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Sample records for classical fear conditioning

  1. 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…

  2. Impaired acquisition of classically conditioned fear-potentiated startle reflexes in humans with focal bilateral basolateral amygdala damage

    PubMed Central

    Morgan, Barak; Terburg, David; Stein, Dan J.; van Honk, Jack

    2015-01-01

    Based on studies in rodents, the basolateral amygdala (BLA) is considered a key site for experience-dependent neural plasticity underlying the acquisition of conditioned fear responses. In humans, very few studies exist of subjects with selective amygdala lesions and those studies have only implicated the amygdala more broadly leaving the role of amygdala sub-regions underexplored. We tested a rare sample of subjects (N = 4) with unprecedented focal bilateral BLA lesions due to a genetic condition called Urbach–Wiethe disease. In a classical delay fear conditioning experiment, these subjects showed impaired acquisition of conditioned fear relative to a group of matched control subjects (N = 10) as measured by fear-potentiation of the defensive eye-blink startle reflex. After the experiment, the BLA-damaged cases showed normal declarative memory of the conditioned association. Our findings provide new evidence that the human BLA is essential to drive fast classically conditioned defensive reflexes. PMID:25552573

  3. 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.

  4. Amygdalar unit activity during three learning tasks: eyeblink classical conditioning, Pavlovian fear conditioning, and signaled avoidance conditioning.

    PubMed

    Rorick-Kehn, Linda M; Steinmetz, Joseph E

    2005-10-01

    Neural activity in central and basolateral amygdala nuclei (CeA and BLA, respectively) was recorded during delay eyeblink conditioning, Pavlovian fear conditioning, and signaled barpress avoidance. During paired training, the CeA exhibited robust learning-related excitatory activity during all 3 tasks. By contrast, the BLA exhibited minimal activity during eyeblink conditioning, while demonstrating pronounced increases in learning-related excitatory responsiveness during fear conditioning and barpress avoidance. In addition, the relative amount of amygdalar activation observed appeared to be related to the relative intensity of the unconditioned stimulus and somatic requirements of the task. Results suggest the CeA mediates the Pavlovian association between sensory stimuli and the BLA mediates the modulation of instrumental responding through the assignment of motivational value to the unconditioned stimulus.

  5. 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.

  6. 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

  7. 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

  8. 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

  9. Towards understanding sex differences in visceral pain: enhanced reactivation of classically-conditioned fear in healthy women.

    PubMed

    Benson, Sven; Kattoor, Joswin; Kullmann, Jennifer S; Hofmann, Sarah; Engler, Harald; Forsting, Michael; Gizewski, Elke R; Elsenbruch, Sigrid

    2014-03-01

    Sex differences in learned fear regarding aversive gastrointestinal stimuli could play a role in the female preponderance of chronic abdominal pain. In a fear conditioning model with rectal pain as unconditioned stimulus (US), we compared healthy males and females with respect to neural responses during aversive visceral learning, extinction and re-activation of fear memory (i.e., reinstatement). To do so, conditioned visual stimuli (CS(+)) were consistently paired with painful rectal distensions as US, while different visual stimuli (CS(-)) were presented without US. During extinction, both CSs were presented without US, whereas during reinstatement, a single, unpaired US was presented. In region-of-interest analyses, sexes were compared with respect to conditioned anticipatory neural activation (CS(+)>CS(-)). The results revealed that in late acquisition, CS+ presentation induced significantly greater anticipatory activation of the insula in women. During extinction, women demonstrated reduced activation of the posterior cingulate cortex. During reinstatement, the CS(+) led to greater activation of the hippocampus, thalamus and cerebellum in women. These group effects in neural activation during learning and memory processes were not accounted for by sex differences in pain thresholds, pain ratings, or stress parameters. In conclusion, this is the first study to support sex differences in neural processes mediating aversive visceral learning. Our finding of enhanced neural responses during reinstatement in key brain areas relevant for memory suggests enhanced reactivation of old fear memory trace in women. Sex differences in "gut memories" could play a role in the female preponderance of chronic abdominal pain.

  10. Fear Conditioning Increases NREM Sleep

    PubMed Central

    Hellman, Kevin; Abel, Ted

    2010-01-01

    To understand the role that sleep may play in memory storage, the authors investigated how fear conditioning affects sleep–wake states by performing electroencephalographic (EEG) and electromyographic recordings of C57BL/6J mice receiving fear conditioning, exposure to conditioning stimuli, or immediate shock treatment. This experimental design allowed us to examine the effects of associative learning, presentation of the conditioning stimuli, and presentation of the unconditioned stimuli on sleep–wake states. During the 24 hr after training, fear-conditioned mice had approximately 1 hr more of nonrapid-eye-movement (NREM) sleep and less wakefulness than mice receiving exposure to conditioning stimuli or immediate shock treatment. Mice receiving conditioning stimuli had more delta power during NREM sleep, whereas mice receiving fear conditioning had less theta power during rapid-eye-movement sleep. These results demonstrate that a single trial of fear conditioning alters sleep–wake states and EEG oscillations over a 24-hr period, supporting the idea that sleep is modified by experience and that such changes in sleep–wake states and EEG oscillations may play a role in memory consolidation. PMID:17469920

  11. What's wrong with fear conditioning?

    PubMed

    Beckers, Tom; Krypotos, Angelos-Miltiadis; Boddez, Yannick; Effting, Marieke; Kindt, Merel

    2013-01-01

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

  12. Where There is Smoke There is Fear-Impaired Contextual Inhibition of Conditioned Fear in Smokers.

    PubMed

    Haaker, Jan; Lonsdorf, Tina B; Schümann, Dirk; Bunzeck, Nico; Peters, Jan; Sommer, Tobias; Kalisch, Raffael

    2017-02-15

    The odds-ratio of smoking is elevated in populations with neuropsychiatric diseases, in particular in the highly prevalent diagnoses of post-traumatic stress and anxiety disorders. Yet, the association between smoking and a key dimensional phenotype of these disorders-maladaptive deficits in fear learning and fear inhibition-is unclear. We therefore investigated acquisition and memory of fear and fear inhibition in healthy smoking and non-smoking participants (N=349, 22% smokers). We employed a well validated paradigm of context-dependent fear and safety learning (day 1) including a memory retrieval on day 2. During fear learning, a geometrical shape was associated with an aversive electrical stimulation (classical fear conditioning, in danger context) and fear responses were extinguished within another context (extinction learning, in safe context). On day 2, the conditioned stimuli were presented again in both contexts, without any aversive stimulation. Autonomic physiological measurements of skin conductance responses as well as subjective evaluations of fear and expectancy of the aversive stimulation were acquired. We found that impairment of fear inhibition (extinction) in the safe context during learning (day 1) was associated with the amount of pack-years in smokers. During retrieval of fear memories (day 2), smokers showed an impairment of contextual (safety context-related) fear inhibition as compared with non-smokers. These effects were found in physiological as well as subjective measures of fear. We provide initial evidence that smokers as compared with non-smokers show an impairment of fear inhibition. We propose that smokers have a deficit in integrating contextual signs of safety, which is a hallmark of post-traumatic stress and anxiety disorders.Neuropsychopharmacology advance online publication, 15 February 2017; doi:10.1038/npp.2017.17.

  13. Quantitative proteomics of auditory fear conditioning.

    PubMed

    Hong, Ingie; Kang, Taewook; Yun, Ki Na; Yoo, YongCheol; Park, Sungmo; Kim, Jihye; An, Bobae; Song, Sukwoon; Lee, Sukwon; Kim, Jeongyeon; Song, Beomjong; Kwon, Kyung-Hoon; Kim, Jin Young; Park, Young Mok; Choi, Sukwoo

    2013-04-26

    Auditory fear conditioning is a well-characterized rodent learning model where a neutral auditory cue is paired with an aversive outcome to induce associative fear memory. The storage of long-term auditory fear memory requires long-term potentiation (LTP) in the lateral amygdala and de novo protein synthesis. Although many studies focused on individual proteins have shown their contribution to LTP and fear conditioning, non-biased genome-wide studies have only recently been possible with microarrays, which nevertheless fall short of measuring changes at the level of proteins. Here we employed quantitative proteomics to examine the expression of hundreds of proteins in the lateral amygdala in response to auditory fear conditioning. We found that various proteins previously implicated in LTP, learning and axon/dendrite growth were regulated by fear conditioning. A substantial number of proteins that were regulated by fear conditioning have not yet been studied specifically in learning or synaptic plasticity.

  14. 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

  15. 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…

  16. 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.

  17. 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.…

  18. Central amygdala activity during fear conditioning.

    PubMed

    Duvarci, Sevil; Popa, Daniela; Paré, Denis

    2011-01-05

    The central amygdala (Ce), particularly its medial sector (CeM), is the main output station of the amygdala for conditioned fear responses. However, there is uncertainty regarding the nature of CeM control over conditioned fear. The present study aimed to clarify this question using unit recordings in rats. Fear conditioning caused most CeM neurons to increase their conditioned stimulus (CS) responsiveness. The next day, CeM cells responded similarly during the recall test, but these responses disappeared as extinction of conditioned fear progressed. In contrast, the CS elicited no significant average change in central lateral (CeL) firing rates during fear conditioning and a small but significant reduction during the recall test. Yet, cell-by-cell analyses disclosed large but heterogeneous CS-evoked responses in CeL. By the end of fear conditioning, roughly equal proportions of CeL cells exhibited excitatory (CeL(+)) or inhibitory (CeL(-)) CS-evoked responses (∼10%). The next day, the proportion of CeL(-) cells tripled with no change in the incidence of CeL(+) cells, suggesting that conditioning leads to overnight synaptic plasticity in an inhibitory input to CeL(-) cells. As in CeM, extinction training caused the disappearance of CS-evoked activity in CeL. Overall, these findings suggest that conditioned freezing depends on increased CeM responses to the CS. The large increase in the incidence of CeL(-) but not CeL(+) cells from conditioning to recall leads us to propose a model of fear conditioning involving the potentiation of an extrinsic inhibitory input (from the amygdala or elsewhere) to CeL, ultimately leading to disinhibition of CeM neurons.

  19. Contextual fear conditioning depresses infralimbic excitability.

    PubMed

    Soler-Cedeño, Omar; Cruz, Emmanuel; Criado-Marrero, Marangelie; Porter, James T

    2016-04-01

    Patients with posttraumatic stress disorder (PTSD) show hypo-active ventromedial prefrontal cortices (vmPFC) that correlate with their impaired ability to discriminate between safe and dangerous contexts and cues. Previously, we found that auditory fear conditioning depresses the excitability of neurons populating the homologous structure in rodents, the infralimbic cortex (IL). However, it is undetermined if IL depression was mediated by the cued or contextual information. The objective of this study was to examine whether contextual information was sufficient to depress IL neuronal excitability. After exposing rats to context-alone, pseudoconditioning, or contextual fear conditioning, we used whole-cell current-clamp recordings to examine the excitability of IL neurons in prefrontal brain slices. We found that contextual fear conditioning reduced IL neuronal firing in response to depolarizing current steps. In addition, neurons from contextual fear conditioned animals showed increased slow afterhyperpolarization potentials (sAHPs). Moreover, the observed changes in IL excitability correlated with contextual fear expression, suggesting that IL depression may contribute to the encoding of contextual fear.

  20. Generalization of conditioned fear along a dimension of increasing fear intensity.

    PubMed

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

    2009-07-01

    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 experimental groups underwent discriminative fear conditioning between a face stimulus of 55% fear intensity (conditioned stimulus, CS+), reinforced with an electric shock, and a second stimulus that was unreinforced (CS-). In Experiment 1 the CS- was a relatively neutral face stimulus, while in Experiment 2 the CS- was the most fear-intense stimulus. Before and following fear conditioning, skin conductance responses (SCR) were recorded to different morph values along the neutral-to-fear dimension. Both experimental groups showed gradients of generalization following fear conditioning that increased with the fear intensity of the stimulus. In Experiment 1 a peak shift in SCRs extended to the most fear-intense stimulus. In contrast, generalization to the most fear-intense stimulus was reduced in Experiment 2, suggesting that discriminative fear learning procedures can attenuate fear generalization. Together, the findings indicate that fear generalization is broadly tuned and sensitive to the amount of fear intensity in nonconditioned stimuli, but that fear generalization can come under stimulus control. These results reveal a novel form of fear generalization in humans that is not merely based on physical similarity to a conditioned exemplar, and may have implications for understanding generalization processes in anxiety disorders characterized by heightened sensitivity to nonthreatening stimuli.

  1. Effects of exercise on Pavlovian fear conditioning.

    PubMed

    Baruch, David E; Swain, Rodney A; Helmstetter, Fred J

    2004-10-01

    Exercise promotes multiple changes in hippocampal morphology and should, as a result, alter behavioral function. The present experiment investigated the effect of exercise on learning using contextual and auditory Pavlovian fear conditioning. Rats remained inactive or voluntarily exercised (VX) for 30 days, after which they received auditory-cued fear conditioning. Twenty-four hours later, rats were tested for learning of the contextual and auditory conditional responses. No differences in freezing behavior to the discrete auditory cue were observed during the training or testing sessions. However, VX rats did freeze significantly more compared to controls when tested in the training context 24 hr after exposure to shock. The enhancement of contextual fear conditioning provides further evidence that exercise alters hippocampal function and learning.

  2. Auditory trace fear conditioning requires perirhinal cortex

    PubMed Central

    Kholodar-Smith, D.B.; Boguszewski, P.; Brown, T.H.

    2008-01-01

    The hippocampus is well-known to be critical for trace fear conditioning, but nothing is known about the importance of perirhinal cortex (PR), which has reciprocal connections with hippocampus. PR damage severely impairs delay fear conditioning to ultrasonic vocalizations (USVs) and discontinuous tones (pips), but has no effect on delay conditioning to continuous tones (Kholodar-Smith, Allen, and Brown, in press). Here we demonstrate that trace auditory fear conditioning also critically depends on PR function. The trace interval between the CS offset and the US onset was 16 s. Pre-training neurotoxic lesions were produced through multiple injections of N-methyl-D-aspartate along the full length of PR, which was directly visualized during the injections. Control animals received injections with phosphate-buffered saline. Three-dimensional reconstructions of the lesion volumes demonstrated that the neurotoxic damage was well-localized to PR and included most of its anterior-posterior extent. Automated video analysis quantified freezing behavior, which served as the conditional response. PR-damaged rats were profoundly impaired in trace conditioning to either of three different CSs (a USV, tone pips, and a continuous tone) as well as conditioning to the training context. Within both the lesion and control groups, the type of cue had no effect on the mean CR. The overall PR lesion effect size was 2.7 for cue conditioning and 3.9 for context conditioning. We suggest that the role of PR in trace fear conditioning may be distinct from some of its more perceptual functions. The results further define the essential circuitry underlying trace fear conditioning to auditory cues. PMID:18678265

  3. Generalisation of conditioned fear and its behavioural expression in mice.

    PubMed

    Laxmi, T Rao; Stork, Oliver; Pape, Hans-Christian

    2003-10-17

    Mice are favourite subjects in molecular and genetic memory research and frequently studied with classical fear conditioning paradigms that use an auditory cue (conditioned stimulus, CS(+)) to predict an aversive, unconditioned stimulus (US). Yet the conditions that control fear memory specificity and generalisation and their behavioural expression in such conditioned mice have not been analysed systematically. In the current study we addressed these issues in the most widely used mouse strain of behavioural genetics, C57Bl/6. In keeping with findings in other species we demonstrate the dependence of fear memory generalisation on training intensity (i.e. both US intensity and the number of CS(+) and US applied) after both excitatory (explicitly paired presentation of CS(+) and US) and inhibitory training (explicitly unpaired presentation of CS(+) and US). Furthermore, inhibitory overtraining was associated with changes of uncued anxiety-like behaviour in a light/dark exploration test, indicative of an emotional sensitisation reaction as consequence of a lack of US predictability. Together our results describe the qualitatively and quantitatively different increases of defensive behaviour in response to conditioned stimuli of different salience and identify training conditions that lead to fear memory generalisation and emotional sensitisation in C57Bl/6 inbred mice.

  4. Generalization of conditioned fear along a dimension of increasing fear intensity

    PubMed Central

    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 experimental groups underwent discriminative fear conditioning between a face stimulus of 55% fear intensity (conditioned stimulus, CS+), reinforced with an electric shock, and a second stimulus that was unreinforced (CS−). In Experiment 1 the CS− was a relatively neutral face stimulus, while in Experiment 2 the CS− was the most fear-intense stimulus. Before and following fear conditioning, skin conductance responses (SCR) were recorded to different morph values along the neutral-to-fear dimension. Both experimental groups showed gradients of generalization following fear conditioning that increased with the fear intensity of the stimulus. In Experiment 1 a peak shift in SCRs extended to the most fear-intense stimulus. In contrast, generalization to the most fear-intense stimulus was reduced in Experiment 2, suggesting that discriminative fear learning procedures can attenuate fear generalization. Together, the findings indicate that fear generalization is broadly tuned and sensitive to the amount of fear intensity in nonconditioned stimuli, but that fear generalization can come under stimulus control. These results reveal a novel form of fear generalization in humans that is not merely based on physical similarity to a conditioned exemplar, and may have implications for understanding generalization processes in anxiety disorders characterized by heightened sensitivity to nonthreatening stimuli. PMID:19553384

  5. 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.

  6. 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.

  7. 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…

  8. 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.

  9. [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.

  10. 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…

  11. 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…

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

    PubMed

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

    2016-05-01

    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.

  13. Prior chronic nicotine impairs cued fear extinction but enhances contextual fear conditioning in rats.

    PubMed

    Tian, S; Gao, J; Han, L; Fu, J; Li, C; Li, Z

    2008-06-02

    Clinical observations have shown a link for the high comorbid rate between smoking and psychiatric disorders, including anxiety disorders. However, little is known about the neural mechanism underlying the progression from nicotine dependence to an anxiety disorder. A deficit in fear extinction in general is considered to contribute to anxiety disorders. The aim of the present study is to investigate the effects of chronic nicotine on fear extinction in rats. Rats were administrated s.c. nicotine twice per day for 14 days. Two weeks after the last injection rats received a cued or contextual fear conditioning session. Twenty-four hours and 48 h after conditioning, rats received an extinction training session and an extinction test session, respectively. Percent freezing was assessed during all phases of training. In the cued task, prior chronic nicotine did not affect the acquisition of fear response or the within-session fear extinction, but impaired the between-session fear extinction. In the contextual task, the same nicotine treatment schedule did not affect the acquisition of fear response or the within- and between-session fear extinction, but enhanced the retention of fear conditioning. This prior chronic nicotine-induced deficit in cued fear extinction and/or enhanced fear to context may be one of the critical components that contribute to the progression from nicotine dependence to an anxiety disorder.

  14. Asymmetrical stimulus generalization following differential fear conditioning.

    PubMed

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

    2008-07-01

    Rodent ultrasonic vocalizations (USVs) are ethologically critical social signals. Rats emit 22kHz USVs and 50kHz 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 22kHz 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 4kHz discontinuous tone with an on-off pattern matched to one of the USVs, and a 50kHz 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 22kHz 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.

  15. Fear memory formation can affect a different memory: fear conditioning affects the extinction, but not retrieval, of conditioned taste aversion (CTA) memory

    PubMed Central

    Joels, Gil; Lamprecht, Raphael

    2014-01-01

    The formation of fear memory to a specific stimulus leads to subsequent fearful response to that stimulus. However, it is not apparent whether the formation of fear memory can affect other memories. We study whether specific fearful experience leading to fear memory affects different memories formation and extinction. We revealed that cued fear conditioning, but not unpaired or naïve training, inhibited the extinction of conditioned taste aversion (CTA) memory that was formed after fear conditioning training in rats. Fear conditioning had no effect on retrieval of CTA memory but specifically impaired its extinction. Extinguished fear memory, after fear extinction training, had no effect on future CTA memory extinction. Fear conditioning had no effect on CTA memory extinction if CTA memory was formed before fear conditioning. Conditioned taste aversion had no effect on fear conditioning memory extinction. We conclude that active cued fear conditioning memory can affect specifically the extinction, but not the formation, of future different memory. PMID:25324744

  16. 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.

  17. 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

  18. 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.

  19. Classical conditioning differences associated with chronic pain: a systematic review.

    PubMed

    Harvie, Daniel S; Moseley, G Lorimer; Hillier, Susan L; Meulders, Ann

    2017-04-03

    Prominent clinical models of chronic pain propose a fundamental role of classical conditioning in the development of pain-related disability. If classical conditioning is key to this process, then people with chronic pain may show a different response to pain-related conditioned stimuli (CS) than healthy controls. We set out to determine whether this is the case by undertaking a comprehensive and systematic review of the literature. To identify studies comparing classical conditioning between people with chronic pain and healthy controls, the databases MEDLINE, PsychINFO, PsychARTICLES, Scopus, CINAHL, were searched using key words and MESH headings consistent with 'classical conditioning' AND 'pain'. Articles were included when a) pain-free control and chronic pain groups were included, and b) a differential classical conditioning design was used. The systematic search revealed seven studies investigating differences in classical conditioning between people with chronic pain and healthy controls. The included studies involved a total of 129 people with chronic pain (Fibromyalgia syndrome, Spinal pain, Hand pain, Irritable bowel syndrome), and 104 healthy controls. Outcomes included indices of pain-related conditioning such as unconditioned stimulus (US) expectancy and contingency awareness, self-report and physiological measures of pain-related fear, evaluative judgments of conditioned stimulus (CS) pleasantness, and muscular and cortical responses. Due to variability in outcomes, meta-analyses included a maximum of four studies. People with chronic pain tended to show reduced differential learning and flatter generalisation gradients with respect to US-expectancy and fear-potentiated eyeblink startle responses. Some studies demonstrated a propensity for greater muscular responses and perceptions of unpleasantness in response to pain-associated cues, relative to control cues.

  20. Fear Conditioning Effects on Sensitivity to Drug Reward

    DTIC Science & Technology

    2009-06-01

    basolateral amygdala The second step is to demonstrate efficacy of the GABAB receptor agonist baclofen in blocking the development of fear conditioning...controls. The fourth step assesses the impact of baclofen given during the development of fear conditioning and measures its impact on subsequent

  1. Oxytocin and Social Support as Synergistic Inhibitors of Aversive Fear Conditioning and Fear-Potentiated Startle in Male Rats

    DTIC Science & Technology

    2009-09-01

    startle amplitude. They then received Pavlovian fear conditioning of five pairings of a 3 s light co-terminating with a 500 ms, 0.6mA footshock. Four...Synergistic Inhibitors of Aversive Fear Conditioning and Fear-Potentiated Startle in Male Rats PRINCIPAL INVESTIGATOR: Jeffrey B. Rosen, Ph.D...NUMBER Oxytocin and Social Support as Synergistic Inhibitors of Aversive Fear Conditioning and Fear-Potentiated Startle in Male Rats 5b. GRANT

  2. Cotinine enhances the extinction of contextual fear memory and reduces anxiety after fear conditioning.

    PubMed

    Zeitlin, Ross; Patel, Sagar; Solomon, Rosalynn; Tran, John; Weeber, Edwin J; Echeverria, Valentina

    2012-03-17

    Posttraumatic stress disorder (PTSD) is an anxiety disorder triggered by traumatic events. Symptoms include anxiety, depression and deficits in fear memory extinction (FE). PTSD patients show a higher prevalence of cigarette smoking than the general population. The present study investigated the effects of cotinine, a tobacco-derived compound, over anxiety and contextual fear memory after fear conditioning (FC) in mice, a model for inducing PTSD-like symptoms. Two-month-old C57BL/6J mice were separated into three experimental groups. These groups were used to investigate the effect of pretreatment with cotinine on contextual fear memory and posttreatment on extinction and stability or retrievability of the fear memory. Also, changes induced by cotinine on the expression of extracellular signal-regulated kinase (ERK)1/2 were assessed after extinction in the hippocampus. An increase in anxiety and corticosterone levels were found after fear conditioning. Cotinine did not affect corticosterone levels but enhanced the extinction of contextual fear, decreased anxiety and the stability and/or retrievability of contextual fear memory. Cotinine-treated mice showed higher levels of the active forms of ERK1/2 than vehicle-treated mice after FC. This evidence suggests that cotinine is a potential new pharmacological treatment to reduce symptoms in individuals with PTSD.

  3. 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.

  4. 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

  5. Sex differences in fear conditioning in posttraumatic stress disorder

    PubMed Central

    Inslicht, Sabra S.; Metzler, Thomas J.; Garcia, Natalia M.; Pineles, Suzanne L.; Milad, Mohammed R.; Orr, Scott P.; Marmar, Charles R.; Neylan, Thomas C.

    2013-01-01

    Background Women are twice as likely as men to develop Posttraumatic Stress Disorder (PTSD). Abnormal acquisition of conditioned fear has been suggested as a mechanism for the development of PTSD. While some studies of healthy humans suggest that women are either no different or express less conditioned fear responses during conditioning relative to men, differences in the acquisition of conditioned fear between men and women diagnosed with PTSD has not been examined. Methods Thirty-one participants (18 men; 13 women) with full or subsyndromal PTSD completed a fear conditioning task. Participants were shown computer-generated colored circles that were paired (CS+) or unpaired (CS−) with an aversive electrical stimulus and skin conductance levels were assessed throughout the task. Results Repeated measures ANOVA indicated a significant sex by stimulus interaction during acquisition. Women had greater differential conditioned skin conductance responses (CS + trials compared to CS− trials) than did men, suggesting greater acquisition of conditioned fear in women with PTSD. Conclusions In contrast to studies of healthy individuals, we found enhanced acquisition of conditioned fear in women with PTSD. Greater fear conditioning in women may either be a pre-existing vulnerability trait or an acquired phenomenon that emerges in a sex-dependent manner after the development of PTSD. Characterizing the underlying mechanisms of these differences is needed to clarify sex-related differences in the pathophysiology of PTSD. PMID:23107307

  6. BDNFval66met affects neural activation pattern during fear conditioning and 24 h delayed fear recall

    PubMed Central

    Golkar, Armita; Lindström, Kara M.; Haaker, Jan; Öhman, Arne; Schalling, Martin; Ingvar, Martin

    2015-01-01

    Brain-derived neurotrophic factor (BDNF), the most abundant neutrophin in the mammalian central nervous system, is critically involved in synaptic plasticity. In both rodents and humans, BDNF has been implicated in hippocampus- and amygdala-dependent learning and memory and has more recently been linked to fear extinction processes. Fifty-nine healthy participants, genotyped for the functional BDNFval66met polymorphism, underwent a fear conditioning and 24h-delayed extinction protocol while skin conductance and blood oxygenation level dependent (BOLD) responses (functional magnetic resonance imaging) were acquired. We present the first report of neural activation pattern during fear acquisition ‘and’ extinction for the BDNFval66met polymorphism using a differential conditioned stimulus (CS)+ > CS− comparison. During conditioning, we observed heightened allele dose-dependent responses in the amygdala and reduced responses in the subgenual anterior cingulate cortex in BDNFval66met met-carriers. During early extinction, 24h later, we again observed heightened responses in several regions ascribed to the fear network in met-carriers as opposed to val-carriers (insula, amygdala, hippocampus), which likely reflects fear memory recall. No differences were observed during late extinction, which likely reflects learned extinction. Our data thus support previous associations of the BDNFval66met polymorphism with neural activation in the fear and extinction network, but speak against a specific association with fear extinction processes. PMID:25103087

  7. 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…

  8. Specific phobia: a disorder of fear conditioning and extinction.

    PubMed

    Stein, Dan J; Matsunaga, Hisato

    2006-04-01

    Specific phobia is the most prevalent of the anxiety disorders. Although there have been relatively few studies of its psychobiology and pharmacotherapy, there is a rich laboratory of literature on fear conditioning and extinction and a clear evolutionary perspective. Advances in the cognitive-affective neuroscience of fear processing may ultimately lead to new approaches to the clinical management of phobias.

  9. Understanding posttraumatic stress disorder through fear conditioning, extinction and reconsolidation.

    PubMed

    Careaga, Mariella Bodemeier Loayza; Girardi, Carlos Eduardo Neves; Suchecki, Deborah

    2016-12-01

    Careaga MBL, Girardi CEN, Suchecki D. Understanding posttraumatic stress disorder through fear conditioning, extinction and reconsolidation. NEUROSCI BIOBEHAV REV -Posttraumatic stress disorder (PTSD) is a psychopathology characterized by exacerbation of fear response. A dysregulated fear response may be explained by dysfunctional learning and memory, a hypothesis that was proposed decades ago. A key component of PTSD is fear conditioning and the study of this phenomenon in laboratory has expanded the understanding of the underlying neurobiological changes in PTSD. Furthermore, traumatic memories are strongly present even years after the trauma and maintenance of this memory is usually related to behavioral and physiological maladaptive responses. Persistence of traumatic memory may be explained by a dysregulation of two memory processes: extinction and reconsolidation. The former may explain the over-expression of fear responses as an imbalance between traumatic and extinction memory. The latter, in turn, explains the maintenance of fear responses as a result of enhancing trauma-related memories. Thus, this review will discuss the importance of fear conditioning for the establishment of PTSD and how failure in extinction or abnormal reconsolidation may contribute to the maintenance of fear response overtime.

  10. Reinstatement of extinguished fear by an unextinguished conditional stimulus.

    PubMed

    Halladay, Lindsay R; Zelikowsky, Moriel; Blair, Hugh T; Fanselow, Michael S

    2012-01-01

    Anxiety disorders are often treated using extinction-based exposure therapy, but relapse is common and can occur as a result of reinstatement, whereby an aversive "trigger" can reinstate extinguished fear. Animal models of reinstatement commonly utilize a Pavlovian fear conditioning procedure, in which subjects are first trained to fear a conditional stimulus (CS) by pairing it with an aversive unconditional stimulus (US), and then extinguished by repeated presentations of the CS alone. Reinstatement is typically induced by exposing subjects to an aversive US after extinction, but here we show that exposure to a non-extinguished CS can reinstate conditional fear responding to an extinguished CS, a phenomenon we refer to as "conditional reinstatement" (CRI). Rats were trained to fear two CSs (light and tone) and subsequently underwent extinction training to only one CS (counterbalanced). Presenting the unextinguished CS (but not a novel cue) immediately after extinction reinstated conditional fear responding to the extinguished CS in a test session given 24 h later. These findings indicate that reinstatement of extinguished fear can be triggered by exposure to conditional as well as unconditional aversive stimuli, and this may help to explain why relapse is common following clinical extinction therapy in humans. Further study of CRI using animal models may prove useful for developing refined extinction therapies that are more resistant to reinstatement.

  11. Skin conductance fear conditioning impairments and aggression: a longitudinal study.

    PubMed

    Gao, Yu; Tuvblad, Catherine; Schell, Anne; Baker, Laura; Raine, Adrian

    2015-02-01

    Autonomic fear conditioning deficits have been linked to child aggression and adult criminal behavior. However, it is unknown if fear conditioning deficits are specific to certain subtypes of aggression, and longitudinal research is rare. In the current study, reactive and proactive aggression were assessed in a sample of males and females when aged 10, 12, 15, and 18 years old. Skin conductance fear conditioning data were collected when they were 18 years old. Individuals who were persistently high on proactive aggression measures had significantly poorer conditioned responses at 18 years old when compared to others. This association was not found for reactive aggression. Consistent with prior literature, findings suggest that persistent antisocial individuals have unique neurobiological characteristics and that poor autonomic fear conditioning is associated with the presence of increased instrumental aggressive behavior.

  12. Skin Conductance Fear Conditioning Impairments and Aggression: A Longitudinal Study

    PubMed Central

    Gao, Yu; Tuvblad, Catherine; Schell, Anne; Baker, Laura; Raine, Adrian

    2014-01-01

    Autonomic fear conditioning deficits have been linked to child aggression and adult criminal behavior. However, it is unknown if fear conditioning deficits are specific to certain subtypes of aggression, and longitudinal research is rare. In the current study, reactive and proactive aggression were assessed in a sample of males and females when aged 10, 12, 15, and 18 years old. Skin conductance fear conditioning data were collected when they were 18 years old. Individuals who were persistently high on proactive aggression measures had significantly poorer conditioned responses at 18 years old when compared to others. This association was not found for reactive aggression. Consistent with prior literature, findings suggest that persistent antisocial individuals have unique neurobiological characteristics and that poor autonomic fear conditioning is associated with the presence of increased instrumental aggressive behavior. PMID:25174802

  13. 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

  14. 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.

  15. 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

    2015-05-05

    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.

  16. 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.

  17. 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

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

    PubMed Central

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

    2015-01-01

    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 12 hr 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. PMID:25746455

  19. 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.

  20. Delayed effects of cortisol enhance fear memory of trace conditioning.

    PubMed

    Cornelisse, Sandra; van Ast, Vanessa A; Joëls, Marian; Kindt, Merel

    2014-02-01

    Corticosteroids induce rapid non-genomic effects followed by slower genomic effects that are thought to modulate cognitive function in opposite and complementary ways. It is presently unknown how these time-dependent effects of cortisol affect fear memory of delay and trace conditioning. This distinction is of special interest because the neural substrates underlying these types of conditioning may be differently affected by time-dependent cortisol effects. Delay conditioning is predominantly amygdala-dependent, while trace conditioning additionally requires the hippocampus. Here, we manipulated the timing of cortisol action during acquisition of delay and trace fear conditioning, by randomly assigning 63 men to one of three possible groups: (1) receiving 10mg hydrocortisone 240 min (slow cort) or (2) 60 min (rapid cort) before delay and trace acquisition, or (3) placebo at both times, in a double-blind design. The next day, we tested memory for trace and delay conditioning. Fear potentiated startle responses, skin conductance responses and unconditioned stimulus expectancy scores were measured throughout the experiment. The fear potentiated startle data show that cortisol intake 240 min before actual fear acquisition (slow cort) uniquely strengthened subsequent trace conditioned memory. No effects of cortisol delivery 60 min prior to fear acquisition were found on any measure of fear memory. Our findings emphasize that slow, presumably genomic, but not more rapid effects of corticosteroids enhance hippocampal-dependent fear memories. On a broader level, our findings underline that basic experimental research and clinically relevant pharmacological treatments employing corticosteroids should acknowledge the timing of corticosteroid administration relative to the learning phase, or therapeutic intervention.

  1. Heart rate reactivity in HAD and LAD rats during Pavlovian fear conditioning.

    PubMed

    Rorick, Linda M; Finn, Peter R; Steinmetz, Joseph E

    2004-01-01

    Recently, we reported that High-Alcohol-Drinking (HAD) rats exhibited selective deficits in active avoidance learning under alcohol-naive conditions, and that administration of moderate doses of alcohol (0.5 and 1.0 g/kg) facilitated learning in these rats (Blankenship et al., 2000; Rorick et al., 2003b). We hypothesized that the deficits resulted from excessive fear in the aversive learning context and that the anxiolytic properties of alcohol may have contributed to the improved learning that was observed after alcohol administration. This hypothesis was supported by a recent study in which prolonged freezing in HAD rats was seen after a classical fear conditioning procedure (Rorick et al., 2003a). To provide additional evidence that HAD rats indeed exhibit behaviors consistent with the expression of increased fear in aversive learning contexts, we employed a Pavlovian fear conditioning task to measure heart rate in HAD and Low-Alcohol-Drinking (LAD) rats. In this study, HAD (HAD-1 and HAD-2) and LAD (LAD-1 and LAD-2) rats were assigned to one of three pre-exposure conditions: Context Only, Context/Tone, or Sequential (Context Only followed by Context/Tone) Pre-Exposure. Following pre-exposure, fear conditioning acquisition and extinction procedures were identical for all groups. Results indicated that although no baseline differences were observed between HAD and LAD rats, HAD rats receiving Context-Only pre-exposure exhibited excessive heart rate reactivity to the tone conditional stimulus during fear conditioning acquisition, compared to LAD rats receiving the same pre-exposure conditions. These findings support the hypothesis that HAD rats exhibit behaviors consistent with increased fear in aversive learning contexts, as measured by autonomic conditioning.

  2. Fear conditioning to discontinuous auditory cues requires perirhinal cortical function.

    PubMed

    Kholodar-Smith, D B; Allen, T A; Brown, T H

    2008-10-01

    Pretraining lesions of rat perirhinal (PR) cortex impair fear conditioning to ultrasonic vocalizations (USVs) but have no effect on conditioning to continuous tones. This study attempted to deconstruct USVs into simpler stimulus features that cause fear conditioning to be PR-dependent. Rats were conditioned to one of three cues: a multicall 19-kHz USV, a 19-kHz discontinuous tone, and a 19-kHz continuous tone. The discontinuous tone duplicated the on/off pattern of the individual calls in the USV, but it lacked the characteristic frequency modulations. Well-localized neurotoxic PR lesions impaired conditioning to the USV, the discontinuous tone, and the training context. However, PR lesions had no effect on conditioning to the continuous tone. The authors suggest that the lesion effects on fear conditioning to both cues and contexts reflect the essential role of PR in binding stimulus elements together into unitary representations.

  3. 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

  4. 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.

  5. 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.

  6. 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…

  7. 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.

  8. Updating versus Exposure to Prevent Consolidation of Conditioned Fear

    PubMed Central

    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

  9. Measuring Pavlovian fear with conditioned freezing and conditioned suppression reveals different roles for the basolateral amygdala.

    PubMed

    McDannald, Michael A; Galarce, Ezequiel M

    2011-02-16

    In Pavlovian fear conditioning, pairing a neutral cue with aversive foot shock endows a cue with fear-eliciting properties. Studies of Pavlovian fear conditioning measuring freezing have demonstrated the basolateral amygdala (BLA) to be critical to both fear learning and memory. The nucleus accumbens core (NAc), while not important to freezing, is important to the enhancement of instrumental responding by cues paired with food reward. In the present study we investigated the role of the BLA and the NAc in another property of fear cues, the ability to suppress instrumental responding for food rewards (conditioned suppression). Sham, BLA and NAc-lesioned rats received a fear discrimination procedure in which one visual cue (CS+) predicted foot shock while a second cue (CS-) did not. Conditioning took place over a baseline of instrumental responding, allowing for concurrent measure of freezing and instrumental suppression. NAc lesions left fear conditioning fully intact. BLA lesions impaired acquisition and discrimination of fear when assessed with conditioned freezing. However, BLA lesions only altered fear acquisition and left discrimination completely intact when assessed with conditioned suppression. These findings suggest a critical role for the BLA in fear when assessed with conditioned freezing but a diminished role when assessed with conditioned suppression.

  10. 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

  11. Expression of conditional fear with and without awareness.

    PubMed

    Knight, David C; Nguyen, Hanh T; Bandettini, Peter A

    2003-12-09

    Conditional responding during simple Pavlovian conditioning is often characterized as a form of implicit memory. The extent to which this type of associative learning is independent of awareness is an issue of continuing debate. Previous studies have demonstrated conditioning in the absence of awareness. However, their results have been questioned based on methodological concerns with postexperimental questionnaires. In the present study, skin conductance response (SCR) and unconditioned stimulus (UCS) expectancy were measured concurrently as participants were exposed to a differential delay fear conditioning procedure in which one tone (CS+) predicted a loud white noise, whereas a second tone (CS-) was presented alone. UCS predictability was varied on a trial-by-trial basis by presenting conditioned stimuli (CSs) at volumes just above or below the perceptual threshold. Differential UCS expectancy (awareness) was observed only on perceived trials, whereas differential SCR developed on both perceived and unperceived trials. Although perceived stimuli elicited larger SCRs, the magnitude of conditioning, indexed by differential conditioned response expression (conditioned SCR to CS+ minus the SCR to CS-), was not influenced by stimulus perception. These data indicate that conditional fear can be expressed when individuals are unaware of fear-eliciting stimuli and suggest that the degree of conditioning is independent of awareness during differential Pavlovian fear conditioning.

  12. Eye movements during recall of aversive memory decreases conditioned fear.

    PubMed

    Leer, Arne; Engelhard, Iris M; Altink, Annemarie; van den Hout, Marcel A

    2013-10-01

    Cognitive-behavioral therapy for anxiety disorders typically involves exposure to the conditioned stimulus (CS). Despite its status as an effective and primary treatment, many patients do not show clinical improvement or relapse. Contemporary learning theory suggests that treatment may be optimized by adding techniques that aim at revaluating the aversive consequence (US) of the feared stimulus. This study tested whether US devaluation via a dual task--imagining the US while making eye movements--decreases conditioned fear. Following fear acquisition one group recalled the US while making eye movements (EM) and one group merely recalled the US (RO). Next, during a test phase, all participants were re-presented the CSs. Dual tasking, relative to the control condition, decreased memory vividness and emotionality. Moreover, only in the dual task condition reductions were observed in self-reported fear, US expectancy, and CS unpleasantness, but not in skin conductance responses. Findings provide the first evidence that the dual task decreases conditioned fear and suggest it may be a valuable addition to exposure therapy.

  13. 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.

  14. 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

  15. 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

  16. 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.

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

    PubMed Central

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

    2015-01-01

    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 1 week 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

  18. Fear conditioning, safety learning, and sleep in humans.

    PubMed

    Marshall, Anisa J; Acheson, Dean T; Risbrough, Victoria B; Straus, Laura D; Drummond, Sean P A

    2014-08-27

    Fear conditioning is considered an animal model of post-traumatic stress disorder. Such models have shown fear conditioning disrupts subsequent rapid eye movement sleep (REM). Here, we provide a translation of these models into humans. Using the fear potentiated startle (FPS) procedure, we examined the effects of fear conditioning and safety signal learning on subsequent REM sleep in healthy adults. We also examined the effects of changes in REM sleep on retention of fear and safety learning. Participants (n = 42 normal controls) spent 3 consecutive nights in the laboratory. The first was an adaptation night. Following the second night, we administered a FPS procedure that included pairing a wrist shock with a threat signal and a safety signal never paired with a shock. The next day, we administered the FPS procedure again, with no wrist shocks to any stimulus, to measure retention of fear and safety. Canonical correlations assessed the relationship between FPS response and REM sleep. Results demonstrated that increased safety signal learning during the initial acquisition phase was associated with increased REM sleep consolidation that night, with 28.4% of the variance in increased REM sleep consolidation from baseline accounted for by safety signal learning. Overnight REM sleep was, in turn, related to overnight retention of fear and safety learning, with 22.5% of the variance in startle retention accounted for by REM sleep. These data suggest that sleep difficulties, specifically REM sleep fragmentation, may play a mechanistic role in post-traumatic stress disorder via an influence on safety signal learning and/or threat-safety discrimination.

  19. 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…

  20. Fear Conditioning Effects on Sensitivity to Drug Reward

    DTIC Science & Technology

    2010-06-01

    morphine . Conditioned drug reward is a relevant model in addiction because environmental cues (e.g. a barroom) induce craving and persistent... morphine . Synaptic plasticity is found in these neural fear and reward circuits and thus drugs which enhance plasticity like histone deacetylase...commercially available drug (sodium butyrate) with high translational utility for human studies. Morphine place conditioning: To measure effects of opiate

  1. 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…

  2. 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…

  3. Post-weaning Social Isolation Impairs Observational Fear Conditioning

    PubMed Central

    Yusufishaq, Shabana; Rosenkranz, J. Amiel

    2013-01-01

    Many mammals can utilize social information to learn by observation of conspecifics (social learning). Social learning of fear is expected to be especially advantageous for survival. However, disruption of social development in early life can impair social cognition and might also be expected to disrupt social learning. Social isolation during a critical period of adolescence disrupts social development. The purpose of this study was to determine whether disruption of social development through post-weaning social isolation leads to impairments of social fear learning. Rats were reared in isolation or pair-housed from immediately post-weaning, for 3 weeks. Social fear learning in rats was acquired by observation of tone-footshock pairings administered to a conspecific. Isolation-reared rats displayed less conditioned freezing than pair-housed rats when tested the next day. This reduction of conditioned freezing was correlated with conspecific-oriented behaviors during conditioning, was measured despite similarities in demonstrator behaviors, and occurred despite a manipulation that equalized freezing during conditioning between the pair-housed and isolation-reared rats. The results could not be explained by abnormal sensitization to a repeated tone or deficits in freezing or direct fear conditioning. These results demonstrate that observational fear conditioning is impaired by social isolation, and provide a model to study impaired social affective learning. Impaired social cognition, manifested as inability to recognize or appropriately interpret social cues, is a symptom of several psychiatric disorders. Better understanding of the mechanisms of impaired social fear learning can lead to novel treatments for social cognition symptoms of psychiatric disorders. PMID:23295398

  4. Post-weaning social isolation impairs observational fear conditioning.

    PubMed

    Yusufishaq, Shabana; Rosenkranz, J Amiel

    2013-04-01

    Many mammals can utilize social information to learn by observation of conspecifics (social learning). Social learning of fear is expected to be especially advantageous for survival. However, disruption of social development in early life can impair social cognition and might also be expected to disrupt social learning. Social isolation during a critical period of adolescence disrupts social development. The purpose of this study was to determine whether disruption of social development through post-weaning social isolation leads to impairments of social fear learning. Rats were reared in isolation or pair-housed from immediately post-weaning, for 3 weeks. Social fear learning in rats was acquired by observation of tone-footshock pairings administered to a conspecific. Isolation-reared rats displayed less conditioned freezing than pair-housed rats when tested the next day. This reduction of conditioned freezing was correlated with conspecific-oriented behaviors during conditioning, was measured despite similarities in demonstrator behaviors, and occurred despite a manipulation that equalized freezing during conditioning between the pair-housed and isolation-reared rats. The results could not be explained by abnormal sensitization to a repeated tone or deficits in freezing or direct fear conditioning. These results demonstrate that observational fear conditioning is impaired by social isolation, and provide a model to study impaired social affective learning. Impaired social cognition, manifested as inability to recognize or appropriately interpret social cues, is a symptom of several psychiatric disorders. Better understanding of the mechanisms of impaired social fear learning can lead to novel treatments for social cognition symptoms of psychiatric disorders.

  5. Fear conditioning in frontotemporal lobar degeneration and Alzheimer's disease

    PubMed Central

    Hoefer, M.; Allison, S. C.; Schauer, G. F.; Neuhaus, J. M.; Hall, J.; Dang, J. N.; Weiner, M. W.; Miller, B. L.; Rosen, H. J.

    2008-01-01

    Emotional blunting and abnormal processing of rewards and punishments represent early features of frontotemporal lobar degeneration (FTLD). Better understanding of the physiological underpinnings of these emotional changes can be facilitated by the use of classical psychology approaches. Fear conditioning (FC) is an extensively used paradigm for studying emotional processing that has rarely been applied to the study of dementia.We studied FC in controls (n = 25), Alzheimer's disease (n =25) and FTLD (n = 25). A neutral stimulus (coloured square on a computer screen) was repeatedly paired with a 1s burst of 100 db white noise. Change in skin conductance response to the neutral stimulus was used to measure conditioning. Physiological–anatomical correlations were examined using voxel-based morphometry (VBM). Both patient groups showed impaired acquisition of conditioned responses. However, the basis for this deficit appeared to differ between groups. In Alzheimer's disease, impaired FC occurred despite normal electrodermal responses to the aversive stimulus. In contrast, FTLD patients showed reduced skin conductance responses to the aversive stimulus, which contributed significantly to their FC deficit.VBM identified correlations with physiological reactivity in the amygdala, anterior cingulate cortex, orbitofrontal cortex and insula. These data indicate that Alzheimer's disease and FTLD both show abnormalities in emotional learning, but they suggest that in FTLD this is associated with a deficit in basic electrodermal response to aversive stimuli, consistent with the emotional blunting described with this disorder. Deficits in responses to aversive stimuli could contribute to both the behavioural and cognitive features of FTLD and Alzheimer's disease. Further study of FC in humans and animal models of dementia could provide a valuable window into these symptoms. PMID:18492729

  6. Fear conditioning in frontotemporal lobar degeneration and Alzheimer's disease.

    PubMed

    Hoefer, M; Allison, S C; Schauer, G F; Neuhaus, J M; Hall, J; Dang, J N; Weiner, M W; Miller, B L; Rosen, H J

    2008-06-01

    Emotional blunting and abnormal processing of rewards and punishments represent early features of frontotemporal lobar degeneration (FTLD). Better understanding of the physiological underpinnings of these emotional changes can be facilitated by the use of classical psychology approaches. Fear conditioning (FC) is an extensively used paradigm for studying emotional processing that has rarely been applied to the study of dementia. We studied FC in controls (n = 25), Alzheimer's disease (n = 25) and FTLD (n = 25). A neutral stimulus (coloured square on a computer screen) was repeatedly paired with a 1 s burst of 100 db white noise. Change in skin conductance response to the neutral stimulus was used to measure conditioning. Physiological-anatomical correlations were examined using voxel-based morphometry (VBM). Both patient groups showed impaired acquisition of conditioned responses. However, the basis for this deficit appeared to differ between groups. In Alzheimer's disease, impaired FC occurred despite normal electrodermal responses to the aversive stimulus. In contrast, FTLD patients showed reduced skin conductance responses to the aversive stimulus, which contributed significantly to their FC deficit. VBM identified correlations with physiological reactivity in the amygdala, anterior cingulate cortex, orbitofrontal cortex and insula. These data indicate that Alzheimer's disease and FTLD both show abnormalities in emotional learning, but they suggest that in FTLD this is associated with a deficit in basic electrodermal response to aversive stimuli, consistent with the emotional blunting described with this disorder. Deficits in responses to aversive stimuli could contribute to both the behavioural and cognitive features of FTLD and Alzheimer's disease. Further study of FC in humans and animal models of dementia could provide a valuable window into these symptoms.

  7. Assessing fear learning via conditioned respiratory amplitude responses.

    PubMed

    Castegnetti, Giuseppe; Tzovara, Athina; Staib, Matthias; Gerster, Samuel; Bach, Dominik R

    2017-02-01

    Respiratory physiology is influenced by cognitive processes. It has been suggested that some cognitive states may be inferred from respiration amplitude responses (RAR) after external events. Here, we investigate whether RAR allow assessment of fear memory in cued fear conditioning, an experimental model of aversive learning. To this end, we built on a previously developed psychophysiological model (PsPM) of RAR, which regards interpolated RAR time series as the output of a linear time invariant system. We first establish that average RAR after CS+ and CS- are different. We then develop the response function of fear-conditioned RAR, to be used in our PsPM. This PsPM is inverted to yield estimates of cognitive input into the respiratory system. We analyze five validation experiments involving fear acquisition and retention, delay and trace conditioning, short and medium CS-US intervals, and data acquired with bellows and MRI-compatible pressure chest belts. In all experiments, CS+ and CS- are distinguished by their estimated cognitive inputs, and the sensitivity of this distinction is higher for model-based estimates than for peak scoring of RAR. Comparing these data with skin conductance responses (SCR) and heart period responses (HPR), we find that, on average, RAR performs similar to SCR in distinguishing CS+ and CS-, but is less sensitive than HPR. Overall, our work provides a novel and robust tool to investigate fear memory in humans that may allow wide and straightforward application to diverse experimental contexts.

  8. The renewal of extinguished conditioned fear with fear-relevant and fear-irrelevant stimuli by a context change after extinction.

    PubMed

    Neumann, David L; Longbottom, Paula L

    2008-02-01

    The acquisition, extinction, and subsequent recovery of conditioned fear can be influenced by the nature of the conditional stimulus (CS) and the context in which the CS is presented. The combined effects of these factors were examined in a differential fear-conditioning procedure with humans. Fear-relevant or fear-irrelevant CSs were followed by a shock unconditional stimulus (US) during acquisition and presented alone during extinction. The CSs were images presented upon different background contexts. Half the participants received the same context during acquisition and extinction and the remaining received different contexts. All participants received test trials in the same context as acquisition. In Experiment 1 (N=64), a renewal of shock expectancy and skin conductance responses was found during test for fear-relevant and fear-irrelevant CSs when extinction was given in a different context. In Experiment 2 (N=72), renewal for fear-relevant stimuli was enhanced when acquisition and test was given in an indoor office context and extinction in an outdoor bush context. The opposite context configuration produced the strongest renewal for fear-irrelevant stimuli. The return of extinguished conditioned fear can occur to fear-relevant stimuli that are commonly associated with clinical fears and its strength may be enhanced when the stimuli are encountered in certain contexts after extinction.

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

    PubMed Central

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

    2009-01-01

    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. PMID:18343048

  10. The accurate measurement of fear memory in Pavlovian conditioning: Resolving the baseline issue.

    PubMed

    Jacobs, Nathan S; Cushman, Jesse D; Fanselow, Michael S

    2010-07-15

    Fear conditioning has become an indispensable behavioral task in an increasingly vast array of research disciplines. Yet one unresolved issue is how conditional fear to an explicit cue interacts with and is potentially confounded by fear prior to tone presentation, referred to as baseline fear. After tone-shock pairings, we experimentally manipulated baseline fear by presenting unpaired shocks in the testing chamber and then analyzed the accuracy of common methods for reporting tone fear. Our findings indicate that baseline fear and tone fear tend to interact, where freezing to the tone increases as baseline fear increases. However, the form of interaction is not linear across all conditions and none of the commonly used reporting methods were consistently able to eliminate the confounding effects of baseline fear. We propose a methodological solution in which baseline fear is reduced to very low levels by first extinguishing fear to the training context and then pre-exposing to the testing context.

  11. 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.

  12. 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.

  13. Auditory-evoked spike firing in the lateral amygdala and Pavlovian fear conditioning: mnemonic code or fear bias?

    PubMed

    Goosens, Ki A; Hobin, Jennifer A; Maren, Stephen

    2003-12-04

    Amygdala neuroplasticity has emerged as a candidate substrate for Pavlovian fear memory. By this view, conditional stimulus (CS)-evoked activity represents a mnemonic code that initiates the expression of fear behaviors. However, a fear state may nonassociatively enhance sensory processing, biasing CS-evoked activity in amygdala neurons. Here we describe experiments that dissociate auditory CS-evoked spike firing in the lateral amygdala (LA) and both conditional fear behavior and LA excitability in rats. We found that the expression of conditional freezing and increased LA excitability was neither necessary nor sufficient for the expression of conditional increases in CS-evoked spike firing. Rather, conditioning-related changes in CS-evoked spike firing were solely determined by the associative history of the CS. Thus, our data support a model in which associative activity in the LA encodes fear memory and contributes to the expression of learned fear behaviors.

  14. Hippocampal encoding of interoceptive context during fear conditioning.

    PubMed

    Yoo, S-W; Bae, M; Tovar-Y-Romo, L B; Haughey, N J

    2017-01-03

    Rodent models of auditory fear conditioning are often used to understand the molecular mechanisms regulating fear- and anxiety-related behaviors. Conditioning and extinction memories are influenced by contextual cues, and the reinstatement of conditioned fear occurs when the conditioning stimulus is presented in a context different from the extinction context. Although it has been proposed that internal state is a feature of context that could influence extinction, contributions of interoception to conditioning have not been experimentally addressed. Here we use ethanol (EtOH) to show that interoceptive cues are encoded through the hippocampus by mechanisms that involve increased phosphorylation of GluR1 on serine 845, and biophysical alterations in neuronal membranes that facilitate stabilization of surface-located calcium-permeable n-2-amino-3-(5-methyl-3-oxo-1,2-oxazol-4-yl) propanoic acid (AMPA) receptor (AMPAR) into membrane microdomains. Conflicting interoceptive cues during extinction and fear relapse testing resulted in a failure to consolidate extinction that was reversed by the administration of AMPAR antagonists immediately following the retrieval cue.

  15. Don't fear 'fear conditioning': Methodological considerations for the design and analysis of studies on human fear acquisition, extinction, and return of fear.

    PubMed

    Lonsdorf, Tina B; Menz, Mareike M; Andreatta, Marta; Fullana, Miguel A; Golkar, Armita; Haaker, Jan; Heitland, Ivo; Hermann, Andrea; Kuhn, Manuel; Kruse, Onno; Drexler, Shira Meir; Meulders, Ann; Nees, Frauke; Pittig, Andre; Richter, Jan; Römer, Sonja; Shiban, Youssef; Schmitz, Anja; Straube, Benjamin; Vervliet, Bram; Wendt, Julia; Baas, Johanna M P; Merz, Christian J

    2017-03-03

    The so-called 'replicability crisis' has sparked methodological discussions in many areas of science in general, and in psychology in particular. This has led to recent endeavours to promote the transparency, rigour, and ultimately, replicability of research. Originating from this zeitgeist, the challenge to discuss critical issues on terminology, design, methods, and analysis considerations in fear conditioning research is taken up by this work, which involved representatives from fourteen of the major human fear conditioning laboratories in Europe. This compendium is intended to provide a basis for the development of a common procedural and terminology framework for the field of human fear conditioning. Whenever possible, we give general recommendations. When this is not feasible, we provide evidence-based guidance for methodological decisions on study design, outcome measures, and analyses. Importantly, this work is also intended to raise awareness and initiate discussions on crucial questions with respect to data collection, processing, statistical analyses, the impact of subtle procedural changes, and data reporting specifically tailored to the research on fear conditioning.

  16. 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.

  17. 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.

  18. 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…

  19. 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.

  20. Dual Functions of Perirhinal Cortex in Fear Conditioning

    PubMed Central

    Kent, Brianne A.; Brown, Thomas H.

    2012-01-01

    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. PMID:22903623

  1. 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.

  2. Oxytocin and Social Support as Synergistic Inhibitors of Aversive Fear Conditioning and Fear-Potentiated Startle in Male Rats

    DTIC Science & Technology

    2011-05-01

    Oxytocin and Social Support as Synergistic Inhibitors of Aversive Fear Conditioning and Fear-Potentiated Startle in Male Rats Dr. Jeff Rosen University of...potentiated startle after 3 weeks of social isolation have been difficult to replicate. We suggest oxytocin is promising as a drug with novel...benefits for patients with PTSD. fear; anxiety; PTSD; startle; social isolation 60 jrosen@udel.edu Table of Contents

  3. 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.

  4. 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

  5. CONTROLLABLE VERSUS UNCONTROLLABLE STRESSORS BI-DIRECTIONALLY MODULATE CONDITIONED BUT NOT INNATE FEAR

    PubMed Central

    Baratta, M. V.; Christianson, J. P.; Gomez, D. M.; Zarza, C. M.; Amat, J.; Masini, C.V.; Watkins, L. R.; Maier, S. F.

    2007-01-01

    Fear conditioning and fear extinction play key roles in the development and treatment of anxiety-related disorders, yet there is little information concerning experiential variables that modulate these processes. Here we examined the impact of exposure to a stressor in a different environment on subsequent fear conditioning and extinction, and whether the degree of behavioral control that the subject has over the stressor is of importance. Rats received a session of either escapable (controllable) tailshock (ES), yoked inescapable (uncontrollable) tailshock (IS), or control treatment (HC) 7 days before fear conditioning in which a tone and footshock were paired. Conditioning was measured 24 h later. In a second experiment rats received ES, IS or HC 24 h after contextual fear conditioning. Extinction then occurred every day beginning 7 days later until a criterion was reached. Spontaneous recovery of fear was assessed 14 days after extinction. IS potentiated fear conditioning when given before fear conditioning, and potentiated fear responding during extinction when given after conditioning. Importantly, ES potently interfered with later fear conditioning, decreased fear responding during fear extinction, and prevented spontaneous recovery of fear. Additionally, we examined if the activation of the ventral medial prefrontal cortex (mPFCv) by ES is critical for the protective effects of ES on later fear conditioning. Inactivation of the mPFCv with muscimol at the time of the initial experience with control prevented ES-induced reductions in later contextual and auditory fear conditioning. Finally, we explored if the protective effects of ES extended to an unconditioned fear stimulus, ferret odor. Unlike conditioned fear, prior ES increased the fear response to ferret odor to the same degree as did IS. PMID:17478046

  6. Differential fear conditioning induces reciprocal changes in the sensory responses of lateral amygdala neurons to the CS(+) and CS(-).

    PubMed

    Collins, D R; Paré, D

    2000-01-01

    In classical fear conditioning, a neutral sensory stimulus (CS) acquires the ability to elicit fear responses after pairing to a noxious unconditioned stimulus (US). As amygdala lesions prevent the acquisition of fear responses and the lateral amygdaloid (LA) nucleus is the main input station of the amygdala for auditory afferents, the effect of auditory fear conditioning on the sensory responsiveness of LA neurons has been examined. Although conditioning was shown to increase CS-evoked LA responses, the specificity of the changes in responsiveness was not tested. Because conditioning might induce nonspecific increases in LA responses to auditory afferents, we re-examined this issue in conscious, head-restrained cats using a differential conditioning paradigm where only one of two tones (CS(+) but not CS(-)) was paired to the US. Differential conditioning increased unit and field responses to the CS(+), whereas responses to the CS(-) decreased. Such changes have never been observed in the amygdala except in cases where the CS(-) had been paired to the US before and fear responses not extinguished. This suggests that fear conditioning is not only accompanied by potentiation of amygdalopetal pathways conveying the CS(+) but also by the depression of sensory inputs unpaired to noxious stimuli.

  7. Fear potentiated startle at short intervals following conditioned stimulus onset during delay but not trace conditioning.

    PubMed

    Asli, Ole; Kulvedrøsten, Silje; Solbakken, Line E; Flaten, Magne Arve

    2009-07-01

    The latency of conditioned fear after delay and trace conditioning was investigated. Some argue that delay conditioning is not dependent on awareness. In contrast, trace conditioning, where there is a gap between the conditioned stimulus (CS) and the unconditioned stimulus (US), is assumed to be dependent on awareness. In the present study, a tone CS signaled a noise US presented 1000 ms after CS onset in the delay conditioning group. In the trace conditioning group, a 200-ms tone CS was followed by an 800-ms gap prior to US presentation. Fear-potentiated startle should be seen at shorter intervals after delay conditioning compared to trace conditioning. Analyses showed increased startle at 30, 50, 100, and 150 ms after CS onset following delay conditioning compared to trace conditioning. This implies that fear-relevant stimuli elicit physiological reactions before extended processing of the stimuli occur, following delay, but not trace conditioning.

  8. Nociception and Conditioned Fear in Rats: Strains Matter

    PubMed Central

    Schaap, Manon W. H.; van Oostrom, Hugo; Doornenbal, Arie; van 't Klooster, José; Baars, Annemarie M.; Arndt, Saskia S.; Hellebrekers, Ludo J.

    2013-01-01

    When using rats in pain research, strain-related differences in outcomes of tests for pain and nociception are acknowledged. However, very little is known about the specific characteristics of these strain differences. In this study four phylogenetically distant inbred rat strains, i.e. Wistar Kyoto (WKY), Fawn Hooded (FH), Brown Norway (BN) and Lewis (LE), were investigated in different tests related to pain and nociception. During Pavlovian fear conditioning, the LE and WKY showed a significantly longer duration of freezing behaviour than the FH and BN. Additionally, differences in c-Fos expression in subregions of the prefrontal cortex and amygdala between rat strains during retrieval and expression of conditioned fear were found. For example, the BN did not show recruitment of the basolateral amygdala, whereas the WKY, FH and LE did. During the hot plate test, the WKY and LE showed a lower thermal threshold compared to the BN and FH. In a follow-up experiment, the two most contrasting strains regarding behaviour during the hot plate test and Pavlovian fear conditioning (i.e. FH and WKY) were selected and the hot plate test, Von Frey test and somatosensory-evoked potential (SEP) were investigated. During the Von Frey test, the WKY showed a lower mechanical threshold compared to the FH. When measuring the SEP, the FH appeared to be less reactive to increasing stimulus intensities when considering both peak amplitudes and latencies. Altogether, the combined results indicate various differences between rat strains in Pavlovian fear conditioning, nociception related behaviours and nociceptive processing. These findings demonstrate the necessity of using multiple rat strains when using tests including noxious stimuli and suggest that the choice of rat strains should be considered. When selecting a strain for a particular study it should be considered how this strain behaves during the tests used in that study. PMID:24376690

  9. COCAINE AND PAVLOVIAN FEAR CONDITIONING: DOSE-EFFECT ANALYSIS

    PubMed Central

    Wood, Suzanne C.; Fay, Jonathon; Sage, Jennifer R.; Anagnostaras, Stephan G.

    2007-01-01

    Emerging evidence suggests that cocaine and other drugs of abuse can interfere with many aspects of cognitive functioning. The authors examined the effects of 0.1 – 15 mg/kg of cocaine on Pavlovian contextual and cued fear conditioning in mice. As expected, pre-training cocaine dose-dependently produced hyperactivity and disrupted freezing. Surprisingly, when the mice were tested off-drug later, the group pre-treated with a moderate dose of cocaine (15 mg/kg) displayed significantly less contextual and cued memory, compared to saline control animals. Conversely, mice pre-treated with a very low dose of cocaine (0.1 mg/kg) showed significantly enhanced fear memory for both context and tone, compared to controls. These results were not due to cocaine’s anesthetic effects, as shock reactivity was unaffected by cocaine. The data suggest that despite cocaine’s reputation as a performance-enhancing and anxiogenic drug, this effect is seen only at very low doses, whereas a moderate dose disrupts hippocampus and amygdala-dependent fear conditioning. PMID:17098299

  10. 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.

  11. 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.

  12. 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

  13. 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…

  14. Sleep Promotes Generalization of Extinction of Conditioned Fear

    PubMed Central

    Pace-Schott, Edward F.; Milad, Mohammed R.; Orr, Scott P.; Rauch, Scott L.; Stickgold, Robert; Pitman, Roger K.

    2009-01-01

    Study Objective: To examine the effects of sleep on fear conditioning, extinction, extinction recall, and generalization of extinction recall in healthy humans. Design: During the Conditioning phase, a mild, 0.5-sec shock followed conditioned stimuli (CS+s), which consisted of 2 differently colored lamps. A third lamp color was interspersed but never reinforced (CS-). Immediately after Conditioning, one CS+ was extinguished (CS+E) by presentation without shocks (Extinction phase). The other CS+ went unextinguished (CS+U). Twelve hours later, following continuous normal daytime waking (Wake group, N = 27) or an equal interval containing a normal night's sleep (Sleep group, N = 26), conditioned responses (CRs) to all CSs were measured (Extinction Recall phase). It was hypothesized that the Sleep versus Wake group would show greater extinction recall and/or generalization of extinction recall from the CS+E to the CS+U. Setting: Academic medical center. Subjects: Paid normal volunteers. Measurements and Results: Square-root transformed skin conductance response (SCR) measured conditioned responding. During Extinction Recall, the Group (Wake or Sleep) × CS+ Type (CS+E or CS+U) interaction was significant (P = 0.04). SCRs to the CS+E did not differ between groups, whereas SCRs to the CS+U were significantly smaller in the Sleep group. Additionally, SCRs were significantly larger to the CS+U than CS+E in the Wake but not the Sleep group. Conclusions: After sleep, extinction memory generalized from an extinguished conditioned stimulus to a similarly conditioned but unextinguished stimulus. Clinically, adequate sleep may promote generalization of extinction memory from specific stimuli treated during exposure therapy to similar stimuli later encountered in vivo. Citation: Pace-Schott EF; Milad MR; Orr SP; Rauch SL; Stickgold R; Pitman RK. Sleep promotes generalization of extinction of conditioned fear. SLEEP 2009;32(1):19-26. PMID:19189775

  15. 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).

  16. 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

  17. 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

    2013-09-05

    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.

  18. Classically conditioned postural reflex in cerebellar patients.

    PubMed

    Kolb, F P; Lachauer, S; Maschke, M; Timmann, D

    2004-09-01

    The aim of the current study was to compare postural responses to repetitive platform-evoked perturbations in cerebellar patients with those of healthy subjects using a classical conditioning paradigm. The perturbations consisted of tilting of the platform (unconditioned stimulus: US) at random time intervals, preceded by an auditory signal that represented the conditioning stimulus (CS). Physiological reactions were recorded biomechanically by measuring the vertical ground forces, yielding the center of vertical pressure (CVP), and electrophysiologically by EMG measurements of the main muscle groups of both legs. The recording session consisted of a control section with US-alone trials, a testing section with paired stimuli and a brief final section with US-alone trials. Healthy control subjects were divided into those establishing conditioned responses (CR) in all muscles tested (strategy I) and those with CR in the gastrocnemius muscles only (strategy II), suggesting an associative motor-related process is involved. Patients with a diffuse, non-localized disease were almost unable to establish CR. This was also true for a patient with a focal surgical lesion with no CR on the affected side but who, simultaneously, showed an essentially normal CR incidence on the intact side. During US-alone trials healthy controls exhibited a remarkable decay of the UR amplitude due to a non-associative motor-related process such as habituation. The decay was most prominent in the paired trials section. In contrast, patients showed no significant differences in the UR amplitude throughout the entire recording session. Analysis of the CVP supported the electrophysiological findings, showing CR in the controls only. The differences between the responses of control subjects and those of the cerebellar patients imply strongly that the cerebellum is involved critically in controlling associative and non-associative motor-related processes.

  19. 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.

  20. Oxytocin and Social Support as Synergistic Inhibitors of Aversive Fear Conditioning and Fear-Potentiated Startle in Male Rats

    DTIC Science & Technology

    2010-09-01

    disorder. Psychoneuroendocrinology 34: 917-923. Heinrichs M, Baumgartner T, Kirschbaum C, Ehlert U (2003). Social support and oxytocin interact to...TITLE: Oxytocin and Social Support as Synergistic Inhibitors of Aversive Fear Conditioning and Fear-Potentiated Startle in Male Rats PRINCIPAL...Annual 3. DATES COVERED (From - To) 4. TITLE AND SUBTITLE Oxytocin and Social Support as Synergistic Inhibitors of 5a. CONTRACT NUMBER

  1. 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…

  2. Avoiding negative outcomes: tracking the mechanisms of avoidance learning in humans during fear conditioning.

    PubMed

    Delgado, Mauricio R; Jou, Rita L; Ledoux, Joseph E; Phelps, Elizabeth A

    2009-01-01

    Previous research across species has shown that the amygdala is critical for learning about aversive outcomes, while the striatum is involved in reward-related processing. Less is known, however, about the role of the amygdala and the striatum in learning how to exert control over emotions and avoid negative outcomes. One potential mechanism for active avoidance of stressful situations is postulated to involve amygdala-striatal interactions. The goal of this study was to investigate the physiological and neural correlates underlying avoidance learning in humans. Specifically, we used a classical conditioning paradigm where three different conditioned stimuli (CS) were presented. One stimulus predicted the delivery of a shock upon stimulus offset (CS+), while another predicted no negative consequences (CS-). A third conditioned cue also predicted delivery of a shock, but participants were instructed that upon seeing this stimulus, they could avoid the shock if they chose the correct action (AV+). After successful learning, participants could then easily terminate the shock during subsequent stimulus presentations (AV-). Physiological responses (as measured by skin conductance responses) confirmed a main effect of conditioning, particularly showing higher arousal responses during pre (AV+) compared to post (AV-) learning of an avoidance response. Consistent with animal models, amygdala-striatal interactions were observed to underlie the acquisition of an avoidance response. These results support a mechanism of active coping with conditioned fear that allows for the control over emotional responses such as fears that can become maladaptive and influence our decision-making.

  3. Dendritic structural plasticity in the basolateral amygdala after fear conditioning and its extinction in mice.

    PubMed

    Heinrichs, Stephen C; Leite-Morris, Kimberly A; Guy, Marsha D; Goldberg, Lisa R; Young, Angela J; Kaplan, Gary B

    2013-07-01

    Previous research suggests that morphology and arborization of dendritic spines change as a result of fear conditioning in cortical and subcortical brain regions. This study uniquely aims to delineate these structural changes in the basolateral amygdala (BLA) after both fear conditioning and fear extinction. C57BL/6 mice acquired robust conditioned fear responses (70-80% cued freezing behavior) after six pairings with a tone cue associated with footshock in comparison to unshocked controls. During fear acquisition, freezing behavior was significantly affected by both shock exposure and trial number. For fear extinction, mice were exposed to the conditioned stimulus tone in the absence of shock administration and behavioral responses significantly varied by shock treatment. In the retention tests over 3 weeks, the percentage time spent freezing varied with the factor of extinction training. In all treatment groups, alterations in dendritic plasticity were analyzed using Golgi-Cox staining of dendrites in the BLA. Spine density differed between the fear conditioned group and both the fear extinction and control groups on third order dendrites. Spine density was significantly increased in the fear conditioned group compared to the fear extinction group and controls. Similarly in Sholl analyses, fear conditioning significantly increased BLA spine numbers and dendritic intersections while subsequent extinction training reversed these effects. In summary, fear extinction produced enduring behavioral plasticity that is associated with a reversal of alterations in BLA dendritic plasticity produced by fear conditioning. These neuroplasticity findings can inform our understanding of structural mechanisms underlying stress-related pathology can inform treatment research into these disorders.

  4. Enhancement of acoustic prepulse inhibition by contextual fear conditioning in mice is maintained even after contextual fear extinction.

    PubMed

    Ishii, Daisuke; Matsuzawa, Daisuke; Fujita, Yuko; Sutoh, Chihiro; Ohtsuka, Hiroyuki; Matsuda, Shingo; Kanahara, Nobuhisa; Hashimoto, Kenji; Iyo, Masaomi; Shimizu, Eiji

    2010-02-01

    Prepulse inhibition (PPI) of the acoustic startle response is one of the few and major paradigms for investigating sensorimotor gating systems in humans and rodents in a similar fashion. PPI deficits are observed not only in patients with schizophrenia, but also in patients with anxiety disorders. Previous studies have shown that PPI in rats can be enhanced by auditory fear conditioning. In this study, we evaluated the effects of contextual fear conditioning (FC) for six times a day and fear extinction (FE) for seven days on PPI in mice. C57BL/6J mice (male, 8-12 weeks) were divided into three groups; no-FC (control), FC and FC + FE. We measured PPI at the following three time points, (1) baseline before FC, (2) after FC, and (3) after FE. The results showed that PPI was increased after FC. Moreover, the enhanced PPI following FC was observed even after FE with decreased freezing behaviors. These results suggested contextual fear conditioning could enhance acoustic PPI, and that contextual fear extinction could decrease freezing behaviors, but not acoustic PPI.

  5. 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…

  6. 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.

  7. 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…

  8. 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.

  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. Histone acetylation rescues contextual fear conditioning in nNOS KO mice and accelerates extinction of cued fear conditioning in wild type mice.

    PubMed

    Itzhak, Yossef; Anderson, Karen L; Kelley, Jonathan B; Petkov, Martin

    2012-05-01

    Epigenetic regulation of chromatin structure is an essential molecular mechanism that contributes to the formation of synaptic plasticity and long-term memory (LTM). An important regulatory process of chromatin structure is acetylation and deacetylation of histone proteins. Inhibition of histone deacetylase (HDAC) increases acetylation of histone proteins and facilitate learning and memory. Nitric oxide (NO) signaling pathway has a role in synaptic plasticity, LTM and regulation of histone acetylation. We have previously shown that NO signaling pathway is required for contextual fear conditioning. The present study investigated the effects of systemic administration of the HDAC inhibitor sodium butyrate (NaB) on fear conditioning in neuronal nitric oxide synthase (nNOS) knockout (KO) and wild type (WT) mice. The effect of single administration of NaB on total H3 and H4 histone acetylation in hippocampus and amygdala was also investigated. A single administration of NaB prior to fear conditioning (a) rescued contextual fear conditioning of nNOS KO mice and (b) had long-term (weeks) facilitatory effect on the extinction of cued fear memory of WT mice. The facilitatory effect of NaB on extinction of cued fear memory of WT mice was confirmed in a study whereupon NaB was administered during extinction. Results suggest that (a) the rescue of contextual fear conditioning in nNOS KO mice is associated with NaB-induced increase in H3 histone acetylation and (b) the accelerated extinction of cued fear memory in WT mice is associated with NaB-induced increase in H4 histone acetylation. Hence, a single administration of HDAC inhibitor may rescue NO-dependent cognitive deficits and afford a long-term accelerating effect on extinction of fear memory of WT mice.

  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. Extract of Ginkgo biloba EGb761 facilitates extinction of conditioned fear measured by fear-potentiated startle.

    PubMed

    Yang, Yi-Ling; Su, Ya-Wen; Ng, Ming-Chong; Chao, Po-Kuan; Tung, Li-Chu; Lu, Kwok-Tung

    2007-02-01

    A standard extract of Ginkgo biloba (EGb761) has been used in the treatment of various common geriatric complaints including vertigo, short-term memory loss, hearing loss, lack of attention, or vigilance. We demonstrated that acute systemic administration of EGb761 facilitated the acquisition of conditioned fear. Many studies suggest the neural mechanism underlies extinction is similar to the acquisition. This raises a possibility that EGb761 may modulate and accelerate the fear extinction process. We tested this possibility by using fear-potentiated startle (FPS) on laboratory rats. Acute systemic injection of EGb761 (10, 20, or 50 mg/kg) 30 min before extinction training facilitated extinction in a dose-dependent manner. Intra-amygdaloid infusion of EGb761 (28 ng/side, bilaterally) 10 min before extinction training also facilitated extinction. Control experiments showed that facilitation effect of EGb761 was not the result of impaired expression of conditioned fear or accelerated forgetting. Rats previously injected with EGb761 showed significant FPS after retraining. Extinction of conditioned fear appeared to result from acute drug effects rather than from toxic action. Systemic administration of EGb761 immediately after extinction training did not facilitate extinction, suggested the EGb761 facilitation effect is contributed to the acquisition phase of extinction learning. Western blot results showed that extinction induced amygdaloid extracellular signal-regulated kinase (ERK1/2) phosphorylation was significantly elevated by EGb761 treatment. Intra-amygdala injection of ERK1/2 inhibitor PD98059 completely blocked the EGb761 effect. Therefore, acute EGb761 administration modulated extinction of conditioned fear by activating ERK1/2.

  13. Effects of pre- or post-training entorhinal cortex AP5 injection on fear conditioning.

    PubMed

    Schenberg, Eduardo Ekman; Soares, Juliana Carlota Kramer; Oliveira, Maria Gabriela Menezes

    2005-11-15

    Fear conditioning is one of the most studied paradigms to assess the neural basis of emotional memory. The circuitry involves NMDA receptor activation in the amygdala and, in the case of contextual conditioning, in the hippocampus. Entorhinal cortex is one of the major input/output structures to the hippocampus and also projects to the amygdala, both through glutamatergic transmission. Other learning tasks involving hippocampus and amygdala, such as inhibitory avoidance, require entorhinal cortex during acquisition and consolidation. However, the involvement of NMDA receptors mediated transmission in entorhinal cortex in fear conditioning acquisition and consolidation is not clear. To investigate that issue, rats were trained in fear conditioning to both contextual and tone conditioned stimulus. Immediately before, immediately, 30 or 90 min after training they received NMDA antagonist AP5 or saline injections bilaterally in the entorhinal cortex (AP-6.8 mm, L +/-5.0 mm DV-6.8 mm). Contextual fear conditioning was measured 24 h after training, and tone fear conditioning 48 h after training. AP5 injections selectively impaired contextual fear conditioning only when injected pre-training. Post-training injections had no effect. These findings suggest that entorhinal cortex NMDA receptors are necessary for acquisition, but not for consolidation, of contextual fear conditioning. On the other hand, both acquisition and consolidation of tone fear conditioning seem to be independent of NMDA receptors in the entorhinal cortex.

  14. Neurotoxic lesions of the dorsal hippocampus and Pavlovian fear conditioning in rats.

    PubMed

    Maren, S; Aharonov, G; Fanselow, M S

    1997-11-01

    Electrolytic lesions of the dorsal hippocampus (DH) produce deficits in both the acquisition and expression of conditional fear to contextual stimuli in rats. To assess whether damage to DH neurons is responsible for these deficits, we performed three experiments to examine the effects of neurotoxic N-methyl-D-aspartate (NMDA) lesions of the DH on the acquisition and expression of fear conditioning. Fear conditioning consisted of the delivery of signaled or unsignaled footshocks in a novel conditioning chamber and freezing served as the measure of conditional fear. In Experiment 1, posttraining DH lesions produced severe retrograde deficits in context fear when made either 1 or 28, but not 100, days following training. Pretraining DH lesions made 1 week before training did not affect contextual fear conditioning. Tone fear was impaired by DH lesions at all training-to-lesion intervals. In Experiment 2, posttraining (1 day), but not pretraining (1 week), DH lesions produced substantial deficits in context fear using an unsignaled shock procedure. In Experiment 3, pretraining electrolytic DH lesions produced modest deficits in context fear using the same signaled and unsignaled shock procedures used in Experiments 1 and 2, respectively. Electrolytic, but not neurotoxic, lesions also increased pre-shock locomotor activity. Collectively, this pattern of results reveals that neurons in the DH are not required for the acquisition of context fear, but have a critical and time-limited role in the expression of context fear. The normal acquisition and expression of context fear in rats with neurotoxic DH lesions made before training may be mediated by conditioning to unimodal cues in the context, a process that may rely less on the hippocampal memory system.

  15. 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…

  16. 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…

  17. 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,…

  18. Chronic stress and sex differences on the recall of fear conditioning and extinction.

    PubMed

    Baran, Sarah E; Armstrong, Charles E; Niren, Danielle C; Hanna, Jeffery J; Conrad, Cheryl D

    2009-03-01

    Chronic stress effects and sex differences were examined on conditioned fear extinction. Male and female Sprague-Dawley rats were chronically stressed by restraint (6 h/d/21 d), conditioned to tone and footshock, followed by extinction after 1 h and 24 h delays. Chronic stress impaired the recall of fear extinction in males, as evidenced by high freezing to tone after the 24 h delay despite exposure to the previous 1 h delay extinction trials, and this effect was not due to ceiling effects from overtraining during conditioning. In contrast, chronic stress attenuated the recall of fear conditioning acquisition in females, regardless of exposure to the 1 h extinction exposure. Since freezing to tone was reinstated following unsignalled footshocks, the deficit in the stressed rats reflected impaired recall rather than impaired consolidation. Sex differences in fear conditioning and extinction were observed in nonstressed controls as well, with control females resisting extinction to tone. Analysis of contextual freezing showed that all groups (control, stress, male, female) increased freezing immediately after the first tone extinction trial, demonstrating contextual discrimination. These findings show that chronic stress and sex interact to influence fear conditioning, with chronic stress impairing the recall of delayed fear extinction in males to implicate the medial prefrontal cortex, disrupting the recall of the fear conditioning acquisition in females to implicate the amygdala, and nonstressed controls exhibiting sex differences in fear conditioning and extinction, which may involve the amygdala and/or corticosterone levels.

  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. 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.

  2. 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

  3. Sustained conditioned responses in prelimbic prefrontal neurons are correlated with fear expression and extinction failure.

    PubMed

    Burgos-Robles, Anthony; Vidal-Gonzalez, Ivan; Quirk, Gregory J

    2009-07-01

    During auditory fear conditioning, it is well established that lateral amygdala (LA) neurons potentiate their response to the tone conditioned stimulus, and that this potentiation is required for conditioned fear behavior. Conditioned tone responses in LA, however, last only a few hundred milliseconds and cannot be responsible for sustained fear responses to a tone lasting tens of seconds. Recent evidence from inactivation and stimulation studies suggests that the prelimbic (PL) prefrontal cortex is necessary for expression of learned fears, but the timing of PL tone responses and correlations with fear behavior have not been studied. Using multichannel unit recording techniques in behaving rats, we observed sustained conditioned tone responses in PL that were correlated with freezing behavior on a second-to-second basis during the presentation of a 30 s tone. PL tone responses were also correlated with conditioned freezing across different experimental phases (habituation, conditioning, extinction). Moreover, the persistence of PL responses after extinction training was associated with failure to express extinction memory. Together with previous inactivation findings, the present results suggest that PL transforms transient amygdala inputs to a sustained output that drives conditioned fear responses and gates the expression of extinction. Given the relatively long latency of conditioned responses we observed in PL (approximately 100 ms after tone onset), we propose that PL integrates inputs from the amygdala, hippocampus, and other cortical sources to regulate the expression of fear memories.

  4. The central nucleus of the amygdala is essential for acquiring and expressing conditional fear after overtraining.

    PubMed

    Zimmerman, Joshua M; Rabinak, Christine A; McLachlan, Ian G; Maren, Stephen

    2007-09-01

    The basolateral complex of the amygdala (BLA) is critical for the acquisition and expression of Pavlovian fear conditioning in rats. Nonetheless, rats with neurotoxic BLA lesions can acquire conditional fear after overtraining (75 trials). The capacity of rats with BLA lesions to acquire fear memory may be mediated by the central nucleus of the amygdala (CEA). To examine this issue, we examined the influence of neurotoxic CEA lesions or reversible inactivation of the CEA on the acquisition and expression of conditional freezing after overtraining in rats. Rats with pretraining CEA lesions (whether alone or in combination with BLA lesions) did not acquire conditional freezing to either the conditioning context or an auditory conditional stimulus after extensive overtraining. Similarly, post-training lesions of the CEA or BLA prevented the expression of overtrained fear. Lastly, muscimol infusions into the CEA prevented both the acquisition and the expression of overtrained fear, demonstrating that the effects of CEA lesions are not likely due to the destruction of en passant axons. These results suggest that the CEA is essential for conditional freezing after Pavlovian fear conditioning. Moreover, overtraining may engage a compensatory fear conditioning circuit involving the CEA in animals with damage to the BLA.

  5. Time-dependent involvement of the dorsal hippocampus in trace fear conditioning in mice.

    PubMed

    Misane, Ilga; Tovote, Philip; Meyer, Michael; Spiess, Joachim; Ogren, Sven Ove; Stiedl, Oliver

    2005-01-01

    Hippocampal and amygdaloid neuroplasticity are important substrates for Pavlovian fear conditioning. The hippocampus has been implicated in trace fear conditioning. However, a systematic investigation of the significance of the trace interval has not yet been performed. Therefore, this study analyzed the time-dependent involvement of N-methyl-D-aspartate (NMDA) receptors in the dorsal hippocampus in one-trial auditory trace fear conditioning in C57BL/6J mice. The NMDA receptor antagonist APV was injected bilaterally into the dorsal hippocampus 15 min before training. Mice were exposed to tone (conditioned stimulus [CS]) and footshock (unconditioned stimulus [US]) in the conditioning context without delay (0 s) or with CS-US (trace) intervals of 1-45 s. Conditioned auditory fear was determined 24 h after training by the assessment of freezing and computerized evaluation of inactivity in a new context; 2 h later, context-dependent memory was tested in the conditioning context. NMDA receptor blockade by APV markedly impaired conditioned auditory fear at trace intervals of 15 s and 30 s, but not at shorter trace intervals. A 45-s trace interval prevented the formation of conditioned tone-dependent fear. Context-dependent memory was always impaired by APV treatment independent of the trace interval. The results indicate that the dorsal hippocampus and its NMDA receptors play an important role in auditory trace fear conditioning at trace intervals of 15-30-s length. In contrast, NMDA receptors in the dorsal hippocampus are unequivocally involved in contextual fear conditioning independent of the trace interval. The results point at a time-dependent role of the dorsal hippocampus in encoding of noncontingent explicit stimuli. Preprocessing of long CS-US contingencies in the hippocampus appears to be important for the final information processing and execution of fear memories through amygdala circuits.

  6. Eyeblink classical conditioning and post-traumatic stress disorder - a model systems approach.

    PubMed

    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.

  7. Electrolytic lesions of the dorsal hippocampus disrupt renewal of conditional fear after extinction.

    PubMed

    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 the DH blunted the expression of conditional freezing to an auditory conditional stimulus (CS), but did not affect the acquisition of extinction to that CS. In contrast, DH lesions impaired the context-specific expression of extinction, eliminating the renewal of fear normally observed to a CS presented outside of the extinction context. Post-extinction DH lesions also eliminated the context dependence of fear extinction. These results are consistent with those using pharmacological inactivation of the DH and suggest that the DH is required for using contextual stimuli to regulate the expression of fear to a Pavlovian CS after extinction.

  8. 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…

  9. 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…

  10. 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

  11. 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…

  12. 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…

  13. 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…

  14. 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…

  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. 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…

  17. Noradrenergic blockade of memory reconsolidation: a failure to reduce conditioned fear responding.

    PubMed

    Bos, Marieke Geerte Nynke; Beckers, Tom; Kindt, Merel

    2014-01-01

    Upon recall, a memory can enter a labile state in which it requires new protein synthesis to restabilize. This two-phased reconsolidation process raises the prospect to directly target excessive fear memory as opposed to the formation of inhibitory memory following extinction training. In our previous studies, we convincingly demonstrated that 40 mg propranolol HCl administration before or after memory reactivation eliminated the emotional expression of fear memory indexed by the fear potentiated startle reflex. To apply this procedure in clinical practice it is important to understand the optimal and boundary conditions of this procedure. As part of a large project aimed at unraveling putative boundary conditions of disrupting reconsolidation of associative fear memory with propranolol HCl, we again tested our memory reconsolidation procedure. Participants (N = 44) underwent a three-day differential fear conditioning procedure. Twenty-four hours after fear acquisition, participants received 40 mg propranolol HCl prior to memory reactivation. The next day, participants were subjected to extinction training and reinstatement testing. In sharp contrast to our previous findings, propranolol HCl before memory reactivation did not attenuate the startle fear response. Remarkably, the startle fear response even persisted during extinction training and did not show the usually observed gradual decline in conditioned physiological responding (startle potentiation and skin conductance) upon repeated unreinforced trials. We discuss these unexpected findings and propose some potential explanations. It remains, however, unclear why we observed a resistance to reduce conditioned fear responding by either disrupting reconsolidation or extinction training. The present results underscore that the success of human fear conditioning research may depend on subtle manipulations and instructions.

  18. Noradrenergic Blockade of Memory Reconsolidation: A Failure to Reduce Conditioned Fear Responding

    PubMed Central

    Bos, Marieke Geerte Nynke; Beckers, Tom; Kindt, Merel

    2014-01-01

    Upon recall, a memory can enter a labile state in which it requires new protein synthesis to restabilize. This two-phased reconsolidation process raises the prospect to directly target excessive fear memory as opposed to the formation of inhibitory memory following extinction training. In our previous studies, we convincingly demonstrated that 40 mg propranolol HCl administration before or after memory reactivation eliminated the emotional expression of fear memory indexed by the fear potentiated startle reflex. To apply this procedure in clinical practice it is important to understand the optimal and boundary conditions of this procedure. As part of a large project aimed at unraveling putative boundary conditions of disrupting reconsolidation of associative fear memory with propranolol HCl, we again tested our memory reconsolidation procedure. Participants (N = 44) underwent a three-day differential fear conditioning procedure. Twenty-four hours after fear acquisition, participants received 40 mg propranolol HCl prior to memory reactivation. The next day, participants were subjected to extinction training and reinstatement testing. In sharp contrast to our previous findings, propranolol HCl before memory reactivation did not attenuate the startle fear response. Remarkably, the startle fear response even persisted during extinction training and did not show the usually observed gradual decline in conditioned physiological responding (startle potentiation and skin conductance) upon repeated unreinforced trials. We discuss these unexpected findings and propose some potential explanations. It remains, however, unclear why we observed a resistance to reduce conditioned fear responding by either disrupting reconsolidation or extinction training. The present results underscore that the success of human fear conditioning research may depend on subtle manipulations and instructions. PMID:25506319

  19. Metabotropic glutamate subtype 5 receptors modulate fear-conditioning induced enhancement of prepulse inhibition in rats.

    PubMed

    Zou, Dan; Huang, Juan; Wu, Xihong; Li, Liang

    2007-02-01

    Non-startling acoustic events presented shortly before an intense startling sound can inhibit the acoustic startle reflex. This phenomenon is called prepulse inhibition (PPI), and is widely used as a model of sensorimotor gating. The present study investigated whether PPI can be modulated by fear conditioning, whose acquisition can be blocked by the specific antagonist of metabotropic glutamate receptors subtype 5 (mGluR5), 2-methyl-6-(phenylethynyl)-pyridine (MPEP). The results show that a gap embedded in otherwise continuous noise sounds, which were delivered by two spatially separated loudspeakers, could inhibit the startle reflex induced by an intense sound that was presented 50 ms after the gap. The inhibitory effect depended on the duration of the gap, and was enhanced by fear conditioning that was introduced by temporally pairing the gap with footshock. Intraperitoneal injection of MPEP (0.5 or 5mg/kg) 30 min before fear conditioning blocked the enhancing effect of fear conditioning on PPI, but did not affect either the baseline startle magnitude or PPI if no fear conditioning was introduced. These results indicate that PPI is enhanced when the prepulse signifies an aversive event after fear conditioning. Also, mGlu5Rs play a role in preserving the fear-conditioning-induced enhancement of PPI.

  20. 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.

  1. 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.

  2. 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.

  3. High-alcohol-drinking rats exhibit persistent freezing responses to discrete cues following Pavlovian fear conditioning.

    PubMed

    Rorick, Linda M; Finn, Peter R; Steinmetz, Joseph E

    2003-09-01

    We previously reported that high-alcohol-drinking (HAD) rats exhibited selective deficits in active avoidance learning and that those deficits were partially reversed by moderate doses of ethanol under certain training conditions [Pharmacol. Biochem. Behav. 75 (2003) 89]. In that study, we hypothesized that HAD deficits resulted from exaggerated fear in the conditioning context and that the anxiolytic properties of ethanol, along with prior exposure to the conditioning apparatus, were responsible for the facilitated avoidance learning that was observed in HAD rats following moderate doses of ethanol. The current study was designed to test whether HAD rats exhibit behaviors consistent with increased fear in aversive learning contexts. We used a standard Pavlovian fear conditioning paradigm to assess behavioral freezing in HAD (HAD-1 and HAD-2) and low-alcohol-drinking (LAD; LAD-1 and LAD-2) rats. No significant differences were observed between HAD-1 and HAD-2 or between LAD-1 and LAD-2 rats, indicating that the replicate lines performed similarly in this study. Both HAD and LAD rats exhibited robust fear conditioning during training. Although no differences were observed between HAD and LAD rats during fear training, HAD rats failed to extinguish freezing behavior in response to the discrete tone conditional stimulus during subsequent fear retention tests. Thus, HAD rats demonstrated prolonged cue-elicited fear that was resistant to extinction.

  4. 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.

  5. 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.

  6. 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.

  7. Acute withdrawal from repeated cocaine treatment enhances latent inhibition of a conditioned fear response.

    PubMed

    Murphy, C A; Heidbreder, C; Feldon, J

    2001-02-01

    Psychostimulant-induced locomotor sensitization and disrupted latent inhibition (LI) of a classically conditioned association are two paradigms that have been widely studied as animal behavioural models of psychosis. In this study we assessed the effects of withdrawal from the repeated intermittent administration of cocaine on LI of a conditioned fear response. Animals which were either preexposed (PE) to a tone conditioned stimulus (CS) or naive to the tone (i.e. non-preexposed: NPE) subsequently experienced 10 pairings of the tone CS with footshock. Afterwards, both groups received five daily injections of cocaine (20 mg/kg, i.p.) or saline. After 3 days of withdrawal from drug treatment, animals were tested for conditioned freezing to the context of the footshock chamber, and 1 day later, for conditioned freezing to the tone CS. Cocaine-sensitized animals exhibited markedly enhanced LI compared to saline-treated animals, due to the fact that NPE-cocaine animals spent more time freezing during the tone CS than NPE-saline animals, whereas PE-cocaine animals showed a tendency toward reduced freezing compared to the saline groups. While these results suggest the presence of increased anxiety in cocaine-withdrawn NPE animals, the absence of this effect in cocaine-withdrawn PE rats indicates that cocaine withdrawal also influences the retrieval of previously learned information.

  8. PKMzeta maintains spatial, instrumental, and classically conditioned long-term memories.

    PubMed

    Serrano, Peter; Friedman, Eugenia L; Kenney, Jana; Taubenfeld, Stephen M; Zimmerman, Joshua M; Hanna, John; Alberini, Cristina; Kelley, Ann E; Maren, Stephen; Rudy, Jerry W; Yin, Jerry C P; Sacktor, Todd C; Fenton, André A

    2008-12-23

    How long-term memories are stored is a fundamental question in neuroscience. The first molecular mechanism for long-term memory storage in the brain was recently identified as the persistent action of protein kinase Mzeta (PKMzeta), an autonomously active atypical protein kinase C (PKC) isoform critical for the maintenance of long-term potentiation (LTP). PKMzeta maintains aversively conditioned associations, but what general form of information the kinase encodes in the brain is unknown. We first confirmed the specificity of the action of zeta inhibitory peptide (ZIP) by disrupting long-term memory for active place avoidance with chelerythrine, a second inhibitor of PKMzeta activity. We then examined, using ZIP, the effect of PKMzeta inhibition in dorsal hippocampus (DH) and basolateral amygdala (BLA) on retention of 1-d-old information acquired in the radial arm maze, water maze, inhibitory avoidance, and contextual and cued fear conditioning paradigms. In the DH, PKMzeta inhibition selectively disrupted retention of information for spatial reference, but not spatial working memory in the radial arm maze, and precise, but not coarse spatial information in the water maze. Thus retention of accurate spatial, but not procedural and contextual information required PKMzeta activity. Similarly, PKMzeta inhibition in the hippocampus did not affect contextual information after fear conditioning. In contrast, PKMzeta inhibition in the BLA impaired retention of classical conditioned stimulus-unconditioned stimulus (CS-US) associations for both contextual and auditory fear, as well as instrumentally conditioned inhibitory avoidance. PKMzeta inhibition had no effect on postshock freezing, indicating fear expression mediated by the BLA remained intact. Thus, persistent PKMzeta activity is a general mechanism for both appetitively and aversively motivated retention of specific, accurate learned information, but is not required for processing contextual, imprecise, or

  9. 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.

  10. 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)

  11. Long-term effects of traumatic stress on subsequent contextual fear conditioning in rats.

    PubMed

    Ryoke, Rie; Yamada, Kazuo; Ichitani, Yukio

    2014-04-22

    Exposure to stressful events affects subsequent sensitivity to fear. We investigated the long-term effects of a traumatic experience on subsequent contextual fear conditioning and anxiety-like behaviors in rats (Experiment 1). In addition, we tested whether the administration of the glucocorticoid synthesis inhibitor metyrapone (MET) attenuated the sensitization of fear induced by traumatic stress (Experiment 2). Male rats were subjected to a multiple stress (MS) session, which consisted of 4 foot shocks (1mA, 1s) and forced swimming for 20min, followed by exposure to a situational reminder 7days after the MS session. MET (25 or 100mg/kg, intraperitoneal) was administered 30min before MS. The contextual fear conditioning was performed 14days after MS. MS enhanced the conditioned fear response for at least 14days after the conditioning, and pretreatment with MET did not affect the enhancement of conditioned fear. These results suggest that glucocorticoid secretion triggered by MS is not involved in regulating the long-term stress-induced sensitization of fear.

  12. Hippocampus and Pavlovian fear conditioning in rats: muscimol infusions into the ventral, but not dorsal, hippocampus impair the acquisition of conditional freezing to an auditory conditional stimulus.

    PubMed

    Maren, Stephen; Holt, William G

    2004-02-01

    The authors compared the effects of pharmacological inactivation of the dorsal hippocampus (DH) or ventral hippocampus (VH) on Pavlovian fear conditioning in rats. Freezing behavior served as the measure of fear. Pretraining infusions of muscimol, a GABAA receptor agonist, into the VH disrupted auditory, but not contextual, fear conditioning; DH infusions did not affect fear conditioning. Pretesting inactivation of the VH or DH did not affect the expression of conditional freezing. Pretraining electrolytic lesions of the VH reproduced the effects of muscimol infusions, whereas posttraining VH lesions disrupted both auditory and contextual freezing. Hence, neurons in the VH are importantly involved in the acquisition of auditory fear conditioning and the expression of auditory and contextual fear under some conditions.

  13. 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.

  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. Conditioned fear is modulated by CRF mechanisms in the periaqueductal gray columns.

    PubMed

    Borelli, Karina G; Albrechet-Souza, Lucas; Fedoce, Alessandra G; Fabri, Denise S; Resstel, Leonardo B; Brandão, Marcus L

    2013-05-01

    The periaqueductal gray (PAG) columns have been implicated in controlling stress responses through corticotropin-releasing factor (CRF), which is a neuropeptide with a prominent role in the etiology of fear- and anxiety-related psychopathologies. Several studies have investigated the involvement of dorsal PAG (dPAG) CRF mechanisms in models of unconditioned fear. However, less is known about the role of this neurotransmission in the expression of conditioned fear memories in the dPAG and ventrolateral PAG (vlPAG) columns. We assessed the effects of ovine CRF (oCRF 0.25 and 1.0 μg/0.2 μL) locally administered into the dPAG and vlPAG on behavioral (fear-potentiated startle and freezing) and autonomic (arterial pressure and heart rate) responses in rats subjected to contextual fear conditioning. The lower dose injected into the columns promoted proaversive effects, enhanced contextual freezing, increased the blood pressure and heart rate and decreased tail temperature. The lower dose of oCRF into the vlPAG, but not into the dPAG, produced a pronounced enhancement of the fear-potentiated startle response. The results imply that the PAG is a heterogeneous structure that is involved in the coordination of distinct behaviors and autonomic control, suggest PAG involvement in the expression of contextual fear memory as well as implicate the CRF as an important modulator of the neural substrates of fear in the PAG.

  16. The GABA-synthetic enzyme GAD65 controls circadian activation of conditioned fear pathways.

    PubMed

    Bergado-Acosta, Jorge R; Müller, Iris; Richter-Levin, Gal; Stork, Oliver

    2014-03-01

    Circadian fluctuations of fear and anxiety symptoms are observable in persons with post-traumatic stress disorder, generalized anxiety, and panic disorder; however, the underlying neurobiological mechanisms are not sufficiently understood. In the present study, we investigated the putative role of inhibitory neurotransmission in the circadian fluctuation of fear symptoms, using mice with genetic ablation of the γ-amino butyric acid (GABA) synthesizing isoenzyme, glutamic acid decarboxylase GAD65. We observed in these mutant mice an altered expression of conditioned fear with a profound reduction of freezing, and an increase of hyperactivity bouts occurring only when both fear conditioning training and retrieval testing were done at the beginning of their active phase. Mutants further showed an increased arousal response at this time of the day, although, circadian rhythm of home cage activity was unaltered. Hyperactivity and reduced freezing during fear memory retrieval were accompanied by an increased induction of the immediate early gene cFos suggesting hyperactivation of the hippocampus, amygdala, and medial hypothalamus. Our data suggest a role of GAD65-mediated GABA synthesis in the encoding of circadian information to fear memory. GAD65 deficits in a state-dependent manner result in increased neural activation in fear circuits and elicit panic-like flight responses during fear memory retrieval.

  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. Microstimulation reveals opposing influences of prelimbic and infralimbic cortex on the expression of conditioned fear.

    PubMed

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

    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 of conditioned fear to the tone. In the present study we used microstimulation to investigate the role of additional mPFC subregions: the prelimbic (PL), dorsal anterior cingulate (ACd), and medial precentral (PrCm) cortices in the expression and extinction of conditioned fear. These are tone-responsive areas that have been implicated in both acquisition and extinction of conditioned fear. In contrast to IL, microstimulation of PL increased the expression of conditioned fear and prevented extinction. Microstimulation of ACd and PrCm had no effect. Under low-footshock conditions (to avoid ceiling levels of freezing), microstimulation of PL and IL had opposite effects, respectively increasing and decreasing freezing to the conditioned tone. We suggest that PL excites amygdala output and IL inhibits amygdala output, providing a mechanism for bidirectional modulation of fear expression.

  19. Fluoxetine pretreatment promotes neuronal survival and maturation after auditory fear conditioning in the rat amygdala.

    PubMed

    Jiang, Lizhu; Liu, Chen; Tong, Jianbin; Mao, Rongrong; Chen, Dan; Wang, Hui; Huang, Jufang; Li, Lingjiang

    2014-01-01

    The amygdala is a critical brain region for auditory fear conditioning, which is a stressful condition for experimental rats. Adult neurogenesis in the dentate gyrus (DG) of the hippocampus, known to be sensitive to behavioral stress and treatment of the antidepressant fluoxetine (FLX), is involved in the formation of hippocampus-dependent memories. Here, we investigated whether neurogenesis also occurs in the amygdala and contributes to auditory fear memory. In rats showing persistent auditory fear memory following fear conditioning, we found that the survival of new-born cells and the number of new-born cells that differentiated into mature neurons labeled by BrdU and NeuN decreased in the amygdala, but the number of cells that developed into astrocytes labeled by BrdU and GFAP increased. Chronic pretreatment with FLX partially rescued the reduction in neurogenesis in the amygdala and slightly suppressed the maintenance of the long-lasting auditory fear memory 30 days after the fear conditioning. The present results suggest that adult neurogenesis in the amygdala is sensitive to antidepressant treatment and may weaken long-lasting auditory fear memory.

  20. Long-term changes in the CA3 associative network of fear-conditioned mice.

    PubMed

    Çalışkan, Gürsel; Albrecht, Anne; Hollnagel, Jan O; Rösler, Anton; Richter-Levin, Gal; Heinemann, Uwe; Stork, Oliver

    2015-01-01

    The CA3 associative network plays a critical role in the generation of network activity patterns related to emotional state and fear memory. We investigated long-term changes in the corticosterone (CORT)-sensitive function of this network following fear conditioning and fear memory reactivation. In acute slice preparations from mice trained in either condition, the ratio of orthodromic population spike (PS) to antidromic PS was reduced compared to unconditioned animals, indicating a decrease in efficacy of neuronal coupling within the associative CA3 network. However, spontaneous sharp wave-ripples (SW-R), which are thought to arise from this network, remained unaltered. Following CORT application, we observed an increase in orthodromic PS and a normalization to control levels of their ratio to antidromic PS, while SW-R increased in slices of fear conditioned and fear reactivated mice, but not in slices of unconditioned controls. Together with our previous observations of altered hippocampal gamma activity under these learning paradigms, these data suggest that fear conditioning and fear reactivation lastingly alters the CORT-sensitive configuration of different network activity patterns generated by the CA3 associational network. Observed changes in the mRNA expression of receptors for glutamate, GABA and cannabinoids in the stratum pyramidale of area CA3 may provide a molecular mechanism for these adaptive changes.

  1. 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.

  2. 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)

  3. Maltreatment Exposure, Brain Structure, and Fear Conditioning in Children and Adolescents.

    PubMed

    McLaughlin, Katie A; Sheridan, Margaret A; Gold, Andrea L; Duys, Andrea; Lambert, Hilary K; Peverill, Matthew; Heleniak, Charlotte; Shechner, Tomer; Wojcieszak, Zuzanna; Pine, Daniel S

    2016-07-01

    Alterations in learning processes and the neural circuitry that supports fear conditioning and extinction represent mechanisms through which trauma exposure might influence risk for psychopathology. Few studies examine how trauma or neural structure relates to fear conditioning in children. Children (n=94) aged 6-18 years, 40.4% (n=38) with exposure to maltreatment (physical abuse, sexual abuse, or domestic violence), completed a fear conditioning paradigm utilizing blue and yellow bells as conditioned stimuli (CS+/CS-) and an aversive alarm noise as the unconditioned stimulus. Skin conductance responses (SCR) and self-reported fear were acquired. Magnetic resonance imaging data were acquired from 60 children. Children without maltreatment exposure exhibited strong differential conditioning to the CS+ vs CS-, based on SCR and self-reported fear. In contrast, maltreated children exhibited blunted SCR to the CS+ and failed to exhibit differential SCR to the CS+ vs CS- during early conditioning. Amygdala and hippocampal volume were reduced among children with maltreatment exposure and were negatively associated with SCR to the CS+ during early conditioning in the total sample, although these associations were negative only among non-maltreated children and were positive among maltreated children. The association of maltreatment with externalizing psychopathology was mediated by this perturbed pattern of fear conditioning. Child maltreatment is associated with failure to discriminate between threat and safety cues during fear conditioning in children. Poor threat-safety discrimination might reflect either enhanced fear generalization or a deficit in associative learning, which may in turn represent a central mechanism underlying the development of maltreatment-related externalizing psychopathology in children.

  4. Fear conditioning enhances γ oscillations and their entrainment of neurons representing the conditioned stimulus.

    PubMed

    Headley, Drew B; Weinberger, Norman M

    2013-03-27

    Learning alters the responses of neurons in the neocortex, typically strengthening their encoding of behaviorally relevant stimuli. These enhancements are studied extensively 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, whereas 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.

  5. p300/CBP-associated factor selectively regulates the extinction of conditioned fear

    PubMed Central

    Wei, Wei; Coelho, Carlos M.; Li, Xiang; Marek, Roger; Yan, Shanzhi; Anderson, Shawn; Meyers, David; Mukherjee, Chandrani; Sbardella, Gianluca; Castellano, Sabrina; Milite, Ciro; Rotili, Dante; Mai, Antonello; Cole, Philip A.; Sah, Pankaj; Kobor, Michael S.; Bredy, Timothy W.

    2012-01-01

    It is well established that the activity of chromatin-modifying enzymes is crucial for regulating gene expression associated with hippocampal-dependent memories. However, very little is known about how these epigenetic mechanisms influence the formation of cortically-dependent memory, particularly when there is competition between opposing memory traces such as that which occurs during the acquisition and extinction of conditioned fear. Here we demonstrate, in C57/Bl6 mice, that the activity of p300/CBP-associated factor (PCAF) within the infralimbic prefrontal cortex is required for long-term potentiation and is necessary for the formation of memory associated with fear extinction, but not for fear acquisition. Further, systemic administration of the PCAF activator SPV106 enhances memory for fear extinction and prevents fear renewal. The selective influence of PCAF on fear extinction is mediated, in part, by a transient recruitment of the repressive transcription factor ATF4 to the promoter of the immediate early gene zif268, which competitively inhibits its expression. Thus, within the context of fear extinction, PCAF functions as a transcriptional co-activator, which may facilitate the formation of memory for fear extinction by interfering with reconsolidation of the original memory trace. PMID:22933779

  6. Social fear conditioning: a novel and specific animal model to study social anxiety disorder.

    PubMed

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

    2012-05-01

    Social anxiety disorder (SAD) is a major health concern with high lifetime prevalence. The current medication is rather unspecific and, despite considerable efforts, its efficacy is still unsatisfactory. However, there are no appropriate and specific animal models available to study the underlying etiology of the disorder. Therefore, we aimed to establish a model of specific social fear in mice and use this social fear conditioning (SFC) model to assess the therapeutic efficacy of the benzodiazepine diazepam and of the antidepressant paroxetine; treatments currently used for SAD patients. We show that by administering electric foot shocks (2-5, 1 s, 0.7 mA) during the investigation of a con-specific, the investigation of unfamiliar con-specifics was reduced for both the short- and long-term, indicating lasting social fear. The induced fear was specific to social stimuli and did not lead to other behavioral alterations, such as fear of novelty, general anxiety, depression, and impaired locomotion. We show that social fear was dose-dependently reversed by acute diazepam, at doses that were not anxiolytic in a non-social context, such as the elevated plus maze. Finally, we show that chronic paroxetine treatment reversed social fear. All in all, we demonstrated robust social fear after exposure to SFC in mice, which was reversed with both acute benzodiazepine and chronic antidepressant treatment. We propose the SFC model as an appropriate animal model to identify the underlying etiology of SAD and possible novel treatment approaches.

  7. The influence of acute stress on the regulation of conditioned fear

    PubMed Central

    Raio, Candace M.; Phelps, Elizabeth A.

    2014-01-01

    Fear learning and regulation is a prominent model for describing the pathogenesis of anxiety disorders and stress-related psychopathology. Fear expression can be modulated using a number of regulatory strategies, including extinction, cognitive emotion regulation, avoidance strategies and reconsolidation. In this review, we examine research investigating the effects of acute stress and stress hormones on these regulatory techniques. We focus on what is known about the impact of stress on the ability to flexibly regulate fear responses that are acquired through Pavlovian fear conditioning. Our primary aim is to explore the impact of stress on fear regulation in humans. Given this, we focus on techniques where stress has been linked to alterations of fear regulation in humans (extinction and emotion regulation), and briefly discuss other techniques (avoidance and reconsolidation) where the impact of stress or stress hormones have been mainly explored in animal models. These investigations reveal that acute stress may impair the persistent inhibition of fear, presumably by altering prefrontal cortex function. Characterizing the effects of stress on fear regulation is critical for understanding the boundaries within which existing regulation strategies are viable in everyday life and can better inform treatment options for those who suffer from anxiety and stress-related psychopathology. PMID:25530986

  8. Individual Differences in Discriminatory Fear Learning under Conditions of Ambiguity: A Vulnerability Factor for Anxiety Disorders?

    PubMed

    Arnaudova, Inna; Krypotos, Angelos-Miltiadis; Effting, Marieke; Boddez, Yannick; Kindt, Merel; Beckers, Tom

    2013-01-01

    Complex fear learning procedures might be better suited than the common differential fear-conditioning paradigm for detecting individual differences related to vulnerability for anxiety disorders. Two such procedures are the blocking procedure and the protection-from-overshadowing procedure. Their comparison allows for the examination of discriminatory fear learning under conditions of ambiguity. The present study examined the role of individual differences in such discriminatory fear learning. We hypothesized that heightened trait anxiety would be related to a deficit in discriminatory fear learning. Participants gave US-expectancy ratings as an index for the threat value of individual CSs following blocking and protection-from-overshadowing training. The difference in threat value at test between the protected-from-overshadowing conditioned stimulus (CS) and the blocked CS was negatively correlated with scores on a self-report tension-stress scale that approximates facets of generalized anxiety disorder (GAD), the Depression Anxiety Stress Scale-Stress (DASS-S), but not with other individual difference variables. In addition, a behavioral test showed that only participants scoring high on the DASS-S avoided the protected-from-overshadowing CS. This observed deficit in discriminatory fear learning for participants with high levels of tension-stress might be an underlying mechanism for fear overgeneralization in diffuse anxiety disorders such as GAD.

  9. Individual Differences in Discriminatory Fear Learning under Conditions of Ambiguity: A Vulnerability Factor for Anxiety Disorders?

    PubMed Central

    Arnaudova, Inna; Krypotos, Angelos-Miltiadis; Effting, Marieke; Boddez, Yannick; Kindt, Merel; Beckers, Tom

    2013-01-01

    Complex fear learning procedures might be better suited than the common differential fear-conditioning paradigm for detecting individual differences related to vulnerability for anxiety disorders. Two such procedures are the blocking procedure and the protection-from-overshadowing procedure. Their comparison allows for the examination of discriminatory fear learning under conditions of ambiguity. The present study examined the role of individual differences in such discriminatory fear learning. We hypothesized that heightened trait anxiety would be related to a deficit in discriminatory fear learning. Participants gave US-expectancy ratings as an index for the threat value of individual CSs following blocking and protection-from-overshadowing training. The difference in threat value at test between the protected-from-overshadowing conditioned stimulus (CS) and the blocked CS was negatively correlated with scores on a self-report tension-stress scale that approximates facets of generalized anxiety disorder (GAD), the Depression Anxiety Stress Scale-Stress (DASS-S), but not with other individual difference variables. In addition, a behavioral test showed that only participants scoring high on the DASS-S avoided the protected-from-overshadowing CS. This observed deficit in discriminatory fear learning for participants with high levels of tension-stress might be an underlying mechanism for fear overgeneralization in diffuse anxiety disorders such as GAD. PMID:23755030

  10. Influence of stress on fear memory processes in an aversive differential conditioning paradigm in humans.

    PubMed

    Bentz, Dorothée; Michael, Tanja; Wilhelm, Frank H; Hartmann, Francina R; Kunz, Sabrina; von Rohr, Isabelle R Rudolf; de Quervain, Dominique J-F

    2013-07-01

    It is widely assumed that learning and memory processes play an important role in the pathogenesis, expression, maintenance and therapy of anxiety disorders, such as phobias or post-traumatic stress disorder (PTSD). Memory retrieval is involved in symptom expression and maintenance of these disorders, while memory extinction is believed to be the underlying mechanism of behavioral exposure therapy of anxiety disorders. There is abundant evidence that stress and stress hormones can reduce memory retrieval of emotional information, whereas they enhance memory consolidation of extinction training. In this study we aimed at investigating if stress affects these memory processes in a fear conditioning paradigm in healthy human subjects. On day 1, fear memory was acquired through a standard differential fear conditioning procedure. On day 2 (24h after fear acquisition), participants either underwent a stressful cold pressor test (CPT) or a control condition, 20 min before memory retrieval testing and extinction training. Possible prolonged effects of the stress manipulation were investigated on day 3 (48 h after fear acquisition), when memory retrieval and extinction were tested again. On day 2, men in the stress group showed a robust cortisol response to stress and showed lower unconditioned stimulus (US) expectancy ratings than men in the control group. This reduction in fear memory retrieval was maintained on day 3. In women, who showed a significantly smaller cortisol response to stress than men, no stress effects on fear memory retrieval were observed. No group differences were observed with respect to extinction. In conclusion, the present study provides evidence that stress can reduce memory retrieval of conditioned fear in men. Our findings may contribute to the understanding of the effects of stress and glucocorticoids on fear symptoms in anxiety disorders and suggest that such effects may be sex-specific.

  11. Interplay between serotonin and cannabinoid function in the amygdala in fear conditioning.

    PubMed

    Nasehi, Mohammad; Davoudi, Kamelia; Ebrahimi-Ghiri, Mohaddeseh; Zarrindast, Mohammad-Reza

    2016-04-01

    The possible interactions between the cannabinoid and serotonin systems in the regions of the brain involved in emotional learning and memory formation have been studied by some researchers. In view of the key role of the amygdala in the acquisition and expression of fear memory, we investigated the involvement of basolateral amygdala (BLA) serotonin 5-HT4 receptors in arachidonylcyclopropylamide (ACPA; selective CB1 cannabinoid receptor agonist)-induced fear memory consolidation impairment. In our study, a context and tone fear conditioning apparatus was used for testing fear conditioning in adult male NMRI mice. The results showed that intraperitoneal administration of ACPA 0.5 or 0.05, 0.1 and 0.5mg/kg immediately after training decreased the percentage of freezing time in context or tone fear conditioning respectively, suggesting a context- or tone-dependent fear memory consolidation impairment. Post-training intra-BLA microinjections of RS67333, as 5-HT4 serotonin receptor agonist, at doses of 0.025 and 0.05 µg/mouse also impaired context or tone memory consolidation, while RS23597, as 5-HT4 serotonin receptor antagonist, did not produce a marked difference in both fear memories as compared with the control group. Moreover, a subthreshold dose of RS67333 did not alter ACPA response in both fear conditionings. Interestingly, a subthreshold dose of RS23597 potentiated or reversed ACPA response at the dose of 0.01 or 0.05 respectively. It is concluded that BLA serotonin 5-HT4 receptors are involved in tone-dependent fear memory consolidation impairment induced by CB1 activation using ACPA, suggesting a modulatory role for serotonin 5-HT4 receptor.

  12. 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…

  13. Genetic background differences and nonassociative effects in mouse trace fear conditioning.

    PubMed

    Smith, Dani R; Gallagher, Michela; Stanton, Mark E

    2007-09-01

    Fear conditioning, including variants such as delay and trace conditioning that depend on different neural systems, is widely used to behaviorally characterize genetically altered mice. We present data from three strains of mice, C57/BL6 (C57), 129/SvlmJ (129), and a hybrid strain of the two (F(1) hybrids), trained on various versions of a trace fear-conditioning protocol. The initial version was taken from the literature but included unpaired control groups to assess nonassociative effects on test performance. We observed high levels of nonassociative freezing in both contextual and cued test conditions. In particular, nonassociative freezing in unpaired control groups was equivalent to freezing shown by paired groups in the tests for trace conditioning. A number of pilot studies resulted in a new protocol that yielded strong context conditioning and low levels of nonassociative freezing in all mouse strains. During the trace-CS test in this protocol, freezing in unpaired controls remained low in all strains, and both the C57s and F(1) hybrids showed reliable associative trace fear conditioning. Trace conditioning, however, was not obtained in the 129 mice. Our findings indicate that caution is warranted in interpreting mouse fear-conditioning studies that lack control conditions to address nonassociative effects. They also reveal a final set of parameters that are important for minimizing such nonassociative effects and demonstrate strain differences across performance in mouse contextual and trace fear conditioning.

  14. Intrinsic Neuronal Excitability Is Reversibly Altered by a Single Experience in Fear Conditioning

    PubMed Central

    Matthews, Elizabeth A.; Oliveira, Fernando A.; Disterhoft, John F.

    2009-01-01

    Learning is known to cause alterations in intrinsic cellular excitability but, to date, these changes have been seen only after multiple training trials. A powerful learning task that can be quickly acquired and extinguished with a single trial is fear conditioning. Rats were trained and extinguished on a hippocampus-dependent form of fear conditioning to determine whether learning-related changes in intrinsic excitability could be observed after a few training trials and a single extinction trial. Following fear training, hippocampal slices were made and intrinsic excitability was assayed via whole cell recordings from CA1 neurons. Alterations in intrinsic excitability, assayed by the postburst afterhyperpolarization and firing frequency accommodation, were observed after only three trials of contextual or trace-cued fear conditioning. Animals that had been trained in contextual and trace-cued fear were then extinguished. Context fear-conditioned animals extinguished in a single trial and the changes in intrinsic excitability were reversed. Trace-cue conditioned animals only partially extinguished in a single trial and reductions in excitability remained. Thus a single learning experience is sufficient to alter intrinsic excitability. This dramatically extends observations of learning-specific changes in intrinsic neuronal excitability previously observed in paradigms requiring many training trials, suggesting the excitability changes have a basic role in acquiring new information. PMID:19726729

  15. 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.

  16. Unconditioned stimulus revaluation to promote conditioned fear extinction in the memory reconsolidation window.

    PubMed

    Zeng, Xiang-Xing; Du, Juan; Zhuang, Chu-Qun; Zhang, Jun-Hua; Jia, Yan-Lei; Zheng, Xi-Fu

    2014-01-01

    The retrieval-extinction paradigm, which disrupts the reconsolidation of fear memories in humans, is a non-invasive technique that can be used to prevent the return of fear in humans. In the present study, unconditioned stimulus revaluation was applied in the retrieval-extinction paradigm to investigate its promotion of conditioned fear extinction in the memory reconsolidation window after participants acquired conditioned fear. This experiment comprised three stages (acquisition, unconditioned stimulus revaluation, retrieval-extinction) and three methods for indexing fear (unconditioned stimulus expectancy, skin conductance response, conditioned stimulus pleasure rating). After the acquisition phase, we decreased the intensity of the unconditioned stimulus in one group (devaluation) and maintained constant for the other group (control). The results indicated that both groups exhibited similar levels of unconditioned stimulus expectancy, but the devaluation group had significantly smaller skin conductance responses and exhibited a growth in conditioned stimulus + pleasure. Thus, our findings indicate unconditioned stimulus revaluation effectively promoted the extinction of conditioned fear within the memory reconsolidation window.

  17. Entorhinal cortex contribution to contextual fear conditioning extinction and reconsolidation in rats.

    PubMed

    Baldi, Elisabetta; Bucherelli, Corrado

    2014-04-01

    During contextual fear conditioning a rat learns a temporal contiguity association between the exposition to a previously neutral context (CS) and an aversive unconditioned stimulus (US) as a footshock. This condition determines in the rat the freezing reaction during the subsequent re-exposition to the context. Potentially the re-exposition without US presentation initiates two opposing and competing processes: reconsolidation and extinction. Reconsolidation process re-stabilizes and strengthens the original memory and it is initiated by a brief re-exposure to context. Instead the extinction process leads to the decrease of the expression of the original memory and it is triggered by prolonged re-exposure to the context. Here we analyzed the entorhinal cortex (ENT) participation in contextual fear conditioning reconsolidation and extinction. The rats were trained in contextual fear conditioning and 24h later they were subjected either to a brief (2 min) reactivation session or to a prolonged (120 min) re-exposition to context to induce extinction of the contextual fear memory. Immediately after the reactivation or the extinction session, the animals were submitted to bilateral ENT TTX inactivation. Memory retention was assessed as conditioned freezing duration measured 72 h after TTX administration. The results showed that ENT inactivation both after reactivation and extinction session was followed by contextual freezing retention impairment. Thus, the present findings point out that ENT is involved in contextual fear memory reconsolidation and extinction. This neural structure might be part of parallel circuits underlying two phases of contextual fear memory processing.

  18. 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

  19. Expatriates' Multiple Fears, from Terrorism to Working Conditions: Development of a Model.

    PubMed

    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.

  20. 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

  1. 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

  2. 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…

  3. Dorsal hippocampus involvement in trace fear conditioning with long, but not short, trace intervals in mice.

    PubMed

    Chowdhury, Najwa; Quinn, Jennifer J; Fanselow, Michael S

    2005-10-01

    Placing a "trace" interval between a warning signal and an aversive shock makes consolidation of the memory for trace conditioning hippocampus dependent. To determine the trace at which memory consolidation requires the hippocampus, mice were trained with 0-s, 1-s, 3-s, or 20-s trace intervals and tested for freezing to context and tone. Posttraining dorsal hippocampus (DH) lesions decreased context conditioning regardless of trace interval. However, DH lesions attenuated only the 20-s trace tone freezing. Like eyeblink conditioning, the DH is necessary for trace fear conditioning only at long trace intervals, but the time scale for the effective interval in fear conditioning is about 40 times longer. Manipulations that alter trace fear conditioning with short trace intervals probably do not reflect altered DH function. Given this difference in time scale along with the use of posttraining DH lesions, hippocampus dependency of trace conditioning is not related to a bridging function or response timing.

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

    PubMed Central

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

    2009-01-01

    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, and 8 years. Results demonstrated that in both boys and girls: (1) fear conditioning increased across age, particularly from ages 5 to 6 years, (2) the three components of skin conductance fear conditioning that reflect different degrees of automatic and controlled cognitive processes exhibited different developmental profiles, and (3) individual differences in arousal, orienting, and the unconditioned response were associated with individual differences in conditioning, with the influence of orienting increasing at later ages. This first longitudinal study of the development of skin conductance fear conditioning in children both demonstrates that children as young as age 3 years evidence fear conditioning in a difficult acquisition paradigm, and that different sub-components of skin conductance conditioning have different developmental trajectories. PMID:20121876

  5. Computer-assisted behavioral assessment of Pavlovian fear conditioning in mice.

    PubMed

    Anagnostaras, S G; Josselyn, S A; Frankland, P W; Silva, A J

    2000-01-01

    In Pavlovian fear conditioning, a conditional stimulus (CS, usually a tone) is paired with an aversive unconditional stimulus (US, usually a foot shock) in a novel context. After even a single pairing, the animal comes to exhibit a long-lasting fear to the CS and the conditioning context, which can be measured as freezing, an adaptive defense reaction in mice. Both context and tone conditioning depend on the integrity of the amygdala, and context conditioning further depends on the hippocampus. The reliability and efficiency of the fear conditioning assay makes it an excellent candidate for the screening of learning and memory deficits in mutant mice. One obstacle is that freezing in mice has been accurately quantified only by human observers, using a tedious method that can be subject to bias. In the present study we generated a simple, high-speed, and highly accurate algorithm that scores freezing of four mice simultaneously using NIH Image on an ordinary Macintosh computer. The algorithm yielded a high correlation and excellent linear fit between computer and human scores across a broad range of conditions. This included the ability to score low pretraining baseline scores and accurately mimic the effects of two independent variables (shock intensity and test modality) on fear. Because we used a computer and digital video, we were able to acquire a secondary index of fear, activity suppression, as well as baseline activity scores. Moreover, we measured the unconditional response to shock. These additional measures can enhance the sensitivity of the assay to detect interesting memory phenotypes and control for possible confounds. Thus, this computer-assisted system for measuring behavior during fear conditioning allows for the standardized and carefully controlled assessment of multiple aspects of the fear conditioning experience.

  6. Early extinction after fear conditioning yields a context-independent and short-term suppression of conditional freezing in rats.

    PubMed

    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 this deficit by assessing the suppression of fear to a CS immediately after extinction training (Experiment 1) and the context specificity of fear after both immediate and delayed extinction training (Experiment 2). We also examined the time course of the immediate extinction deficit (Experiment 3). Our results indicate that immediate extinction produces a short-lived and context-independent suppression of conditional freezing. Deficits in long-term extinction were apparent even when the extinction trials were given up to 6 h after conditioning. Moreover, this deficit was not due to different retention intervals that might have influenced the degree of spontaneous recovery after immediate and delayed extinction (Experiment 4). These results suggest that fear suppression under immediate extinction may be due to a short-term, context-independent habituation process, rather than extinction per se. Long-term extinction memory only develops when extinction training occurs at least six hours after conditioning.

  7. The effect of yohimbine on the extinction of conditioned fear: a role for context.

    PubMed

    Morris, Richard W; Bouton, Mark E

    2007-06-01

    Six experiments with rat subjects examined the effect of yohimbine, an alpha-2 adrenergic autoreceptor antagonist, on the extinction of conditioned fear to a tone. Experiments 1 and 2 demonstrated that systemic administration of yohimbine (1.0 mg/kg) facilitated a long-term decrease in freezing after extinction, and this depended on pairing drug administration with extinction training. However, Experiments 3 and 4 demonstrated that yohimbine did not eradicate the original fear learning: Freezing was renewed when the tone was tested outside of the extinction context. Experiments 5 and 6 found that the contextually specific attenuation of fear produced by yohimbine transferred to another extinguished conditional stimulus (CS) and not to a nonextinguished CS. The results suggest that yohimbine, when administered in the presence of a neutral context, creates a form of inhibition in that context that allows that specific context to reduce fear of an extinguished CS.

  8. Signal transduction mechanisms within the entorhinal cortex that support latent inhibition of cued fear conditioning.

    PubMed

    Lewis, Michael C; Gould, Thomas J

    2007-10-01

    Latent inhibition is a phenomenon by which pre-exposure to a conditioned-stimulus (CS), prior to subsequent pairings of that same CS with an unconditioned-stimulus (US), results in decreased conditioned responding to the CS. Previous work in our laboratory has suggested that the entorhinal cortex is critically involved in the establishment of latent inhibition of cued fear conditioning. Furthermore, utilizing systemic pharmacology, we have demonstrated a role for of NMDA receptors, protein kinase A (PKA), and mitogen activated protein kinase (MAPK, also known as ERK) in latent inhibition of cued fear conditioning, but until now, where these cell signaling cascades are critically activated during latent inhibition of cued fear was unknown. Here, we use direct drug infusion to demonstrate that cell signaling via NMDA receptors, the cAMP/PKA pathway, and the MAPK pathway within the entorhinal cortex are critically involved in latent inhibition of cued fear conditioning. In the present study, CS pre-exposed mice received 20 CS pre-exposures 24h prior to two pairings of the same CS with a 0.53 mA foot shock US, while control animals receive no pre-exposure to the CS. The NMDA antagonist APV (0.25 or 2.5 microg/side), the cAMP inhibitor Rp-cAMP (1.8 or 18.0 microg/side), or the MAPK inhibitor U0126 (0.1 or 1.0 microg/side) were directly infused into the entorhinal cortex prior to pre-exposure. All three drugs produced dose-dependent disruptions in latent inhibition of cued fear conditioning. Importantly, none of the drugs had any effect on cued fear conditioning when administered on training day, suggesting that the effects of each of the drugs were specific to CS pre-exposure. These results are discussed in relation to the potential mechanisms of plasticity that support latent inhibition of cued fear conditioning.

  9. Post-conditioning experience with acute or chronic inflammatory pain reduces contextual fear conditioning in the rat.

    PubMed

    Johnston, Ian N; Maier, Steven F; Rudy, Jerry W; Watkins, Linda R

    2012-01-15

    There is evidence that pain can impact cognitive function in people. The present study evaluated whether Pavlovian fear conditioning in rats would be reduced if conditioning were followed by persistent inflammatory pain induced by a subcutaneous injection of dilute formalin or complete Freund's adjuvant (CFA) on the dorsal lumbar surface of the back. Formalin-induced pain specifically impaired contextual fear conditioning but not auditory cue conditioning (Experiment 1A). Moreover, formalin pain only impaired contextual fear conditioning if it was initiated within 1h of conditioning and did not have a significant effect if initiated 2, 8 or 32 h after (Experiments 1A and 1B). Experiment 2 showed that formalin pain initiated after a session of context pre-exposure reduced the ability of that pre-exposure to facilitate contextual fear when the rat was limited to a brief exposure to the context during conditioning. Similar impairments in context- but not CS-fear conditioning were also observed if the rats received an immediate post-conditioning injection with CFA (Experiment 3). Finally, we confirmed that formalin and CFA injected s.c. on the back induced pain-indicative behaviours, hyperalgesia and allodynia with a similar timecourse to intraplantar injections (Experiment 4). These results suggest that persistent pain impairs learning in a hippocampus-dependent task, and may disrupt processes that encode experiences into long-term memory.

  10. 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.

  11. 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.

  12. The histone deacetylase inhibitor valproic acid enhances acquisition, extinction, and reconsolidation of conditioned fear.

    PubMed

    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 function as a histone deacetylase inhibitor (HDAC). Here we report that VPA enhances long-term memory for both acquisition and extinction of cued-fear. Interestingly, VPA enhances extinction, but also enhances renewal of the original conditioned fear when tested in a within-subjects design. This effect appears to be related to a reconsolidation-like process since a single CS reminder in the presence of VPA can enhance long-term memory for the original fear in the context in which fear conditioning takes place. We also show that by modifying the intertrial interval during extinction training, VPA can strengthen reconsolidation of the original fear memory or enhance long-term memory for extinction such that it becomes independent of context. These findings have important implications for the use of HDAC inhibitors as adjuncts to behavior therapy in the treatment of phobia and related anxiety disorders.

  13. 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,…

  14. 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.

  15. 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

  16. Genetic correlation between alcohol preference and conditioned fear: Exploring a functional relationship.

    PubMed

    Chester, Julia A; Weera, Marcus M

    2017-02-01

    Post-traumatic stress disorder (PTSD) and alcohol-use disorders have a high rate of co-occurrence, possibly because they are regulated by common genes. In support of this idea, mice selectively bred for high (HAP) alcohol preference show greater fear potentiated startle (FPS), a model for fear-related disorders such as PTSD, compared to mice selectively bred for low (LAP) alcohol preference. This positive genetic correlation between alcohol preference and FPS behavior suggests that the two traits may be functionally related. This study examined the effects of fear conditioning on alcohol consumption and the effects of alcohol consumption on the expression of FPS in male and female HAP2 and LAP2 mice. In experiment 1, alcohol consumption (g/kg) under continuous-access conditions was monitored daily for 4 weeks following a single fear-conditioning or control treatment (foot shock and no shock). FPS was assessed three times (once at the end of the 4-week alcohol access period, once at 24 h after removal of alcohol, and once at 6-8 days after removal of alcohol), followed by two more weeks of alcohol access. Results showed no change in alcohol consumption, but alcohol-consuming, fear-conditioned, HAP2 males showed increased FPS at 24 h during the alcohol abstinence period compared to control groups. In experiment 2, alcohol consumption under limited-access conditions was monitored daily for 4 weeks. Fear-conditioning or control treatments occurred four times during the first 12 days and FPS testing occurred four times during the second 12 days of the 4-week alcohol consumption period. Results showed that fear conditioning increased alcohol intake in both HAP2 and LAP2 mice immediately following the first conditioning session. Fear-conditioned HAP2 but not LAP2 mice showed greater alcohol intake compared to control groups on drinking days that occurred between fear conditioning and FPS test sessions. FPS did not change as a function of alcohol consumption in either

  17. Elevated Arc/Arg 3.1 protein expression in the basolateral amygdala following auditory trace-cued fear conditioning.

    PubMed

    Chau, Lily S; Prakapenka, Alesia; Fleming, Stephen A; Davis, Ashley S; Galvez, Roberto

    2013-11-01

    The underlying neuronal mechanisms of learning and memory have been heavily explored using associative learning paradigms. Two of the more commonly employed learning paradigms have been contextual and delay fear conditioning. In fear conditioning, a subject learns to associate a neutral stimulus (conditioned stimulus; CS), such as a tone or the context of the room, with a fear provoking stimulus (unconditioned stimulus; US), such as a mild footshock. Utilizing these two paradigms, various analyses have elegantly demonstrated that the amygdala plays a role in both fear-related associative learning paradigms. However, the amygdala's involvement in trace fear conditioning, a forebrain-dependent fear associative learning paradigm that has been suggested to tap into higher cognitive processes, has not been closely investigated. Furthermore, to our knowledge, the specific amygdala nuclei involved with trace fear conditioning has not been examined. The present study used Arc expression as an activity marker to determine the amygdala's involvement in trace fear associative learning and to further explore involvement of specific amygdalar nuclei. Arc is an immediate early gene that has been shown to be associated with neuronal activation and is believed to be necessary for neuronal plasticity. Findings from the present study demonstrated that trace-conditioned mice, compared to backward-conditioned (stimulation-control), delay-conditioned and naïve mice, exhibited elevated amygdalar Arc expression in the basolateral (BLA) but not the central (CeA) or the lateral amygdala (LA). These findings are consistent with previous reports demonstrating that the amygdala plays a critical role in trace conditioning. Furthermore, these findings parallel studies demonstrating hippocampal-BLA activation following contextual fear conditioning, suggesting that trace fear conditioning and contextual fear conditioning may involve similar amygdala nuclei. Together, findings from this study

  18. 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.

  19. 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.

  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. Effect of Conditioned Stimulus Exposure during Slow Wave Sleep on Fear Memory Extinction in Humans

    PubMed Central

    He, Jia; Sun, Hong-Qiang; Li, Su-Xia; Zhang, Wei-Hua; Shi, Jie; Ai, Si-Zhi; Li, Yun; Li, Xiao-Jun; Tang, Xiang-Dong; Lu, Lin

    2015-01-01

    Study Objectives: Repeated exposure to a neutral conditioned stimulus (CS) in the absence of a noxious unconditioned stimulus (US) elicits fear memory extinction. The aim of the current study was to investigate the effects of mild tone exposure (CS) during slow wave sleep (SWS) on fear memory extinction in humans. Design: The healthy volunteers underwent an auditory fear conditioning paradigm on the experimental night, during which tones served as the CS, and a mild shock served as the US. They were then randomly assigned to four groups. Three groups were exposed to the CS for 3 or 10 min or an irrelevant tone (control stimulus, CtrS) for 10 min during SWS. The fourth group served as controls and was not subjected to any interventions. All of the subjects completed a memory test 4 h after SWS-rich stage to evaluate the effect on fear extinction. Moreover, we conducted similar experiments using an independent group of subjects during the daytime to test whether the memory extinction effect was specific to the sleep condition. Participants: Ninety-six healthy volunteers (44 males) aged 18–28 y. Measurements and Results: Participants exhibited undisturbed sleep during 2 consecutive nights, as assessed by sleep variables (all P > 0.05) from polysomnographic recordings and power spectral analysis. Participants who were re-exposed to the 10 min CS either during SWS and wakefulness exhibited attenuated fear responses (wake-10 min CS, P < 0.05; SWS-10 min CS, P < 0.01). Conclusions: Conditioned stimulus re-exposure during slow wave sleep promoted fear memory extinction without altering sleep profiles. Citation: He J, Sun HQ, Li SX, Zhang WH, Shi J, Ai SZ, Li Y, Li XJ, Tang XD, Lu L. Effect of conditioned stimulus exposure during slow wave sleep on fear memory extinction in humans. SLEEP 2015;38(3):423–431. PMID:25348121

  2. 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

  3. 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…

  4. 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

  5. Fear conditioning induces distinct patterns of gene expression in lateral amygdala.

    PubMed

    Lamprecht, R; Dracheva, S; Assoun, S; LeDoux, J E

    2009-11-01

    The lateral nucleus of the amygdala (LA) has been implicated in the formation of long-term associative memory (LTM) of stimuli associated with danger through fear conditioning. The current study aims to detect genes that are expressed in LA following associative fear conditioning. Using oligonucleotide microarrays, we monitored gene expression in rats subjected to paired training where a tone co-terminates with a footshock, or unpaired training where the tone and footshock are presented in a non-overlapping manner. The paired protocol consistently leads to auditory fear conditioning memory formation, whereas the unpaired protocol does not. When the paired group was compared with the unpaired group 5 h after training, the expression of genes coding for the limbic system-associated membrane protein (Lsamp), kinesin heavy chain member 2 (Kif2), N-ethylmaleimide-sensitive fusion protein (NSF) and Hippocalcin-like 4 protein (Hpcal4) was higher in the paired group. These genes encode proteins that regulate neuronal axonal morphology (Lsamp, Kif2), presynaptic vesicle cycling and release (Hpcal4 and NSF), and AMPA receptor maintenance in synapses (NSF). Quantitative real-time PCR (qPCR) showed that Kif2 and Lsamp are expressed hours following fear conditioning but minutes after unpaired training. Hpcal4 is induced by paired stimulation only 5 h after the training. These results show that fear conditioning induces a unique temporal activation of molecular pathways involved in regulating synaptic transmission and axonal morphology in LA, which is different from non-associative stimulation.

  6. 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

  7. Functional MRI of human amygdala activity during Pavlovian fear conditioning: stimulus processing versus response expression.

    PubMed

    Cheng, Dominic T; Knight, David C; Smith, Christine N; Stein, Elliot A; Helmstetter, Fred J

    2003-02-01

    Although laboratory animal studies have shown that the amygdala plays multiple roles in conditional fear, less is known about the human amygdala. Human subjects were trained in a Pavlovian fear conditioning paradigm during functional magnetic resonance imaging (fMRI). Brain activity maps correlated with reference waveforms representing the temporal pattern of visual conditional stimuli (CSs) and subject-derived autonomic responses were compared. Subjects receiving paired CS-shock presentations showed greater amygdala activity than subjects receiving unpaired CS-shock presentations when their brain activity was correlated with a waveform generated from their behavioral responses. Stimulus-based waveforms revealed learning differences in the visual cortex, but not in the amygdala. These data support the view that the amygdala is important for the expression of learned behavioral responses during Pavlovian fear conditioning.

  8. The role of the nucleus basalis magnocellularis in fear conditioning consolidation in the rat.

    PubMed

    Baldi, Elisabetta; Mariottini, Chiara; Bucherelli, Corrado

    2007-12-01

    The nucleus basalis magnocellularis (NBM) is known to be involved in the memorization of several conditioned responses. To investigate the role of the NBM in fear conditioning memorization, this neural site was subjected to fully reversible tetrodotoxin (TTX) inactivation during consolidation in adult male Wistar rats that had undergone fear training to acoustic conditioned stimulus (CS) and context. TTX was stereotaxically administered to different groups of rats at increasing intervals after the acquisition session. Memory was assessed as the conditioned freezing duration measured during retention testing, always performed 72 and 96 h after TTX administration. In this way, there was no interference with normal NBM function during either acquisition or retrieval phases, allowing any amnesic effect to be due only to consolidation disruption. The results show that for contextual fear response memory consolidation, NBM functional integrity is necessary up to 24 h post-acquisition. On the other hand, NBM functional integrity was shown to be necessary for memory consolidation of the acoustic CS fear response only immediately after acquisition and not 24-h post-acquisition. The present findings help to elucidate the role of the NBM in memory consolidation and better define the neural circuits involved in fear memories.

  9. 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

  10. The acquisition of fear of movement-related pain and associative learning: a novel pain-relevant human fear conditioning paradigm.

    PubMed

    Meulders, Ann; Vansteenwegen, Debora; Vlaeyen, Johan W S

    2011-11-01

    Current fear-avoidance models consider fear of pain as a key factor in the development of chronic musculoskeletal pain. Generally, the idea is that by virtue of the formation of associations or acquired propositional knowledge about the relation between neutral movements and pain, these movements may signal pain, and hence start to elicit defensive fear responses (eg, avoidance behavior). This assumption has never been investigated experimentally. Therefore, we developed a pain-relevant fear conditioning paradigm using a movement as a conditioned stimulus (CS) and a painful electrocutaneous stimulus as an unconditioned stimulus (US) to examine the acquisition of fear of movement-related pain in healthy subjects. In a within-subjects design, participants manipulated a joystick to the left/right in the experimental (predictable) condition, and upward/downward in the control (unpredictable) condition or vice versa. In the predictable condition, one movement direction (CS+), and not the other (CS-), was followed by painful stimuli. In the unpredictable condition, painful stimuli were always delivered during the intertrial interval. Both fear of movement-related pain ratings and eyeblink startle measures were more elevated in response to the CS+ than to the CS-, whereas no differences occurred between both unreinforced CSs in the control condition. Participants were slower initiating a CS+ movement than a CS- movement, while response latencies to CSs in the control condition did not differ. These data support the acquisition of fear of movement-related pain by associative learning. Results are discussed in the broader context of the acquisition of pain-related fear in patients with musculoskeletal pain.

  11. 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

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

    PubMed

    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

    2007-07-19

    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.

  13. Pavlov's cockroach: classical conditioning of salivation in an insect.

    PubMed

    Watanabe, Hidehiro; Mizunami, Makoto

    2007-06-13

    Secretion of saliva to aid swallowing and digestion is an important physiological function found in many vertebrates and invertebrates. Pavlov reported classical conditioning of salivation in dogs a century ago. Conditioning of salivation, however, has been so far reported only in dogs and humans, and its underlying neural mechanisms remain elusive because of the complexity of the mammalian brain. We previously reported that, in cockroaches Periplaneta americana, salivary neurons that control salivation exhibited increased responses to an odor after conditioning trials in which the odor was paired with sucrose solution. However, no direct evidence of conditioning of salivation was obtained. In this study, we investigated the effects of conditioning trials on the level of salivation. Untrained cockroaches exhibited salivary responses to sucrose solution applied to the mouth but not to peppermint or vanilla odor applied to an antenna. After differential conditioning trials in which an odor was paired with sucrose solution and another odor was presented without pairing with sucrose solution, sucrose-associated odor induced an increase in the level of salivation, but the odor presented alone did not. The conditioning effect lasted for one day after conditioning trials. This study demonstrates, for the first time, classical conditioning of salivation in species other than dogs and humans, thereby providing the first evidence of sophisticated neural control of autonomic function in insects. The results provide a useful model system for studying cellular basis of conditioning of salivation in the simpler nervous system of insects.

  14. Prior fear conditioning does not impede enhanced active avoidance in serotonin transporter knockout rats.

    PubMed

    Schipper, Pieter; Henckens, Marloes J A G; Borghans, Bart; Hiemstra, Marlies; Kozicz, Tamas; Homberg, Judith R

    2017-03-07

    Stressors can be actively or passively coped with, and adequate adaption of the coping response to environmental conditions can reduce their potential deleterious effects. One major factor influencing stress coping behaviour is serotonin transporter (5-HTT) availability. Abolishment of 5-HTT is known to impair fear extinction but facilitates acquisition of signalled active avoidance (AA), a behavioural task in which an animal learns to avoid an aversive stimulus that is predicted by a cue. Flexibility in adapting coping behaviour to the nature of the stressor shapes resilience to stress-related disorders. Therefore, we investigated the relation between 5-HTT expression and ability to adapt a learned coping response to changing environmental conditions. To this end, we first established and consolidated a cue-conditioned passive fear response in 5-HTT(-/-) and wildtype rats. Next, we used the conditioned stimulus (CS) to signal oncoming shocks during signalled AA training in 5-HTT(-/-) and wildtype rats to study their capability to acquire an active coping response to the CS following fear conditioning. Finally, we investigated the behavioural response to the CS in a novel environment and measured freezing, exploration and self-grooming, behaviours reflective of stress coping strategy. We found that fear conditioned and sham conditioned 5-HTT(-/-) animals acquired the signalled AA response faster than wildtypes, while prior conditioning briefly delayed AA learning similarly in both genotypes. Subsequent exposure to the CS in the novel context reduced freezing and increased locomotion in 5-HTT(-/-) compared to wildtype rats. This indicates that improved AA performance in 5-HTT(-/-) rats resulted in a weaker residual passive fear response to the CS in a novel context. Fear conditioning prior to AA training did not affect freezing upon re-encountering the CS, although it did reduce locomotion in 5-HTT(-/-) rats. We conclude that independent of 5-HTT signalling, prior

  15. 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.

  16. 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.

  17. 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…

  18. Impaired auditory and contextual fear conditioning in soman-exposed rats.

    PubMed

    Moffett, Mark C; Schultz, Mark K; Schwartz, Julia E; Stone, Michael F; Lumley, Lucille A

    2011-03-01

    Exposure to soman (GD) can result in prolonged seizures and subsequent neuropathology in a variety of brain regions including the amygdala and hippocampus. Both regions are believed to play important roles in the development and expression of fear conditioning. The purpose of this experiment was to test these conditioning tasks as a possible behavioral correlate of the observed neuropathology. Male rats were exposed to GD (1.0 or 1.2×LD50) or saline followed with injections of atropine sulfate, the oxime HI-6 and diazepam. Fear conditioning was conducted on post-exposure day (PED) 8 followed by measuring freezing to contextual and auditory conditioned stimuli on PED 9 and 10 respectively. Contextual and auditory fear conditioning was severely impaired in both the 1.0×LD50 and 1.2×LD50 GD groups. Both GD groups spent less time freezing than controls when returned to the context in which conditioning occurred. The 1.0×LD50 and 1.2×LD50 groups had very low levels of freezing following presentation of the auditory conditioned stimulus. Neuronal fiber degeneration was present in the piriform cortex, thalamus, and amygdala in GD-exposed animals regardless of dose. The present study suggests that contextual and auditory fear conditioning is impaired in GD-exposed rats possibly due to neuropathology observed in the hippocampus, amygdala and thalamus.

  19. 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…

  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. Stress-induced enhancement of fear conditioning and sensitization facilitates extinction-resistant and habituation-resistant fear behaviors in a novel animal model of posttraumatic stress disorder.

    PubMed

    Corley, Michael J; Caruso, Michael J; Takahashi, Lorey K

    2012-01-18

    Posttraumatic stress disorder (PTSD) is characterized by stress-induced symptoms including exaggerated fear memories, hypervigilance and hyperarousal. However, we are unaware of an animal model that investigates these hallmarks of PTSD especially in relation to fear extinction and habituation. Therefore, to develop a valid animal model of PTSD, we exposed rats to different intensities of footshock stress to determine their effects on either auditory predator odor fear extinction or habituation of fear sensitization. In Experiment 1, rats were exposed to acute footshock stress (no shock control, 0.4 mA, or 0.8 mA) immediately prior to auditory fear conditioning training involving the pairing of auditory clicks with a cloth containing cat odor. When presented to the conditioned auditory clicks in the next 5 days of extinction testing conducted in a runway apparatus with a hide box, rats in the two shock groups engaged in higher levels of freezing and head out vigilance-like behavior from the hide box than the no shock control group. This increase in fear behavior during extinction testing was likely due to auditory activation of the conditioned fear state because Experiment 2 demonstrated that conditioned fear behavior was not broadly increased in the absence of the conditioned auditory stimulus. Experiment 3 was then conducted to determine whether acute exposure to stress induces a habituation resistant sensitized fear state. We found that rats exposed to 0.8 mA footshock stress and subsequently tested for 5 days in the runway hide box apparatus with presentations of nonassociative auditory clicks exhibited high initial levels of freezing, followed by head out behavior and culminating in the occurrence of locomotor hyperactivity. In addition, Experiment 4 indicated that without delivery of nonassociative auditory clicks, 0.8 mA footshock stressed rats did not exhibit robust increases in sensitized freezing and locomotor hyperactivity, albeit head out vigilance

  2. Tracking the fear memory engram: discrete populations of neurons within amygdala, hypothalamus, and lateral septum are specifically activated by auditory fear conditioning

    PubMed Central

    Wilson, Yvette M.; Gunnersen, Jenny M.; Murphy, Mark

    2015-01-01

    Memory formation is thought to occur via enhanced synaptic connectivity between populations of neurons in the brain. However, it has been difficult to localize and identify the neurons that are directly involved in the formation of any specific memory. We have previously used fos-tau-lacZ (FTL) transgenic mice to identify discrete populations of neurons in amygdala and hypothalamus, which were specifically activated by fear conditioning to a context. Here we have examined neuronal activation due to fear conditioning to a more specific auditory cue. Discrete populations of learning-specific neurons were identified in only a small number of locations in the brain, including those previously found to be activated in amygdala and hypothalamus by context fear conditioning. These populations, each containing only a relatively small number of neurons, may be directly involved in fear learning and memory. PMID:26179231

  3. Tracking the fear memory engram: discrete populations of neurons within amygdala, hypothalamus, and lateral septum are specifically activated by auditory fear conditioning.

    PubMed

    Butler, Christopher W; Wilson, Yvette M; Gunnersen, Jenny M; Murphy, Mark

    2015-08-01

    Memory formation is thought to occur via enhanced synaptic connectivity between populations of neurons in the brain. However, it has been difficult to localize and identify the neurons that are directly involved in the formation of any specific memory. We have previously used fos-tau-lacZ (FTL) transgenic mice to identify discrete populations of neurons in amygdala and hypothalamus, which were specifically activated by fear conditioning to a context. Here we have examined neuronal activation due to fear conditioning to a more specific auditory cue. Discrete populations of learning-specific neurons were identified in only a small number of locations in the brain, including those previously found to be activated in amygdala and hypothalamus by context fear conditioning. These populations, each containing only a relatively small number of neurons, may be directly involved in fear learning and memory.

  4. 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…

  5. 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

  6. 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.

  7. 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

  8. Calcitonin gene-related peptide released within the amygdala is involved in Pavlovian auditory fear conditioning.

    PubMed

    Kocorowski, L H; Helmstetter, F J

    2001-03-01

    The effects of CGRP and the CGRP receptor antagonist hCGRP(8-37) injected into the amygdala on both the acquisition and expression of fear behavior to a discrete auditory conditional stimulus (CS) and the training context were assessed. In Experiment 1, pretraining injections of CGRP but not hCGRP(8-37) produced fear-like behavior before any aversive stimuli were presented. While both compounds attenuated freezing to the contextual CS on the test day, neither affected learning about the auditory CS. In Experiment 2, pretesting injections of hCGRP(8-37) (0.63 mM) selectively attenuated freezing to the auditory CS but left freezing to the contextual CS intact. These data suggest that CGRP in the amygdala may selectively contribute to the expression of learning about auditory stimuli during fear conditioning.

  9. Fear conditioning and extinction: emotional states encoded by distinct signaling pathways

    PubMed Central

    Tronson, Natalie C.; Corcoran, Kevin A.; Jovasevic, Vladimir; Radulovic, Jelena

    2011-01-01

    Conditioning and extinction of fear have traditionally been viewed as two independent learning processes for encoding representations of contexts or cues (conditioned stimuli, CS), aversive events (unconditioned stimuli, US), and their relationship. Based on the analysis of protein kinase signaling patterns in neurons of the fear circuit, we propose that fear and extinction are best conceptualized as emotional states triggered by a single CS representation with two opposing values: aversive and non-aversive. These values are conferred by the presence or absence of the US and encoded by distinct sets of kinase signaling pathways and their downstream targets. Modulating specific protein kinases thus has the potential to modify emotional states, and hence, may emerge as a promising treatment for anxiety disorders. PMID:22118930

  10. Genetic variation in brain-derived neurotrophic factor and human fear conditioning.

    PubMed

    Hajcak, G; Castille, C; Olvet, D M; Dunning, J P; Roohi, J; Hatchwell, E

    2009-02-01

    Brain-derived neurotrophic factor (BDNF) has been implicated in hippocampal-dependent learning processes, and carriers of the Met allele of the Val66Met BDNF genotype are characterized by reduced hippocampal structure and function. Recent nonhuman animal work suggests that BDNF is also crucial for amygdala-dependent associative learning. The present study sought to examine fear conditioning as a function of the BDNF polymorphism. Fifty-seven participants were genotyped for the BDNF polymorphism and took part in a differential-conditioning paradigm. Participants were shocked following a particular conditioned stimulus (CS+) and were also presented with stimuli that ranged in perceptual similarity to the CS+ (20, 40 or 60% smaller or larger than the CS+). The eye blink component of the startle response was measured to quantify fear conditioning; post-task shock likelihood ratings for each stimulus were also obtained. All participants reported that shock likelihood varied with perceptual similarity to the CS+ and showed potentiated startle in response to CS +/- 20% stimuli. However, only the Val/Val group had potentiated startle responses to the CS+. Met allele carrying individuals were characterized by deficient fear conditioning--evidenced by an attenuated startle response to CS+ stimuli. Variation in the BDNF genotype appears related to abnormal fear conditioning, consistent with nonhuman animal work on the importance of BDNF in amygdala-dependent associative learning. The relation between genetic variation in BDNF and amygdala-dependent associative learning deficits is discussed in terms of potential mechanisms of risk for psychopathology.

  11. Changes in cutaneous and body temperature during and after conditioned fear to context in the rat.

    PubMed

    Vianna, Daniel M L; Carrive, Pascal

    2005-05-01

    Infrared thermography was used to image changes in cutaneous temperature during a conditioned fear response to context. Changes in heart rate, arterial pressure, activity and body (i.p.) temperature were recorded at the same time by radio-telemetry, in addition to freezing immobility. A marked drop in tail and paws temperature (-5.3 and -7.5 degrees C, respectively, down to room temperature), which lasted for the entire duration of the response (30 min), was observed in fear-conditioned rats. In sham-conditioned rats, the drop was on average half the magnitude and duration. In contrast, temperature of the eye, head and back increased (between + 0.8 and + 1.5 degrees C), with no difference between the two groups of rats. There was a similar increase in body temperature although it was slightly higher and delayed in the fear-conditioned animals. Finally, ending of the fear response was associated with a gradual decrease in body temperature and a rebound increase in the temperature of the tail (+ 3.3 degrees C above baseline). This study shows that fear, and to some extent arousal, evokes a strong cutaneous vasoconstriction that is restricted to the tail and paws. This regionally specific reduction in blood flow may be part of a preparatory response to a possible fight and flight to reduce blood loss in the most exposed parts of the rat's body in case of injury. The data also show that the tail is the main part of the body used for dissipating internal heat accumulated during fear once the animal has returned to a safe environment.

  12. Conditioned fear and extinction learning performance and its association with psychiatric symptoms in active duty Marines

    PubMed Central

    Acheson, D.T.; Geyer, M.A.; Baker, D.G.; Nievergelt, C.M.; Yurgil, K.; Risbrough, V.B.

    2014-01-01

    Summary Background Posttraumatic Stress Disorder (PTSD) is a major public health concern, especially given the recent wars in Iraq and Afghanistan. Nevertheless, despite a sharp increase in the incidence of psychiatric disorders in returning veterans, empirically based prevention strategies are still lacking. To develop effective prevention and treatment strategies, it is necessary to understand the underlying biological mechanisms contributing to PTSD and other trauma related symptoms. Methods The “Marine Resiliency Study II” (MRS-II; October 2011–October 2013) Neurocognition project is an investigation of neurocognitive performance in Marines about to be deployed to Afghanistan. As part of this investigation, 1195 Marines and Navy corpsmen underwent a fear conditioning and extinction paradigm and psychiatric symptom assessment prior to deployment. The current study assesses (1) the effectiveness of the fear potentiated startle paradigm in producing fear learning and extinction and (2) the association of performance in the paradigm with baseline psychiatric symptom classes (healthy: n = 923, PTSD symptoms: n = 42, anxiety symptoms: n = 37, and depression symptoms: n = 12). Results Results suggest that the task was effective in producing differential fear learning and fear extinction in this cohort. Further, distinct patterns emerged differentiating the PTSD and anxiety symptom classes from both healthy and depression classes. During fear acquisition, the PTSD symptom group was the only group to show deficient discrimination between the conditioned stimulus (CS+) and safety cue (CS−), exhibiting larger startle responses during the safety cue compared to the healthy group. During extinction learning, the PTSD symptom group showed significantly less reduction in their CS+ responding over time compared to the healthy group, as well as reduced extinction of self-reported anxiety to the CS+ by the end of the extinction session. Conversely, the anxiety symptom

  13. 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.

  14. EXTENDED FEAR CONDITIONING REVEALS A ROLE FOR BOTH N-METHYL-d-ASPARTIC ACID AND NON-N-METHYL-d-ASPARTIC ACID RECEPTORS IN THE AMYGDALA IN THE ACQUISITION OF CONDITIONED FEAR

    PubMed Central

    PISTELL, P. J.; FALLS, W. A.

    2009-01-01

    Pavlovian conditioning is a useful tool for elucidating the neural mechanisms involved with learning and memory, especially in regard to the stimuli associated with aversive events. The amygdala has been repeatedly implicated as playing a significant role in the acquisition and expression of fear. If the amygdala is critical for the acquisition of fear, then it should contribute to this processes regardless of the parameters used to induce or evaluate conditioned fear. A series of experiments using reversible inactivation techniques evaluated the role of the amygdala in the acquisition of conditioned fear when training was conducted over several days in rats. Fear-potentiated startle was used to evaluate the acquisition of conditioned fear. Pretraining infusions of N-methyl-d-aspartic acid (NMDA) or non-NMDA receptor antagonists alone into the amygdala interfered with the acquisition of fear early in training, but not later. Pretraining infusions of a cocktail consisting of both an NMDA and non-NMDA antagonist interfered with the acquisition of conditioned fear across all days of training. Taken together these results suggest the amygdala may potentially be critical for the acquisition of conditioned fear regardless of the parameters utilized. PMID:18675886

  15. 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.

  16. 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

  17. Classical olfactory conditioning in the oriental fruit fly, Bactrocera dorsalis.

    PubMed

    Liu, Jia Li; Chen, Xiao Yan; 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.

  18. Safety signals from avoidance learning but not from yoked classical conditioning training pass both summation and retardation tests for inhibition.

    PubMed

    Cándido, Antonio; González, Felisa; de Brugada, Isabel

    2004-05-31

    In one experiment half of the animals were trained to avoid a signaled footshock by jumping (30 or 160 trials), whereas the rest of the animals received the same events as yoked. For all of them the termination of the warning signal and of the shock was followed by a safety signal. Several tests were conducted to assess the ability of the stimuli to suppress licking by measuring the latency in completing 25 consecutive licks in the presence of the stimuli. Fear of the warning signal and inhibitory properties of the safety signal (summation and retardation tests) were measured. The results showed that there were no differences in fear to the warning signal, and that the safety signal behaves as a conditioned inhibitor only for animals trained with a long avoidance procedure, but not in the yoked (classical conditioning) procedure. These results highlight the role played by the avoidance response and its consequences in avoidance learning.

  19. Fear conditioned potentiation of the acoustic blink reflex in patients with cerebellar lesions

    PubMed Central

    Maschke, M.; Drepper, J.; Kindsvater, K.; Kolb, F.; Diener, H.; Timmann, D.

    2000-01-01

    OBJECTIVE—To investigate whether the human cerebellum takes part in fear conditioned potentiation of the acoustic blink reflex.
METHODS—A group of 10 cerebellar patients (eight patients with lesions involving the medial cerebellum, two patients with circumscribed lesions of the cerebellar hemispheres) was compared with a group of 16 age and sex matched healthy control subjects. The fear conditioned potentiation paradigm consisted of three phases. During the first, habituation phase subjects received 20 successive acoustic blink stimuli. In the subsequent fear conditioning phase, subjects passed through 20 paired presentations of the unconditioned fear stimulus (US; an electric shock) and the conditioned stimulus (CS; a light). Thereafter, subjects underwent the potentiation phase, which consisted of a pseudorandom order of 12 trials of the acoustic blink stimulus alone, 12 acoustic blink stimuli paired with the conditioned stimulus, and six conditioned stimuli paired with the unconditioned stimulus. The EMG of the acoustic blink reflex was recorded at the orbicularis oculi muscles. The potentiation effect was determined as the difference in normalised peak amplitude of the blink reflex evoked by pairs of CS and acoustic blink stimuli and evoked by the acoustic stimulus alone.
RESULTS—In the habituation phase, short term habituation of the acoustic blink reflex was preserved in all cerebellar patients. However, in the potentiation phase, the potentiation effect of the blink reflex was significantly reduced in patients with medial cerebellar lesions compared with the controls (mean (SD) potentiation effect (%), patients: −6.4 (15.3), controls: 21.6 (35.6)), but was within normal limits in the two patients with lateral lesions.
CONCLUSIONS—The present findings suggest that the human medial cerebellum is involved in associative learning of non-specific aversive reactions—that is, the fear conditioned potentiation of the acoustic blink reflex

  20. Developmental lead exposure impairs extinction of conditioned fear in young adult rats.

    PubMed

    McGlothan, Jennifer L; Karcz-Kubicha, Marzena; Guilarte, Tomás R

    2008-11-01

    Pavlovian fear conditioning is a model of emotional learning in which a neutral stimulus such as a tone is paired with an aversive stimulus such as a foot shock. Presentation of a tone with a foot shock in a context (test box) elicits a freezing response representative of stereotypic fear behavior. After conditioning has occurred, presentation of the context (test box) or tone in the absence of the unconditioned stimulus (shock) causes extinction of the fear response. Rats chronically exposed to environmentally relevant levels of lead (Pb(2+)) and controls were tested in a fear-conditioning (FC) paradigm at 50 days of age (PN50). Littermates to FC rats received an immediate shock (IS) when placed in the test box with no tone. Blood Pb(2+) levels in control and Pb(2+)-exposed animals were (mean+/-S.E.M.): 0.76+/-0.11 (n=15) and 25.8+/-1.28microg/dL (n=14). Freezing behavior was recorded during acquisition (day of training) or during 4 consecutive extinction days. Control and Pb(2+)-exposed FC rats exhibited the same level of freezing time on the acquisition day. No freezing behavior occurred in IS rats regardless of treatment. Presentation of context 24h later produced a freezing response on both control and Pb(2+)-exposed FC rats but not in IS rats. When tested in the extinction phase, Pb(2+)-exposed FC rats exhibited deficits in extinction compared to control FC rats. That is, when presented with context on 4 consecutive days after acquisition of the fear response, Pb(2+)-exposed FC rats exhibited a greater freezing response than control FC rats. These findings indicate that chronic Pb(2+) exposure produces a deficit in extinction learning and the animals remain more fearful than controls.

  1. Potentiation rather than distraction in a trace fear conditioning procedure.

    PubMed

    Pezze, M A; Marshall, H J; Cassaday, H J

    2016-07-01

    Trace conditioning procedures are defined by the introduction of a trace interval between conditioned stimulus (CS, e.g. noise or light) offset and unconditioned stimulus (US, e.g. footshock). The introduction of an additional stimulus as a distractor has been suggested to increase the attentional demands of the task and to extend the usefulness of the behavioural model. In Experiment 1, the CS was noise and the distractor was provided by an intermittent light. In Experiment 2, the CS was light and the distractor was provided by an intermittent noise. In both experiments, the introduction of a 10s trace interval weakened associative learning compared with that seen in a 0s delay conditioned group. However, there was no consistent evidence of distraction. On the contrary, in Experiment 1, associative learning was stronger (in both trace and delay conditioned groups) for rats conditioned also in the presence of the intermittent light. In Experiment 2, there was no such effect when the roles of the stimuli were reversed. The results of Experiment 2 did however confirm the particular salience of the noise stimulus. The finding of increased associative learning dependent on salience is consistent with arousal-mediated effects on associative learning.

  2. 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…

  3. 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…

  4. 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…

  5. 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…

  6. 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…

  7. Context Pre-Exposure Obscures Amygdala Modulation of Contextual-Fear Conditioning

    ERIC Educational Resources Information Center

    Huff, Nicole C.; Wright-Hardesty, Karli J.; Higgins, Emily A.; Matus-Amat, Patricia; Rudy, Jerry W.

    2005-01-01

    We report that post-training inactivation of basolateral amygdala region (BLA) with muscimol impaired memory for contextual-fear conditioning (as measured by freezing) and intra-BLA norepinephrine enhanced this memory. However, pre-exposure to the context eliminated both of these effects. These findings provide a likely explanation of why an…

  8. 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…

  9. 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…

  10. 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…

  11. 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…

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

    PubMed

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

    2013-02-01

    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 for contextual 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 with wild-type mice, PNMT-KO mice showed reduced contextual fear but normal cued fear. Mice exhibited normal memory performance in the short-term version of the novel object recognition task, suggesting that 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 that 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, whereas 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.

  13. 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

  14. 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…

  15. Early postnatal stress alters the extinction of context-dependent conditioned fear in adult rats.

    PubMed

    Matsumoto, Machiko; Togashi, Hiroko; Konno, Kohtaro; Koseki, Hiroyo; Hirata, Riki; Izumi, Takeshi; Yamaguchi, Taku; Yoshioka, Mitsuhiro

    2008-05-01

    Fear extinction is hypothesized to be a learning process based on a new inhibitory memory. The present study was conducted to elucidate the effect of early postnatal stress on the extinction of context-dependent fear memory in adult rats, with a focus on the serotonergic system. Extinction was estimated by the expression of freezing behavior during repeated extinction trials (i.e., repeated exposure to contextual fear conditioning) on consecutive days. The decrease in fear expression was attenuated in adult rats that had been subjected to footshock (FS) at the third postnatal week (3wFS), but not in those exposed to footshock at the second postnatal week (2wFS). The decreased attenuation of freezing behavior observed in 3wFS was abolished by repeated treatment with the partial N-methyl-D-aspartate receptor agonist D-cycloserine (15 mg/kg, i.p., for 4 days), which has been shown to facilitate cue-dependent extinction. Repeated treatment with the serotonin 5-hydroxytryptamine-1A (5-HT(1A)) receptor agonist tandospirone (1 mg/kg, i.p., for 4 days) prevented the expression of freezing behavior in 3wFS, whereas diazepam treatment (1 mg/kg, i.p., for 4 days) in 3wFS did not. These results suggest that exposure to early postnatal stress at the third week is responsible for attenuating extinction of contextual fear conditioning and is mediated by a serotonergic 5-HT(1A) receptor mechanism. In other words, exposure to traumatic events during the early postnatal period might precipitate long-lasting alterations in synaptic function that underlie extinction processes of context-dependent fear memory.

  16. Deletion of PTEN produces deficits in conditioned fear and increases fragile X mental retardation protein.

    PubMed

    Lugo, Joaquin N; Smith, Gregory D; Morrison, Jessica B; White, Jessika

    2013-11-15

    The phosphatase and tensin homolog detected on chromosome 10 (PTEN) gene product modulates activation of the phosphatidylinositol 3-kinase (PI3K)/AKT pathway. The PI3K pathway has been found to be involved in the regulation of the fragile X mental retardation protein, which is important for long-term depression and in the formation of new memories. We used delayed fear conditioning and trace fear conditioning to determine learning and memory deficits in neuron subset-specific Pten (NS-Pten) conditional knockout (KO) mice. We found that NS-Pten KO mice had deficits in contextual learning and trace conditioning, but did not have deficits in the ability to learn a conditioned stimulus. Furthermore, we found increased levels in the total and phosphorylated forms of the fragile X mental retardation protein (FMRP) in the hippocampus of NS-Pten KO mice.

  17. Deficient fear conditioning in psychopathy as a function of interpersonal and affective disturbances

    PubMed Central

    Veit, Ralf; Konicar, Lilian; Klinzing, Jens G.; Barth, Beatrix; Yilmaz, Özge; Birbaumer, Niels

    2013-01-01

    The diminished fear reactivity is one of the most valid physiological findings in psychopathy research. In a fear conditioning paradigm, with faces as conditioned stimulus (CS) and electric shock as unconditioned stimulus (US), we investigated a sample of 14 high psychopathic violent offenders. Event related potentials, skin conductance responses (SCR) as well as subjective ratings of the CSs were collected. This study assessed to which extent the different facets of the psychopathy construct contribute to the fear conditioning deficits observed in psychopaths. Participants with high scores on the affective facet subscale of the Psychopathy Checklist-Revised (PCL-R) showed weaker conditioned fear responses and lower N100 amplitudes compared to low scorers. In contrast, high scorers on the affective facet rated the CS+ (paired) more negatively than low scorers regarding the CS− (unpaired). Regarding the P300, high scores on the interpersonal facet were associated with increased amplitudes to the CS+ compared to the CS−, while the opposed pattern was found for the antisocial facet. Both, the initial and terminal contingent negative variation indicated a divergent pattern: participants with pronounced interpersonal deficits, showed increased cortical negativity to the CS+ compared to the CS−, whereas a reversed CS+/CS− differentiation was found in offenders scoring high on the antisocial facet. The present study revealed that deficient fear conditioning in psychopathy was most pronounced in offenders with high scores on the affective facet. Event related potentials suggest that participants with distinct interpersonal deficits showed increased information processing, whereas the antisocial facet was linked to decreased attention and interest to the CS+. These data indicate that an approach to the facets of psychopathy can help to resolve ambiguous findings in psychopathy research and enables a more precise and useful description of this disorder. PMID:24298245

  18. 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

  19. Bi-directional effects of pituitary adenylate cyclase-activating polypeptide (PACAP) on fear-related behavior and c-Fos expression after fear conditioning in rats

    PubMed Central

    Meloni, Edward G.; Venkataraman, Archana; Donahue, Rachel J.; Carlezon, William A.

    2015-01-01

    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 ug) or vehicle followed 30 min later by fear conditioning. Freezing was measured early (1, 4, and 7days) 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

  20. Rapid learning dynamics in individual honeybees during classical conditioning.

    PubMed

    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.

  1. Is there savings for pavlovian fear conditioning after neurotoxic basolateral amygdala lesions in rats?

    PubMed

    Maren, S

    2001-11-01

    Considerable evidence indicates an important role for amygdaloid nuclei in both the acquisition and expression of Pavlovian fear conditioning. Recent reports from my laboratory have focused on the impact of neurotoxic lesions of the basolateral complex of the amygdala (BLA) on conditional freezing behavior in rats. In these studies, I have observed severe effects of posttraining BLA lesions on the expression of conditional freezing even after extensive presurgical overtraining (25-75 trials). Moreover, I have found no evidence for sparing of fear memory (i.e., savings) in these rats when I assess their rate of reacquisition relative to BLA rats receiving minimal training (1 trial). In these experiments, freezing behavior was assessed using a conventional time-sampling procedure and expressed as a response probability. Although this measure is well established in the literature, it is conceivable that it is not sensitive to spared memory in rats with BLA lesions. To address this issue, I present a more detailed analysis of freezing behavior that quantifies latency to freeze, the number of freezing bouts, the duration of freezing bouts, and the probability distribution of bout lengths. I also include control data from untrained (no-shock) rats. Consistent with my earlier reports, I find no evidence of savings of fear memory in rats with neurotoxic BLA lesions using several measures of freezing behavior. These results reiterate the conclusion that fear memory, as it is expressed in freezing behavior, requires neurons in the BLA.

  2. Extinction and Retrieval + Extinction of Conditioned Fear Differentially Activate Medial Prefrontal Cortex and Amygdala in Rats

    PubMed Central

    Lee, Hongjoo J.; Haberman, Rebecca P.; Roquet, Rheall F.; Monfils, Marie-H.

    2016-01-01

    Pairing a previously neutral conditioned stimulus (CS; e.g., a tone) to an aversive unconditioned stimulus (US; e.g., a footshock) leads to associative learning such that the tone alone comes to elicit a conditioned response (e.g., freezing). We have previously shown that an extinction session that occurs within the reconsolidation window (termed retrieval + extinction) attenuates fear responding and prevents the return of fear in Pavlovian fear conditioning (Monfils et al., 2009). To date, the mechanisms that explain the different behavioral outcomes between standard extinction and retrieval + extinction remain poorly understood. Here we sought to examine the differential temporal engagement of specific neural systems by these two approaches using Arc catFISH (cellular compartment analysis of temporal activity using fluorescence in situ hybridization (FISH)). Our results demonstrate that extinction and retrieval + extinction lead to differential patterns of expression, suggesting that they engage different networks. These findings provide insight into the neural mechanisms that allow extinction during reconsolidation to prevent the return of fear in rodents. PMID:26834596

  3. 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.

  4. Failure to condition to a cue is associated with sustained contextual fear.

    PubMed

    Baas, J M P; van Ooijen, L; Goudriaan, A; Kenemans, J L

    2008-03-01

    The acquisition of a conditioned fear response is adaptive, as it enables the organism to appropriately respond to predictors of aversive events. Consequently, the absence of predictive cues can be used as a signal for safety. We aimed to study whether deficient fear conditioning might lead to maladaptive fear. Following previous work, we predicted that failure to learn the CS-US association would result in higher contextual fear, and that participants who failed to learn would tend to exhibit higher trait anxiety. Conditioning took place in a virtual environment with two contexts. In one of the two contexts, offset of a CS (light) was associated with a shock. Each participant visited two places (a house and an apartment) in each of 12 blocks. In one of these places shocks were administered at the offset of an 8-s period of lights on (CS). The results showed that half of the participants demonstrated differential shock expectancy between situations in the shock context in which the CS was present versus absent. This indicates that these participants learned the contingencies between the shocks and both the context and the light CS. In contrast, the other half of the participants learned only the association with the context. As predicted, learning the CS-US contingency resulted in reduced self-reported fear in the absence of the CS in the danger context compared to the presence of the CS. On the other hand, participants who failed to learn the association displayed a sustained aversive state throughout the duration of the danger context. Skin conductance measures confirmed this pattern of results. Fear-potentiated startle during the threat context compared to the safe context was significant in both groups, while startle was only potentiated during the CS in the threat context in the group that learned the CS association (trend-level significant). Finally, scores on Spielberger's self-report scale of trait anxiety tended to be higher in the group of participants

  5. 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.

  6. Sex differences in the behavioural and hypothalamic-pituitary-adrenal response to contextual fear conditioning in rats.

    PubMed

    Daviu, Núria; Andero, Raül; Armario, Antonio; Nadal, Roser

    2014-11-01

    In recent years, special attention is being paid to sex differences in susceptibility to disease. In this regard, there is evidence that male rats present higher levels of both cued and contextual fear conditioning than females. However, little is known about the concomitant hypothalamic-pituitary-adrenal (HPA) axis response to those situations which are critical in emotional memories. Here, we studied the behavioural and HPA responses of male and female Wistar rats to context fear conditioning using electric footshock as the aversive stimulus. Fear-conditioned rats showed a much greater ACTH and corticosterone response than those merely exposed to the fear conditioning chamber without receiving shocks. Moreover, males presented higher levels of freezing whereas HPA axis response was greater in females. Accordingly, during the fear extinction tests, female rats consistently showed less freezing and higher extinction rate, but greater HPA activation than males. Exposure to an open-field resulted in lower activity/exploration in fear-conditioned males, but not in females, suggesting greater conditioned cognitive generalization in males than females. It can be concluded that important sex differences in fear conditioning are observed in both freezing and HPA activation, but the two sets of variables are affected in the opposite direction: enhanced behavioural impact in males, but enhanced HPA responsiveness in females. Thus, the role of sex differences on fear-related stimuli may depend on the variables chosen to evaluate it, the greater responsiveness of the HPA axis in females perhaps being an important factor to be further explored.

  7. A role for amygdaloid PKA and PKC in the acquisition of long-term conditional fear memories in rats.

    PubMed

    Goosens, K A; Holt, W; Maren, S

    2000-09-01

    Although there is great interest in the cellular mechanisms underlying Pavlovian conditioning, few studies have directly examined the contribution of intracellular signaling pathways in the amygdala to the acquisition and expression of conditional fear memories. In the present study, we examined this issue by infusing 1-(5'-isoquinolinesulfonyl)-2-methylpiperazine (H7), a potent inhibitor of both protein kinase C (PKC) and cAMP-dependent protein kinase (PKA), directly into the amygdala prior to fear conditioning or retention testing. We found that infusion of H7 prior to training attenuated long-term conditional fear in a dose-dependent manner (Experiment 1), but short-term fear memories were spared. The contribution of protein kinases to conditional fear was region-specific within the amygdala: infusion of H7 into the basolateral amygdala (BLA) but not the central nucleus of the amygdala (CEA) resulted in attenuated freezing (Experiment 2). Moreover, the deficits in fear conditioning produced by PKA/PKC inhibition were not modality-specific, insofar as intra-BLA H7 reduced both contextual and auditory fear. The effects of H7 on conditional freezing were not attributable to either state-dependency or performance deficits (Experiment 3). Together, these experiments suggest that amygdaloid PKA and PKC play an important role in the acquisition of fear memories.

  8. 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.

  9. Contributions of the amygdala central nucleus and ventrolateral periaqueductal grey to freezing and instrumental suppression in Pavlovian fear conditioning

    PubMed Central

    McDannald, Michael A.

    2010-01-01

    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 gray (vlPAG) have 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 may be 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. PMID:20298722

  10. Classic conditioning of the ventilatory responses in rats.

    PubMed

    Nsegbe, E; Vardon, G; Perruchet, P; Gallego, J

    1997-10-01

    Recent authors have stressed the role of conditioning in the control of breathing, but experimental evidence of this role is still sparse and contradictory. To establish that classic conditioning of the ventilatory responses can occur in rats, we performed a controlled experiment in which a 1-min tone [conditioned stimulus (CS)] was paired with a hypercapnic stimulus [8.5% CO2, unconditioned stimulus (US)]. The experimental group (n = 9) received five paired CS-US presentations, followed by one CS alone to test conditioning. This sequence was repeated six times. The control group (n = 7) received the same number of CS and US, but each US was delivered 3 min after the CS. We observed that after the CS alone, breath duration was significantly longer in the experimental than in the control group and mean ventilation was significantly lower, thus showing inhibitory conditioning. This conditioning may have resulted from the association between the CS and the inhibitory and aversive effects of CO2. The present results confirmed the high sensitivity of the respiratory controller to conditioning processes.

  11. Alterations in fear conditioning and amygdalar activation following chronic wheel running in rats.

    PubMed

    Burghardt, Paul R; Pasumarthi, Ravi K; Wilson, Marlene A; Fadel, Jim

    2006-06-01

    Several convergent lines of evidence point to the amygdala as a key site of plasticity underlying most forms of fear conditioning. Studies have shown that chronic physical activity, such as wheel running, can alter learning in a variety of contexts, including aversive conditioning. The ability of chronic wheel running (WR) to alter both behavioral correlates of fear conditioning and indices of amygdalar activation, however, has not been simultaneously assessed. Here, rats were given constant access to either free-turning or--as a control--locked (LC) running wheels in their home cages. After 8 weeks of housing under these conditions, animals were exposed to a series of shocks in a separate testing chamber. Twenty-four hours later, the animals were returned to the shock chamber and freezing behavior was measured as an indicator of contextual fear conditioning. The animals were then sacrificed and their brains processed for immunohistochemical detection of Fos to assess patterns of putative neuronal activation. WR rats spent significantly more time freezing than their LC counterparts upon return to the shock-paired context. The enhanced conditioned freezing response was most pronounced in animals showing high levels of nightly wheel running activity. WR animals also had significantly higher levels of neuronal activation, as indicated by Fos expression in the central nucleus of the amygdala, but less activation in the basolateral nucleus, compared to sedentary controls. These data demonstrate the ability of chronic physical activity to alter contextual fear conditioning and implicate the amygdala as a potential site of plasticity underlying this phenomenon.

  12. 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.

  13. Role of the basolateral amygdala in the reinstatement and extinction of fear responses to a previously extinguished conditioned stimulus.

    PubMed

    Laurent, Vincent; Westbrook, R Frederick

    2010-02-01

    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 the restoration and the reinstatement of fear responses to the extinguished CS. In Experiment 2, BLA inactivation before extinction impaired long-term inhibition of fear responses, but its inactivation before extinction of fear responses restored by CS-US pairing did not impair long-term inhibition. In Experiment 3, BLA inactivation before extinction of fear responses or before the extinction of fear responses reinstated by US-alone exposure impaired long-term inhibition. In Experiment 4, BLA inactivation did not impair long-term inhibition of fear responses reinstated by US-alone exposure if the context where the US-alone exposure occurred had been previously extinguished. These results confirm that the BLA is critical for both learning fear and fear inhibition, but not for relearning this inhibition. The results are consistent with the view that reinstatement is due to the extinguished CS being tested in a dangerous context and are discussed in terms of a contemporary neural model of fear inhibition.

  14. Conditioned inhibitory and excitatory gain modulations of visual cortex in fear conditioning: Effects of analysis strategies of magnetocortical responses.

    PubMed

    Moratti, Stephan; Giménez-Fernández, Tamara; Méndez-Bértolo, Constantino; de Vicente-Pérez, Francisco

    2017-02-07

    In unpredictable environments, stimuli that predict potential danger or its absence can change rapidly. Therefore, it is highly adaptive to prioritize incoming sensory information flexibly as a function of prior experience. Previously, these changes have only been conceptualized as excitatory gain increases in sensory cortices for acquired fear-relevant stimuli during associative learning. However, formal descriptions of associative processes by Rescorla and Wagner predict both conditioned excitatory and inhibitory processes in response systems for fear and safety cues, respectively. Magnetocortical steady-state visual evoked fields (ssVEFs) have been shown to vary in amplitude as a function of associative strength. Therefore, we wondered why previous studies reporting ssVEF modulations by fear learning did not observe conditioned inhibition of ssVEF responses for the safety cue. Three analysis strategies were applied: (1) traditional analysis of ssVEF amplitude at occipital MEG sensors, (2) applying a general linear model (GLM) at each sensor, and (3) fitting the same GLM to cortically localized ssVEF responses. First, we replicated previous findings of increased ssVEFs for acquired fear-relevant stimuli using all three analysis strategies. Critically, we demonstrated conditioned inhibition of ssVEF responses for fear-irrelevant cues for specific gradiometer sensor types using the traditional analysis technique and for all sensor types when applying a GLM to the sensor space. However, sensor space effects were rather small. In stark contrast, cortical source space effect sizes were most pronounced. The results of opposing CS+ and CS- modulations in sensory cortex reflect predictions of the Rescorla-Wagner model and current neurobiological findings.

  15. 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

  16. 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.

  17. Lack of predictive power of trait fear and anxiety for conditioned pain modulation (CPM).

    PubMed

    Horn-Hofmann, Claudia; Priebe, Janosch A; Schaller, Jörg; Görlitz, Rüdiger; Lautenbacher, Stefan

    2016-12-01

    In recent years the association of conditioned pain modulation (CPM) with trait fear and anxiety has become a hot topic in pain research due to the assumption that such variables may explain the low CPM efficiency in some individuals. However, empirical evidence concerning this association is still equivocal. Our study is the first to investigate the predictive power of fear and anxiety for CPM by using a well-established psycho-physiological measure of trait fear, i.e. startle potentiation, in addition to two self-report measures of pain-related trait anxiety. Forty healthy, pain-free participants (female: N = 20; age: M = 23.62 years) underwent two experimental blocks in counter-balanced order: (1) a startle paradigm with affective picture presentation and (2) a CPM procedure with hot water as conditioning stimulus (CS) and contact heat as test stimulus (TS). At the end of the experimental session, pain catastrophizing (PCS) and pain anxiety (PASS) were assessed. PCS score, PASS score and startle potentiation to threatening pictures were entered as predictors in a linear regression model with CPM magnitude as criterion. We were able to show an inhibitory CPM effect in our sample: pain ratings of the heat stimuli were significantly reduced during hot water immersion. However, CPM was neither predicted by self-report of pain-related anxiety nor by startle potentiation as psycho-physiological measure of trait fear. These results corroborate previous negative findings concerning the association between trait fear/anxiety and CPM efficiency and suggest that shifting the focus from trait to state measures might be promising.

  18. 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.

  19. 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

  20. Nicotinic receptors in the dorsal and ventral hippocampus differentially modulate contextual fear conditioning.

    PubMed

    Kenney, Justin W; Raybuck, Jonathan D; Gould, Thomas J

    2012-08-01

    Nicotine administration alters various forms of hippocampus-dependent learning and memory. Increasing work has found that the dorsal and ventral hippocampus differentially contribute to multiple behaviors. Thus, the present study examined whether the effects of nicotine in the dorsal and ventral hippocampus have distinct influences on contextual fear learning in male C57BL/6J mice. Direct infusion of nicotine into the dorsal hippocampus resulted in an enhancement of contextual fear learning, whereas nicotine infused into the ventral hippocampus resulted in deficits. Nicotine infusions into the ventral hippocampus did not alter hippocampus-independent cued fear conditioning or time spent in the open arm of the elevated plus maze, a measure of anxiety, suggesting that the effects are due to alterations in contextual learning and not other general processes. Finally, results from using direct infusions of MLA, a low-affinity α7 nicotinic acetylcholine receptor (nAChR) antagonist, in conjunction with systemic nicotine, provide evidence that α7-nAChRs in the ventral hippocampus mediate the detrimental effect of ventral hippocampal nicotine on contextual fear learning. These results suggest that with systemic nicotine administration, competition exists between the dorsal and ventral hippocampus for behavioral control over contextual learning.

  1. An inhibitor of DNA recombination blocks memory consolidation, but not reconsolidation, in context fear conditioning.

    PubMed

    Colón-Cesario, Melissa; Wang, Jianpeng; Ramos, Xiomara; García, Hermes G; Dávila, Jorge J; Laguna, Jessenia; Rosado, Claribel; Peña de Ortiz, Sandra

    2006-05-17

    Genomic recombination requires cutting, processing, and rejoining of DNA by endonucleases, polymerases, and ligases, among other factors. We have proposed that DNA recombination mechanisms may contribute to long-term memory (LTM) formation in the brain. Our previous studies with the nucleoside analog 1-beta-D-arabinofuranosylcytosine triphosphate (ara-CTP), a known inhibitor of DNA ligases and polymerases, showed that this agent blocked consolidation of conditioned taste aversion without interfering with short-term memory (STM). However, because polymerases and ligases are also essential for DNA replication, it remained unclear whether the effects of this drug on consolidation were attributable to interference with DNA recombination or neurogenesis. Here we show, using C57BL/6 mice, that ara-CTP specifically blocks consolidation but not STM of context fear conditioning, a task previously shown not to require neurogenesis. The effects of a single systemic dose of cytosine arabinoside (ara-C) on LTM were evident as early as 6 h after training. In addition, although ara-C impaired LTM, it did not impair general locomotor activity nor induce brain neurotoxicity. Importantly, hippocampal, but not insular cortex, infusions of ara-C also blocked consolidation of context fear conditioning. Separate studies revealed that context fear conditioning training significantly induced nonhomologous DNA end joining activity indicative of DNA ligase-dependent recombination in hippocampal, but not cortex, protein extracts. Finally, unlike inhibition of protein synthesis, systemic ara-C did not block reconsolidation of context fear conditioning. Our results support the idea that DNA recombination is a process specific to consolidation that is not involved in the postreactivation editing of memories.

  2. D-cycloserine does not facilitate fear extinction by reducing conditioned stimulus processing or promoting conditioned inhibition to contextual cues.

    PubMed

    Baker, Kathryn D; McNally, Gavan P; Richardson, Rick

    2012-09-14

    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 in conditioned stimulus (CS) processing or (2) by promoting the development of conditioned inhibition to contextual cues. Rats administered DCS prior to extinction showed enhanced long-term extinction retention (Experiments 3 and 4). The same nonreinforced CS procedure used in extinction also reduced freezing at test when presented as pre-exposure before conditioning, demonstrating latent inhibition (Experiment 1). DCS administered shortly prior to pre-exposure had no effect on latent inhibition using parameters which produced weak (Experiment 2) or strong (Experiment 3) expression of latent inhibition. Therefore, DCS facilitated learning involving CS-alone exposures, but only when these exposures occurred after (extinction) and not before (latent inhibition) conditioning. We also used a retardation test procedure to examine whether the extinction context gained inhibitory properties for rats given DCS prior to extinction. With three different footshock intensities, there was no evidence that DCS promoted accrual of associative inhibition to the extinction context (Experiment 4). The present findings demonstrate that DCS does not facilitate extinction by reducing CS processing or causing the extinction context to become a conditioned inhibitor. Investigations into the mechanisms underlying the augmentation of extinction by DCS are valuable for understanding how fear can be inhibited.

  3. Protein synthesis in the amygdala, but not the auditory thalamus, is required for consolidation of Pavlovian fear conditioning in rats.

    PubMed

    Maren, Stephen; Ferrario, Carrie R; Corcoran, Kevin A; Desmond, Timothy J; Frey, Kirk A

    2003-12-01

    The amygdala is an essential neural substrate for Pavlovian fear conditioning. Nevertheless, long-term synaptic plasticity in amygdaloid afferents, such as the auditory thalamus, may contribute to the formation of fear memories. We therefore compared the influence of protein synthesis inhibition in the amygdala and the auditory thalamus on the consolidation of Pavlovian fear conditioning in Long-Evans rats. Rats received three tone-footshock trials in a novel conditioning chamber. Immediately after fear conditioning, rats were infused intra-cranially with the protein synthesis inhibitor, anisomycin. Conditional fear to the tone and conditioning context was assessed by measuring freezing behaviour in separate retention tests conducted at least 24 h following conditioning. Post-training infusion of anisomycin into the amygdala impaired conditional freezing to both the auditory and contextual stimuli associated with footshock. In contrast, intra-thalamic infusions of anisomycin or a broad-spectrum protein kinase inhibitor [1-(5'-isoquinolinesulphonyl)-2-methylpiperazine, H7] did not affect conditional freezing during the retention tests. Pre-training intra-thalamic infusion of the NMDA receptor antagonist 2-amino-5-phosphonopentanoic acid (APV), which blocks synaptic transmission in the auditory thalamus, produced a selective deficit in the acquisition of auditory fear conditioning. Autoradiographic assays of cerebral [14C]-leucine incorporation revealed similar levels of protein synthesis inhibition in the amygdala and thalamus following intra-cranial anisomycin infusions. These results reveal that the establishment of long-term fear memories requires protein synthesis in the amygdala, but not the thalamus, after auditory fear conditioning. Forms of synaptic plasticity that depend on protein synthesis, such as long-term potentiation, are likely candidates for the encoding and long-term storage of fear memories in the amygdala.

  4. Prefrontal infralimbic cortex mediates competition between excitation and inhibition of body movements during pavlovian fear conditioning.

    PubMed

    Halladay, Lindsay R; Blair, Hugh T

    2017-03-01

    The infralimbic subregion of the prefrontal cortex (IL) is broadly involved in behavioral flexibility, risk assessment, and outcome reinforcement. In aversive conditioning tasks, the IL has been implicated in fear extinction and in mediating transitions between Pavlovian and instrumental responses. Here we examine the role of the IL in mediating transitions between two competing Pavlovian fear responses, conditioned motor inhibition (CMI) and conditioned motor excitation (CME). Rats were trained to fear an auditory conditioned stimulus (CS) by pairing it with periorbital shock to one eyelid (the unconditioned stimulus [US]). Trained animals exhibited CMI responses (movement suppression) to the CS when they had not recently encountered the US (>24 hr), but, after recent encounters with the US (<5 min), the CS evoked CME responses (turning in circles away from anticipated shock). Animals then received bilateral infusions of muscimol or picrotoxin to inactivate or hyperactivate the IL, respectively. Neither drug reliably affected CMI responses, but there was a bidirectional effect on CME responses; inactivation of the IL attenuated CME responses, whereas hyperactivation potentiated CME responses. These results provide evidence that activation of the IL may promote behavioral strategies that involve mobilizing the body and suppress strategies that involve immobilizing the body. © 2016 Wiley Periodicals, Inc.

  5. 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.

  6. Cholinergic modulation of pavlovian fear conditioning: effects of intrahippocampal scopolamine infusion.

    PubMed

    Gale, G D; Anagnostaras, S G; Fanselow, M S

    2001-01-01

    Cholinergic neurotransmission has been implicated in the acquisition of a variety of tasks, including Pavlovian fear conditioning. To more precisely define the role of cholinergic modulation in this process, the effect of site-specific cholinergic antagonism was assessed. Male Long-Evans rats were implanted with chronic, bilateral cannulae aimed at the dorsal hippocampus. Infusions of scopolamine hydrobromide (50 microg bilaterally) or phosphate-buffered saline (PBS) were made immediately prior to a signaled Pavlovian fear conditioning procedure. On consecutive days following training, all rats were given independent tests assessing freezing to both the training context and the tone conditional stimulus (CS). Relative to PBS infused controls, rats that received intrahippocampal infusions of scopolamine showed a significant attenuation of contextual freezing but comparable levels of freezing to the tone CS. Neither shock sensitivity nor general activity levels differed between rats infused with scopolamine or PBS. These findings suggest that fear conditioning to context, but not discrete CS, requires intact cholinergic neurotransmission in the hippocampus.

  7. Does pre-exposure inhibit fear context conditioning? A Virtual Reality Study.

    PubMed

    Tröger, Christian; Ewald, Heike; Glotzbach, Evelyn; Pauli, Paul; Mühlberger, Andreas

    2012-06-01

    Several studies in animals and humans have indicated that familiarity toward cues reduces cue-conditioning effects. The influence of familiarity of a context on context conditioning has been confirmed in animal studies only. Thus, this study examined contextual fear conditioning in humans depending on pre-exposure to the to-be-conditioned context. To accomplish this, a virtual reality paradigm presented via a head mounted display was realized. During conditioning, participants were exposed to one of two office rooms (contexts), of which one became associated with aversive electric stimuli (UCS). 1 day before conditioning, participants were randomly exposed to either the later to-be-conditioned context (n = 20) or to an unrelated virtual environment (n = 20). Startle reflex, skin conductance response, heart rate, and ratings of valence, arousal, and anxiety were measured to assess context conditioning. Successful context conditioning was demonstrated for both ratings and physiological indicators. Pre-exposure did not prevent successful context conditioning. We conclude that in humans, contextual fear conditioning is not easily modified by pre-exposure to the context.

  8. 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…

  9. 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.

  10. Retrograde abolition of conditional fear after excitotoxic lesions in the basolateral amygdala of rats: absence of a temporal gradient.

    PubMed

    Maren, S; Aharonov, G; Fanselow, M S

    1996-08-01

    The role of the basolateral amygdala (LA) in the acquisition and expression of Pavlovian fear conditioning was examined in 80 rats. Excitotoxic lesions were made in the BLA using N-methyl-D-aspartate 7 days before or 1, 14, or 28 days after Pavlovian fear conditioning. Conditioning consisted of three pairings of a tone with an aversive footshock in a novel chamber, and freezing behavior served as an index of conditional fear. BLA lesions abolished conditional freezing to both the contextual and acoustic conditional stimuli at all training-to-lesion intervals, and the magnitude of the impairment did not vary as a function of the training-to-lesion interval. Reacquisition training elevated levels of freezing in rats with BLA lesions but did not reduce the magnitude of their deficit in relation to that of controls. These results reveal that neurons in the BLA have an enduring role in the expression of conditional fear.

  11. Effects of dopamine D1 modulation of the anterior cingulate cortex in a fear conditioning procedure.

    PubMed

    Pezze, M A; Marshall, H J; Domonkos, A; Cassaday, H J

    2016-02-04

    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 10s 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 (0.05μg/side) or D1 antagonist SCH23390 (0.5μg/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.

  12. 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

  13. Pavlovian Fear Conditioning Activates a Common Pattern of Neurons in the Lateral Amygdala of Individual Brains

    DTIC Science & Technology

    2011-01-12

    Janssen WG, Rodrigues SM, et al. (2007) Distribution of NMDA and AMPA receptor subunits at thalamo- amygdaloid dendritic spines. Brain Res 1134: 87–94. 7...central, but not other, amygdaloid nuclei prevents the acquisition of auditory fear conditioning. Learn Mem 8: 156–163. 28. Doron NN, Ledoux JE (1999...MJ, Goodchild MF, Longly PA (2009) Geospatial Analysis: Matador. 30. Sah P, Faber ES, Lopez De Armentia M, Power J (2003) The amygdaloid complex

  14. Role of Sleep Deprivation in Fear Conditioning and Extinction: Implications for Treatment of PTSD

    DTIC Science & Technology

    2013-10-01

    of the model is the impact on sleep . In animals, fear conditioning disrupts sleep , especially REM sleep . Sleep deprivation, in whole or just of REM ...was tested. We examined the effects of initial learning on REM sleep and whether REM sleep subsequent to learning facilitated memory consolidation of...threat and safety. Results showed increased safety learning was associated with increased consolidation of REM sleep the subsequent night. Increased

  15. Role of Sleep Deprivation in Fear Conditioning and Extinction: Implications for Treatment of PTSD

    DTIC Science & Technology

    2015-12-01

    safety learning , and sleep in humans. The Journal of Neuroscience , 34(35), 11754-11760. Fear conditioning is considered an animal model of...recall of extinction learning , and that the REM sleep stage is associated with ability to recall extinction as well as recall safety signal learning ...Drummond also conducted a number of media interviews related to the Journal of Neuroscience paper described below. In 2015 Ms. Straus has made national

  16. 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.

  17. AMYGDALA MICROCIRCUITS CONTROLLING LEARNED FEAR

    PubMed Central

    Duvarci, Sevil; Pare, Denis

    2014-01-01

    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. PMID:24908482

  18. Optimization of Ultrafilter Feed Conditions Using Classical Filtration Models

    SciTech Connect

    Geeting, John GH; Hallen, Richard T.; Peterson, Reid A.

    2005-11-15

    Two classical models were evaluated to assess their applicability to test data obtained from filtration of a High Level Waste Sludge sample from the Hanford tank farms. One model was then selected for use in evaluation of the optimal feed conditions for maximizing filter throughput for the proposed Waste Treatment Plant at the Hanford site. This analysis indicates that an optimal feed composition does exists, but that this optimal composition is different depending upon the product (permeate or retentate) that is to be maximized. A basic premise of the design for the WTP had been that evaporation of the feed to 5 M Na (or higher if possible) was required to achieve optimum throughput. However, these results indicate that optimum throughput from a filtration perspective is achieved at lower sodium molarities (either 3.22 M for maximum LAW throughput or 4.33 M for maximum HLW throughput).

  19. Venlafaxine facilitates between-session extinction and prevents reinstatement of auditory-cue conditioned fear.

    PubMed

    Yang, Cheng-Hao; Shi, Hai-Shui; Zhu, Wei-Li; Wu, Ping; Sun, Li-Li; Si, Ji-Jian; Liu, Meng-Meng; Zhang, Yan; Suo, Lin; Yang, Jian-Li

    2012-04-21

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

  20. Glutamate receptor antagonist infusions into the basolateral and medial amygdala reveal differential contributions to olfactory vs. context fear conditioning and expression

    PubMed Central

    Walker, David L.; Paschall, Gayla Y.; Davis, Michael

    2005-01-01

    The basolateral amygdala's involvement in fear acquisition and expression to visual and auditory stimuli is well known. The involvement of the basolateral and other amygdala areas in fear acquisition and expression to stimuli of other modalities is less certain. We evaluated the contribution of the basolateral and medial amygdala to olfactory and to context fear and fear conditioning by infusing into these areas the NMDA receptor antagonist AP5, the AMPA/kainate receptor antagonist NBQX, or vehicle prior to either odor-shock pairings or fear-potentiated startle testing. Pre-training AP5 infusions into the basolateral amygdala disrupted fear conditioning to the odor but not the context conditioned stimulus (CS). Pre-test NBQX infusions disrupted fear-potentiated startle to the odor but not context CS. Neither compound blocked fear conditioning when infused into the medial amygdala prior to training, but pre-test NBQX infusions did block fear-potentiated startle. The results confirm and extend recent findings suggesting a role for the basolateral amygdala in olfactory fear and fear conditioning, reveal an unexpected dissociation of the basolateral amygdala's involvement in discrete cue versus context fear and fear conditioning, and implicate for the first time the medial amygdala in fear-potentiated startle. PMID:15774945

  1. Factors regulating the effects of hippocampal inactivation on renewal of conditional fear after extinction.

    PubMed

    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 after extinction is related to the history of CS presentations in the context used for retrieval testing. We used infusions of muscimol to inactivate the dorsal hippocampus (DH) during postextinction retrieval tests that were conducted in contexts that differed in their history of CS presentations in that context. We found that DH inactivation affected the context-dependent retrieval of extinction (i.e., renewal) when testing occurred in a context that had no history of CS exposure, but not in a context that reliably predicted the CS. These results are discussed in terms of theories regarding the role of the hippocampus in contextual memory retrieval.

  2. Delay and trace fear conditioning in C57BL/6 and DBA/2 mice: issues of measurement and performance.

    PubMed

    Tipps, Megan E; Raybuck, Jonathan D; Buck, Kari J; Lattal, K Matthew

    2014-08-01

    Strain comparison studies have been critical to the identification of novel genetic and molecular mechanisms in learning and memory. However, even within a single learning paradigm, the behavioral data for the same strain can vary greatly, making it difficult to form meaningful conclusions at both the behavioral and cellular level. In fear conditioning, there is a high level of variability across reports, especially regarding responses to the conditioned stimulus (CS). Here, we compare C57BL/6 and DBA/2 mice using delay fear conditioning, trace fear conditioning, and a nonassociative condition. Our data highlight both the significant strain differences apparent in these fear conditioning paradigms and the significant differences in conditioning type within each strain. We then compare our data to an extensive literature review of delay and trace fear conditioning in these two strains. Finally, we apply a number of commonly used baseline normalization approaches to compare how they alter the reported differences. Our findings highlight three major sources of variability in the fear conditioning literature: CS duration, number of CS presentations, and data normalization to baseline measures.

  3. Fear Conditioning Potentiates Synaptic Transmission onto Long-Range Projection Neurons in the Lateral Subdivision of Central Amygdala

    PubMed Central

    Penzo, Mario A.; Robert, Vincent

    2014-01-01

    Recent studies indicate that the lateral subdivision of the central amygdala (CeL) is essential for fear learning. Specifically, fear conditioning induces cell-type-specific synaptic plasticity in CeL neurons that is required for the storage of fear memories. The CeL also controls fear expression by gating the activity of the medial subdivision of the central amygdala (CeM), the canonical amygdala output to areas that mediate defensive responses. In addition to the connection with CeM, the CeL sends long-range projections to innervate extra-amygdala areas. However, the long-range projection CeL neurons have not been well characterized, and their role in fear regulation is unknown. Here we show in mice that a subset of CeL neurons directly project to the midbrain periaqueductal gray (PAG) and the paraventricular nucleus of the thalamus, two brain areas implicated in defensive behavior. These long-range projection CeL neurons are predominantly somatostatin-positive (SOM+) neurons, which can directly inhibit PAG neurons, and some of which innervate both the PAG and paraventricular nucleus of the thalamus. Notably, fear conditioning potentiates excitatory synaptic transmission onto these long-range projection CeL neurons. Thus, our study identifies a subpopulation of SOM+ CeL neurons that may contribute to fear learning and regulate fear expression independent of CeM. PMID:24523533

  4. Fear conditioning potentiates synaptic transmission onto long-range projection neurons in the lateral subdivision of central amygdala.

    PubMed

    Penzo, Mario A; Robert, Vincent; Li, Bo

    2014-02-12

    Recent studies indicate that the lateral subdivision of the central amygdala (CeL) is essential for fear learning. Specifically, fear conditioning induces cell-type-specific synaptic plasticity in CeL neurons that is required for the storage of fear memories. The CeL also controls fear expression by gating the activity of the medial subdivision of the central amygdala (CeM), the canonical amygdala output to areas that mediate defensive responses. In addition to the connection with CeM, the CeL sends long-range projections to innervate extra-amygdala areas. However, the long-range projection CeL neurons have not been well characterized, and their role in fear regulation is unknown. Here we show in mice that a subset of CeL neurons directly project to the midbrain periaqueductal gray (PAG) and the paraventricular nucleus of the thalamus, two brain areas implicated in defensive behavior. These long-range projection CeL neurons are predominantly somatostatin-positive (SOM(+)) neurons, which can directly inhibit PAG neurons, and some of which innervate both the PAG and paraventricular nucleus of the thalamus. Notably, fear conditioning potentiates excitatory synaptic transmission onto these long-range projection CeL neurons. Thus, our study identifies a subpopulation of SOM(+) CeL neurons that may contribute to fear learning and regulate fear expression independent of CeM.

  5. Involvement of GluD2 in Fear-Conditioned Bradycardia in Mice

    PubMed Central

    Kotajima-Murakami, Hiroko; Narumi, Sakae; Yuzaki, Michisuke; Yanagihara, Dai

    2016-01-01

    Lesions in the cerebellar vermis abolish acquisition of fear-conditioned bradycardia in animals and human patients. The δ2 glutamate receptor (GluD2) is predominantly expressed in cerebellar Purkinje cells. The mouse mutant ho15J carries a spontaneous mutation in GluD2 and these mice show a primary deficiency in parallel fiber-Purkinje cell synapses, multiple innervations of Purkinje cells by climbing fibers, and impairment of long-term depression. In the present study, we used ho15J mice to investigate the role of the cerebellum in fear-conditioned bradycardia. We recorded changes in heart rate of ho15J mice induced by repeated pairing of an acoustic (conditioned) stimulus (CS) with an aversive (unconditioned) stimulus (US). The mice acquired conditioned bradycardia on Day 1 of the CS-US phase, similarly to wild-type mice. However, the magnitude of the conditioned bradycardia was not stable in the mutant mice, but rather was exaggerated on Days 2–5 of the CS-US phase. We examined the effects of reversibly inactivating the cerebellum by injection of an antagonist against the α-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptor (AMPAR). The antagonist abolished expression of conditioned responses in both wild-type and ho15J mice. We conclude that the GluD2 mutation in the ho15J mice affects stable retention of the acquired conditioned bradycardia. PMID:27820843

  6. Interoceptive awareness and unaware fear conditioning: are subliminal conditioning effects influenced by the manipulation of visceral self-perception?

    PubMed

    Raes, An K; De Raedt, Rudi

    2011-12-01

    Research has shown repeatedly that attention influences implicit learning effects. In a similar vein, interoceptive awareness might be involved in unaware fear conditioning: The fact that the CS is repeatedly presented in the context of aversive bodily experiences might facilitate the development of conditioned responding. We investigated the role of interoceptive attention in a subliminal conditioning paradigm. Conditioning was embedded in a spatial cueing task with subliminally presented cues that were followed by a masking stimulus. Response times to the targets that were either validly or invalidly predicted by the cues served as index of conditioning. Interoceptive attention was manipulated between-subjects. Half the participants completed a heartbeat detection task before conditioning. This task tunes attention to one's own bodily signals. We found that conditioned responding was facilitated in this latter group of participants. These results are in line with the hypothesis that a rise interoceptive attention enhances unaware conditioned responding.

  7. 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.

  8. Serotonergic modulation of plasticity of the auditory cortex elicited by fear conditioning.

    PubMed

    Ji, Weiqing; Suga, Nobuo

    2007-05-02

    In the awake big brown bat, 30 min auditory fear conditioning elicits conditioned heart rate decrease and long-term best frequency (BF) shifts of cortical auditory neurons toward the frequency of the conditioned tone; 15 min conditioning elicits subthreshold cortical BF shifts that can be augmented by acetylcholine. The fear conditioning causes stress and an increase in the cortical serotonin (5-HT) level. Serotonergic neurons in the raphe nuclei associated with stress and fear project to the cerebral cortex and cholinergic basal forebrain. Recently, it has been shown that 5-HT(2A) receptors are mostly expressed on pyramidal neurons and their activation improves learning and memory. We applied 5-HT, an agonist (alpha-methyl-5-HT), or an antagonist (ritanserin) of 5-HT(2A) receptors to the primary auditory cortex and discovered the following drug effects: (1) 5-HT had no effect on the conditioned heart rate change, although it reduced the auditory responses; (2) 4 mm 5-HT augmented the subthreshold BF shifts, whereas 20 mm 5-HT did not; (3) 20 mm 5-HT reduced the long-term BF shifts and changed them into short-term; (4) alpha-methyl-5-HT increased the auditory responses and augmented the subthreshold BF shifts as well as the long-term BF shifts; (5) in contrast, ritanserin reduced the auditory responses and reversed the direction of the BF shifts. Our data indicate that the BF shift can be modulated by serotonergic neurons that augment or reduce the BF shift or even reverse the direction of the BF shift. Therefore, not only the cholinergic system, but also the serotonergic system, plays an important role in cortical plasticity according to behavioral demands.

  9. Role of the amygdala GABA-A receptors in ACPA-induced deficits during conditioned fear learning.

    PubMed

    Nasehi, Mohammad; Roghani, Farnaz; Ebrahimi-Ghiri, Mohaddeseh; Zarrindast, Mohammad-Reza

    2017-04-04

    The basolateral amygdala (BLA) is a key structure for the emotional processing and storage of memories associated with emotional events, especially fear. On the other hand, endocannabinoids and CB1 receptors play a key role in learning and memory partly through long-term synaptic depression of GABAergic synapses in the BLA. The aim of this study was to explore the effects of GABA-A receptor agonist and antagonist in the fear-related memory acquisition deficits induced by ACPA (a selective CB1 cannabinoid receptor agonist). This study used context and tone fear conditioning paradigms to assess fear-related memory in male NMRI mice. Our results showed that the pre-training intraperitoneal administration of ACPA (0.5mg/kg) or (0.1 and 0.5mg/kg) decreased the percentage of freezing time in the contextual and tone fear conditioning, respectively. This indicated an impaired context- or tone-dependent fear memory acquisition. Moreover, the pre-training intra-BLA microinjection of GABA-A receptor agonist, muscimol, at 0.05 and 0.5μg/mouse impaired context-dependent fear memory, while the same doses of GABA-A antagonist, bicuculline, impaired tone-dependent fear memory. However, a subthreshold dose of muscimol or bicuculline increased the effect of ACPA at 0.1 and 0.5 or 0.05mg/kg on context- or tone-dependent fear memory, respectively. In addition, bicuculline at the lower dose increased the ACPA response on locomotor activity compared to its respective group. Such findings highlighted an interaction between BLA GABAergic and cannabinoidergic systems during the acquisition phase of conditioned fear memories.

  10. 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

  11. ERK activation in the amygdala and hippocampus induced by fear conditioning in ethanol withdrawn rats: modulation by MK-801.

    PubMed

    Bertotto, María Eugenia; Maldonado, Noelia Martina; Bignante, Elena Anahi; Gorosito, Silvana Vanesa; Cambiasso, María Julia; Molina, Víctor Alejandro; Martijena, Irene Delia

    2011-12-01

    The extracellular signal-regulated kinase (ERK) pathway, which can be activated by NMDA receptor stimulation, is involved in fear conditioning and drug addiction. We have previously shown that withdrawal from chronic ethanol administration facilitated the formation of contextual fear memory. In order to explore the neural substrates and the potential mechanism involved in this effect, we examined: 1) the ERK1/2 activation in the central (CeA) and basolateral (BLA) nuclei of the amygdala and in the dorsal hippocampus (dHip), 2) the effect of the NMDA receptor antagonist MK-801 on fear conditioning and ERK activation and 3) the effect of the infusion of U0126, a MEK inhibitor, into the BLA on fear memory formation in ethanol withdrawn rats. Rats made dependent via an ethanol-containing liquid diet were subjected to contextual fear conditioning on day 3 of ethanol withdrawal. High basal levels of p-ERK were found in CeA and dHip from ethanol withdrawn rats. ERK activation was significantly increased both in control (60min) and ethanol withdrawn rats (30 and 60min) in BLA after fear conditioning. Pre-training administration of MK-801, at a dose that had no effect on control rats, prevented the increase in ERK phosphorylation in BLA and attenuated the freezing response 24h later in ethanol withdrawn rats. Furthermore, the infusion of U0126 into the BLA, but not the CeA, before fear conditioning disrupted fear memory formation. These results suggest that the increased fear memory can be linked to changes in ERK phosphorylation, probably due to NMDA receptor activation in BLA in ethanol withdrawn rats.

  12. The conditioning of dyspneic suffocation fear. Effects of carbon dioxide concentration on behavioral freezing and analgesia.

    PubMed

    Mongeluzi, Donna L; Rosellini, Robert A; Ley, Ronald; Caldarone, Barbara J; Stock, Howard S

    2003-10-01

    Previous studies in our laboratory have shown that a single exposure to 100% carbon dioxide (CO2) can serve as an effective unconditioned stimulus (US) in a Pavlovian aversive-context conditioning paradigm in rats. Although the US exposure parameters employed in the initial studies were sufficient for producing a context-specific enhancement of behavioral freezing and analgesia, it had yet to be determined whether variations of these CO2 conditioning procedures would produce other conditioning effects. Thus, the purpose of the following experiment was to investigate the intensity of the US on the conditioned response (CR). The findings confirm that variations in CO2 concentrations produce changes in the CR that are consistent with principles of Pavlovian conditioning. The findings lend additional support to the tenability of a dyspneic suffocation fear theory of panic disorder, a theory that postulates that at least one type of panic attack could be a consequence of Pavlovian conditioning.

  13. Odor Fear Conditioning Modifies Piriform Cortex Local Field Potentials Both during Conditioning and during Post-Conditioning Sleep

    PubMed Central

    Barnes, Dylan C.; Chapuis, Julie; Chaudhury, Dipesh; Wilson, Donald A.

    2011-01-01

    Background Sleep plays an active role in memory consolidation. Sleep structure (REM/Slow wave activity [SWS]) can be modified after learning, and in some cortical circuits, sleep is associated with replay of the learned experience. While the majority of this work has focused on neocortical and hippocampal circuits, the olfactory system may offer unique advantages as a model system for exploring sleep and memory, given the short, non-thalamic pathway from nose to primary olfactory (piriform cortex), and rapid cortex-dependent odor learning. Methodology/Principal Findings We examined piriform cortical odor responses using local field potentials (LFPs) from freely behaving Long-Evans hooded rats over the sleep-wake cycle, and the neuronal modifications that occurred within the piriform cortex both during and after odor-fear conditioning. We also recorded LFPs from naïve animals to characterize sleep activity in the piriform cortex and to analyze transient odor-evoked cortical responses during different sleep stages. Naïve rats in their home cages spent 40% of their time in SWS, during which the piriform cortex was significantly hypo-responsive to odor stimulation compared to awake and REM sleep states. Rats trained in the paired odor-shock conditioning paradigm developed enhanced conditioned odor evoked gamma frequency activity in the piriform cortex over the course of training compared to pseudo-conditioned rats. Furthermore, conditioned rats spent significantly more time in SWS immediately post-training both compared to pre-training days and compared to pseudo-conditioned rats. The increase in SWS immediately after training significantly correlated with the duration of odor-evoked freezing the following day. Conclusions/Significance The rat piriform cortex is hypo-responsive to odors during SWS which accounts for nearly 40% of each 24 hour period. The duration of slow-wave activity in the piriform cortex is enhanced immediately post-conditioning, and this increase

  14. 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

  15. Extinguished second-order conditioned fear responses are renewed but not reinstated.

    PubMed

    Holmes, Nathan M; Cai, Stefanie Yuxuan; Lay, Belinda Po Pyn; Watts, Nicola R; Westbrook, R Frederick

    2014-10-01

    A series of experiments used rats to examine renewal and reinstatement of extinguished second-order conditioned fear (freezing) responses. The initial experiment demonstrated that freezing responses to a stimulus (S2) were contingent on its pairings with a second stimulus (S1) and on the prior pairings of S1 and an aversive unconditioned stimulus (US). Subsequent experiments showed that these freezing responses extinguished across S2 alone presentations, but were renewed when: S2-S1 pairings and S2 alone presentations occurred in the same context and testing of S2 occurred elsewhere; S2-S1 pairings and testing were in the same context and S2 alone presentations were elsewhere; and when S2-S1 pairings, S2 alone presentations and testing occurred in different contexts. Freezing responses to an extinguished S1 were reinstated by US alone presentations. However, these responses were not reinstated to an extinguished S2 by US or S1 alone presentations, and, conversely, freezing to a nonextinguished S2 was unaffected by extinction of S1. The results were interpreted to mean that S2-S1 pairings produced an association between S2 and the fear responses elicited by S1 and that extinction of this association is controlled by context. The failure to reinstate fear responses to S2 is discussed in terms of theories developed to explain reinstatement of S1.

  16. Neurotoxic basolateral amygdala lesions impair learning and memory but not the performance of conditional fear in rats.

    PubMed

    Maren, S

    1999-10-01

    We examined the influence of extensive overtraining (75 trials) on the impact of neurotoxic basolateral amygdala (BLA) lesions on Pavlovian fear conditioning in rats. As we have shown previously, pretraining BLA lesions yielded severe deficits in the acquisition of conditional freezing in rats trained with either 1 or 25 conditioning trials. However, extensive overtraining (50 or 75 trials) mitigated deficits in conditional freezing. Under these conditions the rats with BLA lesions expressed normal and robust freezing behavior, although they required at least 10 times as much training as control rats to reach this level of performance. The ability of rats with BLA lesions to acquire and express conditional freezing after extensive overtraining was modality-specific; conditional freezing in individual rats was acquired to contextual, but not acoustic, conditional stimuli. These results suggest that neural circuitry outside of the amygdala can mediate contextual fear conditioning under some conditions. In contrast to pretraining lesions, post-training BLA lesions eradicated the memory for Pavlovian fear in rats trained with either 1 or 75 trials; this deficit was not modality-specific. Together, these results reveal that impairments in the acquisition and expression of conditional fear in rats with BLA lesions are not attributable to deficits in the performance of the freezing response but are attributable to disruptions in the learning and memory of Pavlovian fear conditioning.

  17. 5-HT7 receptor-mediated fear conditioning and possible involvement of extracellular signal-regulated kinase.

    PubMed

    Takeda, Kotaro; Tsuji, Minoru; Miyagawa, Kazuya; Takeda, Hiroshi

    2017-01-18

    Fear conditioning is a valuable behavioral paradigm for studying the neural basis of emotional learning and memory. The present study examined the involvement of extracellular signal-regulated kinase 1/2 (ERK) signaling on the serotonin (5-HT)7 receptor-mediated fear conditioning. Conditioning was performed in a trial in which a tone was followed by an electrical foot-shock. Context- and tone-dependent fear were examined in tests conducted 24 and 48h after conditioning, respectively. The selective 5-HT7 receptor antagonist 2a-[4-(4-phenyl-1,2,3,6-tetrahydropyridyl)butyl]-2a,3,4,-tetrahydrobenzo(c,d)indol-2-(1H)-one (DR4004) (5mg/kg), when administered intraperitoneally (i.p.) immediately after conditioning, caused a significant decrease in both context- and tone-dependent fear responses (freezing behavior). A significant increase in ERK activity was observed in the amygdala of mice that displayed context- or tone-dependent fear responses, and these changes were also inhibited by the administration of DR4004 (5mg/kg, i.p.) immediately after conditioning. In contrast, the increase in hippocampal ERK activity in mice that displayed context-dependent fear responses was further enhanced by the administration of DR4004 (5mg/kg, i.p.). These results suggest that 5-HT7 receptor-mediated ERK signaling may play a significant role in the processes of emotional learning and memory.

  18. 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…

  19. 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.…

  20. Eyeblink Classical Conditioning in Alcoholism and Fetal Alcohol Spectrum Disorders

    PubMed Central

    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. PMID:26578987

  1. Extinction of a classically conditioned response: red nucleus and interpositus.

    PubMed

    Robleto, Karla; Thompson, Richard F

    2008-03-05

    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.

  2. 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.

  3. Differential roles of the basolateral amygdala and nucleus basalis magnocellularis during post-reactivation contextual fear conditioning reconsolidation in rats.

    PubMed

    Baldi, Elisabetta; Mariottini, Chiara; Bucherelli, Corrado

    2008-11-01

    The roles of the basolateral amygdala and nucleus basalis magnocellularis in fear conditioning reconsolidation were investigated by means of tetrodotoxin bilateral inactivation performed 96 h after conditioning, immediately after reactivation training. Footshocks of 1.2 mA intensity were employed to induce the generalization phenomenon. Basolateral amygdala inactivation disrupts the contextual fear response and its generalization but not acoustic CS trace retention, when measured 72 and 96 h after tetrodotoxin administration. Nucleus basalis magnocellularis functional inactivation does not affect memory post-reactivation phase of any of the three conditioned fear responses. The present findings show a differential role of the two structures in fear memory reconsolidation and can be a starting point for future investigation of the neural circuits subserving generalization.

  4. A bout of voluntary running enhances context conditioned fear, its extinction, and its reconsolidation

    PubMed Central

    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 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. PMID:24429425

  5. A bout of voluntary running enhances context conditioned fear, its extinction, and its reconsolidation.

    PubMed

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

    2014-01-15

    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.

  6. Fimbria-fornix and entorhinal cortex differential contribution to contextual and cued fear conditioning consolidation in rats.

    PubMed

    Baldi, Elisabetta; Liuzzo, Antonino; Bucherelli, Corrado

    2013-04-10

    The Fimbria-Fornix (FF) and Entorhinal Cortex (EC) are the primary interfaces between the hippocampus and, respectively, subcortical structures and cortical areas. Their mnemonic role has been repeatedly proposed. In order to investigate their role in fear conditioning, FF and EC were subjected to bilateral fully reversible tetrodotoxin (TTX) inactivation during consolidation in adult male Wistar rats that had undergone training for fear conditioning to an acoustic stimulus (CS) and context. TTX was stereotaxically injected into animals of different groups at increasing post-acquisition delays. Memory was assessed as conditioned freezing duration measured during retention testing, performed 72 and 96 h after TTX administration in a counterbalanced manner. The results showed that FF inactivation, performed immediately after conditioning, did not disrupt consolidation of either contextual or auditory fear memory. On the contrary, EC inactivation performed at the same time was followed by both contextual and CS fear response retention impairment. EC inactivation performed 1.5h post-acquisition impaired only contextual fear response retention. EC inactivation performed 24h after acquisition training had no effect on the consolidation process. The present findings show a clearly different role of FF and EC in fear conditioning consolidation in the rat. The results are discussed in relation to their known connections with the hippocampus.

  7. Compensation in the neural circuitry of fear conditioning awakens learning circuits in the bed nuclei of the stria terminalis.

    PubMed

    Poulos, Andrew M; Ponnusamy, Ravikumar; Dong, Hong-Wei; Fanselow, Michael S

    2010-08-17

    The basolateral amygdala (BLA) is thought to be essential for fear learning. However, extensive training can overcome the loss of conditional fear evident following lesions and inactivation of the BLA. Such results suggest the existence of a primary BLA-dependent and a compensatory BLA-independent neural circuit. We tested the hypothesis that the bed nuclei of the stria terminalis (BST) provides this compensatory plasticity. Using extensive context-fear conditioning, we demonstrate that combined BLA and BST lesions prevented fear acquisition and expression. Additionally, protein synthesis in the BST was critical only for consolidation of BLA-independent but not BLA-dependent fear. Moreover, fear acquired after BLA lesions resulted in greater activation of BST regions that receive hippocampal efferents. These results suggest that the BST is capable of functioning as a compensatory site in the acquisition and consolidation of context-fear memories. Unlocking such neural compensation holds promise for understanding situations when brain damage impairs normal function or failure to regulate compensatory sites leads to anxiety disorders.

  8. Conditioned Fear Extinction and Generalization in Post-Traumatic Stress Disorder

    DTIC Science & Technology

    2012-08-01

    ORGANIZATION: Emory University Atlanta, GA 30322-1018 REPORT DATE: August 2012 TYPE OF REPORT: Annual Report PREPARED FOR: U.S...To) 1 August 2011–31 July 2012 4. TITLE AND SUBTITLE Conditioned Fear Extinction and Generalization in Post-Traumatic Stress Disorder...TT   100   RS4606   RGS2   CC   109   CG   88   GG   28   RS4680   COMT   AA   44   GA   99   GG   83   RS4875113

  9. 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.

  10. Sex differences in contextual fear conditioning are associated with differential ventral hippocampal extracellular signal-regulated kinase activation.

    PubMed

    Gresack, J E; Schafe, G E; Orr, P T; Frick, K M

    2009-03-17

    Although sex differences have been reported in hippocampal-dependent learning and memory, including contextual fear memories, the underlying molecular mechanisms contributing to such differences are not well understood. The present study examined the extent to which sex differences in contextual fear conditioning are related to differential activation of the extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK), a protein kinase critically involved in memory formation. We first show that male rats exhibit more long-term retention of contextual fear conditioning than female rats. During a tone test, females spent more time freezing than males, although both sexes exhibited robust retention of auditory fear learning. Using Western blot analysis, we then show that phosphorylated ERK levels in ventral, but not dorsal, hippocampus are higher in males than females, relative to same-sex controls, 60 minutes after fear conditioning. Post-conditioning increases in ERK activation were observed in the amygdala in both males and females, suggesting a selective effect of sex on hippocampal ERK activation. Together, these findings suggest that differential activation of the ERK signal transduction pathway in male and female rats, particularly in the ventral hippocampus, is associated with sex differences in contextual fear.

  11. 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.

  12. Differential contribution of dorsal and ventral hippocampus to trace and delay fear conditioning.

    PubMed

    Esclassan, Frederic; Coutureau, Etienne; Di Scala, Georges; Marchand, Alain R

    2009-01-01

    Trace conditioning relies on the maintained representation of a stimulus across a trace interval, and may involve a persistent trace of the conditioned stimulus (CS) and/or a contribution of contextual conditioning. The role of hippocampal structures in these two types of conditioning was studied by means of pretraining lesions and reversible inactivation of the hippocampus in rats. Similar levels of conditioning to a tone CS and to the context were obtained with a trace interval of 30 s. Neurotoxic lesions of the whole hippocampus or reversible muscimol inactivation of the ventral hippocampus impaired both contextual and tone freezing in both trace- and delay-conditioned rats. Dorsal hippocampal injections impaired contextual freezing and trace conditioning, but not delay conditioning. No dissociation between trace and contextual conditioning was observed under any of these conditions. Altogether, these data indicate that the ventral and dorsal parts of the hippocampus compute different aspects of trace conditioning, with the ventral hippocampus being involved in fear and anxiety processes, and the dorsal hippocampus in the temporal and contextual aspects of event representation.

  13. Pavlovian conditional vocalizations of the rat: a model system for analyzing the fear of pain.

    PubMed

    Borszcz, G S

    1995-08-01

    Presentation of a 6-s light conditional stimulus (CS) that overlapped with a 1-s tailshock unconditional stimulus (US) generated audible conditional vocalization responses (VCRs) during the CS period. The rate of conditioning was observed to be directly related to the intensity of the tailshock US (0.15 mA-0.80 mA). The amplitude, duration, and number of VCRs was also directly related to US intensity, whereas the latency of VCRs from CS onset was inversely related to US intensity. VCRs were not observed in rats given explicitly unpaired presentations of CS and US (0.80 mA). The capacity of tailshock to support development of VCRs was found to depend on its capacity to elicit vocalization afterdischarges (VADs). Sonographic analysis of vocalizations revealed that VCRs and VADs share spectrographic characteristics. Results are discussed in terms of VCRs' providing a model system for analyzing the fear of pain and its suppression.

  14. 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.

  15. 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

  16. Conditioned fear to context is associated with increased Fos expression in the caudal ventrolateral region of the midbrain periaqueductal gray.

    PubMed

    Carrive, P; Leung, P; Harris, J; Paxinos, G

    1997-05-01

    Immunohistochemical detection of Fos was used to determine which regions of the periaqueductal gray are activated during conditioned fear to a context in the rat. More specifically, the aim of the study was to test the role of its lateral and ventrolateral columns in freezing behaviour during fear. Conditioned fear was evoked by re-exposing rats to the same footshock chamber in which they had received footshocks 4 h earlier. Conditioned Re-exposed rats were compared to Not Conditioned Re-exposed and Conditioned Not Re-exposed rats. Freezing was observed in the Conditioned-Re-exposed group only. It was associated with an overall increase in Fos expression in the entire periaqueductal gray that was significantly greater than in the two other groups. The largest and most significant increase in Fos immunoreactivity was found in the ventrolateral column (especially in its caudal part), whereas only a moderate increase was found in the lateral column. The present results argue in favour of the ventrolateral column as the region of the periaqueductal gray that is preferentially involved in expression of conditioned fear. As previous lesion studies suggested, the ventrolateral periaqueductal gray may play a role in mediating the immobility component of freezing induced by fear. Other lines of evidence suggest that it may also play a role in mediating the quiescence immobility associated with deep pain. We propose that the ventrolateral column of the periaqueductal gray acts as an integrating centre mediating behavioural inhibition.

  17. 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

  18. 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…

  19. Divergent effects of brain interleukin-1ß in mediating fever, lethargy, anorexia and conditioned fear memory.

    PubMed

    Baartman, Tamzyn L; Swanepoel, Tanya; Barrientos, Ruth M; Laburn, Helen P; Mitchell, Duncan; Harden, Lois M

    2017-05-01

    The influence of brain interleukin-1 (IL-1ß) on memory processes includes both detrimental and beneficial effects. To further explore the dynamics of brain IL-1ß in mediating learning and memory during acute sickness, we injected species-homologous rat IL-1ß (100ng/5μl) or vehicle (0.1% bovine serum albumin, 5μl) directly into the cisterna magna (i.c.m.) of male Sprague-Dawley rats. We measured, in parallel, body temperature, food intake, body mass, cage activity, as well as learning and memory using contextual fear conditioning. To investigate the effects of IL-1ß on learning and memory processes we used: (1) a retrograde experiment that involved injecting rats i.c.m. with IL-1ß immediately after training in the novel context, and (2) an anterograde experiment that involved injecting rats i.c.m. with IL-1ß two hours before training in the novel context. In addition, hypothalamic and hippocampal concentrations of IL-1β were measured at several time points following injection. Administration of IL-1ß induced fever, lethargy and anorexia for∼two-to-three days and increased the concentration of IL-1ß in the hippocampus and hypothalamus for at least eight hours. Training in the context immediately before IL-1ß administration (retrograde experiment), did not impair contextual and auditory fear memory. However, when training in the context occurred concurrently with elevated hippocampal IL-1ß levels, two hours after IL-1ß administration (anterograde experiment), contextual, but not auditory, fear memory was impaired. Our results show that there are instances where memory consolidation can occur concurrently with elevated levels of IL-1ß in the hippocampus, fever, anorexia and lethargy during acute short-term sickness.

  20. 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…

  1. Investigating the impact of sex and cortisol on implicit fear conditioning with fMRI.

    PubMed

    Merz, Christian J; Tabbert, Katharina; Schweckendiek, Jan; Klucken, Tim; Vaitl, Dieter; Stark, Rudolf; Wolf, Oliver T

    2010-01-01

    Fear conditioning is influenced by stress but opposing effects in males and females have often been reported. In a previous human functional magnetic resonance imaging (fMRI) study, we observed acute effects of the stress hormone cortisol on prefrontal structures. Men showed evidence for impaired fear conditioning after cortisol treatment, while the opposite pattern was found for women. In the current experiment, we tested whether similar sex-dependent effects would occur on the neural level if contingency awareness was prevented experimentally to investigate implicit learning processes. A differential fear conditioning experiment with transcutaneous electrical stimulation as unconditioned stimulus and geometric figures as conditioned stimuli (CS) was conducted. One figure was always paired (CS+), whereas the other (CS-) was never paired with the UCS. Thirty-nine (19 female) subjects participated in this fMRI study, receiving either placebo or 30 mg cortisol (hydrocortisone) before conditioning. Dependent variables were skin conductance responses (SCRs) and neural activity (BOLD signal). In line with prior findings in unaware participants, no differential learning could be observed for the SCRs. However, a sex x cortisol interaction was detected with a reduced mean response to the CS after cortisol treatment in men, while the opposite pattern was observed in women (enhanced mean SCR under cortisol). In the contrast CS+ minus CS-, neural activity showed a sex x cortisol interaction in the insula and further trends in the hippocampus and the thalamus. In these regions, cortisol reduced the CS+/CS- differentiation in men but enhanced it in women. In contrast to these sex specific effects, differential amygdala activation was found in the placebo group but not in the cortisol group, irrespective of sex. Further, differential neural activity in the amygdala and thalamus were positively correlated with the SCRs in the placebo group only. The present study in contingency

  2. Using the conditioned fear stress (CFS) animal model to understand the neurobiological mechanisms and pharmacological treatment of anxiety

    PubMed Central

    Li, Xiaobai

    2012-01-01

    Summary The mechanisms underlying the etiology and pathophysiology of anxiety disorders — the most prevalent class of mental disorders — remain unclear. Over the last 30 years investigators have used the animal model of conditioned fear stress (CFS) to investigate the brain structures and neurotransmitter systems involved in aversive emotional learning and memory. Recent studies have focused on the neuronal circuitry and cellular mechanisms of fearful emotional experiences. This review describes the CFS paradigm, discusses the neural circuit and neurotransmission underlying CFS, and explains the mechanism of action of pharmacological treatments of CFS. The focus of the review is on the molecular mechanisms of fear extinction, a phenomenon directly implicated in the clinical treatment of anxiety. Based on our assessment of previous work we will conclude by considering potential molecular targets for treating symptoms of anxiety and fear. PMID:25328347

  3. 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

  4. 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.

  5. 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.

  6. 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.

  7. Genome-wide association for fear conditioning in an advanced intercross mouse line.

    PubMed

    Parker, Clarissa C; Sokoloff, Greta; Cheng, Riyan; Palmer, Abraham A

    2012-05-01

    Fear conditioning (FC) may provide a useful model for some components of post-traumatic stress disorder (PTSD). We used a C57BL/6J × DBA/2J F(2) intercross (n = 620) and a C57BL/6J × DBA/2J F(8) advanced intercross line (n = 567) to fine-map quantitative trait loci (QTL) associated with FC. We conducted an integrated genome-wide association analysis in QTLRel and identified five highly significant QTL affecting freezing to context as well as four highly significant QTL associated with freezing to cue. The average percent decrease in QTL width between the F(2) and the integrated analysis was 59.2%. Next, we exploited bioinformatic sequence and expression data to identify candidate genes based on the existence of non-synonymous coding polymorphisms and/or expression QTLs. We identified numerous candidate genes that have been previously implicated in either fear learning in animal models (Bcl2, Btg2, Dbi, Gabr1b, Lypd1, Pam and Rgs14) or PTSD in humans (Gabra2, Oprm1 and Trkb); other identified genes may represent novel findings. The integration of F(2) and AIL data maintains the advantages of studying FC in model organisms while significantly improving resolution over previous approaches.

  8. Proteins linked to extinction in contextual fear conditioning in the C57BL/6J mouse.

    PubMed

    Li, Lin; Boddul, Sanjay V; Patil, Sudarshan S; Zheng, Jun-Fang; An, Gunyong; Höger, Harald; Lubec, Gert

    2011-09-01

    Studying fear extinction is a major topic in neuroscience. No information on systematic studies on the linkage of contextual fear conditioning (cFC) with hippocampal protein levels is available and we were therefore interested in protein differences between animals with poor and good extinction. cFC was carried out in C57BL/6J mice, hippocampi were taken and proteins were run on two-dimensional gel electrophoresis with subsequent quantification of protein spots. In-gel digestion with trypsin and identification by ion trap MS/MS (high-capacity ion trap) was used for the identification of significantly different hippocampal proteins between mice with good and poor performance of extinction. Signaling protein ras-related protein rab-7A and septin 8 levels were significantly higher in hippocampus of poor extinguishers, whereas ubiquitin carboxyterminal hydrolase isozyme L1 showed higher levels in animals with good extinction performance. A series of additional proteins showed significantly different levels between groups but the abovementioned were confirmed by immunoblotting. The abovementioned proteins have never been reported to be linked to extinction, memory, or learning and herein evidence for the involvement of several proteins in extinction mechanism as well as probably representing pharmaceutical targets is provided. Moreover, it is intriguing to demonstrate the differences between good and poor extinction performance at the protein level.

  9. 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…

  10. The role of NCAM in auditory fear conditioning and its modulation by stress: a focus on the amygdala.

    PubMed

    Bisaz, R; Sandi, C

    2010-06-01

    Chronic stress in rodents was shown to induce structural shrinkage and functional alterations in the hippocampus that were linked to spatial memory impairments. Effects of chronic stress on the amygdala have been linked to a facilitation of fear conditioning. Although the underlying molecular mechanisms are still poorly understood, increasing evidence highlights the neural cell adhesion molecule (NCAM) as an important molecular mediator of stress-induced structural and functional alterations. In this study, we investigated whether altered NCAM expression levels in the amygdala might be related to stress-induced enhancement of auditory fear conditioning and anxiety-like behavior. In adult C57BL/6J wild-type mice, chronic unpredictable stress resulted in an isoform-specific increase of NCAM expression (NCAM-140 and NCAM-180) in the amygdala, as well as enhanced auditory fear conditioning and anxiety-like behavior. Strikingly, forebrain-specific conditional NCAM-deficient mice (NCAM-floxed mice that express the cre-recombinase under the control of the promoter of the alpha-subunit of the calcium-calmodulin-dependent protein kinase II), whose amygdala NCAM expression levels are reduced, displayed impaired auditory fear conditioning which was not altered following chronic stress exposure. Likewise, chronic stress in these conditional NCAM-deficient mice did not modify NCAM expression levels in the amygdala or hippocampus, while they showed enhanced anxiety-like behavior, questioning the involvement of NCAM in this type of behavior. Together, our results strongly support the involvement of NCAM in the amygdala in the consolidation of auditory fear conditioning and highlight increased NCAM expression in the amygdala among the mechanisms whereby stress facilitates fear conditioning processes.

  11. Differences in extinction of conditioned fear in C57BL/6 substrains are unrelated to expression of alpha-synuclein.

    PubMed

    Siegmund, Anja; Langnaese, Kristina; Wotjak, Carsten T

    2005-02-28

    C57BL/6 mice are commonly used as background strains for genetically modified mice, and little attention is usually paid to the notification of the specific substrain. However, it is known that C57BL/6NCrl (B6N) and C57BL/6JOlaHsd (B6JOla) mice differ in the course of extinction of conditioned fear (Stiedl O, Radulovic J, Lohmann R, Birkenfeld K, Palve M, Kammermeier J, et al. Strain and substrain differences in context- and tone-dependent fear conditioning of inbred mice. Behav Brain Res 1999;104:1-12), as well as in the expression of alpha-synuclein (Specht CG, Schoepfer R. Deletion of the alpha-synuclein locus in a subpopulation of C57BL/6J inbred mice. BMC Neurosci 2001;2:11). We tested for a causal relationship between the two findings by employing B6N (expressing alpha-synuclein), B6JOla (not expressing alpha-syn) and the third strain C57BL/6JCrl (B6Jax, expressing alpha-syn). We show that alpha-syn does not account for differences in extinction in a fear conditioning task, as its expression did not covary with the decrease of freezing on repeated non-reinforced tone and context exposure in the three strains: B6Jax exhibited fastest extinction followed by B6JOla. In contrast, B6N showed persistent fear over the course of extinction training. The differences in extinction between B6JOla and B6N were unrelated to sensorimotor processing (pain threshold and basal tone reaction) and innate fear (light-dark test). However, B6Jax displayed less innate fear than B6JOla and B6N. Our results of marked differences in innate and conditioned fear in three B6 substrains illustrate the necessity of a strict adherence to an exact mouse strain nomenclature.

  12. Facilitating actions of an AMPA receptor potentiator upon extinction of contextually conditioned fear response in stressed mice.

    PubMed

    Yamada, Daisuke; Wada, Keiji; Sekiguchi, Masayuki

    2011-01-25

    Extinction of conditioned fear response is thought to be a biological process underlying exposure therapy for anxiety disorders. We have previously reported that an AMPA receptor potentiator, 4-[2-(phenylsulfonylamino)ethylthio]-2,6-difluorophenoxyacetamide (PEPA), facilitates extinction of fear memory formed through contextual fear conditioning in mice that had never been exposed to experimental stress. On the other hand, recent findings suggest that the fear extinction is impaired in stressed rats or mice. The purpose of the present study was to examine whether PEPA facilitates impaired extinction of fear in stressed mice. For this purpose, mice were applied stress (a 2h restraint, a 20min forced swim, and ether inhalation), and contextual fear conditioning was carried out 7 days later. After 1-3 days of conditioning, mice were re-exposed to the context for 6min, and behavioral freezing response was measured. The time mice spent frozen decreased following every extinction session, and the decrease was remarkably slower in the stressed mice than in control non-stressed mice. PEPA (3, 10, 30mg/kg body weight) or vehicle was intraperitoneally administered into stressed mice once before the first extinction session. The significant decrease of the freezing response in the extinction sessions was only seen in the 30mg/kg PEPA-administered stressed mice, compared with vehicle-administered stressed mice. A similar extent of decrease in the freezing response in the extinction sessions was observed in the PEPA-administered (30mg/kg) and d-cycloserine-administered (30mg/kg) mice. These results suggest that PEPA facilitates extinction of contextual fear in stressed mice.

  13. 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.

  14. 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

  15. Exposure to a novel context after extinction causes a renewal of extinguished conditioned responses: implications for the treatment of fear.

    PubMed

    Neumann, David L; Kitlertsirivatana, Edward

    2010-06-01

    Renewal gives an experimental model for the relapse of fear symptoms following exposure therapy. While renewal of extinguished fear in humans has been observed following a return to the original context in which fear was acquired (ABA design), it has been more difficult to show upon presentation of a novel context (ABC design). The present experiment used a particularly strong context manipulation in a fear conditioning procedure. Context was manipulated by using large photographs of real environments taken from various angles and was present throughout the entire experiment. A renewal of cognitive expectancy was found in both ABA and ABC renewal designs, although it was larger in the former than in the latter. Response times in making the expectancy judgments increased when there was a change to a new context. The results demonstrate consistency in fear renewal effects between human and animal studies and suggest that relapse following exposure therapy via renewal remains a danger when people encounter a previously feared object in a novel context.

  16. 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.

  17. 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…

  18. 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

  19. Corticosteroid-endocannabinoid loop supports decrease of fear-conditioned response in rats.

    PubMed

    Bitencourt, R M; Pamplona, F A; Takahashi, R N

    2014-07-01

    The endocannabinoid (eCB) and glucocorticoid systems contribute to the modulation of emotional states. Noteworthy, glucocorticoid hormones are released by adrenal glands during stressful events and endocannabinoids are released in the brain during fear-conditioned responses. Since it was already suggested that glucocorticoids may trigger the release of endocannabinoids in the brain, our objective was to investigate whether the interaction between these neuromodulatory systems contributes to the decrease of conditioned freezing behavior over successive 9-min exposures to the conditioning context. Present results suggest a bidirectional interdependence between glucocorticoid and endocannabinoid systems. CB1 receptors blockade prevents glucocorticoid-induced facilitation of conditioned freezing decrease and inhibition of glucocorticoid synthesis renders boosting of endocannabinoid signaling innocuous, while preserving the efficacy of direct CB1 receptors activation by an exogenous cannabinoid agonist. This suggests that CB1 receptors are somehow "downstream" to glucocorticoid release, which in its turn, is reduced by CB1 activation, contributing to the persistent reduction of conditioned freezing responses.

  20. The GABAB receptor positive modulator BHF177 attenuated anxiety, but not conditioned fear, in rats

    PubMed Central

    Li, Xia; Kaczanowska, Katarzyna; Finn, M. G.; Markou, Athina; Risbrough, Victoria B.

    2015-01-01

    GABAB (γ-aminobutyric acid B) receptors may be a therapeutic target for anxiety disorders. Here we characterized the effects of the GABAB receptor positive allosteric modulator (PAM) BHF177 on conditioned and unconditioned physiological responses to threat in the light-enhanced startle (LES), stress-induced hyperthermia, and fear-potentiated startle (FPS) procedures in rats. The effects of BHF177 on LES were compared with those of the GABAB receptor agonists baclofen and CGP44532, and the positive control buspirone, a 5-HT1A receptor partial agonist with anxiolytic activity in humans. Baclofen (0.4, 0.9 and 1.25 mg/kg) and CGP44532 (0.065, 0.125 and 0.25 mg/kg) administration had significant sedative, but not anxiolytic, activity reflected in overall decrease in the startle response in the LES tests. BHF177 (10, 20 and 40 mg/kg) had no effect on LES, nor did it produce an overall sedative effect. Interesting, however, when rats were grouped by high and low LES responses, BHF177 had anxiolytic-like effects only on LES in high, but not low, LES responding rats. BHF177 also blocked stress-induced hyperthermia, but had no effect on conditioned fear responses in the FPS test. Buspirone (1 and 3 mg/kg) had an anxiolytic-like profile in both LES and FPS tests. These results indicate that BHF177 may specifically attenuate unconditioned anxiety in individuals that exhibit a high anxiety state, and has fewer sedative effects than direct agonists. Thus, BHF177 or other GABAB receptor PAMs may be promising compounds for alleviating increased anxiety seen in various psychiatric disorders with a superior side-effect profile compared to GABAB receptor agonists. PMID:26002628

  1. Dietary-induced obesity disrupts trace fear conditioning and decreases hippocampal reelin expression.

    PubMed

    Reichelt, Amy C; Maniam, Jayanthi; Westbrook, R Frederick; Morris, Margaret J

    2015-01-01

    Both obesity and over-consumption of palatable high fat/high sugar "cafeteria" diets in rats has been shown to induce cognitive deficits in executive function, attention and spatial memory. Adult male Sprague-Dawley rats were fed a diet that supplemented standard lab chow with a range of palatable foods eaten by people for 8 weeks, or regular lab chow. Memory was assessed using a trace fear conditioning procedure, whereby a conditioned stimulus (CS) is presented for 10s and then 30s after its termination a foot shock (US) is delivered. We assessed freezing to the CS (flashing light) in a neutral context, and freezing in the context associated with footshock. A dissociation was observed between levels of freezing in the context and to the CS associated with footshock. Cafeteria diet fed rats froze less than control chow fed rats in the context associated with footshock (P<0.01), indicating that encoding of a hippocampus-dependent context representation was impaired in these rats. Conversely, cafeteria diet fed rats froze more (P<0.05) to the CS than chow fed rats, suggesting that when hippocampal function was compromised the cue was the best predictor of footshock, as contextual information was not encoded. Dorsal hippocampal mRNA expression of inflammatory and neuroplasticity markers was analysed at the end of the experiment, 10 weeks of diet. Of these, mRNA expression of reelin, which is known to be important in long term potentiation and neuronal plasticity, was significantly reduced in cafeteria diet fed rats (P=0.003). This implicates reductions in hippocampal plasticity in the contextual fear memory deficits seen in the cafeteria diet fed rats.

  2. Fear conditioning leads to alteration in specific genes expression in cortical and thalamic neurons that project to the lateral amygdala.

    PubMed

    Katz, Ira K; Lamprecht, Raphael

    2015-02-01

    RNA transcription is needed for memory formation. However, the ability to identify genes whose expression is altered by learning is greatly impaired because of methodological difficulties in profiling gene expression in specific neurons involved in memory formation. Here, we report a novel approach to monitor the expression of genes after learning in neurons in specific brain pathways needed for memory formation. In this study, we aimed to monitor gene expression after fear learning. We retrogradely labeled discrete thalamic neurons that project to the lateral amygdala (LA) of rats. The labeled neurons were dissected, using laser microdissection microscopy, after fear conditioning learning or unpaired training. The RNAs from the dissected neurons were subjected to microarray analysis. The levels of selected RNAs detected by the microarray analysis to be altered by fear conditioning were also assessed by nanostring analysis. We observed that the expression of genes involved in the regulation of translation, maturation and degradation of proteins was increased 6 h after fear conditioning compared to unpaired or naïve trained rats. These genes were not expressed 24 h after training or in cortical neurons that project to the LA. The expression of genes involved in transcription regulation and neuronal development was altered after fear conditioning learning in the cortical-LA pathway. The present study provides key information on the identity of genes expressed in discrete thalamic and cortical neurons that project to the LA after fear conditioning. Such an approach could also serve to identify gene products as targets for the development of a new generation of therapeutic agents that could be aimed to functionally identified brain circuits to treat memory-related disorders.

  3. Increased skin conductance responses and neural activity during fear conditioning are associated with a repressive coping style

    PubMed Central

    Klucken, Tim; Kruse, Onno; Schweckendiek, Jan; Stark, Rudolf

    2015-01-01

    The investigation of individual differences in coping styles in response to fear conditioning is an important issue for a better understanding of the etiology and treatment of psychiatric disorders. It has been assumed that an avoidant (repressive) coping style is characterized by increased emotion regulation efforts in context of fear stimuli as compared to a more vigilant coping style. However, no study so far has investigated the neural correlates of fear conditioning of repressors and sensitizers. In the present fMRI study, 76 participants were classified as repressors or as sensitizers and were exposed to a fear conditioning paradigm, in which the CS+ predicted electrical stimulation, while another neutral stimulus (CS−) did not. In addition, skin conductance responses (SCRs) were measured continuously. As the main findings, we found increased neural activity in repressors as compared to sensitizers in the ventromedial prefrontal cortex and the anterior cingulate cortex (ACC) during fear conditioning. In addition, elevated activity to the CS+ in amygdala, insula, occipital, and orbitofrontal cortex (OFC) as well as elevated conditioned SCRs were found in repressors. The present results demonstrate increased neural activations in structures linked to emotion down-regulation mechanisms like the ventromedial prefrontal cortex, which may reflect the increased coping effort in repressors. At the same time, repressors showed increased activations in arousal and evaluation-associated structures like the amygdala, the occipital cortex (OCC), and the OFC, which was mirrored in increased SCRs. The present results support recent assumptions about a two-process model of repression postulating a fast vigilant response to fear stimuli, and a second process associated with the down-regulation of emotional responses. PMID:26082695

  4. Hemodynamic responses in amygdala and hippocampus distinguish between aversive and neutral cues during Pavlovian fear conditioning in behaving rats

    PubMed Central

    McHugh, Stephen B; Marques-Smith, Andre; Li, Jennifer; Rawlins, J N P; Lowry, John; Conway, Michael; Gilmour, Gary; Tricklebank, Mark; Bannerman, David M

    2013-01-01

    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. PMID:23173719

  5. Infant rats can learn time intervals before the maturation of the striatum: evidence from odor fear conditioning

    PubMed Central

    Boulanger Bertolus, Julie; Hegoburu, Chloe; Ahers, Jessica L.; Londen, Elizabeth; Rousselot, Juliette; Szyba, Karina; Thévenet, Marc; Sullivan-Wilson, Tristan A.; Doyère, Valérie; Sullivan, Regina M.; Mouly, Anne-Marie

    2014-01-01

    Interval timing refers to the ability to perceive, estimate and discriminate durations in the range of seconds to minutes. Very little is currently known about the ontogeny of interval timing throughout development. On the other hand, even though the neural circuit sustaining interval timing is a matter of debate, the striatum has been suggested to be an important component of the system and its maturation occurs around the third post-natal (PN) week in rats. The global aim of the present study was to investigate interval timing abilities at an age for which striatum is not yet mature. We used odor fear conditioning, as it can be applied to very young animals. In odor fear conditioning, an odor is presented to the animal and a mild footshock is delivered after a fixed interval. Adult rats have been shown to learn the temporal relationships between the odor and the shock after a few associations. The first aim of the present study was to assess the activity of the striatum during odor fear conditioning using 2-Deoxyglucose autoradiography during development in rats. The data showed that although fear learning was displayed at all tested ages, activation of the striatum was observed in adults but not in juvenile animals. Next, we assessed the presence of evidence of interval timing in ages before and after the inclusion of the striatum into the fear conditioning circuit. We used an experimental setup allowing the simultaneous recording of freezing and respiration that have been demonstrated to be sensitive to interval timing in adult rats. This enabled the detection of duration-related temporal patterns for freezing and/or respiration curves in infants as young as 12 days PN during odor fear conditioning. This suggests that infants are able to encode time durations as well as and as quickly as adults while their striatum is not yet functional. Alternative networks possibly sustaining interval timing in infant rats are discussed. PMID:24860457

  6. Classical Conditioning of Profoundly Retarded, Multiply Handicapped Children.

    ERIC Educational Resources Information Center

    Hogg, J.; And Others

    1979-01-01

    Conditioning was established for the two most developmentally advanced Ss, and the intermediate pair showed different patterns of orienting response to the conditioned stimulus but no evidence of conditioning. The fifth and most developmentally delayed child did not respond to the stimuli. Journal Availability: J. B. Lippincott Co., East…

  7. 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

  8. Effects of acute and subchronic treatments with fluoxetine and desipramine on the memory of fear in moderate and high-intensity contextual conditioning.

    PubMed

    Santos, Julia M; Martinez, Raquel C R; Brandão, Marcus L

    2006-08-07

    Selective serotonin and noradrenalin reuptake inhibitors such as fluoxetine and desipramine, respectively, are efficacious in the treatment of depression and chronic stress. Although they inhibit the reuptake of the biogenic monoamines soon after administration, therapeutic improvements occur only after 2 or 3 weeks. Freezing response and potentiated startle are common responses to moderate fear contextual conditioning. However, freezing but not startle is increased in rats that undergo intense fear conditioning. In this study, we evaluated the effects of acute and subchronic administration of fluoxetine and desipramine on these responses in testing sessions, as indices of fear in moderate and high fear conditioning. Fluoxetine did not show any significant effect on the moderate fear conditioning but reduced freezing and restored the startle response in rats under intense fear conditioning. In comparison, desipramine had no effect on the startle response when administered acutely or subchronically while freezing of the intense fear conditioning was reduced. Our findings indicate that intense contextual fear conditioning is sensitive to subchronic treatment with fluoxetine and resistant to desipramine. Fluoxetine appears to restore the serotoninergic function in brain areas recruited by intense contextual fear conditioning. These effects of fluoxetine may underlie its reported efficacy in the pharmacotherapy of panic disorders.

  9. Impairment of contextual conditioned fear extinction after microinjection of alpha-1-adrenergic blocker prazosin into the medial prefrontal cortex.

    PubMed

    Do-Monte, Fabrício H M; Allensworth, Melody; Carobrez, Antônio P

    2010-07-29

    Long-lasting memories of aversive or stressful events have been associated with the noradrenergic system activation. Alpha-1-adrenergic antagonist prazosin has successfully been used in the last years to treat anxiety disorders related to aversive memories recurrence in humans. Contextual conditioned fear extinction paradigm in rats has been used to better understand the mechanisms involved in the attenuation of defensive behaviour after a traumatic situation. Here we investigated the effects of systemic administration of prazosin in the fear extinction processes. Rats were previously paired in a contextual fear conditioning box (1 footshock, 1 mA, 2s duration), further returning to the same box during three consecutive days receiving an intraperitoneal injection of vehicle or prazosin 30 min before (acquisition of extinction; 0.1 or 0.5mg/kg) or immediately after (consolidation of extinction, 0.5 or 1.5mg/kg) each extinction session (10 min). On the last day, all animals were re-exposed undrugged to the apparatus. Since the medial prefrontal cortex (mPFC) has been described as a key structure in the modulation of conditioned fear extinction, the effects of intra-mPFC microinjection (0.2 microl per side) of vehicle (PBS) or prazosin (0.75 or 2.5 nmol) in the acquisition of fear extinction (10 min before extinction session 1) were further evaluated. Subjects were drug-free re-exposed to the same box in the next day (extinction session 2). The percentage of freezing time was used as the memory retention parameter. The results showed that either systemic or intra-mPFC-alpha-1-adrenergic blockade increased the freezing time in the last extinction sessions, suggesting impairment of the extinction of contextual conditioned fear in rats.

  10. 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.

  11. Juvenile stress potentiates aversive 22-kHz ultrasonic vocalizations and freezing during auditory fear conditioning in adult male rats.

    PubMed

    Yee, Nicole; Schwarting, Rainer K W; Fuchs, Eberhard; Wöhr, Markus

    2012-09-01

    Traumatic experiences that occur during adolescence can render individuals vulnerable to mood and anxiety disorders. A model in juvenile rats (age: 27-29 days) was developed previously to study the long-term effects of adolescent stress exposure on behaviour and physiology. This paradigm, termed juvenile stress, involves subjecting juvenile rats to different stressors on consecutive days over a 3-day period. Here, we investigated the effects of the juvenile stress paradigm on freezing behaviour and aversive 22-kHz ultrasonic vocalizations (USVs) during auditory fear conditioning in adult male rats (age: 68-90 days). We found that rats previously subjected to juvenile stress increased aversive 22-kHz USVs (total calls and time spent calling) compared with controls during fear-conditioning training. The acoustic USV parameters between control and juvenile stress rats were largely equivalent, including duration, peak frequency and amplitude. While rats did not differ in freezing behaviour during fear conditioning, juvenile stress rats exhibited greater cue-conditioned freezing upon testing 24 h later. Our results show that juvenile stress elicited different long-term changes in freezing and aversive USVs during fear conditioning. Furthermore, they highlight the importance of assessing USVs to detect experience-dependent differences between control and stress-exposed animals which are not detectable by measuring visible behaviour.

  12. Amygdaloid lesions produced similar contextual fear conditioning disruption in the Carioca high- and low-conditioned freezing rats.

    PubMed

    de Castro Gomes, Vitor; Landeira-Fernandez, J

    2008-10-03

    Rats selectively bred for high or low levels of emotionality represent an important and powerful tool to investigate the role of genetic variables in the occurrence of different anxiety disorders. In the present study, albino rats were selectively bred for differences in defensive freezing behavior in response to contextual cues previously associated with footshock, an animal model of general anxiety disorder. The results indicate that these two new lines of rats, which we refer to as Carioca High-Freezing (CHF) and Carioca Low-Freezing (CLF), show a reliable difference in conditioned freezing after three generations of selection. CHF and CLF rats did not present any differences during baseline or post-shock periods. Males from both lines consistently exhibit more conditioned freezing to contextual cues than females. A second experiment used male rats from the fourth generation to investigate the participation of the amygdala during contextual fear conditioning in the CHF and CLF lines. The results indicate that post-training amygdaloid electrolytic lesions lead to similar disruptions in conditioned freezing behavior in both animal lines.

  13. Modulation of Gene Expression in Contextual Fear Conditioning in the Rat

    PubMed Central

    Macchi, Monica; Ciampini, Cristina; Bernardi, Rodolfo; Baldi, Elisabetta; Bucherelli, Corrado; Brunelli, Marcello; Scuri, Rossana

    2013-01-01

    In contextual fear conditioning (CFC) a single training leads to long-term memory of context-aversive electrical foot-shocks association. Mid-temporal regions of the brain of trained and naive rats were obtained 2 days after conditioning and screened by two-directional suppression subtractive hybridization. A pool of differentially expressed genes was identified and some of them were randomly selected and confirmed with qRT-PCR assay. These transcripts showed high homology for rat gene sequences coding for proteins involved in different cellular processes. The expression of the selected transcripts was also tested in rats which had freely explored the experimental apparatus (exploration) and in rats to which the same number of aversive shocks had been administered in the same apparatus, but temporally compressed so as to make the association between painful stimuli and the apparatus difficult (shock-only). Some genes resulted differentially expressed only in the rats subjected to CFC, others only in exploration or shock-only rats, whereas the gene coding for translocase of outer mitochondrial membrane 20 protein and nardilysin were differentially expressed in both CFC and exploration rats. For example, the expression of stathmin 1 whose transcripts resulted up regulated was also tested to evaluate the transduction and protein localization after conditioning. PMID:24278235

  14. 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…

  15. The effects of galantamine on nicotine withdrawal-induced deficits in contextual fear conditioning in C57BL/6 mice.

    PubMed

    Wilkinson, Derek S; Gould, Thomas J

    2011-09-30

    Current smoking cessation aids are relatively ineffective at maintaining abstinence during withdrawal. Nicotine withdrawal is associated with a variety of symptoms including cognitive deficits and targeting these deficits may be a useful strategy for maintaining abstinence. Galantamine is an acetylcholinesterase inhibitor and allosteric modulator of nicotinic acetylcholine receptors (nAChRs) with cognitive enhancing effects that may alleviate cognitive deficits associated with nicotine withdrawal. The effects of galantamine on nicotine withdrawal-induced deficits in contextual fear conditioning in C57BL/6 mice were examined. An initial acute dose-response experiment revealed that 0.5 and 1mg/kg galantamine had no effect on fear conditioning. To determine if galantamine would reverse nicotine withdrawal-related deficits in contextual fear conditioning, mice were implanted with osmotic mini-pumps that delivered chronic saline or 6.3mg/kg/d nicotine for 12 days and then pumps were removed. Training and testing of fear conditioning occurred 24 and 48 h later, respectively. Nicotine withdrawal disrupted contextual fear conditioning, which was reversed with 1 but not 0.5mg/kg galantamine. Across all conditions in both studies 2mg/kg galantamine led to high levels of freezing that were likely due to nonspecific effects. The ability of galantamine to reverse nicotine withdrawal-deficits in contextual conditioning is likely mediated through enhanced levels of acetylcholine via inhibition of acetylcholinesterase, potentiation of hippocampal α4β2* nAChRs, or both. The present study suggests that acetylcholinesterase inhibitors and/or drugs that act as allosteric modulators of nAChRs might be targets for smoking cessation aids because they may alleviate withdrawal symptoms such as cognitive deficits that can lead to relapse.

  16. 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…

  17. Induction of immediate early genes in the mouse auditory cortex after auditory cued fear conditioning to complex sounds.

    PubMed

    Peter, M; Scheuch, H; Burkard, T R; Tinter, J; Wernle, T; Rumpel, S

    2012-04-01

    Immediate early genes (IEGs) are widely used as markers to delineate neuronal circuits because they show fast and transient expression induced by various behavioral paradigms. In this study, we investigated the expression of the IEGs c-fos and Arc in the auditory cortex of the mouse after auditory cued fear conditioning using quantitative polymerase chain reaction and microarray analysis. To test for the specificity of the IEG induction, we included several control groups that allowed us to test for factors other than associative learning to sounds that could lead to an induction of IEGs. We found that both c-fos and Arc showed strong and robust induction after auditory fear conditioning. However, we also observed increased expression of both genes in any control paradigm that involved shocks, even when no sounds were presented. Using mRNA microarrays and comparing the effect of the various behavioral paradigms on mRNA expression levels, we did not find genes being selectively upregulated in the auditory fear conditioned group. In summary, our results indicate that the use of IEGs to identify neuronal circuits involved specifically in processing of sound cues in the fear conditioning paradigm can be limited by the effects of the aversive unconditional stimulus and that activity levels in a particular primary sensory cortical area can be strongly influenced by stimuli mediated by other modalities.

  18. 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,…

  19. 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…

  20. 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…

  1. 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…

  2. Immunohistochemical analyses of long-term extinction of conditioned fear in adolescent rats.

    PubMed

    Kim, Jee Hyun; Li, Stella; Richardson, Rick

    2011-03-01

    Adolescence is a period of heightened emotional reactivity and vulnerability to poor outcomes (e.g., suicide, anxiety, and depression). Recent human and animal neuroimaging studies suggest that dramatic changes in prefrontal cortical areas during adolescence are involved in these effects. The present study explored the functional implications of prefrontal cortical changes during adolescence by examining conditioned fear extinction in adolescent rats. Experiment 1 showed that preadolescent (i.e., postnatal day [P] 24), adolescent (P35), and adult (P70) rats express identical extinction acquisition following 3 white-noise conditioned stimulus (CS) and shock pairings. When tested the next day, however, adolescent rats showed almost complete failure to maintain extinction of CS-elicited freezing compared with P24 and P70 rats. It was observed in experiment 2 that following extinction, P24 and P70 rats express significantly elevated levels of phosphorylated mitogen-activated protein kinase (pMAPK) in the infralimbic cortex (IL) compared with adolescent rats. Interestingly, adolescent rats successfully exhibited long-term extinction if the amount of extinction training was doubled (experiment 3). More extinction training also led to increased phosphorylation of MAPK in the IL in these rats. These findings suggest that adolescents are less efficient in utilizing prefrontal areas, which may lead to an impairment in the maintenance of extinguished behavior.

  3. Appetitive context conditioning proactively, but transiently, interferes with expression of counterconditioned context fear

    PubMed Central

    Holmes, Nathan M.

    2014-01-01

    Four experiments used rats to study appetitive–aversive transfer. Rats trained to eat a palatable food in a distinctive context and shocked in that context ate and did not freeze when tested 1 d later but froze and did not eat when tested 14 d later. These results were associatively mediated (Experiments 1 and 2), observed when rats were or were not food deprived (Experiments 1 and 2), and were not due to latent inhibition (Experiment 3). In contrast, rats trained to eat in the context and shocked there 13 d later froze and did not eat when tested 1 d after the shocked exposure. However, rats that received an additional eating session in the context 1 d before the shocked exposure ate and did not freeze when tested 1 d after the shocked exposure (Experiment 4). The results show that appetitive conditioning transiently interferes with aversive conditioning. They are discussed in terms of a weak context–shock association becoming stronger with the lapse of time (so-called fear incubation) or of the interference by the context–food association becoming weaker with the lapse of time. PMID:25320352

  4. 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

  5. The α1 adrenoceptor antagonist prazosin enhances sleep continuity in fear-conditioned Wistar-Kyoto rats.

    PubMed

    Laitman, Benjamin M; Gajewski, Nicholas D; Mann, Graziella L; Kubin, Leszek; Morrison, Adrian R; Ross, Richard J

    2014-03-03

    Fragmentation of rapid eye movement sleep (REMS) is well described in individuals with posttraumatic stress disorder (PTSD) and likely has significant functional consequences. Fear-conditioned rodents may offer an attractive model of the changes in sleep that characterize PTSD. Following fear conditioning (FC), Wistar-Kyoto (WKY) rats, a strain known to be particularly stress-sensitive, have increased REMS fragmentation that can be quantified as a shift in the distribution of REMS episodes towards the more frequent occurrence of sequential REMS (inter-REMS episode interval≤3 min) vs. single REMS (interval>3 min). The α1 adrenoceptor antagonist prazosin has demonstrated efficacy in normalizing sleep in PTSD. To determine the utility of fear-conditioned WKY rats as a model of sleep disturbances typical of PTSD and as a platform for the development of new treatments, we tested the hypothesis that prazosin would reduce REMS fragmentation in fear-conditioned WKY rats. Sleep parameters and freezing (a standard measure of anxiety in rodents) were quantified at baseline and on Days 1, 7, and 14 following FC, with either prazosin (0.01mg/kg, i.p.) or vehicle injections administered prior to testing in a between-group design. Fear conditioning was achieved by pairing tones with a mild electric foot shock (1.0mA, 0.5s). One, 7, and 14 days following FC, prazosin or vehicle was injected, the tone was presented, freezing was measured, and then sleep was recorded from 11 AM to 3 PM. WKY rats given prazosin, compared to those given vehicle, had a lower amount of seq-REMS relative to total REMS time 14 days after FC. They also had a shorter non-REMS latency and fewer non-REMS arousals at baseline and on Days 1 and 7 after FC. Thus, in FC rats, prazosin reduced both REMS fragmentation and non-REMS discontinuity.

  6. Conditioned turning behavior: A Pavlovian fear response expressed during the post-encounter period following aversive stimulation

    PubMed Central

    Tarpley, Jason W.; Shlifer, I. Gary; Halladay, Lindsay R.; Blair, Hugh T.

    2010-01-01

    Rats were trained to fear an auditory conditioned stimulus (CS) by pairing it with a mild electric shock (the unconditioned stimulus, or US) delivered to one eyelid. After training, the CS elicited two different conditioned fear responses from rats: a passive freezing response, and an active turning response. The balance between these two modes of conditioned responding depended upon the rat's recent history of encounters with the US. If rats had not recently encountered the US, then they responded to the CS by freezing. But after recently encountering the US, rats exhibited CS-evoked turning responses that were always directed away from the trained eyelid, even if the US had recently been delivered to the opposite (untrained) eyelid. This post-encounter turning behavior was not observed in rats that had been trained with unpaired presentations of the CS and US, indicating that even though CS-evoked turning was selectively expressed after recent encounters with the US, it was nonetheless a conditioned Pavlovian fear response that depended upon a learned association between the CS and US. Further supporting this conclusion, pharmacological inactivation experiments showed that expression of both freezing and turning behaviors depended upon lateralized circuits in the amygdala and periaqueductal gray (PAG) that are known to support expression of Pavlovian fear responses. These findings indicate that even though the ability of a CS to elicit Pavlovian fear responses depend upon the long-term history of CS-US pairings, the mode of conditioned responding (freezing versus turning in the present experiments) can be modulated by short-term factors, such as the recent history of US encounters. We discuss neural mechanisms that might mediate such short-term transitions between different modes of defensive responding, and consider how dysregulation of such mechanisms might contribute to clinical anxiety disorders. PMID:20600645

  7. Classical Conditioning of Hippocampal Theta Patterns in the Rat.

    DTIC Science & Technology

    1976-08-01

    associated with changes in performance of learned tasks , 1,4,5, 8,9 there have been very few studies of neurona l plasticity of the hippocampus It self...rapid development of a conditioned hippocampal theta response to a visual sti mulus demonstrates tha t there is considerable neurona l plasticity in the

  8. 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…

  9. 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.

  10. High endogenous estradiol is associated with enhanced cognitive emotion regulation of physiological conditioned fear responses in women.

    PubMed

    Graham, Bronwyn M; Ash, Catherine; Den, Miriam L

    2017-02-28

    The sex hormone estradiol has a modifying role in the underlying neurobiology of cognitive emotion regulation, although whether estradiol is associated with outcomes of techniques like cognitive restructuring is unknown. In the present study 34 women with regular menstrual cycles participated in a one-day differential fear conditioning procedure. Women then received cognitive restructuring training, involving the reappraisal of their initial thoughts about the conditioning procedure to reduce their emotional responses, before repeating the conditioning procedure. Endogenous estradiol levels (ascertained by a blood sample) were not associated with subjective or physiological indices of conditioned fear during the first conditioning session. Following cognitive restructuring, however, women with high estradiol exhibited significantly reduced physiological arousal in the presence of the conditioned stimulus, relative to women with low estradiol. No group differences were observed in subjective fear ratings obtained after the second conditioning procedure, although those obtained during the second habitation phase (taking place immediately following cognitive restructuring) were lower amongst high estradiol women. Progesterone was not associated with any outcomes measures. Together, these results suggest that the outcomes of cognitive emotion regulation may be enhanced during periods of naturally high estradiol.

  11. Brain activation during fear conditioning in humans depends on genetic variations related to functioning of the hypothalamic–pituitary–adrenal axis: first evidence from two independent subsamples

    PubMed Central

    Ridder, S.; Treutlein, J.; Nees, F.; Lang, S.; Diener, S.; Wessa, M.; Kroll, A.; Pohlack, S.; Cacciaglia, R.; Gass, P.; Schütz, G.; Schumann, G.; Flor, H.

    2012-01-01

    Background Enhanced acquisition and delayed extinction of fear conditioning are viewed as major determinants of anxiety disorders, which are often characterized by a dysfunctional hypothalamic–pituitary–adrenal (HPA) axis. Method In this study we employed cued fear conditioning in two independent samples of healthy subjects (sample 1: n=60, sample 2: n=52). Two graphical shapes served as conditioned stimuli and painful electrical stimulation as the unconditioned stimulus. In addition, guided by findings from published animal studies on HPA axis-related genes in fear conditioning, we examined variants of the glucocorticoid receptor and corticotropin-releasing hormone receptor 1 genes. Results Variation in these genes showed enhanced amygdala activation during the acquisition and reduced prefrontal activation during the extinction of fear as well as altered amygdala–prefrontal connectivity. Conclusions This is the first demonstration of the involvement of genes related to the HPA axis in human fear conditioning. PMID:22410078

  12. 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.

  13. The Protein Kinase KIS Impacts Gene Expression during Development and Fear Conditioning in Adult Mice

    PubMed Central

    Manceau, Valérie; Kremmer, Elisabeth; Nabel, Elizabeth G.; Maucuer, Alexandre

    2012-01-01

    The brain-enriched protein kinase KIS (product of the gene UHMK1) has been shown to phosphorylate the human splicing factor SF1 in vitro. This phosphorylation in turn favors the formation of a U2AF65-SF1-RNA complex which occurs at the 3′ end of introns at an early stage of spliceosome assembly. Here, we analyzed the effects of KIS knockout on mouse SF1 phosphorylation, physiology, adult behavior, and gene expression in the neonate brain. We found SF1 isoforms are differently expressed in KIS-ko mouse brains and fibroblasts. Re-expression of KIS in fibroblasts restores a wild type distribution of SF1 isoforms, confirming the link between KIS and SF1. Microarray analysis of transcripts in the neonate brain revealed a subtle down-regulation of brain specific genes including cys-loop ligand-gated ion channels and metabolic enzymes. Q-PCR analyses confirmed these defects and point to an increase of pre-mRNA over mRNA ratios, likely due to changes in splicing efficiency. While performing similarly in prepulse inhibition and most other behavioral tests, KIS-ko mice differ in spontaneous activity and contextual fear conditioning. This difference suggests that disregulation of gene expression due to KIS inactivation affects specific brain functions. PMID:22937132

  14. Estradiol is associated with altered cognitive and physiological responses during fear conditioning and extinction in healthy and spider phobic women.

    PubMed

    Li, Stella; Graham, Bronwyn M

    2016-12-01

    The first-line psychological treatment for anxiety disorders is exposure therapy, which can be modeled in the laboratory using fear extinction. In healthy women, estradiol levels predict return of fear following extinction, whereas low levels are associated with greater return of fear. Investigating whether estradiol is similarly associated with extinction in clinically anxious women may provide insight to mechanisms underlying symptom relapse following exposure therapy. In the present study, women with spider phobia and healthy women participated in a 2-day fear conditioning and extinction procedure during a period of high or low estradiol levels. Skin conductance responses, shock expectancy, and valence ratings were measured throughout. Women exhibited comparable decreases in physiological arousal from conditioning to the end of extinction training on Day 1. However, compared to women with high estradiol, and irrespective of clinical status, women with low estradiol exhibited significant return of physiological arousal at extinction recall on Day 2, despite accurate ratings regarding the likelihood of shock. Low estradiol women also reported heightened threat expectancy and physiological responding during presentation of safety cues. These results may point to novel means of enhancing exposure therapy in women by timing treatment delivery during periods of higher estradiol levels. (PsycINFO Database Record

  15. 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

  16. Breaking generalized covariance, classical renormalization, and boundary conditions from superpotentials

    SciTech Connect

    Livshits, Gideon I.

    2014-02-15

    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.

  17. 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,…

  18. Dorsal hippocampus involvement in delay fear conditioning depends upon the strength of the tone-footshock association.

    PubMed

    Quinn, Jennifer J; Wied, Heather M; Ma, Quang D; Tinsley, Matthew R; Fanselow, Michael S

    2008-01-01

    The hippocampus is important for the formation of spatial, contextual, and episodic memories. For instance, lesions of the dorsal hippocampus (DH) produce demonstrable deficits in contextual fear conditioning. By contrast, it is generally agreed that the DH is not important for conditioning to a discrete cue (such as a tone or light) that is paired with footshock in a temporally contiguous fashion (delay conditioning). There are, however, some reports of hippocampus involvement in delay conditioning. The present series of experiments was designed to assess the conditions under which the hippocampus-dependent component of delay fear conditioning performance may be revealed. Here, we manipulated the number of conditioning trials and the intensity of the footshock in order to vary the strength of conditioning. The results indicate that the DH contributes to freezing performance to a delay conditioned tone when the conditioning parameters are relatively weak (few trials or low footshock intensity), but not when strong parameters are used. The results are discussed in terms of two parallel memory systems: a direct tone-footshock association that is independent of the hippocampus and a hippocampus-dependent memory for the conditioning session.

  19. 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…

  20. Like Extinction, Latent Inhibition of Conditioned Fear in Mice Is Blocked by Systemic Inhibition of L-Type Voltage-Gated Calcium Channels

    ERIC Educational Resources Information Center

    Blouin, Ashley M.; Cain, Chris K.; Barad, Mike

    2004-01-01

    Having recently shown that extinction of conditioned fear depends on L-type voltage-gated calcium channels (LVGCCs), we have been seeking other protocols that require this unusual induction mechanism. We tested latent inhibition (LI) of fear, because LI resembles extinction except that cue exposures precede, rather than follow, cue-shock pairing.…

  1. Protein Profiles Associated With Context Fear Conditioning and Their Modulation by Memantine*

    PubMed Central

    Ahmed, Md. Mahiuddin; Dhanasekaran, A. Ranjitha; Block, Aaron; Tong, Suhong; Costa, Alberto C. S.; Gardiner, Katheleen J.

    2014-01-01

    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

  2. Prediction of “Fear” Acquisition in Healthy Control Participants in a De Novo Fear-Conditioning Paradigm

    PubMed Central

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

    2006-01-01

    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, we 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, we 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, we found that anxiety sensitivity was more linked to individual differences in orienting response than differences in conditioning per se. PMID:17179530

  3. Perceived location specificity in perceptual separation-induced but not fear conditioning-induced enhancement of prepulse inhibition in rats.

    PubMed

    Lei, Ming; Luo, Lu; Qu, Tianshu; Jia, Hongxiao; Li, Liang

    2014-08-01

    Prepulse inhibition (PPI) is the suppression of the startle reflex when the startling stimulus is shortly preceded by a non-startling stimulus (the prepulse). Previous studies have shown that both fear conditioning of a prepulse and precedence-effect-induced perceptual separation between the conditioned prepulse and a noise masker facilitate selective attention to the prepulse and consequently enhance PPI with a remarkable prepulse-feature specificity. This study investigated whether the two types of attentional enhancements of PPI in rats also exhibit a prepulse-location specificity. The results showed that when a prepulse was delivered by each of the two spatially separated loudspeakers, fear conditioning of the prepulse at a particularly perceived location (left or right to the tested rat) enhanced PPI without exhibiting any perceived-location specificity. However, when a noise masker was presented, the precedence-effect-induced perceptual separation between the conditioned prepulse and the noise masker further enhanced PPI when the prepulse was perceived as coming from the location that was conditioned but not the location without being conditioned. Moreover, both conditioning-induced and perceptual separation-induced PPI enhancements were eliminated by extinction learning, whose effect could be blocked by systemic injection of the selective antagonist of metabotropic glutamate receptor subtype 5 (mGluR5), 2-methyl-6-(phenylethynyl)-pyridine (MPEP). Thus, fear conditioning of a prepulse perceived at a particular location not only facilitates selective attention to the conditioned prepulse but also induces a learning-based spatial gating effect on the spatial unmasking of the conditioned prepulse, leading to that the perceptual separation-induced PPI enhancement becomes perceived-location specific.

  4. Single-unit firing in rat perirhinal cortex caused by fear conditioning to arbitrary and ecological stimuli.

    PubMed

    Furtak, Sharon C; Allen, Timothy A; Brown, Thomas H

    2007-11-07

    Pretraining lesions of rat perirhinal cortex (PR) severely impair pavlovian fear conditioning to a 22 kHz ultrasonic vocalization (USV) cue. However, PR lesions are without significant effect when the cue is a continuous tone at the same or a lower frequency. Here we examined fear-conditioning-produced changes in single-unit firing elicited in rat PR by a 22 kHz tone cue or a 22 kHz USV cue. Chronic recording electrodes were introduced from the lateral surface of the skull. Altogether, 200 well isolated units were studied in 28 rats. Overall, 73% of the recorded single units (145 of 200 units) evidenced statistically significant firing changes in response to the tone or USV conditional stimulus (CS) after it had been paired several times with an aversive unconditional stimulus (US). Interestingly, 33% of units (66 of 200 units) that were initially CS-unresponsive became CS-responsive after conditioning. After conditioning, there were two notable differences between single-unit responses elicited by the USV cue and those elicited by the tone cue. First, 11% of the units (14 of 123 units) recorded from the USV-conditioned group displayed a precisely timed increase in firing rate during the 260 ms interval in which the US had previously occurred. This US-timed response was unique to the USV-conditioned group. Second, the mean latency of cue-elicited firing was approximately 30 ms longer in the USV-conditioned group than in the tone-conditioned group. These cue-specific differences in acquired firing latencies and acquired firing patterns suggest that spectrotemporal properties of a CS can control the essential circuitry or neurophysiological mechanisms underlying fear conditioning.

  5. 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.

  6. Cat odor causes long-lasting contextual fear conditioning and increased pituitary-adrenal activation, without modifying anxiety.

    PubMed

    Muñoz-Abellán, Cristina; Daviu, Nuria; Rabasa, Cristina; Nadal, Roser; Armario, Antonio

    2009-10-01

    A single exposure to a cat or cat odors has been reported by some groups to induce contextual and auditory fear conditioning and long-lasting changes in anxiety-like behaviour, but there is no evidence for parallel changes in biological stress markers. In the present study we demonstrated in male rats that exposure to a novel environment containing a cloth impregnated with cat fur odor resulted in avoidance of the odor, lower levels of activity and higher pituitary-adrenal (PA) response as compared to those exposed to the novel environment containing a clean cloth, suggesting increased levels of stress in the former animals. When re-exposed 9 days later to the same environment with a clean cloth, previously cat fur exposed rats again showed avoidance of the cloth area and lower levels of activity, suggesting development of contextual fear conditioning, which again was associated with a higher PA activation. In contrast, unaltered both anxiety-like behaviour and PA responsiveness to an elevated plus-maze were found 7 days after cat odor exposure. It is concluded that: (i) PA activation is able to reflect both the stressful properties of cat fur odor and odor-induced contextual fear conditioning; (ii) development of cat odor-induced contextual fear conditioning is independent of the induction of long-lasting changes in anxiety-like behaviour; and (iii) greater PA activation during exposure to the odor context is not explained by non-specific sensitization of the PA axis caused by previous exposure to cat fur odor.

  7. 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

  8. Inhibiting 11β-hydroxysteroid dehydrogenase type 1 prevents stress effects on hippocampal synaptic plasticity and impairs contextual fear conditioning.

    PubMed

    Sarabdjitsingh, R Angela; Zhou, Ming; Yau, Joyce L W; Webster, Scott P; Walker, Brian R; Seckl, Jonathan R; Joëls, Marian; Krugers, Harm J

    2014-06-01

    11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) catalyzes intracellular regeneration of corticosterone and cortisol, thereby enhancing glucocorticoid action. Inhibition of 11β-HSD1 reverses the deficits in cognition with aging, a state of elevated glucocorticoid levels. However, any impact of 11β-HSD1 inhibition during high glucocorticoid states in younger animals is unknown. Here we examined whether a single injection of the selective 11β-HSD1 inhibitor UE2316 modifies the effect of stress on hippocampal long-term potentiation and fear conditioning, a learning paradigm that is strongly modulated by glucocorticoids. We found that novelty stress suppresses hippocampal synaptic potentiation. This effect was completely prevented by administration of UE2316 one hour before stress exposure. A single injection of UE2316 also impaired contextual, but not tone-cue-fear conditioning. These observations suggest that local metabolism of glucocorticoids is relevant for the outcome of stress effects on hippocampal synaptic plasticity and contextual fear conditioning. Selective 11β-HSD1 inhibitors may be an interesting new approach to the prevention of trauma-associated psychopathology.

  9. Differential impact of the first and second wave of a stress response on subsequent fear conditioning in healthy men.

    PubMed

    Antov, Martin I; Wölk, Christoph; Stockhorst, Ursula

    2013-10-01

    Stress is a process of multiple neuroendocrine changes over time. We examined effects of the first-wave and second-wave stress response on acquisition and immediate extinction of differential fear conditioning, assessed by skin conductance responses. In Experiment 1, we placed acquisition either close to the (second-wave) salivary cortisol peak, induced by a psychosocial stressor (experimental group, EG), or after non-stressful pretreatment (control group, CG). Contrary to predictions, groups did not differ in differential responding. In the EG only, mean differential responding was negatively correlated with cortisol increases. In Experiment 2, we placed conditioning near the first-wave stress response, induced by a cold pressor test (CPT), or after a warm-water condition (CG). CPT-stress increased extinction resistance. Moreover, acquisition performance after CPT was positively correlated with first-wave blood pressure increases. Data suggest that mediators of the first-wave stress response enhance fear maintenance whereas second-wave cortisol responsivity to stress might attenuate fear learning.

  10. Cannabinoid CB1 receptor deficiency increases contextual fear memory under highly aversive conditions and long-term potentiation in vivo.

    PubMed

    Jacob, Wolfgang; Marsch, Rudolph; Marsicano, Giovanni; Lutz, Beat; Wotjak, Carsten T

    2012-07-01

    The cannabinoid receptor type 1 (CB1) is abundantly expressed in the central nervous system where it negatively controls the release of several neurotransmitters. CB1 activity plays a crucial role in learning and memory and in synaptic plasticity. In the present study, the role of CB1 was investigated in three different hippocampus-dependent memory tasks and in in vivo hippocampal synaptic plasticity in knockout (CB1-ko) and wildtype mice. There was no difference in short-term and long-term social and object recognition memory between CB1-ko and wildtype mice. In contrast, in background contextual fear conditioning CB1-ko mice showed enhanced freezing levels in the conditioning context and increased generalised contextual fear after a high-intensity conditioning foot shock of 1.5 mA, but not after 0.7 mA. In in vivo field potential recordings in the dentate gyrus, CB1-ko mice displayed a decreased paired-pulse facilitation of the populations spikes, suggesting an altered inhibitory synaptic drive onto hippocampal granule cells. Furthermore, CB1-ko mice displayed significantly higher levels of in vivo long-term potentiation (LTP) in the dentate gyrus. In conclusion, CB1 deficiency leads to enhanced contextual fear memory and altered synaptic plasticity in the hippocampus, supporting the key role of endocannabinoid signalling in learning and memory, in particular following highly aversive encounters.

  11. Overt behavior and ultrasonic vocalization in a fear conditioning paradigm: a dose-response study in the rat.

    PubMed

    Wöhr, Markus; Borta, Andreas; Schwarting, Rainer K W

    2005-11-01

    The behavioral analysis of laboratory rats is usually confined to the level of overt behavior, like locomotion, behavioral inhibition, instrumental responses, and others. Apart from such visible outcome, however, behaviorally relevant information can also be obtained when analyzing the animals' ultrasonic vocalization, which is typically emitted in highly motivational situations, like 22-kHz calls in response to acute or conditioned threat. To further investigate such vocalizations and their relationship with overt behavior, we tested male Wistar rats in a paradigm of Pavlovian fear conditioning, where a tone stimulus (CS) was preceding an aversive foot-shock (US) in a distinct environment. Importantly, the shock dose was varied between groups (0-1.1 mA), and its acute and conditioned outcome were determined. The analysis of visible behavior confirms the usefulness of immobility as a measure of fear conditioning, especially when higher shock doses were used. Rearing and grooming, on the other hand, were more useful to detect conditioned effects with lower shock levels. Ultrasonic vocalization occurred less consistently than changes in overt behavior; however, dose-response relationships were also observed during the phase of conditioning, for example, in latency, call rate and lengths, intervals between calls, and sound amplitude. Furthermore, total calling time (and rate) were highly correlated with overt behavior, namely behavioral inhibition as measured through immobility. These correlations were observed during the phase of fear conditioning, and the subsequent tests. Importantly, conditioned effects in overt behavior were observed, both, to the context and to the CS presented in this context, whereas conditioned vocalization to the context was not observed (except for one rat). In support and extent of previous results, the present data show that a detailed analysis of ultrasonic vocalization can substantially broaden and refine the spectrum of analysis in

  12. Distinct effects of haloperidol in the mediation of conditioned fear in the mesolimbic system and processing of unconditioned aversive information in the inferior colliculus.

    PubMed

    Muthuraju, S; Nobre, M J; Saito, V M N; Brandao, M L

    2014-03-07

    Chemical and electrical stimulation of the inferior colliculus (IC) causes defensive behavior. Electrical stimulation of the IC at the escape threshold enhances dopamine (DA) release in the prefrontal cortex. Intra-ventral tegmental area injections of quinpirole at doses that act presynaptically reduce the release of DA in the terminal fields of the mesolimbic system and clearly reduce conditioned fear in several animal models of anxiety. However, little is known about the involvement of DA in the mediation of unconditioned fear, such as the reactivity to acute stressors. The present study investigated the neural substrates mediated by DA transmission associated with emotional changes triggered by the activation or inhibition of D2 receptors during conditioned and unconditioned fear. We examined the effects of systemic or local injections of the DA-receptor antagonist and agonist haloperidol and quinpirole, respectively, into the IC in rats subjected to fear-potentiated startle, a Pavlovian paradigm that uses loud sounds as the unconditioned stimulus and light previously paired with footshock as the conditioned stimulus. We also assessed auditory-evoked potentials (AEPs) recorded from electrodes implanted in the IC. Intraperitoneal haloperidol administration dose-dependently enhanced AEPs induced by loud tones and inhibited fear-potentiated startle. Intra-IC injections of quinpirole left AEPs unchanged, suggesting that an optimal level of postsynaptic D2 receptors in the IC may regulate the transmission of aversive information through the midbrain tectum. These findings provide evidence of opposing DA-mediated mechanisms in fear/anxiety processes that depend on the area under study. The activity of the neural substrates of conditioned fear was attenuated by haloperidol, whereas midbrain neural substrates of unconditioned fear were enhanced. Thus, DA appears to regulate unconditioned fear at the midbrain level, likely by reducing the sensory gating of aversive

  13. Origins of common fears in South African children.

    PubMed

    Muris, Peter; du Plessis, Michelle; Loxton, Helene

    2008-12-01

    The present study examined the origins of common childhood fears within a South African context. Six-hundred-and-fifty-five 10- to 14-year-old children were given a brief fear list that helped them to identify their most intense fear and then completed a brief questionnaire for assessing the origins of fears that was based on Rachman's [Rachman, S. (1977). The conditioning theory of fear acquisition: A critical examination. Behaviour Research and Therapy, 15, 375-387; Rachman, S. (1991). Neoconditioning and the classical theory of fear acquisition. Clinical Psychology Review, 17, 47-67] three-pathways theory. More precisely, children were asked to report whether they had experienced conditioning, modeling, and negative information experiences in relation to their most feared stimulus or situation, and also had to indicate to what extent such experiences had actually played a role in the onset and/or intensification of their fears. Results showed that children most frequently reported indirect learning experiences (i.e., modeling and negative information) in relation to their fears, whereas conditioning was clearly less often mentioned. The majority of the children had no precise idea of how their fear had actually begun, but a substantial proportion of them reported various learning experiences in relation to the onset and intensification of fears. Significant cultural differences were not only observed in the prevalence of common fears, but also in the pathways reported for the origins of fears. The results are briefly discussed in terms of the living conditions of South African children from various cultural backgrounds.

  14. 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…

  15. 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…

  16. Vacuum state squeezing versus squeezed classical noise: a test using conditional homodyne detection

    NASA Astrophysics Data System (ADS)

    Carmichael, Howard J.

    2003-05-01

    Measurement of the squeezed fluctuations of an optical field by the method of conditional homodyne detection is discussed. It is shown that conditional homodyne detection is able to distinguish qualitatively between vacuum-state squeezing and squeezed classical noise. Whereas for conventional squeezed-light detection, only a quantitative distinction can be made, based on the setting of the shot-noise level, under conditional detection, the presence of classical noise changes the actual shape of the measured correlation function. The correlations show a positive peak due to the unsqeezed classical noise frequencies, set inside the negative dip associated with the squeezed fluctuations. The width in time of the positive peak is the larger of the detector response time and the inverse of the classical noise bandwidth. The fundamental distinction between vacuum-state squeezing and squeezed classical noise is that there is no positive peak, even in the limiting form of a delta-function, when the unsqueezed frequencies correspond to vacuum state modes. Implications for the literal interpretation of vacuum fluctuations, such as is adopted in stochastic electrodynamics, are discussed. The ideas are presented in general terms and illustrated by an example which treats the generation and detection of broadband squeezed light, including finite-bandwidth classical noise, within the framework of the quantum trajectory theory of cascaded open systems.

  17. Feeding Behavior of Aplysia: A Model System for Comparing Cellular Mechanisms of Classical and Operant Conditioning

    ERIC Educational Resources Information Center

    Baxter, Douglas A.; Byrne, John H.

    2006-01-01

    Feeding behavior of Aplysia provides an excellent model system for analyzing and comparing mechanisms underlying appetitive classical conditioning and reward operant conditioning. Behavioral protocols have been developed for both forms of associative learning, both of which increase the occurrence of biting following training. Because the neural…

  18. Agoraphobia: Fear of Fear.

    ERIC Educational Resources Information Center

    Musetto, Andrew P.

    1984-01-01

    Agoraphobia is a complex phobia in which individuals react with intense anxiety to certain stress situations. Basically, agoraphobics live in fear of becoming afraid. Describes the psychotherapeutic treatment that helps agoraphobics to become more self-sufficient and to face their fears by understanding themselves better. (CS)

  19. Viral delivery of shRNA to amygdala neurons leads to neurotoxicity and deficits in Pavlovian fear conditioning

    PubMed Central

    de Solis, Christopher A.; Holehonnur, Roopashri; Banerjee, Anwesha; Luong, Jonathan A.; Lella, Srihari K; Ho, Anthony; Pahlavan, Bahram; Ploski, Jonathan E.

    2015-01-01

    The use of viral vector technology to deliver short hairpin RNAs (shRNAs) to cells of the nervous system of many model organisms has been widely utilized by neuroscientists to study the influence of genes on behavior. However, there have been numerous reports that delivering shRNAs to the nervous system can lead to neurotoxicity. Here we report the results of a series of experiments where adeno-associated viruses (AAV), that were engineered to express shRNAs designed to target known plasticity associated genes (i.e. Arc, Egr1 and GluN2A) or control shRNAs that were designed not to target any rat gene product for depletion, were delivered to the rat basal and lateral nuclei of the amygdala (BLA), and auditory Pavlovian fear conditioning was examined. In our first set of experiments we found that animals that received AAV (3.16E13 – 1E13 GC/mL; 1ul/side), designed to knockdown Arc (shArc), or control shRNAs targeting either luciferase (shLuc), or nothing (shCntrl), exhibited impaired fear conditioning compared to animals that received viruses that did not express shRNAs. Notably, animals that received shArc did not exhibit differences in fear conditioning compared to animals that received control shRNAs despite gene knockdown of Arc. Viruses designed to harbor shRNAs did not induce obvious morphological changes to the cells/tissue of the BLA at any dose of virus tested, but at the highest dose of shRNA virus examined (3.16E13 GC/mL; 1ul/side), a significant increase in microglia activation occurred as measured by an increase in IBA1 immunoreactivity. In our final set of experiments we infused viruses into the BLA at a titer of (1.60E+12 GC/mL; 1ul/side), designed to express shRNAs designed to target Egr1 (shEgr1), GluN2A (shGluN2A), shArc, shLuc, shCntrl, or a virus which did not express an shRNA, and found that all groups exhibited impaired fear conditioning compared to the group which received a virus that did not express an shRNA. The shEgr1 and shGluN2A groups

  20. Viral delivery of shRNA to amygdala neurons leads to neurotoxicity and deficits in Pavlovian fear conditioning.

    PubMed

    de Solis, Christopher A; Holehonnur, Roopashri; Banerjee, Anwesha; Luong, Jonathan A; Lella, Srihari K; Ho, Anthony; Pahlavan, Bahram; Ploski, Jonathan E

    2015-10-01

    The use of viral vector technology to deliver short hairpin RNAs (shRNAs) to cells of the nervous system of many model organisms has been widely utilized by neuroscientists to study the influence of genes on behavior. However, there have been numerous reports that delivering shRNAs to the nervous system can lead to neurotoxicity. Here we report the results of a series of experiments where adeno-associated viruses (AAV), that were engineered to express shRNAs designed to target known plasticity associated genes (i.e. Arc, Egr1 and GluN2A) or control shRNAs that were designed not to target any rat gene product for depletion, were delivered to the rat basal and lateral nuclei of the amygdala (BLA), and auditory Pavlovian fear conditioning was examined. In our first set of experiments we found that animals that received AAV (3.16E13-1E13 GC/mL; 1 μl/side), designed to knockdown Arc (shArc), or control shRNAs targeting either luciferase (shLuc), or nothing (shCntrl), exhibited impaired fear conditioning compared to animals that received viruses that did not express shRNAs. Notably, animals that received shArc did not exhibit differences in fear conditioning compared to animals that received control shRNAs despite gene knockdown of Arc. Viruses designed to harbor shRNAs did not induce obvious morphological changes to the cells/tissue of the BLA at any dose of virus tested, but at the highest dose of shRNA virus examined (3.16E13 GC/mL; 1 μl/side), a significant increase in microglia activation occurred as measured by an increase in IBA1 immunoreactivity. In our final set of experiments we infused viruses into the BLA at a titer of (1.60E+12 GC/mL; 1 μl/side), designed to express shArc, shLuc, shCntrl or shRNAs designed to target Egr1 (shEgr1), or GluN2A (shGluN2A), or no shRNA, and found that all groups exhibited impaired fear conditioning compared to the group which received a virus that did not express an shRNA. The shEgr1 and shGluN2A groups exhibited gene

  1. Vagus nerve stimulation enhances extinction of conditioned fear and modulates plasticity in the pathway from the ventromedial prefrontal cortex to the amygdala

    PubMed Central

    Peña, David Frausto; Childs, Jessica E.; Willett, Shawn; Vital, Analicia; McIntyre, Christa K.; Kroener, Sven

    2014-01-01

    Fearful experiences can produce long-lasting and debilitating memories. Extinction of the fear response requires consolidation of new memories that compete with fearful associations. Subjects with posttraumatic stress disorder (PTSD) show impaired extinction of conditioned fear, which is associated with decreased ventromedial prefrontal cortex (vmPFC) control over amygdala activity. Vagus nerve stimulation (VNS) enhances memory consolidation in both rats and humans, and pairing VNS with exposure to conditioned cues enhances the consolidation of extinction learning in rats. Here we investigated whether pairing VNS with extinction learning facilitates plasticity between the infralimbic (IL) medial prefrontal cortex and the basolateral complex of the amygdala (BLA). Rats were trained on an auditory fear conditioning task, which was followed by a retention test and 1 day of extinction training. Vagus nerve stimulation or sham-stimulation was administered concurrently with exposure to the fear-conditioned stimulus and retention of fear conditioning was tested again 24 h later. Vagus nerve stimulation-treated rats demonstrated a significant reduction in freezing after a single extinction training session similar to animals that received 5× the number of extinction pairings. To study plasticity in the IL-BLA pathway, we recorded evoked field potentials (EFPs) in the BLA in anesthetized animals 24 h after retention testing. Brief burst stimulation in the IL produced LTD in the BLA field response in fear-conditioned and sham-treated animals. In contrast, the same stimulation resulted in potentiation of the IL-BLA pathway in the VNS-treated group. The present findings suggest that VNS promotes plasticity in the IL-BLA pathway to facilitate extinction of conditioned fear responses (CFRs). PMID:25278857

  2. Maternal dietary loads of α-tocopherol differentially influence fear conditioning and spatial learning in adult offspring.

    PubMed

    Ambrogini, Patrizia; Ciuffoli, Stefano; Lattanzi, Davide; Minelli, Andrea; Bucherelli, Corrado; Baldi, Elisabetta; Betti, Michele; Cuppini, Riccardo

    2011-10-24

    α-Tocopherol, the main component of vitamin E, is well known to be a radical scavenger, so an increased intake of vitamin E is recommended in complicated pregnancy, to prevent possible fetus damage by free radical. In a previous work, we found that maternal α-tocopherol supplementation affects PKC-mediated cellular signaling and hippocampal synaptic plasticity in developing brain; the latter effect persists in adulthood. Here, adult rats maternally exposed to supranutritional doses of α-tocopherol were evaluated for Contextual Fear Conditioning and spatial learning in Morris Water Maze, two different hippocampus-dependent learning tasks. Moreover, anxiety, spontaneous activity, and explorative drive were also evaluated as factors potentially affecting learning performance. Treated rats showed a different behavior with respect to controls: performance in Contextual Fear Conditioning was improved, while spatial learning tested in Morris Water Maze, was impaired. The improvement of fear response was not ascribable to differences in anxiety level and/or spontaneous activity; thus it appears to be a specific effect of α-tocopherol overloading during brain development. On the contrary, the impaired performance in Morris Water Maze exhibited by treated rats can be in part explained by their enhanced explorative drive. Although extrapolation from rats to humans is difficult, a caveat in assuming supranutritional doses of vitamin E in pregnancy arises from this study.

  3. Reinstatement of conditioned fear and the hippocampus: An attentional-associative model

    PubMed Central

    Schmajuk, Nestor A.; Larrauri, José A.; LaBar, Kevin S.

    2007-01-01

    An existing attentional-associative model of classical conditioning (Schmajuk, Lam, and Gray, 1996) is applied to the description of reinstatement in animals and humans. According to the model, inhibitory associations between the context (CX) and unconditioned stimulus (US) are formed during extinction, which help preserve the association between the conditioned stimulus (CS) and the US. However, summation and retardation tests fail to reveal these associations because (a) the CX is not attended or (b) a CX-CS configural stimulus formed during extinction is both poorly attended and weakly active during testing. When US presentations and testing occur in the same context, reinstatement is the consequence of a decreased CX inhibition and the increased attention to the CS, which activates the remaining CS-US association. When US presentations occur in the context of extinction but the CS is tested in a different context, reinstatement results from an increased attention to the CS and the combination of CS-CX and CX-US excitatory associations. The assumption that associations between CSs are impaired following neurotoxic hippocampal lesions or in amnesia, is sufficient to describe absence of reinstatement in those cases. PMID:17178163

  4. Quantum versus classical foundation of statistical mechanics under experimentally realistic conditions.

    PubMed

    Reimann, Peter; Evstigneev, Mykhaylo

    2013-11-01

    Focusing on isolated macroscopic systems, described in terms of either a quantum mechanical or a classical model, our two key questions are how far does an initial ensemble (usually far from equilibrium and largely unknown in detail) evolve towards a stationary long-time behavior (equilibration) and how far is this steady state in agreement with the microcanonical ensemble as predicted by statistical mechanics (thermalization). A recently developed quantum mechanical treatment of the problem is briefly summarized, putting particular emphasis on the realistic modeling of experimental measurements and nonequilibrium initial conditions. Within this framework, equilibration can be proven under very weak assumptions about those measurements and initial conditions, while thermalization still requires quite strong additional hypotheses. An analogous approach within the framework of classical mechanics is developed and compared with the quantum case. In particular, the assumptions to guarantee classical equilibration are now rather strong, while thermalization then follows under relatively weak additional conditions.

  5. Clozapine and Olanzapine Exhibit an Intrinsic Anxiolytic Property in Two Conditioned Fear Paradigms: Contrast with Haloperidol and Chlordiazepoxide

    PubMed Central

    Mead, Alexa; Li, Ming; Kapur, Shitij

    2008-01-01

    Psychotic fear and anxiety disturbances are seen at a relatively high frequency in patients with schizophrenia. Atypical antipsychotics are believed to show superior efficacy in reducing these symptoms. However, clinical and preclinical evidence regarding their anxiolytic efficacy has been mixed. In this study, we evaluated the possible anxiolytic property of two atypicals clozapine and olanzapine and compared them with typical haloperidol and chlordiazepoxide (a prototype of sedative-anxiolytic drug) in two preclinical models of fear. In Experiment 1, we used a fear-induced passive avoidance and conditioned place aversion paradigm and examined the effects of clozapine (20 mg/kg, sc), haloperidol (0.05 mg/kg, sc) and chlordiazepoxide (10 mg/kg, ip). In Experiments 2 and 3, we used a two-way active avoidance conditioning paradigm and further compared the effects of clozapine (20 mg/kg, sc), haloperidol (0.05 mg/kg, sc), chlordiazepoxide (10 mg/kg, ip) and three doses of olanzapine (0.5, 1.0, and 2.0 mg/kg, sc). Results show that clozapine and chlordiazepoxide, but not haloperidol, significantly attenuated the shock conditioning-induced place aversion, decreased the amount of defecations and the number of the 22 kHz vocalizations. Clozapine also reduced the shock conditioning-induced hyperthermia. Similar to clozapine, olanzapine also significantly decreased the amount of defecations and reduced the shock conditioning-induced hyperthermia, but it did not inhibit the 22 kHz vocalizations. This study demonstrates that clozapine and olanzapine possess an intrinsic anxiolytic property, which is not attributable to its superior anti-“psychotic” effect or its favorable effects on motor functions or learning and memory processes. These findings also suggest that the combined use of passive avoidance and active avoidance conditioning models can be useful in better differentiating typical and atypical antipsychotics as well as anxiolytics. PMID:18547622

  6. Effects of environmental and physiological covariates on sex differences in unconditioned and conditioned anxiety and fear in a large sample of genetically heterogeneous (N/Nih-HS) rats

    PubMed Central

    2011-01-01

    Physiological and environmental variables, or covariates, can account for an important portion of the variability observed in behavioural/physiological results from different laboratories even when using the same type of animals and phenotyping procedures. We present the results of a behavioural study with a sample of 1456 genetically heterogeneous N/Nih-HS rats, including males and females, which are part of a larger genome-wide fine-mapping QTL (Quantitative Trait Loci) study. N/Nih-HS rats have been derived from 8 inbred strains and provide very small distance between genetic recombinations, which makes them a unique tool for fine-mapping QTL studies. The behavioural test battery comprised the elevated zero-maze test for anxiety, novel-cage (open-field like) activity, two-way active avoidance acquisition (related to conditioned anxiety) and context-conditioned freezing (i.e. classically conditioned fear). Using factorial analyses of variance (ANOVAs) we aimed to analyse sex differences in anxiety and fear in this N/Nih-HS rat sample, as well as to assess the effects of (and interactions with) other independent factors, such as batch, season, coat colour and experimenter. Body weight was taken as a quantitative covariate and analysed by covariance analysis (ANCOVA). Obliquely-rotated factor analyses were also performed separately for each sex, in order to evaluate associations among the most relevant variables from each behavioural test and the common dimensions (i.e. factors) underlying the different behavioural responses. ANOVA analyses showed a consistent pattern of sex effects, with females showing less signs of anxiety and fear than males across all tests. There were also significant main effects of batch, season, colour and experimenter on almost all behavioural variables, as well as "sex × batch", "sex × season" and "sex × experimenter" interactions. Body weight showed significant effects in the ANCOVAs of most behavioural measures, but sex effects were

  7. Sea slugs, subliminal pictures, and vegetative state patients: boundaries of consciousness in classical conditioning.

    PubMed

    Bekinschtein, Tristan A; Peeters, Moos; Shalom, Diego; Sigman, Mariano

    2011-01-01

    Classical (trace) conditioning is a specific variant of associative learning in which a neutral stimulus leads to the subsequent prediction of an emotionally charged or noxious stimulus after a temporal gap. When conditioning is concurrent with a distraction task, only participants who can report the relationship (the contingency) between stimuli explicitly show associative learning. This suggests that consciousness is a prerequisite for trace conditioning. We review and question three main controversies concerning this view. Firstly, virtually all animals, even invertebrate sea slugs, show this type of learning; secondly, unconsciously perceived stimuli may elicit trace conditioning; and thirdly, some vegetative state patients show trace learning. We discuss and analyze these seemingly contradictory arguments to find the theoretical boundaries of consciousness in classical conditioning. We conclude that trace conditioning remains one of the best measures to test conscious processing in the absence of explicit reports.

  8. The role of the amygdala in the extinction of conditioned fear.

    PubMed

    Barad, Mark; Gean, Po-Wu; Lutz, Beat

    2006-08-15

    The amygdala has long been known to play a central role in the acquisition and expression of fear. More recently, convergent evidence has implicated the amygdala in the extinction of fear as well. In rodents, some of this evidence comes from the infusion of drugs directly into the amygdala and, in particular, into the basolateral complex of the amygdala, during or after extinction learning. In vivo electrophysiology has identified cellular correlates of extinction learning and memory in the lateral nucleus of that structure. Human imaging experiments also indicate that amygdaloid activity correlates with extinction training. In addition, some studies have directly identified changes in molecular constituents of the basolateral amygdala. Together these experiments strongly indicate that the basolateral amygdala plays a crucial role in extinction learning. Interpreted in the light of these findings, several recent in vitro electrophysiology studies in amygdala-containing brain slices are suggestive of potential synaptic and circuit bases of extinction learning.

  9. GABAergic regulation of auditory sensory gating in low- and high-anxiety rats submitted to a fear conditioning procedure.

    PubMed

    Nobre, M J; Cabral, A; Brandão, M L

    2010-12-29

    The inferior colliculus (IC) is primarily involved in the processing of acoustic stimuli, being in a position to send auditory information to motor centers that participate in behaviors such as prey catching and predators' avoidance. The role of the central nucleus of the IC (CIC) on fear and anxiety has been suggested on the basis that rats are able to engage in tasks to decrease the aversiveness of CIC stimulation, increased Fos immunolabeling during diverse aversive states and increased CIC auditory evoked potentials (AEP) induced by conditioned fear stimuli. Additionally, it was shown that brainstem AEP, represented by wave V, for which the main generator is the IC, is increased during experimentally-induced anxiety. Rats segregated according to their low or high emotional reactivity have been used as an important tool in the study of fear and anxiety. The IC contains a high density of GABA receptors. Since the efficacy of an anxiolytic compound is a function of the animal's anxiety level, it is possible that GABA-benzodiazepine (Bzp) agents affect LA and HA animals differently. In this study we investigated the GABA-Bzp influence on the modulation of AEP in rats with low- (LA) or high-anxiety (HA) levels, as assessed by the elevated plus-maze test (EPM). GABA-Bzp modulation on the unconditioned AEP response was analyzed by using intra-CIC injections (0.2 μl) of the GABA-B