain how abnormalities in fear conditioning or extinction may reflect a general biomarker of anxiety disorders. Finally, we explore drug and neuromodulation treatments that may enhance therapeutic extinction in anxiety disorders. PMID:24321650

  11. Classical conditioning in patients with severe memory problems.

    PubMed Central

    Daum, I; Channon, S; Canavan, A G

    1989-01-01

    Classical conditioning is one of the most fundamental forms of learning, and yet little is known regarding the effects of brain injury on conditioning processes in humans. Three patients with temporal lobe lesions and severe memory problems were therefore assessed in terms of eyeblink conditioning, extinction, discrimination and reversal learning, and in one patient electrodermal conditioning was also investigated. The acquisition of conditioned responses was seen to be intact, but the evidence regarding extinction was ambiguous. All of the patients were impaired in discrimination learning and also reversal learning. PMID:2496204

  12. Brain Mechanisms of Extinction of the Classically Conditioned Eyeblink Response

    ERIC Educational Resources Information Center

    Thompson, Richard F.; Robleto, Karla; Poulos, Andrew M.

    2004-01-01

    It is well established that the cerebellum and its associated circuitry are essential for classical conditioning of the eyeblink response and other discrete motor responses (e.g., limb flexion, head turn, etc.) learned with an aversive unconditioned stimulus (US). However, brain mechanisms underlying extinction of these responses are still…

  13. Inhibition of the amygdala central nucleus by stimulation of cerebellar output in rats: a putative mechanism for extinction of the conditioned fear response.

    PubMed

    Magal, Ari; Mintz, Matti

    2014-11-01

    The amygdala and the cerebellum serve two distinctively different functions. The amygdala plays a role in the expression of emotional information, whereas the cerebellum is involved in the timing of discrete motor responses. Interaction between these two systems is the basis of the two-stage theory of learning, according to which an encounter with a challenging event triggers fast classical conditioning of fear-conditioned responses in the amygdala and slow conditioning of motor-conditioned responses in the cerebellum. A third stage was hypothesised when an apparent interaction between amygdala and cerebellar associative plasticity was observed: an adaptive rate of cerebellum-dependent motor-conditioned responses was associated with a decrease in amygdala-dependent fear-conditioned responses, and was interpreted as extinction of amygdala-related fear-conditioned responses by the cerebellar output. To explore this hypothesis, we mimicked some components of classical eyeblink conditioning in anesthetised rats by applying an aversive periorbital pulse as an unconditioned stimulus and a train of pulses to the cerebellar output nuclei as a cerebellar neuronal-conditioned response. The central amygdala multiple unit response to the periorbital pulse was measured with or without a preceding train to the cerebellar output nuclei. The results showed that activation of the cerebellar output nuclei prior to periorbital stimulation produced diverse patterns of inhibition of the amygdala response to the periorbital aversive stimulus, depending upon the nucleus stimulated, the laterality of the nucleus stimulated, and the stimulus interval used. These results provide a putative extinction mechanism of learned fear behavior, and could have implications for the treatment of pathologies involving abnormal fear responses by using motor training as therapy.

  14. Inhibition of the amygdala central nucleus by stimulation of cerebellar output in rats: a putative mechanism for extinction of the conditioned fear response.

    PubMed

    Magal, Ari; Mintz, Matti

    2014-11-01

    The amygdala and the cerebellum serve two distinctively different functions. The amygdala plays a role in the expression of emotional information, whereas the cerebellum is involved in the timing of discrete motor responses. Interaction between these two systems is the basis of the two-stage theory of learning, according to which an encounter with a challenging event triggers fast classical conditioning of fear-conditioned responses in the amygdala and slow conditioning of motor-conditioned responses in the cerebellum. A third stage was hypothesised when an apparent interaction between amygdala and cerebellar associative plasticity was observed: an adaptive rate of cerebellum-dependent motor-conditioned responses was associated with a decrease in amygdala-dependent fear-conditioned responses, and was interpreted as extinction of amygdala-related fear-conditioned responses by the cerebellar output. To explore this hypothesis, we mimicked some components of classical eyeblink conditioning in anesthetised rats by applying an aversive periorbital pulse as an unconditioned stimulus and a train of pulses to the cerebellar output nuclei as a cerebellar neuronal-conditioned response. The central amygdala multiple unit response to the periorbital pulse was measured with or without a preceding train to the cerebellar output nuclei. The results showed that activation of the cerebellar output nuclei prior to periorbital stimulation produced diverse patterns of inhibition of the amygdala response to the periorbital aversive stimulus, depending upon the nucleus stimulated, the laterality of the nucleus stimulated, and the stimulus interval used. These results provide a putative extinction mechanism of learned fear behavior, and could have implications for the treatment of pathologies involving abnormal fear responses by using motor training as therapy. PMID:25185877

  15. The retrosplenial cortex is involved in the formation of memory for context and trace fear conditioning.

    PubMed

    Kwapis, Janine L; Jarome, Timothy J; Lee, Jonathan L; Helmstetter, Fred J

    2015-09-01

    The retrosplenial cortex (RSC) is known to play a role in the retrieval of context memory, but its involvement in memory formation and consolidation is unclear. To better characterize the role of the RSC, we tested its involvement in the formation and retrieval of memory for trace fear conditioning, a task that requires the association of two cues separated by an empty period of time. We have previously shown that trace fear extinction requires the RSC (Kwapis, Jarome, Lee, Gilmartin, & Helmstetter, 2014) and have hypothesized that trace memory may be stored in a distributed cortical network that includes prelimbic and retrosplenial cortices (Kwapis, Jarome, & Helmstetter, 2015). Whether the RSC participates in acquiring and storing cued trace fear, however, is currently unknown. Here, we demonstrate that blocking protein synthesis in the RSC before, but not after acquisition impairs rats' memory for trace CS and context fear without affecting memory for the CS in standard delay fear conditioning. We also show that NMDA receptor blockade in the RSC transiently impairs memory retrieval for trace, but not delay memory. The RSC therefore appears to critically contribute to formation of trace and context fear memory in addition to its previously recognized role in context memory retrieval.

  16. Opioid receptors in the midbrain periaqueductal gray regulate extinction of pavlovian fear conditioning.

    PubMed

    McNally, Gavan P; Pigg, Michael; Weidemann, Gabrielle

    2004-08-01

    Four experiments studied the role of opioid receptors in the midbrain periaqueductal gray matter (PAG), an important structure eliciting conditioned fear responses, in the extinction of Pavlovian fear. Rats received pairings of an auditory conditioned stimulus (CS) with a foot shock unconditioned stimulus (US). The freezing conditioned response (CR) elicited by the CS was then extinguished via nonreinforced presentations of the CS. Microinjection of the opioid receptor antagonist naloxone into the ventrolateral PAG (vlPAG) before nonrein-forced CS presentations impaired development of extinction, but such microinjections at the end of extinction did not reinstate an already extinguished freezing CR. This role for opioid receptors in fear extinction was specific to the vlPAG because infusions of naloxone into the dorsal PAG did not impair fear extinction. Finally, the impairment of fear extinction produced by vlPAG infusions of naloxone was dose-dependent. These results show for the first time that the midbrain PAG contributes to fear extinction and specifically identify a role for vlPAG opioid receptors in the acquisition but not the expression of such extinction. Taken together with our previous findings, we suggest that, during fear conditioning, activation of vlPAG opioid receptors contributes to detection of the discrepancy between the actual and expected outcome of the conditioning trial. vlPAG opioid receptors regulate the learning that accrues to the CS and other stimuli present on a trial because they instantiate an associative error correction process influencing US information reaching the site of CS-US convergence in the amygdala. During nonreinforcement, this vlPAG opioid receptor contribution signals extinction.

  17. Brain region-specific activity patterns after recent or remote memory retrieval of auditory conditioned fear.

    PubMed

    Kwon, Jeong-Tae; Jhang, Jinho; Kim, Hyung-Su; Lee, Sujin; Han, Jin-Hee

    2012-01-01

    Memory is thought to be sparsely encoded throughout multiple brain regions forming unique memory trace. Although evidence has established that the amygdala is a key brain site for memory storage and retrieval of auditory conditioned fear memory, it remains elusive whether the auditory brain regions may be involved in fear memory storage or retrieval. To investigate this possibility, we systematically imaged the brain activity patterns in the lateral amygdala, MGm/PIN, and AuV/TeA using activity-dependent induction of immediate early gene zif268 after recent and remote memory retrieval of auditory conditioned fear. Consistent with the critical role of the amygdala in fear memory, the zif268 activity in the lateral amygdala was significantly increased after both recent and remote memory retrieval. Interesting, however, the density of zif268 (+) neurons in both MGm/PIN and AuV/TeA, particularly in layers IV and VI, was increased only after remote but not recent fear memory retrieval compared to control groups. Further analysis of zif268 signals in AuV/TeA revealed that conditioned tone induced stronger zif268 induction compared to familiar tone in each individual zif268 (+) neuron after recent memory retrieval. Taken together, our results support that the lateral amygdala is a key brain site for permanent fear memory storage and suggest that MGm/PIN and AuV/TeA might play a role for remote memory storage or retrieval of auditory conditioned fear, or, alternatively, that these auditory brain regions might have a different way of processing for familiar or conditioned tone information at recent and remote time phases. PMID:22993170

  18. Pharmacological depletion of serotonin in the basolateral amygdala complex reduces anxiety and disrupts fear conditioning

    PubMed Central

    Johnson, Philip L.; Molosh, Andrei; Fitz, Stephanie D.; Arendt, Dave; Deehan, Gerald A.; Federici, Lauren M.; Bernabe, Cristian; Engleman, Eric A.; Rodd, Zachary A.; Lowry, Christopher A.; Shekhar, Anantha

    2015-01-01

    The basolateral and lateral amygdala nuclei complex (BLC) is implicated in a number of emotional responses including conditioned fear and social anxiety. Based on previous studies demonstrating that enhanced serotonin release in the BLC leads to increased anxiety and fear responses, we hypothesized that pharmacologically depleting serotonin in the BLC using 5,7-dihydroxytryptamine (5,7-DHT) injections would lead to diminished anxiety and disrupted fear conditioning. To test this hypothesis, 5,7-DHT (a serotonin-depleting agent) was bilaterally injected into the BLC. Desipramine (a norepinephrine reuptake inhibitor) was systemically administered to prevent non-selective effects on norepinephrine. After 5 days, 5-7-DHT-treated rats showed increases in the duration of social interaction (SI) time, suggestive of reduced anxiety-like behavior. We then used a cue-induced fear conditioning protocol with shock as the unconditioned stimulus and tone as the conditioned stimulus for rats pretreated with bilateral 5,7-DHT, or vehicle, injections into the BLC. Compared to vehicle-treated rats, 5,7-DHT rats had reduced acquisition of fear during conditioning (measured by freezing time during tone), also had reduced fear retrieval/recall on subsequent testing days. Ex vivo analyses revealed that 5,7-DHT reduced local 5-HT concentrations in the BLC by ∼40% without altering local norepinephrine or dopamine concentrations. These data provide additional support for 5-HT playing a critical role in modulating anxiety-like behavior and fear-associated memories through its actions within the BLC. PMID:26476009

  19. Pharmacological depletion of serotonin in the basolateral amygdala complex reduces anxiety and disrupts fear conditioning.

    PubMed

    Johnson, Philip L; Molosh, Andrei; Fitz, Stephanie D; Arendt, Dave; Deehan, Gerald A; Federici, Lauren M; Bernabe, Cristian; Engleman, Eric A; Rodd, Zachary A; Lowry, Christopher A; Shekhar, Anantha

    2015-11-01

    The basolateral and lateral amygdala nuclei complex (BLC) is implicated in a number of emotional responses including conditioned fear and social anxiety. Based on previous studies demonstrating that enhanced serotonin release in the BLC leads to increased anxiety and fear responses, we hypothesized that pharmacologically depleting serotonin in the BLC using 5,7-dihydroxytryptamine (5,7-DHT) injections would lead to diminished anxiety and disrupted fear conditioning. To test this hypothesis, 5,7-DHT(a serotonin-depleting agent) was bilaterally injected into the BLC. Desipramine (a norepinephrine reuptake inhibitor) was systemically administered to prevent non-selective effects on norepinephrine. After 5days, 5-7-DHT-treated rats showed increases in the duration of social interaction (SI) time, suggestive of reduced anxiety-like behavior. We then used a cue-induced fear conditioning protocol with shock as the unconditioned stimulus and tone as the conditioned stimulus for rats pretreated with bilateral 5,7-DHT, or vehicle, injections into the BLC. Compared to vehicle-treated rats, 5,7-DHT rats had reduced acquisition of fear during conditioning (measured by freezing time during tone), also had reduced fear retrieval/recall on subsequent testing days. Ex vivo analyses revealed that 5,7-DHT reduced local 5-HT concentrations in the BLC by ~40% without altering local norepinephrine or dopamine concentrations. These data provide additional support for 5-HT playing a critical role in modulating anxiety-like behavior and fear-associated memories through its actions within the BLC. PMID:26476009

  20. Pharmacological depletion of serotonin in the basolateral amygdala complex reduces anxiety and disrupts fear conditioning.

    PubMed

    Johnson, Philip L; Molosh, Andrei; Fitz, Stephanie D; Arendt, Dave; Deehan, Gerald A; Federici, Lauren M; Bernabe, Cristian; Engleman, Eric A; Rodd, Zachary A; Lowry, Christopher A; Shekhar, Anantha

    2015-11-01

    The basolateral and lateral amygdala nuclei complex (BLC) is implicated in a number of emotional responses including conditioned fear and social anxiety. Based on previous studies demonstrating that enhanced serotonin release in the BLC leads to increased anxiety and fear responses, we hypothesized that pharmacologically depleting serotonin in the BLC using 5,7-dihydroxytryptamine (5,7-DHT) injections would lead to diminished anxiety and disrupted fear conditioning. To test this hypothesis, 5,7-DHT(a serotonin-depleting agent) was bilaterally injected into the BLC. Desipramine (a norepinephrine reuptake inhibitor) was systemically administered to prevent non-selective effects on norepinephrine. After 5days, 5-7-DHT-treated rats showed increases in the duration of social interaction (SI) time, suggestive of reduced anxiety-like behavior. We then used a cue-induced fear conditioning protocol with shock as the unconditioned stimulus and tone as the conditioned stimulus for rats pretreated with bilateral 5,7-DHT, or vehicle, injections into the BLC. Compared to vehicle-treated rats, 5,7-DHT rats had reduced acquisition of fear during conditioning (measured by freezing time during tone), also had reduced fear retrieval/recall on subsequent testing days. Ex vivo analyses revealed that 5,7-DHT reduced local 5-HT concentrations in the BLC by ~40% without altering local norepinephrine or dopamine concentrations. These data provide additional support for 5-HT playing a critical role in modulating anxiety-like behavior and fear-associated memories through its actions within the BLC.

  1. Transference in view of a classical conditioning model.

    PubMed

    Rabinovich, Merav; Kacen, Lea

    2012-01-01

    This article presents a qualitative metasynthetic study, addressing 33 transference case studies, that investigates the interrelationship of the transference concept from psychoanalysis and cognitive-behavioral concepts in an attempt to construct a theoretical platform for clinical integration. Relationship between categories analysis was used to compare Luborsky's (1998) transference components (wish, response from other, and response of self) and cognitive-behavioral ones. Results showed reciprocal relations between transference and classical conditioning. Furthermore, explicit occurrences of distorted thinking due to overgeneralization were found in more than 90% of the cases. A conceptual model describes transference as a conditioned response activated by thematic conditioning, a particular case of classical conditioning that repeatedly pairs a given interpersonal situation with internal thematic stimuli, thus shaping the person's narrative. Theoretical and practical implications are discussed as well.

  2. Relationship between Fear Conditionability and Aversive Memories: Evidence from a Novel Conditioned-Intrusion Paradigm

    PubMed Central

    Wegerer, Melanie; Blechert, Jens; Kerschbaum, Hubert; Wilhelm, Frank H.

    2013-01-01

    Intrusive memories – a hallmark symptom of posttraumatic stress disorder (PTSD) – are often triggered by stimuli possessing similarity with cues that predicted or accompanied the traumatic event. According to learning theories, intrusive memories can be seen as a conditioned response to trauma reminders. However, direct laboratory evidence for the link between fear conditionability and intrusive memories is missing. Furthermore, fear conditioning studies have predominantly relied on standardized aversive stimuli (e.g. electric stimulation) that bear little resemblance to typical traumatic events. To investigate the general relationship between fear conditionability and aversive memories, we tested 66 mentally healthy females in a novel conditioned-intrusion paradigm designed to model real-life traumatic experiences. The paradigm included a differential fear conditioning procedure with neutral sounds as conditioned stimuli and short violent film clips as unconditioned stimuli. Subsequent aversive memories were assessed through a memory triggering task (within 30 minutes, in the laboratory) and ambulatory assessment (involuntary aversive memories in the 2 days following the experiment). Skin conductance responses and subjective ratings demonstrated successful differential conditioning indicating that naturalistic aversive film stimuli can be used in a fear conditioning experiment. Furthermore, aversive memories were elicited in response to the conditioned stimuli during the memory triggering task and also occurred in the 2 days following the experiment. Importantly, participants who displayed higher conditionability showed more aversive memories during the memory triggering task and during ambulatory assessment. This suggests that fear conditioning constitutes an important source of persistent aversive memories. Implications for PTSD and its treatment are discussed. PMID:24244407

  3. The development of an attentional bias for angry faces following Pavlovian fear conditioning.

    PubMed

    Pischek-Simpson, Leah K; Boschen, Mark J; Neumann, David L; Waters, Allison M

    2009-04-01

    Although it is well documented that fear responses develop following aversive Pavlovian conditioning, it is unclear whether fear learning also manifests in the form of attentional biases for fear-related stimuli. Boschen, Parker, and Neumann (Boschen, M. J., Parker, I., & Neumann, D. L. (2007). Changes in implicit associations do not occur simultaneously to Pavlovian conditioning of physiological anxiety responses. Journal of Anxiety Disorders, 21, 788-803.) showed that despite the acquisition of differential skin conductance conditioned responses to angry faces paired (CS+) and unpaired (CS-) with an aversive shock, development of implicit associations was not subsequently observed on the Implicit Association Test. In the present study, participants (N=76) were assigned either to a Shock or NoShock group and completed a similar aversive Pavlovian conditioning procedure with angry face CS+ and CS- stimuli. Participants next completed a visual probe task in which the angry face CS+ and CS- stimuli were paired with angry face control stimuli and neutral faces. Results confirmed that differential fear conditioning was observed in the Shock group but not in the NoShock group, and that the Shock group subsequently showed a selective attentional bias for the angry face CS+ compared with the CS- and control stimuli during the visual probe task. The findings confirm the interplay between learning-based mechanisms and cognitive processes, such as attentional biases, in models of fear acquisition and have implications for treatment of the anxiety disorders.

  4. [The Manifestation of the Anxiety during Fear Conditioning in Wistar Rats].

    PubMed

    Pavlova, I V; Rysakova, M P

    2015-01-01

    In order to identify the correlation between anxiety and conditioned fear, the behavior of the same male Wistar rats was compared in three anxiety tests (open field, light-dark box and elevated plus-maze) and in Pavlovian auditory fear conditioning paradigm using correlation, factor and variance analyses. The correlation between anxiety/bravery and locomotion indexes in different tests was not revealed. Positive correlations between grooming, urinations and defecations, rearing in three tests were revealed. These data suggest that animals reacted to various tests differently, resulting, apparently in the emergence of different anxiety levels, specific for each test. Vegetative reactions, inclination to exploration and substituting behavior were more stable characteristics of rats. Anxiety behavior in elevated plus-maze correlated to freezing response to context after fear conditioning, while high-anxiety rats had higher level of freezing to context than low-anxiety rats. The higher freezing response to sound after fear conditioning was found in rats with middle locomotor activity in open field. Conditioned fear to the context and to the sound was associated with different forms of rat anxiety during different tests. PMID:26841660

  5. [The Manifestation of the Anxiety during Fear Conditioning in Wistar Rats].

    PubMed

    Pavlova, I V; Rysakova, M P

    2015-01-01

    In order to identify the correlation between anxiety and conditioned fear, the behavior of the same male Wistar rats was compared in three anxiety tests (open field, light-dark box and elevated plus-maze) and in Pavlovian auditory fear conditioning paradigm using correlation, factor and variance analyses. The correlation between anxiety/bravery and locomotion indexes in different tests was not revealed. Positive correlations between grooming, urinations and defecations, rearing in three tests were revealed. These data suggest that animals reacted to various tests differently, resulting, apparently in the emergence of different anxiety levels, specific for each test. Vegetative reactions, inclination to exploration and substituting behavior were more stable characteristics of rats. Anxiety behavior in elevated plus-maze correlated to freezing response to context after fear conditioning, while high-anxiety rats had higher level of freezing to context than low-anxiety rats. The higher freezing response to sound after fear conditioning was found in rats with middle locomotor activity in open field. Conditioned fear to the context and to the sound was associated with different forms of rat anxiety during different tests.

  6. A mouse model of posttraumatic stress disorder that distinguishes between conditioned and sensitised fear.

    PubMed

    Siegmund, Anja; Wotjak, Carsten T

    2007-11-01

    The pathomechanisms of posttraumatic stress disorder (PTSD) are still unknown, but both fear conditioning and stress sensitisation are supposed to play a crucial role. Hence, valid animal models that model both associative and non-associative components of fear will facilitate elucidation of the biological substrates of the illness, and to develop novel and specific approaches for its prevention and therapy. Here we applied a single electric footshock to C57BL/6N (B6N) and C57BL/6JOla (B6JOla) mice and recorded the conditioned response to contextual trauma reminders (associative fear), the sensitised reaction to a neutral tone in a novel environment (non-associative fear, hyperarousal), social interaction and various emotional behaviours using Modified Holeboard, Test for Novelty-Induced Suppression of Feeding and Forced Swimming Test, after different incubation times (1, 14, 28 days). Freezing generally increased as a function of shock intensity. In B6N mice, sensitised fear was maximal 28 days after trauma and was accompanied by signs of emotional blunting and social withdrawal. B6JOla mice, in contrast, were less susceptible to develop PTSD-like symptoms. The phenotype of B6N exhibited high behavioural variance, allowing distinction between vulnerable and resilient individuals. Only in vulnerable B6N mice, chronic fluoxetine treatment - initiated after an incubation period of 28 days - ameliorated sensitised fear. This new mouse model fulfils common criteria for face and predictive validity and can be used to investigate the biological correlates of individual fear susceptibility, as well as the impact and interrelationship of associative and non-associative fear components in the development and maintenance of PTSD. PMID:17027033

  7. Generalization of Pain-Related Fear Using a Left-Right Hand Judgment Conditioning Task.

    PubMed

    Meulders, Ann; Harvie, Daniel S; Lorimer Moseley, G; Vlaeyen, Johan W S

    2015-09-01

    Recent research suggests that the mere intention to perform a painful movement can elicit pain-related fear. Based on these findings, the present study aimed to determine whether imagining a movement that is associated with pain (CS+) can start to elicit conditioned pain-related fear as well and whether pain-related fear elicited by imagining a painful movement can spread towards novel, similar but distinct imagined movements. We proposed a new experimental paradigm that integrates the left-right hand judgment task (HJT) with a differential fear conditioning procedure. During Acquisition, one hand posture (CS+) was consistently followed by a painful electrocutaneous stimulus (pain-US) and another hand posture (CS-) was not. Participants were instructed to make left-right judgments, which involve mentally rotating their own hand to match the displayed hand postures (i.e., motor imagery). During Generalization, participants were presented with a series of novel hand postures with six grades of perceptual similarity to the CS+ (generalization stimuli; GSs). Finally, during Extinction, the CS+ hand posture was no longer reinforced. The results showed that (1) a painful hand posture triggers fear and increased US-expectancy as compared to a nonpainful hand posture, (2) this pain-related fear spreads to similar but distinct hand postures following a generalization gradient, and subsequently, (3) it can be successfully reduced during extinction. These effects were apparent in the verbal ratings, but not in the startle measures. Because of the lack of effect in the startle measures, we cannot draw firm conclusions about whether the "imagined movements" (i.e., motor imagery of the hand postures) gained associative strength rather than the hand posture pictures itself. From a clinical perspective, basic research into generalization of pain-related fear triggered by covert CSs such as intentions, imagined movements and movement-related cognitions might further our

  8. A Different Recruitment of the Lateral and Basolateral Amygdala Promotes Contextual or Elemental Conditioned Association in Pavlovian Fear Conditioning

    ERIC Educational Resources Information Center

    Calandreau, Ludovic; Desmedt, Aline; Decorte, Laurence; Jaffard, Robert

    2005-01-01

    Convergent data suggest dissociated roles for the lateral (LA) and basolateral (BLA) amygdaloid nuclei in fear conditioning, depending on whether a discrete conditioned stimulus (CS)-unconditional stimulus (US) or context-US association is considered. Here, we show that pretraining inactivation of the BLA selectively impaired conditioning to…

  9. Knockdown of corticotropin-releasing factor 1 receptors in the ventral tegmental area enhances conditioned fear.

    PubMed

    Chen, Nicola A; Ganella, Despina E; Bathgate, Ross A D; Chen, Alon; Lawrence, Andrew J; Kim, Jee Hyun

    2016-09-01

    The neuropeptide corticotropin-releasing factor (CRF) coordinates the physiological and behavioural responses to stress. CRF receptors are highly expressed in the ventral tegmental area (VTA), an important region for motivated behaviour. Therefore, we examined the role of CRF receptor type 1 (CRFR1) in the VTA in conditioned fear, using a viral-mediated RNA interference approach. Following stereotaxic injection of a lentivirus that contained either shCRF-R1 or a control sequence, mice received tone-footshock pairings. Intra-VTA shCRF-R1 did not affect tone-elicited freezing during conditioning. Once conditioned fear was acquired, however, shCRF-R1 mice consistently showed stronger freezing to the tone even after extinction and reinstatement. These results implicate a novel role of VTA CRF-R1 in conditioned fear, and suggest how stress may modulate aversive learning and memory. PMID:27397862

  10. Brain c-Fos immunocytochemistry and cytochrome oxidase histochemistry after a fear conditioning task.

    PubMed

    Conejo, Nélida M; González Pardo, Héctor; López, Matías; Cantora, Raúl; Arias, Jorge L

    2007-05-01

    The involvement of the basolateral and the medial amygdala in fear conditioning was evaluated using different markers of neuronal activation. The method described here is a combination of cytochrome oxidase (CO) histochemistry and c-Fos immunocytochemistry on fresh frozen brain sections. Freezing behavior was used as an index of auditory and contextual fear conditioning. As expected, freezing scores were significantly higher in rats exposed to tone-shock pairings in a distinctive environment (conditioned; COND), as compared to rats that did not receive any shocks (UNCD). CO labeling was increased in the basolateral and medial amygdala of the COND group. Conversely, c-Fos expression in the basolateral and medial amygdala was lower in the COND group as compared to the UNCD group. Furthermore, c-Fos expression was particularly high in the medial amygdala of the UNCD group. The data provided by both techniques indicate that these amygdalar nuclei could play different roles on auditory and contextual fear conditioning. PMID:17425902

  11. Contextual fear conditioning in virtual reality is affected by 5HTTLPR and NPSR1 polymorphisms: effects on fear-potentiated startle

    PubMed Central

    Glotzbach-Schoon, Evelyn; Andreatta, Marta; Reif, Andreas; Ewald, Heike; Tröger, Christian; Baumann, Christian; Deckert, Jürgen; Mühlberger, Andreas; Pauli, Paul

    2013-01-01

    The serotonin (5-HT) and neuropeptide S (NPS) systems are discussed as important genetic modulators of fear and sustained anxiety contributing to the etiology of anxiety disorders. Sustained anxiety is a crucial characteristic of most anxiety disorders which likely develops through contextual fear conditioning. This study investigated if and how genetic alterations of the 5-HT and the NPS systems as well as their interaction modulate contextual fear conditioning; specifically, function polymorphic variants in the genes coding for the 5-HT transporter (5HTT) and the NPS receptor (NPSR1) were studied. A large group of healthy volunteers was therefore stratified for 5HTTLPR (S+ vs. LL carriers) and NPSR1 rs324981 (T+ vs. AA carriers) polymorphisms resulting in four genotype groups (S+/T+, S+/AA, LL/T+, LL/AA) of 20 participants each. All participants underwent contextual fear conditioning and extinction using a virtual reality (VR) paradigm. During acquisition, one virtual office room (anxiety context, CXT+) was paired with an unpredictable electric stimulus (unconditioned stimulus, US), whereas another virtual office room was not paired with any US (safety context, CXT−). During extinction no US was administered. Anxiety responses were quantified by fear-potentiated startle and ratings. Most importantly, we found a gene × gene interaction on fear-potentiated startle. Only carriers of both risk alleles (S+/T+) exhibited higher startle responses in CXT+ compared to CXT−. In contrast, anxiety ratings were only influenced by the NPSR1 polymorphism with AA carriers showing higher anxiety ratings in CXT+ as compared to CXT−. Our results speak in favor of a two level account of fear conditioning with diverging effects on implicit vs. explicit fear responses. Enhanced contextual fear conditioning as reflected in potentiated startle responses may be an endophenotype for anxiety disorders. PMID:23630477

  12. Cholesterol enhances classical conditioning of the rabbit heart rate response

    PubMed Central

    Schreurs, Bernard G.; Smith-Bell, Carrie A.; Darwish, Deya S.; Wang, Desheng; Burhans, Lauren B.; Gonzales-Joekes, Jimena; Deci, Stephen; Stankovic, Goran; Sparks, D. Larry

    2007-01-01

    The cholesterol-fed rabbit is a model of atherosclerosis and has been proposed as an animal model of Alzheimer's disease. Feeding rabbits cholesterol has been shown to increase the number of beta amyloid immunoreactive neurons in the cortex. Addition of copper to the drinking water of cholesterol-fed rabbits can increase this number still further and may lead to plaque-like structures. Classical conditioning of the nictitating membrane response in cholesterol-fed rabbits is retarded in the presence of these plaque-like structures but may be facilitated in their absence. In a factorial design, rabbits fed 2% cholesterol or a normal diet (0% cholesterol) for 8 weeks with or without copper added to the drinking water were given trace classical conditioning using a tone and periorbital electrodermal stimulation to study the effects of cholesterol and copper on classical conditioning of heart rate and the nictitating membrane response. Cholesterol-fed rabbits showed significant facilitation of heart rate conditioning and conditioning-specific modification of heart rate relative to normal diet controls. Consistent with previous research, cholesterol had minimal effects on classical conditioning of the nictitating membrane response when periorbital electrodermal stimulation was used as the unconditioned stimulus. Immunohistochemical analysis showed a significant increase in the number of beta amyloid positive neurons in the cortex, hippocampus and amygdala of the cholesterol-fed rabbits. Supplementation of drinking water with copper increased the number of beta amyloid positive neurons in the cortex of cholesterol-fed rabbits but did not produce plaque-like structures or have a significant effect on heart rate conditioning. The data provide additional support for our finding that, in the absence of plaques, dietary cholesterol may facilitate learning and memory. PMID:17466388

  13. In vitro classical conditioning of abducens nerve discharge in turtles.

    PubMed

    Keifer, J; Armstrong, K E; Houk, J C

    1995-07-01

    In vitro classical conditioning of abducens nerve activity was performed using an isolated turtle brainstem-cerebellum preparation by direct stimulation of the cranial nerves. Using a delayed training procedure, the in vitro preparation was presented with paired stimuli consisting of a 1 sec train stimulus applied to the auditory nerve (CS), which immediately preceded a single shock US applied to the trigeminal nerve. Conditioned and unconditioned responses were recorded in the ipsilateral abducens nerve. Acquisition exhibited a positive slope of conditioned responding in 60% of the preparations. Application of unpaired stimuli consisting of CS-alone, alternate CS and US, or backward conditioning failed to result in conditioning, or resulted in extinction of CRs. Latencies of CR onset were timed such that they occurred midway through the CS. Activity-dependent uptake of the dye sulforhodamine was used to examine the spatial distribution of neurons labeled during conditioning. These data showed label in the cerebellum and red nucleus during conditioning whereas these regions failed to label during unconditioned responses. Furthermore, the principal abducens nucleus labeled heavily during conditioning. These findings suggest the feasibility of examining classical conditioning in a vertebrate in vitro brainstem-cerebellum preparation. It is postulated that the abducens nerve CR represents a behavioral correlate of a blink-related eye movement. Multiple sites of conditioning are hypothesized, including the cerebellorubral circuitry and brainstem pathways that activate the principal abducens nucleus.

  14. Ketamine administration diminishes operant responding but does not impair conditioned fear.

    PubMed

    Groeber Travis, Caitlin M; Altman, Daniel E; Genovese, Raymond F

    2015-12-01

    While not well understood, the NMDA (N-methyl-D-aspartate) antagonist ketamine, a dissociative anesthetic, has been reported to be efficacious in depression and related psychological disorders. Conditioned fear is a normal emotional conditioning process that is known to become dysfunctional in individuals suffering from Post-Traumatic Stress Disorder (PTSD) and related stress disorders. We examined the effects of ketamine to determine the potential modulation of the acquisition and extinction of a conditioned fear using a conditioned suppression procedure. Rats were trained on a variable interval (VI), food maintained, operant conditioning task to establish a general measure of performance. Rats were exposed to inescapable shock (IES, unconditioned stimulus) paired (×20) with an audio/visual conditioned stimulus (CS) to establish conditioning. Conditioning was quantified by measuring response suppression following CS presentation during subsequent extinction trials where the CS alone was presented. Ketamine or vehicle was administered either after initial conditioning or after each of the subsequent extinction trials. For each regimen, a series of four injections were administered 60 min apart (100, 50, 50, 50 mg/kg, respectively) in order to sustain a ketamine effect for a minimum of 4 h. Ketamine produced a general decrease in responding on the VI, relative to baseline, as response rates were slower on the operant task when tested 24 h later and longer. Ketamine did not affect the acquisition of the conditioned fear when the regimen was administered shortly after the initial pairings of IES and CS. Ketamine did not alter extinction to the conditioned fear when the regimen was administered following each CS only presentation following initial conditioning. Our conclusion from these findings is that while ketamine alters behavior on an appetitively motivated operant task it does not, however, appear to directly modulate learning and memory processes associated

  15. Ketamine administration diminishes operant responding but does not impair conditioned fear.

    PubMed

    Groeber Travis, Caitlin M; Altman, Daniel E; Genovese, Raymond F

    2015-12-01

    While not well understood, the NMDA (N-methyl-D-aspartate) antagonist ketamine, a dissociative anesthetic, has been reported to be efficacious in depression and related psychological disorders. Conditioned fear is a normal emotional conditioning process that is known to become dysfunctional in individuals suffering from Post-Traumatic Stress Disorder (PTSD) and related stress disorders. We examined the effects of ketamine to determine the potential modulation of the acquisition and extinction of a conditioned fear using a conditioned suppression procedure. Rats were trained on a variable interval (VI), food maintained, operant conditioning task to establish a general measure of performance. Rats were exposed to inescapable shock (IES, unconditioned stimulus) paired (×20) with an audio/visual conditioned stimulus (CS) to establish conditioning. Conditioning was quantified by measuring response suppression following CS presentation during subsequent extinction trials where the CS alone was presented. Ketamine or vehicle was administered either after initial conditioning or after each of the subsequent extinction trials. For each regimen, a series of four injections were administered 60 min apart (100, 50, 50, 50 mg/kg, respectively) in order to sustain a ketamine effect for a minimum of 4 h. Ketamine produced a general decrease in responding on the VI, relative to baseline, as response rates were slower on the operant task when tested 24 h later and longer. Ketamine did not affect the acquisition of the conditioned fear when the regimen was administered shortly after the initial pairings of IES and CS. Ketamine did not alter extinction to the conditioned fear when the regimen was administered following each CS only presentation following initial conditioning. Our conclusion from these findings is that while ketamine alters behavior on an appetitively motivated operant task it does not, however, appear to directly modulate learning and memory processes associated

  16. A neural network approach to hippocampal function in classical conditioning.

    PubMed

    Schmajuk, N A; DiCarlo, J J

    1991-02-01

    Hippocampal participation in classical conditioning in terms of Grossberg's (1975) attentional theory is described. According to the present rendition of this theory, pairing of a conditioned stimulus (CS) with an unconditioned stimulus (US) causes both an association of the sensory representation of the CS with the US (conditioned reinforcement learning) and an association of the sensory representation of the CS with the drive representation of the US (incentive motivation learning). Sensory representations compete among themselves for a limited-capacity short-term memory (STM) that is reflected in a long-term memory storage. The STM regulation hypothesis, which proposes that the hippocampus controls incentive motivation, self-excitation, and competition among sensory representations thereby regulating the contents of a limited capacity STM, is introduced. Under the STM regulation hypothesis, nodes and connections in Grossberg's neural network are mapped onto regional hippocampal-cerebellar circuits. The resulting neural model provides (a) a framework for understanding the dynamics of information processing and storage in the hippocampus and cerebellum during classical conditioning of the rabbit's nictitating membrane, (b) principles for understanding the effect of different hippocampal manipulations on classical conditioning, and (c) numerous novel and testable predictions.

  17. Resistance to extinction of conditioned electrodermal responses: a study of the incubation fear hypothesis.

    PubMed

    Sandin, Bonifacio; Chorot, Paloma

    2002-08-01

    In the present study we examined Eysenck's incubation hypothesis of fear. Probability of skin conductance response (SCR) was analyzed for a sample of 79 undergraduate women, ranging in age from 18 to 25 years. Different groups of participants were conditioned to two levels of unconditioned stimuli (UCS) intensity and presented to three levels of unreinforced conditioned stimuli (CS) exposures (extinction phase) in a delay differential conditioning paradigm. The CSs were fear-relevant slides (snakes and spiders) and the UCSs were aversive tones. Analysis did not show a clear incubation effect; instead an increased resistance to extinction of SCR probability in association to the high-UCS and the short unreinforced CS presentation was evident. Findings support partially Eysenck's incubation theory of fear/anxiety.

  18. Heart rate response to fear conditioning and virtual reality in subthreshold PTSD.

    PubMed

    Roy, Michael J; Costanzo, Michelle E; Jovanovic, Tanja; Leaman, Suzanne; Taylor, Patricia; Norrholm, Seth D; Rizzo, Albert A

    2013-01-01

    Posttraumatic stress disorder (PTSD) is a significant health concern for U.S. military service members (SMs) returning from Afghanistan and Iraq. Early intervention to prevent chronic disability requires greater understanding of subthreshold PTSD symptoms, which are associated with impaired physical health, mental health, and risk for delayed onset PTSD. We report a comparison of physiologic responses for recently deployed SMs with high and low subthreshold PTSD symptoms, respectively, to a fear conditioning task and novel virtual reality paradigm (Virtual Iraq). The high symptom group demonstrated elevated heart rate (HR) response during fear conditioning. Virtual reality sequences evoked significant HR responses which predicted variance of the PTSD Checklist-Military Version self-report. Our results support the value of physiologic assessment during fear conditioning and combat-related virtual reality exposure as complementary tools in detecting subthreshold PTSD symptoms in Veterans. PMID:23792855

  19. Histaminergic ligands injected into the nucleus basalis magnocellularis differentially affect fear conditioning consolidation.

    PubMed

    Benetti, Fernando; Baldi, Elisabetta; Bucherelli, Corrado; Blandina, Patrizio; Passani, Maria Beatrice

    2013-04-01

    The role of the nucleus basalis magnocellularis (NBM) in fear conditioning encoding is well established. In the present report, we investigate the involvement of the NBM histaminergic system in consolidating fear memories. The NBM was injected bilaterally with ligands of histaminergic receptors immediately after contextual fear conditioning. Histaminergic compounds, either alone or in combination, were stereotaxically administered to different groups of adult male Wistar rats and memory was assessed as conditioned freezing duration 72 h after administration. This protocol prevents interference with NBM function during either acquisition or retrieval phases, hence restricting the effect of pharmacological manipulations to fear memory consolidation. The results presented here demonstrate that post-training H3 receptors (H3R) blockade with the antagonist/inverse agonist thioperamide or activation with immepip in the NBM potentiates or decreases, respectively, freezing response at retrieval. Thioperamide induced memory enhancement seems to depend on H2R, but not H1R activation, as the H2R antagonist zolantidine blocked the effect of thioperamide, whereas the H1R antagonist pyrilamine was ineffective. Furthermore, the H2R agonist ampthamine improved fear memory expression independently of the H3R agonist effect. Our results indicate that activation of post-synaptic H2R within the NBM by endogenous histamine is responsible for the potentiated expression of fear responses. The results are discussed in terms of activation of H3 auto- and heteroreceptors within the NBM and the differential effect of H3R ligands on fear memory consolidation in distinct brain regions.

  20. L-type Voltage-Gated Calcium Channels in Conditioned Fear: A Genetic and Pharmacological Analysis

    ERIC Educational Resources Information Center

    McKinney, Brandon C.; Sze, Wilson; White, Jessica A.; Murphy, Geoffrey G.

    2008-01-01

    Using pharmacological approaches, others have suggested that L-type voltage-gated calcium channels (L-VGCCs) mediate both consolidation and extinction of conditioned fear. In the absence of L-VGCC isoform-specific antagonists, we have begun to investigate the subtype-specific role of LVGCCs in consolidation and extinction of conditioned fear…

  1. Cholinergic Modulation of the Hippocampus during Encoding and Retrieval of Tone/Shock-Induced Fear Conditioning

    ERIC Educational Resources Information Center

    Rogers, Jason L.; Kesner, Raymond P.

    2004-01-01

    We investigated the role of acetylcholine (ACh) during encoding and retrieval of tone/shock-induced fear conditioning with the aim of testing Hasselmo's cholinergic modulation model of encoding and retrieval using a task sensitive to hippocampal disruption. Lesions of the hippocampus impair acquisition and retention of contextual conditioning with…

  2. Extensive Extinction in Multiple Contexts Eliminates the Renewal of Conditioned Fear in Rats

    ERIC Educational Resources Information Center

    Thomas, Brian L.; Vurbic, Drina; Novak, Cheryl

    2009-01-01

    Two studies examined whether nonreinforcement of a stimulus in multiple contexts, instead of a single context, would decrease renewal of conditioned fear in rats (as assessed by conditioned suppression of lever pressing). In Experiment 1, renewal was measured after 36 nonreinforced CS trials delivered during six extinction sessions in a single…

  3. Nonassociative Learning Processes Determine Expression and Extinction of Conditioned Fear in Mice

    ERIC Educational Resources Information Center

    Kamprath, Kornelia; Wotjak, Carsten T.

    2004-01-01

    Freezing to a tone following auditory fear conditioning is commonly considered as a measure of the strength of the tone-shock association. The decrease in freezing on repeated nonreinforced tone presentation following conditioning, in turn, is attributed to the formation of an inhibitory association between tone and shock that leads to a…

  4. Microstimulation Reveals Opposing Influences of Prelimbic and Infralimbic Cortex on the Expression of Conditioned Fear

    ERIC Educational Resources Information Center

    Vidal-Gonzalez, Ivan; Rauch, Scott L.; Quirk, Gregory J.; Vidal-Gonzalez, Benjamin

    2006-01-01

    Recent studies using lesion, infusion, and unit-recording techniques suggest that the infralimbic (IL) subregion of medial prefrontal cortex (mPFC) is necessary for the inhibition of conditioned fear following extinction. Brief microstimulation of IL paired with conditioned tones, designed to mimic neuronal tone responses, reduces the expression…

  5. Fear conditioning in mouse lines genetically selected for binge-like ethanol drinking.

    PubMed

    Crabbe, John C; Schlumbohm, Jason P; Hack, Wyatt; Barkley-Levenson, Amanda M; Metten, Pamela; Lattal, K Matthew

    2016-05-01

    The comorbidity of substance- and alcohol-use disorders (AUD) with other psychiatric conditions, especially those related to stress such as post-traumatic stress disorder (PTSD), is well-established. Binge-like intoxication is thought to be a crucial stage in the development of the chronic relapsing nature of the addictions, and self-medication through binge-like drinking is commonly seen in PTSD patients. We have selectively bred two separate High Drinking in the Dark (HDID-1 and HDID-2) mouse lines to reach high blood ethanol concentrations (BECs) after a 4-h period of access to 20% ethanol starting shortly after the onset of circadian dark. As an initial step toward the eventual goal of employing binge-prone HDID mice to study PTSD-like behavior including alcohol binge drinking, we sought first to determine their ability to acquire conditioned fear. We asked whether these mice acquired, generalized, or extinguished conditioned freezing to a greater or lesser extent than unselected control HS/Npt mice. In two experiments, we trained groups of 16 adult male mice in a standard conditioned fear protocol. Mice were tested for context-elicited freezing, and then, in a novel context, for cue-induced freezing. After extinction tests, renewal of conditioned fear was tested in the original context. Mice of all three genotypes showed typical fear responding. Context paired with shock elicited freezing behavior in a control experiment, but cue unpaired with shock did not. These studies indicate that fear learning per se does not appear to be influenced by genes causing predisposition to binge drinking, suggesting distinct neural mechanisms. However, HDID mice are shown to be a suitable model for studying the role of conditioned fear specifically in binge-like drinking. PMID:27139234

  6. Fear conditioning in mouse lines genetically selected for binge-like ethanol drinking.

    PubMed

    Crabbe, John C; Schlumbohm, Jason P; Hack, Wyatt; Barkley-Levenson, Amanda M; Metten, Pamela; Lattal, K Matthew

    2016-05-01

    The comorbidity of substance- and alcohol-use disorders (AUD) with other psychiatric conditions, especially those related to stress such as post-traumatic stress disorder (PTSD), is well-established. Binge-like intoxication is thought to be a crucial stage in the development of the chronic relapsing nature of the addictions, and self-medication through binge-like drinking is commonly seen in PTSD patients. We have selectively bred two separate High Drinking in the Dark (HDID-1 and HDID-2) mouse lines to reach high blood ethanol concentrations (BECs) after a 4-h period of access to 20% ethanol starting shortly after the onset of circadian dark. As an initial step toward the eventual goal of employing binge-prone HDID mice to study PTSD-like behavior including alcohol binge drinking, we sought first to determine their ability to acquire conditioned fear. We asked whether these mice acquired, generalized, or extinguished conditioned freezing to a greater or lesser extent than unselected control HS/Npt mice. In two experiments, we trained groups of 16 adult male mice in a standard conditioned fear protocol. Mice were tested for context-elicited freezing, and then, in a novel context, for cue-induced freezing. After extinction tests, renewal of conditioned fear was tested in the original context. Mice of all three genotypes showed typical fear responding. Context paired with shock elicited freezing behavior in a control experiment, but cue unpaired with shock did not. These studies indicate that fear learning per se does not appear to be influenced by genes causing predisposition to binge drinking, suggesting distinct neural mechanisms. However, HDID mice are shown to be a suitable model for studying the role of conditioned fear specifically in binge-like drinking.

  7. Strain and substrain differences in context- and tone-dependent fear conditioning of inbred mice.

    PubMed

    Stiedl, O; Radulovic, J; Lohmann, R; Birkenfeld, K; Palve, M; Kammermeier, J; Sananbenesi, F; Spiess, J

    1999-10-01

    The performance of C57BL/6J (6J), C57BL/6N (6N), DBA/2J (2J) and DBA/2N (2N) mice in context- and tone-dependent fear conditioning was determined 24 h after fear conditioning to evaluate and compare different behavioral measures as indices of emotional learning. Freezing, the change in activity and the size of the explored area were evaluated as behavioral parameters indicating fear. Additionally, the heart rate (HR) increase elicited by tone presentation was evaluated as an autonomic indicator of fear. During the context-dependent memory test, freezing was high only in 6J and 6N mice, whereas a drop of activity and a reduced exploratory area was measured in all strains. During the tone-dependent memory test, high freezing, low activity, reduced exploratory area and a strong HR increase were demonstrated only in 6N and 6J mice, whereas behavioral and HR changes of 2J and 2N mice were always low. In extinction tests, context- and tone-dependent freezing of 6J mice decayed significantly faster than the freezing of 6N mice, whereas in both substrains the conditioned tachycardia to tone extinguished similarly in the home cage. The data demonstrate that monitoring of additional behavioral measures besides freezing and autonomic measures is necessary to interpret differences in associative learning performance of mouse strains that could be related to a differential expression of fear.

  8. Mice selectively bred for High and Low fear behavior show differences in the number of pMAPK (p44/42 ERK) expressing neurons in lateral amygdala following Pavlovian fear conditioning.

    PubMed

    Coyner, Jennifer; McGuire, Jennifer L; Parker, Clarissa C; Ursano, Robert J; Palmer, Abraham A; Johnson, Luke R

    2014-07-01

    Individual variability in the acquisition, consolidation and extinction of conditioned fear potentially contributes to the development of fear pathology including posttraumatic stress disorder (PTSD). Pavlovian fear conditioning is a key tool for the study of fundamental aspects of fear learning. Here, we used a selected mouse line of High and Low Pavlovian conditioned fear created from an advanced intercrossed line (AIL) in order to begin to identify the cellular basis of phenotypic divergence in Pavlovian fear conditioning. We investigated whether phosphorylated MAPK (p44/42 ERK/MAPK), a protein kinase required in the amygdala for the acquisition and consolidation of Pavlovian fear memory, is differentially expressed following Pavlovian fear learning in the High and Low fear lines. We found that following Pavlovian auditory fear conditioning, High and Low line mice differ in the number of pMAPK-expressing neurons in the dorsal sub nucleus of the lateral amygdala (LAd). In contrast, this difference was not detected in the ventral medial (LAvm) or ventral lateral (LAvl) amygdala sub nuclei or in control animals. We propose that this apparent increase in plasticity at a known locus of fear memory acquisition and consolidation relates to intrinsic differences between the two fear phenotypes. These data provide important insights into the micronetwork mechanisms encoding phenotypic differences in fear. Understanding the circuit level cellular and molecular mechanisms that underlie individual variability in fear learning is critical for the development of effective treatment of fear-related illnesses such as PTSD.

  9. Delay and trace fear conditioning in a complex virtual learning environment—neural substrates of extinction

    PubMed Central

    Ewald, Heike; Glotzbach-Schoon, Evelyn; Gerdes, Antje B. M.; Andreatta, Marta; Müller, Mathias; Mühlberger, Andreas; Pauli, Paul

    2014-01-01

    Extinction is an important mechanism to inhibit initially acquired fear responses. There is growing evidence that the ventromedial prefrontal cortex (vmPFC) inhibits the amygdala and therefore plays an important role in the extinction of delay fear conditioning. To our knowledge, there is no evidence on the role of the prefrontal cortex in the extinction of trace conditioning up to now. Thus, we compared brain structures involved in the extinction of human delay and trace fear conditioning in a between-subjects-design in an fMRI study. Participants were passively guided through a virtual environment during learning and extinction of conditioned fear. Two different lights served as conditioned stimuli (CS); as unconditioned stimulus (US) a mildly painful electric stimulus was delivered. In the delay conditioning group (DCG) the US was administered with offset of one light (CS+), whereas in the trace conditioning group (TCG) the US was presented 4 s after CS+ offset. Both groups showed insular and striatal activation during early extinction, but differed in their prefrontal activation. The vmPFC was mainly activated in the DCG, whereas the TCG showed activation of the dorsolateral prefrontal cortex (dlPFC) during extinction. These results point to different extinction processes in delay and trace conditioning. VmPFC activation during extinction of delay conditioning might reflect the inhibition of the fear response. In contrast, dlPFC activation during extinction of trace conditioning may reflect modulation of working memory processes which are involved in bridging the trace interval and hold information in short term memory. PMID:24904363

  10. The Role of Muscarinic and Nicotinic Cholinergic Neurotransmission in Aversive Conditioning: Comparing Pavlovian Fear Conditioning and Inhibitory Avoidance

    ERIC Educational Resources Information Center

    Tinsley, Matthew R.; Quinn, Jennifer J.; Fanselow, Michael S.

    2004-01-01

    Aversive conditioning is an ideal model for studying cholinergic effects on the processes of learning and memory for several reasons. First, deficits produced by selective lesions of the anatomical structures shown to be critical for Pavlovian fear conditioning and inhibitory avoidance (such as the amygdala and hippocampus) resemble those deficits…

  11. Social buffering enhances extinction of conditioned fear responses in male rats.

    PubMed

    Mikami, Kaori; Kiyokawa, Yasushi; Takeuchi, Yukari; Mori, Yuji

    2016-09-01

    In social species, the phenomenon in which the presence of conspecific animals mitigates stress responses is called social buffering. We previously reported that social buffering in male rats ameliorated behavioral fear responses, as well as hypothalamic-pituitary-adrenal axis activation, elicited by an auditory conditioned stimulus (CS). However, after social buffering, it is not clear whether rats exhibit fear responses when they are re-exposed to the same CS in the absence of another rat. In the present study, we addressed this issue using an experimental model of extinction. High stress levels during extinction training impaired extinction, suggesting that extinction is enhanced when stress levels during extinction training are low. Therefore, we hypothesized that rats that had received social buffering during extinction training would not show fear responses to a CS, even in the absence of another rat, because social buffering had enhanced the extinction of conditioned fear responses. To test this, we subjected male fear-conditioned rats to extinction training either alone or with a non-conditioned male rat. The subjects were then individually re-exposed to the CS in a recall test. When the subjects individually underwent extinction training, no responses were suppressed in the recall test. Conversely, when the subjects received social buffering during extinction training, freezing and Fos expression in the paraventricular nucleus of the hypothalamus and lateral amygdala were suppressed. Additionally, the effects of social buffering were absent when the recall test was conducted in a different context from the extinction training. The present results suggest that social buffering enhances extinction of conditioned fear responses.

  12. Dissociable roles for hippocampal and amygdalar volume in human fear conditioning.

    PubMed

    Cacciaglia, Raffaele; Pohlack, Sebastian T; Flor, Herta; Nees, Frauke

    2015-09-01

    Fear conditioning is a basic learning process which involves the association of a formerly neutral conditioned stimulus (CS) with a biologically relevant aversive unconditioned stimulus (US). Previous studies conducted in brain-lesioned patients have shown that while the acquisition of autonomic fear responses requires an intact amygdala, a spared hippocampus is necessary for the development of the CS-US contingency awareness. Although these data have been supported by studies using functional neuroimaging techniques in healthy people, attempts to extend these findings to the morphological aspects of amygdala and hippocampus are missing. Here we tested the hypothesis that amygdalar and hippocampal volumes play dissociable roles in determining autonomic responses and contingency awareness during fear conditioning. Fifty-two healthy individuals (mean age 21.83) underwent high-resolution magnetic resonance imaging. We used a differential delay fear conditioning paradigm while assessing skin conductance responses (SCRs), subjective ratings of CS-US contingency, as well as emotional valence and perceived arousal. Left amygdalar volume significantly predicted the magnitude of differential SCRs during fear acquisition, but had no impact on contingency learning. Conversely, bilateral hippocampal volumes were significantly related to contingency ratings, but not to SCRs. Moreover, left amygdalar volume predicted SCRs to the reinforced CS alone, but not those elicited by the US. Our findings bridge the gap between previous lesion and functional imaging studies, by showing that amygdalar and hippocampal volumes differentially modulate the acquisition of conditioned fear. Further, our results reveal that the morphology of these limbic structures moderate learning and memory already in healthy persons.

  13. Sex-selective effects of neonatal isolation on fear conditioning and foot shock sensitivity.

    PubMed

    Kosten, Therese A; Miserendino, Mindy J D; Bombace, Joan C; Lee, Hongjoo J; Kim, Jeansok J

    2005-02-28

    Our previous work demonstrates enduring effects of the early life stress of neonatal isolation (ISO). ISO facilitates appetitive response learning in adult female, but not male rats, and enhances corticosterone levels and stress responsivity in infant and juvenile rats of both sexes. Corticosterone acts at brain areas such as hippocampus that are rich in glucocorticoid receptors, differentiate postnatally, are sexually dimorphic, and involved in learning. Thus, ISO is hypothesized to alter aversive learning in adult rats in a sex-specific manner. This study tests this hypothesis using context and cue fear conditioning. Pups were isolated for 1h a day on postnatal (PN) days 2-9 or were non-handled and were then tested in adulthood (PN70-90). In Experiment 1, context- and cue-elicited freezing and ultrasonic vocalizations (USVs; 22 kHz range) were measured. Experiments 2-4, respectively, examined three unconditioned foot shock responses (flinch, jump, vocalization), unconditioned fear (time in center of an open, novel arena), and appetitive (stroking-induced; 50 kHz range) USVs. ISO had a sex-selective effect on context-induced USVs that may reflect changes in foot shock sensitivity. ISO increases foot shock sensitivity and tends to enhance context-induced fear in female rats, whereas ISO tends to impair context-induced fear in male rats. Overall, male rats show greater conditioned fear, and female rats show greater unconditioned fear as well as enhanced responses to the aversive and appetitive stimuli. The sex-specific effect of ISO on context fear may reflect neuronal reorganization in stress responsive areas and/or sex differences in some unconditioned responses.

  14. Classical olfactory conditioning in the cockroach Periplaneta americana.

    PubMed

    Watanabe, Hidehiro; Kobayashi, Yuko; Sakura, Midori; Matsumoto, Yukihisa; Mizunami, Makoto

    2003-12-01

    We established a classical conditioning procedure for the cockroach, Periplaneta americana, by which odors were associated with reward or punishment. Cockroaches underwent differential conditioning trials in which peppermint odor was associated with sucrose solution and vanilla odor was associated with saline solution. Odor preference of cockroaches was tested by allowing them to choose between peppermint and vanilla sources. Cockroaches that had undergone one set of differential conditioning trials exhibited a significantly greater preference for peppermint odor than did untrained cockroaches. Memory formed by three sets of differential conditioning trials, with an inter-trial interval of 5 min, was retained at least 4 days after conditioning. This conditioning procedure was effective even for cockroaches that had been harnessed in plastic tubes. This study shows, for the first time in hemimetaborous insects, that both freely moving and harnessed insects are capable of forming olfactory memory by classical conditioning procedure. This procedure may be useful for future electrophysiological and pharmacological studies aimed at elucidation of neural mechanisms underlying olfactory learning and memory.

  15. Pavlovian fear conditioning activates a common pattern of neurons in the lateral amygdala of individual brains.

    PubMed

    Bergstrom, Hadley C; McDonald, Craig G; Johnson, Luke R

    2011-01-12

    Understanding the physical encoding of a memory (the engram) is a fundamental question in neuroscience. Although it has been established that the lateral amygdala is a key site for encoding associative fear memory, it is currently unclear whether the spatial distribution of neurons encoding a given memory is random or stable. Here we used spatial principal components analysis to quantify the topography of activated neurons, in a select region of the lateral amygdala, from rat brains encoding a Pavlovian conditioned fear memory. Our results demonstrate a stable, spatially patterned organization of amygdala neurons are activated during the formation of a Pavlovian conditioned fear memory. We suggest that this stable neuronal assembly constitutes a spatial dimension of the engram.

  16. The effect of counterconditioning on evaluative responses and harm expectancy in a fear conditioning paradigm.

    PubMed

    Raes, An K; De Raedt, Rudi

    2012-12-01

    In fear conditioning, extinction targets harm expectancy as well as the fear response, but it often fails to eradicate the negative affective value that is associated with the conditioned stimulus. In the present study, we examined whether counterconditioning can serve to reduce evaluative responses within fear conditioning. The sample consisted of 70 nonselected students, 12 of whom were men. All participants received acquisition with human face stimuli as the conditioned stimuli and an unpleasant white noise as the unconditioned stimulus. After acquisition, one third of the sample was allocated to an extinction procedure. The other participants received counterconditioning with either a neutral stimulus (neutral tone) or a positive stimulus (baby laugh). Results showed that counterconditioning (with both neutral and positive stimuli), in contrast to extinction, successfully reduced evaluative responses. This effect was found on an indirect measure (affective priming task), but not on self-report. Counterconditioning with a positive stimulus also tended to enhance the reduction of conditioned skin conductance reactivity. The present data suggest that counterconditioning procedures might be a promising approach in diminishing evaluative learning and even expectancy learning in the context of fear conditioning.

  17. Increasing implicit self-esteem through classical conditioning.

    PubMed

    Baccus, Jodene R; Baldwin, Mark W; Packer, Dominic J

    2004-07-01

    Implicit self-esteem is the automatic, nonconscious aspect of self-esteem. This study demonstrated that implicit self-esteem can be increased using a computer game that repeatedly pairs self-relevant information with smiling faces. These findings, which are consistent with principles of classical conditioning, establish the associative and interpersonal nature of implicit self-esteem and demonstrate the potential benefit of applying basic learning principles in this domain. PMID:15200636

  18. Contextual Change After Fear Acquisition Affects Conditioned Responding and the Time Course of Extinction Learning—Implications for Renewal Research

    PubMed Central

    Sjouwerman, Rachel; Niehaus, Johanna; Lonsdorf, Tina B.

    2015-01-01

    Context plays a central role in retrieving (fear) memories. Accordingly, context manipulations are inherent to most return of fear (ROF) paradigms (in particular renewal), involving contextual changes after fear extinction. Context changes are, however, also often embedded during earlier stages of ROF experiments such as context changes between fear acquisition and extinction (e.g., in ABC and ABA renewal). Previous studies using these paradigms have however focused exclusively on the context switch after extinction (i.e., renewal). Thus, the possibility of a general effect of context switch on conditioned responding that may not be conditional to preceding extinction learning remains unstudied. Hence, the current study investigated the impact of a context switch between fear acquisition and extinction on immediate conditioned responding and on the time-course of extinction learning by using a multimodal approach. A group that underwent contextual change after fear conditioning (AB; n = 36) was compared with a group without a contextual change from acquisition to extinction (AA; n = 149), while measuring physiological (skin conductance and fear potentiated startle) measures and subjective fear ratings. Contextual change between fear acquisition and extinction had a pronounced effect on both immediate conditioned responding and on the time course of extinction learning in skin conductance responses and subjective fear ratings. This may have important implications for the mechanisms underlying and the interpretation of the renewal effect (i.e., contextual switch after extinction). Consequently, future studies should incorporate designs and statistical tests that disentangle general effects of contextual change from genuine ROF effects. PMID:26696855

  19. Human fear conditioning and extinction: Timing is everything . . . or is it?

    PubMed Central

    Prenoveau, Jason M.; Craske, Michelle G.; Liao, Betty; Ornitz, Edward M.

    2012-01-01

    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 4 minute CS durations during Day 2 extinction. Extinction re-test was examined on Day 3 using the original acquisition CS duration (2 minutes). 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. PMID:22349998

  20. Fear conditioning of SCR but not the startle reflex requires conscious discrimination of threat and safety.

    PubMed

    Sevenster, Dieuwke; Beckers, Tom; Kindt, Merel

    2014-01-01

    There is conflicting evidence as to whether awareness is required for conditioning of the skin conductance response (SCR). Recently, Schultz and Helmstetter (2010) reported SCR conditioning in contingency unaware participants by using difficult to discriminate stimuli. These findings are in stark contrast with other observations in human fear conditioning research, showing that SCR predominantly reflects contingency learning. Therefore, we repeated the study by Schultz and Helmstetter and additionally measured conditioning of the startle response, which seems to be less sensitive to declarative knowledge than SCR. While we solely observed SCR conditioning in participants who reported awareness of the contingencies (n = 16) and not in the unaware participants (n = 18), we observed startle conditioning irrespective of awareness. We conclude that SCR but not startle conditioning depends on conscious discriminative fear learning.

  1. The conditioning and extinction of fear in youths: What’s sex got to do with it?

    PubMed Central

    Chauret, Mélissa; La Buissonnière-Ariza, Valérie; Tremblay, Vickie Lamoureux; Suffren, Sabrina; Servonnet, Alice; Pine, Daniel S.; Maheu, Françoise S.

    2015-01-01

    Adult work shows differences in emotional processing influenced by sexes of both the viewer and expresser of facial expressions. We investigated this in 120 healthy youths (57 boys; 10–17 years old) randomly assigned to fear conditioning and extinction tasks using either neutral male or female faces as the conditioned threat and safety cues, and a fearful face paired with a shrieking scream as the unconditioned stimulus. Fear ratings and skin conductance responses (SCRs) were assessed. Male faces triggered increased fear ratings in all participants during conditioning and extinction. Greater differential SCRs were observed in boys viewing male faces and in girls viewing female faces during conditioning. During extinction, differential SCR findings remained significant in boys viewing male faces. Our findings demonstrate how sex of participant and sex of target interact to shape fear responses in youths, and how the type of measure may lead to distinct profiles of fear responses. PMID:24929048

  2. Classical Olfactory Conditioning in the Oriental Fruit Fly, Bactrocera dorsalis

    PubMed Central

    Zeng, Xin Nian

    2015-01-01

    The oriental fruit fly, Bactrocera dorsalis, is a serious pest of fruits and vegetables. Methyl eugenol (ME), a male attractant, is used to against this fly by mass trapping. Control effect may be influenced by learning, which could modify the olfactory response of the fly to this attractant. To collect the behavioral evidence, studies on the capability of this fly for olfactory learning are necessary. We investigated olfactory learning in male flies with a classical olfactory conditioning procedure using restrained individuals under laboratory conditions. The acquisition of the proboscis extension reflex was used as the criterion for conditioning. A high conditioned response level was found in oriental fruit flies when an odor was presented in paired association with a sucrose reward but not when the odor and sucrose were presented unpaired. We also found that the conditioning performance was influenced by the odor concentration, intertrial interval, and starvation time. A slight sensitization elicited by imbibing sucrose was observed. These results indicate that oriental fruit flies have a high capacity to form an olfactory memory as a result of classical conditioning. PMID:25837420

  3. Pair exposure with conspecific during fear conditioning induces the link between freezing and passive avoidance behaviors in rats.

    PubMed

    Lee, Hyunchan; Noh, Jihyun

    2016-07-01

    Social factor plays an important role in dealing with posttraumatic stress disorder related to excessive physiological fear response and insufficient fear memory extinction of the brain. However, although social circumstances occurred not only during contextual retrieval but also during fear conditioning, most previous studies focused on the advantageous aspects of social buffering in fear retrieval period. To demonstrate the association between fear responses and fear memory from social stimuli during fear conditioning, pair exposed rats with conspecific as social buffering were subjected to a fear conditioning of passive avoidance test to evaluate memory function and freezing behavior. Whereas single exposed rats showed the significant increase of freezing behaviors and passive avoidance behaviors compared to control rats, pair exposed rats showed significant alleviation of the freezing behaviors and passive avoidance behaviors compared to single exposed rats. Furthermore, we determined a significant correlation between freezing and passive avoidance behavioral alteration in pair exposed rats. Taken together, we suggest that pair exposure with conspecific during fear conditioning helps to cope with both freezing response and fear memory systems and their reciprocal interaction has a crucial potential as a resource for the relief of unreasonable stress responses in posttraumatic stress disorder.

  4. Prefrontal oscillations during recall of conditioned and extinguished fear in humans.

    PubMed

    Mueller, Erik M; Panitz, Christian; Hermann, Christiane; Pizzagalli, Diego A

    2014-05-21

    Human neuroimaging studies indicate that the anterior midcingulate cortex (AMC) and the ventromedial prefrontal cortex (vmPFC) play important roles in the expression and extinction of fear, respectively. Electrophysiological rodent studies further indicate that oscillatory neuronal activity in homolog regions (i.e., prelimbic and infralimbic cortices) changes during fear expression and fear extinction recall. Whether similar processes occur in humans remains largely unexplored. By assessing scalp surface EEG in conjunction with LORETA source estimation of CS-related theta and gamma activity, we tested whether a priori defined ROIs in the human AMC and vmPFC similarly modulate their oscillatory activity during fear expression and extinction recall, respectively. To this end, 42 healthy individuals underwent a differential conditioning/differential extinction protocol with a Recall Test on the next day. In the Recall Test, nonextinguished versus extinguished stimuli evoked an increased differential (CS(+) vs CS(-)) response with regard to skin conductance and AMC-localized theta power. Conversely, extinguished versus nonextinguished stimuli evoked an increased differential response with regard to vmPFC-localized gamma power. Finally, individuals who failed to show a suppressed skin conductance response to the extinguished versus nonextinguished CS(+) also failed to show the otherwise observed alterations in vmPFC gamma power to extinguished CS(+). These results indicate that fear expression is associated with AMC theta activity, whereas successful fear extinction recall relates to changes in vmPFC gamma activity. The present work thereby bridges findings from prior rodent electrophysiological research and human neuroimaging studies and indicates that EEG is a valuable tool for future fear extinction research.

  5. The Fragrant Power of Collective Fear

    PubMed Central

    Harb, Roa; Taulor, Jane R.

    2015-01-01

    Fear is a well-characterized biological response to threatening or stressful situations in humans and other social animals. Importantly, fearful stimuli in the natural environment are likely to be encountered concurrently by a group of animals. The modulation of fear acquisition and fear memory by a group as opposed to an individual experience, however, remains largely unknown. Here, we demonstrate a robust reduction in fear memory to an aversive event undertaken in a group despite similar fear learning between individually- and group-conditioned rats. This reduction persists outside the group confines, appears to be a direct outcome of group cognizance and is counteracted by loss of olfactory signaling among the group members. These results show that a group experience of fear can be protective and suggest that distinct neural pathways from those classically studied in individuals modulate collective fear memories. PMID:25945800

  6. The fragrant power of collective fear.

    PubMed

    Harb, Roa; Taylor, Jane R; Taulor, Jane R

    2015-01-01

    Fear is a well-characterized biological response to threatening or stressful situations in humans and other social animals. Importantly, fearful stimuli in the natural environment are likely to be encountered concurrently by a group of animals. The modulation of fear acquisition and fear memory by a group as opposed to an individual experience, however, remains largely unknown. Here, we demonstrate a robust reduction in fear memory to an aversive event undertaken in a group despite similar fear learning between individually- and group-conditioned rats. This reduction persists outside the group confines, appears to be a direct outcome of group cognizance and is counteracted by loss of olfactory signaling among the group members. These results show that a group experience of fear can be protective and suggest that distinct neural pathways from those classically studied in individuals modulate collective fear memories. PMID:25945800

  7. Effects of Post-Training Hippocampal Injections of Midazolam on Fear Conditioning

    ERIC Educational Resources Information Center

    Gafford, Georgette M.; Parsons, Ryan G.; Helmstetter, Fred J.

    2005-01-01

    Benzodiazepines have been useful tools for investigating mechanisms underlying learning and memory. The present set of experiments investigates the role of hippocampal GABA[subscript A]/benzodiazepine receptors in memory consolidation using Pavlovian fear conditioning. Rats were prepared with cannulae aimed at the dorsal hippocampus and trained…

  8. Neonatal Odor-Shock Conditioning Alters the Neural Network Involved in Odor Fear Learning at Adulthood

    ERIC Educational Resources Information Center

    Sevelinges, Yannick; Sullivan, Regina M.; Messaoudi, Belkacem; Mouly, Anne-Marie

    2008-01-01

    Adult learning and memory functions are strongly dependent on neonatal experiences. We recently showed that neonatal odor-shock learning attenuates later life odor fear conditioning and amygdala activity. In the present work we investigated whether changes observed in adults can also be observed in other structures normally involved, namely…

  9. Blockade of Dopamine Activity in the Nucleus Accumbens Impairs Learning Extinction of Conditioned Fear

    ERIC Educational Resources Information Center

    Holtzman-Assif, Orit; Laurent, Vincent; Westbrook, R. Frederick

    2010-01-01

    Three experiments used rats to investigate the role of dopamine activity in learning to inhibit conditioned fear responses (freezing) in extinction. In Experiment 1, rats systemically injected with the D2 dopamine antagonist, haloperidol, froze more across multiple extinction sessions and on a drug-free retention test than control rats. In…

  10. Involvement of the Lateral Septal Area in the Expression of Fear Conditioning to Context

    ERIC Educational Resources Information Center

    Reis, Daniel G.; Scopinho, America A.; Guimaraes, Francisco S.; Correa, Fernando M. A.; Resstel, Leonardo B. M.

    2010-01-01

    Considering the evidence that the lateral septal area (LSA) modulates defensive responses, the aim of the present study is to verify if this structure is also involved in contextual fear conditioning responses. Neurotransmission in the LSA was reversibly inhibited by bilateral microinjections of cobalt chloride (CoCl[subscript 2], 1 mM) 10 min…

  11. The Histone Deacetylase Inhibitor Valproic Acid Enhances Acquisition, Extinction, and Reconsolidation of Conditioned Fear

    ERIC Educational Resources Information Center

    Bredy, Timothy W.; Barad, Mark

    2008-01-01

    Histone modifications contribute to the epigenetic regulation of gene expression, a process now recognized to be important for the consolidation of long-term memory. Valproic acid (VPA), used for many years as an anticonvulsant and a mood stabilizer, has effects on learning and memory and enhances the extinction of conditioned fear through its…

  12. DHPG Activation of Group 1 mGluRs in BLA Enhances Fear Conditioning

    ERIC Educational Resources Information Center

    Rudy, Jerry W.; Matus-Amat, Patricia

    2009-01-01

    Group 1 metabotropic glutamate receptors are known to play an important role in both synaptic plasticity and memory. We show that activating these receptors prior to fear conditioning by infusing the group 1 mGluR agonist, (R.S.)-3,5-dihydroxyphenylglycine (DHPG), into the basolateral region of the amygdala (BLA) of adult Sprague-Dawley rats…

  13. A Bout of Voluntary Running Enhances Context Conditioned Fear, Its Extinction, and Its Reconsolidation

    ERIC Educational Resources Information Center

    Siette, Joyce; Reichelt, Amy C.; Westbrook, R. Frederick

    2014-01-01

    Three experiments used rats to examine the effect of a single bout of voluntary activity (wheel running) on the acquisition, extinction, and reconsolidation of context conditioned fear. In Experiment 1, rats provided with access to a wheel for 3 h immediately before or after a shocked exposure to a context froze more when tested in that context…

  14. Dorsal hippocampus infusions of CNQX into the dentate gyrus disrupt expression of trace fear conditioning.

    PubMed

    Pierson, Jamie L; Pullins, Shane E; Quinn, Jennifer J

    2015-07-01

    The hippocampus is essential for the consolidation of some explicit long-term memories, including trace conditioning. Lesions and pharmacological manipulations of the dorsal hippocampus (DH) have provided strong evidence for its involvement in the acquisition and expression of trace fear memories. However, no studies have specifically targeted DH subregions [CA1 and dentate gyrus (DG)] to determine their involvement in trace fear conditioning. In the present study, rats received bilateral cannulation targeting either the DG or CA1 of the DH. Following surgery, animals were trace fear conditioned. Forty-eight hours following training, rats received bilateral infusions of the AMPA/kainate glutamate receptor antagonist, CNQX, or vehicle. Following the infusion, rats were placed in a novel context for the tone test. Rats that received CNQX into the DG froze significantly less during the tone and trace interval as compared to controls. Rats that received CNQX into the DH CA1 showed no difference in freezing during the tone or trace interval as compared to controls. These data support a role for the DG in the expression of trace tone fear conditioning.

  15. A Model of Amygdala-Hippocampal-Prefrontal Interaction in Fear Conditioning and Extinction in Animals

    ERIC Educational Resources Information Center

    Moustafa, Ahmed A.; Gilbertson, Mark W.; Orr, Scott P.; Herzallah, Mohammad M.; Servatius, Richard J.; Myers, Catherine E.

    2013-01-01

    Empirical research has shown that the amygdala, hippocampus, and ventromedial prefrontal cortex (vmPFC) are involved in fear conditioning. However, the functional contribution of each brain area and the nature of their interactions are not clearly understood. Here, we extend existing neural network models of the functional roles of the hippocampus…

  16. Neural Correlates of Appetitive-Aversive Interactions in Pavlovian Fear Conditioning

    ERIC Educational Resources Information Center

    Nasser, Helen M.; McNally, Gavan P.

    2013-01-01

    We used Pavlovian counterconditioning in rats to identify the neural mechanisms for appetitive-aversive motivational interactions. In Stage I, rats were trained on conditioned stimulus (CS)-food (unconditioned stimulus [US]) pairings. In Stage II, this appetitive CS was transformed into a fear CS via pairings with footshock. The development of…

  17. Selectivity of conditioned fear of touch is modulated by somatosensory precision.

    PubMed

    Harvie, Daniel S; Meulders, Ann; Reid, Emily; Camfferman, Danny; Brinkworth, Russell S A; Moseley, G Lorimer

    2016-06-01

    Learning to initiate defenses in response to specific signals of danger is adaptive. Some chronic pain conditions, however, are characterized by widespread anxiety, avoidance, and pain consistent with a loss of defensive response specificity. Response specificity depends on ability to discriminate between safe and threatening stimuli; therefore, specificity might depend on sensory precision. This would help explain the high prevalence of chronic pain in body areas of low tactile acuity, such as the lower back, and clarify why improving sensory precision may reduce chronic pain. We compared the acquisition and generalization of fear of pain-associated vibrotactile stimuli delivered to either the hand (high tactile acuity) or the back (low tactile acuity). During acquisition, tactile stimulation at one location (CS+) predicted the noxious electrocutaneous stimulation (US), while tactile stimulation at another location (CS-) did not. Responses to three stimuli with decreasing spatial proximity to the CS+ (generalizing stimuli; GS1-3) were tested. Differential learning and generalization were compared between groups. The main outcome of fear-potentiated startle responses showed differential learning only in the hand group. Self-reported fear and expectancy confirmed differential learning and limited generalization in the hand group, and suggested undifferentiated fear and expectancy in the back group. Differences in generalization could not be inferred from the startle data. Specificity of fear responses appears to be affected by somatosensory precision. This has implications for our understanding of the role of sensory imprecision in the development of chronic pain. PMID:26950514

  18. Deep brain stimulation of the ventral striatum enhances extinction of conditioned fear.

    PubMed

    Rodriguez-Romaguera, Jose; Do Monte, Fabricio H M; Quirk, Gregory J

    2012-05-29

    Deep brain stimulation (DBS) of the ventral capsule/ventral striatum (VC/VS) reduces symptoms of intractable obsessive-compulsive disorder (OCD), but the mechanism of action is unknown. OCD is characterized by avoidance behaviors that fail to extinguish, and DBS could act, in part, by facilitating extinction of fear. We investigated this possibility by using auditory fear conditioning in rats, for which the circuits of fear extinction are well characterized. We found that DBS of the VS (the VC/VS homolog in rats) during extinction training reduced fear expression and strengthened extinction memory. Facilitation of extinction was observed for a specific zone of dorsomedial VS, just above the anterior commissure; stimulation of more ventrolateral sites in VS impaired extinction. DBS effects could not be obtained with pharmacological inactivation of either dorsomedial VS or ventrolateral VS, suggesting an extrastriatal mechanism. Accordingly, DBS of dorsomedial VS (but not ventrolateral VS) increased expression of a plasticity marker in the prelimbic and infralimbic prefrontal cortices, the orbitofrontal cortex, the amygdala central nucleus (lateral division), and intercalated cells, areas known to learn and express extinction. Facilitation of fear extinction suggests that, in accord with clinical observations, DBS could augment the effectiveness of cognitive behavioral therapies for OCD. PMID:22586125

  19. Impaired conditioned fear response and startle reactivity in epinephrine deficient mice

    PubMed Central

    Toth, Mate; Ziegler, Michael; Sun, Ping; Gresack, Jodi; Risbrough, Victoria

    2013-01-01

    Norepinephrine and epinephrine signaling is thought to facilitate cognitive processes related to emotional events and heightened arousal, however, the specific role of epinephrine in these processes is less known. To investigate the selective impact of epinephrine on arousal and fear-related memory retrieval, mice unable to synthesize epinephrine (phenylethanolamine N-methyltransferase knockout, PNMT-KO) were tested in context and cued fear conditioning. To assess the role of epinephrine in other cognitive and arousal-based behaviors these mice were also tested for acoustic startle, prepulse inhibition, novel object recognition and open field activity. Our results show that compared to wild-type (WT) mice, PNMT-KO mice displayed reduced context fear but normal cued fear. Mice exhibited normal memory performance in the short-term version of the novel object recognition task suggesting PNMT mice exhibit more selective memory effects on highly emotional and/or long term memories. Similarly, open field activity was unaffected by epinephrine deficiency, suggesting differences in freezing are not related to changes in overall anxiety or exploratory drive. Startle reactivity to acoustic pulses was reduced in PNMT-KO mice while prepulse inhibition was increased. These findings provide further evidence for a selective role of epinephrine in contextual fear learning, and support its potential role in acoustic startle. PMID:23268986

  20. Reinstatement of an Extinguished Fear Conditioned Response in Infant Rats

    ERIC Educational Resources Information Center

    Revillo, Damian A.; Trebucq, Gastón; Paglini, Maria G.; Arias, Carlos

    2016-01-01

    Although it is currently accepted that the extinction effect reflects new context-dependent learning, this is not so clear during infancy, because some studies did not find recovery of the extinguished conditioned response (CR) in rodents during this ontogenetic stage. However, recent studies have shown the return of an extinguished CR in infant…

  1. Protocol for Studying Extinction of Conditioned Fear in Naturally Cycling Female Rats

    PubMed Central

    Maeng, Lisa Y.; Cover, Kara K.; Landau, Aaron J.; Milad, Mohammed R.; Lebron-Milad, Kelimer

    2015-01-01

    Extinction of conditioned fear has been extensively studied in male rodents. Recently, there have been an increasing number of studies indicating that neural mechanisms for certain behavioral tasks and response behaviors are different in females and males. Using females in research studies can represent a challenge because of the variation of gonadal hormones during their estrous cycle. This protocol describes well-established procedures that are useful in investigating the role of estrogen in fear extinction memory consolidation in female rats. Phase of the estrous cycle and exogenous estrogen administration prior to extinction training can influence extinction recall 24 hr later. The vaginal swabbing technique for estrous phase identification described here aids the examination and manipulation of naturally cycling gonadal hormones. The use of this basic rodent model may further delineate the mechanisms by which estrogen can modulate fear extinction memory in females. PMID:25741747

  2. Learning and memory in conditioned fear extinction: effects of D-cycloserine.

    PubMed

    Vervliet, Bram

    2008-03-01

    This review addresses the effects of the cognitive enhancer D-cycloserine (DCS) on the memory processes that occur in conditioned fear extinction, which is the experimental model for exposure techniques to reduce clinical anxiety. All reported rat studies show an enhanced fear extinction effect when DCS is administered acutely before or shortly after extinction training. DCS also promotes the generalization of this fear extinction effect. In addition, DCS reduces some forms of relapse (reduced reinstatement, reduced spontaneous recovery), but not others (contextual renewal, rapid reacquisition). It is argued that this pattern of results is best explained by assuming that DCS promotes extinction learning to the background context, resulting in enhanced contextual inhibition. Four human studies have produced mixed results, but some methodological issues complicate the reported failures. It is concluded that DCS is a promising tool as an adjunct to extinction techniques in exposure treatment, but that more pre-clinical and clinical research is needed to fully characterize its behavioral consequences.

  3. Role of L-type Ca2+ channel isoforms in the extinction of conditioned fear

    PubMed Central

    Busquet, Perrine; Hetzenauer, Alfred; Sinnegger-Brauns, Martina J.; Striessnig, Jörg; Singewald, Nicolas

    2008-01-01

    Dihydropyridine (DHP) L-type Ca2+ channel (LTCC) antagonists, such as nifedipine, have been reported to impair the extinction of conditioned fear without interfering with its acquisition. Identification of the LTCC isoforms mediating this DHP effect is an essential basis to reveal their role as potential drug targets for the treatment of specific anxiety disorders. CaV1.2 and CaV1.3 are the predominant LTCCs in the mammalian brain. However, since no isoform-selective DHP blockers are available, their individual contribution to fear memory extinction is unknown. We used a novel mouse model expressing DHP-insensitive CaV1.2 LTCCs (CaV1.2DHP−/− mice) to address this question. In line with previous studies, wild-type (WT) mice treated with systemic nifedipine displayed markedly impaired fear extinction. This DHP effect was completely abolished in CaV1.2DHP−/− mice, indicating that it is mediated by CaV1.2, but not by CaV1.3 LTCCs. Supporting this conclusion, CaV1.3-deficient mice (CaV1.3−/−) showed extinction identical to the respective WT mice. The inhibition of fear extinction was not observed after intracerebroventricular (i.c.v.) application of different doses of nifedipine, suggesting that this effect is secondary to inhibition of peripheral CaV1.2 channels. The LTCC activator BayK, which lacks neurotoxic effects in CaV1.2DHP−/− mice, did not influence the extinction time course. In summary, we demonstrate that LTCC signaling through the CaV1.2 isoform of LTCCs interferes with fear memory extinction, presumably via a peripherally mediated mechanism. Activation of other LTCC isoforms (predominantly CaV1.3) is not sufficient to accelerate extinction of conditioned fear in mice. PMID:18441296

  4. Rapid learning dynamics in individual honeybees during classical conditioning

    PubMed Central

    Pamir, Evren; Szyszka, Paul; Scheiner, Ricarda; Nawrot, Martin P.

    2014-01-01

    Associative learning in insects has been studied extensively by a multitude of classical conditioning protocols. However, so far little emphasis has been put on the dynamics of learning in individuals. The honeybee is a well-established animal model for learning and memory. We here studied associative learning as expressed in individual behavior based on a large collection of data on olfactory classical conditioning (25 datasets, 3298 animals). We show that the group-averaged learning curve and memory retention score confound three attributes of individual learning: the ability or inability to learn a given task, the generally fast acquisition of a conditioned response (CR) in learners, and the high stability of the CR during consecutive training and memory retention trials. We reassessed the prevailing view that more training results in better memory performance and found that 24 h memory retention can be indistinguishable after single-trial and multiple-trial conditioning in individuals. We explain how inter-individual differences in learning can be accommodated within the Rescorla–Wagner theory of associative learning. In both data-analysis and modeling we demonstrate how the conflict between population-level and single-animal perspectives on learning and memory can be disentangled. PMID:25309366

  5. Epigenetic modulation of Homer1a transcription regulation in amygdala and hippocampus with pavlovian fear conditioning.

    PubMed

    Mahan, Amy L; Mou, Liping; Shah, Nirali; Hu, Jia-Hua; Worley, Paul F; Ressler, Kerry J

    2012-03-28

    The consolidation of conditioned fear involves upregulation of genes necessary for long-term memory formation. An important question remains as to whether this results in part from epigenetic regulation and chromatin modulation. We examined whether Homer1a, which is required for memory formation, is necessary for Pavlovian cued fear conditioning, whether it is downstream of BDNF-TrkB activation, and whether this pathway utilizes histone modifications for activity-dependent transcriptional regulation. We initially found that Homer1a knock-out mice exhibited deficits in cued fear conditioning (5 tone-shock presentations with 70 dB, 6 kHz tones and 0.5 s, 0.6 mA footshocks). We then demonstrated that: (1) Homer1a mRNA increases after fear conditioning in vivo within both amygdala and hippocampus of wild-type mice; (2) it increases after BDNF application to primary hippocampal and amygdala cultures in vitro; and (3) these increases are dependent on transcription and MAPK signaling. Furthermore, using chromatin immunoprecipitation we found that both in vitro and in vivo manipulations result in decreases in Homer1 promoter H3K9 methylation in amygdala cells but increases in Homer1 promoter H3 acetylation in hippocampal cells. However, no changes were observed in H4 acetylation or H3K27 dimethylation. Inhibition of histone deacetylation by sodium butyrate enhanced contextual but not cued fear conditioning and enhanced Homer1 H3 acetylation in the hippocampus. These data provide evidence for dynamic epigenetic regulation of Homer1a following BDNF-induced plasticity and during a BDNF-dependent learning process. Furthermore, upregulation of this gene may be regulated through distinct epigenetic modifications in the hippocampus and amygdala.

  6. Bi-directional effects of pituitary adenylate cyclase-activating polypeptide (PACAP) on fear-related behavior and c-Fos expression after fear conditioning in rats.

    PubMed

    Meloni, Edward G; Venkataraman, Archana; Donahue, Rachel J; Carlezon, William A

    2016-02-01

    Pituitary adenylate cyclase-activating polypeptide (PACAP) is implicated in stress regulation and learning and memory. PACAP has neuromodulatory actions on brain structures within the limbic system that could contribute to its acute and persistent effects in animal models of stress and anxiety-like behavior. Here, male Sprague-Dawley rats were implanted with intracerebroventricular (ICV) cannula for infusion of PACAP-38 (0.5, 1, or 1.5 μg) or vehicle followed 30 min later by fear conditioning. Freezing was measured early (1, 4, and 7 days) or following a delay (7, 10, and 13 days) after conditioning. PACAP (1.5 μg) produced a bi-phasic response in freezing behavior across test days: relative to controls, PACAP-treated rats showed a reduction in freezing when tested 1 or 7 days after fear conditioning that evolved into a significant elevation in freezing by the third test session in the early, but not delayed, group. Corticosterone (CORT) levels were significantly elevated in PACAP-treated rats following fear conditioning, but not at the time of testing (Day 1). Brain c-Fos expression revealed PACAP-dependent alterations within, as well as outside of, areas typically implicated in fear conditioning. Our findings raise the possibility that PACAP disrupts fear memory consolidation by altering synaptic plasticity within neurocircuits normally responsible for encoding fear-related cues, producing a type of dissociation or peritraumatic amnesia often seen in people early after exposure to a traumatic event. However, fear memories are retained such that repeated testing and memory reactivation (e.g., re-experiencing) causes the freezing response to emerge and persist at elevated levels. PACAP systems may represent an axis on which stress and exposure to trauma converge to promote maladaptive behavioral responses characteristic of psychiatric illnesses such as post-traumatic stress disorder (PTSD). PMID:26590791

  7. Amygdala kindling disrupts trace and delay fear conditioning with parallel changes in Fos protein expression throughout the limbic brain.

    PubMed

    Botterill, J J; Fournier, N M; Guskjolen, A J; Lussier, A L; Marks, W N; Kalynchuk, L E

    2014-04-18

    Amygdala kindling is well known to increase unconditioned fear and anxiety. However, relatively little is known about whether this form of kindling causes functional changes within the neural circuitry that mediates fear learning and the retrieval of fear memories. To address this issue, we examined the effect of short- (i.e., 30 stimulations) and long-term (i.e., 99 stimulations) amygdala kindling in rats on trace and delay fear conditioning, which are aversive learning tasks that rely predominantly on the hippocampus and amygdala, respectively. After memory retrieval, we analyzed the pattern of neural activity with Fos, the protein product of the immediate early gene c-fos. We found that kindling had no effect on acquisition of the trace fear conditioning task but it did selectively impair retrieval of this fear memory. In contrast, kindling disrupted both acquisition and retrieval of fear memory in the delay fear conditioning task. We also found that kindling-induced impairments in memory retrieval were accompanied by decreased Fos expression in several subregions of the hippocampus, parahippocampus, and amygdala. Interestingly, decreased freezing in the trace conditioning task was significantly correlated with dampened Fos expression in hippocampal and parahippocampal regions whereas decreased freezing in the delay conditioning task was significantly correlated with dampened Fos expression in hippocampal, parahippocampal, and amygdaloid circuits. Overall, these results suggest that amygdala kindling promotes functional changes in brain regions involved in specific types of fear learning and memory.

  8. Observational fear conditioning in the acquisition and extinction of attentional bias for threat: an experimental evaluation.

    PubMed

    Kelly, Megan M; Forsyth, John P

    2007-05-01

    Anxious persons show automatic and strategic attentional biases for threatening information. Yet, the mechanisms and processes that underlie such biases remain unclear. The central aim of the present study was to elucidate the relation between observational threat learning and the acquisition and extinction of biased threat processing by integrating emotional Stroop color naming tasks within an observational differential fear conditioning procedure. Forty-three healthy female participants underwent several consecutive observational fear conditioning phases. During acquisition, participants watched a confederate displaying mock panic attacks (UCS) paired with a verbal stimulus (CS+), but not with a second nonreinforced verbal stimulus (CS-). As expected, participants showed greater magnitude electrodermal and verbal-evaluative (e.g., distress, fear) conditioned responses to the CS+ over the CS- word. Participants also demonstrated slower color-naming latencies to CS+ compared to the CS- word following acquisition and showed attenuation of this preferential processing bias for threat following extinction. Findings are discussed broadly in the context of the interplay between fear learning and processing biases for threat as observed in persons suffering from anxiety disorders. PMID:17516811

  9. Reduced Electrodermal Fear Conditioning from Ages 3 to 8 Years Is Associated with Aggressive Behavior at Age 8 Years

    PubMed Central

    Gao, Yu; Raine, Adrian; Venables, Peter H.; Dawson, Michael E.; Mednick, Sarnoff A.

    2010-01-01

    Background Poor fear conditioning characterizes adult psychopathy and criminality, but it is not known whether it is related to aggressive/antisocial behavior in early childhood. Methods Using a differential, partial reinforcement conditioning paradigm, electrodermal activity was recorded from 200 male and female children at ages 3, 4, 5, 6, and 8 years. Antisocial/aggressive and hyperactive-inattentive measures were collected at age 8, while social adversity was assessed at age 3. Results Poor electrodermal fear conditioning from ages 3 to 8 years was associated with aggressive behavior at age 8 in both males and females. Conclusions Results indicate that the relationship between poor fear conditioning and aggression occurs early in childhood. Enhanced electrodermal fear conditioning may protect children against future aggressive/violent behavior. Abnormal amygdala functioning, as indirectly assessed by fear conditioning, may be one of the factors influencing the development of childhood aggression. PMID:19788551

  10. Resting-state connectivity of the amygdala is altered following Pavlovian fear conditioning.

    PubMed

    Schultz, Douglas H; Balderston, Nicholas L; Helmstetter, Fred J

    2012-01-01

    Neural plasticity in the amygdala is necessary for the acquisition and storage of memory in Pavlovian fear conditioning, but most neuroimaging studies have focused only on stimulus-evoked responses during the conditioning session. This study examined changes in the resting-state functional connectivity (RSFC) of the amygdala before and after Pavlovian fear conditioning, an emotional learning task. Behavioral results from the conditioning session revealed that participants learned normally and fMRI data recorded during learning identified a number of stimulus-evoked changes that were consistent with previous work. A direct comparison between the pre- and post-conditioning amygdala connectivity revealed a region of dorsal prefrontal cortex (PFC) in the superior frontal gyrus that showed a significant increase in connectivity following the conditioning session. A behavioral measure of explicit memory performance was positively correlated with the change in amygdala connectivity within a neighboring region in the superior frontal gyrus. Additionally, an implicit autonomic measure of conditioning was positively correlated with the change in connectivity between the amygdala and the anterior cingulate cortex (ACC). The resting-state data show that amygdala connectivity is altered following Pavlovian fear conditioning and that these changes are also related to behavioral outcomes. These alterations may reflect the operation of a consolidation process that strengthens neural connections to support memory after the learning event.

  11. The amygdala is not necessary for unconditioned stimulus inflation after Pavlovian fear conditioning in rats.

    PubMed

    Rabinak, Christine A; Orsini, Caitlin A; Zimmerman, Joshua M; Maren, Stephen

    2009-10-01

    The basolateral complex (BLA) and central nucleus (CEA) of the amygdala play critical roles in associative learning, including Pavlovian conditioning. However, the precise role for these structures in Pavlovian conditioning is not clear. Recent work in appetitive conditioning paradigms suggests that the amygdala, particularly the BLA, has an important role in representing the value of the unconditioned stimulus (US). It is not known whether the amygdala performs such a function in aversive paradigms, such as Pavlovian fear conditioning in rats. To address this issue, Experiments 1 and 2 used temporary pharmacological inactivation of the amygdala prior to a US inflation procedure to assess its role in revaluing shock USs after either overtraining (Experiment 1) or limited training (Experiment 2), respectively. Inactivation of the BLA or CEA during the inflation session did not affect subsequent increases in conditioned freezing observed to either the tone conditioned stimulus (CS) or the conditioning context in either experiment. In Experiment 3, NBQX infusions into the BLA impaired the acquisition of auditory fear conditioning with an inflation-magnitude US, indicating that the amygdala is required for associative learning with intense USs. Together, these results suggest that the amygdala is not required for revaluing an aversive US despite being required for the acquisition of fear to that US.

  12. Application of Pavlovian higher-order conditioning to the analysis of the neural substrates of fear conditioning.

    PubMed

    Gewirtz, J C; Davis, M

    1998-01-01

    In Pavlovian first-order conditioning, a conditioned response is acquired by pairing a neutral stimulus (S1) with a stimulus that has innate motivational value. In higher-order conditioning, a neutral stimulus (S2) is paired with S1 either after (second-order conditioning) or before (sensory preconditioning) first-order conditioning has been acquired. Thus, in higher-order conditioning the motivational value of the reinforcer is acquired rather than innate. This review describes some of the potential uses of higher-order conditioning in investigating the neural substrates of fearful memories. First, because in second-order fear conditioning S2 is not paired directly with a painful stimulus, any effect of a treatment on the acquisition of fear cannot be attributed to the treatment's possible effects on transmission of nociceptive information. Second, higher-order conditioning provides opportunities for analyzing where and how different types of events, or different aspects of the same events, are represented in the brain.

  13. Sufficient Conditions for Efficient Classical Simulation of Quantum Optics

    NASA Astrophysics Data System (ADS)

    Rahimi-Keshari, Saleh; Ralph, Timothy C.; Caves, Carlton M.

    2016-04-01

    We provide general sufficient conditions for the efficient classical simulation of quantum-optics experiments that involve inputting states to a quantum process and making measurements at the output. The first condition is based on the negativity of phase-space quasiprobability distributions (PQDs) of the output state of the process and the output measurements; the second one is based on the negativity of PQDs of the input states, the output measurements, and the transition function associated with the process. We show that these conditions provide useful practical tools for investigating the effects of imperfections in implementations of boson sampling. In particular, we apply our formalism to boson-sampling experiments that use single-photon or spontaneous-parametric-down-conversion sources and on-off photodetectors. Considering simple models for loss and noise, we show that above some threshold for the probability of random counts in the photodetectors, these boson-sampling experiments are classically simulatable. We identify mode mismatching as the major source of error contributing to random counts and suggest that this is the chief challenge for implementations of boson sampling of interesting size.

  14. Thermal signature of fear conditioning in mild post traumatic stress disorder.

    PubMed

    Di Giacinto, A; Brunetti, M; Sepede, G; Ferretti, A; Merla, A

    2014-04-25

    Fear conditioning has been proposed as an important factor involved in the etiology of posttraumatic stress disorder (PTSD). We examined fear processing in PTSD patients with mild symptoms and in individuals who did not develop symptoms (both groups consisting of victims of a bank robbery), through the study of fear-conditioned response. Conditioned responses were quantified by the skin conductance response (SCR) and the facial thermal response, the latter being measured by high-resolution functional thermal infrared (fIR) imaging. We found: (a) a change of the physiological parameters with respect to the baseline condition in both control subjects and PTSD patients during the conditioning phase; (b) the permanence of the conditioning effect in the maintenance phase in both control and PTSD patients; (c) patients and controls did differ for the variation across the phases of the physiological parameters rather than for their absolute values, showing that PTSD patients had a prolonged excitation and higher tonic component of autonomic activity. These results, although preliminary, indicate that the analysis of SCR and facial thermal response during the conditioning paradigm is a promising psychometric method of investigation, even in the case of low level of PTSD symptom severity. To the best of our knowledge, this study is the first attempt to discriminate between control subjects and PTSD patients with mild symptoms through infrared thermal imaging. It may suggest feasible approaches for diagnostic screening in the early phases of the disorder and in the assessment of preventive measures and therapies. PMID:24561216

  15. Effects of Extinction on Classical Conditioning and Conditioning-Specific Reflex Modification of Rabbit Heart Rate

    PubMed Central

    Burhans, Lauren B.; Smith-Bell, Carrie; Schreurs, Bernard G.

    2009-01-01

    Understanding the mechanisms of fear extinction has become increasingly important for treating a number of disorders, particularly post-traumatic stress disorder. Conditioning of rabbit heart rate (HR) is an established model for studying fear, yet little is known about procedures for extinguishing it other than repeated presentations of cue(s) associated with the fear-inducing event. The following study examined the effects of conditioned stimulus (CS) alone, unconditioned stimulus (US) alone, unpaired CS/US presentations, continued CS-US pairings, or no further stimulation on rabbit HR following HR conditioning. We have previously shown the rabbit HR response to the US can change as a function of learning when measured in the absence of the CS, a phenomenon referred to as conditioning-specific reflex modification (CRM). More specifically, the HR exhibits a deceleration in response to the US reminiscent of the conditioned bradycardia that develops to the CS. Consequently, the following study also examined the effects of extinction treatments on HR CRM. For HR conditioned responses (CRs), CS-alone and unpaired CS/US presentations were the most successful extinction treatments. For HR CRM, all conditions led to a reduction in CRM except for a subset of rabbits that maintained high levels following unpaired extinction, indicating a dissociation between extinction of HR CRs and CRM. The findings highlight the parameters of HR extinction, the transient nature of HR CRM, vagal involvement in both acquisition and extinction of HR CRM, and suggest that HR CRM cannot be fully explained as a CR that has generalized from the CS to the US. PMID:19747508

  16. Antenatal Maternal Stress Alters Functional Brain Responses In Adult Offspring During Conditioned Fear

    PubMed Central

    Sadler, Theodore R.; Nguyen, Peter T.; Yang, Jun; Givrad, Tina K.; Mayer, Emeran A.; Maarek, Jean-Michel I.; Hinton, David R.; Holschneider, Daniel P.

    2011-01-01

    Antenatal maternal stress has been shown in rodent models and in humans to result in altered behavioral and neuroendocrine responses, yet little is known about its effects on functional brain activation. Pregnant female rats received a daily foot-shock stress or sham-stress two days after testing plug-positive and continuing for the duration of their pregnancy. Adult male offspring (age 14 weeks) with and without prior maternal stress (MS) were exposed to an auditory fear conditioning (CF) paradigm. Cerebral blood flow (CBF) was assessed during recall of the tone cue in the nonsedated, nontethered animal using the 14C-iodoantipyrine method, in which the tracer was administered intravenously by remote activation of an implantable minipump. Regional CBF distribution was examined by autoradiography and analyzed by statistical parametric mapping in the three-dimensionally reconstructed brains. Presence of fear memory was confirmed by behavioral immobility (‘freezing’). Corticosterone plasma levels during the CF paradigm were measured by ELISA in a separate group of rats. Antenatal MS exposure altered functional brain responses to the fear conditioned cue in adult offspring. Rats with prior MS exposure compared to those without demonstrated heightened fear responsivity, exaggerated and prolonged corticosterone release, increased functional cerebral activation of limbic/paralimbic regions (amygdala, ventral hippocampus, insula, ventral striatum, nucleus acumbens), the locus coeruleus, and white matter, and deactivation of medial prefrontal cortical regions. Dysregulation of corticolimbic circuits may represent risk factors in the future development of anxiety disorders and associated alterations in emotional regulation. PMID:21300034

  17. Contributions of the amygdala central nucleus and ventrolateral periaqueductal grey to freezing and instrumental suppression in Pavlovian fear conditioning.

    PubMed

    McDannald, Michael A

    2010-07-29

    In Pavlovian fear conditioning animals receive pairings of a neutral cue and an aversive stimulus such as an electric foot-shock. Through such pairings, the cue will come to elicit a central state of fear that produces a variety of autonomic and behavioral responses, among which are conditioned freezing and suppression of instrumental responding, termed conditioned suppression. The central nucleus of the amygdala (CeA) and the ventrolateral periaqueductal grey (vlPAG) has been strongly implicated in the acquisition and expression of conditioned fear. However, previous work suggests different roles for the CeA and vlPAG in fear learning maybe revealed when fear is assessed with conditioned freezing or conditioned suppression. To further explore this possibility we gave rats selective lesions of either the CeA or vlPAG and trained them in Pavlovian first-order fear conditioning as well as Pavlovian second-order fear conditioning. We concurrently assessed the acquisition of conditioned freezing and conditioned suppression. We found that vlPAG and CeA lesions impaired both first- and second-order conditioned freezing. VlPAG lesions did not impair, and CeA lesions only transiently impaired, first-order conditioned suppression. However, both vlPAG and CeA lesions impaired second-order conditioned suppression. These results suggest that the CeA and vlPAG are critically important to expressing fear through conditioned freezing but play different and less critical roles in expressing fear through conditioned suppression.

  18. Effect of continuous and partial reinforcement on the acquisition and extinction of human conditioned fear.

    PubMed

    Grady, Ashley K; Bowen, Kenton H; Hyde, Andrew T; Totsch, Stacie K; Knight, David C

    2016-02-01

    Extinction of Pavlovian conditioned fear in humans is a popular paradigm often used to study learning and memory processes that mediate anxiety-related disorders. Fear extinction studies often only pair the conditioned stimulus (CS) and unconditioned stimulus (UCS) on a subset of acquisition trials (i.e., partial reinforcement/pairing) to prolong extinction (i.e., partial reinforcement extinction effect; PREE) and provide more time to study the process. However, there is limited evidence that the partial pairing procedures typically used during fear conditioning actually extend the extinction process, while there is strong evidence these procedures weaken conditioned response (CR) acquisition. Therefore, determining conditioning procedures that support strong CR acquisition and that also prolong the extinction process would benefit the field. The present study investigated 4 separate CS-UCS pairing procedures to determine methods that support strong conditioning and that also exhibit a PREE. One group (C-C) of participants received continuous CS-UCS pairings; a second group (C-P) received continuous followed by partial CS-UCS pairings; a third group (P-C) received partial followed by continuous CS-UCS pairings; and a fourth group (P-P) received partial CS-UCS pairings during acquisition. A strong skin conductance CR was expressed by C-C and P-C groups but not by C-P and P-P groups at the end of the acquisition phase. The P-C group maintained the CR during extinction. In contrast, the CR extinguished quickly within the C-C group. These findings suggest that partial followed by continuous CS-UCS pairings elicit strong CRs and prolong the extinction process following human fear conditioning. PMID:26692449

  19. Effect of continuous and partial reinforcement on the acquisition and extinction of human conditioned fear.

    PubMed

    Grady, Ashley K; Bowen, Kenton H; Hyde, Andrew T; Totsch, Stacie K; Knight, David C

    2016-02-01

    Extinction of Pavlovian conditioned fear in humans is a popular paradigm often used to study learning and memory processes that mediate anxiety-related disorders. Fear extinction studies often only pair the conditioned stimulus (CS) and unconditioned stimulus (UCS) on a subset of acquisition trials (i.e., partial reinforcement/pairing) to prolong extinction (i.e., partial reinforcement extinction effect; PREE) and provide more time to study the process. However, there is limited evidence that the partial pairing procedures typically used during fear conditioning actually extend the extinction process, while there is strong evidence these procedures weaken conditioned response (CR) acquisition. Therefore, determining conditioning procedures that support strong CR acquisition and that also prolong the extinction process would benefit the field. The present study investigated 4 separate CS-UCS pairing procedures to determine methods that support strong conditioning and that also exhibit a PREE. One group (C-C) of participants received continuous CS-UCS pairings; a second group (C-P) received continuous followed by partial CS-UCS pairings; a third group (P-C) received partial followed by continuous CS-UCS pairings; and a fourth group (P-P) received partial CS-UCS pairings during acquisition. A strong skin conductance CR was expressed by C-C and P-C groups but not by C-P and P-P groups at the end of the acquisition phase. The P-C group maintained the CR during extinction. In contrast, the CR extinguished quickly within the C-C group. These findings suggest that partial followed by continuous CS-UCS pairings elicit strong CRs and prolong the extinction process following human fear conditioning.

  20. Differences in hippocampal CREB phosphorylation in trace fear conditioning of two inbred mouse strains.

    PubMed

    Hwang, Yoo Kyeong; Song, Jae-Chun; Han, Seol-Heui; Cho, Jeiwon; Smith, Dani R; Gallagher, Michela; Han, Jung-Soo

    2010-07-23

    The effects of genetic background on fear trace conditioning were evaluated in relation to phosphorylated levels of cAMP response element-binding protein (CREB) in the hippocampus using two different inbred strains of mice, C57BL/6 and DBA/2. The male mice received a trace fear conditioning protocol and unpaired control groups were included to assess nonassociative effects on test performance. Both C57BL/6 and DBA/2 mice with paired training displayed higher freezing responses during testing than those with unpaired training, respectively. The C57BL/6 mice with paired training also displayed higher freezing responses to the tone-CS during testing than the DBA/2 mice with paired training. Because much evidence implicates the hippocampus as an important neural substrate for trace fear conditioning, the engagement of the hippocampus was examined after testing by measuring levels of CREB and phosphorylated CREB (pCREB). The results revealed that hippocampal CREB levels in both strains of mice were not significantly altered according to the type of training (unpaired vs. paired). However, the hippocampal pCREB levels were significantly higher in the paired training group than the unpaired control group in C57BL/6 mice, but not in DBA/2 mice. These findings indicate that hippocampal pCREB is closely tied to this form of associative conditioning only in C57BL/6 mice and that different neural substrates may support trace conditioning in C57BL/6 and DBA/2 strains. PMID:20501325

  1. GABAB receptor ligands do not modify conditioned fear responses in BALB/c mice.

    PubMed

    Sweeney, Fabian F; O'Leary, Olivia F; Cryan, John F

    2013-11-01

    The GABA(B) receptor has been well characterised as a substrate of unconditioned anxiety behaviour. Indeed, the anxiolytic effects of positive modulators of the GABA(B) receptor have been demonstrated across a range of behavioural tests of innate anxiety, whereas GABA(B) receptor deficient mice have an elevated anxiety phenotype. However, the role of the GABA(B) receptor in regulating conditioned anxiety behaviour; an important facet of the preclinical study of anxiety disorders such as post-traumatic stress disorder is less well understood. In vitro data suggests that the GABA(B) receptor plays an important role in regulating the neural circuitry that underpins conditioned fear learning and extinction, but whether these effects translate into alterations in conditioned anxiety behaviour has not been widely investigated. This represents a crucial deficit in the preclinical characterisation of these drugs as putative anxiolytic agents. Using the highly anxious mouse strain, BALB/c, and an auditory fear conditioning protocol, we sought to characterise the GABA(B) receptor positive modulator GS39783 and GABA(B) receptor antagonist CGP52432, two compounds not previously evaluated for their effects on conditioned fear. Neither GS39783 nor CGP52432 altered freezing behaviour irrespective of whether drugs were administered before the acquisition, recall or extinction training sessions. These findings suggest limitations to the potential role of GABA(B) receptor active drugs as clinical agents in the treatment of anxiety.

  2. Angiotensin type 1a receptors on corticotropin-releasing factor neurons contribute to the expression of conditioned fear.

    PubMed

    Hurt, R C; Garrett, J C; Keifer, O P; Linares, A; Couling, L; Speth, R C; Ressler, K J; Marvar, P J

    2015-09-01

    Although generally associated with cardiovascular regulation, angiotensin II receptor type 1a (AT1a R) blockade in mouse models and humans has also been associated with enhanced fear extinction and decreased post-traumatic stress disorder (PTSD) symptom severity, respectively. The mechanisms mediating these effects remain unknown, but may involve alterations in the activities of corticotropin-releasing factor (CRF)-expressing cells, which are known to be involved in fear regulation. To test the hypothesis that AT1a R signaling in CRFergic neurons is involved in conditioned fear expression, we generated and characterized a conditional knockout mouse strain with a deletion of the AT1a R gene from its CRF-releasing cells (CRF-AT1a R((-/-)) ). These mice exhibit normal baseline heart rate, blood pressure, anxiety and locomotion, and freeze at normal levels during acquisition of auditory fear conditioning. However, CRF-AT1a R((-/-)) mice exhibit less freezing than wild-type mice during tests of conditioned fear expression-an effect that may be caused by a decrease in the consolidation of fear memory. These results suggest that central AT1a R activity in CRF-expressing cells plays a role in the expression of conditioned fear, and identify CRFergic cells as a population on which AT1 R antagonists may act to modulate fear extinction.

  3. Angiotensin Type 1a Receptors on Corticotropin-Releasing Factor Neurons Contribute to the Expression of Conditioned Fear

    PubMed Central

    Hurt, Robert C.; Garrett, Jacob C.; Keifer, Orion P.; Linares, Andrea; Couling, Leena; Speth, Robert C.; Ressler, Kerry J.; Marvar, Paul J.

    2015-01-01

    Although generally associated with cardiovascular regulation, angiotensin II receptor type 1 (AT1aR) blockade in mouse models and humans has also been associated with enhanced fear extinction and decreased post-traumatic stress disorder (PTSD) symptom severity, respectively. The mechanisms mediating these effects remain unknown, but may involve alterations in the activities of corticotropin-releasing factor (CRF)-expressing cells, which are known to be involved in fear regulation. To test the hypothesis that AT1aR signaling in CRFergic neurons is involved in conditioned fear expression, we generated and characterized a conditional knockout mouse strain with a deletion of the AT1aR gene from its CRF-releasing cells (CRF-AT1aR(−/−)). These mice exhibit normal baseline heart rate, blood pressure, anxiety, and locomotion, and freeze at normal levels during acquisition of auditory fear conditioning. However, CRF-AT1aR(−/−) mice exhibit less freezing than wild type mice during tests of conditioned fear expression—an effect that may be caused by a decrease in the consolidation of fear memory. These results suggest that central AT1R activity in CRF-expressing cells plays a role in the expression of conditioned fear, and identify CRFergic cells as a population on which AT1R antagonists may act to modulate fear extinction. PMID:26257395

  4. Olfactory classical conditioning in neonatal mouse pups using thermal stimuli.

    PubMed

    Bollen, Bieke; Matrot, Boris; Ramanantsoa, Nelina; Van den Bergh, Omer; D'Hooge, Rudi; Gallego, Jorge

    2012-04-01

    Mouse models are increasingly used to investigate genetic contributions to developmental disorders in children, especially newborns. In particular, early cognitive assessment in newborn mice is critical to evaluate pediatric drug efficacy and toxicity. Unfortunately, methods for behavioral tests in newborn mice are scarce. Therefore, developing such tests for newborn mice is a priority challenge for neurogenetics and pharmacological research. The aim of the present study was to develop a conditioning method well suited to high-throughput cognitive screening in newborn mice. To this end, we developed an odor-preference conditioning test using ambient temperature as an unconditioned stimulus (US) and artificial odors as conditioned stimuli (CS). First, we showed that mouse pups move toward the thermoneutral temperature when offered a choice between a thermoneutral and cold environment, thus showing thermotaxis. Second, we conducted a classical conditioning paradigm in pups aged six to ten days. In terms of central nervous system development, this period corresponds to extreme prematurity to early post-term period in humans. During acquisition, the pups were alternatively exposed to odor CS paired with either cold or warm temperatures. Immediately after acquisition, the pups underwent a two-odor choice test, which showed preference for the odor previously paired with the warm temperature, thus showing conditioning. The proposed paradigm is easy to conduct, and requires modest experimenter interference. The method is well suited for high-throughput screening of early associative disorders in newborn mice.

  5. RNA sequencing from neural ensembles activated during fear conditioning in the mouse temporal association cortex.

    PubMed

    Cho, Jin-Hyung; Huang, Ben S; Gray, Jesse M

    2016-01-01

    The stable formation of remote fear memories is thought to require neuronal gene induction in cortical ensembles that are activated during learning. However, the set of genes expressed specifically in these activated ensembles is not known; knowledge of such transcriptional profiles may offer insights into the molecular program underlying stable memory formation. Here we use RNA-Seq to identify genes whose expression is enriched in activated cortical ensembles labeled during associative fear learning. We first establish that mouse temporal association cortex (TeA) is required for remote recall of auditory fear memories. We then perform RNA-Seq in TeA neurons that are labeled by the activity reporter Arc-dVenus during learning. We identify 944 genes with enriched expression in Arc-dVenus+ neurons. These genes include markers of L2/3, L5b, and L6 excitatory neurons but not glial or inhibitory markers, confirming Arc-dVenus to be an excitatory neuron-specific but non-layer-specific activity reporter. Cross comparisons to other transcriptional profiles show that 125 of the enriched genes are also activity-regulated in vitro or induced by visual stimulus in the visual cortex, suggesting that they may be induced generally in the cortex in an experience-dependent fashion. Prominent among the enriched genes are those encoding potassium channels that down-regulate neuronal activity, suggesting the possibility that part of the molecular program induced by fear conditioning may initiate homeostatic plasticity. PMID:27557751

  6. Fear conditioning and extinction in anxiety- and depression-prone persons.

    PubMed

    Dibbets, Pauline; van den Broek, Anne; Evers, Elisabeth A T

    2015-01-01

    Anxiety and depression frequently co-occur and may share similar deficits in the processing of emotional stimuli. High anxiety is associated with a failure in the acquisition and extinction of fear conditioning. Despite the supposed common deficits, no research has been conducted on fear acquisition and extinction in depression. The main aim of the present study was to investigate and compare fear acquisition and extinction in anxiety- and depression-prone participants. Non-clinical anxious, depressive, anxious-depressive and control participants performed a fear discrimination task. During acquisition, the CS+ predicted an aversive event (unconditioned stimulus, US) and the CS- safety (no US). During extinction, the CS+ was no longer followed by the US, rendering it (temporarily) into a safety signal. On each CS participants rated their US expectancy; skin conductance responses (SCRs) were measured throughout. The expectancy scores indicated that high anxiety resulted in less safety learning during acquisition and extinction; no effect of depression was observed. SCRs showed that high-anxiety persons displayed less discrimination learning (CS+ minus CS-) during acquisition than low-anxiety persons. During extinction, high-depression persons demonstrated more discriminative SCR than low-depression persons. The observed discrepancies in response patterns of high-anxiety and -depression persons seem to indicate distinctive information processing of emotional stimuli.

  7. RNA sequencing from neural ensembles activated during fear conditioning in the mouse temporal association cortex

    PubMed Central

    Cho, Jin-Hyung; Huang, Ben S.; Gray, Jesse M.

    2016-01-01

    The stable formation of remote fear memories is thought to require neuronal gene induction in cortical ensembles that are activated during learning. However, the set of genes expressed specifically in these activated ensembles is not known; knowledge of such transcriptional profiles may offer insights into the molecular program underlying stable memory formation. Here we use RNA-Seq to identify genes whose expression is enriched in activated cortical ensembles labeled during associative fear learning. We first establish that mouse temporal association cortex (TeA) is required for remote recall of auditory fear memories. We then perform RNA-Seq in TeA neurons that are labeled by the activity reporter Arc-dVenus during learning. We identify 944 genes with enriched expression in Arc-dVenus+ neurons. These genes include markers of L2/3, L5b, and L6 excitatory neurons but not glial or inhibitory markers, confirming Arc-dVenus to be an excitatory neuron-specific but non-layer-specific activity reporter. Cross comparisons to other transcriptional profiles show that 125 of the enriched genes are also activity-regulated in vitro or induced by visual stimulus in the visual cortex, suggesting that they may be induced generally in the cortex in an experience-dependent fashion. Prominent among the enriched genes are those encoding potassium channels that down-regulate neuronal activity, suggesting the possibility that part of the molecular program induced by fear conditioning may initiate homeostatic plasticity. PMID:27557751

  8. Eyeblink classical conditioning differentiates normal aging from Alzheimer's disease.

    PubMed

    Woodruff-Pak, D S

    2001-01-01

    Eyeblink classical conditioning is a useful paradigm for the study of the neurobiology of learning, memory, and aging, which also has application in the differential diagnosis of neurodegenerative diseases expressed in advancing age. Converging evidence from studies of eyeblink conditioning in neurological patients and brain imaging in normal adults document parallels in the neural substrates of this form of associative learning in humans and non-human mammals. Age differences in the short-delay procedure (400 ms CS-US interval) appear in middle age in humans and may be caused at least in part by cerebellar cortical changes such as loss of Purkinje cells. Whereas the hippocampus is not essential for conditioning in the delay procedure, disruption of hippocampal cholinergic neurotransmission impairs acquisition and slows the rate of learning. Alzheimer's disease (AD) profoundly disrupts the hippocampaL cholinergic system, and patients with AD consistently perform poorly in eyeblink conditioning. We hypothesize that disruption of hippocampal cholinergic pathways in AD in addition to age-associated Purkinje cell loss results in severely impaired eyeblink conditioning. The earliest pathology in AD occurs in entorhinal cortical input to hippocampus, and eyeblink conditioning may detect this early disruption before declarative learning and memory circuits become impaired. A case study is presented in which eyeblink conditioning detected impending dementia six years before changes on other screening tests indicated impairment. Because eyeblink conditioning is simple, non-threatening, and non-invasive, it may become a useful addition to test batteries designed to differentiate normal aging from mild cognitive impairment that progresses to AD and AD from other types of dementia.

  9. An ERP study of the interaction between verbal information and conditioning pathways to fear.

    PubMed

    Ugland, Carina C O; Dyson, Benjamin J; Field, Andy P

    2013-01-01

    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. PMID:22366224

  10. A role for alpha-adrenergic receptors in extinction of conditioned fear and cocaine conditioned place preference.

    PubMed

    Bernardi, Rick E; Lattal, K Matthew

    2010-04-01

    Previous work has demonstrated an important role for adrenergic receptors in memory processes in fear and drug conditioning paradigms. Recent studies have also demonstrated alterations in extinction in these paradigms using drug treatments targeting beta- and alpha2-adrenergic receptors, but little is known about the role of alpha-adrenergic receptors in extinction. The current study examined whether antagonism of alpha-adrenergic receptors would impair the consolidation of extinction in fear and cocaine conditioned place preference paradigms. After contextual fear conditioning, injections of the alpha-adrenergic receptor antagonist prazosin (1.0 or 3.0 mg/kg) following nonreinforced context exposures slowed the loss of conditioned freezing over the course of 5 extinction sessions (Experiment 1). After cocaine place conditioning, prazosin had no effect on the rate of extinction over 8 nonreinforced test sessions. Following postextinction reconditioning, however, prazosin-treated mice showed a robust place preference, but vehicle-treated mice did not, suggesting that prazosin reduced the persistent effects of extinction (Experiment 2). These results confirm the involvement of the alpha-adrenergic receptor in extinction processes in both appetitive and aversive preparations.

  11. Role of the Ventral Medial Prefrontal Cortex in Mediating Behavioral Control-Induced Reduction of Later Conditioned Fear

    ERIC Educational Resources Information Center

    Baratta, Michael V.; Lucero, Thomas R.; Amat, Jose; Watkins, Linda R.; Maier, Steven F.

    2008-01-01

    A prior experience of behavioral control over a stressor interferes with subsequent Pavlovian fear conditioning, and this effect is dependent on the activation of the ventral medial prefrontal cortex (mPFCv) at the time of the initial experience with control. It is unknown whether mPFCv activity is necessary during fear learning and/or testing for…

  12. Voxel-based morphometry predicts shifts in dendritic spine density and morphology with auditory fear conditioning.

    PubMed

    Keifer, O P; Hurt, R C; Gutman, D A; Keilholz, S D; Gourley, S L; Ressler, K J

    2015-07-07

    Neuroimaging has provided compelling data about the brain. Yet the underlying mechanisms of many neuroimaging techniques have not been elucidated. Here we report a voxel-based morphometry (VBM) study of Thy1-YFP mice following auditory fear conditioning complemented by confocal microscopy analysis of cortical thickness, neuronal morphometric features and nuclei size/density. Significant VBM results included the nuclei of the amygdala, the insula and the auditory cortex. There were no significant VBM changes in a control brain area. Focusing on the auditory cortex, confocal analysis showed that fear conditioning led to a significantly increased density of shorter and wider dendritic spines, while there were no spine differences in the control area. Of all the morphology metrics studied, the spine density was the only one to show significant correlation with the VBM signal. These data demonstrate that learning-induced structural changes detected by VBM may be partially explained by increases in dendritic spine density.

  13. Effects of dopamine D1 modulation of the anterior cingulate cortex in a fear conditioning procedure

    PubMed Central

    Pezze, M.A.; Marshall, H.J.; Domonkos, A.; Cassaday, H.J.

    2016-01-01

    The anterior cingulate cortex (AC) component of the medial prefrontal cortex (mPFC) has been implicated in attention and working memory as measured by trace conditioning. Since dopamine (DA) is a key modulator of mPFC function, the present study evaluated the role of DA receptor agents in rat AC, using trace fear conditioning. A conditioned stimulus (CS, noise) was followed by an unconditioned stimulus (US, shock) with or without a 10 s trace interval interposed between these events in a between-subjects design. Conditioned suppression of drinking was assessed in response to presentation of the CS or an experimental background stimulus (flashing lights, previously presented for the duration of the conditioning session). The selective D1 agonist SKF81297 (0.05 μg/side) or D1 antagonist SCH23390 (0.5 μg/side) was administered by intra-cerebral microinfusion directly into AC. It was predicted that either of these manipulations should be sufficient to impair trace (but not delay) conditioning. Counter to expectation, there was no effect of DA D1 modulation on trace conditioning as measured by suppression to the noise CS. However, rats infused with SKF81297 acquired stronger conditioned suppression to the experimental background stimulus than those infused with SCH23390 or saline. Thus, the DA D1 agonist SKF81297 increased conditioned suppression to the contextual background light stimulus but was otherwise without effect on fear conditioning. PMID:26343307

  14. The association between the 5-HTTLPR and neural correlates of fear conditioning and connectivity.

    PubMed

    Klucken, Tim; Schweckendiek, Jan; Blecker, Carlo; Walter, Bertram; Kuepper, Yvonne; Hennig, Juergen; Stark, Rudolf

    2015-05-01

    Strong evidence links the 5-HTTLPR genotype to the modulation of amygdala reactivity during fear conditioning, which is considered to convey the increased vulnerability for anxiety disorders in s-allele carriers. In addition to amygdala reactivity, the 5-HTTLPR has been shown to be related to alterations in structural and effective connectivity. The aim of this study was to investigate the effects of 5-HTTLPR genotype on amygdala reactivity and effective connectivity during fear conditioning, as well as structural connectivity [as measured by diffusion tensor imaging (DTI)]. To integrate different classification strategies, we used the bi-allelic (s-allele vs l/l-allele group) as well as the tri-allelic (low-functioning vs high-functioning) classification approach. S-allele carriers showed exaggerated amygdala reactivity and elevated amygdala-insula coupling during fear conditioning (CS + > CS-) compared with the l/l-allele group. In addition, DTI analysis showed increased fractional anisotropy values in s-allele carriers within the uncinate fasciculus. Using the tri-allelic classification approach, increased amygdala reactivity and amygdala insula coupling were observed in the low-functioning compared with the high-functioning group. No significant differences between the two groups were found in structural connectivity. The present results add to the current debate on the influence of the 5-HTTLPR on brain functioning. These differences between s-allele and l/l-allele carriers may contribute to altered vulnerability for psychiatric disorders.

  15. Mice lacking synapsin III show abnormalities in explicit memory and conditioned fear

    PubMed Central

    Porton, Barbara; Rodriguiz, Ramona M.; Phillips, Lindsey E.; Gilbert, John W.; Feng, Jian; Greengard, Paul; Kao, Hung-Teh; Wetsel, William C.

    2010-01-01

    Synapsin III is a neuron-specific phosphoprotein that plays an important role in synaptic transmission and neural development. While synapsin III is abundant in embryonic brain, expression of the protein in adults is reduced and limited primarily to the hippocampus, olfactory bulb, and cerebral cortex. Given the specificity of synapsin III to these brain areas and because it plays a role in neurogenesis in the dentate gyrus, we investigated whether it may affect learning and memory processes in mice. To address this point, synapsin III knockout mice were examined in a general behavioral screen, several tests to assess learning and memory function, and conditioned fear. Mutant animals displayed no anomalies in sensory and motor function or in anxiety- and depressive-like behaviors. Although mutants showed minor alterations in the Morris water maze, they were deficient in object recognition 24 hr and 10 days after training and in social transmission of food preference at 20 min and 24 hr. Additionally, mutants displayed abnormal responses in contextual and cued fear conditioning when tested 1 or 24 hr after conditioning. The synapsin III knockout mice also showed aberrant responses in fear-potentiated startle. Since synapsin III protein is decreased in schizophrenic brain and because the mutant mice do not harbor obvious anatomical deficits or neurological disorders, these mutants may represent a unique neurodevelopmental model for dissecting the molecular pathways that are related to certain aspects of schizophrenia and related disorders. PMID:20050925

  16. Amygdala microcircuits controlling learned fear.

    PubMed

    Duvarci, Sevil; Pare, Denis

    2014-06-01

    We review recent work on the role of intrinsic amygdala networks in the regulation of classically conditioned defensive behaviors, commonly known as conditioned fear. These new developments highlight how conditioned fear depends on far more complex networks than initially envisioned. Indeed, multiple parallel inhibitory and excitatory circuits are differentially recruited during the expression versus extinction of conditioned fear. Moreover, shifts between expression and extinction circuits involve coordinated interactions with different regions of the medial prefrontal cortex. However, key areas of uncertainty remain, particularly with respect to the connectivity of the different cell types. Filling these gaps in our knowledge is important because much evidence indicates that human anxiety disorders results from an abnormal regulation of the networks supporting fear learning.

  17. Differential effects of CB1 receptor agonism in behavioural tests of unconditioned and conditioned fear in adult male rats.

    PubMed

    Simone, Jonathan J; Green, Matthew R; Hodges, Travis E; McCormick, Cheryl M

    2015-02-15

    We investigated the effects of the highly selective CB1 receptor agonist ACEA and the CB1 receptor antagonist/inverse agonist AM251 on two behavioural tests of unconditioned fear, the elevated plus maze (EPM) and open field test (OFT), as well as on the recall and extinction of a conditioned auditory fear. Both ACEA and AM251 increased anxiety-like behaviour in the EPM and OFT. There was no effect of either drug on recall of the conditioned fear, and ACEA enhanced and AM251 impaired fear extinction. Further, though both the low (0.1 mg/kg) and high (0.5 mg/kg) dose of ACEA facilitated fear extinction, the low dose attenuated, and the high dose potentiated, fear induced corticosterone release suggesting independent effects of the drug on fear and stress responses. Although the extent to which cannabinoids are anxiogenic or anxiolytic has been proposed to be dose-dependent, these results indicate that the same dose has differential effects across tasks, likely based in differences in sensitivities of CB1 receptors to the agonist in the neural regions subserving unconditioned and conditioned fear.

  18. Dissociable Roles of Prelimbic and Infralimbic Cortices, Ventral Hippocampus, and Basolateral Amygdala in the Expression and Extinction of Conditioned Fear

    PubMed Central

    Sierra-Mercado, Demetrio; Padilla-Coreano, Nancy; Quirk, Gregory J

    2011-01-01

    Current models of conditioned fear expression and extinction involve the basolateral amygdala (BLA), ventral medial prefrontal cortex (vmPFC), and the hippocampus (HPC). There is some disagreement with respect to the specific roles of these structures, perhaps due to subregional differences within each area. For example, growing evidence suggests that infralimbic (IL) and prelimbic (PL) subregions of vmPFC have opposite influences on fear expression. Moreover, it is the ventral HPC (vHPC), rather than the dorsal HPC, that projects to vmPFC and BLA. To help determine regional specificity, we used small doses of the GABAA agonist muscimol to selectively inactivate IL, PL, BLA, or vHPC in an auditory fear conditioning and extinction paradigm. Infusions were performed prior to extinction training, allowing us to assess the effects on both fear expression and subsequent extinction memory. Inactivation of IL had no effect on fear expression, but impaired the within-session acquisition of extinction as well as extinction memory. In contrast, inactivation of PL impaired fear expression, but had no effect on extinction memory. Inactivation of the BLA or vHPC impaired both fear expression and extinction memory. Post-extinction inactivations had no effect in any structure. We suggest a model in which amygdala-dependent fear expression is modulated by inputs from PL and vHPC, whereas extinction memory requires extinction-induced plasticity in IL, BLA, and/or vHPC. PMID:20962768

  19. Fear conditioning induces guinea pig auditory cortex activation by foot shock alone.

    PubMed

    Ide, Yoshinori; Takahashi, Muneyoshi; Lauwereyns, Johan; Sandner, Guy; Tsukada, Minoru; Aihara, Takeshi

    2013-02-01

    The present study used an optical imaging paradigm to investigate plastic changes in the auditory cortex induced by fear conditioning, in which a sound (conditioned stimulus, CS) was paired with an electric foot-shock (unconditioned stimulus, US). We report that, after conditioning, auditory information could be retrieved on the basis of an electric foot-shock alone. Before conditioning, the auditory cortex showed no response to a foot-shock presented in the absence of sound. In contrast, after conditioning, the mere presentation of a foot-shock without any sound succeeded in eliciting activity in the auditory cortex. Additionally, the magnitude of the optical response in the auditory cortex correlated with variation in the electrocardiogram (correlation coefficient: -0.68). The area activated in the auditory cortex, in response to the electric foot-shock, statistically significantly had a larger cross-correlation value for tone response to the CS sound (12 kHz) compared to the non-CS sounds in normal conditioning group. These results suggest that integration of different sensory modalities in the auditory cortex was established by fear conditioning. PMID:24427192

  20. Preparing for an Important Event: Demonstrating the Modern View of Classical Conditioning.

    ERIC Educational Resources Information Center

    Kohn, Art; Kalat, James W.

    1992-01-01

    Explains a simple classroom demonstration of the modern view of classical conditioning. Suggests that the exercise is a useful demonstration of the view that classical conditioning helps prepare an organism for an upcoming event. Argues that the demonstration can show students that classical conditioning is broader and more intriguing than…

  1. Automated assessment of conditioning parameters for context and cued fear in mice.

    PubMed

    Contarino, Angelo; Baca, Leonardo; Kennelly, Arthur; Gold, Lisa H

    2002-01-01

    A behavioral technique often used to evaluate the cognitive performance of rats and mice is the fear conditioning paradigm. During conditioned fear experiments, freezing responses shown by rodents after exposure to environmental stimuli previously paired to an aversive experience provide a behavioral index of the animal's associative abilities. The present study examined the ability of a computer-controlled automated Freeze Monitor system for recording immobility behavior in mice. The sensitivity of the automated procedure to detect group differences caused by the application of various training protocols was also evaluated. Statistical analyses revealed significant positive correlations between immobility scores obtained with the automated apparatus and hand-scored data collected by a continuous or a time-sampling method. Behavioral patterns recorded by the computerized system were very similar to those obtained by the hand-scoring methods adopted. In particular, during context testing, exposure to environmental stimuli previously paired with a mild foot shock (unconditioned stimulus [US]) evoked increased immobility behavior in mice conditioned with the US compared with levels of immobility displayed by mice previously confined to the same contextual stimuli without receiving the US. Moreover, although during conditioned stimulus (CS) testing, mice previously exposed to the US displayed high levels of immobility when confined to environmental cues much different from those paired with the US (contextual fear generalization), both hand-scored and automated results revealed the effect of CS-US pairing (increased immobility) only in mice trained to associate the two stimuli (paired group) but not in mice exposed to both CS and US separated by a 40-sec time interval (unpaired group) or in mice receiving only the US (US group) during conditioning sessions. Overall, the results show associative conditioning measured in an automated apparatus and highlight the utility

  2. Time course of dorsal and ventral hippocampal involvement in the expression of trace fear conditioning.

    PubMed

    Cox, David; Czerniawski, Jennifer; Ree, Fredrick; Otto, Tim

    2013-11-01

    While a number of early studies demonstrated that hippocampal damage attenuates the expression of recent, but not remotely trained tasks, an emerging body of evidence has shown that damage to, or inactivation of, the hippocampus often impairs recall across a wide range of training-testing intervals. Collectively, these data suggest that the time course of hippocampal involvement in the storage or recall of previously-acquired memories may differ according to hippocampal subregion and the particular learning task under consideration. The present study examined the contributions of dorsal (DH) and ventral (VH) hippocampus to the expression of previously-acquired trace fear conditioning, a form of Pavlovian conditioning in which the offset of an initially neutral cue or cues and the onset of an aversive stimulus is separated by a temporal (trace) interval. Specifically, either saline or the GABA-A agonist muscimol was infused into DH or VH prior to testing either 1, 7, 28, or 42 days after trace fear conditioning. The results revealed a marked dissociation: pre-testing inactivation of DH failed to impair performance at any time-point, while pre-testing inactivation of VH impaired performance at all time-points. Importantly, pre-testing inactivation of VH had no effect on the performance of previously-acquired delay conditioning, suggesting that the deficits observed in trace conditioning cannot be attributed to a deficit in performance of the freezing response. Collectively, these data suggest that VH, but not DH, remains a neuroanatomical locus critical to the recall or expression of trace fear conditioning over an extended period of time.

  3. Pavlovian conditioning of phobic fear: effects on skin and salivary pH.

    PubMed

    Chorot, P; Sandin, B; Fernandez-Trespalacios, J L

    1992-01-01

    This experimental work was designed to investigate the relationships between pH and conditioned fear. The levels of pH were measured in skin and saliva, and were studied in connection with conditioned electrodermal and heart rate (HR) responses (extinction versus resistance to extinction or enhancement). The results of this investigation show that the changes in skin and salivary pH have a tendency to occur in an inverse pattern to the changes in skin conductance and HR. The data are interpreted in terms of skin and salivary pH as new psychophysiological variables and as new tools for psychopathological and psychosomatic research.

  4. Glutamate uptake determines pathway specificity of long-term potentiation in the neural circuitry of fear conditioning.

    PubMed

    Tsvetkov, Evgeny; Shin, Ryong Moon; Bolshakov, Vadim Y

    2004-01-01

    Long-term synaptic modifications in afferent inputs to the amygdala underlie fear conditioning in animals. Fear conditioning to a single sensory modality does not generalize to other cues, implying that synaptic modifications in fear conditioning pathways are input specific. The mechanisms of pathway specificity of long-term potentiation (LTP) are poorly understood. Here we show that inhibition of glutamate transporters leads to the loss of input specificity of LTP in the amygdala slices, as assessed by monitoring synaptic responses at two independent inputs converging on a single postsynaptic neuron. Diffusion of glutamate ("spillover") from stimulated synapses, paired with postsynaptic depolarization, is sufficient to induce LTP in the heterosynaptic pathway, whereas an enzymatic glutamate scavenger abolishes this effect. These results establish active glutamate uptake as a crucial mechanism maintaining the pathway specificity of LTP in the neural circuitry of fear conditioning.

  5. Contextual and cued fear conditioning test using a video analyzing system in mice.

    PubMed

    Shoji, Hirotaka; Takao, Keizo; Hattori, Satoko; Miyakawa, Tsuyoshi

    2014-03-01

    The contextual and cued fear conditioning test is one of the behavioral tests that assesses the ability of mice to learn and remember an association between environmental cues and aversive experiences. In this test, mice are placed into a conditioning chamber and are given parings of a conditioned stimulus (an auditory cue) and an aversive unconditioned stimulus (an electric footshock). After a delay time, the mice are exposed to the same conditioning chamber and a differently shaped chamber with presentation of the auditory cue. Freezing behavior during the test is measured as an index of fear memory. To analyze the behavior automatically, we have developed a video analyzing system using the ImageFZ application software program, which is available as a free download at http://www.mouse-phenotype.org/. Here, to show the details of our protocol, we demonstrate our procedure for the contextual and cued fear conditioning test in C57BL/6J mice using the ImageFZ system. In addition, we validated our protocol and the video analyzing system performance by comparing freezing time measured by the ImageFZ system or a photobeam-based computer measurement system with that scored by a human observer. As shown in our representative results, the data obtained by ImageFZ were similar to those analyzed by a human observer, indicating that the behavioral analysis using the ImageFZ system is highly reliable. The present movie article provides detailed information regarding the test procedures and will promote understanding of the experimental situation.

  6. Contextual and Cued Fear Conditioning Test Using a Video Analyzing System in Mice

    PubMed Central

    Shoji, Hirotaka; Takao, Keizo; Hattori, Satoko; Miyakawa, Tsuyoshi

    2014-01-01

    The contextual and cued fear conditioning test is one of the behavioral tests that assesses the ability of mice to learn and remember an association between environmental cues and aversive experiences. In this test, mice are placed into a conditioning chamber and are given parings of a conditioned stimulus (an auditory cue) and an aversive unconditioned stimulus (an electric footshock). After a delay time, the mice are exposed to the same conditioning chamber and a differently shaped chamber with presentation of the auditory cue. Freezing behavior during the test is measured as an index of fear memory. To analyze the behavior automatically, we have developed a video analyzing system using the ImageFZ application software program, which is available as a free download at http://www.mouse-phenotype.org/. Here, to show the details of our protocol, we demonstrate our procedure for the contextual and cued fear conditioning test in C57BL/6J mice using the ImageFZ system. In addition, we validated our protocol and the video analyzing system performance by comparing freezing time measured by the ImageFZ system or a photobeam-based computer measurement system with that scored by a human observer. As shown in our representative results, the data obtained by ImageFZ were similar to those analyzed by a human observer, indicating that the behavioral analysis using the ImageFZ system is highly reliable. The present movie article provides detailed information regarding the test procedures and will promote understanding of the experimental situation. PMID:24637495

  7. An Overview of Translationally Informed Treatments for Posttraumatic Stress Disorder: Animal Models of Pavlovian Fear Conditioning to Human Clinical Trials.

    PubMed

    Bowers, Mallory E; Ressler, Kerry J

    2015-09-01

    Posttraumatic stress disorder manifests after exposure to a traumatic event and is characterized by avoidance/numbing, intrusive symptoms and flashbacks, mood and cognitive disruptions, and hyperarousal/reactivity symptoms. These symptoms reflect dysregulation of the fear system likely caused by poor fear inhibition/extinction, increased generalization, and/or enhanced consolidation or acquisition of fear. These phenotypes can be modeled in animal subjects using Pavlovian fear conditioning, allowing investigation of the underlying neurobiology of normative and pathological fear. Preclinical studies reveal a number of neurotransmitter systems and circuits critical for aversive learning and memory that have informed the development of therapies used in human clinical trials. In this review, we discuss the evidence for a number of established and emerging pharmacotherapies and device-based treatments for posttraumatic stress disorder that have been developed via a bench to bedside translational model.

  8. An overview of translationally informed treatments for PTSD: animal models of Pavlovian fear conditioning to human clinical trials

    PubMed Central

    Bowers, Mallory E.; Ressler, Kerry J.

    2015-01-01

    Posttraumatic stress disorder (PTSD) manifests after exposure to a traumatic event and is characterized by avoidance/numbing, intrusive symptoms and flashbacks, mood and cognitive disruptions, and hyperarousal/reactivity symptoms. These symptoms reflect dysregulation of the fear system likely caused by poor fear inhibition/extinction, increased generalization, and/or enhanced consolidation or acquisition of fear. These phenotypes can be modeled in animal subjects using Pavlovian fear conditioning, allowing investigation of the underlying neurobiology of normative and pathological fear. Pre-clinical studies reveal a number of neurotransmitter systems and circuits critical for aversive learning and memory, which have informed the development of therapies used in human clinical trials. In this review, we discuss the evidence for a number of established and emerging pharmacotherapies and device-based treatments for PTSD that have been developed via a bench to bedside translational model. PMID:26238379

  9. An Overview of Translationally Informed Treatments for Posttraumatic Stress Disorder: Animal Models of Pavlovian Fear Conditioning to Human Clinical Trials.

    PubMed

    Bowers, Mallory E; Ressler, Kerry J

    2015-09-01

    Posttraumatic stress disorder manifests after exposure to a traumatic event and is characterized by avoidance/numbing, intrusive symptoms and flashbacks, mood and cognitive disruptions, and hyperarousal/reactivity symptoms. These symptoms reflect dysregulation of the fear system likely caused by poor fear inhibition/extinction, increased generalization, and/or enhanced consolidation or acquisition of fear. These phenotypes can be modeled in animal subjects using Pavlovian fear conditioning, allowing investigation of the underlying neurobiology of normative and pathological fear. Preclinical studies reveal a number of neurotransmitter systems and circuits critical for aversive learning and memory that have informed the development of therapies used in human clinical trials. In this review, we discuss the evidence for a number of established and emerging pharmacotherapies and device-based treatments for posttraumatic stress disorder that have been developed via a bench to bedside translational model. PMID:26238379

  10. Low levels of estradiol are associated with elevated conditioned responding during fear extinction and with intrusive memories in daily life.

    PubMed

    Wegerer, Melanie; Kerschbaum, Hubert; Blechert, Jens; Wilhelm, Frank H

    2014-12-01

    Posttraumatic stress disorder (PTSD) can be conceptualized as a disorder of emotional memory showing strong (conditioned) responses to trauma reminders and intrusive memories among other symptoms. Women are at greater risk of developing PTSD than men. Recent studies have demonstrated an influence of ovarian steroid hormones in both fear conditioning and intrusive memory paradigms. However, although intrusive memories are considered non-extinguished emotional reactions to trauma reminders, none of the previous studies has investigated effects of ovarian hormones on fear conditioning mechanisms and intrusive memories in conjunction. This may have contributed to an overall inconsistent picture of the role of these hormones in emotional learning and memory. To remedy this, we exposed 37 healthy women with a natural menstrual cycle (during early follicular or luteal cycle phase) to a novel conditioned-intrusion paradigm designed to model real-life traumatic experiences. The paradigm included a differential fear conditioning procedure with short violent film clips as unconditioned stimuli. Intrusive memories about the film clips were assessed ambulatorily on subsequent days. Women with lower levels of estradiol displayed elevated differential conditioned skin conductance responding during fear extinction and showed stronger intrusive memories. The inverse relationship between estradiol and intrusive memories was at least partially accounted for by the conditioned responding observed during fear extinction. Progesterone levels were not associated with either fear acquisition/extinction or with intrusive memories. This suggests that lower levels of estradiol might promote stronger symptoms of PTSD through associative processes.

  11. Low levels of estradiol are associated with elevated conditioned responding during fear extinction and with intrusive memories in daily life.

    PubMed

    Wegerer, Melanie; Kerschbaum, Hubert; Blechert, Jens; Wilhelm, Frank H

    2014-12-01

    Posttraumatic stress disorder (PTSD) can be conceptualized as a disorder of emotional memory showing strong (conditioned) responses to trauma reminders and intrusive memories among other symptoms. Women are at greater risk of developing PTSD than men. Recent studies have demonstrated an influence of ovarian steroid hormones in both fear conditioning and intrusive memory paradigms. However, although intrusive memories are considered non-extinguished emotional reactions to trauma reminders, none of the previous studies has investigated effects of ovarian hormones on fear conditioning mechanisms and intrusive memories in conjunction. This may have contributed to an overall inconsistent picture of the role of these hormones in emotional learning and memory. To remedy this, we exposed 37 healthy women with a natural menstrual cycle (during early follicular or luteal cycle phase) to a novel conditioned-intrusion paradigm designed to model real-life traumatic experiences. The paradigm included a differential fear conditioning procedure with short violent film clips as unconditioned stimuli. Intrusive memories about the film clips were assessed ambulatorily on subsequent days. Women with lower levels of estradiol displayed elevated differential conditioned skin conductance responding during fear extinction and showed stronger intrusive memories. The inverse relationship between estradiol and intrusive memories was at least partially accounted for by the conditioned responding observed during fear extinction. Progesterone levels were not associated with either fear acquisition/extinction or with intrusive memories. This suggests that lower levels of estradiol might promote stronger symptoms of PTSD through associative processes. PMID:25463649

  12. Low levels of estradiol are associated with elevated conditioned responding during fear extinction and with intrusive memories in daily life

    PubMed Central

    Wegerer, Melanie; Kerschbaum, Hubert; Blechert, Jens; Wilhelm, Frank H.

    2014-01-01

    Posttraumatic stress disorder (PTSD) can be conceptualized as a disorder of emotional memory showing strong (conditioned) responses to trauma reminders and intrusive memories among other symptoms. Women are at greater risk of developing PTSD than men. Recent studies have demonstrated an influence of ovarian steroid hormones in both fear conditioning and intrusive memory paradigms. However, although intrusive memories are considered non-extinguished emotional reactions to trauma reminders, none of the previous studies has investigated effects of ovarian hormones on fear conditioning mechanisms and intrusive memories in conjunction. This may have contributed to an overall inconsistent picture of the role of these hormones in emotional learning and memory. To remedy this, we exposed 37 healthy women with a natural menstrual cycle (during early follicular or luteal cycle phase) to a novel conditioned-intrusion paradigm designed to model real-life traumatic experiences. The paradigm included a differential fear conditioning procedure with short violent film clips as unconditioned stimuli. Intrusive memories about the film clips were assessed ambulatorily on subsequent days. Women with lower levels of estradiol displayed elevated differential conditioned skin conductance responding during fear extinction and showed stronger intrusive memories. The inverse relationship between estradiol and intrusive memories was at least partially accounted for by the conditioned responding observed during fear extinction. Progesterone levels were not associated with either fear acquisition/extinction or with intrusive memories. This suggests that lower levels of estradiol might promote stronger symptoms of PTSD through associative processes. PMID:25463649

  13. Extinction of a classically conditioned response: red nucleus and interpositus.

    PubMed

    Robleto, Karla; Thompson, Richard F

    2008-03-01

    It is well established that the cerebellum and its associated circuitry are essential for classical conditioning of the eyeblink response and other discrete motor responses (e.g., limb flexion, head turn, etc.) learned with an aversive unconditioned stimulus. However, brain mechanisms underlying extinction of these responses are still relatively unclear. Behavioral studies have demonstrated extinction to be an active learning process distinct from acquisition. Accordingly, this current understanding of extinction has guided neural studies that have tried to identify possible brain structures that could support this new learning. However, whether extinction engages the same brain sites necessary for acquisition is not yet clear. This poses an overriding problem for understanding brain mechanisms necessary for extinction because such analysis cannot be done without first identifying brain sites and pathways involved in this phenomenon. Equally elusive is the validity of a behavioral theory of extinction that can account for the properties of extinction. In this study, we looked at the involvement of the interpositus and the red nucleus in extinction. Results show that, although inactivation of both nuclei blocks response expression, only inactivation of the interpositus has a detrimental effect on extinction. Moreover, this detrimental effect was completely removed when inactivation of the interpositus was paired with electrical stimulation of the red nucleus. These findings speak to the important role of cerebellar structures in the extinction of discrete motor responses and provide important insight as to the validity of a particular theory of extinction.

  14. Extinction of a classically conditioned response: red nucleus and interpositus.

    PubMed

    Robleto, Karla; Thompson, Richard F

    2008-03-01

    It is well established that the cerebellum and its associated circuitry are essential for classical conditioning of the eyeblink response and other discrete motor responses (e.g., limb flexion, head turn, etc.) learned with an aversive unconditioned stimulus. However, brain mechanisms underlying extinction of these responses are still relatively unclear. Behavioral studies have demonstrated extinction to be an active learning process distinct from acquisition. Accordingly, this current understanding of extinction has guided neural studies that have tried to identify possible brain structures that could support this new learning. However, whether extinction engages the same brain sites necessary for acquisition is not yet clear. This poses an overriding problem for understanding brain mechanisms necessary for extinction because such analysis cannot be done without first identifying brain sites and pathways involved in this phenomenon. Equally elusive is the validity of a behavioral theory of extinction that can account for the properties of extinction. In this study, we looked at the involvement of the interpositus and the red nucleus in extinction. Results show that, although inactivation of both nuclei blocks response expression, only inactivation of the interpositus has a detrimental effect on extinction. Moreover, this detrimental effect was completely removed when inactivation of the interpositus was paired with electrical stimulation of the red nucleus. These findings speak to the important role of cerebellar structures in the extinction of discrete motor responses and provide important insight as to the validity of a particular theory of extinction. PMID:18322108

  15. Eyeblink Classical Conditioning in Alcoholism and Fetal Alcohol Spectrum Disorders.

    PubMed

    Cheng, Dominic T; Jacobson, Sandra W; Jacobson, Joseph L; Molteno, Christopher D; Stanton, Mark E; Desmond, John E

    2015-01-01

    Alcoholism is a debilitating disorder that can take a significant toll on health and professional and personal relationships. Excessive alcohol consumption can have a serious impact on both drinkers and developing fetuses, leading to long-term learning impairments. Decades of research in laboratory animals and humans have demonstrated the value of eyeblink classical conditioning (EBC) as a well-characterized model system to study the neural mechanisms underlying associative learning. Behavioral EBC studies in adults with alcohol use disorders and in children with fetal alcohol spectrum disorders report a clear learning deficit in these two patient populations, suggesting alcohol-related damage to the cerebellum and associated structures. Insight into the neural mechanisms underlying these learning impairments has largely stemmed from laboratory animal studies. In this mini-review, we present and discuss exemplary animal findings and data from patient and neuroimaging studies. An improved understanding of the neural mechanisms underlying learning deficits in EBC related to alcoholism and prenatal alcohol exposure has the potential to advance the diagnoses, treatment, and prevention of these and other pediatric and adult disorders.

  16. Trace but not delay fear conditioning requires attention and the anterior cingulate cortex.

    PubMed

    Han, C J; O'Tuathaigh, Colm M; van Trigt, Laurent; Quinn, Jennifer J; Fanselow, Michael S; Mongeau, Raymond; Koch, Christof; Anderson, David J

    2003-10-28

    Higher cognitive functions such as attention have been difficult to model in genetically tractable organisms. In humans, attention-distracting stimuli interfere with trace but not delay conditioning, two forms of associative learning. Attention has also been correlated with activation of anterior cingulate cortex (ACC), but its functional significance is unclear. Here we show that a visual distractor interferes selectively with trace but not delay auditory fear conditioning in mice. Trace conditioning is associated with increased neuronal activity in ACC, as assayed by relative levels of c-fos expression, and is selectively impaired by lesions of this structure. The effects of the ACC lesions are unlikely to be caused by indirect impairment of the hippocampus, which is required for mnemonic aspects of trace conditioning. These data suggest that trace conditioning may be useful for studying neural substrates of attention in mice, and implicate the ACC as one such substrate. PMID:14555761

  17. Chronic stress, cyclic 17β-estradiol, and daily handling influences on fear conditioning in the female rat.

    PubMed

    Hoffman, Ann N; Armstrong, Charles E; Hanna, Jeffery J; Conrad, Cheryl D

    2010-10-01

    Chronic stress and estrogens alter many forebrain regions in female rats that affect cognition. In order to investigate how chronic stress and estrogens influence fear learning and memory, we ovariectomized (OVX) female Sprague-Dawley rats and repeatedly injected them (s.c.) with 17β-estradiol (E, 10 μg/250 g or sesame oil vehicle, VEH). Concurrently, rats were restrained for 6 h/d/21 d (STR) or left undisturbed (CON). Rats were then fear conditioned with 4 tone-footshock pairings and then after 1 h and 24 h delays, given 15 tone extinction trials. Regardless of E treatment, chronic stress (VEH, E) facilitated freezing to tone during acquisition and extinction following a 1h delay, but not during extinction after a 24 h delay. E did not influence freezing to tone during any phase of fear conditioning for either the control or chronically stressed rats, but did influence contextual conditioning that may have been carried predominately by the STR group. In the second experiment, we investigated "handling" influences on fear conditioning acquisition, given the disparate findings from the current study and previous work (Baran, Armstrong, Niren, & Conrad, 2010; Baran, Armstrong, Niren, Hanna, & Conrad, 2009). Female rats remained gonadally-intact since E did not influence tone fear conditioning. Indeed, brief daily handling (1-3 m/d/21 d) facilitated acquisition of fear conditioning in chronically stressed female rats, and either had no effect or slightly attenuated fear conditioning in controls. Thus, chronic stress impacts amygdala-mediated fear learning in both OVX- and gonadally-intact females as found previously in males, with handling significantly influencing these outcomes.

  18. Reciprocal Patterns of c-Fos Expression in the Medial Prefrontal Cortex and Amygdala after Extinction and Renewal of Conditioned Fear

    ERIC Educational Resources Information Center

    Knapska, Ewelina; Maren, Stephen

    2009-01-01

    After extinction of conditioned fear, memory for the conditioning and extinction experiences becomes context dependent. Fear is suppressed in the extinction context, but renews in other contexts. This study characterizes the neural circuitry underlying the context-dependent retrieval of extinguished fear memories using c-Fos immunohistochemistry.…

  19. Systemic or Intra-Amygdala Injection of a Benzodiazepine (Midazolam) Impairs Extinction but Spares Re-Extinction of Conditioned Fear Responses

    ERIC Educational Resources Information Center

    Hart, Genevra; Harris, Justin A.; Westbrook, R. Frederick

    2009-01-01

    Rats were subjected to one or two cycles of fear conditioning and extinction, injected with a benzodiazepine, midazolam, before the first or second extinction, and tested for long-term inhibition of fear responses (freezing). In Experiment 1, inhibition of context-conditioned fear was spared when midazolam was injected before the second…

  20. The role of nucleus accumbens shell in learning about neutral versus excitatory stimuli during Pavlovian fear conditioning.

    PubMed

    Bradfield, Laura A; McNally, Gavan P

    2010-07-01

    We studied the role of nucleus accumbens shell (AcbSh) in Pavlovian fear conditioning. Rats were trained to fear conditioned stimulus A (CSA) in Stage I, which was then presented in compound with a neutral stimulus and paired with shock in Stage II. AcbSh lesions had no effect on fear-learning to CSA in Stage I, but selectively prevented learning about the neutral conditioned stimulus (CS) in Stage II. These results add to a growing body of evidence indicating an important role for the ventral striatum in fear-learning. They suggest that the ventral striatum and AcbSh, in particular, directs learning toward or away from a CS as a consequence of how well that CS predicts the shock unconditioned stimulus (US). AcbSh is required to reduce the processing of established predictors, thereby permitting neutral or less predictive stimuli to be learned about.

  1. A risk variant for alcoholism in the NMDA receptor affects amygdala activity during fear conditioning in humans.

    PubMed

    Cacciaglia, Raffaele; Nees, Frauke; Pohlack, Sebastian T; Ruttorf, Michaela; Winkelmann, Tobias; Witt, Stephanie H; Nieratschker, Vanessa; Rietschel, Marcella; Flor, Herta

    2013-09-01

    People at high risk for alcoholism show deficits in aversive learning, as indicated by impaired electrodermal responses during fear conditioning, a basic form of associative learning that depends on the amygdala. A positive family history of alcohol dependence has also been related to decreased amygdala responses during emotional processing. In the present study we report reduced amygdala activity during the acquisition of conditioned fear in healthy carriers of a risk variant for alcoholism (rs2072450) in the NR2A subunit-containing N-methyl-d-aspartate (NMDA)-receptor. These results indicate that rs2072450 might confer risk for alcohol dependence through deficient fear acquisition indexed by a diminished amygdala response during aversive learning, and provide a neural basis for a weak behavioral inhibition previously documented in individuals at high risk for alcohol dependence. Carriers of the risk variant additionally exhibit dampened insula activation, a finding that further strengthens our data, given the importance of this brain region in fear conditioning.

  2. A bout of voluntary running enhances context conditioned fear, its extinction, and its reconsolidation.

    PubMed

    Siette, Joyce; Reichelt, Amy C; Westbrook, R Frederick

    2014-02-01

    Three experiments used rats to examine the effect of a single bout of voluntary activity (wheel running) on the acquisition, extinction, and reconsolidation of context conditioned fear. In Experiment 1, rats provided with access to a wheel for 3 h immediately before or after a shocked exposure to a context froze more when tested in that context than rats provided with access to the wheels 6 h after the shocked exposure or rats not provided with access to the wheels. In Experiment 2, rats provided with access to the wheels immediately before or after a nonshocked exposure to the conditioned context froze less when tested in that context than rats provided with access to the wheels 6 h after the nonshocked exposure or rats not provided with access to the wheels. In Experiment 3, rats provided with access to wheels immediately after an extended nonshocked exposure to the conditioned context again froze less, whereas rats provided with access to the wheels after a brief nonshocked exposure froze more on the subsequent test than sedentary controls. These results show that a single bout of running can enhance acquisition, extinction, and reconsolidation of context conditioned fear.

  3. Glutamate receptors in the medial geniculate nucleus are necessary for expression and extinction of conditioned fear in rats.

    PubMed

    Orsini, Caitlin A; Maren, Stephen

    2009-11-01

    Auditory fear conditioning requires anatomical projections from the medial geniculate nucleus (MGN) of the thalamus to the amygdala. Several lines of work indicate that the MGN is a critical sensory relay for auditory information during conditioning, but is not itself involved in the encoding of long-term fear memories. In the present experiments, we examined whether the MGN plays a similar role in the extinction of conditioned fear. Twenty-four hours after Pavlovian fear conditioning, rats received bilateral intra-thalamic infusions of either with NBQX (an AMPA receptor antagonist; Experiment 1) or MK-801 (an NMDA receptor antagonist; Experiment 1), anisomycin (a protein synthesis inhibitor; Experiment 2) or U0126 (a MEK inhibitor; Experiment 3) immediately prior to an extinction session in a novel context. The next day rats received a tone test in a drug-free state to assess their extinction memory; freezing served as an index of fear. Glutamate receptor antagonism prevented both the expression and extinction of conditioned fear. In contrast, neither anisomycin nor U0126 affected extinction. These results suggest that the MGN is a critical sensory relay for auditory information during extinction training, but is not itself a site of plasticity underlying the formation of the extinction memory.

  4. Enhancement of Odor Sensitivity Following Repeated Odor and Visual Fear Conditioning.

    PubMed

    Parma, Valentina; Ferraro, Stefania; Miller, Stacie S; Åhs, Fredrik; Lundström, Johan N

    2015-09-01

    Odor detection sensitivity can be rapidly altered by fear conditioning; whether this effect is augmented over time is not known. The present study aimed to test whether repeated conditioning sessions induce changes in odor detection threshold as well as in conditioned responses and whether olfactory stimuli evoke stronger conditioned responses than visual stimuli. The repeated conditioning group participated in repeated sessions over 2 weeks whereas the single conditioning group participated in 1 conditioning session; both groups were presented with visual and olfactory stimuli, were paired with an electric shock (CS+) and 2 matched control stimuli not paired with shock (CS-) while olfactory detection threshold and skin conductance responses (SCRs) were measured before and after the last session. We found increased sensitivity for the CS+ odor in the repeated but not in the single conditioning group, consistent with changes in olfactory sensitivity following repeated aversive learning and of a similar magnitude to what has previously been demonstrated in the periphery. SCR to the visual and olfactory CS+ were similar between groups, indicating that sensory thresholds can change without corresponding change in conditioned responses. In conclusion, repeated conditioning increases detection sensitivity and reduces conditioned responses, suggesting that segregated processes influence perception and conditioned responses.

  5. Extinction reverses olfactory fear-conditioned increases in neuron number and glomerular size.

    PubMed

    Morrison, Filomene G; Dias, Brian G; Ressler, Kerry J

    2015-10-13

    Although much work has investigated the contribution of brain regions such as the amygdala, hippocampus, and prefrontal cortex to the processing of fear learning and memory, fewer studies have examined the role of sensory systems, in particular the olfactory system, in the detection and perception of cues involved in learning and memory. The primary sensory receptive field maps of the olfactory system are exquisitely organized and respond dynamically to cues in the environment, remaining plastic from development through adulthood. We have previously demonstrated that olfactory fear conditioning leads to increased odorant-specific receptor representation in the main olfactory epithelium and in glomeruli within the olfactory bulb. We now demonstrate that olfactory extinction training specific to the conditioned odor stimulus reverses the conditioning-associated freezing behavior and odor learning-induced structural changes in the olfactory epithelium and olfactory bulb in an odorant ligand-specific manner. These data suggest that learning-induced freezing behavior, structural alterations, and enhanced neural sensory representation can be reversed in adult mice following extinction training.

  6. Cannabinoid modulation of chronic mild stress-induced selective enhancement of trace fear conditioning in adolescent rats.

    PubMed

    Reich, Christian G; Iskander, Anthony N; Weiss, Michael S

    2013-10-01

    History of stress is considered a major risk factor for the development of major depression and posttraumatic stress disorder (PTSD). Elucidating the neurobiological mechanisms of Pavlovian fear conditioning may provide insight into the etiology of PTSD. In the current study, adolescent male Sprague-Dawley rats were exposed to 3 weeks of a chronic-mild-unpredictable stress (CMS) protocol. Immediately following the CMS, the animals were subjected to hippocampal-dependent (trace and contextual) and hippocampal-independent (delay) fear conditioning. CMS exposure enhanced trace freezing behavior compared to non-stress controls. This effect was not observed in contextual or delay conditioned animals. Given that the endocannabinoid system is negatively affected by CMS procedures, separate groups of stressed rats were administered the CB1 receptor agonist, ACEA (0.1 mg/kg), prior to trace fear conditioning or a memory-recall test. Regardless of administration time, ACEA significantly reduced freezing behavior in stressed animals. Furthermore, when administered during the first memory recall test, ACEA enhanced long-term extinction in both stress and non-stress groups. The results demonstrate that chronic unpredictable stress selectively enhances hippocampal-dependent episodic fear memories. Pathologies of the episodic memory and fear response may increase the susceptibility of developing PTSD. Reduction in fear responses via exogenous activation of the CB1 receptor suggests that a deficiency in the endocannabinoid system contributes to this pathology.

  7. Fear-potentiated startle processing in humans: Parallel fMRI and orbicularis EMG assessment during cue conditioning and extinction.

    PubMed

    Lindner, Katja; Neubert, Jörg; Pfannmöller, Jörg; Lotze, Martin; Hamm, Alfons O; Wendt, Julia

    2015-12-01

    Studying neural networks and behavioral indices such as potentiated startle responses during fear conditioning has a long tradition in both animal and human research. However, most of the studies in humans do not link startle potentiation and neural activity during fear acquisition and extinction. Therefore, we examined startle blink responses measured with electromyography (EMG) and brain activity measured with functional MRI simultaneously during differential conditioning. Furthermore, we combined these behavioral fear indices with brain network activity by analyzing the brain activity evoked by the startle probe stimulus presented during conditioned visual threat and safety cues as well as in the absence of visual stimulation. In line with previous research, we found a fear-induced potentiation of the startle blink responses when elicited during a conditioned threat stimulus and a rapid decline of amygdala activity after an initial differentiation of threat and safety cues in early acquisition trials. Increased activation during processing of threat cues was also found in the anterior insula, the anterior cingulate cortex (ACC), and the periaqueductal gray (PAG). More importantly, our results depict an increase of brain activity to probes presented during threatening in comparison to safety cues indicating an involvement of the anterior insula, the ACC, the thalamus, and the PAG in fear-potentiated startle processing during early extinction trials. Our study underlines that parallel assessment of fear-potentiated startle in fMRI paradigms can provide a helpful method to investigate common and distinct processing pathways in humans and animals and, thus, contributes to translational research.

  8. Estradiol levels in women predict skin conductance response but not valence and expectancy ratings in conditioned fear extinction.

    PubMed

    White, Emily C; Graham, Bronwyn M

    2016-10-01

    Anxiety disorders are more prevalent in women than men. One contributing factor may be the sex hormone estradiol, which is known to impact the long term recall of conditioned fear extinction, a laboratory procedure that forms the basis of exposure therapy for anxiety disorders. To date, the literature examining estradiol and fear extinction in humans has focused primarily on physiological measures of fear, such as skin conductance response (SCR) and fear potentiated startle. This is surprising, given that models of anxiety identify at least three important components: physiological symptoms, cognitive beliefs, and avoidance behavior. To help address this gap, we exposed women with naturally high (n=20) or low estradiol (n=19), women using hormonal contraceptives (n=16), and a male control group (n=18) to a fear extinction task, and measured SCR, US expectancy and CS valence ratings. During extinction recall, low estradiol was associated with greater recovery of SCR, but was not related to US expectancy or CS evaluation. Importantly, women using hormonal contraceptives showed a dissociation between SCR and cognitive beliefs: they exhibited a greater recovery of SCR during extinction recall, yet reported similar US expectancy and CS valence ratings to the other female groups. This divergence underscores the importance of assessing multiple measures of fear when examining the role of estradiol in human fear extinction, especially when considering the potential of estradiol as an enhancement for psychological treatments for anxiety disorders. PMID:27544848

  9. Estradiol levels in women predict skin conductance response but not valence and expectancy ratings in conditioned fear extinction.

    PubMed

    White, Emily C; Graham, Bronwyn M

    2016-10-01

    Anxiety disorders are more prevalent in women than men. One contributing factor may be the sex hormone estradiol, which is known to impact the long term recall of conditioned fear extinction, a laboratory procedure that forms the basis of exposure therapy for anxiety disorders. To date, the literature examining estradiol and fear extinction in humans has focused primarily on physiological measures of fear, such as skin conductance response (SCR) and fear potentiated startle. This is surprising, given that models of anxiety identify at least three important components: physiological symptoms, cognitive beliefs, and avoidance behavior. To help address this gap, we exposed women with naturally high (n=20) or low estradiol (n=19), women using hormonal contraceptives (n=16), and a male control group (n=18) to a fear extinction task, and measured SCR, US expectancy and CS valence ratings. During extinction recall, low estradiol was associated with greater recovery of SCR, but was not related to US expectancy or CS evaluation. Importantly, women using hormonal contraceptives showed a dissociation between SCR and cognitive beliefs: they exhibited a greater recovery of SCR during extinction recall, yet reported similar US expectancy and CS valence ratings to the other female groups. This divergence underscores the importance of assessing multiple measures of fear when examining the role of estradiol in human fear extinction, especially when considering the potential of estradiol as an enhancement for psychological treatments for anxiety disorders.

  10. Food and water deprivation disrupts latent inhibition with an auditory fear conditioning procedure.

    PubMed

    De la Casa, Luis G

    2013-11-01

    Latent inhibition (LI), operationally defined as the reduced conditioned response to a stimulus that has been preexposed before conditioning, seems to be determined by the interaction of different processes that includes attentional, associative, memory, motivational, and emotional factors. In this paper we focused on the role of deprivation level on LI intensity using an auditory fear conditioning procedure with rats. LI was observed when the animals were non-deprived, but it was disrupted when the rats were water- or food-deprived. We propose that deprivation induced an increase in attention to the to-be-CS, and, as a result, LI was disrupted in deprived animals. The implications of the results for the current interpretations of LI are also discussed.

  11. Impaired extinction of fear conditioning after REM deprivation is magnified by rearing in an enriched environment.

    PubMed

    Hunter, Amy Silvestri

    2015-07-01

    Evidence from both human and animal studies indicates that rapid eye movement sleep (REM) is essential for the acquisition and retention of information, particularly of an emotional nature. Learning and memory can also be impacted by manipulation of housing condition such as exposure to an enriched environment (EE). This study investigated the effects of REM deprivation and EE, both separately and combined, on the extinction of conditioned fear in rats. Consistent with prior studies, conditioning was enhanced in EE-reared rats and extinction was impaired in REM deprived rats. In addition, rats exposed to both REM deprivation and EE showed the greatest impairment in extinction, with effects persisting through the first two days of extinction training. This study is the first to explore the combination of REM deprivation and EE and suggests that manipulations that alter sleep, particularly REM, can have persisting deleterious effects on emotional memory processing.

  12. Effects of mild TBI from repeated blast overpressure on the expression and extinction of conditioned fear in rats.

    PubMed

    Genovese, R F; Simmons, L P; Ahlers, S T; Maudlin-Jeronimo, E; Dave, J R; Boutte, A M

    2013-12-19

    Mild traumatic brain injury (mTBI) and post-traumatic stress disorder (PTSD) are pressing medical issues for the Warfighter. Symptoms of mTBI can overlap with those of PTSD, suggesting the possibility of a causal or mediating role of mTBI in PTSD. To address whether mTBI can exacerbate the neurobiological processes associated with traumatic stress, we evaluated the impact of mTBI from a blast overpressure (BOP) on the expression of a conditioned fear. In the rat, conditioned fear models are used to evaluate the emotional conditioning processes that are known to become dysfunctional in PTSD. Rats were first trained on a variable interval (VI), food maintained, operant conditioning task that established a general measure of performance. Inescapable electric shock (IES) was paired with an audio-visual conditioned stimulus (CS) and followed 1day later by three daily exposures to BOP (75kPa). Subsequently, the CS alone was presented once every 7days for 2months, beginning 4days following the last BOP. The CS was presented during the VI sessions allowing a concurrent measure of performance. Treatment groups (n=10, each group) received IES+BOP, IES+sham-BOP, sham-IES+BOP or sham-IES+sham-BOP. As expected, pairing the CS with IES produced a robust conditioned fear that was quantified by a suppression of responding on the VI. BOP significantly decreased the expression of the conditioned fear. No systematic short- or long-term performance deficits were observed on the VI from BOP. These results show that mTBI from BOP can affect the expression of a conditioned fear and suggests that BOP caused a decrease in inhibitory behavioral control. Continued presentation of the CS produced progressively less response suppression in both fear conditioned treatments, consistent with extinction of the conditioned fear. Taken together, these results show that mTBI from BOP can affect the expression of a conditioned fear but not necessarily in a manner that increases the conditioned fear or

  13. Limbic areas are functionally decoupled and visual cortex takes a more central role during fear conditioning in humans

    PubMed Central

    Lithari, Chrysa; Moratti, Stephan; Weisz, Nathan

    2016-01-01

    Going beyond the focus on isolated brain regions (e.g. amygdala), recent neuroimaging studies on fear conditioning point to the relevance of a network of mutually interacting brain regions. In the present MEG study we used Graph Theory to uncover changes in the architecture of the brain functional network shaped by fear conditioning. Firstly, induced power analysis revealed differences in local cortical excitability (lower alpha and beta power) between CS+ and CS− localized to somatosensory cortex and insula. What is more striking however is that the graph theoretical measures unveiled a re-organization of brain functional connections, not evident using conventional power analysis. Subcortical fear-related structures exhibited reduced connectivity with temporal and frontal areas rendering the overall brain functional network more sparse during fear conditioning. At the same time, the calcarine took on a more central role in the network. Interestingly, the more the connectivity of limbic areas is reduced, the more central the role of the occipital cortex becomes. We speculated that both, the reduced coupling in some regions and the emerging centrality of others, contribute to the efficient processing of fear-relevant information during fear learning. PMID:27381479

  14. Limbic areas are functionally decoupled and visual cortex takes a more central role during fear conditioning in humans.

    PubMed

    Lithari, Chrysa; Moratti, Stephan; Weisz, Nathan

    2016-01-01

    Going beyond the focus on isolated brain regions (e.g. amygdala), recent neuroimaging studies on fear conditioning point to the relevance of a network of mutually interacting brain regions. In the present MEG study we used Graph Theory to uncover changes in the architecture of the brain functional network shaped by fear conditioning. Firstly, induced power analysis revealed differences in local cortical excitability (lower alpha and beta power) between CS+ and CS- localized to somatosensory cortex and insula. What is more striking however is that the graph theoretical measures unveiled a re-organization of brain functional connections, not evident using conventional power analysis. Subcortical fear-related structures exhibited reduced connectivity with temporal and frontal areas rendering the overall brain functional network more sparse during fear conditioning. At the same time, the calcarine took on a more central role in the network. Interestingly, the more the connectivity of limbic areas is reduced, the more central the role of the occipital cortex becomes. We speculated that both, the reduced coupling in some regions and the emerging centrality of others, contribute to the efficient processing of fear-relevant information during fear learning. PMID:27381479

  15. Revisiting classical silicate dissolution rate laws under hydrothermal conditions

    NASA Astrophysics Data System (ADS)

    Pollet-Villard, Marion; Daval, Damien; Saldi, Giuseppe; Knauss, Kevin; Wild, Bastien; Fritz, Bertrand

    2015-04-01

    In the context of geothermal energy, the relative intensities of primary mineral leaching and secondary mineral precipitation can affect porosity and permeability of the reservoir, thereby influencing its hydraulic performance and the efficiency of the geothermal power station. That is why the prediction of reaction kinetics of fluid/rock interactions represents a critical issue in this context. Moreover, in several geothermal systems such as the one of Soultz-sous-Forêts (Alsace, France), the circulation of aqueous fluids induces only modest modifications of their chemical composition. Therefore, fluid-rock interactions take place at close-to-equilibrium conditions, where the rate-affinity relations are poorly known and intensively debated [1]. To describe more precisely the dissolution processes, our strategy consists in investigating the dissolution of the main cleavages of K-spar minerals (one of the prevalent primary minerals in the reservoir of Soultz-sous-Forêts geothermal system) over a wide range of Gibbs free energy (ΔG) conditions. The aims are to decipher the impact of crystallographic orientation and microstructural surface modifications on the dissolution kinetics and to propose a relation between K-spar dissolution rate and ΔG. Our experimental work relies on a coupled approach which combines classical experiments of K-spar dissolution monitored by aqueous chemical analyses (ICP-AES) and innovative techniques of nm- to μm-scale characterization of solid surface (SEM, AFM, VSI) [2]. Our results confirm that K-spar dissolution is an anisotropic process: we measure a tenfold factor between the slowest and the fastest-dissolving surfaces. Moreover, the formation of etch pits on surfaces during their alteration has been evidenced on all of the different faces that have been studied. This complex evolution of the surface topography casts doubt of the relevance of a surface model based on shrinking particles and represents a possible cause of an

  16. Conditioning- and Time-Dependent Increases in Context Fear and Generalization

    ERIC Educational Resources Information Center

    Poulos, Andrew M.; Mehta, Nehali; Lu, Bryan; Amir, Dorsa; Livingston, Briana; Santarelli, Anthony; Zhuravka, Irina; Fanselow, Michael S.

    2016-01-01

    A prominent feature of fear memories and anxiety disorders is that they endure across extended periods of time. Here, we examine how the severity of the initial fear experience influences incubation, generalization, and sensitization of contextual fear memories across time. Adult rats were presented with either five, two, one, or zero shocks (1.2…

  17. The role of "interoceptive" fear conditioning in the development of panic disorder.

    PubMed

    De Cort, Klara; Griez, Eric; Büchler, Marjolein; Schruers, Koen

    2012-03-01

    More than 20% of the general population experience a panic attack at least once in their lives; however, only a minority goes on to develop panic disorder (PD). Conditioning mechanisms have been proposed to explain this evolution in persons who are susceptible to developing panic disorder upon a "traumatic" panic attack. According to preparedness theory, some cues are more likely to condition than others, namely, those referring to internal, bodily signals of danger. The aim of the present study was to test this theory in a differential conditioning paradigm, making use of scripts referring to different internal, bodily sensations as conditioned stimulus (CS) and inhalation of 35% CO(2) as unconditioned stimulus (UCS). Thirty-three healthy volunteers were assigned to three scripts conditions: "suffocation," "neutral," or "urgency." During acquisition, one of two versions of a particular script was always followed by an inhalation of 35% CO(2) (CS+) and the other by room air (CS-). Acquisition was followed by a test phase, where only inhalations of room air were administered. In line with our hypothesis, only participants in the suffocation condition exhibited a selective conditioning effect. They were more fearful and showed a significantly higher increase in tidal volume than participants in the two control conditions. Results are discussed with relation to interoceptive conditioning, preparedness, and the possible role of tidal volume in PD.

  18. Reinstatement of Extinguished Conditioned Responses and Negative Stimulus Valence as a Pathway to Return of Fear in Humans

    ERIC Educational Resources Information Center

    Dirikx, Trinette; Hermans, Dirk; Vansteenwegen, Debora; Baeyens, Frank; Eelen, Paul

    2004-01-01

    The present study investigated reinstatement of conditioned responses in humans by using a differential Pavlovian conditioning procedure. Evidence for reinstatement was established in a direct (fear rating) and in an indirect measure (secondary reaction time task) of conditioning. Moreover, the amount of reinstatement in the secondary reaction…

  19. Immediate Extinction Causes a Less Durable Loss of Performance than Delayed Extinction following Either Fear or Appetitive Conditioning

    ERIC Educational Resources Information Center

    Woods, Amanda M.; Bouton, Mark E.

    2008-01-01

    Five experiments with rat subjects compared the effects of immediate and delayed extinction on the durability of extinction learning. Three experiments examined extinction of fear conditioning (using the conditioned emotional response method), and two experiments examined extinction of appetitive conditioning (using the food-cup entry method). In…

  20. A pragmatic comparison of noise burst and electric shock unconditioned stimuli for fear conditioning research with many trials.

    PubMed

    Sperl, Matthias F J; Panitz, Christian; Hermann, Christiane; Mueller, Erik M

    2016-09-01

    Several methods that are promising for studying the neurophysiology of fear conditioning (e.g., EEG, MEG) require a high number of trials to achieve an adequate signal-to-noise ratio. While electric shock and white noise burst are among the most commonly used unconditioned stimuli (US) in conventional fear conditioning studies with few trials, it is unknown whether these stimuli are equally well suited for paradigms with many trials. Here, N = 32 participants underwent a 260-trial differential fear conditioning and extinction paradigm with a 240-trial recall test 24 h later and neutral faces as conditioned stimuli. In a between-subjects design, either white noise bursts (n = 16) or electric shocks (n = 16) served as US, and intensities were determined using the most common procedure for each US (i.e., a fixed 95 dB noise burst and a work-up procedure for electric shocks, respectively). In addition to differing US types, groups also differed in closely linked US-associated characteristics (e.g., calibration methods, stimulus intensities, timing). Subjective ratings (arousal/valence), skin conductance, and evoked heart period changes (i.e., fear bradycardia) indicated more reliable, extinction-resistant, and stable conditioning in the white noise burst versus electric shock group. In fear conditioning experiments where many trials are presented, white noise burst should serve as US.

  1. A pragmatic comparison of noise burst and electric shock unconditioned stimuli for fear conditioning research with many trials.

    PubMed

    Sperl, Matthias F J; Panitz, Christian; Hermann, Christiane; Mueller, Erik M

    2016-09-01

    Several methods that are promising for studying the neurophysiology of fear conditioning (e.g., EEG, MEG) require a high number of trials to achieve an adequate signal-to-noise ratio. While electric shock and white noise burst are among the most commonly used unconditioned stimuli (US) in conventional fear conditioning studies with few trials, it is unknown whether these stimuli are equally well suited for paradigms with many trials. Here, N = 32 participants underwent a 260-trial differential fear conditioning and extinction paradigm with a 240-trial recall test 24 h later and neutral faces as conditioned stimuli. In a between-subjects design, either white noise bursts (n = 16) or electric shocks (n = 16) served as US, and intensities were determined using the most common procedure for each US (i.e., a fixed 95 dB noise burst and a work-up procedure for electric shocks, respectively). In addition to differing US types, groups also differed in closely linked US-associated characteristics (e.g., calibration methods, stimulus intensities, timing). Subjective ratings (arousal/valence), skin conductance, and evoked heart period changes (i.e., fear bradycardia) indicated more reliable, extinction-resistant, and stable conditioning in the white noise burst versus electric shock group. In fear conditioning experiments where many trials are presented, white noise burst should serve as US. PMID:27286734

  2. MR Diffusion Tensor Imaging Detects Rapid Microstructural Changes in Amygdala and Hippocampus Following Fear Conditioning in Mice

    PubMed Central

    Ding, Abby Y.; Li, Qi; Zhou, Iris Y.; Ma, Samantha J.; Tong, Gehua; McAlonan, Grainne M.; Wu, Ed X.

    2013-01-01

    Background Following fear conditioning (FC), ex vivo evidence suggests that early dynamics of cellular and molecular plasticity in amygdala and hippocampal circuits mediate responses to fear. Such altered dynamics in fear circuits are thought to be etiologically related to anxiety disorders including posttraumatic stress disorder (PTSD). Consistent with this, neuroimaging studies of individuals with established PTSD in the months after trauma have revealed changes in brain regions responsible for processing fear. However, whether early changes in fear circuits can be captured in vivo is not known. Methods We hypothesized that in vivo magnetic resonance diffusion tensor imaging (DTI) would be sensitive to rapid microstructural changes elicited by FC in an experimental mouse PTSD model. We employed a repeated measures paired design to compare in vivo DTI measurements before, one hour after, and one day after FC-exposed mice (n = 18). Results Using voxel-wise repeated measures analysis, fractional anisotropy (FA) significantly increased then decreased in amygdala, decreased then increased in hippocampus, and was increasing in cingulum and adjacent gray matter one hour and one day post-FC respectively. These findings demonstrate that DTI is sensitive to early changes in brain microstructure following FC, and that FC elicits distinct, rapid in vivo responses in amygdala and hippocampus. Conclusions Our results indicate that DTI can detect rapid microstructural changes in brain regions known to mediate fear conditioning in vivo. DTI indices could be explored as a translational tool to capture potential early biological changes in individuals at risk for developing PTSD. PMID:23382811

  3. NMDA receptor antagonism in the basolateral but not central amygdala blocks the extinction of Pavlovian fear conditioning in rats.

    PubMed

    Zimmerman, Joshua M; Maren, Stephen

    2010-05-01

    Glutamate receptors in the basolateral complex of the amygdala (BLA) are essential for the acquisition, expression and extinction of Pavlovian fear conditioning in rats. Recent work has revealed that glutamate receptors in the central nucleus of the amygdala (CEA) are also involved in the acquisition of conditional fear, but it is not known whether they play a role in fear extinction. Here we examine this issue by infusing glutamate receptor antagonists into the BLA or CEA prior to the extinction of fear to an auditory conditioned stimulus (CS) in rats. Infusion of the alpha-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) receptor antagonist, 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo[f]quinoxaline-2,3-dione (NBQX), into either the CEA or BLA impaired the expression of conditioned freezing to the auditory CS, but did not impair the formation of a long-term extinction memory to that CS. In contrast, infusion of the N-methyl-D-aspartate (NMDA) receptor antagonist, D,L-2-amino-5-phosphonopentanoic acid (APV), into the amygdala, spared the expression of fear to the CS during extinction training, but impaired the acquisition of a long-term extinction memory. Importantly, only APV infusions into the BLA impaired extinction memory. These results reveal that AMPA and NMDA receptors within the amygdala make dissociable contributions to the expression and extinction of conditioned fear, respectively. Moreover, they indicate that NMDA receptor-dependent processes involved in extinction learning are localized to the BLA. Together with previous work, these results reveal that NMDA receptors in the CEA have a selective role acquisition of fear memory.

  4. Inactivation of the central nucleus of the amygdala blocks classical conditioning but not conditioning-specific reflex modification of rabbit heart rate.

    PubMed

    Burhans, Lauren B; Schreurs, Bernard G

    2013-02-01

    Heart rate (HR) conditioning in rabbits is a widely used model of classical conditioning of autonomic responding that is noted for being similar to the development of conditioned heart rate slowing (bradycardia) in humans. We have shown previously that in addition to HR changes to a tone conditioned stimulus (CS), the HR reflex itself can undergo associative change called conditioning-specific reflex modification (CRM) that manifests when tested in the absence of the CS. Because CRM resembles the conditioned bradycardic response to the CS, we sought to determine if HR conditioning and CRM share a common neural substrate. The central nucleus of the amygdala (CeA) is a critical part of the pathway through which conditioned bradycardia is established. To test whether the CeA is also involved in the acquisition and/or expression of CRM, we inactivated the CeA with muscimol during HR conditioning or CRM testing. CeA inactivation blocked HR conditioning without completely preventing CRM acquisition or expression. These results suggest that the CeA may therefore only play a modulatory role in CRM. Theories on the biological significance of conditioned bradycardia suggest that it may represent a state of hypervigilance that facilitates the detection of new and changing contingencies in the environment. We relate these ideas to our results and discuss how they may be relevant to the hypersensitivity observed in fear conditioning disorders like post-traumatic stress.

  5. Activation of ERK/MAP kinase in the amygdala is required for memory consolidation of pavlovian fear conditioning.

    PubMed

    Schafe, G E; Atkins, C M; Swank, M W; Bauer, E P; Sweatt, J D; LeDoux, J E

    2000-11-01

    Although much has been learned about the neurobiological mechanisms underlying Pavlovian fear conditioning at the systems and cellular levels, relatively little is known about the molecular mechanisms underlying fear memory consolidation. The present experiments evaluated the role of the extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK) signaling cascade in the amygdala during Pavlovian fear conditioning. We first show that ERK/MAPK is transiently activated-phosphorylated in the amygdala, specifically the lateral nucleus (LA), at 60 min, but not 15, 30, or 180 min, after conditioning, and that this activation is attributable to paired presentations of tone and shock rather than to nonassociative auditory stimulation, foot shock sensitization, or unpaired tone-shock presentations. We next show that infusions of U0126, an inhibitor of ERK/MAPK activation, aimed at the LA, dose-dependently impair long-term memory of Pavlovian fear conditioning but leaves short-term memory intact. Finally, we show that bath application of U0126 impairs long-term potentiation in the LA in vitro. Collectively, these results demonstrate that ERK/MAPK activation is necessary for both memory consolidation of Pavlovian fear conditioning and synaptic plasticity in the amygdala.

  6. Maladaptive behavioral consequences of conditioned fear-generalization: a pronounced, yet sparsely studied, feature of anxiety pathology.

    PubMed

    van Meurs, Brian; Wiggert, Nicole; Wicker, Isaac; Lissek, Shmuel

    2014-06-01

    Fear-conditioning experiments in the anxiety disorders focus almost exclusively on passive-emotional, Pavlovian conditioning, rather than active-behavioral, instrumental conditioning. Paradigms eliciting both types of conditioning are needed to study maladaptive, instrumental behaviors resulting from Pavlovian abnormalities found in clinical anxiety. One such Pavlovian abnormality is generalization of fear from a conditioned danger-cue (CS+) to resembling stimuli. Though lab-based findings repeatedly link overgeneralized Pavlovian-fear to clinical anxiety, no study assesses the degree to which Pavlovian overgeneralization corresponds with maladaptive, overgeneralized instrumental-avoidance. The current effort fills this gap by validating a novel fear-potentiated startle paradigm including Pavlovian and instrumental components. The paradigm is embedded in a computer game during which shapes appear on the screen. One shape paired with electric-shock serves as CS+, and other resembling shapes, presented in the absence of shock, serve as generalization stimuli (GSs). During the game, participants choose whether to behaviorally avoid shock at the cost of poorer performance. Avoidance during CS+ is considered adaptive because shock is a real possibility. By contrast, avoidance during GSs is considered maladaptive because shock is not a realistic prospect and thus unnecessarily compromises performance. Results indicate significant Pavlovian-instrumental relations, with greater generalization of Pavlovian fear associated with overgeneralization of maladaptive instrumental-avoidance.

  7. Maladaptive Behavioral Consequences of Conditioned Fear-Generalization: A Pronounced, Yet Sparsely Studied, Feature of Anxiety Pathology

    PubMed Central

    van Meurs, Brian; Wiggert, Nicole; Wicker, Isaac; Lissek, Shmuel

    2016-01-01

    Fear-conditioning experiments in the anxiety disorders focus almost exclusively on passive-emotional, Pavlovian conditioning, rather than active-behavioral, instrumental conditioning. Paradigms eliciting both types of conditioning are needed to study maladaptive, instrumental behaviors resulting from Pavlovian abnormalities found in clinical anxiety. One such Pavlovian abnormality is generalization of fear from a conditioned danger-cue (CS+) to resembling stimuli. Though lab-based findings repeatedly link overgeneralized Pavlovian-fear to clinical anxiety, no study assesses the degree to which Pavlovian overgeneralization corresponds with maladaptive, overgeneralized instrumental-avoidance. The current effort fills this gap by validating a novel fear-potentiated startle paradigm including Pavlovian and instrumental components. The paradigm is embedded in a computer game during which shapes appear on the screen. One shape paired with electric-shock serves as CS+, and other resembling shapes, presented in the absence of shock, serve as generalization stimuli (GSs). During the game, participants choose whether to behaviorally avoid shock at the cost of poorer performance. Avoidance during CS+ is considered adaptive because shock is a real possibility. By contrast, avoidance during GSs is considered maladaptive because shock is not a realistic prospect and thus unnecessarily compromises performance. Results indicate significant Pavlovian-instrumental relations, with greater generalization of Pavlovian fear associated with overgeneralization of maladaptive instrumental-avoidance. PMID:24768950

  8. A Classical Conditioning Procedure for the Hearing Assessment of Multiply Handicapped Persons.

    ERIC Educational Resources Information Center

    Lancioni, Giulio E.; And Others

    1989-01-01

    Hearing assessments of multiply handicapped children/adolescents were conducted using classical conditioning (with an air puff as unconditioned stimulus) and operant conditioning (with a modified visual reinforcement audiometry procedure or edible reinforcement). Findings indicate that classical conditioning was successful with 21 of the 23…

  9. Exploratory studies of classical conditioning of the preoral cavity in harnessed carpenter ants (Camponotus pennsylvanicus).

    PubMed

    Sauer, Dustin L; Abramson, Charles I; Lawson, Adam L

    2002-06-01

    An attempt was made to classically condition the mouthparts of harnessed worker ants (Camponotus pennsylvanicus) in anticipation of feeding. Experiments were designed to investigate classical conditioning with one CS, discrimination between two CSs, and pseudoconditioning. Analysis indicated a small acquisition effect that could be accounted for by pseudoconditioning. The preparation can be used to study nonassociative learning and some instrumental conditioning situations.

  10. Exploratory studies of classical conditioning of the preoral cavity in harnessed carpenter ants (Camponotus pennsylvanicus).

    PubMed

    Sauer, Dustin L; Abramson, Charles I; Lawson, Adam L

    2002-06-01

    An attempt was made to classically condition the mouthparts of harnessed worker ants (Camponotus pennsylvanicus) in anticipation of feeding. Experiments were designed to investigate classical conditioning with one CS, discrimination between two CSs, and pseudoconditioning. Analysis indicated a small acquisition effect that could be accounted for by pseudoconditioning. The preparation can be used to study nonassociative learning and some instrumental conditioning situations. PMID:12090495

  11. Extending In Vitro Conditioning in "Aplysia" to Analyze Operant and Classical Processes in the Same Preparation

    ERIC Educational Resources Information Center

    Brembs, Bjorn; Baxter, Douglas A.; Byrne, John H.

    2004-01-01

    Operant and classical conditioning are major processes shaping behavioral responses in all animals. Although the understanding of the mechanisms of classical conditioning has expanded significantly, the understanding of the mechanisms of operant conditioning is more limited. Recent developments in "Aplysia" are helping to narrow the gap in the…

  12. Effects of enhanced zinc and copper in drinking water on spatial memory and fear conditioning

    USGS Publications Warehouse

    Chrosniak, L.D.; Smith, L.N.; McDonald, C.G.; Jones, B.F.; Flinn, J.M.

    2006-01-01

    Ingestion of enhanced zinc can cause memory impairments and copper deficiencies. This study examined the effect of zinc supplementation, with and without copper, on two types of memory. Rats raised pre- and post-natally on 10 mg/kg ZnCO3 or ZnSO4 in the drinking water were tested in a fear-conditioning experiment at 11 months of age. Both zinc groups showed a maladaptive retention of fearful memories compared to controls raised on tap water. Rats raised on 10 mg/kg ZnCO3, 10 mg/kg ZnCO3 + 0.25 mg/kg CuCl2, or tap water, were tested for spatial memory ability at 3 months of age. Significant improvements in performance were found in the ZnCO3 + CuCl2 group compared to the ZnCO3 group, suggesting that some of the cognitive deficits associated with zinc supplementation may be remediated by addition of copper. ?? 2005 Elsevier B.V. All rights reserved.

  13. Long-term retention of early Pavlovian fear conditioning in infant rats.

    PubMed

    Coulter, X; Collier, A C; Campbell, B A

    1976-01-01

    That organisms cannot remember events occurring during infancy may be the result of common forgetting processes exacerbated by the organism's increase in size during development or a unique process such as insufficient neurological development at the time of the early experience. To establish the uniqueness of infantile forgetting, size change was made irrelevant by exposing infant rats to "off-baseline" Pavlovian fear conditioning and assessing the effect of an apparatus-free conditioned stimulus upon independently established bar pressing. In Experiment 1, bar pressing by rats exposed to Pavlovian contingencies when 20-22 days old was substantially suppressed by the conditioned stimulus both 1 and 42 days after conditioning. In Experiment 2, pups conditioned when 17-19 and 20-22 days old again showed excellent retention, whereas pups conditioned when 11-13 and 14-16 days old showed total forgetting 42 days later. In Experiment 3, pups conditioned when 14-16 days old remembered well after 5 days, less well 10 days later, and not at all after 20 days. These findings suggest that size change may contribute to the forgetting of events occurring late in development, but that neurological immaturity may underly the forgetting of earlier events.

  14. Individual differences in conditioned fear expression are associated with enduring differences in endogenous Fibroblast Growth Factor-2 and hippocampal-mediated memory performance.

    PubMed

    Walters, Emily; Richardson, Rick; Graham, Bronwyn M

    2016-10-01

    Rodent studies of individual differences in fear expression following Pavlovian fear conditioning are thought to provide useful means by which to examine the factors associated with vulnerability and resilience to anxiety and trauma- and stressor-related disorders in humans. We have recently demonstrated that rats that naturally exhibit low levels of conditioned fear have greater hippocampal expression of the neurotrophic factor Fibroblast Growth Factor-2 (FGF2), relative to rats that naturally exhibit high levels of conditioned fear. In the present study we determined whether individual variance in conditioned fear expression is associated with distinct behavioral profiles across a range of tasks designed to assess expression of trait anxiety and non-emotional memory performance, and whether the differences in hippocampal FGF2 are relatively stable across time. Results indicated that, relative to rats naturally exhibiting low levels of fear, rats naturally exhibiting high levels of fear in the presence of a previously conditioned cue and context also showed heightened levels of trait anxiety, reduced ability to discriminate between a previously conditioned context and a safe context, and impaired performance on the hippocampal-mediated place recognition task, but not on the non-hippocampal-mediated object recognition task. Moreover, differences in hippocampal FGF2 expression were evident between high and low fear rats even three months following the tests for conditioned fear expression. Together, these results suggest that individual differences in conditioned fear expression may be mediated partly by enduring differences in hippocampal functioning.

  15. Individual differences in neural correlates of fear conditioning as a function of 5-HTTLPR and stressful life events.

    PubMed

    Klucken, Tim; Alexander, Nina; Schweckendiek, Jan; Merz, Christian J; Kagerer, Sabine; Osinsky, Roman; Walter, Bertram; Vaitl, Dieter; Hennig, Juergen; Stark, Rudolf

    2013-03-01

    Fear learning is a crucial process in the pathogeneses of psychiatric disorders, which highlights the need to identify specific factors contributing to interindividual variation. We hypothesized variation in the serotonin transporter gene (5-HTTLPR) and stressful life events (SLEs) to be associated with neural correlates of fear conditioning in a sample of healthy male adults (n = 47). Subjects were exposed to a differential fear conditioning paradigm after being preselected regarding 5-HTTLPR genotype and SLEs. Individual differences in brain activity as measured by functional magnetic resonance imaging (fMRI), skin conductance responses and preference ratings were assessed. We report significant variation in neural correlates of fear conditioning as a function of 5-HTTLPR genotype. Specifically, the conditioned stimulus (CS(+)) elicited elevated activity within the fear-network (amygdala, insula, thalamus, occipital cortex) in subjects carrying two copies of the 5-HTTLPR S' allele. Moreover, our results revealed preliminary evidence for a significant gene-by-environment interaction, such as homozygous carriers of the 5-HTTLPR S' allele with a history of SLEs demonstrated elevated reactivity to the CS(+) in the occipital cortex and the insula. Our findings contribute to the current debate on 5-HTTLPR x SLEs interaction by investigating crucial alterations on an intermediate phenotype level which may convey an elevated vulnerability for the development of psychopathology.

  16. Encoding of fear learning and memory in distributed neuronal circuits.

    PubMed

    Herry, Cyril; Johansen, Joshua P

    2014-12-01

    How sensory information is transformed by learning into adaptive behaviors is a fundamental question in neuroscience. Studies of auditory fear conditioning have revealed much about the formation and expression of emotional memories and have provided important insights into this question. Classical work focused on the amygdala as a central structure for fear conditioning. Recent advances, however, have identified new circuits and neural coding strategies mediating fear learning and the expression of fear behaviors. One area of research has identified key brain regions and neuronal coding mechanisms that regulate the formation, specificity and strength of fear memories. Other work has discovered critical circuits and neuronal dynamics by which fear memories are expressed through a medial prefrontal cortex pathway and coordinated activity across interconnected brain regions. Here we review these recent advances alongside prior work to provide a working model of the extended circuits and neuronal coding mechanisms mediating fear learning and memory.

  17. Encoding of fear learning and memory in distributed neuronal circuits.

    PubMed

    Herry, Cyril; Johansen, Joshua P

    2014-12-01

    How sensory information is transformed by learning into adaptive behaviors is a fundamental question in neuroscience. Studies of auditory fear conditioning have revealed much about the formation and expression of emotional memories and have provided important insights into this question. Classical work focused on the amygdala as a central structure for fear conditioning. Recent advances, however, have identified new circuits and neural coding strategies mediating fear learning and the expression of fear behaviors. One area of research has identified key brain regions and neuronal coding mechanisms that regulate the formation, specificity and strength of fear memories. Other work has discovered critical circuits and neuronal dynamics by which fear memories are expressed through a medial prefrontal cortex pathway and coordinated activity across interconnected brain regions. Here we review these recent advances alongside prior work to provide a working model of the extended circuits and neuronal coding mechanisms mediating fear learning and memory. PMID:25413091

  18. Effect of the NMDA antagonist MK-801 on latent inhibition of fear conditioning.

    PubMed

    Traverso, Luis M; Ruiz, Gabriel; De la Casa, Luis G

    2012-10-01

    N-methyl-D-aspartate (NMDA) receptors seem to play a central role in learning and memory processes involved in Latent Inhibition (LI). In fact, MK-801, a non-competitive NMDA receptor antagonist, has proved its effectiveness as a drug for attenuating LI when administered before or after stimulus preexposure and conditioning stages. This paper presents three experiments designed to analyze the effect of MK-801 on LI when the drug is administered before (Experiment 1A) or after (Experiment 1B) preexposure and conditioning stages with a conditioned emotional response procedure. Additionally, we analyze the effect of the drug when it was administered before preexposure, before conditioning or before both phases (Experiment 2). The results show that the effect of the drug varied as a function of the dose (with only the highest dose being effective), the moment of administration (with only the drug administered before the experimental treatments being effective), and the phase of procedure (reducing LI when the drug was administered only at preexposure, and disrupting fear conditioning when administered at conditioning). These differences may be due to several factors ranging from the role played by NMDA receptors in the processing of stimuli of different sensorial modalities to the molecular processes triggered by drug administration.

  19. Effect of Circadian Phase on Memory Acquisition and Recall: Operant Conditioning vs. Classical Conditioning

    PubMed Central

    Garren, Madeleine V.; Sexauer, Stephen B.; Page, Terry L.

    2013-01-01

    There have been several studies on the role of circadian clocks in the regulation of associative learning and memory processes in both vertebrate and invertebrate species. The results have been quite variable and at present it is unclear to what extent the variability observed reflects species differences or differences in methodology. Previous results have shown that following differential classical conditioning in the cockroach, Rhyparobia maderae, in an olfactory discrimination task, formation of the short-term and long-term memory is under strict circadian control. In contrast, there appeared to be no circadian regulation of the ability to recall established memories. In the present study, we show that following operant conditioning of the same species in a very similar olfactory discrimination task, there is no impact of the circadian system on either short-term or long-term memory formation. On the other hand, ability to recall established memories is strongly tied to the circadian phase of training. On the basis of these data and those previously reported for phylogenetically diverse species, it is suggested that there may be fundamental differences in the way the circadian system regulates learning and memory in classical and operant conditioning. PMID:23533587

  20. Effect of circadian phase on memory acquisition and recall: operant conditioning vs. classical conditioning.

    PubMed

    Garren, Madeleine V; Sexauer, Stephen B; Page, Terry L

    2013-01-01

    There have been several studies on the role of circadian clocks in the regulation of associative learning and memory processes in both vertebrate and invertebrate species. The results have been quite variable and at present it is unclear to what extent the variability observed reflects species differences or differences in methodology. Previous results have shown that following differential classical conditioning in the cockroach, Rhyparobia maderae, in an olfactory discrimination task, formation of the short-term and long-term memory is under strict circadian control. In contrast, there appeared to be no circadian regulation of the ability to recall established memories. In the present study, we show that following operant conditioning of the same species in a very similar olfactory discrimination task, there is no impact of the circadian system on either short-term or long-term memory formation. On the other hand, ability to recall established memories is strongly tied to the circadian phase of training. On the basis of these data and those previously reported for phylogenetically diverse species, it is suggested that there may be fundamental differences in the way the circadian system regulates learning and memory in classical and operant conditioning.

  1. Consequences of adolescent ethanol exposure in male Sprague-Dawley rats on fear conditioning and extinction in adulthood

    NASA Astrophysics Data System (ADS)

    Broadwater, Margaret A.

    Some evidence suggests that adolescents are more vulnerable than adults to alcohol-induced cognitive deficits and that these deficits may persist into adulthood. Five experiments were conducted to assess long-term consequences of ethanol exposure on tone and context Pavlovian fear conditioning in male Sprague-Dawley rats. Experiment 1 examined age-related differences in sensitivity to ethanol-induced disruptions of fear conditioning to a pre-conditioning ethanol challenge. Experiments 2 examined fear conditioning 22 days after early-mid adolescent (P28-48) or adult (P70-90) exposure to 4 g/kg i.g. ethanol or water given every other day (total of 11 exposures). In Experiment 3, mid-late adolescents (P35-55) were exposed in the same manner to assess whether timing of ethanol exposure within the adolescent period would differentially affect later fear conditioning. Experiment 4 assessed the influence of prior adolescent or adult ethanol exposure on the disrupting effects of a pre-conditioning ethanol challenge. In Experiment 5, neurogenesis (doublecortin---DCX) and cholinergic (choline acetyltransferase---ChAT) markers were measured to assess potential long-term ethanol-induced changes in neural mechanisms important for learning and memory. Results indicated that the long-lasting behavioral effects of ethanol exposure varied depending on exposure age, with early-mid adolescent exposed animals showing attenuated context fear retention (a relatively hippocampal-dependent task), whereas mid-late adolescent and adult exposed animals showed slower context extinction (thought to be reliant on the mPFC). Early-mid adolescent ethanol-exposed animals also had significantly less DCX and ChAT expression than their water-exposed counterparts, possibly contributing to deficits in context fear. Tone fear was not influenced by prior ethanol exposure at any age. In terms of age differences in ethanol sensitivity, adolescents were less sensitive than adults to ethanol

  2. Fear conditioning and early life vulnerabilities: two distinct pathways of emotional dysregulation and brain dysfunction in PTSD

    PubMed Central

    Lanius, Ruth A.; Frewen, Paul A.; Vermetten, Eric; Yehuda, Rachel

    2010-01-01

    The newly proposed criteria for posttraumatic stress disorder (PTSD) in the Diagnostic and Statistical Manual (DSM-V) include dysregulation of a variety of emotional states including fear, anger, guilt, and shame, in addition to dissociation and numbing. Consistent with these revisions, we postulate two models of emotion dysregulation in PTSD in which fear is not the prevailing emotion but is only one of several components implicated in a dysregulated emotional system that also mediates problems regulating anger, guilt, shame, dissociation, and numbing. We discuss whether there is a relationship between fear and other emotion regulation systems that may help further our understanding of PTSD and its underlying neurocircuitry. Two pathways describing the relationship between fear and other emotion regulation systems in PTSD are proposed. The first pathway describes emotion dysregulation as an outcome of fear conditioning through stress sensitization and kindling. The second pathway views emotion dysregulation as a distal vulnerability factor and hypothesizes a further exacerbation of fear and other emotion regulatory problems, including the development of PTSD after exposure to one or several traumatic event(s) later in life. Future research and treatment implications are discussed. PMID:22893793

  3. Post-training corticosterone inhibits the return of fear evoked by platform stress and a subthreshold conditioning procedure in Sprague-Dawley rats.

    PubMed

    Xing, Xiaoli; Wang, Hongbo; Zhang, Lili; Bai, Yunjing; Liang, Jing; Liu, Zhengkui; Zheng, Xigeng

    2015-06-01

    The return of fear is an important issue in anxiety disorder research. Each time a fear memory is reactivated, it may further strengthen overactivation of the fear circuit, which may contribute to long-term maintenance of the fear memory. Recent evidence indicates that glucocorticoids may help attenuate pathological fear, but its role in the return of fear is unclear. In the present study, systemic corticosterone (CORT; 25mg/kg) administration 1h after fear conditioning did not impair the consolidation process but significantly suppressed the return of fear evoked by a subthreshold conditioning (SC) procedure and elevated platform (EP) stress. Compared with the SC-induced return of fear, acute stress-induced return was state-dependent. In addition, post-training CORT treatment increased the adrenocorticotropic response after EP stress, which indicates that the drug-induced suppression of the return of fear may possibly derive from its regulation effect of the hypothalamic-pituitary-adrenal axis reactivity to stress. These results suggest that post-training CORT administration may help inhibit the return of fear evoked by EP or SC stress. The possible mechanisms involved in the high-dose CORT-induced suppression of the SC- and EP-induced return of fear are discussed. PMID:25818040

  4. Post-training corticosterone inhibits the return of fear evoked by platform stress and a subthreshold conditioning procedure in Sprague-Dawley rats.

    PubMed

    Xing, Xiaoli; Wang, Hongbo; Zhang, Lili; Bai, Yunjing; Liang, Jing; Liu, Zhengkui; Zheng, Xigeng

    2015-06-01

    The return of fear is an important issue in anxiety disorder research. Each time a fear memory is reactivated, it may further strengthen overactivation of the fear circuit, which may contribute to long-term maintenance of the fear memory. Recent evidence indicates that glucocorticoids may help attenuate pathological fear, but its role in the return of fear is unclear. In the present study, systemic corticosterone (CORT; 25mg/kg) administration 1h after fear conditioning did not impair the consolidation process but significantly suppressed the return of fear evoked by a subthreshold conditioning (SC) procedure and elevated platform (EP) stress. Compared with the SC-induced return of fear, acute stress-induced return was state-dependent. In addition, post-training CORT treatment increased the adrenocorticotropic response after EP stress, which indicates that the drug-induced suppression of the return of fear may possibly derive from its regulation effect of the hypothalamic-pituitary-adrenal axis reactivity to stress. These results suggest that post-training CORT administration may help inhibit the return of fear evoked by EP or SC stress. The possible mechanisms involved in the high-dose CORT-induced suppression of the SC- and EP-induced return of fear are discussed.

  5. Cholinergic modulation of Pavlovian fear conditioning in rats: differential effects of intrahippocampal infusion of mecamylamine and methyllycaconitine.

    PubMed

    Vago, David R; Kesner, Raymond P

    2007-03-01

    The cholinergic system has consistently been implicated in Pavlovian fear conditioning. Considerable work has been done to localize specific nicotinic receptor subtypes in the hippocampus and determine their functional importance; however, the specific function of many of these subtypes has yet to be determined. An alpha7 nicotinic antagonist methyllycaconitine (MLA) (35 microg), and a broad spectrum non-alpha7 nicotinic antagonist mecamylamine (35 microg) was injected directly into the dorsal hippocampus or overlying cortex either 15 min pre-, 1 min post-, or 6h post-fear conditioning. One week after conditioning, retention of contextual and cue (tone) conditioning were assessed. A significant impairment in retention of contextual fear was observed when mecamylamine was injected 15 min pre- and 1 min post-conditioning. No significant impairment was observed when mecamylamine was injected 6h post-conditioning. Likewise, a significant impairment in retention of contextual fear was observed when MLA was injected 1 min post-conditioning; however, in contrast, MLA did not show any significant impairments when injected 15 min pre-conditioning, but did show a significant impairment when injected 6h post-conditioning. There were no significant impairments observed when either drug was injected into overlying cortex. No significant impairments were observed in cue conditioning for either drug. In general, specific temporal dynamics involved in nicotinic receptor function were found relative to time of receptor dysfunction. The results indicate that the greatest deficits in long-term retention (1 week) of contextual fear are produced by central infusion of MLA minutes to hours post-conditioning or mecamylamine within minutes of conditioning.

  6. On the costs and benefits of directing attention towards or away from threat-related stimuli: a classical conditioning experiment.

    PubMed

    Van Bockstaele, Bram; Verschuere, Bruno; De Houwer, Jan; Crombez, Geert

    2010-07-01

    In attentional bias modification programs, individuals are trained to attend away from threat in order to reduce emotional reactivity to stressful situations. However, attending towards threat is considered to be a prerequisite for fear reduction in other models of anxiety. We compared both views by manipulating attention towards or away from an acquired signal of threat. The strength of extinction and reacquisition was assessed with threat and US-expectancy ratings. We found more extinction in the attend towards threat group, compared to both the attend away from threat group and a control group in which attention was not manipulated. The results are in line with the Emotional Processing Theory and cognitive accounts of classical conditioning.

  7. On the costs and benefits of directing attention towards or away from threat-related stimuli: a classical conditioning experiment.

    PubMed

    Van Bockstaele, Bram; Verschuere, Bruno; De Houwer, Jan; Crombez, Geert

    2010-07-01

    In attentional bias modification programs, individuals are trained to attend away from threat in order to reduce emotional reactivity to stressful situations. However, attending towards threat is considered to be a prerequisite for fear reduction in other models of anxiety. We compared both views by manipulating attention towards or away from an acquired signal of threat. The strength of extinction and reacquisition was assessed with threat and US-expectancy ratings. We found more extinction in the attend towards threat group, compared to both the attend away from threat group and a control group in which attention was not manipulated. The results are in line with the Emotional Processing Theory and cognitive accounts of classical conditioning. PMID:20451175

  8. Reduced Electrodermal Fear Conditioning from Ages 3 to 8 Years Is Associated with Aggressive Behavior at Age 8 Years

    ERIC Educational Resources Information Center

    Gao, Yu; Raine, Adrian; Venables, Peter H.; Dawson, Michael E.; Mednick, Sarnoff A.

    2010-01-01

    Background: Poor fear conditioning characterizes adult psychopathy and criminality, but it is not known whether it is related to aggressive/antisocial behavior in early childhood. Methods: Using a differential, partial reinforcement conditioning paradigm, electrodermal activity was recorded from 200 male and female children at ages 3, 4, 5, 6, and…

  9. Testing conditions in shock-based contextual fear conditioning influence both the behavioral responses and the activation of circuits potentially involved in contextual avoidance.

    PubMed

    Viellard, Juliette; Baldo, Marcus Vinicius C; Canteras, Newton Sabino

    2016-12-15

    Previous studies from our group have shown that risk assessment behaviors are the primary contextual fear responses to predatory and social threats, whereas freezing is the main contextual fear response to physically harmful events. To test contextual fear responses to a predator or aggressive conspecific threat, we developed a model that involves placing the animal in an apparatus where it can avoid the threat-associated environment. Conversely, in studies that use shock-based fear conditioning, the animals are usually confined inside the conditioning chamber during the contextual fear test. In the present study, we tested shock-based contextual fear responses using two different behavioral testing conditions: confining the animal in the conditioning chamber or placing the animal in an apparatus with free access to the conditioning compartment. Our results showed that during the contextual fear test, the animals confined to the shock chamber exhibited significantly more freezing. In contrast, the animals that could avoid the conditioning compartment displayed almost no freezing and exhibited risk assessment responses (i.e., crouch-sniff and stretch postures) and burying behavior. In addition, the animals that were able to avoid the shock chamber had increased Fos expression in the juxtadorsomedial lateral hypothalamic area, the dorsomedial part of the dorsal premammillary nucleus and the lateral and dorsomedial parts of the periaqueductal gray, which are elements of a septo/hippocampal-hypothalamic-brainstem circuit that is putatively involved in mediating contextual avoidance. Overall, the present findings show that testing conditions significantly influence both behavioral responses and the activation of circuits involved in contextual avoidance. PMID:27544875

  10. The effects of social housing on extinction of fear conditioning in rapid eye movement sleep-deprived rats.

    PubMed

    Hunter, Amy Silvestri

    2014-05-01

    Both human and animal research indicate that rapid eye movement sleep (REM) plays an important role in the processing of emotional information. REM is altered after fear conditioning in rats, but this alteration can be mitigated by exposure to a naïve conspecific. In addition, both the housing condition (isolated vs paired) and the experiences of rats' cagemates can influence the response to aversive events. Based on this prior work, the present study sought to determine the effects of social housing on the previously demonstrated impairment in the extinction of conditioned fear responses produced by REM deprivation. Rats were assigned to one of three housing conditions: housed with a naïve rat, housed with another fear-conditioned rat, or housed alone. The results demonstrated that rats housed with either a naïve or a fear-conditioned conspecific exhibited an impairment in the acquisition of extinction as a consequence of REM deprivation, as observed in previous studies. However, rats in the isolated condition demonstrated a trend toward an impairment only after continued extinction training. These results indicate that the effects of social housing on REM deprivation-induced impairments in learning and memory are subtle, but may explain some conflicting findings in the literature.

  11. Hemodynamic responses in amygdala and hippocampus distinguish between aversive and neutral cues during Pavlovian fear conditioning in behaving rats.

    PubMed

    McHugh, Stephen B; Marques-Smith, Andre; Li, Jennifer; Rawlins, J N P; Lowry, John; Conway, Michael; Gilmour, Gary; Tricklebank, Mark; Bannerman, David M

    2013-02-01

    Lesion and electrophysiological studies in rodents have identified the amygdala and hippocampus (HPC) as key structures for Pavlovian fear conditioning, but human functional neuroimaging studies have not consistently found activation of these structures. This could be because hemodynamic responses cannot detect the sparse neuronal activity proposed to underlie conditioned fear. Alternatively, differences in experimental design or fear levels could account for the discrepant findings between rodents and humans. To help distinguish between these alternatives, we used tissue oxygen amperometry to record hemodynamic responses from the basolateral amygdala (BLA), dorsal HPC (dHPC) and ventral HPC (vHPC) in freely-moving rats during the acquisition and extinction of conditioned fear. To enable specific comparison with human studies we used a discriminative paradigm, with one auditory cue [conditioned stimulus (CS)+] that was always followed by footshock, and another auditory cue (CS-) that was never followed by footshock. BLA tissue oxygen signals were significantly higher during CS+ than CS- trials during training and early extinction. In contrast, they were lower during CS+ than CS- trials by the end of extinction. dHPC and vHPC tissue oxygen signals were significantly lower during CS+ than CS- trials throughout extinction. Thus, hemodynamic signals in the amygdala and HPC can detect the different patterns of neuronal activity evoked by threatening vs. neutral stimuli during fear conditioning. Discrepant neuroimaging findings may be due to differences in experimental design and/or fear levels evoked in participants. Our methodology offers a way to improve translation between rodent models and human neuroimaging.

  12. Some relations between classically conditioned aggression and conditioned suppression in squirrel monkeys.

    PubMed Central

    Hake, D F; Campbell, R L

    1980-01-01

    During three experiments with squirrel monkeys, stimulus and shock pairings were given in the presence of a bite tube. Experiments 1 and 2 used a conditioned-suppression procedure in which bar pressing was reinforced with food. A transparent shield prevented biting of the bar. When the stimulus was paired with shock, bar pressing decreased (conditioned suppression) and tube biting increased during the stimulus (classically conditioned aggression). When the bite tube was removed on alternate sessions in Experiment 2, there was more suppression when the tube was present, thus suggesting that biting competed with bar pressing. However, this simple competing-response interpretation was complicated by the findings of Experiment 3 where, with naive monkeys, bar pressing was never reinforced with food, yet bar pressing was induced during the stimulus and was highest when the bite tube was absent. The fact that stimulus-induced bar pressing developed inciated that bar pressing in conditioned-suppression procedures, suppressed or not, may be maintained by two types of control--the food reinforcer and induced CS control. The higher rate of induced bar pressing during the stimulus with the bite tube absent confounds a simple competing response interpretation of conditioned suppression. It suggests that shock-induced responses during conditioned suppression could be both contributing to and competing with responding maintained by food, with the net effect depending on specific but ill-defined features of the situation. PMID:7190996

  13. Using powerpoint to demonstrate human classical salivary conditioning in a classroom situation.

    PubMed

    Abramson, Charles I; Brown, Erika A; Langley, Dillon

    2011-02-01

    Classical conditioning is one of the most fundamental types of learning, yet demonstrating its principles in a classroom setting can be challenging. This study introduces using PowerPoint as a new, practical technique that can be used in a classroom setting to demonstrate classical conditioning. The PowerPoint file is flexible and easy to adapt for demonstrating various aspects of classical conditioning (including higher order conditioning) in a concrete manner. Moreover, this study was designed to measure salivation in a more objective and valid way which could be used by student researchers interested in measuring salivation as a conditioned response.

  14. Dynamic competition between large-scale functional networks differentiates fear conditioning and extinction in humans.

    PubMed

    Marstaller, Lars; Burianová, Hana; Reutens, David C

    2016-07-01

    The high evolutionary value of learning when to respond to threats or when to inhibit previously learned associations after changing threat contingencies is reflected in dedicated networks in the animal and human brain. Recent evidence further suggests that adaptive learning may be dependent on the dynamic interaction of meta-stable functional brain networks. However, it is still unclear which functional brain networks compete with each other to facilitate associative learning and how changes in threat contingencies affect this competition. The aim of this study was to assess the dynamic competition between large-scale networks related to associative learning in the human brain by combining a repeated differential conditioning and extinction paradigm with independent component analysis of functional magnetic resonance imaging data. The results (i) identify three task-related networks involved in initial and sustained conditioning as well as extinction, and demonstrate that (ii) the two main networks that underlie sustained conditioning and extinction are anti-correlated with each other and (iii) the dynamic competition between these two networks is modulated in response to changes in associative contingencies. These findings provide novel evidence for the view that dynamic competition between large-scale functional networks differentiates fear conditioning from extinction learning in the healthy brain and suggest that dysfunctional network dynamics might contribute to learning-related neuropsychiatric disorders.

  15. Dynamic competition between large-scale functional networks differentiates fear conditioning and extinction in humans.

    PubMed

    Marstaller, Lars; Burianová, Hana; Reutens, David C

    2016-07-01

    The high evolutionary value of learning when to respond to threats or when to inhibit previously learned associations after changing threat contingencies is reflected in dedicated networks in the animal and human brain. Recent evidence further suggests that adaptive learning may be dependent on the dynamic interaction of meta-stable functional brain networks. However, it is still unclear which functional brain networks compete with each other to facilitate associative learning and how changes in threat contingencies affect this competition. The aim of this study was to assess the dynamic competition between large-scale networks related to associative learning in the human brain by combining a repeated differential conditioning and extinction paradigm with independent component analysis of functional magnetic resonance imaging data. The results (i) identify three task-related networks involved in initial and sustained conditioning as well as extinction, and demonstrate that (ii) the two main networks that underlie sustained conditioning and extinction are anti-correlated with each other and (iii) the dynamic competition between these two networks is modulated in response to changes in associative contingencies. These findings provide novel evidence for the view that dynamic competition between large-scale functional networks differentiates fear conditioning from extinction learning in the healthy brain and suggest that dysfunctional network dynamics might contribute to learning-related neuropsychiatric disorders. PMID:27079532

  16. Demonstrating Classical Conditioning in Introductory Psychology: Needles Do Not Always Make Balloons Pop!

    ERIC Educational Resources Information Center

    Vernoy, Mark W.

    1987-01-01

    Describes a method of teaching classical conditioning to an introductory psychology class which involves demonstrating the conditioned response that occurs when a needle pierces, but does not pop, a balloon. (GEA)

  17. The Relationship Between Religious Attitudes, Fear of Death and Dying with General Health Condition: A Survey in College Students.

    PubMed

    Nazarzadeh, Milad; Sarokhani, Mandana; Sayehmiri, Kourosh

    2015-10-01

    This study aims to assess the relationship between religious attitudes of Ilam universities students (west of Iran), their perspectives about the fear of self and other's death and dying, with their general health. This paper is an analytic survey in which 351 college students, who were selected by multistage sampling, participated. To measure interested variables, Persian format of standardized self-administered questionnaires was employed. Religious attitudes with odds ratio (OR) of 0.94 (95% CI 0.91-0.97) and fear of self dying with 0.88 (95% CI 0.81-0.96) were identified as a protective factors against the inappropriate general health condition. However, the fear of other's death (OR 1.16; 95% CI 1.05-1.28) was identified as a risk factor. This study showed that people who had more religious attitudes and fear of self dying had better general health as well as the fear of other's death had a significant direct relationship with inappropriate general health condition.

  18. Enhancement of Synaptic Potentials in Rabbit CA1 Pyramidal Neurons Following Classical Conditioning

    NASA Astrophysics Data System (ADS)

    Loturco, Joseph J.; Coulter, Douglas A.; Alkon, Daniel L.

    1988-03-01

    A synaptic potential elicited by high-frequency stimulation of the Schaffer collaterals was enhanced in hippocampal CA1 pyramidal cells from rabbits that were classically conditioned relative to cells from control rabbits. In addition, confirming previous reports, the after-hyperpolarization was reduced in cells from conditioned animals. We suggest that reduced after-hyperpolarization and enhanced synaptic responsiveness in cells from conditioned animals work in concert to contribute to the functioning of hippocampal CA1 pyramidal cells during classical conditioning.

  19. Fast, transient cardiac accelerations and decelerations during fear conditioning in rats.

    PubMed

    Knippenberg, J M J; Barry, R J; Kuniecki, M J; van Luijtelaar, G

    2012-02-01

    The current study reports on a number of heart rate responses observed in rats subjected to a discriminatory Pavlovian fear conditioning procedure. Rats learned that a series of six auditory pips was followed by a footshock when presented alone, but not when the pip series was preceded by a visual safety signal. Each auditory pip in the series evoked a fast transient (<1s) cardiac deceleration. This was the case on both trials followed by shock and on trials not followed by shock. The onset of the safety light evoked a similar fast deceleration. We propose that these transient decelerations are similar to the human Evoked Cardiac Response 1 (ECR1), a brief modest deceleration evoked by simple sensory stimuli that is thought to reflect an early process of stimulus registration. Immediately following these pip-evoked decelerations, modest fast accelerations were observed. These accelerations were larger when the pip series was followed by shock than when it was not followed by shock. We propose a potential linkage between these accelerations and the human acceleratory ECR2 component, which is associated with more elaborate processing following stimulus registration; something likely to take place when the pip series predicts an aversive event. Both the ECR1- and ECR2-like responses were embedded within a slow, gradual heart rate increase across the entire pip series. This tonic increase was significantly larger on trials with footshock and is therefore probably associated with anticipatory fear of the upcoming shock. An additional special type of cardiac response was found to the first pip in the series not preceded by the safety signal; here, a much larger and more sustained deceleration was apparent. This response appears relatable to the prolonged deceleration reported in humans in response to aversive picture content. We discuss the cardiac responses found in rats in the current study in the context of heart rate responses known in the human literature.

  20. Behavioral verification of associative learning in whiskers-related fear conditioning in mice.

    PubMed

    Cybulska-Kłosowicz, Anita

    2016-01-01

    Fear-conditioning is one of the most widely used paradigms in attempts to unravel the processes and mechanisms underlying learning and plasticity. In most of the Pavlovian conditioning paradigms auditory stimulus is used as a conditioned stimulus (CS), but conditioning can be accomplished also to tactile CS. The whisker-to-barrel tactile system in mice offers convenient way to investigate the brain pathways and mechanisms of learning, and plasticity of the brain cortex. To support a claim that an animal learns during conditioning session and that the plastic changes are associative in nature, objective measures of behavior are necessary. Multiple types of conditioned responses can develop, depending on the training situation, CS and unconditioned stimulus (UCS) characteristics. These include physiological responses, such as salivation, heart rate, galvanic skin reaction, and also behavioral responses, such as startle reflex potentiation or suppression of the ongoing behavior. When studying learning with the whisker system in behaving mice, stimulation of individual whiskers in a well-controlled manner may require animal restrain with a disadvantage of only limited behavioral responses observed. Stimulation of whiskers in the neck-restraining apparatus evokes head movements. When whiskers stimulation (CS) is paired with an aversive UCS during conditioning, the head movements decrease in the course of the training. This reaction, called minifreezing, resembles freezing response, frequently used behavioral measure, however applicable only in freely moving animals. This article will review experimental evidences confirming that minifreezing is a relevant index of association formation between the neutral CS and the and the aversive UCS. PMID:27373946

  1. c-Jun-N-terminal kinase 1 is necessary for nicotine-induced enhancement of contextual fear conditioning.

    PubMed

    Leach, Prescott T; Kenney, Justin W; Gould, Thomas J

    2016-08-01

    Acute nicotine enhances hippocampus-dependent learning. Identifying how acute nicotine improves learning will aid in understanding how nicotine facilitates the development of maladaptive memories that contribute to drug-seeking behaviors, help development of medications to treat disorders associated with cognitive decline, and advance understanding of the neurobiology of learning and memory. The effects of nicotine on learning may involve recruitment of signaling through the c-Jun N-terminal kinase family (JNK 1-3). Learning in the presence of acute nicotine increases the transcription of mitogen-activated protein kinase 8 (MAPK8, also known as JNK1), likely through a CREB-dependent mechanism. The functional significance of JNK1 in the effects of acute nicotine on learning, however, is unknown. The current studies undertook a backward genetic approach to determine the functional contribution JNK1 protein makes to nicotine-enhanced contextual fear conditioning. JNK1 wildtype (WT) and knockout (KO) mice were administered acute nicotine prior to contextual and cued fear conditioning. 24h later, mice were evaluated for hippocampus-dependent (contextual fear conditioning) and hippocampus-independent (cued fear conditioning) memory. Nicotine selectively enhanced contextual conditioning in WT mice, but not in KO mice. Nicotine had no effect on hippocampus-independent learning in either genotype. JNK1 KO and WT mice given saline showed similar levels of learning. These data suggest that JNK1 may be recruited by nicotine and is functionally necessary for the acute effects of nicotine on learning and memory. PMID:27235579

  2. Trace eyeblink classical conditioning in the monkey: a nonsurgical method and behavioral analysis.

    PubMed

    Clark, R E; Zola, S

    1998-10-01

    Classical eyeblink conditioning has been used extensively to study the neurobiology of associative learning and memory in rabbits and in humans. During the last several years, new developments have renewed interest in the possibility of studying classical conditioning in monkeys. Specifically, it is now known that impaired conditioning can be observed in humans with various neurologic problems, including amnesia, and thus there is now considerable interest in the neurobiology of human eyeblink conditioning. Research involving monkeys, in which discrete lesions of anatomically defined neural structures can be produced, has the potential to provide information that might not be readily available from work in humans. Here, the authors present a simple, nonsurgical method for classically conditioning the eyeblink response in monkeys and report behavioral results using a trace conditioning paradigm that is sensitive to hippocampal damage in both rabbits and humans. This method is reliable and effective for recording eyeblinks and shows that robust eyeblink classical conditioning can be readily established in the monkey.

  3. Cholinergic Modulation during Acquisition of Olfactory Fear Conditioning Alters Learning and Stimulus Generalization in Mice

    ERIC Educational Resources Information Center

    Pavesi, Eloisa; Gooch, Allison; Lee, Elizabeth; Fletcher, Max L.

    2013-01-01

    We investigated the role of cholinergic neurotransmission in olfactory fear learning. Mice receiving pairings of odor and foot shock displayed fear to the trained odor the following day. Pretraining injections of the nicotinic antagonist mecamylamine had no effect on subsequent freezing, while the muscarinic antagonist scopolamine significantly…

  4. Hippocampal unit activity during classical aversive and appetitive conditioning.

    PubMed

    Segal, M; Disterhoft, J F; Olds, J

    1972-02-18

    Rats were trained with a tone being followed by either food or electric shock, on alternate days. Unit activity during application of the conditioned stimulus was recorded from the dorsal hippocampus. The results indicate differentiation of the hippocampal system. Dentate units respond by augmentation to a conditioned stimulus which leads to food and by inhibition to the same stimulus when it precedes electric shock. The hippocampus proper responds by augmentation in both situations. The intensity of the hippocampal response to the conditioned stimulus on the first day of training is higher if the unconditioned stimulus is food than if it is electric shock. These data cast light on the functions of the dorsal dentate-hippocampal connections and the hippocampus proper during aversive and appetitive conditioning.

  5. Changes in complex spike activity during classical conditioning

    PubMed Central

    Rasmussen, Anders; Jirenhed, Dan-Anders; Wetmore, Daniel Z.; Hesslow, Germund

    2014-01-01

    The cerebellar cortex is necessary for adaptively timed conditioned responses (CRs) in eyeblink conditioning. During conditioning, Purkinje cells acquire pause responses or “Purkinje cell CRs” to the conditioned stimuli (CS), resulting in disinhibition of the cerebellar nuclei (CN), allowing them to activate motor nuclei that control eyeblinks. This disinhibition also causes inhibition of the inferior olive (IO), via the nucleo-olivary pathway (N-O). Activation of the IO, which relays the unconditional stimulus (US) to the cortex, elicits characteristic complex spikes in Purkinje cells. Although Purkinje cell activity, as well as stimulation of the CN, is known to influence IO activity, much remains to be learned about the way that learned changes in simple spike firing affects the IO. In the present study, we analyzed changes in simple and complex spike firing, in extracellular Purkinje cell records, from the C3 zone, in decerebrate ferrets undergoing training in a conditioning paradigm. In agreement with the N-O feedback hypothesis, acquisition resulted in a gradual decrease in complex spike activity during the conditioned stimulus, with a delay that is consistent with the long N-O latency. Also supporting the feedback hypothesis, training with a short interstimulus interval (ISI), which does not lead to acquisition of a Purkinje cell CR, did not cause a suppression of complex spike activity. In contrast, observations that extinction did not lead to a recovery in complex spike activity and the irregular patterns of simple and complex spike activity after the conditioned stimulus are less conclusive. PMID:25140129

  6. Role of L-Type Ca[superscript 2+] Channel Isoforms in the Extinction of Conditioned Fear

    ERIC Educational Resources Information Center

    Busquet, Perrine; Hetzenauer, Alfred; Sinnegger-Brauns, Martina J.; Striessnig, Jorg; Singewald, Nicolas

    2008-01-01

    Dihydropyridine (DHP) L-type Ca[superscript 2+] channel (LTCC) antagonists, such as nifedipine, have been reported to impair the extinction of conditioned fear without interfering with its acquisition. Identification of the LTCC isoforms mediating this DHP effect is an essential basis to reveal their role as potential drug targets for the…

  7. Pavlovian fear conditioning regulates Thr286 autophosphorylation of Ca2+/calmodulin-dependent protein kinase II at lateral amygdala synapses.

    PubMed

    Rodrigues, Sarina M; Farb, Claudia R; Bauer, Elizabeth P; LeDoux, Joseph E; Schafe, Glenn E

    2004-03-31

    Ca2+/calmodulin-dependent protein kinase II (CaMKII) plays a critical role in synaptic plasticity and memory formation in a variety of learning systems and species. The present experiments examined the role of CaMKII in the circuitry underlying pavlovian fear conditioning. First, we reveal by immunocytochemical and tract-tracing methods that alphaCaMKII is postsynaptic to auditory thalamic inputs and colocalized with the NR2B subunit of the NMDA receptor. Furthermore, we show that fear conditioning results in an increase of the autophosphorylated (active) form of alphaCaMKII in lateral amygdala (LA) spines. Next, we demonstrate that intra-amygdala infusion of a CaMK inhibitor, 1-[NO-bis-1,5-isoquinolinesulfonyl]-N-methyl-l-tyrosyl-4-phenylpiperazine, KN-62, dose-dependently impairs the acquisition, but not the expression, of auditory and contextual fear conditioning. Finally, in electrophysiological experiments, we demonstrate that an NMDA receptor-dependent form of long-term potentiation at thalamic input synapses to the LA is impaired by bath application of KN-62 in vitro. Together, the results of these experiments provide the first comprehensive view of the role of CaMKII in the amygdala during fear conditioning.

  8. Substantia nigra, nucleus basalis magnocellularis and basolateral amygdala roles in extinction of contextual fear conditioning in the rat.

    PubMed

    Baldi, Elisabetta; Bucherelli, Corrado

    2010-09-01

    Fear conditioning is accepted as a useful experimental paradigm to investigate anxious disorders following stress. In this field it is important to understand the mechanisms underlying the extinction of conditioned fear. In the rat it has been shown that the amygdalar basolateral nucleus plays a crucial role in all memorization phases of this type of memory (acquisition, consolidation, retrieval, and also reconsolidation and extinction). Recent results show that both the substantia nigra and nucleus basalis magnocellularis, two sites strongly connected with the basolateral amygdala are also involved in the consolidation of contextual fear conditioning. The aim of the present work is to investigate if latter two sites, besides the basolateral amygdala, are also involved in the extinction of the conditioned fear response. The results show that tetrodotoxin-induced inactivation of post-extinction training of either site does not impair the extinction process, which instead is impaired by inactivation of the basolateral amygdala. Thus, the present results confirm previous ones which show that diverse memorization phases (post-acquisition consolidation, extinction, reconsolidation) may be sustained by different neural sites and circuits.

  9. Histone Modifications around Individual BDNF Gene Promoters in Prefrontal Cortex Are Associated with Extinction of Conditioned Fear

    ERIC Educational Resources Information Center

    Bredy, Timothy W.; Wu, Hao; Crego, Cortney; Zellhoefer, Jessica; Sun, Yi E.; Barad, Mark

    2007-01-01

    Extinction of conditioned fear is an important model both of inhibitory learning and of behavior therapy for human anxiety disorders. Like other forms of learning, extinction learning is long-lasting and depends on regulated gene expression. Epigenetic mechanisms make an important contribution to persistent changes in gene expression; therefore,…

  10. Distinct Contributions of the Basolateral Amygdala and the Medial Prefrontal Cortex to Learning and Relearning Extinction of Context Conditioned Fear

    ERIC Educational Resources Information Center

    Laurent, Vincent; Westbrook, R. Frederick

    2008-01-01

    We studied the roles of the basolateral amygdala (BLA) and the medial prefrontal cortex (mPFC) in learning and relearning to inhibit context conditioned fear (freezing) in extinction. In Experiment 1, pre-extinction BLA infusion of the NMDA receptor (NMDAr) antagonist, ifenprodil, impaired the development and retention of inhibition but…

  11. Role of the Basolateral Amygdala in the Reinstatement and Extinction of Fear Responses to a Previously Extinguished Conditioned Stimulus

    ERIC Educational Resources Information Center

    Laurent, Vincent; Westbrook, R. Frederick

    2010-01-01

    Four experiments used rats to study the role of the basolateral amygdala (BLA) in the reinstatement and extinction of fear responses (freezing) to a previously extinguished conditioned stimulus (CS). In Experiment 1, BLA inactivation before pairing the extinguished CS with the shock unconditioned stimulus (US) or before US-alone exposure impaired…

  12. Trace and Contextual Fear Conditioning Require Neural Activity and NMDA Receptor-Dependent Transmission in the Medial Prefrontal Cortex

    ERIC Educational Resources Information Center

    Gilmartin, Marieke R.; Helmstetter, Fred J.

    2010-01-01

    The contribution of the medial prefrontal cortex (mPFC) to the formation of memory is a subject of considerable recent interest. Notably, the mechanisms supporting memory acquisition in this structure are poorly understood. The mPFC has been implicated in the acquisition of trace fear conditioning, a task that requires the association of a…

  13. D-Cycloserine Does Not Facilitate Fear Extinction by Reducing Conditioned Stimulus Processing or Promoting Conditioned Inhibition to Contextual Cues

    ERIC Educational Resources Information Center

    Baker, Kathryn D.; McNally, Gavan P.; Richardson, Rick

    2012-01-01

    The NMDA receptor partial agonist d-cycloserine (DCS) enhances the extinction of learned fear in rats and exposure therapy in humans with anxiety disorders. Despite these benefits, little is known about the mechanisms by which DCS promotes the loss of fear. The present study examined whether DCS augments extinction retention (1) through reductions…

  14. Dysbindin-1 loss compromises NMDAR-dependent synaptic plasticity and contextual fear conditioning.

    PubMed

    Glen, W Bailey; Horowitz, Bryant; Carlson, Gregory C; Cannon, Tyrone D; Talbot, Konrad; Jentsch, J David; Lavin, Antonieta

    2014-02-01

    Genetic variants in DTNBP1 encoding the protein dysbindin-1 have often been associated with schizophrenia and with the cognitive deficits prominent in that disorder. Because impaired function of the hippocampus is thought to play a role in these memory deficits and because NMDAR-dependent synaptic plasticity in this region is a proposed biological substrate for some hippocampal-dependent memory functions in schizophrenia, we hypothesized that reduced dysbindin-1 expression would lead to impairments in NMDAR-dependent synaptic plasticity and in contextual fear conditioning. Acute slices from male mice carrying 0, 1, or 2 null mutant alleles of the Dtnbp1 gene were prepared, and field recordings from the CA1 striatum radiatum were obtained before and after tetanization of Schaffer collaterals of CA3 pyramidal cells. Mice homozygous for the null mutation in Dtnbp1 exhibited significantly reduced NMDAR-dependent synaptic potentiation compared to wild type mice, an effect that could be rescued by bath application of the NMDA receptor coagonist glycine (10 μM). Behavioral testing in adult mice revealed deficits in hippocampal memory processes. Homozygous null mice exhibited lower conditional freezing, without a change in the response to shock itself, indicative of a learning and memory deficit. Taken together, these results indicate that a loss of dysbindin-1 impairs hippocampal plasticity which may, in part, explain the role dysbindin-1 plays in the cognitive impairments of schizophrenia. PMID:24446171

  15. Interpreting the effects of exercise on fear conditioning: the influence of time of day.

    PubMed

    Hopkins, Michael E; Bucci, David J

    2010-12-01

    Previous studies indicate that physical exercise improves contextual fear memory, as evidenced by increased freezing behavior when rats are returned to a training environment that was initially paired with footshock. However, freezing behavior could also be affected by fatigue, especially because rats were tested shortly after the end of the dark cycle, which is when most wheel running was likely to occur. In addition, exercise has been shown to have anxiolytic effects, further confounding interpretation of the effects of exercise on cognition when using aversive conditioning tasks. These factors were examined in the present study by comparing freezing behavior in exercising and nonexercising rats that were tested at different times in the light cycle. In addition, all rats were tested on an elevated plus maze to assess anxiety-like behavior and in an open-field apparatus to measure locomotor activity in order to directly examine interactions between freezing, anxiety-like behavior, and locomotion. Consistent with prior studies, exercising rats exhibited more context freezing than did sedentary rats when tested early in the light cycle. However, the opposite pattern of results was obtained when testing occurred late in the light cycle, an effect driven by a difference in the amount of freezing exhibited by the sedentary control groups. Indeed, the levels of context freezing exhibited by exercising rats were comparable regardless of when the rats were tested during the light cycle. These data have implications for interpreting the effects of exercise on aversive conditioning.

  16. Behavioral determination of stimulus pair discrimination of auditory acoustic and electrical stimuli using a classical conditioning and heart-rate approach.

    PubMed

    Morgan, Simeon J; Paolini, Antonio G

    2012-06-06

    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 implants and auditory midbrain implants. 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 devices. Several techniques such as reward-based operant conditioning, conditioned avoidance, or classical fear conditioning 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

  17. The L-Type Voltage-Gated Calcium Channel Ca[subscript v]1.3 Mediates Consolidation, but Not Extinction, of Contextually Conditioned Fear in Mice

    ERIC Educational Resources Information Center

    McKinney, Brandon C.; Murphy, Geoffrey G.

    2006-01-01

    Using pharmacological techniques, it has been demonstrated that both consolidation and extinction of Pavlovian fear conditioning are dependent to some extent upon L-type voltage-gated calcium channels (LVGCCs). Although these studies have successfully implicated LVGCCs in Pavlovian fear conditioning, they do not provide information about the…

  18. Age differences in fear retention and extinction in male Sprague-Dawley rats: effects of ethanol challenge during conditioning.

    PubMed

    Broadwater, Margaret; Spear, Linda P

    2013-09-01

    Pavlovian fear conditioning is an ideal model to investigate how learning and memory are influenced by alcohol use during adolescence because the neural mechanisms involved have been studied extensively. In Exp 1, adolescent and adult male Sprague-Dawley rats were non-injected or injected with saline, 1 or 1.5 g/kg ethanol intraperitoneally 10 min prior to tone or context conditioning. Twenty-four hours later, animals were tested for tone or context retention and extinction, with examination of extinction retention conducted 24h thereafter. In Exp 2, a context extinction session was inserted between the tone conditioning and the tone fear retention/extinction days to reduce pre-CS baseline freezing levels at test. Basal levels of acquisition, fear retention, extinction, and extinction retention after tone conditioning were similar between adolescent and adult rats. In contrast adolescents showed faster context extinction than adults, while again not differing from adults during context acquisition, retention or extinction retention. In terms of ethanol effects, adolescents were less sensitive to ethanol-induced context retention deficits than adults. No age differences emerged in terms of tone fear retention, with ethanol disrupting tone fear retention at both ages in Exp 1, but at neither age in Exp 2, a difference seemingly due to group differences in pre-CS freezing during tone testing in Exp 1, but not Exp 2. These results suggest that age differences in the acute effects of ethanol on cognitive function are task-specific, and provide further evidence for age differences cognitive functioning in a task thought to be hippocampally related.

  19. C57BL/6J and DBA/2J mice differ in extinction and renewal of extinguished conditioned fear.

    PubMed

    Waddell, Jaylyn; Dunnett, Claire; Falls, William A

    2004-10-01

    While a number of studies have examined the acquisition and expression of conditioned fear in inbred mice, very few have examined extinction of conditioned fear in inbred mice and few attempts have been made to compare extinction learning between inbred strains. Because inbred strains differ in a number of physiological and biochemical variables, differences in extinction learning may provide insight into the genetic influence of extinction learning. The purpose of this study was to examine extinction and renewal of conditioned fear in two common inbred strains of mice. C57BL/6J and DBA/2J mice were conditioned with pairings of either a tone or light and foot shock in a single session. On the following 4 days, mice were given extinction training, consisting of tone or light alone trials (Experiment 1A). C57 mice exhibited robust spontaneous recovery between sessions, but did extinguish both within and between sessions. DBA mice extinguished more quickly relative to C57 mice, and this extinction was stable between sessions (i.e., DBA mice did not exhibit spontaneous recovery). The rapid loss of fear in DBA relative to C57 mice was extinction-dependent and not merely due to poor long-term memory (Experiment 1B). Renewal testing (Experiment 2) replicated the strain difference in extinction and also showed that DBA mice have a deficit in the context specificity of extinction. C57 mice, but not DBA mice showed renewal of extinguished fear when tested in a context different from the one in which extinction training took place. These data suggest that the nature of extinction learning is influenced by characteristics of the inbred mouse strain.

  20. The incubation theory of fear/anxiety: experimental investigation in a human laboratory model of Pavlovian conditioning.

    PubMed

    Sandin, B; Chorot, P

    1989-01-01

    The aim of this work was to test Eysenck's incubation theory of fear/anxiety in human Pavlovian B conditioning of heart rate (HR) responses. The conditioned stimuli (CSs) were phobia-relevant slides (snakes and spiders) and the unconditioned stimuli (UCSs) were aversive noises. The subjects were presented with two levels of noise intensity during acquisition and three levels of nonreinforced CS presentation (CS-only) in a delay differential (CS+/CS-) conditioning paradigm (2 x 3 x 2). Consistent with the incubation theory, conditioned HR acceleratory responses were sustained (resistance to extinction) for high-noise intensity and short-presentations of CS-only subjects. During the extinction phase, HR acceleratory responses quickly extinguished in low-noise intensity groups after the first presentations of CS-only. These findings were interpreted as support for the incubation theory of phobic fear.

  1. Induction of c-Fos expression in the mammillary bodies, anterior thalamus and dorsal hippocampus after fear conditioning.

    PubMed

    Conejo, Nélida M; González-Pardo, Héctor; López, Matías; Cantora, Raúl; Arias, Jorge L

    2007-09-14

    The aim of the present study was to provide further evidence on the role of particular subdivisions of the mammillary bodies, anterior thalamus and dorsal hippocampus to contextual and auditory fear conditioning. We used c-Fos expression as a marker of neuronal activation to compare rats that received tone-footshock pairings in a distinctive context (conditioned group) to rats being exposed to both the context and the auditory CS without receiving footshocks (unconditioned group), and naïve rats that were only handled. Fos immunoreactivity was significantly increased only in the anterodorsal thalamic nucleus and the lateral mammillary nucleus of the conditioned group. However, the dorsal hippocampus showed the highest density of c-Fos positive nuclei in the naïve group as compared to the other groups. Together, our data support previous studies indicating a particular involvement of the mammillary bodies and anterior thalamus in fear conditioning. PMID:17683804

  2. PACAP modulates the consolidation and extinction of the contextual fear conditioning through NMDA receptors.

    PubMed

    Schmidt, S D; Myskiw, J C; Furini, C R G; Schmidt, B E; Cavalcante, L E; Izquierdo, I

    2015-02-01

    Pituitary adenylate cyclase-activating polypeptide (PACAP) has a broad spectrum of biological functions including neurotransmitter, neurotrophic and neuroprotective. Moreover, it has been suggested that PACAP plays a role in the modulation of learning and memory as well as on the modulation of glutamate signaling. Thus, in the current study we investigated in the CA1 region of hippocampus and in the basolateral amygdala (BLA) the role of PACAP in the consolidation and extinction of contextual fear conditioning (CFC) and the interaction between PACAP and NMDA receptors. Male rats with cannulae implanted in the CA1 region of the hippocampus or in the BLA received immediately after the training or extinction training of the CFC infusions of the Vehicle, PACAP-38 (40 pg/side), PACAP 6-38 (40 pg/side) or PACAP 6-38 plus D-serine (50 μg/side). After 24h, the animals were subjected to a 3-min retention test. The results indicated that in the CA1 region of hippocampus, PACAP participates in the consolidation and extinction of the CFC, and in the BLA, PACAP participates only in the consolidation of the CFC. Additionally, the results suggest that the action of PACAP on the consolidation and extinction of the CFC is mediated by the glutamate NMDA receptors.

  3. Facial Expression Recognition, Fear Conditioning, and Startle Modulation in Female Subjects with Conduct Disorder

    PubMed Central

    Fairchild, Graeme; Stobbe, Yvette; van Goozen, Stephanie H.M.; Calder, Andrew J.; Goodyer, Ian M.

    2010-01-01

    Background Recent behavioral and psychophysiological studies have provided converging evidence for emotional dysfunction in conduct disorder (CD). Most of these studies focused on male subjects and little is known about emotional processing in female subjects with CD. Our primary aim was to characterize explicit and implicit aspects of emotion function to determine whether deficits in these processes are present in girls with CD. Methods Female adolescents with CD (n = 25) and control subjects with no history of severe antisocial behavior and no current psychiatric disorder (n = 30) completed tasks measuring facial expression and facial identity recognition, differential autonomic conditioning, and affective modulation of the startle reflex by picture valence. Results Compared with control subjects, participants with CD showed impaired recognition of anger and disgust but no differences in facial identity recognition. Impaired sadness recognition was observed in CD participants high in psychopathic traits relative to those lower in psychopathic traits. Participants with CD displayed reduced skin conductance responses to an aversive unconditioned stimulus and impaired autonomic discrimination between the conditioned stimuli, indicating impaired fear conditioning. Participants with CD also showed reduced startle magnitudes across picture valence types, but there were no significant group differences in the pattern of affective modulation. Conclusions Adolescent female subjects with CD exhibited deficits in explicit and implicit tests of emotion function and reduced autonomic responsiveness across different output systems. There were, however, no differences in emotional reactivity. These findings suggest that emotional recognition and learning are impaired in female subjects with CD, consistent with results previously obtained in male subjects with CD. PMID:20447616

  4. Testicular hormones do not regulate sexually dimorphic Pavlovian fear conditioning or perforant-path long-term potentiation in adult male rats.

    PubMed

    Anagnostaras, S G; Maren, S; DeCola, J P; Lane, N I; Gale, G D; Schlinger, B A; Fanselow, M S

    1998-04-01

    We recently reported that Pavlovian fear conditioning and hippocampal perforant-path long-term potentiation (LTP) are sexually dimorphic in rats. Males show greater contextual fear conditioning, which depends on the hippocampus, as well as greater hippocampal LTP. In order to examine the role of circulating gonadal hormones in adult male rats, animals were castrated in two experiments, and Pavlovian fear conditioning and in vivo perforant-path LTP were examined. It was found that sexually-dimorphic LTP and fear conditioning are not regulated by the activational effects of testicular hormones in adult male rats. That is, in every respect, castrated male rats were similar to intact male rats in Pavlovian fear conditioning and hippocampal LTP. It is likely that sexual dimorphism in this system is established earlier in development by the organizational effects of gonadal hormones.

  5. Acquisition of contextual Pavlovian fear conditioning is blocked by application of an NMDA receptor antagonist D,L-2-amino-5-phosphonovaleric acid to the basolateral amygdala.

    PubMed

    Fanselow, M S; Kim, J J

    1994-02-01

    Rats, with chronic cannula placed bilaterally in the amygdala, received infusions of the N-methyl-D-aspartate (NMDA) receptor antagonist D,L-2-amino-5-phosphonovaleric acid (APV) before contextual Pavlovian fear conditioning. Administration of APV to the basolateral nucleus prevented acquisition of fear. Central nucleus infusions had no effect. It is concluded that an NMDA-mediated process near the basolateral region of the amygdala (e.g., lateral or basolateral nucleus) is essential for the learning of fear.

  6. Breaking generalized covariance, classical renormalization, and boundary conditions from superpotentials

    NASA Astrophysics Data System (ADS)

    Livshits, Gideon I.

    2014-02-01

    Superpotentials offer a direct means of calculating conserved charges associated with the asymptotic symmetries of space-time. Yet superpotentials have been plagued with inconsistencies, resulting in nonphysical or incongruent values for the mass, angular momentum, and energy loss due to radiation. The approach of Regge and Teitelboim, aimed at a clear Hamiltonian formulation with a boundary, and its extension to the Lagrangian formulation by Julia and Silva have resolved these issues, and have resulted in a consistent, well-defined and unique variational equation for the superpotential, thereby placing it on a firm footing. A hallmark solution of this equation is the KBL superpotential obtained from the first-order Lovelock Lagrangian. Nevertheless, here we show that these formulations are still insufficient for Lovelock Lagrangians of higher orders. We present a paradox, whereby the choice of fields affects the superpotential for equivalent on-shell dynamics. We offer two solutions to this paradox: either the original Lagrangian must be effectively renormalized, or that boundary conditions must be imposed, so that space-time be asymptotically maximally symmetric. Non-metricity is central to this paradox, and we show how quadratic non-metricity in the bulk of space-time contributes to the conserved charges on the boundary, where it vanishes identically. This is a realization of the gravitational Higgs mechanism, proposed by Percacci, where the non-metricity is the analogue of the Goldstone boson.

  7. Pre-test metyrapone impairs memory recall in fear conditioning tasks: lack of interaction with β-adrenergic activity

    PubMed Central

    Careaga, Mariella B. L.; Tiba, Paula A.; Ota, Simone M.; Suchecki, Deborah

    2015-01-01

    Cognitive processes, such as learning and memory, are essential for our adaptation to environmental changes and consequently for survival. Numerous studies indicate that hormones secreted during stressful situations, such as glucocorticoids (GCs), adrenaline and noradrenaline, regulate memory functions, modulating aversive memory consolidation and retrieval, in an interactive and complementary way. Thus, the facilitatory effects of GCs on memory consolidation as well as their suppressive effects on retrieval are substantially explained by this interaction. On the other hand, low levels of GCs are also associated with negative effects on memory consolidation and retrieval and the mechanisms involved are not well understood. The present study sought to investigate the consequences of blocking the rise of GCs on fear memory retrieval in multiple tests, assessing the participation of β-adrenergic signaling on this effect. Metyrapone (GCs synthesis inhibitor; 75 mg/kg), administered 90 min before the first test of contextual or tone fear conditioning (TFC), negatively affected animals’ performances, but this effect did not persist on a subsequent test, when the conditioned response was again expressed. This result suggested that the treatment impaired fear memory retrieval during the first evaluation. The administration immediately after the first test did not affect the animals’ performances in contextual fear conditioning (CFC), suggesting that the drug did not interfere with processes triggered by memory reactivation. Moreover, metyrapone effects were independent of β-adrenergic signaling, since concurrent administration with propranolol (2 mg/kg), a β-adrenergic antagonist, did not modify the effects induced by metyrapone alone. These results demonstrate that pre-test metyrapone administration led to negative effects on fear memory retrieval and this action was independent of a β-adrenergic signaling. PMID:25784866

  8. Variants of contextual fear conditioning induce differential patterns of Egr-1 activity within the young adult prefrontal cortex.

    PubMed

    Chakraborty, T; Asok, A; Stanton, M E; Rosen, J B

    2016-04-01

    Contextual fear conditioning is a form of associative learning where animals must experience a context before they can associate it with an aversive stimulus. Single-trial contextual fear conditioning (sCFC) and the context preexposure facilitation effect (CPFE) are two variants of CFC where learning about the context is temporally contiguous (sCFC) with or separated (CPFE) from receiving a footshock in that context. Neural activity within CA1 of the dorsal hippocampus (CA1), amygdala (LA), and prefrontal cortex (PFC) may play a critical role when animals learn to associate a context with a footshock (i.e., training). Previous studies from our lab have found that early-growth-response gene 1 (Egr-1), an immediate early gene, exhibits unique patterns of activity within regions of the PFC following training in sCFC and the CPFE of juvenile rats. In the present study, we extended our studies by examining Egr-1 expression in young adult rats to determine (1) if our previous work reflected changes unique to development or extend into adulthood and (2) to contrast expression profiles between sCFC and the CPFE. Rats that learned context fear with sCFC showed increased Egr-1 in the anterior cingulate, orbitofrontal and infralimbic cortices relative to non-associative controls following training, but expression in prelimbic cortex did not differ between fear conditioned and non-associative controls. In contrast, rats trained in the CPFE also showed increased Egr-1 in all the prefrontal cortex regions, including prelimbic cortex. These findings replicate our previous findings in juveniles and suggest that Egr-1 in specific PFC subregions may be uniquely involved in learning context-fear in the CPFE compared to sCFC. PMID:26778782

  9. Classical Conditioning of Eyelid and Mystacial Vibrissae Responses in Conscious Mice

    ERIC Educational Resources Information Center

    Delgado-Garcia, Jose Maria; Troncoso, Julieta; Munera, Alejandro

    2004-01-01

    The murine vibrissae sensorimotor system has been scrutinized as a target of motor learning through trace classical conditioning. Conditioned eyelid responses were acquired by using weak electrical whisker-pad stimulation as conditioned stimulus (CS) and strong electrical periorbital stimulation as unconditioned stimulus (US). In addition,…

  10. Absence of verbal recall or memory for symptom acquisition in fear and trauma exposure: a conceptual case for fear conditioning and learned nonuse in assessment and treatment.

    PubMed

    Seifert, A Ronald

    2012-01-01

    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

  11. Absence of verbal recall or memory for symptom acquisition in fear and trauma exposure: a conceptual case for fear conditioning and learned nonuse in assessment and treatment.

    PubMed

    Seifert, A Ronald

    2012-01-01

    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

  12. Protein profiles associated with context fear conditioning and their modulation by memantine.

    PubMed

    Ahmed, Md Mahiuddin; Dhanasekaran, A Ranjitha; Block, Aaron; Tong, Suhong; Costa, Alberto C S; Gardiner, Katheleen J

    2014-04-01

    Analysis of the molecular basis of learning and memory has revealed details of the roles played by many genes and the proteins they encode. Because most individual studies focus on a small number of proteins, many complexities of the relationships among proteins and their dynamic responses to stimulation are not known. We have used the technique of reverse phase protein arrays (RPPA) to assess the levels of more than 80 proteins/protein modifications in subcellular fractions from hippocampus and cortex of mice trained in Context Fear Conditioning (CFC). Proteins include components of signaling pathways, several encoded by immediate early genes or involved in apoptosis and inflammation, and subunits of glutamate receptors. At one hour after training, levels of more than half the proteins had changed in one or more fractions, among them multiple components of the Mitogen-activated protein kinase, MAPK, and Mechanistic Target of Rapamycin, MTOR, pathways, subunits of glutamate receptors, and the NOTCH pathway modulator, NUMB homolog (Drosophila). Levels of 37 proteins changed in the nuclear fraction of hippocampus alone. Abnormalities in levels of thirteen proteins analyzed have been reported in brains of patients with Alzheimer's Disease. We therefore further investigated the protein profiles of mice treated with memantine, a drug approved for treatment of AD. In hippocampus, memantine alone induced many changes similar to those seen after CFC and altered the levels of seven proteins associated with Alzheimer's Disease abnormalities. Lastly, to further explore the relevance of these datasets, we superimposed responses to CFC and memantine onto components of the long term potentiation pathway, a process subserving learning and memory formation. Fourteen components of the long term potentiation pathway and 26 proteins interacting with components responded to CFC and/or memantine. Together, these datasets provide a novel view of the diversity and complexity in protein

  13. Oxytocin Signaling in Basolateral and Central Amygdala Nuclei Differentially Regulates the Acquisition, Expression, and Extinction of Context-Conditioned Fear in Rats

    ERIC Educational Resources Information Center

    Campbell-Smith, Emma J.; Holmes, Nathan M.; Lingawi, Nura W.; Panayi, Marios C.; Westbrook, R. Frederick

    2015-01-01

    The present study investigated how oxytocin (OT) signaling in the central (CeA) and basolateral (BLA) amygdala affects acquisition, expression, and extinction of context-conditioned fear (freezing) in rats. In the first set of experiments, acquisition of fear to a shocked context was impaired by a preconditioning infusion of synthetic OT into the…

  14. Immediate extinction causes a less durable loss of performance than delayed extinction following either fear or appetitive conditioning.

    PubMed

    Woods, Amanda M; Bouton, Mark E

    2008-12-01

    Five experiments with rat subjects compared the effects of immediate and delayed extinction on the durability of extinction learning. Three experiments examined extinction of fear conditioning (using the conditioned emotional response method), and two experiments examined extinction of appetitive conditioning (using the food-cup entry method). In all experiments, conditioning and extinction were accomplished in single sessions, and retention testing took place 24 h after extinction. In both fear and appetitive conditioning, immediate extinction (beginning 10 min after conditioning) caused a faster loss of responding than delayed extinction (beginning 24 h after conditioning). However, immediate extinction was less durable than delayed extinction: There was stronger spontaneous recovery during the final retention test. There was also substantial renewal of responding when the physical context was changed between immediate extinction and testing (Experiment 1). The results suggest that, in these two widely used conditioning preparations, immediate extinction does not erase or depotentiate the original learning, and instead creates a less permanent reduction in conditioned responding. Results did not support the possibility that the strong recovery after immediate extinction was due to a mismatch in the recent "context" provided by the presence or absence of a recent conditioning experience. Several other accounts are considered.

  15. Stronger learning recruits additional cell-signaling cascades: c-Jun-N-terminal kinase 1 (JNK1) is necessary for expression of stronger contextual fear conditioning.

    PubMed

    Leach, Prescott T; Kenney, Justin W; Gould, Thomas J

    2015-02-01

    Increased training often results in stronger memories but the neural changes responsible for these stronger memories are poorly understood. It is proposed here that higher levels of training that result in stronger memories recruit additional cell signaling cascades. This study specifically examined if c-Jun N-terminal kinase 1 (JNK1) is involved in the formation of stronger fear conditioning memories. Wildtype (WT), JNK1 heterozygous (Het), and JNK1 knockout (KO) mice were fear conditioned with 1 trial, 2 trials, or 4 trials. All mice learned both contextual (hippocampus-dependent) and cued (hippocampus-independent) fear conditioning but for contextual fear conditioning only, the JNK1 KO mice did not show higher levels of learning with increased trials. That is, WT mice showed a significant linear increase in contextual fear conditioning as training trials increased from 1 to 2 to 4 trials whereas KO mice showed the same level of contextual fear conditioning as WT mice for 1 trial training but did not have increased levels of contextual fear conditioning with additional trials. These data suggest that JNK1 may not be critical for learning but when higher levels of hippocampus-dependent learning occur, JNK1 signaling is recruited and is necessary for stronger hippocampus-dependent memory formation.

  16. A review on experimental and clinical genetic associations studies on fear conditioning, extinction and cognitive-behavioral treatment.

    PubMed

    Lonsdorf, T B; Kalisch, R

    2011-09-20

    Fear conditioning and extinction represent basic forms of associative learning with considerable clinical relevance and have been implicated in the pathogenesis of anxiety disorders. There is considerable inter-individual variation in the ability to acquire and extinguish conditioned fear reactions and the study of genetic variants has recently become a focus of research. In this review, we give an overview of the existing genetic association studies on human fear conditioning and extinction in healthy individuals and of related studies on cognitive-behavioral treatment (CBT) and exposure, as well as pathology development after trauma. Variation in the serotonin transporter (5HTT) and the catechol-o-methyltransferase (COMT) genes has consistently been associated with effects in pre-clinical and clinical studies. Interesting new findings, which however require further replication, have been reported for genetic variation in the dopamine transporter (DAT1) and the pituitary adenylate cyclase 1 receptor (ADCYAP1R1) genes, whereas the current picture is inconsistent for variation in the brain-derived neurotrophic factor (BDNF) gene. We end with a discussion of the findings and their limitations, as well as future directions that we hope will aid the field to develop further.

  17. Role of sensory input distribution and intrinsic connectivity in lateral amygdala during auditory fear conditioning – A computational study

    PubMed Central

    Ball, John M.; Hummos, Ali M.; Nair, Satish S.

    2012-01-01

    We propose a novel reduced order neuronal network modeling framework that includes an enhanced firing rate model and a corresponding synaptic calcium-based synaptic learning rule. Specifically, we propose enhancements to the Wilson-Cowan firing rate neuron model that permits full spike frequency adaptation seen in biological LA neurons, while being sufficiently general to accommodate other spike frequency patterns. We also report a technique to incorporate calcium-dependent plasticity in the synapses of the network using a regression scheme to link firing rate to postsynaptic calcium. Together, the single cell model and the synaptic learning scheme constitute a general framework to develop computationally efficient neuronal networks that employ biologically-realistic synaptic learning. The reduced order modeling framework was validated using a previously reported biophysical conductance-based neuronal network model of a rodent lateral amygdala (LA) that modeled features of Pavlovian conditioning and extinction of auditory fear (Li et al., 2009). The framework was then used to develop a larger LA network model to investigate the roles of tone and shock distributions and of intrinsic connectivity in auditory fear learning. The model suggested combinations of tone and shock densities that would provide experimental estimates of tone responsive and conditioned cell proportions. Furthermore, it provided several insights including how intrinsic connectivity might help distribute sensory inputs to produce conditioned responses in cells that do not directly receive both tone and shock inputs, and how a balance between potentiation of excitation and inhibition prevents stimulus generalization during fear learning. PMID:22917618

  18. Sleep deprivation impairs contextual fear conditioning and attenuates subsequent behavioural, endocrine and neuronal responses.

    PubMed

    Hagewoud, Roelina; Bultsma, Lillian J; Barf, R Paulien; Koolhaas, Jaap M; Meerlo, Peter

    2011-06-01

    Sleep deprivation (SD) affects hippocampus-dependent memory formation. Several studies in rodents have shown that brief SD immediately following a mild foot shock impairs consolidation of contextual fear memory as reflected in a reduced behavioural freezing response during re-exposure to the shock context later. In the first part of this study, we examined whether this reduced freezing response is accompanied by an attenuated fear-induced activation of the hypothalamic-pituitary-adrenal (HPA) axis. Results show that 6h of SD immediately following the initial shock results in a diminished adrenal corticosterone (CORT) response upon re-exposure to the shock context the next day. In the second part, we established whether the attenuated freezing response in SD animals is associated with reduced activation of relevant brain areas known to be involved in the retrieval and expression of fear memory. Immunohistochemical analysis of brain slices showed that the normal increase in phosphorylation of the transcription factor 3',5'-cyclic AMP response-element binding protein (CREB) upon re-exposure to the shock context was reduced in SD animals in the CA1 region of the hippocampus and in the amygdala. In conclusion, brief SD impairs the consolidation of contextual fear memory. Upon re-exposure to the context, this is reflected in a diminished behavioural freezing response, an attenuated HPA axis response and a reduction of the normal increase of phosphorylated CREB expression in the hippocampus and amygdala. PMID:20946438

  19. CB1 Cannabinoid Receptors Modulate Kinase and Phosphatase Activity during Extinction of Conditioned Fear in Mice

    ERIC Educational Resources Information Center

    Kamprath, Kornelia; Hermann, Heike; Lutz, Beat; Marsicano, Giovanni; Cannich, Astrid; Wotjak, Carsten T.

    2004-01-01

    Cannabinoid receptors type 1 (CB1) play a central role in both short-term and long-term extinction of auditory-cued fear memory. The molecular mechanisms underlying this function remain to be clarified. Several studies indicated extracellular signal-regulated kinases (ERKs), the phosphatidylinositol 3-kinase with its downstream effector AKT, and…

  20. Neuronal Correlates of Fear Conditioning in the Bed Nucleus of the Stria Terminalis

    ERIC Educational Resources Information Center

    Haufler, Darrell; Nagy, Frank Z.; Pare, Denis

    2013-01-01

    Lesion and inactivation studies indicate that the central amygdala (CeA) participates in the expression of cued and contextual fear, whereas the bed nucleus of the stria terminalis (BNST) is only involved in the latter. The basis for this functional dissociation is unclear because CeA and BNST form similar connections with the amygdala and…