Kwon, Jeong-Tae; Jhang, Jinho; Kim, Hyung-Su; Lee, Sujin; Han, Jin-Hee
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…
Full Text Available Fear is one of the most potent emotional experiences and is an adaptive component of response to potentially threatening stimuli. On the other hand, too much or inappropriate fear accounts for many common psychiatric problems. Cumulative evidence suggests that the amygdala plays a central role in the acquisition, storage and expression of fear memory. Here, we developed an inducible striatal neuron ablation system in transgenic mice. The ablation of striatal neurons in the adult brain hardly affected the auditory fear learning under the standard condition in agreement with previous studies. When conditioned with a low-intensity unconditioned stimulus, however, the formation of long-term fear memory but not short-tem memory was impaired in striatal neuron-ablated mice. Consistently, the ablation of striatal neurons 24 h after conditioning with the low-intensity unconditioned stimulus, when the long-term fear memory was formed, diminished the retention of the long-term memory. Our results reveal a novel form of the auditory fear memory depending on striatal neurons at the low-intensity unconditioned stimulus.
Pereira, C W; Santos, F N; Sánchez-Pérez, A M; Otero-García, M; Marchioro, M; Ma, S; Gundlach, A L; Olucha-Bordonau, F E
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. Copyright © 2013 Elsevier B.V. All rights reserved.
De la Casa, Luis G
Latent inhibition (LI), operationally defined as the reduced conditioned response to a stimulus that has been preexposed before conditioning, seems to be determined by the interaction of different processes that includes attentional, associative, memory, motivational, and emotional factors. In this paper we focused on the role of deprivation level on LI intensity using an auditory fear conditioning procedure with rats. LI was observed when the animals were non-deprived, but it was disrupted when the rats were water- or food-deprived. We propose that deprivation induced an increase in attention to the to-be-CS, and, as a result, LI was disrupted in deprived animals. The implications of the results for the current interpretations of LI are also discussed. Copyright © 2013 Elsevier B.V. All rights reserved.
Elisa Mari Akagi Jordão
Full Text Available The basolateral amygdala complex (BLA, including the lateral (LA, basal (BA and accessory basal (AB nuclei, is involved in acquisition of contextual and auditory fear conditioning. The BA is one of the main targets for hippocampal information, a brain structure critical for contextual learning, which integrates several discrete stimuli into a single configural representation. Congruent with the hodology, selective neurotoxic damage to the BA results in impairments in contextual, but not auditory, fear conditioning, similarly to the behavioral impairments found after hippocampal damage. This study evaluated the effects of muscimol-induced reversible inactivation of the BA during a simultaneous contextual and auditory fear conditioning training on later fear responses to both the context and the tone, tested separately, without muscimol administration. As compared to control rats micro-infused with vehicle, subjects micro-infused with muscimol before training exhibited, during testing without muscimol, significant reduction of freezing responses to the conditioned context, but not to the conditioned tone. Therefore, reversible inactivation of the BA during training impaired contextual, but not auditory fear conditioning, thus confirming and extending similar behavioral observations following selective neurotoxic damage to the BA and, in addition, revealing that this effect is not related to the lack of a functional BA during testing.
Burman, Michael A.; Erickson, Kristen J.; Deal, Alex L.; Jacobson, Rose E.
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 for...
Michael A Burman
Full Text Available 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.
Yee, Nicole; Schwarting, Rainer K W; Fuchs, Eberhard; Wöhr, Markus
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.
Full Text Available BACKGROUND: In auditory fear conditioning, repeated presentation of the tone in the absence of shock leads to extinction of the acquired fear responses. The glutamate N-methyl-D-aspartate receptor (NMDAR is thought to be involved in the extinction of the conditioned fear responses, but its detailed role in initiating and consolidating or maintaining the fear extinction memory is unclear. Here we investigated this issue by using a NMDAR antagonist, MK-801. METHODS/MAIN FINDINGS: The effects of immediate (beginning at 10 min after the conditioning and delayed (beginning at 24 h after conditioning extinctions were first compared with the finding that delayed extinction caused a better and long-lasting (still significant on the 20(th day after extinction depression on the conditioned fear responses. In a second experiment, MK-801 was intraperitoneally (i.p. injected at 40 min before, 4 h or 12 h after the delayed extinction, corresponding to critical time points for initiating, consolidating or maintaining the fear extinction memory. i.p. injection of MK-801 at either 40 min before or 4 h after delayed extinction resulted in an impairment of initiating and consolidating fear extinction memory, which caused a long lasting increased freezing score that was still significant on the 7th day after extinction, compared with extinction group. However, MK-801 administered at 12 h after the delayed extinction, when robust consolidation has been occurred and stabilized, did not affect the established extinction memory. Furthermore, the changed freezing behaviors was not due to an alteration in general anxiety levels, since MK-801 treatment had no effect on the percentage of open-arm time or open-arm entries in an Elevated Plus Maze (EPM task. CONCLUSIONS/SIGNIFICANCE: Our data suggested that the activation of NMDARs plays important role in initiation and consolidation but not maintenance of fear extinction memory. Together with the fact that NMDA receptor is
Boukezzi, Sarah; Silva, Catarina; Nazarian, Bruno; Rousseau, Pierre-François; Guedj, Eric; Valenzuela-Moguillansky, Camila; Khalfa, Stéphanie
Disruption of fear conditioning, its extinction and its retrieval are at the core of posttraumatic stress disorder (PTSD). Such deficits, especially fear extinction delay, disappear after alternating bilateral stimulations (BLS) during eye movement desensitization and reprocessing (EMDR) therapy. An animal model of fear recovery, based on auditory cued fear conditioning and extinction learning, recently showed that BLS facilitate fear extinction and fear extinction retrieval. Our goal was to ...
Full Text Available Adolescence is a period of major physical, hormonal, and psychological changes. It is also characterized by a significant increase in the incidence of psychopathologies and this increase is gender-specific. Stress during adolescence is associated with the development of psychiatric disorders later in life. In this study, we evaluated the impact of psychogenic stress (exposure to predator odor followed by placement on an elevated platform experienced before puberty (days 28–30 on fear memories and hormonal response of male and female rats during adolescence and early adulthood. Stress before puberty impacted in a sex- and age-specific way on the responses to auditory and contextual fear conditioning in adolescence and adulthood: (a increased conditioned fear to the tone in males during adolescence but not during adulthood; (b impaired extinction to the tone in adult males; and (c reduced freezing responses to the context in adolescent females. Stress before puberty did not influence the corticosterone levels 30 minutes after an additional stressor given in adulthood. These results indicate that stress experienced prior to puberty can exert a sex-related differential impact on fear-related behaviors displayed by individuals during late adolescence and early adulthood.
Full Text Available Posttraumatic stress disorder (PTSD is characterized by acute and chronic changes in the stress response, manifested as conditioned fear memory. Previously formed memories that are susceptible to disruption immediately after retrieval undergo a protein synthesis-dependent process to become persistent, termed reconsolidation, a process that is regulated by many distinct molecular mechanisms that control gene expression. Increasing evidence supports the participation of the transcription factor NF-κB in the different phases of memory. Here, we demonstrate that inhibition of NF-κB in the basolateral amygdala (BLA, but not central nucleus of the amygdala, after memory reactivation impairs the retention of amygdala-dependent auditory fear conditioning (AFC. We used two independent pharmacological strategies to disrupt the reconsolidation of AFC. Bilateral intra-BLA infusion of sulfasalazine, an inhibitor of IκB kinase that activates NF-κB, and bilateral intra-BLA infusion of SN50, a direct inhibitor of the NF-κB DNA-binding complex, immediately after retrieval disrupted the reconsolidation of AFC. We also found that systemic pretreatment with sodium butyrate, a histone deacetylase inhibitor that enhances histone acetylation, in the amygdala rescued the disruption of reconsolidation induced by NF-κB inhibition in the BLA. These findings indicate that NF-κB activity in the BLA is required for memory reconsolidation in AFC, suggesting that NF-κB might be a potential pharmacotherapy target for posttraumatic stress disorder.
Jing, He; Hao, Yongxin; Bi, Qiang; Zhang, Jiaozhen; Yang, Pingting
During an inflammatory or infectious process, innate immune cells produce large amount of pro-inflammatory cytokines that act on the brain to cause cognitive dysfunctions. Tumor necrosis factor alpha (TNF-α) is one of the main pro-inflammatory cytokines. Thus, it is important to study how the excessive TNF-α affects the cognitive functions of central nervous system and possible antagonists to its effects. In the present study, we conducted behavioral experiments of rats to determine whether murine TNF-α administered directly into the brain would elicit behavioral effects related to learning and memory impairments. Rats subjected to single-dose intra-amygdala TNF-α infusion showed a significant delay in the acquisition and extinction of auditory fear conditioning. Accordingly, the glutamate level of the tissue samples from amygdala was elevated after the TNF-α treatment. Furthermore, pharmacological blockade of NMDAR before the TNF-α treatment reversed the TNF-α induced impairments in fear learning. Our findings suggest that TNF-α can impair the learning and memory functions through glutamate-NMDAR neurotoxicity, and present the possibility to develop therapeutic modalities directing at glutamate transmission for the treatment of neuro-inflammative dysfunctions. Copyright © 2014 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.
Ota, Kristie T.; Monsey, Melissa S.; Wu, Melissa S.; Young, Grace J.; Schafe, Glenn E.
We have recently hypothesized that NO-cGMP-PKG signaling in the lateral nucleus of the amygdala (LA) during auditory fear conditioning coordinately regulates ERK-driven transcriptional changes in both auditory thalamic (MGm/PIN) and LA neurons that serve to promote pre- and postsynaptic alterations at thalamo-LA synapses, respectively. In the…
Boukezzi, Sarah; Silva, Catarina; Nazarian, Bruno; Rousseau, Pierre-François; Guedj, Eric; Valenzuela-Moguillansky, Camila; Khalfa, Stéphanie
Disruption of fear conditioning, its extinction and its retrieval are at the core of posttraumatic stress disorder (PTSD). Such deficits, especially fear extinction delay, disappear after alternating bilateral stimulations (BLS) during eye movement desensitization and reprocessing (EMDR) therapy. An animal model of fear recovery, based on auditory cued fear conditioning and extinction learning, recently showed that BLS facilitate fear extinction and fear extinction retrieval. Our goal was to determine if these previous results found in animals can be reproduced in humans. Twenty-two healthy participants took part in a classical fear conditioning, extinction, and extinction recall paradigm. Behavioral responses (fear expectations) as well as psychophysiological measures (skin conductance responses, SCRs) were recorded. The results showed a significant fear expectation decrease during fear extinction with BLS. Additionally, SCR for fear extinction retrieval were significantly lower with BLS. Our results demonstrate the importance of BLS to reduce negative emotions, and provide a successful model to further explore the neural mechanisms underlying the sole BLS effect in the EMDR.
Full Text Available Disruption of fear conditioning, its extinction and its retrieval are at the core of posttraumatic stress disorder (PTSD. Such deficits, especially fear extinction delay, disappear after alternating bilateral stimulations (BLS during eye movement desensitization and reprocessing (EMDR therapy. An animal model of fear recovery, based on auditory cued fear conditioning and extinction learning, recently showed that BLS facilitate fear extinction and fear extinction retrieval. Our goal was to determine if these previous results found in animals can be reproduced in humans. Twenty-two healthy participants took part in a classical fear conditioning, extinction, and extinction recall paradigm. Behavioral responses (fear expectations as well as psychophysiological measures (skin conductance responses, SCRs were recorded. The results showed a significant fear expectation decrease during fear extinction with BLS. Additionally, SCR for fear extinction retrieval were significantly lower with BLS. Our results demonstrate the importance of BLS to reduce negative emotions, and provide a successful model to further explore the neural mechanisms underlying the sole BLS effect in the EMDR.
Judith R. Homberg
Full Text Available Conditioned fear plays a key role in anxiety disorders as well as depression and other neuropsychiatric conditions. Understanding how neuromodulators drive the associated learning and memory processes, including memory consolidation, retrieval/expression, and extinction (recall, is essential in the understanding of (individual differences in vulnerability to these disorders and their treatment. The human and rodent studies I review here together reveal, amongst others, that acute selective serotonin reuptake inhibitor (SSRI treatment facilitates fear conditioning, reduces contextual fear, and increases cued fear, chronic SSRI treatment reduces both contextual and cued fear, 5-HT1A receptors inhibit the acquisition and expression of contextual fear, 5-HT2A receptors facilitates the consolidation of cued and contextual fear, inactivation of 5-HT2C receptors facilitate the retrieval of cued fear memory, the 5-HT3 receptor mediates contextual fear, genetically induced increases in serotonin levels are associated with increased fear conditioning, impaired cued fear extinction, or impaired extinction recall, and that genetically induced 5-HT depletion increases fear conditioning and contextual fear. Several explanations are presented to reconcile seemingly paradoxical relationships between serotonin levels and conditioned fear.
Bauer, Elizabeth P
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. Copyright © 2014. Published by Elsevier B.V.
Javiera P Oyarzún
Full Text Available Learning to fear danger in the environment is essential to survival, but dysregulation of the fear system is at the core of many anxiety disorders. As a consequence, a great interest has emerged in developing strategies for suppressing fear memories in maladaptive cases. Recent research has focused in the process of reconsolidation where memories become labile after being retrieved. In a behavioral manipulation, Schiller et al., (2010 reported that extinction training, administrated during memory reconsolidation, could erase fear responses. The implications of this study are crucial for the possible treatment of anxiety disorders without the administration of drugs. However, attempts to replicate this effect by other groups have been so far unsuccessful. We sought out to reproduce Schiller et al., (2010 findings in a different fear conditioning paradigm based on auditory aversive stimuli instead of electric shock. Following a within-subject design, participants were conditioned to two different sounds and skin conductance response (SCR was recorded as a measure of fear. Our results demonstrated that only the conditioned stimulus that was reminded 10 minutes before extinction training did not reinstate a fear response after a reminder trial consisting of the presentation of the unconditioned stimuli. For the first time, we replicated Schiller et al., (2010 behavioral manipulation and extended it to an auditory fear conditioning paradigm.
Koelsch, Stefan; Skouras, Stavros; Fritz, Thomas; Herrera, Perfecto; Bonhage, Corinna; Küssner, Mats B; Jacobs, Arthur M
This study investigates neural correlates of music-evoked fear and joy with fMRI. Studies on neural correlates of music-evoked fear are scant, and there are only a few studies on neural correlates of joy in general. Eighteen individuals listened to excerpts of fear-evoking, joy-evoking, as well as neutral music and rated their own emotional state in terms of valence, arousal, fear, and joy. Results show that BOLD signal intensity increased during joy, and decreased during fear (compared to the neutral condition) in bilateral auditory cortex (AC) and bilateral superficial amygdala (SF). In the right primary somatosensory cortex (area 3b) BOLD signals increased during exposure to fear-evoking music. While emotion-specific activity in AC increased with increasing duration of each trial, SF responded phasically in the beginning of the stimulus, and then SF activity declined. Psychophysiological Interaction (PPI) analysis revealed extensive emotion-specific functional connectivity of AC with insula, cingulate cortex, as well as with visual, and parietal attentional structures. These findings show that the auditory cortex functions as a central hub of an affective-attentional network that is more extensive than previously believed. PPI analyses also showed functional connectivity of SF with AC during the joy condition, taken to reflect that SF is sensitive to social signals with positive valence. During fear music, SF showed functional connectivity with visual cortex and area 7 of the superior parietal lobule, taken to reflect increased visual alertness and an involuntary shift of attention during the perception of auditory signals of danger. Copyright © 2013 Elsevier Inc. All rights reserved.
Ottmar V Lipp
Full Text Available A growing body of evidence suggests that conscious visual awareness is not a prerequisite for human fear learning. For instance, humans can learn to be fearful of subliminal fear relevant images--images depicting stimuli thought to have been fear relevant in our evolutionary context, such as snakes, spiders, and angry human faces. Such stimuli could have a privileged status in relation to manipulations used to suppress usually salient images from awareness, possibly due to the existence of a designated sub-cortical 'fear module'. Here we assess this proposition, and find it wanting. We use binocular masking to suppress awareness of images of snakes and wallabies (particularly cute, non-threatening marsupials. We find that subliminal presentations of both classes of image can induce differential fear conditioning. These data show that learning, as indexed by fear conditioning, is neither contingent on conscious visual awareness nor on subliminal conditional stimuli being fear relevant.
Sui, Li; Huang, SiJia; Peng, BinBin; Ren, Jie; Tian, FuYing; Wang, Yan
Deep brain stimulation (DBS) of the amygdala has been demonstrated to modulate hyperactivity of the amygdala, which is responsible for the symptoms of post-traumatic stress disorder (PTSD), and thus might be used for the treatment of PTSD. However, the underlying mechanism of DBS of the amygdala in the modulation of the amygdala is unclear. The present study investigated the effects of DBS of the amygdala on synaptic transmission and synaptic plasticity at cortical inputs to the amygdala, which is critical for the formation and storage of auditory fear memories, and fear memories. The results demonstrated that auditory fear conditioning increased single-pulse-evoked field excitatory postsynaptic potentials in the cortical-amygdala pathway. Furthermore, auditory fear conditioning decreased the induction of paired-pulse facilitation and long-term potentiation, two neurophysiological models for studying short-term and long-term synaptic plasticity, respectively, in the cortical-amygdala pathway. In addition, all these auditory fear conditioning-induced changes could be reversed by DBS of the amygdala. DBS of the amygdala also rescued auditory fear conditioning-induced enhancement of long-term retention of fear memory. These findings suggested that DBS of the amygdala alleviating fear conditioning-induced alterations in synaptic plasticity in the cortical-amygdala pathway and fear memory may underlie the neuromodulatory role of DBS of the amygdala in activities of the amygdala.
Castegnetti, G.; Tzovara, A.; Staib, M.; Paulus, P. C.; Hofer, N.; Bach, D. R.
Across species, cued fear conditioning is a common experimental paradigm to investigate aversive Pavlovian learning. While fear-conditioned stimuli (CS+) elicit overt behavior in many mammals, this is not the case in humans. Typically, autonomic nervous system activity is used to quantify fear memory in humans, measured by skin conductance responses (SCR). Here, we investigate whether heart period responses (HPR) evoked by the CS, often observed in humans and small mammals, are suitable to co...
Castegnetti, Giuseppe; Tzovara, Athina; Staib, Matthias; Paulus, Philipp C.; Hofer, Nicolas; Bach, Dominik R.
Abstract Across species, cued fear conditioning is a common experimental paradigm to investigate aversive Pavlovian learning. While fear?conditioned stimuli (CS+) elicit overt behavior in many mammals, this is not the case in humans. Typically, autonomic nervous system activity is used to quantify fear memory in humans, measured by skin conductance responses (SCR). Here, we investigate whether heart period responses (HPR) evoked by the CS, often observed in humans and small mammals, are suita...
Tovote, P.; Meyer, M.; Pilz, P.K.D.; Ronnenberg, A.; Ögren, S.O.; Stiedl, O.
Fear-inducing stimuli were hypothesized to elicit fast heart rate (HR) responses but slow mean arterial blood pressure (MAP) responses and thus were studied in auditory fear conditioning and acoustic startle at high temporal resolution in freely moving mice and rats. Fear-induced instantaneous
Castegnetti, Giuseppe; Tzovara, Athina; Staib, Matthias; Paulus, Philipp C; Hofer, Nicolas; Bach, Dominik R
Across species, cued fear conditioning is a common experimental paradigm to investigate aversive Pavlovian learning. While fear-conditioned stimuli (CS+) elicit overt behavior in many mammals, this is not the case in humans. Typically, autonomic nervous system activity is used to quantify fear memory in humans, measured by skin conductance responses (SCR). Here, we investigate whether heart period responses (HPR) evoked by the CS, often observed in humans and small mammals, are suitable to complement SCR as an index of fear memory in humans. We analyze four datasets involving delay and trace conditioning, in which heart beats are identified via electrocardiogram or pulse oximetry, to show that fear-conditioned heart rate deceleration (bradycardia) is elicited and robustly distinguishes CS+ from CS-. We then develop a psychophysiological model (PsPM) of fear-conditioned HPR. This PsPM is inverted to yield estimates of autonomic input into the heart. We show that the sensitivity to distinguish CS+ and CS- (predictive validity) is higher for model-based estimates than peak-scoring analysis, and compare this with SCR. Our work provides a novel tool to investigate fear memory in humans that allows direct comparison between species. © 2016 The Authors. Psychophysiology published by Wiley Periodicals, Inc. on behalf of Society for Psychophysiological Research.
Kent, Brianne A; Brown, Thomas H
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. Copyright © 2012 Wiley Periodicals, Inc.
DaSilva, Jamie K; Husain, Eram; Lei, Yanlin; Mann, Graziella L; Morrison, Adrian R; Tejani-Butt, Shanaz
Social support, when provided following a traumatic experience, is associated with a lower incidence of stress-related psychiatric disorders. Our hypothesis was that providing a social interaction period with a naive conspecific would improve sleep architecture in response to cued fear conditioning in Wistar rats. Rats were randomly assigned to either the socially isolated or socially partnered groups. Rats assigned to the socially isolated group were individually housed following electrode implantation and fear conditioning. Rats assigned to the socially partnered group were initially paired-housed, and then one rat from each pair was randomly chosen for sleep electrode implantation and fear conditioning. Rats from both groups were habituated to a recording chamber, and baseline sleep was recorded over 22 hours. One day later (Training Day), they were fear-conditioned to 10 presentations of a tone (800 Hz, 90 dB, 5 sec) co-terminating with a mild electric foot shock (1.0 mA, 0.5 sec), at 30-sec intervals. While rats in the socially isolated group were left undisturbed in their home cage for 30-min, socially partnered rats interacted for 30 minutes with their non-stressed rat partner immediately after fear conditioning and while the auditory tones were presented on Days 1 and 14. The results indicated that social interaction increased sleep efficiency in partnered rats compared to isolated rats following the fear conditioning procedure. This was due to an increase in the amount of rapid eye movement sleep (REMS) during the light phase. Evaluation of REMS microarchitecture revealed that the increase in REMS was due to an increase in the number of single REMS episodes (siREMS), which represented a more consolidated REMS pattern. A surprising finding was that partnered rats had a greater number of sequential REMS episodes (seqREMS) at Baseline, on the Training Day and on Day 1 when compared to isolated rats. The greater number of seqREMS episodes in partnered rats may
Peña, David F.; Engineer, Navzer D.; McIntyre, Christa K.
Background Fearful experiences can produce long-lasting and debilitating memories. Extinction of conditioned fear requires consolidation of new memories that compete with fearful associations. In human subjects, as well as rats, posttraining stimulation of the vagus nerve enhances memory consolidation. Subjects with posttraumatic stress disorder (PTSD) show impaired extinction of conditioned fear. The objective of this study was to determine whether vagus nerve stimulation (VNS) can enhance the consolidation of extinction of conditioned fear. Methods Male Sprague-Dawley rats were trained on an auditory fear conditioning task followed by 1–10 days of extinction training. Treatment with vagus nerve or sham stimulation was administered concurrently with exposure to the fear conditioned stimulus. Another group was given VNS and extinction training but the VNS was not paired with exposure to conditioned cues. Retention of fear conditioning was tested 24 hours after each treatment. Results VNS paired with exposure to conditioned cues enhanced the extinction of conditioned fear. After a single extinction trial, rats given VNS stimulation demonstrated a significantly lower level of freezing, compared to that of sham controls. When extinction trials were extended to 10 days, paired VNS accelerated extinction of the conditioned response. Conclusions Extinction paired with VNS is more rapid than extinction paired with sham stimulation. As it is currently approved by the Federal Food and Drug Administration for depression and seizure prevention, VNS is a readily-available and promising adjunct to exposure therapy for the treatment of severe anxiety disorders. PMID:23245749
Mertens, Gaëtan; Raes, An K.; De Houwer, Jan
Evolutionary fear-relevant stimuli such as snakes or spiders are thought to be prepared to elicit fear reactions. This implies that the acquisition of conditioned fear responses is facilitated when these stimuli serve as conditioned stimuli (CSs). Moreover, extinction of conditioned fear responses
Nasehi, Mohammad; Soltanpour, Reyhaneh; Ebrahimi-Ghiri, Mohaddeseh; Zarrabian, Shahram; Zarrindast, Mohammad-Reza
The effects of pharmacological interventions on fear memory have widely been studied, but there are very few studies about the effects of brain electrical stimulation on fear memory function. Therefore, our aim was to determine whether anodal/cathodal transcranial direct current stimulation (tDCS) over the right frontal cortex would modify propranolol-induced contextual and auditory fear memory deficits, before or after training. The adult NMRI male mice were randomly assigned into three groups: the sham group, the anodal tDCS group, and the cathodal tDCS group. Fear memories were evaluated using a classical fear conditioning apparatus. While the anodal stimulation did not affect fear retrieval, post-training cathodal stimulation improved fear memory retrieval. Regardless of when propranolol (0.1 mg/kg) was administered, it impaired fear memory retrieval. However, when anodal stimulation and propranolol were applied prior to the training, contextual fear memory retrieval was increased and auditory fear memory was reversed. An enhanced contextual retrieval was also observed when propranolol was administered prior to the training and stimulation occurred after the training. Only when the stimulation occurred prior to the training and propranolol was administered after the training was there a selective improvement in contextual fear memory retrieval, leaving the auditory fear memory retrieval impaired. Interestingly, cathodal stimulation improved the effects of propranolol on auditory fear memory only when it occurred prior to the training. The results highlight possible improving effects for anodal/cathodal tDCS on propranolol-induced deficits on fear memories. The timing of the interventions related to the specific phases of memory formation is important in modulating fear behaviors.
Stress is a complex biological reaction common to all living organisms that allows them to adapt to their environments. Chronic stress alters the dendritic architecture and function of the limbic brain areas that affect memory, learning, and emotional processing. This review summarizes our research about chronic stress effects on the auditory system, providing the details of how we developed the main hypotheses that currently guide our research. The aims of our studies are to (1) determine how chronic stress impairs the dendritic morphology of the main nuclei of the rat auditory system, the inferior colliculus (auditory mesencephalon), the medial geniculate nucleus (auditory thalamus), and the primary auditory cortex; (2) correlate the anatomic alterations with the impairments of auditory fear learning; and (3) investigate how the stress-induced alterations in the rat limbic system may spread to nonlimbic areas, affecting specific sensory system, such as the auditory and olfactory systems, and complex cognitive functions, such as auditory attention. Finally, this article gives a new evolutionary approach to understanding the neurobiology of stress and the stress-related disorders.
Thompson, Alina; Lipp, Ottmar V
Extant literature suggests that extinction training delivered during the memory reconsolidation period is superior to traditional extinction training in the reduction of fear recovery, as it targets the original fear memory trace. At present it is debated whether different types of fear memories are differentially sensitive to behavioral manipulations of reconsolidation. Here, we examined post-reconsolidation recovery of fear as a function of conditioned stimulus (CS) fear-relevance, using the unconditioned stimulus (US) to reactivate and destabilize conditioned fear memories. Participants (N = 56; 25 male; M = 24.39 years, SD = 7.71) in the US-reactivation and control group underwent differential fear conditioning to fear-relevant (spiders/snakes) and fear-irrelevant (geometric shapes) CSs on Day 1. On Day 2, participants received either reminded (US-reactivation) or non-reminded extinction training. Tests of fear recovery, conducted 24 h later, revealed recovery of differential electrodermal responding to both classes of CSs in the control group, but not in the US-reactivation group. These findings indicate that the US reactivation-extinction procedure eliminated recovery of extinguished responding not only to fear-irrelevant, but also to fear-relevant CSs. Contrasting previous reports, our findings show that post-reconsolidation recovery of conditioned responding is not a function of CS fear-relevance and that persistent reduction of fear, conditioned to fear-relevant CSs, can be achieved through behavioral manipulations of reconsolidation. Copyright © 2017 Elsevier Ltd. All rights reserved.
Vinish Agarwal; Saurabh Varshney; Sampan Singh Bist; Sanjiv Bhagat; Sarita Mishra; Vivek Jha
Auditory neuropathy (AN)/auditory dyssynchrony (AD) is a very often missed diagnosis, hence an underdiagnosed condition in clinical practice. Auditory neuropathy is a condition in which patients, on audiologic evaluation, are found to have normal outer hair cell function and abnormal neural function at the level of the eighth nerve. These patients, on clinical testing, are found to have normal otoacoustic emissions, whereas auditory brainstem response audiometry reveals the absence of neural ...
Kunze, A.E.; Arntz, A.; Kindt, M.
Background and objectives: We argue that the stimuli used in traditional fear conditioning paradigms are too simple to model the learning and unlearning of complex fear memories. We therefore developed and tested an adapted fear conditioning paradigm, specifically designed for the study of complex
Dunsmoor, Joseph E.; Mitroff, Stephen R.; LaBar, Kevin S.
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…
Giachero, Marcelo; Calfa, Gaston D.; Molina, Victor A.
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…
Gökdemir, Selim; Gündüz, Ayşegül; Özkara, Çiğdem; Kızıltan, Meral E
We hypothesized that fear-conditioning may increase motor cortical excitability in preparation for response to fear. We tested our hypothesis in healthy subjects and in the second step, to determine the role of amygdala in alterations of motor cortex excitability, we included a group of patients who previously underwent unilateral amygdalo-hippocampectomy for temporal lobe epilepsy. In the first step, we included 16 healthy volunteers. In the second step, 14 patients who previously underwent unilateral amygdalo-hippocampectomy for temporal lobe epilepsy and who were seizure-free were included in the study. Motor evoked potentials (MEPs) recorded over right hand were recorded twice before and after the observation of fearful faces (fear-conditioning). Auditory startle response (ASR) was also recorded. Comparisons of before and after fear-conditioning MEP parameters within the healthy subjects group showed MEP amplitude was higher after fear-conditioning (p=0.019). Same comparison in patients with unilateral amygdalo-hippocampectomy demonstrated shorter MEP latency (p=0.036) and higher MEP amplitudes after fear-conditioning (p=0.046). CSPs did not show any change after this paradigm in both groups. Comparisons of ASR findings before and after fear-conditioning demonstrated enhanced responses after fear-conditioning in both healthy subjects and in patients with unilateral amygdalo-hippocampectomy. For MEPs or ASRs, there was a similar enhancement in patients with left- or right-sided operation. Fear-potentiation of both corticospinal and reticulospinal pathways occurs in healthy humans and bilateral potentiation of ASR and potentiation of MEPs are maintained even after resection of unilateral amygdala regardless of its side. Copyright © 2017 Elsevier B.V. All rights reserved.
Michael Lukas Meier
Full Text Available Experimental fear conditioning in humans is widely used as a model to investigate the neural basis of fear learning and to unravel the pathogenesis of anxiety disorders. It has been observed that fear conditioning depends on stimulus salience and subject vulnerability to fear. It is further known that the prevalence of dental-related fear and phobia is exceedingly high in the population. Dental phobia is unique as no other body part is associated with a specific phobia. Therefore, we hypothesized that painful dental stimuli exhibit an enhanced susceptibility to fear conditioning when comparing to equal perceived stimuli applied to other body sites. Differential susceptibility to pain-related fear was investigated by analyzing responses to an unconditioned stimulus (UCS applied to the right maxillary canine (UCS-c versus the right tibia (UCS-t. For fear conditioning, UCS-c and USC-t consisted of painful electric stimuli, carefully matched at both application sites for equal intensity and quality perception. UCSs were paired to simple geometrical forms which served as conditioned stimuli (CS+. Unpaired CS+ were presented for eliciting and analyzing conditioned fear responses. Outcome parameter were 1 skin conductance changes and 2 time-dependent brain activity (BOLD responses in fear-related brain regions such as the amygdala, anterior cingulate cortex, insula, thalamus, orbitofrontal cortex and medial prefrontal cortex.A preferential susceptibility of dental pain to fear conditioning was observed, reflected by heightened skin conductance responses and enhanced time-dependent brain activity (BOLD responses in the fear network. For the first time, this study demonstrates fear-related neurobiological mechanisms that point towards a superior conditionability of tooth pain. Beside traumatic dental experiences our results offer novel evidence that might explain the high prevalence of dental-related fears in the population.
Dityatev, Alexander E; Bolshakov, Vadim Y
Fear conditioning, during which emotional significance is attached to an initially biologically insignificant conditioned stimulus, when such neutral stimulus is paired with an aversive unconditioned stimulus, provides an experimental paradigm that is most commonly used to study fear learning. The amygdala, a sub-cortical nuclear group, is a brain structure critically important for fear conditioning. Recent studies indicate that both fear conditioning-induced neuronal plasticity and LTP at the amygdala synapses share common mechanisms of induction and expression. These findings provide the most direct evidence yet available that the mechanisms of LTP are recruited in the experimental animals during behavioral training and that such mechanisms might be utilized for memory storage.
Kunze, Anna E; Arntz, Arnoud; Kindt, Merel
We argue that the stimuli used in traditional fear conditioning paradigms are too simple to model the learning and unlearning of complex fear memories. We therefore developed and tested an adapted fear conditioning paradigm, specifically designed for the study of complex associative memories. Second, we explored whether manipulating the meaning and complexity of the CS-UCS association strengthened the learned fear association. In a two-day differential fear conditioning study, participants were randomly assigned to two experimental conditions. All participants were subjected to the same CSs (i.e., pictures) and UCS (i.e., 3 s film clip) during fear conditioning. However, in one of the conditions (negative-relevant context), the reinforced CS and UCS were meaningfully connected to each other by a 12 min aversive film clip presented prior to fear acquisition. Participants in the other condition (neutral context) were not able to make such meaningful connection between these stimuli, as they viewed a neutral film clip. Fear learning and unlearning were observed on fear-potentiated startle data and distress ratings within the adapted paradigm. Moreover, several group differences on these measures indicated increased UCS valence and enhanced associative memory strength in the negative-relevant context condition compared to the neutral context condition. Due to technical equipment failure, skin conductance data could not be interpreted. The fear conditioning paradigm as presented in the negative-relevant context condition holds considerable promise for the study of complex associative fear memories and therapeutic interventions for such memories. Copyright © 2014 Elsevier Ltd. All rights reserved.
Fredrikson, Mats; Annas, Peter; Hettema, John M
Fear conditioning seems to account for the acquisition of post-traumatic stress disorder, whereas conscious recall of events in aftermath of trauma reflects episodic memory. Studies show that both fear conditioning and episodic memory are heritable, but no study has evaluated whether they reflect common or separate genetic factors. To this end, we studied episodic memory and fear conditioning in 173 healthy twin pairs using visual stimuli predicting unconditioned electric shocks. Fear conditioning acquisition and extinction was determined using conditioned visual stimuli predicting unconditioned mild electric shocks, whereas electrodermal activity served as the fear learning index. Episodic memory was evaluated using cued recall of pictorial stimuli unrelated to conditioning. We used multivariate structural equation modeling to jointly analyze memory performance and acquisition as well as extinction of fear conditioning. Best-fit twin models estimated moderate genetic loadings for conditioning and memory measures, with no genetic covariation between them. Individual differences in fear conditioning and episodic memory reflect distinct genetically influenced processes, suggesting that the genetic risk for learning-induced anxiety disorders includes at least two memory-related genetic factors. These findings are consistent with the facts that the two separate learning forms are distant in their evolutionary development, involve different brain mechanisms, and support that genetically independent memory systems are pivotal in the development and maintenance of syndromes related to fear learning.
Silva, R. C. B.; Cruz, A. P. M.; Avanzi, V.; Landeira-Fernandez, J.; Brandão, M. L.
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
Findings from animal and human experimental studies highlight the importance of fear conditioning processes in the development and treatment of anxiety disorders. The work reported in this thesis was focused on potential abnormalities in the acquisition and extinction of fear in patients with
Catlow, Briony J; Song, Shijie; Paredes, Daniel A; Kirstein, Cheryl L; Sanchez-Ramos, Juan
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.
Full Text Available "nThe purpose of the present study was to determine the role of medial prefrontal cortex (mPFC dopaminergic system in fear conditioning response considering individual differences. Animals were initially counterbalanced and classified based on open field test, and then were given a single infusion of the dopamine agonist, amphetamine (AMPH and antagonist, clozapine (CLZ into the medial prefrontal cortex. Rats received tone-shock pairing in a classical fear conditioning test and then exposed to the tone alone. Freezing responses were measured as conditioned fear index. The results showed that both AMPH and CLZ infusion in mPFC reduced the expression of conditioned fear. This finding indicates that elevation or reduction in the dopaminergic activity is associated with the decrease of fear responses, despite preexisting individual-typological differences.
Pickens, Charles L; Golden, Sam A; Adams-Deutsch, Tristan; Nair, Sunila G; Shaham, Yavin
In 1937, Diven reported that human fear responses to cues previously paired with shock progressively increase or incubate over 24 hours. Since then, fear incubation has been demonstrated in both humans and nonhumans. However, the difficulty of demonstrating long-lasting fear incubation in rodents has hampered the study of the underlying mechanisms of this incubation. Here, we describe a rat procedure where fear reliably incubates over time. We trained food-restricted rats to lever-press for food pellets in daily 90-min sessions. We then gave each rat 100 30-sec tones co-terminating with a .5-sec .5-mA footshock over 10 days (10 pairings/day). Groups of rats (n = 10-15) were then given four presentations of the tone (the fear cue) 2, 15, 31, or 61 days after fear conditioning training and were assessed for conditioned suppression of lever-pressing. We found that conditioned fear responses were significantly higher 31 and 61 days after fear training than after 2 or 15 days. In control experiments, we showed that extensive tone-shock pairing is necessary for the emergence of fear incubation and that it is unlikely that non-associative factors contribute to this incubation. We describe a procedure for generating reliable and long-lasting conditioned fear incubation. Our procedure can be used to study mechanisms of fear incubation and might provide a model for studying the mechanisms of delayed-onset posttraumatic stress disorder that occur in a sub-population of people previously exposed to chronic stressors.
Pickens, Charles L.; Golden, Sam A.; Adams-Deutsch, Tristan; Nair, Sunila G.; Shaham, Yavin
Background In 1937, Diven (1) reported that human fear responses to cues previously paired with shock progressively increase or incubate over 24 hours. Since then, fear incubation has been demonstrated in both humans and nonhumans. However, the difficulty of demonstrating long-lasting fear incubation in rodents has hampered the study of the underlying mechanisms of this incubation. Here, we describe a rat procedure where fear reliably incubates over time. Methods We trained food-restricted rats to lever-press for food pellets in daily 90-min sessions. We then gave each rat one-hundred 30-s tones co-terminating with a 0.5-s, 0.5 mA footshock over 10 days (10 pairings per day). Groups of rats (n=10-15) were then given 4 presentations of the tone (the fear cue) 2, 15, 31 or 61 days after fear conditioning training and were assessed for conditioned suppression of lever-pressing. Results We found that conditioned fear responses were significantly higher 31 and 61 days after fear training than after 2 or 15 days. In control experiments, we showed that extensive tone-shock pairing is necessary for the emergence of fear incubation, and that it is unlikely that non-associative factors contribute to this incubation. Conclusions We describe a procedure for generating reliable and long-lasting conditioned fear incubation. Our procedure can be used to study mechanisms of fear incubation, and may provide a model for studying the mechanisms of delayed-onset posttraumatic stress disorder that occur in a sub-population of people previously exposed to chronic stressors. PMID:19167702
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
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. 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. Ninety-six healthy volunteers (44 males) aged 18-28 y. 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 memory extinction without altering sleep profiles. © 2015 Associated Professional Sleep Societies, LLC.
Zorawski, Michael; Cook, Craig A; Kuhn, Cynthia M; LaBar, Kevin S
It has long been recognized that humans vary in their conditionability, yet the factors that contribute to individual variation in emotional learning remain to be delineated. The goal of the present study was to investigate the relationship among sex, stress hormones, and fear conditioning in humans. Forty-five healthy adults (22 females) underwent differential delay conditioning, using fear-relevant conditioned stimuli and a shock unconditioned stimulus. Salivary cortisol samples were taken at baseline and after acquisition training and a 24-h-delayed retention test. The results showed that acquisition of conditioning significantly correlated with postacquisition cortisol levels in males, but not in females. This sex-specific relationship was found despite similar overall levels of conditioning, unconditioned responding, and cortisol. There was no effect of postacquisition cortisol on consolidation of fear learning in either sex. These findings have implications for the understanding of individual differences in fear acquisition and risk factors for the development of affective disorders.
Parvin Babaei; Bahram Soltani Tehrani; Arsalan Alizadeh; Morteza Nakhostin
"nThe purpose of the present study was to determine the role of medial prefrontal cortex (mPFC) dopaminergic system in fear conditioning response considering individual differences. Animals were initially counterbalanced and classified based on open field test, and then were given a single infusion of the dopamine agonist, amphetamine (AMPH) and antagonist, clozapine (CLZ) into the medial prefrontal cortex. Rats received tone-shock pairing in a classical fear conditioning test and then e...
Pace-Schott, Edward F.; Germain, Anne; Milad, Mohammed R.
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
Full Text Available 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.
Cornelisse, Sandra; van Ast, Vanessa A; Joëls, Marian; Kindt, Merel
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. Copyright © 2013 Elsevier Ltd. All rights reserved.
Mikami, Kaori; Kiyokawa, Yasushi; Takeuchi, Yukari; Mori, Yuji
In social species, the phenomenon in which the presence of conspecific animals mitigates stress responses is called social buffering. We previously reported that social buffering in male rats ameliorated behavioral fear responses, as well as hypothalamic-pituitary-adrenal axis activation, elicited by an auditory conditioned stimulus (CS). However, after social buffering, it is not clear whether rats exhibit fear responses when they are re-exposed to the same CS in the absence of another rat. In the present study, we addressed this issue using an experimental model of extinction. High stress levels during extinction training impaired extinction, suggesting that extinction is enhanced when stress levels during extinction training are low. Therefore, we hypothesized that rats that had received social buffering during extinction training would not show fear responses to a CS, even in the absence of another rat, because social buffering had enhanced the extinction of conditioned fear responses. To test this, we subjected male fear-conditioned rats to extinction training either alone or with a non-conditioned male rat. The subjects were then individually re-exposed to the CS in a recall test. When the subjects individually underwent extinction training, no responses were suppressed in the recall test. Conversely, when the subjects received social buffering during extinction training, freezing and Fos expression in the paraventricular nucleus of the hypothalamus and lateral amygdala were suppressed. Additionally, the effects of social buffering were absent when the recall test was conducted in a different context from the extinction training. The present results suggest that social buffering enhances extinction of conditioned fear responses. Copyright © 2016 Elsevier Inc. All rights reserved.
Funamizu, Akihiro; Kanzaki, Ryohei; Takahashi, Hirokazu
Neural representation in the auditory cortex is rapidly modulated by both top-down attention and bottom-up stimulus properties, in order to improve perception in a given context. Learning-induced, pre-attentive, map plasticity has been also studied in the anesthetized cortex; however, little attention has been paid to rapid, context-dependent modulation. We hypothesize that context-specific learning leads to pre-attentively modulated, multiplex representation in the auditory cortex. Here, we investigate map plasticity in the auditory cortices of anesthetized rats conditioned in a context-dependent manner, such that a conditioned stimulus (CS) of a 20-kHz tone and an unconditioned stimulus (US) of a mild electrical shock were associated only under a noisy auditory context, but not in silence. After the conditioning, although no distinct plasticity was found in the tonotopic map, tone-evoked responses were more noise-resistive than pre-conditioning. Yet, the conditioned group showed a reduced spread of activation to each tone with noise, but not with silence, associated with a sharpening of frequency tuning. The encoding accuracy index of neurons showed that conditioning deteriorated the accuracy of tone-frequency representations in noisy condition at off-CS regions, but not at CS regions, suggesting that arbitrary tones around the frequency of the CS were more likely perceived as the CS in a specific context, where CS was associated with US. These results together demonstrate that learning-induced plasticity in the auditory cortex occurs in a context-dependent manner.
Full Text Available Neural representation in the auditory cortex is rapidly modulated by both top-down attention and bottom-up stimulus properties, in order to improve perception in a given context. Learning-induced, pre-attentive, map plasticity has been also studied in the anesthetized cortex; however, little attention has been paid to rapid, context-dependent modulation. We hypothesize that context-specific learning leads to pre-attentively modulated, multiplex representation in the auditory cortex. Here, we investigate map plasticity in the auditory cortices of anesthetized rats conditioned in a context-dependent manner, such that a conditioned stimulus (CS of a 20-kHz tone and an unconditioned stimulus (US of a mild electrical shock were associated only under a noisy auditory context, but not in silence. After the conditioning, although no distinct plasticity was found in the tonotopic map, tone-evoked responses were more noise-resistive than pre-conditioning. Yet, the conditioned group showed a reduced spread of activation to each tone with noise, but not with silence, associated with a sharpening of frequency tuning. The encoding accuracy index of neurons showed that conditioning deteriorated the accuracy of tone-frequency representations in noisy condition at off-CS regions, but not at CS regions, suggesting that arbitrary tones around the frequency of the CS were more likely perceived as the CS in a specific context, where CS was associated with US. These results together demonstrate that learning-induced plasticity in the auditory cortex occurs in a context-dependent manner.
McDannald, Michael A; Galarce, Ezequiel M
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. Copyright © 2011 Elsevier B.V. All rights reserved.
Leung, Hiu T.; Holmes, Nathan M.; Westbrook, R. Frederick
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…
Geller, Daniel A; McGuire, Joseph F; Orr, Scott P; Pine, Daniel S; Britton, Jennifer C; Small, Brent J; Murphy, Tanya K; Wilhelm, Sabine; Storch, Eric A
Fear acquisition and extinction are central constructs in the cognitive-behavioral model of obsessive-compulsive disorder (OCD), which underlies exposure-based cognitive-behavioral therapy. Youths with OCD may have impairments in fear acquisition and extinction that carry treatment implications. Eighty youths (39 OCD, 41 healthy controls [HC]) completed clinical interviews, rating scales, and a differential conditioning task that included habituation, acquisition, and extinction phases. Skin conductance response (SCR) served as the primary dependent measure. During habituation, participants with OCD exhibited a stronger orienting SCR to initial stimuli relative to HC participants. During acquisition, differential fear conditioning was observed for both groups as evidenced by larger SCRs to the visual conditioned stimulus paired with an aversive unconditioned stimulus (CS+) compared with a CS-; OCD participants exhibited a larger SCR to the CS+ relative to HC participants. The absolute magnitude of the unconditioned fear response was significantly larger in participants with OCD, compared with HC participants. During extinction, OCD participants continued to exhibit a differential SCR to the CS+ and CS-, whereas HC participants exhibited diminished SCR to both stimuli. Participants with OCD exhibit a different pattern of fear extinction relative to HC participants, suggestive of greater fear acquisition and impaired inhibitory learning.
Full Text Available Fear conditioning and extinction are basic forms of associative learning that have gained considerable clinical relevance in enhancing our understanding of anxiety disorders and facilitating their treatment. Modern neuroimaging techniques have significantly aided the identification of anatomical structures and networks involved in fear conditioning. On closer inspection, there is considerable variation in methodology and results between studies. This systematic review provides an overview of the current neuroimaging literature on fear conditioning and extinction on healthy subjects, taking into account methodological issues such as the conditioning paradigm. A Pubmed search, as of December 2008, was performed and supplemented by manual searches of bibliographies of key articles. Two independent reviewers made the final study selection and data extraction. A total of 46 studies on cued fear conditioning and/or extinction on healthy volunteers using positron emission tomography or functional magnetic resonance imaging were reviewed. The influence of specific experimental factors, such as contingency and timing parameters, assessment of conditioned responses, and characteristics of conditioned and unconditioned stimuli, on cerebral activation patterns was examined. Results were summarized descriptively. A network consisting of fear-related brain areas, such as amygdala, insula, and anterior cingulate cortex, is activated independently of design parameters. However, some neuroimaging studies do not report these findings in the presence of methodological heterogeneities. Furthermore, other brain areas are differentially activated, depending on specific design parameters. These include stronger hippocampal activation in trace conditioning and tactile stimulation. Furthermore, tactile unconditioned stimuli enhance activation of pain related, motor, and somatosensory areas. Differences concerning experimental factors may partly explain the variance
Pace-Schott, Edward F; Germain, Anne; Milad, Mohammed R
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 (c) 2015 APA, all rights reserved).
Full Text Available The ability to flexibly adapt responses to changes in the environment is important for survival. Previous research in humans separately examined the mechanisms underlying acquisition and extinction of aversive and appetitive conditioned responses. It is yet unclear how aversive and appetitive learning interact on a neural level during counterconditioning in humans. This functional magnetic resonance imaging (fMRI study investigated the interaction of fear conditioning and subsequent reward learning. In the first phase (fear acquisition, images predicted aversive electric shocks or no aversive outcome. In the second phase (counterconditioning, half of the CS+ and CS- were associated with monetary reward in the absence of electric stimulation. The third phase initiated reinstatement of fear through presentation of electric shocks, followed by CS presentation in the absence of shock or reward. Results indicate that participants were impaired at learning the reward contingencies for stimuli previously associated with shock. In the counterconditioning phase, prior fear association interacted with reward representation in the amygdala, where activation was decreased for rewarded compared to unrewarded CS- trials, while there was no reward-related difference in CS+ trials. In the reinstatement phase, an interaction of previous fear association and previous reward status was observed in a reward network consisting of substantia nigra / ventral tegmental area (SN/VTA, striatum and orbitofrontal cortex (OFC, where activation was increased by previous reward association only for CS- but not for CS+ trials. These findings suggest that during counterconditioning, prior fear conditioning interferes with reward learning, subsequently leading to lower activation of the reward network.
Biggs, Emma E; Meulders, Ann; Kaas, Amanda L; Goebel, R.; Vlaeyen, Johan W S
Fear of touch, due to allodynia and spontaneous pain, is not well-understood. Experimental methods to advance this topic are lacking, and therefore we propose a novel tactile conditioning paradigm. Seventy-six pain-free participants underwent acquisition in both a predictable and unpredictable pain
Guhn, Anne; Dresler, Thomas; Andreatta, Marta; Müller, Laura D; Hahn, Tim; Tupak, Sara V; Polak, Thomas; Deckert, Jürgen; Herrmann, Martin J
The extinction of conditioned fear depends on an efficient interplay between the amygdala and the medial prefrontal cortex (mPFC). In rats, high-frequency electrical mPFC stimulation has been shown to improve extinction by means of a reduction of amygdala activity. However, so far it is unclear whether stimulation of homologues regions in humans might have similar beneficial effects. Healthy volunteers received one session of either active or sham repetitive transcranial magnetic stimulation (rTMS) covering the mPFC while undergoing a 2-day fear conditioning and extinction paradigm. Repetitive TMS was applied offline after fear acquisition in which one of two faces (CS+ but not CS-) was associated with an aversive scream (UCS). Immediate extinction learning (day 1) and extinction recall (day 2) were conducted without UCS delivery. Conditioned responses (CR) were assessed in a multimodal approach using fear-potentiated startle (FPS), skin conductance responses (SCR), functional near-infrared spectroscopy (fNIRS), and self-report scales. Consistent with the hypothesis of a modulated processing of conditioned fear after high-frequency rTMS, the active group showed a reduced CS+/CS- discrimination during extinction learning as evident in FPS as well as in SCR and arousal ratings. FPS responses to CS+ further showed a linear decrement throughout both extinction sessions. This study describes the first experimental approach of influencing conditioned fear by using rTMS and can thus be a basis for future studies investigating a complementation of mPFC stimulation to cognitive behavioral therapy (CBT).
Full Text Available The extinction of conditioned fear is dependent on an efficient interplay between the amygdala and the medial prefrontal cortex (mPFC. In rats, high-frequency electrical mPFC stimulation was shown to improve extinction by a reduction of amygdala activity. However, so far it is unclear whether stimulation of homologues regions in humans might have similar beneficial effects.Healthy volunteers received one-session of either active or sham repetitive transcranial magnetic stimulation (rTMS covering the mPFC while undergoing a two-day fear conditioning and extinction paradigm. rTMS was applied offline after fear acquisition in which one of two faces (CS+ but not CS- was associated with an aversive scream (UCS. Immediate extinction learning (day 1 and extinction recall (day 2 were conducted without UCS delivery. Conditioned responses were assessed in a multimodal approach using fear-potentiated startle (FPS, skin conductance responses (SCR, functional near-infrared spectroscopy (fNIRS and self-report scales. Consistent with the hypothesis of a modulated processing of conditioned fear after high-frequency rTMS, the active group showed a reduced CS+/CS- discrimination during extinction learning as evident in FPS as well as in SCR and arousal ratings. FPS responses to CS+ further showed a linear decrement throughout both extinction sessions. This study describes the first experimental approach of influencing conditioned fear by using rTMS which can be a basis for future studies investigating a complementation of mPFC stimulation to cognitive behavioral therapy.
Shin, Jung-Won; Park, Hyunwoo; Cho, Yoonju; Lee, Suck; Yoon, Jiwon; Maeng, Sungho
The therapeutic goal for the treatment of posttraumatic stress disorder (PTSD) is to promote extinction and to prevent the relapse of fearful memories. Research has identified pharmacological treatments that may regulate the formation and extinction of fear memories, but not many reagents that block the relapse of extinguished fear are known. Radix Polygalae (RP) is an Asian herb used for sedation, and its ingredients have anxiolytic and antidepressant properties. As various neurological effects have been identified, we tested whether RP affects the relapse of fear. Freezing in response to a conditioned context and cues was used to measure the effects of RP in mice. In cohort 1 (n = 30), consolidation, extinction, and reinstatement were tested during the course of 18 days of treatment. In cohort 2 (n = 30), consolidation, extinction, and renewal were tested during 10 days of treatment. The consolidation, extinction, reinstatement, and possibly the renewal of context-induced freezing were inhibited due to the administration of RP in animal subjects. However, the effects of RP on the freezing responses of subjects elicited by conditioned auditory cues were less obvious. Because it effectively suppresses the consolidation of fear memories, RP may be used for primary and secondary prevention of symptoms in PTSD patients. Additionally, because it effectively suppresses the reinstatement and renewal of fear memories, RP may be applied for the prevention of fear relapse in PTSD patients who have undergone exposure therapy. PMID:28620325
Deal, Alex L.; Erickson, Kristen J.; Shiers, Stephanie I.; Burman, Michael A.
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
Deal, Alex L; Erickson, Kristen J; Shiers, Stephanie I; Burman, Michael A
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 (c) 2016 APA, all rights reserved).
Kaag, Anne Marije; Levar, Nina; Woutersen, Karlijn; Homberg, Judith; van den Brink, Wim; Reneman, Liesbeth; van Wingen, Guido
The authors investigated whether cocaine use disorder is associated with abnormalities in the neural underpinnings of aversive conditioning and extinction learning, as these processes may play an important role in the development and persistence of drug abuse. Forty male regular cocaine users and 51 male control subjects underwent a fear conditioning and extinction protocol during functional MRI. Skin conductance response was measured throughout the experiment as an index of conditioned responses. Cocaine users showed hyperresponsiveness of the amygdala and insula during fear conditioning, as well as hyporesponsiveness of the dorsomedial prefrontal cortex during extinction learning. In cocaine users, but not in control subjects, skin conductance responses were positively correlated with responsiveness of the insula, amygdala, and dorsomedial prefrontal cortex during fear conditioning but negatively correlated with responsiveness of the ventromedial prefrontal cortex during extinction learning. Increased sensitivity to aversive conditioned cues in cocaine users might be a risk factor for stress-relief craving in cocaine use disorder. These results support the postulated role of altered aversive conditioning in cocaine use disorder and may be an important step in understanding the role of aversive learning in the pathology of cocaine use disorder.
Nichola M Brydges
Full Text Available Functional magnetic resonance imaging (fMRI is a powerful method for exploring emotional and cognitive brain responses in humans. However rodent fMRI has not previously been applied to the analysis of learned behaviour in awake animals, limiting its use as a translational tool. Here we have developed a novel paradigm for studying brain activation in awake rats responding to conditioned stimuli using fMRI. Using this method we show activation of the amygdala and related fear circuitry in response to a fear-conditioned stimulus and demonstrate that the magnitude of fear circuitry activation is increased following early life stress, a rodent model of affective disorders. This technique provides a new translatable method for testing environmental, genetic and pharmacological manipulations on emotional and cognitive processes in awake rodent models.
Eifert, G H; Schermelleh, K
This study compared the effects of experimentally induced self-verbalizations (SV) on conditioned responses to fear-relevant (snakes) and fear-irrelevant (rabbits) stimuli. To extend the analysis of "preparedness theory" beyond its former reliance on physiological measures of fear, subjective and behavioral measures were also included. Using aversive tones (UCS) and slides of snakes or rabbits (CS), fear was classically conditioned in 44 volunteers. In 20 subsequent language conditioning trials without aversive tones, the same slides were paired with verbalizations referring either to positive features of the animals (stimulus-referent SV) or to approach behavior (response-referent SV). Skin conductance responses to fear-relevant stimuli were more readily acquired, of higher magnitude, and more resistant to extinction. Extinction was differentially affected by the two types of SV. Snakes were consistently evaluated more negatively than rabbits and approached less in a behavior test. Results are discussed in relation to preparedness theory and interpreted within Staats' social-behavioral learning paradigm.
Uwaya, Akemi; Lee, Hyunjin; Park, Jonghyuk; Lee, Hosung; Muto, Junko; Nakajima, Sanae; Ohta, Shigeo; Mikami, Toshio
Histone acetylation is regulated in response to stress and plays an important role in learning and memory. Chronic stress is known to deteriorate cognition, whereas acute stress facilitates memory formation. However, whether acute stress facilitates memory formation when it is applied after fear stimulation is not yet known. Therefore, this study aimed to investigate the effect of acute stress applied after fear training on memory formation, mRNA expression of brain-derived neurotrophic factor (BDNF), epigenetic regulation of BDNF expression, and corticosterone level in mice in vivo. Mice were subjected to acute immobilization stress for 30 min at 60 or 90 min after contextual fear conditioning training, and acetylation of histone 3 at lysine 14 (H3K14) and level of corticosterone were measured using western blot analysis and enzyme-linked immunosorbent assay (ELISA), respectively. A freezing behavior test was performed 24 h after training, and mRNA expression of BDNF was measured using real-time polymerase chain reactions. Different groups of mice were used for each test. Freezing behavior significantly decreased with the down-regulation of BDNF mRNA expression caused by acute immobilization stress at 60 min after fear conditioning training owing to the reduction of H3K14 acetylation. However, BDNF mRNA expression and H3K14 acetylation were not reduced in animals subjected to immobilization stress at 90 min after the training. Further, the corticosterone level was significantly high in mice subjected to immobilization stress at 60 min after the training. Acute immobilization stress for 30 min at 60 min after fear conditioning training impaired memory formation and reduced BDNF mRNA expression and H3K14 acetylation in the hippocampus of mice owing to the high level of corticosterone.
Pickens, C L; Navarre, B M; Nair, S G
We recently adapted the conditioned suppression of operant responding method to study fear incubation. We found that food-restricted rats show low fear 2 days after extended (10 d; 100 30-s tone-shock pairings) fear training and high fear after 1-2 months. Here, we studied a potential mechanism of fear incubation: extended food-restriction stress. We also studied whether fear incubation is observed after fear training with a prolonged-duration (6-min) tone conditioned stimulus (CS), and whether conditioned freezing incubates after extended training in rats with or without a concurrent operant task. Conditioned fear was assessed 2 days and 1 month after training. In the conditioned suppression method, fear incubation was reliably observed in rats under moderate food-restriction conditions (18-20 g food/day) that allowed for weight gain, and after extended (10 d), but not limited (1 d), fear training with the 6-min CS. Incubation of conditioned freezing was observed after extended fear training in rats lever-pressing for food and, to a lesser degree, in rats not performing an operant task. Results indicate that prolonged hunger-related stress does not account for fear incubation in the conditioned suppression method, and that fear incubation occurs to a longer-duration (6-min) fear CS. Extended training also leads to robust fear incubation of conditioned freezing in rats performing an operant task and weaker fear incubation in rats not performing an operant task. (c) 2010 IBRO. Published by Elsevier Ltd. All rights reserved.
Duvarci, Sevil; Nader, Karim
.... We show that the reconsolidation deficit does not show renewal after a contextual shift, whereas an extinguished auditory fear memory does under the same conditions and the deficit occurs regardless...
McGuire, Joseph F.; Orr, Scott P.; Wu, Monica S.; Lewin, Adam B.; Small, Brent J.; Phares, Vicky; Murphy, Tanya K.; Wilhelm, Sabine; Pine, Daniel S.; Geller, Daniel; Storch, Eric A.
Background Fear acquisition and extinction are central constructs in the cognitive-behavioral model of obsessive-compulsive disorder (OCD), which underlies exposure-based cognitive-behavioral therapy (CBT). Youth with OCD may have impairments in fear acquisition and extinction that carry treatment implications. We examined these processes using a differential conditioning procedure. Methods Forty-one youth (19 OCD, 22 community comparisons) completed a battery of clinical interviews, rating scales, and a differential conditioning task that included habituation, acquisition, and extinction phases. Skin conductance response (SCR) served as the primary dependent measure. Results During habituation, no difference between groups was observed. During acquisition, differential fear conditioning was observed across participants as evidenced by larger SCRs to the CS+ compared to CS−; there were no between-group differences. Across participants, the number and frequency of OCD symptoms and anxiety severity was associated with greater reactivity to stimuli during acquisition. During extinction, a three-way interaction and follow-up tests revealed that youth with OCD showed a different pattern of SCR extinction compared to the community comparison group. Conclusions Youth with OCD exhibit a different pattern of fear extinction relative to community comparisons. This may be attributed to impaired inhibitory learning and contingency awareness in extinction. Findings suggest the potential benefit of utilizing inhibitory-learning principles in CBT for youth with OCD, and/or augmentative retraining interventions prior to CBT to reduce threat bias and improve contingency detection. PMID:26799264
Lonsdorf, Tina B; Menz, Mareike M; Andreatta, Marta; Fullana, Miguel A; Golkar, Armita; Haaker, Jan; Heitland, Ivo; Hermann, Andrea; Kuhn, Manuel; Kruse, Onno; Meir Drexler, Shira; 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
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. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.
Yoshida, Masayuki; Okamura, Izumi; Uematsu, Kazumasa
To investigate the cognitive role of the cerebellum of fish, we conducted experiments examining effects of cerebellar manipulations on fear-related classical heart rate conditioning in goldfish. We performed two types of manipulations, one was total ablation of the corpus cerebelli and the other was localized cooling of the corpus cerebelli for reversible inactivation of the cerebellar function. Both the cardiac arousal response to the first presentation of the conditioned stimulus and the ca...
Noble, L J; Gonzalez, I J; Meruva, V B; Callahan, K A; Belfort, B D; Ramanathan, K R; Meyers, E; Kilgard, M P; Rennaker, R L; McIntyre, C K
Exposure-based therapies help patients with post-traumatic stress disorder (PTSD) to extinguish conditioned fear of trauma reminders. However, controlled laboratory studies indicate that PTSD patients do not extinguish conditioned fear as well as healthy controls, and exposure therapy has high failure and dropout rates. The present study examined whether vagus nerve stimulation (VNS) augments extinction of conditioned fear and attenuates PTSD-like symptoms in an animal model of PTSD. To model PTSD, rats were subjected to a single prolonged stress (SPS) protocol, which consisted of restraint, forced swim, loss of consciousness, and 1 week of social isolation. Like PTSD patients, rats subjected to SPS show impaired extinction of conditioned fear. The SPS procedure was followed, 1 week later, by auditory fear conditioning (AFC) and extinction. VNS or sham stimulation was administered during half of the extinction days, and was paired with presentations of the conditioned stimulus. One week after completion of extinction training, rats were given a battery of behavioral tests to assess anxiety, arousal and avoidance. Results indicated that rats given SPS 1 week prior to AFC (PTSD model) failed to extinguish the freezing response after eleven consecutive days of extinction. Administration of VNS reversed the extinction impairment and attenuated reinstatement of the conditioned fear response. Delivery of VNS during extinction also eliminated the PTSD-like symptoms, such as anxiety, hyperarousal and social avoidance for more than 1 week after VNS treatment. These results provide evidence that extinction paired with VNS treatment can lead to remission of fear and improvements in PTSD-like symptoms. Taken together, these findings suggest that VNS may be an effective adjunct to exposure therapy for the treatment of PTSD. PMID:28892066
Baartman, Tamzyn L; Swanepoel, Tanya; Barrientos, Ruth M; Laburn, Helen P; Mitchell, Duncan; Harden, Lois M
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. Copyright © 2017 Elsevier B.V. All rights reserved.
Schaap, Manon W. H.; van Oostrom, Hugo; Doornenbal, Arie; van 't Klooster, José; Baars, Annemarie M.; Arndt, Saskia S.; Hellebrekers, Ludo J.
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
Malkani, Seema; Wallace, Karin J; Donley, Melanie P; Rosen, Jeffrey B
Studies of gene expression following fear conditioning have demonstrated that the inducible transcription factor, egr-1, is increased in the lateral nucleus of the amygdala shortly following fear conditioning...
Misane, I.; Tovote, P.; Meyer, M.; Spiess, J.; Ögren, S.O.; Stiedl, O.
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
Amber N Baysinger
Full Text Available Intelligent behavior requires transient memory, which entails the ability to retain information over short time periods. A newly-emerging hypothesis posits that endogenous persistent firing (EPF is the neurophysiological foundation for aspects or types of transient memory. EPF is enabled by the activation of muscarinic acetylcholine receptors (mAChRs and is triggered by suprathreshold stimulation. EPF occurs in several brain regions, including the lateral amygdala (LA. The present study examined the role of amygdalar mAChRs in trace fear conditioning, a paradigm that requires transient memory. If mAChR-dependent EPF selectively supports transient memory, then blocking amygdalar mAChRs should impair trace conditioning, while sparing delay and context conditioning, which presumably do not rely upon transient memory. To test the EPF hypothesis, LA was bilaterally infused, prior to trace or delay conditioning, with either a mAChR antagonist (scopolamine or saline. Computerized video analysis quantified the amount of freezing elicited by the cue and by the training context. Scopolamine infusion profoundly reduced freezing in the trace conditioning group but had no significant effect on delay or context conditioning. This pattern of results was uniquely anticipated by the EPF hypothesis. The present findings are discussed in terms of a systems-level theory of how EPF in LA and several other brain regions might help support trace fear conditioning.
Wood, Suzanne C; Fay, Jonathan; Sage, Jennifer R; Anagnostaras, Stephan G
Emerging evidence suggests that cocaine and other drugs of abuse can interfere with many aspects of cognitive functioning. The authors examined the effects of 0.1-15mg/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 (15mg/kg) displayed significantly less contextual and cued memory, compared to saline control animals. Conversely, mice pre-treated with a very low dose of cocaine (0.1mg/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.
Fear – an emotion that we all experience in our life – may assume a variety of expressions. It occupies the intimate part of our being and may produce symptoms in our bodies; it may be manipulated for purposes of repression and social control. A frequent kind of this emotion is connected to the fear of losing or being abandoned by a loved one, a fear that we experience from the beginning of our life, when we are separated from our mother’s body. Fear is often connected with violence: there is...
Korte, S M; Bohus, B; de Boer, Sietse
The purpose of the study was to determine which stressor qualities (escapable vs. inescapable stress and unconditioned vs. conditioned stress) can potentiate fear in the elevated plus-maze. While inescapable stress potentiated fear, escapable stress did not, but escapable stress increased the
Osman, Homira; Sullivan, Jessica R
The objectives of this study were to determine (a) whether school-age children with typical hearing demonstrate poorer auditory working memory performance in multitalker babble at degraded signal-to-noise ratios than in quiet; and (b) whether the amount of cognitive demand of the task contributed to differences in performance in noise. It was hypothesized that stressing the working memory system with the presence of noise would impede working memory processes in real time and result in poorer working memory performance in degraded conditions. Twenty children with typical hearing between 8 and 10 years old were tested using 4 auditory working memory tasks (Forward Digit Recall, Backward Digit Recall, Listening Recall Primary, and Listening Recall Secondary). Stimuli were from the standardized Working Memory Test Battery for Children. Each task was administered in quiet and in 4-talker babble noise at 0 dB and -5 dB signal-to-noise ratios. Children's auditory working memory performance was systematically decreased in the presence of multitalker babble noise compared with quiet. Differences between low-complexity and high-complexity tasks were observed, with children performing more poorly on tasks with greater storage and processing demands. There was no interaction between noise and complexity of task. All tasks were negatively impacted similarly by the addition of noise. Auditory working memory performance was negatively impacted by the presence of multitalker babble noise. Regardless of complexity of task, noise had a similar effect on performance. These findings suggest that the addition of noise inhibits auditory working memory processes in real time for school-age children.
Full Text Available This study aimed to investigate whether interindividual differences in autonomic inhibitory control predict safety learning and fear extinction in an interoceptive fear conditioning paradigm. Data from a previously reported study (N = 40 were extended (N = 17 and re-analyzed to test whether healthy participants' resting heart rate variability (HRV - a proxy of cardiac vagal tone - predicts learning performance. The conditioned stimulus (CS was a slight sensation of breathlessness induced by a flow resistor, the unconditioned stimulus (US was an aversive short-lasting suffocation experience induced by a complete occlusion of the breathing circuitry. During acquisition, the paired group received 6 paired CS-US presentations; the control group received 6 explicitly unpaired CS-US presentations. In the extinction phase, both groups were exposed to 6 CS-only presentations. Measures included startle blink EMG, skin conductance responses (SCR and US-expectancy ratings. Resting HRV significantly predicted the startle blink EMG learning curves both during acquisition and extinction. In the unpaired group, higher levels of HRV at rest predicted safety learning to the CS during acquisition. In the paired group, higher levels of HRV were associated with better extinction. Our findings suggest that the strength or integrity of prefrontal inhibitory mechanisms involved in safety- and extinction learning can be indexed by HRV at rest.
This article examines the subject of fear. It's purpose is to get clearer about what it is, to find out what grounds it and to see if there is a way of living which is free of it. As a necessary preliminary to understanding, the paper points out the importance of staying with the feeling of fear as it arises. By direct and careful observation of one's own case-which is different from introspection-it is possible to see fear arise in relation to a variety of objects, and from that to perceive ...
Chang, Chun-hui; Maren, Stephen
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…
Kamprath, Kornelia; Hermann, Heike; Lutz, Beat; Marsicano, Giovanni; Cannich, Astrid; Wotjak, Carsten T.
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…
David S Reis
Full Text Available The cellular mechanisms supporting plasticity during memory consolidation have been a subject of considerable interest. De novo protein and mRNA synthesis in several brain areas are critical, and more recently protein degradation, mediated by the ubiquitin-proteasome system (UPS, has been shown to be important. Previous work clearly establishes a relationship between protein synthesis and protein degradation in the amygdala, but it is unclear whether cortical mechanisms of memory consolidation are similar to those in the amygdala. Recent work demonstrating a critical role for prefrontal cortex (PFC in the acquisition and consolidation of fear memory allows us to address this question. Here we use a PFC-dependent fear conditioning protocol to determine whether UPS mediated protein degradation is necessary for memory consolidation in PFC. Groups of rats were trained with auditory delay or trace fear conditioning and sacrificed 60 min after training. PFC tissue was then analyzed to quantify the amount of polyubiquinated protein. Other animals were trained with similar procedures but were infused with either a proteasome inhibitor (clasto-lactacystin β-lactone or a translation inhibitor (anisomycin in the PFC immediately after training. Our results show increased UPS-mediated protein degradation in the PFC following trace but not delay fear conditioning. Additionally, post-training proteasome or translation inhibition significantly impaired trace but not delay fear memory when tested the next day. Our results further support the idea that the PFC is critical for trace but not delay fear conditioning highlight the role of UPS-mediated degradation as critical for synaptic plasticity.
Full Text Available 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.The results suggest that an effective strategy to treat pathological anxiety should address cognitive re-evaluation of traumatic experiences
Nicholas L Balderston
Full Text Available The role of consciousness in learning has been debated for nearly 50 years. Recent studies suggest that conscious awareness is needed to bridge the gap when learning about two events that are separated in time, as is true for trace fear conditioning. This has been repeatedly shown and seems to apply to other forms of classical conditioning as well. In contrast to these findings, we show that individuals can learn to associate a face with the later occurrence of a shock, even if they are unable to perceive the face. We used a novel application of magnetoencephalography (MEG to non-invasively record neural activity from the amygdala, which is known to be important for fear learning. We demonstrate rapid (∼ 170-200 ms amygdala responses during the stimulus free period between the face and the shock. These results suggest that unperceived faces can serve as signals for impending threat, and that rapid, automatic activation of the amygdala contributes to this process. In addition, we describe a methodology that can be applied in the future to study neural activity with MEG in other subcortical structures.
De la Casa, Luís Gonzalo; Mena, Auxiliadora; Ruiz-Salas, Juán Carlos; Quintero, Esperanza; Papini, Mauricio R
Three experiments explored the link between reward shifts and latent inhibition (LI). Using consummatory procedures, rewards were either downshifted from 32% to 4% sucrose (Experiments 1-2), or upshifted from 4% to 32% sucrose (Experiment 3). In both cases, appropriate unshifted controls were also included. LI was implemented in terms of fear conditioning involving a single tone-shock pairing after extensive tone-only preexposure. Nonpreexposed controls were also included. Experiment 1 demonstrated a typical LI effect (i.e., disruption of fear conditioning after preexposure to the tone) in animals previously exposed only to 4% sucrose. However, the LI effect was eliminated by preexposure to a 32%-to-4% sucrose devaluation. Experiment 2 replicated this effect when the LI protocol was administered immediately after the reward devaluation event. However, LI was restored when preexposure was administered after a 60-min retention interval. Finally, Experiment 3 showed that a reward upshift did not affect LI. These results point to a significant role of negative emotion related to reward devaluation in the enhancement of stimulus processing despite extensive nonreinforced preexposure experience.
Balderston, Nicholas L; Schultz, Douglas H; Baillet, Sylvain; Helmstetter, Fred J
The role of consciousness in learning has been debated for nearly 50 years. Recent studies suggest that conscious awareness is needed to bridge the gap when learning about two events that are separated in time, as is true for trace fear conditioning. This has been repeatedly shown and seems to apply to other forms of classical conditioning as well. In contrast to these findings, we show that individuals can learn to associate a face with the later occurrence of a shock, even if they are unable to perceive the face. We used a novel application of magnetoencephalography (MEG) to non-invasively record neural activity from the amygdala, which is known to be important for fear learning. We demonstrate rapid (∼ 170-200 ms) amygdala responses during the stimulus free period between the face and the shock. These results suggest that unperceived faces can serve as signals for impending threat, and that rapid, automatic activation of the amygdala contributes to this process. In addition, we describe a methodology that can be applied in the future to study neural activity with MEG in other subcortical structures.
Robert S. Thompson
Full Text Available Activation of the stress response evokes a cascade of physiological reactions that may be detrimental when repeated or chronic, and when triggered after exposure to psychological/emotional stressors. Investigation of the physiological mechanisms responsible for the health damaging effects requires animal paradigms that repeatedly evoke a response to psychological/emotional stressors. To this end, adult male Sprague Dawley rats were repeatedly exposed (2X per day for 20 days to a context that they were conditioned to fear (conditioned fear test, CFT. Repeated exposure to CFT produced body weight loss, adrenal hypertrophy, thymic involution, and basal corticosterone elevation. In vivo biotelemetry measures revealed that CFT evokes sympathetic nervous system driven increases in heart rate (HR, mean arterial pressure (MAP, and core body temperature. Extinction of behavioral (freezing and physiological responses to CFT was prevented using minimal reinstatement footshock. MAP responses to the CFT did not diminish across 20 days of exposure. In contrast, HR and cardiac contractility responses declined by day 15, suggesting a shift toward vascular-dominated MAP (a pre-clinical marker of CV dysfunction. Flattened diurnal rhythms, common to stress-related mood/anxiety disorders, were found for most physiological measures. Thus, repeated CFT produces adaptations indicative of the health damaging effects of psychological/emotional stress.
Okada, R; Fujiwara, H; Mizuki, D; Araki, R; Yabe, T; Matsumoto, K
Post-weaning social isolation rearing (SI) in rodents elicits various behavioral abnormalities including attention deficit hyperactivity disorder-like behaviors. In order to obtain a better understanding of SI-induced behavioral abnormalities, we herein investigated the effects of SI on social affiliation and conditioned fear memory as well as the neuronal mechanism(s) underlying these effects. Four-week-old male mice were group-housed (GH) or socially isolated for 2-4 weeks before the experiments. The social affiliation test and fear memory conditioning were conducted at the age of 6 and 7 weeks, respectively. SI mice were systemically administered saline or test drugs 30 min before the social affiliation test and fear memory conditioning. Contextual and auditory fear memories were elucidated 1 and 4 days after fear conditioning. Social affiliation and contextual and auditory fear memories were weaker in SI mice than in GH mice. Methylphenidate (MPH), an inhibitor for dopamine transporters, ameliorated the SI-induced social affiliation deficit and the effect was attenuated by SCH23390, a D1 receptor antagonist, but not by sulpiride, a D2 receptor antagonist. On the other hand, tacrine, an acetylcholinesterase inhibitor, had no effect on this deficit. In contrast, tacrine improved SI-induced deficits in fear memories in a manner that was reversed by the muscarinic receptor antagonist scopolamine, while MPH had no effect on memory deficits. Neurochemical studies revealed that SI down-regulated the expression levels of the phosphorylated forms of neuro-signaling proteins, calmodulin-dependent kinase II (p-CaMKII), and cyclic AMP-responsive element binding protein (p-CREB), as well as early growth response protein-1 (Egr-1) in the hippocampus. The administration of MPH or tacrine before fear conditioning had no effect on the levels of the phosphorylated forms of the neuro-signaling proteins elucidated following completion of the auditory fear memory test; however
Kwapis, Janine L; Alaghband, Yasaman; López, Alberto J; White, André O; Campbell, Rianne R; Dang, Richard T; Rhee, Diane; Tran, Ashley V; Carl, Allison E; Matheos, Dina P; Wood, Marcelo A
Histone acetylation is a fundamental epigenetic mechanism that is dynamically regulated during memory formation. Histone acetyltransferases (HATs) and histone deacetylases (HDACs) compete to modulate histone acetylation, allowing for rapid changes in acetylation in response to a learning event. HDACs are known to be powerful negative regulators of memory formation, but it is not clear whether this function depends on HDAC enzymatic activity per se. Here, we tested whether the enzymatic activity of an individual Class I HDAC, HDAC3, has a role in fear memory formation in subregions of the hippocampus and amygdala. We found that fear conditioning drove expression of the immediate early genes cFos and Nr4a2 in the hippocampus, which coincided with reduced HDAC3 occupancy at these promoters. Using a dominant-negative, deacetylase-dead point mutant virus (AAV-HDAC3(Y298H)-v5), we found that selectively blocking HDAC3 deacetylase activity in either the dorsal hippocampus or basal nucleus of the amygdala enhanced context fear without affecting tone fear. Blocking HDAC3 activity in the lateral nucleus of the amygdala, on the other hand, enhanced tone, but not context fear memory. These results show for the first time that the enzymatic activity of HDAC3 functions to negatively regulate fear memory formation. Further, HDAC3 activity regulates different aspects of fear memory in the basal and lateral subregions of the amygdala. Thus, the deacetylase activity of HDAC3 is a powerful negative regulator of fear memory formation in multiple subregions of the fear circuit.
David Frausto Peña
Full Text Available 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 one 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 hours later. VNS-treated rats demonstrated a significant reduction in freezing after a single extinction training session similar to animals that received 5x the number of extinction pairings. To study plasticity in the IL-BLA pathway, we recorded evoked field potentials 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.
Wilensky, Ann E; Schafe, Glenn E; Kristensen, Morten Pilgaard
of the amygdala (CE), which serves as the principal output nucleus for the expression of conditioned fear responses. In the present study, we reexamined the roles of LA and CE. Specifically, we asked whether CE, like LA, might also be involved in fear learning and memory consolidation. Using functional...... inactivation methods, we first show that CE is involved not only in the expression but also the acquisition of fear conditioning. Next, we show that inhibition of protein synthesis in CE after training impairs fear memory consolidation. These findings indicate that CE is not only involved in fear expression...... but, like LA, is also involved in the learning and consolidation of pavlovian fear conditioning....
Mehta, Nehali; Lu, Bryan; Amir, Dorsa; Livingston, Briana; Santarelli, Anthony; Zhuravka, Irina
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 mA, 2 sec) during contextual fear conditioning. Following a recent (1 d) or remote (28 d) retention interval all subjects were returned to the original training context to measure fear memory and/or to a novel context to measure the specificity of fear conditioning. Our results indicate rats that received two or five shocks show an “incubation”-like enhancement of fear between recent and remote retention intervals, while single-shocked animals show stable levels of context fear memory. Moreover, when fear was tested in a novel context, 1 and 2 shocked groups failed to freeze, whereas five shocked rats showed a time-dependent generalization of context memory. Stress enhancement of fear learning to a second round of conditioning was evident in all previously shocked animals. Based on these results, we conclude that the severity or number of foot shocks determines not only the level of fear memory, but also the time-dependent incubation of fear and its generalization across distinct contexts. PMID:27317198
Full Text Available In a previous study we could show that social fear can be induced and extinguished using virtual reality (VR. In the present study, we aimed to investigate the belongingness effect in an operant social fear conditioning (SFC paradigm which consisted of an acquisition and an extinction phase. Forty-three participants used a joystick to approach different virtual male agents that served as conditioned stimuli. Participants were randomly allocated to one of two experimental conditions. In the electroshock condition, the unconditioned stimulus (US used during acquisition was an electric stimulation. In the social threat condition, the US consisted of an offense: a spit in the face, mimicked by a sound and a weak air blast to the participant’s neck combined with an insult. In both groups the US was presented when participants were close to the agent (75% contingency for CS+. Outcome variables included subjective, psychophysiological and behavioral data. As expected, fear and contingency ratings increased significantly during acquisition and the differentiation between CS+ and CS- vanished during extinction. Furthermore, a clear difference in skin conductance between CS+ and CS- at the beginning of the acquisition indicated that SFC had been successful. However, a fast habituation to the US was found toward the end of the acquisition phase for the physiological response. Furthermore, participants showed avoidance behavior toward CS+ in both conditions. The results show that social fear can successfully be induced and extinguished in VR in a human sample. Thus, our paradigm can help to gain insight into learning and unlearning of social fear. Regarding the belongingness effect, the social threat condition benefits from a better differentiation between the aversive and the non-aversive stimuli. As next step we suggest comparing social-phobic patients to healthy controls in order to investigate possible differences in discrimination learning and to
Raybuck, Jonathan D.; Lattal, K. Matthew
A key finding in studies of the neurobiology of learning memory is that the amygdala is critically involved in Pavlovian fear conditioning. This is well established in delay-cued and contextual fear conditioning; however, surprisingly little is known of the role of the amygdala in trace conditioning. Trace fear conditioning, in which the CS and US are separated in time by a trace interval, requires the hippocampus and prefrontal cortex. It is possible that recruitment of cortical structures by trace conditioning alters the role of the amygdala compared to delay fear conditioning, where the CS and US overlap. To investigate this, we inactivated the amygdala of male C57BL/6 mice with GABA A agonist muscimol prior to 2-pairing trace or delay fear conditioning. Amygdala inactivation produced deficits in contextual and delay conditioning, but had no effect on trace conditioning. As controls, we demonstrate that dorsal hippocampal inactivation produced deficits in trace and contextual, but not delay fear conditioning. Further, pre- and post-training amygdala inactivation disrupted the contextual but the not cued component of trace conditioning, as did muscimol infusion prior to 1- or 4-pairing trace conditioning. These findings demonstrate that insertion of a temporal gap between the CS and US can generate amygdala-independent fear conditioning. We discuss the implications of this surprising finding for current models of the neural circuitry involved in fear conditioning. PMID:21283812
Wang, Melissa E; Fraize, Nicolas P; Yin, Linda; Yuan, Robin K; Petsagourakis, Despina; Wann, Ellen G; Muzzio, Isabel A
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. Copyright © 2013 Wiley Periodicals, Inc.
Lauren S Hopkins
Full Text Available 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.
Kim, Woong Bin; Cho, Jun-Hyeong
In auditory fear conditioning, experimental subjects learn to associate an auditory conditioned stimulus (CS) with an aversive unconditioned stimulus. With sufficient training, animals fear conditioned to an auditory CS show fear response to the CS, but not to irrelevant auditory stimuli. Although long-term potentiation (LTP) in the lateral amygdala (LA) plays an essential role in auditory fear conditioning, it is unknown whether LTP is induced selectively in the neural pathways conveying specific CS information to the LA in discriminative fear learning. Here, we show that postsynaptically expressed LTP is induced selectively in the CS-specific auditory pathways to the LA in a mouse model of auditory discriminative fear conditioning. Moreover, optogenetically induced depotentiation of the CS-specific auditory pathways to the LA suppressed conditioned fear responses to the CS. Our results suggest that input-specific LTP in the LA contributes to fear memory specificity, enabling adaptive fear responses only to the relevant sensory cue. VIDEO ABSTRACT. Copyright © 2017 Elsevier Inc. All rights reserved.
Huang, F; Yang, Z; Li, C-Q
Resistance to extinction of certain conditioned responses forms the basis of anxieties, phobias, and compulsions. There has been an available effective means of extinction-based exposure psychotherapy for the treatment of anxiety disorders, such as posttraumatic stress disorder (PTSD) that has been hypothesized to result from impaired extinction of fear memory. PTSD is considered as a memory disorder within a Pavlovian fear conditioning and extinction framework. Therefore, the aim of this review was to report the preclinical profile of melatonin, a pineal gland hormone, as a potential pharmacological option in the treatment of anxiety disorders such as PTSD, tested with the Pavlovian fear conditioning paradigm. We performed a literature review regarding studies that evaluated the effects of melatonin on fear conditioning and fear extinction. Results showed that a single administration 30min before conditioning has no effect on the acquisition of cued fear, but impaired contextual fear conditioning. Compared to rats injected with vehicle, rats injected with melatonin 30min before extinction training presented a significant lower freezing during both extinction training and extinction test phases. However, melatonin injected immediately after extinction training was ineffective on extinction learning. Melatonin impaired contextual fear conditioning, a hippocampus-dependent task. On the contrary, melatonin facilitates the extinction of conditional cued fear without affecting its acquisition or expression, and melatonin facilitates cued fear extinction only when it is present during extinction training. Although further studies are necessary, the research undertaken until now shows that melatonin modulates fear conditioning and fear extinction and consequently melatonin may serve as an agent for the treatment of PTSD. © 2017 Elsevier Inc. All rights reserved.
Chauret, Mélissa; La Buissonnière-Ariza, Valérie; Lamoureux Tremblay, Vickie; Suffren, Sabrina; Servonnet, Alice; Pine, Daniel S; Maheu, Françoise S
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. Copyright © 2014 Elsevier B.V. All rights reserved.
Itzhak, Yossef; Anderson, Karen L; Kelley, Jonathan B; Petkov, Martin
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. Copyright © 2012 Elsevier Inc. All rights reserved.
Koelsch, Stefan; Skouras, Stavros; Lohmann, Gabriele
Sound is a potent elicitor of emotions. Auditory core, belt and parabelt regions have anatomical connections to a large array of limbic and paralimbic structures which are involved in the generation of affective activity. However, little is known about the functional role of auditory cortical regions in emotion processing. Using functional magnetic resonance imaging and music stimuli that evoke joy or fear, our study reveals that anterior and posterior regions of auditory association cortex have emotion-characteristic functional connectivity with limbic/paralimbic (insula, cingulate cortex, and striatum), somatosensory, visual, motor-related, and attentional structures. We found that these regions have remarkably high emotion-characteristic eigenvector centrality, revealing that they have influential positions within emotion-processing brain networks with "small-world" properties. By contrast, primary auditory fields showed surprisingly strong emotion-characteristic functional connectivity with intra-auditory regions. Our findings demonstrate that the auditory cortex hosts regions that are influential within networks underlying the affective processing of auditory information. We anticipate our results to incite research specifying the role of the auditory cortex-and sensory systems in general-in emotion processing, beyond the traditional view that sensory cortices have merely perceptual functions.
Shechner, Tomer; Hong, Melanie; Britton, Jennifer C; Pine, Daniel S; Fox, Nathan A
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. Copyright © 2014 Elsevier B.V. All rights reserved.
Shechner, Tomer; Hong, Melanie; Britton, Jennifer C.; Pine, Daniel S.; Fox, Nathan A.
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. PMID:24746848
Cannich, Astrid; Carsten T. Wotjak; Kamprath, Kornelia; Hermann, Heike; Lutz, Beat; Marsicano, Giovanni
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 the phosphatase calcineurin as potential molecular substrates of extinction behavior. To test the involvement of these kinase and phosphatase activit...
Feng, Tingyong; Feng, Pan; Chen, Zhencai
Investigations of fear conditioning in rodents and humans have illuminated the neural mechanisms of fear acquisition and extinction. However, the neural mechanism of automatic memory consolidation of fear conditioning is still unclear. To address this question, we measured brain activity following fear acquisition using resting-state functional magnetic resonance imaging (rs-fMRI). In the current study, we used a marker of fMRI, amplitude of low-frequency (0.01-0.08Hz) fluctuation (ALFF) to quantify the spontaneous brain activity. Brain activity correlated to fear memory consolidation was observed in parahippocampus, insula, and thalamus in resting-state. Furthermore, after acquired fear conditioning, compared with control group some brain areas showed ALFF increased in ventromedial prefrontal cortex (vmPFC) and anterior cingulate cortex (ACC) in the experimental group, whereas some brain areas showed decreased ALFF in striatal regions (caudate, putamen). Moreover, the change of ALFF in vmPFC was positively correlated with the subjective fear ratings. These findings suggest that the parahippocampus, insula, and thalamus are the neural substrates of fear memory consolidation. The difference in activity could be attributed to a homeostatic process in which the vmPFC and ACC were involved in the fear recovery process, and change of ALFF in vmPFC predicts subjective fear ratings. Copyright © 2013 Elsevier B.V. All rights reserved.
Alina Beatrice Chesca
Full Text Available This paper approaches Otto Rank’s theory according to which the main cause of anxiety is the individual’s separation from the loved beings and objects. Along one’s life, anxiety takes two forms: the fear of life and the fear of death. The fear of life is the anxiety which appears when the person becomes aware of his creative abilities which could separate him from the existing relationships. Writers like Emil Cioran, Mihail Sebastian, Octavian Paler, Yukio Mishima, Ernest Hemingway suffered from the fear of life, they were haunted by a tragic that brought about theloneliness of death. It is what Kierkegaard called: ”the fatal disease”, the sin of the artist’s existence. The artistic process implies an oscillation between acceptance and rejection, satisfaction and negation, life and death, loneliness and happiness.
Kochli, Daniel E.; Thompson, Elaine C.; Fricke, Elizabeth A.; Postle, Abagail F.; Quinn, Jennifer J.
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…
Wilson, Yvette M.; Murphy, Mark
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…
Lazzaro, Stephanie C.; Hou, Mian; Cunha, Catarina; LeDoux, Joseph E.; Cain, Christopher K.
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…
Marschner, A.; Kalish, R.; Vervliet, B.; Vansteenwegen, D.; Büchel, C.
Lesion studies in animals have identified a critical role of the hippocampus in context fear conditioning. To extend these findings to human volunteers, we used functional magnetic resonance imaging to investigate neural responses associated with context fear conditioning in humans. Our novel
Full Text Available The extinction of conditioned fear is known to be context specific, and often referred to as more robustly contextually bound than the fear memory itself (Bouton, 2004. Yet, recent findings in rodents have challenged the notion that contextual fear retention is initially generalized. The context specificity of a cued-fear memory to the learning context has not been addressed in the human literature largely due to limitations in methodology. Here we adapt a novel technology to test the context specificity of cued fear conditioning using full immersion 3-dimensional virtual reality (VR. During acquisition training, healthy participants navigated through virtual environments containing dynamic snake and spider conditioned stimuli (CSs, one of which was paired with electrical wrist stimulation. During a 24-hour delayed retention test, one group returned to the same context as acquisition training whereas another group experienced the CSs in a novel context. Unconditioned stimulus (US expectancy ratings were assayed on-line during fear acquisition as an index of contingency awareness. Skin conductance responses (SCR time-locked to CS onset were the dependent measure of cued fear, and skin conductance levels during the interstimulus interval were an index of context fear. Findings indicate that early in acquisition training, participants express contingency awareness as well as differential contextual fear, whereas differential cued fear emerged later in acquisition. During the retention test, differential cued fear retention was enhanced in the group who returned to the same context as acquisition training relative to the context shift group. The results extend recent rodent work to illustrate differences in cued and context fear acquisition and the contextual specificity of recent fear memories. Findings support the use of full immersion VR as a novel tool in cognitive neuroscience to bridge rodent models of contextual phenomena underlying human
Zoicas, Iulia; Slattery, David A; Neumann, Inga D
Central oxytocin (OXT) has anxiolytic and pro-social properties both in humans and rodents, and has been proposed as a therapeutic option for anxiety and social dysfunctions. Here, we utilized a mouse model of social fear conditioning (SFC) to study the effects of OXT on social fear, and to determine whether SFC causes alterations in central OXT receptor (OXTR) binding and local OXT release. Central infusion of OXT, but not arginine vasopressin, prior to social fear extinction training completely abolished social fear expression in an OXTR-mediated fashion without affecting general anxiety or locomotion. SFC caused increased OXTR binding in the dorso-lateral septum (DLS), central amygdala, dentate gyrus, and cornu ammunis 1, which normalized after social fear extinction, suggesting that these areas form part of a brain network involved in the development and neural support of social fear. Microdialysis revealed that the increase in OXT release observed in unconditioned mice within the DLS during social fear extinction training was attenuated in conditioned mice. Consequently, increasing the availability of local OXT by infusion of OXT into the DLS reversed social fear. Thus, alterations in the brain OXT system, including altered OXTR binding and OXT release within the DLS, play an important role in SFC and social fear extinction. Thus, we suggest that the OXT system is adversely affected in disorders associated with social fear, such as social anxiety disorder and reinstalling an appropriate balance of the OXT system may alleviate some of the symptoms.
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
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.
Marks, Wendie N; Kalynchuk, Lisa E
Repeated exposure to high levels of stress hormones can enhance contextual and discrete fear conditioning in rats. A common belief is that this enhanced fear memory is largely mediated by the amygdala because both contextual and discrete fear conditioning are dependent on an intact amygdala. However, trace fear conditioning is thought to be amygdala independent, and therefore, it is not clear what impact stress would have on this form of fear learning. Here, we examined whether the stress hormone corticosterone (CORT) would enhance memory in a hippocampal-dependent trace fear conditioning test. Male Long-Evans rats received either 40mg/kg of CORT or vehicle injections for 21 consecutive days. On day 22, rats received either 1, 2, or 5 tone-trace-shock pairings. On day 23, the rats were tested for behavior to the conditioned tone cues in a novel context. We found that CORT significantly increased the acquisition of trace conditioned fear. We also found that CORT significantly increased recall of trace conditioned cues, but only when a 2 trace-pairing protocol was used during training. These results suggest that CORT can enhance non-amygdala forms of fear learning and memory and that high levels of stress hormones modify the physiological substrates that mediate emotionally driven behavior in tasks that are less dependent on amygdala functioning. Copyright © 2017 Elsevier Inc. All rights reserved.
Zoicas, Iulia; Slattery, David A.; Neumann, Inga D
Central oxytocin (OXT) has anxiolytic and pro-social properties both in humans and rodents, and has been proposed as a therapeutic option for anxiety and social dysfunctions. Here, we utilized a mouse model of social fear conditioning (SFC) to study the effects of OXT on social fear, and to determine whether SFC causes alterations in central OXT receptor (OXTR) binding and local OXT release. Central infusion of OXT, but not arginine vasopressin, prior to social fear extinction training comple...
Ponnusamy, Ravikumar; Nissim, Helen A.; Barad, Mark
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 that blockade of D2 receptors might facilitate extinction in mice, while agonists should block extinction, as they do in rats. One day after fear con...
Morgan, Simeon J; Paolini, Antonio G
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
Parkes, Shauna L; Westbrook, R Frederick
Laboratory rats learn to fear relatively innocuous stimuli which signal the imminent arrival of an innate source of danger, typically brief but aversive foot shock. Much is now known about the neural substrates underlying the acquisition, consolidation and subsequent expression of this fear. Rats also learn to fear stimuli which signal learned sources of danger but relatively little is known about the neural substrates underlying this form of fear. Two Pavlovian conditioning paradigms used to study this form of fear are second-order conditioning and sensory preconditioning. In second-order conditioning, rats are first exposed to a signaling relationship between one stimulus, such as a tone, and aversive foot shock, and then to a signaling relationship between a second stimulus, such as a light, and the now dangerous tone. In sensory preconditioning, these phases are reversed: rats are first exposed to a signaling relationship between the light and the tone and then to a signaling relationship between the tone and the foot shock. In both paradigms, rats exhibit fear when tested with the light. In this review paper, we describe the evidence for higher-order forms of conditioning, the conditions which promote this learning and its contents. We compare and contrast the substrates of the learning underlying second-order and sensory preconditioning fear with those known to underlie the better studied first-order conditioned fear. We conclude with some comments as to the role of higher-order processes in anxiety disorders.
Skelly, M J; Ariwodola, O J; Weiner, J L
Inappropriate fear memory formation is symptomatic of many psychopathologies, and delineating the neurobiology of non-pathological fear learning may provide critical insight into treating these disorders. Fear memory formation is associated with decreased inhibitory signaling in the basolateral amygdala (BLA), and disrupted noradrenergic signaling may contribute to this decrease. BLA noradrenergic neurotransmission has been implicated in fear memory formation, and distinct adrenoreceptor (AR) subtypes modulate excitatory and inhibitory neurotransmission in this region. For example, α1-ARs promote GABA release from local inhibitory interneurons, while β3-ARs potentiate neurotransmission at lateral paracapsular (LPC) GABAergic synapses. Conversely, β1/2-ARs amplify excitatory signaling at glutamatergic synapses in the BLA. As increased BLA excitability promotes fear memory formation, we hypothesized that fear learning shifts the balanced regional effects of noradrenergic signaling toward excitation. To test this hypothesis, we used the fear-potentiated startle paradigm in combination with whole cell patch clamp electrophysiology to examine the effects of AR activation on BLA synaptic transmission following fear conditioning in male Long-Evans rats. We first demonstrated that inhibitory neurotransmission is decreased at both local and LPC synapses following fear conditioning. We next measured noradrenergic facilitation of BLA inhibitory signaling at local and LPC synapses using α1-and β3-AR agonists (1 μM A61603 and 10 μM BRL37344), and found that the ability of these agents to facilitate inhibitory neurotransmission is disrupted following fear conditioning. Conversely, we found that fear learning does not disrupt noradrenergic modulation of glutamatergic signaling via a β1/2-AR agonist (1 μM isoproterenol). Taken together, these studies suggest that fear learning increases BLA excitability by selectively disrupting the inhibitory effects of noradrenaline
Thomas Francis Giustino
Full Text Available 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.
Heroux, Nicholas A.; Robinson-Drummer, Patrese A.; Sanders, Hollie R.; Rosen, Jeffrey B.; Stanton, Mark E.
The context preexposure facilitation effect (CPFE) is a contextual fear conditioning paradigm in which learning about the context, acquiring the context-shock association, and retrieving/expressing contextual fear are temporally dissociated into three distinct phases. In contrast, learning about the context and the context-shock association…
Graham, Bronwyn M.; Richardson, Rick
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…
This review addresses the effects of the cognitive enhancer D-cycloserine (DCS) on the memory processes that occur in conditioned fear extinction, which is the experimental model for exposure techniques to reduce clinical anxiety. All reported rat studies show an enhanced fear extinction effect when
Sabiha K Barot
Full Text Available Associative conditioning is a ubiquitous form of learning throughout the animal kingdom and fear conditioning is one of the most widely researched models for studying its neurobiological basis. Fear conditioning is also considered a model system for understanding phobias and anxiety disorders. A fundamental issue in fear conditioning regards the existence and location of neurons in the brain that receive convergent information about the conditioned stimulus (CS and unconditioned stimulus (US during the acquisition of conditioned fear memory. Convergent activation of neurons is generally viewed as a key event for fear learning, yet there has been almost no direct evidence of this critical event in the mammalian brain.Here, we used Arc cellular compartmental analysis of temporal gene transcription by fluorescence in situ hybridization (catFISH to identify neurons activated during single trial contextual fear conditioning in rats. To conform to temporal requirements of catFISH analysis we used a novel delayed contextual fear conditioning protocol which yields significant single- trial fear conditioning with temporal parameters amenable to catFISH analysis. Analysis yielded clear evidence that a population of BLA neurons receives convergent CS and US information at the time of the learning, that this only occurs when the CS-US arrangement is supportive of the learning, and that this process requires N-methyl-D-aspartate receptor activation. In contrast, CS-US convergence was not observed in dorsal hippocampus.Based on the pattern of Arc activation seen in conditioning and control groups, we propose that a key requirement for CS-US convergence onto BLA neurons is the potentiation of US responding by prior exposure to a novel CS. Our results also support the view that contextual fear memories are encoded in the amygdala and that the role of dorsal hippocampus is to process and transmit contextual CS information.
Haaker, Jan; Golkar, Armita; Selbing, Ida; Olsson, Andreas
Across the human life span, fear is often acquired indirectly by observation of the emotional expressions of others. The observational fear conditioning protocol was previously developed as a laboratory model for investigating socially acquired threat responses. This protocol serves as a suitable alternative to the widely used Pavlovian fear conditioning, in which threat responses are acquired through direct experiences. In the observational fear conditioning protocol, the participant (observer) watches a demonstrator being presented with a conditioned stimulus (CS) paired with an aversive unconditioned stimulus (US). The expression of threat learning is measured as the conditioned response (CR) expressed by the observer in the absence of the demonstrator. CRs are commonly measured as skin conductance responses, but behavioral and neural measures have also been implemented. The experimental procedure is suitable for divergent populations, can be administered by a graduate student and takes ∼40 min. Similar protocols are used in animals, emphasizing its value as a translational tool for studying socioemotional learning.
Ryoke, Rie; Yamada, Kazuo; Ichitani, Yukio
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. Copyright © 2014 Elsevier Inc. All rights reserved.
Duits, Puck; Cath, Danielle C; Lissek, Shmuel; Hox, Joop J; Hamm, Alfons O; Engelhard, Iris M; van den Hout, Marcel A; Baas, Joke M P
The aim of the current study was twofold: (1) to systematically examine differences in fear conditioning between anxiety patients and healthy controls using meta-analytic methods, and (2) to examine the extent to which study characteristics may account for the variability in findings across studies. Forty-four studies (published between 1920 and 2013) with data on 963 anxiety disordered patients and 1,222 control subjects were obtained through PubMed and PsycINFO, as well as from a previous meta-analysis on fear conditioning (Lissek et al.). Results demonstrated robustly increased fear responses to conditioned safety cues (CS-) in anxiety patients compared to controls during acquisition. This effect may represent an impaired ability to inhibit fear in the presence of safety cues (CS-) and/or may signify an increased tendency in anxiety disordered patients to generalize fear responses to safe stimuli resembling the conditioned danger cue (CS+). In contrast, during extinction, patients show stronger fear responses to the CS+ and a trend toward increased discrimination learning (differentiation between the CS+ and CS-) compared to controls, indicating delayed and/or reduced extinction of fear in anxiety patients. Finally, none of the included study characteristics, such as the type of fear measure (subjective vs. psychophysiological index of fear), could account significantly for the variance in effect sizes across studies. Further research is needed to investigate the predictive value of fear extinction on treatment outcome, as extinction processes are thought to underlie the beneficial effects of exposure treatment in anxiety disorders. © 2015 Wiley Periodicals, Inc.
Gewirtz, J C; Davis, M
Antagonists of NMDA (N-methyl-D-aspartate)-type glutamate receptors disrupt several forms of learning. Although this might indicate that NMDA-receptor-mediated processes are critical for synaptic plasticity, there may be other mechanisms by which NMDA-receptor antagonism could interfere with learning. For instance, fear conditioning would be blocked by microinfusion of the NMDA-receptor antagonist AP5 (D,L-2-amino-5-phosphonovalerate) into the basolateral amygdala if AP5 inhibited routine synaptic transmission, thereby reducing the ability of stimuli to activate amygdala neurons. In second-order fear conditioning, the reinforcer is a fear-eliciting conditioned stimulus rather than an unconditioned stimulus. Expression of conditioned fear is amygdala-dependent and so provides a behavioural assessment of the ability of the reinforcer to activate amygdala neurons in the presence of AP5. We report here that intra-amygdala AP5 actually enhances expression of conditioned fear to the conditioned stimulus that provides the reinforcement signal for second-order conditioning. Nevertheless, acquisition of second-order fear conditioning is completely blocked. Our findings strongly support the view that NMDA receptors are critically involved in synaptic plasticity.
Full Text Available Abstract Background Fear conditioning-induced changes in cerebellar Purkinje cell responses to a conditioned stimulus have been reported in rabbits. It has been suggested that synaptic long-term potentiation and the resulting increases in firing rates of Purkinje cells are related to the acquisition of conditioned fear in mammals. However, Purkinje cell activities during acquisition of conditioned fear have not been analysed, and changes in Purkinje cell activities throughout the development of conditioned fear have not yet been investigated. In the present study, we tracked Purkinje cell activities throughout a fear conditioning procedure and aimed to elucidate further how cerebellar circuits function during the acquisition and expression of conditioned fear. Methods Activities of single Purkinje cells in the corpus cerebelli were tracked throughout a classical fear conditioning procedure in goldfish. A delayed conditioning paradigm was used with cardiac deceleration as the conditioned response. Conditioning-related changes of Purkinje cell responses to a conditioned stimulus and unconditioned stimulus were examined. Results The majority of Purkinje cells sampled responded to the conditioned stimulus by either increasing or decreasing their firing rates before training. Although there were various types of conditioning-related changes in Purkinje cells, more than half of the cells showed suppressed activities in response to the conditioned stimulus after acquisition of conditioned fear. Purkinje cells that showed unconditioned stimulus-coupled complex-spike firings also exhibited conditioning-related suppression of simple-spike responses to the conditioned stimulus. A small number of Purkinje cells showed increased excitatory responses in the acquisition sessions. We found that the magnitudes of changes in the firing frequencies of some Purkinje cells in response to the conditioned stimulus correlated with the magnitudes of the conditioned
Barela, Peter B
Summary.-A preparation for the study of classical fear conditioning in vertebrates is described. Its unique features are that it is inexpensive and easy to construct and operate. The following classical conditioning phenomena are demonstrated using this preparation: excitatory conditioning, extinction, contextual conditioning, blocking, a conditioned inhibition discrimination, and latent inhibition.
Yoshida, Masayuki; Hirano, Ruriko
Besides the amygdala, of which emotion roles have been intensively studied, the cerebellum has also been demonstrated to play a critical role in simple classical fear conditioning in both mammals and fishes...
Cohn, M.D.; Popma, A.; van den Brink, W.; Pape, L.E.; Kindt, M.; van Domburgh, L.; Doreleijers, T.A.H.; Veltman, D.J.
Children diagnosed with Disruptive Behavior Disorders (DBD), especially those with psychopathic traits, are at risk of developing persistent and severe antisocial behavior. Deficient fear conditioning may be a key mechanism underlying persistence, and has been associated with altered regional brain
Kroon, Juliana A V; Carobrez, Antonio Pádua
In rodents, fear conditioned responses are more pronounced toward olfactory stimulus, since olfaction is a dominant sense in these subjects. The present study was outlined to investigate if the association between coffee odor (CS1) and electrical footshock (US) would be an effective model for the study of fear-induced behavior and whether compounds used in humans for emotional-related disorders such as midazolam, propranolol, or scopolamine, applied during the different stages of fear conditioning (acquisition, consolidation and expression), affect the defensive responses to both, the olfactory CS1, and the context (CS2) where the CS1 had been presented (second order conditioning). The results revealed that five pairings between coffee odor (CS1) and electrical footshock (US) were able to elicit consistent defensive responses and a second order conditioning to the context (CS2). Midazolam (0.375-0.5 mg/kg; i.p.) treatment was able to interfere with the CS1-US association and with the consolidation of the aversive information. The propranolol (5-10 mg/kg; i.p.) treatment interfered with the CS1-US association, with the retention of fear memory and with the CS1-CS2 association. Propranolol also attenuated the expression of conditioned fear responses when applied before the CS1 test session. Scopolamine (0.6-1.2 mg/kg; i.p.) treatment impaired the acquisition of CS1-US and CS1-CS2 associations, and also disrupted the expression of conditioned fear responses when injected prior to the CS1 test session. These findings have pointed out the usefulness for the olfactory fear conditioning paradigm to investigate drug effects on the acquisition, consolidation and expression of fear conditioned responses.
Hirano Ruriko; Yoshida Masayuki
Abstract Background Besides the amygdala, of which emotion roles have been intensively studied, the cerebellum has also been demonstrated to play a critical role in simple classical fear conditioning in both mammals and fishes. In the present study, we examined the effect of local administration of the anesthetic agent lidocaine into the cerebellum on fear-related, classical heart-rate conditioning in goldfish. Methods The effects of microinjection of the anesthetic agent lidocaine into the c...
Candace M. Raio
Full Text Available 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.
Bentz, Dorothée; Michael, Tanja; Wilhelm, Frank H; Hartmann, Francina R; Kunz, Sabrina; von Rohr, Isabelle R Rudolf; de Quervain, Dominique J-F
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. Copyright © 2013 Elsevier Ltd. All rights reserved.
Alvarez-Dieppa, Amanda C; Griffin, Kimberly; Cavalier, Sheridan; McIntyre, Christa K
Vagus nerve stimulation (VNS) enhances the consolidation of extinction of conditioned fear. High frequency stimulation of the infralimbic cortex (IL) produces long-term potentiation in the basolateral amygdala (BLA) in rats given VNS-paired extinction training, whereas the same stimulation produces long-term depression in sham-treated rats. The present study investigated the state of synaptic plasticity-associated proteins in the BLA that could be responsible for this shift. Male Sprague-Dawley rats were separated into 4 groups: auditory fear conditioning only (fear-conditioned); fear conditioning + 20 extinction trials (extended-extinction); fear conditioning + 4 extinction trials paired with sham stimulation (sham-extinction); fear conditioning + 4 extinction trials paired with VNS (VNS-extinction). Freezing was significantly reduced in extended-extinction and VNS-extinction rats. Western blots were used to quantify expression and phosphorylation state of synaptic plasticity-associated proteins such as Arc, CaMKII, ERK, PKA, and AMPA and NMDA receptors. Results show significant increases in GluN2B expression and phosphorylated CaMKII in BLA samples from VNS- and extended-extinction rats. Arc expression was significantly reduced in VNS-extinction rats compared to all groups. Administration of the GluN2B antagonist ifenprodil immediately after fear extinction training blocked consolidation of extinction learning. Results indicate a role for BLA CaMKII-induced GluN2B expression and reduced Arc protein in VNS-enhanced extinction.
Bouchet, Courtney A.; Lloyd, Brian A.; Loetz, Esteban C.; Farmer, Caroline E.; Ostrovskyy, Mykola; Haddad, Natalie; Foright, Rebecca M.; Greenwood, Benjamin N.
Fear extinction-based exposure therapy is the most common behavioral therapy for anxiety and trauma-related disorders, but fear extinction memories are labile and fear tends to return even after successful extinction. The relapse of fear contributes to the poor long-term efficacy of exposure therapy. A single session of voluntary exercise can…
Qureshi, Munazah F.; Jha, Sushil K.
The conditioning tasks have been widely used to model fear and anxiety and to study their association with sleep. Many reports suggest that sleep plays a vital role in the consolidation of fear memory. Studies have also demonstrated that fear-conditioning influences sleep differently in mice strains having a low or high anxiety level. It is, therefore, necessary to know, how sleep influences fear-conditioning and how fear-conditioning induces changes in sleep architecture in moderate anxious strains. We have used Swiss mice, a moderate anxious strain, to study the effects of: (i) sleep deprivation on contextual fear conditioned memory, and also (ii) contextual fear conditioning on sleep architecture. Animals were divided into three groups: (a) non-sleep deprived (NSD); (b) stress control (SC); and (c) sleep-deprived (SD) groups. The SD animals were SD for 5 h soon after training. We found that the NSD and SC animals showed 60.57% and 58.12% freezing on the testing day, while SD animals showed significantly less freezing (17.13% only; p sleep. REM sleep, however, significantly decreased in NSD and SC animals on the training and testing days. Interestingly, REM sleep did not decrease in the SD animals on the testing day. Our results suggest that short-term sleep deprivation impairs fear memory in moderate anxious mice. It also suggests that NREM sleep, but not REM sleep, may have an obligatory role in memory consolidation. PMID:29238297
Full Text Available 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.
Sun, P; Zhang, Q; Zhang, Y; Wang, F; Wang, L; Yamamoto, R; Sugai, T; Kato, N
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. Copyright © 2014 Elsevier Inc. All rights reserved.
Klumpers, Floris; Denys, Damiaan; Kenemans, J. Leon; Grillon, Christian; van der Aart, Jasper; Baas, Johanna M. P.
Preclinical evidence implicates several neurotransmitter systems in the extinction of conditioned fear. These results are of great interest, because the reduction of acquired fear associations is critical in therapies for anxiety disorders. We tested whether findings with respect to the
Klumpers, F.; Denys, D.; Kenemans, J.L.; Grillon, C.; van der Aart, J.; Baas, J.M.
Preclinical evidence implicates several neurotransmitter systems in the extinction of conditioned fear. These results are of great interest, because the reduction of acquired fear associations is critical in therapies for anxiety disorders. We tested whether findings with respect to the
Giorgi, Gabriele; Montani, Francesco; Fiz-Perez, Javier; Arcangeli, Giulio; Mucci, Nicola
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
Giorgi, Gabriele; Montani, Francesco; Fiz-Perez, Javier; Arcangeli, Giulio; Mucci, Nicola
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.
Full Text Available 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.
Akagi, Kie; Yamada, Misa; Saitoh, Akiyoshi; Oka, Jun-Ichiro; Yamada, Mitsuhiko
Recently, we demonstrated that riluzole, which has been shown to block the glutamatergic system, facilitates fear extinction in rats. Here, we undertook experiments on contextual fear conditioning to clarify the actions of riluzole on the reconsolidation of fear memory in rats. We used the fast-acting benzodiazepine midazolam as a reconsolidation-inhibiting control drug. We demonstrated that riluzole (3 mg/kg) and midazolam (1 mg/kg) impaired the reconsolidation of contextual fear memory. Results from spontaneous recovery experiments also suggested that riluzole attenuated reconsolidation. Indeed, conditioned fear did not recover spontaneously 4 weeks after a short (3 min) reexposure and riluzole administration, whereas it recovered after a long (10 min) reexposure. Using western blotting, we demonstrated that a short reexposure increased the phosphorylation of cyclic adenosine monophosphate response element binding protein significantly in the dorsal part of hippocampus, but not in the medial prefrontal cortex. Interestingly, this phosphorylation was attenuated by riluzole with short reexposure. In addition, bilateral microinjection of riluzole (2 μM/0.2 μl/side) directly into the dorsal hippocampus clearly attenuated the reconsolidation. These findings suggested that the attenuating effect of riluzole on the reconsolidation of fear memory involves, at least in part, the dorsal part of the hippocampus. In conclusion, we demonstrated that riluzole attenuates the reconsolidation of fear memory in rats. Copyright © 2017 Elsevier Ltd. All rights reserved.
Ferrara, Nicole C.; Cullen, Patrick K.; Pullins, Shane P.; Rotondo, Elena K.; Helmstetter, Fred J.
Generalization of fear can involve abnormal responding to cues that signal safety and is common in people diagnosed with post-traumatic stress disorder. Differential auditory fear conditioning can be used as a tool to measure changes in fear discrimination and generalization. Most prior work in this area has focused on elevated amygdala activity…
Shechner, Tomer; Hong, Melanie; Britton, Jennifer C.; Pine, Daniel S.; Fox, Nathan A.
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 cu...
Vansteenwegen, D.; Iberico, C.; Vervliet, B.; Hermans, D.
The present study was set up to investigate cued and contextual fear in situations of (un)predictability in a human fear conditioning paradigm. Forty-nine participants were presented with two different contexts (switching on and off the central lighting of the experimental room). In the predictable
Quiñones, María M.; Maldonado, Lizette; Velazquez, Bethzaly; Porter, James T.
Patients with post-traumatic stress disorder (PTSD) tend to show signs of a relatively increased inflammatory state suggesting that activation of the immune system may contribute to the development of PTSD. In the present study, we tested whether activation of the innate immune system can disrupt acquisition or recall of auditory fear extinction using an animal model of PTSD. Male adolescent rats received auditory fear conditioning in context A. The next day, an intraperitoneal injection of l...
VanElzakker, Michael B; Dahlgren, M Kathryn; Davis, F Caroline; Dubois, Stacey; Shin, Lisa M
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. Copyright © 2013 Elsevier Inc. All rights reserved.
VanElzakker, Michael B.; Dahlgren, M. Kathryn; Davis, F. Caroline; Dubois, Stacey; Shin, Lisa M.
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
Chester, Julia A; Weera, Marcus M
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
Wegerer, Melanie; Blechert, Jens; Kerschbaum, Hubert; Wilhelm, Frank H.
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
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
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. Copyright © 2015 Elsevier Inc. All rights reserved.
Butler, Ryan K; Ehling, Sarah; Barbar, Megan; Thomas, Jess; Hughes, Mary A; Smith, Charles E; Pogorelov, Vladimir M; Aryal, Dipendra K; Wetsel, William C; Lascelles, B Duncan X
Fear-conditioned analgesia (FCA) is modulated by brain areas involved in the descending inhibitory pain pathway such as the basolateral (BLA) and central amygdala (CEA). The BLA contains Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) and parvalbumin (PV) neurons. CEA neurons are primarily inhibitory (GABAergic) that comprise enkephalin (ENK) interneurons and corticotropin-releasing factor (CRF) - neurons that project to the periaqueductal grey. The purpose of our experiment was to determine the pattern of activation of CaMKII/PV and ENK/CRF neurons following the expression of acute pain, conditioned fear, and FCA. A significant reduction was observed in nociceptive behaviors in mice re-exposed to a contextually-aversive environment. Using NeuN and cFos as markers for activated neurons, CaMKII, PV, ENK, or CRF were used to identify neuronal subtypes. We find that mice expressing conditioned fear displayed an increase in c-Fos/CaMKII co-localization in the lateral amygdala and BLA compared to controls. Additionally a significant increase in cFos/CRF co-localization was observed in mice expressing FCA. These results show that amygdala processing of conditioned contextual aversive, nociceptive, and FCA behaviors involve different neuronal phenotypes and neural circuits between, within, and from various amygdala nuclei. This information will be important in developing novel therapies for treating pain and emotive disorders in humans. Copyright © 2017 Elsevier B.V. All rights reserved.
Park, Chun Hui J; Ganella, Despina E; Kim, Jee Hyun
We investigated whether juvenile rats do not express renewal following extinction of conditioned fear due to their inability to form a long-term contextual fear memory. In experiment 1, postnatal day (P) 18 and 25 rats received 3 white-noise and footshock pairings, followed by 60 white-noise alone presentations the next day. When tested in a different context to extinction, P25 rats displayed renewal whereas P18 rats did not. Experiments 2A and 2B surprisingly showed that P18 and P25 rats do not show differences in contextual and cued fear, regardless of the conditioning-test intervals and the number of white-noise-footshock pairings received. Finally, we observed age differences in contextual fear when P25 rats were weaned at P21 in experiment 3. These results indicate that the developmental dissociation observed in renewal of extinguished fear is not related to the widely believed late emergence of contextual fear learning. © 2017 Wiley Periodicals, Inc.
Kwapis, Janine L; Jarome, Timothy J; Lee, Jonathan L; Helmstetter, Fred J
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. Copyright © 2015 Elsevier Inc. All rights reserved.
Davis, Jennifer A.; James, John R.; Siegel, Steven J.; Gould, Thomas J.
The effects of acute nicotine administration (0.09 mg/kg nicotine), chronic nicotine administration (6.3 mg/kg/d nicotine for 14 d), and withdrawal from chronic nicotine administration on fear conditioning in C57BL/6 mice were examined. Mice were trained using two coterminating conditioned stimulus (30 s; 85 dB white noise)– unconditioned stimulus (2 s; 0.57 mA foot shock) pairings and tested 24 h later for contextual and cued fear conditioning. Acute nicotine administration enhanced contextu...
Munazah F. Qureshi
Full Text Available The conditioning tasks have been widely used to model fear and anxiety and to study their association with sleep. Many reports suggest that sleep plays a vital role in the consolidation of fear memory. Studies have also demonstrated that fear-conditioning influences sleep differently in mice strains having a low or high anxiety level. It is, therefore, necessary to know, how sleep influences fear-conditioning and how fear-conditioning induces changes in sleep architecture in moderate anxious strains. We have used Swiss mice, a moderate anxious strain, to study the effects of: (i sleep deprivation on contextual fear conditioned memory, and also (ii contextual fear conditioning on sleep architecture. Animals were divided into three groups: (a non-sleep deprived (NSD; (b stress control (SC; and (c sleep-deprived (SD groups. The SD animals were SD for 5 h soon after training. We found that the NSD and SC animals showed 60.57% and 58.12% freezing on the testing day, while SD animals showed significantly less freezing (17.13% only; p < 0.001 on the testing day. Further, we observed that contextual fear-conditioning did not alter the total amount of wakefulness and non-rapid eye movement (NREM sleep. REM sleep, however, significantly decreased in NSD and SC animals on the training and testing days. Interestingly, REM sleep did not decrease in the SD animals on the testing day. Our results suggest that short-term sleep deprivation impairs fear memory in moderate anxious mice. It also suggests that NREM sleep, but not REM sleep, may have an obligatory role in memory consolidation.
Kaag, A.M.; Levar, N.; Woutersen, K.; Homberg, J.; van den Brink, W.; Reneman, L.; van Wingen, G.
OBJECTIVE: The authors investigated whether cocaine use disorder is associated with abnormalities in the neural underpinnings of aversive conditioning and extinction learning, as these processes may play an important role in the development and persistence of drug abuse. METHOD: Forty male regular
Kaag, Anne Marije; Levar, Nina; Woutersen, Karlijn; Homberg, Judith; van den Brink, Wim; Reneman, Liesbeth; van Wingen, Guido
The authors investigated whether cocaine use disorder is associated with abnormalities in the neural underpinnings of aversive conditioning and extinction learning, as these processes may play an important role in the development and persistence of drug abuse. Forty male regular cocaine users and 51
Thomas, Brian L.; Vurbic, Drina; Novak, Cheryl
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…
Suppiej, Agnese; Cainelli, Elisa; Cappellari, Ambra; Ermani, Mario; Sartori, Stefano; Bisiacchi, Patrizia S
Cortical auditory evoked potentials may serve as an early indicator of developmental problems in the auditory cortex. The aim of the study was to determine the effect on neonatal cortical auditory processing of clinical conditions occurring in early prematurity. Sixty-seven preterm infants born at 29 weeks mean gestational age (range, 23-34 weeks) were recorded at a mean postconception age of 35 weeks, before discharge from the third level neonatal intensive care unit. The average of 330 responses to standard 1000 Hz pure tones delivered in an oddball paradigm was recorded at frontal location. Data of 45 of 67 recruited premature infants were available for analysis. Mean amplitudes calculated from the data points of 30 milliseconds centered on P1 and N2 peaks in the waveforms of each subject were measured. The effect of perinatal clinical factors on cortical auditory evoked responses was evaluated. The amplitude of P1 component was significantly lower in infants with bronco-pulmonary dysplasia (P = 0.004) and retinopathy of prematurity (P = 0.03). The multivariate analysis, done to evaluate the relative weight of gestational age and bronco-pulmonary dysplasia and/or retinopathy of prematurity on cortical auditory evoked potentials components, showed an effect of clinical factors on P1 (P = 0.005) and of gestational age on N2 (P = 0.02). Cortical auditory processing seems to be influenced by clinical conditions complicating extremely preterm birth.
Full Text Available Individual differences in appetitive learning have long been reported, and generally divide into two classes of responses: cue- vs. reward-directed. The influence of cue- vs. reward-directed phenotypes on aversive cue processing, is less well understood. In the current study, we first categorized rats based on their predominant cue-directed orienting responses during appetitive Pavlovian conditioning. Then, we investigated the effect of phenotype on the latency to exit a familiar dark environment and enter an unfamiliar illuminated open field. Next, we examined whether the two phenotypes responded differently to a reconsolidation updating manipulation (retrieval+extinction after fear conditioning. We report that the rats with a cue-directed (orienting phenotype differentially respond to the open field, and also to fear conditioning, depending on US-intensity. In addition, our findings suggest that, regardless of appetitive phenotype or shock intensity, extinction within the reconsolidation window prevents spontaneous recovery of fear.
Portugal, George S.; Wilkinson, Derek S.; Kenney, Justin W.; Sullivan, Colleen
The effects of nicotine on cognitive processes such as learning and memory may play an important role in the addictive liability of tobacco. However, it remains unknown whether genetic variability modulates the effects of nicotine on learning and memory. The present study characterized the effects of acute, chronic, and withdrawal from chronic nicotine administration on fear conditioning, somatic signs, and the elevated plus maze in 8 strains of inbred mice. Strain-dependent effects of acute nicotine and nicotine withdrawal on contextual fear conditioning, somatic signs, and the elevated plus maze were observed, but no association between the effects of acute nicotine and nicotine withdrawal on contextual fear conditioning were observed, suggesting that different genetic substrates may mediate these effects. The identification of genetic factors that may alter the effects of nicotine on cognition may lead to more efficacious treatments for nicotine addiction. PMID:21822688
Glotzbach-Schoon, Evelyn; Andreatta, Marta; Reif, Andreas; Ewald, Heike; Tröger, Christian; Baumann, Christian; Deckert, Jürgen; Mühlberger, Andreas; Pauli, Paul
The serotonin (5-HT) and neuropeptide S (NPS) systems are discussed as important genetic modulators of fear and sustained anxiety contributing to the etiology of anxiety disorders. Sustained anxiety is a crucial characteristic of most anxiety disorders which likely develops through contextual fear conditioning. This study investigated if and how genetic alterations of the 5-HT and the NPS systems as well as their interaction modulate contextual fear conditioning; specifically, function polymorphic variants in the genes coding for the 5-HT transporter (5HTT) and the NPS receptor (NPSR1) were studied. A large group of healthy volunteers was therefore stratified for 5HTTLPR (S+ vs. LL carriers) and NPSR1 rs324981 (T+ vs. AA carriers) polymorphisms resulting in four genotype groups (S+/T+, S+/AA, LL/T+, LL/AA) of 20 participants each. All participants underwent contextual fear conditioning and extinction using a virtual reality (VR) paradigm. During acquisition, one virtual office room (anxiety context, CXT+) was paired with an unpredictable electric stimulus (unconditioned stimulus, US), whereas another virtual office room was not paired with any US (safety context, CXT-). During extinction no US was administered. Anxiety responses were quantified by fear-potentiated startle and ratings. Most importantly, we found a gene × gene interaction on fear-potentiated startle. Only carriers of both risk alleles (S+/T+) exhibited higher startle responses in CXT+ compared to CXT-. In contrast, anxiety ratings were only influenced by the NPSR1 polymorphism with AA carriers showing higher anxiety ratings in CXT+ as compared to CXT-. Our results speak in favor of a two level account of fear conditioning with diverging effects on implicit vs. explicit fear responses. Enhanced contextual fear conditioning as reflected in potentiated startle responses may be an endophenotype for anxiety disorders.
Crabbe, John C; Schlumbohm, Jason P; Hack, Wyatt; Barkley-Levenson, Amanda M; Metten, Pamela; Lattal, K Matthew
The comorbidity of substance- and alcohol-use disorders (AUD) with other psychiatric conditions, especially those related to stress such as post-traumatic stress disorder (PTSD), is well-established. Binge-like intoxication is thought to be a crucial stage in the development of the chronic relapsing nature of the addictions, and self-medication through binge-like drinking is commonly seen in PTSD patients. We have selectively bred two separate High Drinking in the Dark (HDID-1 and HDID-2) mouse lines to reach high blood ethanol concentrations (BECs) after a 4-h period of access to 20% ethanol starting shortly after the onset of circadian dark. As an initial step toward the eventual goal of employing binge-prone HDID mice to study PTSD-like behavior including alcohol binge drinking, we sought first to determine their ability to acquire conditioned fear. We asked whether these mice acquired, generalized, or extinguished conditioned freezing to a greater or lesser extent than unselected control HS/Npt mice. In two experiments, we trained groups of 16 adult male mice in a standard conditioned fear protocol. Mice were tested for context-elicited freezing, and then, in a novel context, for cue-induced freezing. After extinction tests, renewal of conditioned fear was tested in the original context. Mice of all three genotypes showed typical fear responding. Context paired with shock elicited freezing behavior in a control experiment, but cue unpaired with shock did not. These studies indicate that fear learning per se does not appear to be influenced by genes causing predisposition to binge drinking, suggesting distinct neural mechanisms. However, HDID mice are shown to be a suitable model for studying the role of conditioned fear specifically in binge-like drinking. Published by Elsevier Inc.
Raybuck, J. D.; Gould, T. J.
Acute nicotine enhances multiple types of learning including trace fear conditioning but the underlying neural substrates of these effects are not well understood. Trace fear conditioning critically involves the medial prefrontal cortex and hippocampus, which both express nicotinic acetylcholine receptors (nAChRs). Therefore, nicotine could act in either or both areas to enhance trace fear conditioning. To identify the underlying neural areas and nAChR subtypes, we examined the effects of infusion of nicotine, or nicotinic antagonists dihydro-beta-erythroidine (DHβE: high-affinity nAChRs) or methyllycaconitine (MLA: low-affinity nAChRs) into the dorsal hippocampus, ventral hippocampus, and medial prefrontal cortex (mPFC) on trace and contextual fear conditioning. We found that the effects of nicotine on trace and contextual fear conditioning vary by brain region and nAChR subtype. The dorsal hippocampus was involved in the effects of nicotine on both trace and contextual fear conditioning but each task was sensitive to different doses of nicotine. Additionally, dorsal hippocampal infusion of the antagonist DHβE produced deficits in trace but not contextual fear conditioning. Nicotine infusion into the ventral hippocampus produced deficits in both trace and contextual fear conditioning. In the mPFC, nicotine enhanced trace but not contextual fear conditioning. Interestingly, infusion of the antagonists MLA or DHβE in the mPFC also enhanced trace fear conditioning. These findings suggest that nicotine acts on different substrates to enhance trace versus contextual fear conditioning, and that nicotine-induced desensitization of nAChRs in the mPFC may contribute to the effects of nicotine on trace fear conditioning. PMID:20727979
Cacciaglia, Raffaele; Pohlack, Sebastian T; Flor, Herta; Nees, Frauke
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.
Miriam J J Lommen
Full Text Available Anxiety disorders are the most common mental disorder worldwide. Although anxiety disorders differ in the nature of feared objects or situations, they share a common mechanism by which fear generalizes to related but innocuous objects, eliciting avoidance of objects and situations that pose no objective risk. This overgeneralization appears to be a crucial mechanism in the persistence of anxiety psychopathology. In this study we test whether an intervention that promotes discrimination learning reduces generalization of fear, in particular, harm expectancy and avoidance compared to an irrelevant (control training. Healthy participants (N = 80 were randomly allocated to a training condition. Using a fear conditioning paradigm, participants first learned visual danger and safety signals (set 1. Baseline level of stimulus generalization was tested with ambiguous stimuli on a spectrum between the danger and safety signals. There were no differences between the training groups. Participants then received the stimulus discrimination training or a control training. After training, participants learned a new set of danger and safety signals (set 2, and the level of harm expectancy generalization and behavioural avoidance of ambiguous stimuli was tested. Although the training groups did not differ in fear generalization on a cognitive level (harm expectancy, the results showed a different pattern of avoidance of ambiguous stimuli, with the discrimination training group showing less avoidance of stimuli that resembled the safety signals. These results support the potential of interventions that promote discrimination learning in the treatment of anxiety disorders.
Cohn, M D; Popma, A; van den Brink, W; Pape, L E; Kindt, M; van Domburgh, L; Doreleijers, T A H; Veltman, D J
Children diagnosed with Disruptive Behavior Disorders (DBD), especially those with psychopathic traits, are at risk of developing persistent and severe antisocial behavior. Deficient fear conditioning may be a key mechanism underlying persistence, and has been associated with altered regional brain function in adult antisocial populations. In this study, we investigated the associations between the neural correlates of fear conditioning, persistence of childhood-onset DBD during adolescence and psychopathic traits. From a cohort of children arrested before the age of 12 years, participants who were diagnosed with Oppositional Defiant Disorder or Conduct Disorder in previous waves (mean age of onset 6.5 years, s.d. 3.2) were reassessed at mean age 17.6 years (s.d. 1.4) and categorized as persistent (n=25) or desistent (n=25) DBD. Using the Youth Psychopathic Traits Inventory and functional magnetic resonance imaging during a fear conditioning task, these subgroups were compared with 26 matched healthy controls from the same cohort. Both persistent and desistent DBD subgroups were found to show higher activation in fear processing-related brain areas during fear conditioning compared with healthy controls. In addition, regression analyses revealed that impulsive-irresponsible and grandiose-manipulative psychopathic traits were associated with higher activation, whereas callous-unemotional psychopathic traits were related to lower activation in fear-related areas. Finally, the association between neural activation and DBD subgroup membership was mediated by impulsive-irresponsible psychopathic traits. These results provide evidence for heterogeneity in the neurobiological mechanisms underlying psychopathic traits and antisocial behavior and, as such, underscore the need to develop personalized interventions.
Revillo, Damian A.; Trebucq, Gastón; Paglini, Maria G.; Arias, Carlos
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…
Lissek, Shmuel; Levenson, Jessica; Biggs, Arter L.; Johnson, Linda L.; Ameli, Rezvan; Pine, Daniel S.; Grillon, Christian
Objective Though conditioned fear has long been acknowledged as an important etiologic mechanism in social anxiety disorder, past psychophysiological experiments have found no differences in general conditionability among social anxiety patients using generally aversive but socially nonspecific unconditioned stimuli (e.g., unpleasant odors and painful pressure). The authors applied a novel fear conditioning paradigm consisting of socially relevant unconditioned stimuli of critical facial expressions and verbal feedback. This study represents the first effort to assess the conditioning correlates of social anxiety disorder within an ecologically enhanced paradigm. Method Subjects with social anxiety disorder and age- and gender-matched healthy comparison subjects underwent differential classical conditioning. Conditioned stimuli included images of three neutral facial expressions, each of which was paired with one of three audiovisual unconditioned stimuli: negative insults with critical faces (USneg), positive compliments with happy faces (USpos), or neutral comments with neutral faces (USneu). The conditioned response was measured as the fear-potentiation of the startle-blink reflex elicited during presentation of the conditioned stimuli. Results Only social anxiety subjects demonstrated fear conditioning in response to facial expressions, as the startle-blink reflex was potentiated by the CSneg versus both CSneu and CSpos among those with the disorder, while healthy comparison subjects displayed no evidence of conditioned startle-potentiation. Such group differences in conditioning were independent of levels of anxiety to the unconditioned stimulus, implicating associative processes rather than increased unconditioned stimulus reactivity as the active mechanism underlying enhanced conditioned startle-potentiation among social anxiety subjects. Conclusions Results support a conditioning contribution to social anxiety disorder and underscore the importance of
Isiegas, Carolina; Stein, Joel; Hellman, Kevin; Hannenhalli, Sridhar; Abel, Ted; Keeley, Michael B.; Wood, Marcelo A.
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…
Chauret, Mélissa; La Buissonnière-Ariza, Valérie; Tremblay, Vickie Lamoureux; Suffren, Sabrina; Servonnet, Alice; Pine, Daniel S.; Maheu, Françoise S.
Adult work shows differences in emotional processing influenced by sexes of both the viewer and expresser of facial expressions. We investigated this in 120 healthy youths (57 boys; 10–17 years old) randomly assigned to fear conditioning and extinction tasks using either neutral male or female faces as the conditioned threat and safety cues, and a fearful face paired with a shrieking scream as the unconditioned stimulus. Fear ratings and skin conductance responses (SCRs) were assessed. Male faces triggered increased fear ratings in all participants during conditioning and extinction. Greater differential SCRs were observed in boys viewing male faces and in girls viewing female faces during conditioning. During extinction, differential SCR findings remained significant in boys viewing male faces. Our findings demonstrate how sex of participant and sex of target interact to shape fear responses in youths, and how the type of measure may lead to distinct profiles of fear responses. PMID:24929048
Gafford, Georgette M.; Parsons, Ryan G.; Helmstetter, Fred J.
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…
Moustafa, Ahmed A.; Gilbertson, Mark W.; Orr, Scott P.; Herzallah, Mohammad M.; Servatius, Richard J.; Myers, Catherine E.
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…
Holtzman-Assif, Orit; Laurent, Vincent; Westbrook, R. Frederick
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…
Moradi, Shahram; Lidestam, Björn; Saremi, Amin; Rönnberg, Jerker
This study aimed to measure the initial portion of signal required for the correct identification of auditory speech stimuli (or isolation points, IPs) in silence and noise, and to investigate the relationships between auditory and cognitive functions in silence and noise. Twenty-one university students were presented with auditory stimuli in a gating paradigm for the identification of consonants, words, and final words in highly predictable and low predictable sentences. The Hearing in Noise Test (HINT), the reading span test, and the Paced Auditory Serial Attention Test were also administered to measure speech-in-noise ability, working memory and attentional capacities of the participants, respectively. The results showed that noise delayed the identification of consonants, words, and final words in highly predictable and low predictable sentences. HINT performance correlated with working memory and attentional capacities. In the noise condition, there were correlations between HINT performance, cognitive task performance, and the IPs of consonants and words. In the silent condition, there were no correlations between auditory and cognitive tasks. In conclusion, a combination of hearing-in-noise ability, working memory capacity, and attention capacity is needed for the early identification of consonants and words in noise.
Dash Pramod K
Full Text Available Abstract Background The extent of similarity between consolidation and reconsolidation is not yet fully understood. One of the differences noted is that not every brain region involved in consolidation exhibits reconsolidation. In trace fear conditioning, the hippocampus and the medial prefrontal cortex (mPFC are required for consolidation of long-term memory. We have previously demonstrated that trace fear memory is susceptible to infusion of the protein synthesis inhibitor anisomycin into the hippocampus following recall. In the present study, we examine whether protein synthesis inhibition in the mPFC following recall similarly results in the observation of reconsolidation of trace fear memory. Results Targeted intra-mPFC infusions of anisomycin or vehicle were performed immediately following recall of trace fear memory at 24 hours, or at 30 days, following training in a one-day or a two-day protocol. The present study demonstrates three key findings: 1 trace fear memory does not undergo protein synthesis dependent reconsolidation in the PFC, regardless of the intensity of the training, and 2 regardless of whether the memory is recent or remote, and 3 intra-mPFC inhibition of protein synthesis immediately following training impaired remote (30 days memory. Conclusion These results suggest that not all structures that participate in memory storage are involved in reconsolidation. Alternatively, certain types of memory-related information may reconsolidate, while other components of memory may not.
Markram, Kamila; Rinaldi, Tania; La Mendola, Deborah
A core feature of autism spectrum disorders is the impairment in social interactions. Among other brain regions, a deficit in amygdala processing has been suggested to underlie this impairment, but whether the amygdala is processing fear abnormally in autism, is yet not clear. We used the valproic...... acid (VPA) rat model of autism to (a) screen for autism-like symptoms in rats, (b) test for alterations in amygdala-dependent fear processing, and (c) evaluate neuronal reactivity and synaptic plasticity in the lateral amygdala by means of in vitro single-cell electrophysiological recordings. VPA....... On the cellular level, the amygdala was hyperreactive to electrical stimulation and displayed boosted synaptic plasticity as well as a deficit in inhibition. We show for the first time enhanced, overgeneralized and resistant conditioned fear memories in an animal model of autism. Such hyperfear could be caused...
Johansen, Joshua P.; Cain, Christopher K.; Ostroff, Linnaea E.; LeDoux, Joseph E.
Pavlovian fear conditioning is a useful behavioral paradigm for exploring the molecular mechanisms of learning and memory because a well-defined response to a specific environmental stimulus is produced through associative learning processes. Synaptic plasticity in the lateral nucleus of the amygdala (LA) underlies this form of associative learning. Here we summarize the molecular mechanisms that contribute to this synaptic plasticity in the context of auditory fear conditioning, the form of fear conditioning best understood at the molecular level. We discuss the neurotransmitter systems and signaling cascades that contribute to three phases of auditory fear conditioning: acquisition, consolidation, and reconsolidation. These studies suggest that multiple intracellular signaling pathways, including those triggered by activation of Hebbian processes and neuromodulatory receptors, interact to produce neural plasticity in the LA and behavioral fear conditioning. Together, this research illustrates the power of fear conditioning as a model system for characterizing the mechanisms of learning and memory in mammals, and potentially for understanding fear related disorders, such as PTSD and phobias. PMID:22036561
Full Text Available 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 with 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.
Ota, Kristie T.; Monsey, Melissa S.; Wu, Melissa S.; Schafe, Glenn E.
In vertebrate models of synaptic plasticity, signaling via the putative “retrograde messenger” nitric oxide (NO) has been hypothesized to serve as a critical link between functional and structural alterations at pre- and postsynaptic sites. In the present study, we show that auditory Pavlovian fear conditioning is associated with significant and long-lasting increases in the expression of the postsynaptically-localized protein GluR1 and the presynaptically-localized proteins synaptophysin and synapsin in the lateral amygdala (LA) within 24 hrs following training. Further, we show that rats given intra-LA infusion of either the NR2B-selective antagonist Ifenprodil, the NOS inhibitor 7-Ni, or the PKG inhibitor Rp-8-Br-PET-cGMPS exhibit significant decreases in training-induced expression of GluR1, synaptophysin, and synapsin immunoreactivity in the LA, while those rats infused with the PKG activator 8-Br-cGMP exhibit a significant increase in these proteins in the LA. In contrast, rats given intra-LA infusion of the NO scavenger c-PTIO exhibit a significant decrease in synapsin and synaptophysin expression in the LA, but no significant impairment in the expression of GluR1. Finally, we show that intra-LA infusions of the ROCK inhibitor Y-27632 or the CaMKII inhibitor KN-93 impair training-induced expression of GluR1, synapsin, and synaptophysin in the LA. These findings suggest that the NO-cGMP-PKG, Rho/ROCK, and CaMKII signaling pathways regulate fear memory consolidation, in part, by promoting both pre- and post-synaptic alterations at LA synapses. They further suggest that synaptic plasticity in the LA during auditory fear conditioning promotes alterations at presynaptic sites via NO-driven “retrograde signaling”. PMID:20574537
Claassen, J; Labrenz, F; Ernst, T M; Icenhour, A; Langhorst, J; Forsting, M; Timmann, D; Elsenbruch, S
There is evidence to support a role of the cerebellum in emotional learning processes, which are demonstrably altered in patients with chronic pain. We tested if cerebellar activation is altered during visceral pain-related fear conditioning and extinction in irritable bowel syndrome (IBS). Cerebellar blood oxygenation level-dependent (BOLD) data from N = 17 IBS patients and N = 21 healthy controls, collected as part of a previous fMRI study, was reanalyzed utilizing an advanced normalizing method of the cerebellum. The differential fear conditioning paradigm consisted of acquisition, extinction, and reinstatement phases. During acquisition, two visual conditioned stimuli (CS) were presented either paired (CS+) or unpaired (CS-) with painful rectal distension as unconditioned stimulus (US). In the extinction phase, the CS+ and CS- were presented without US. For reinstatement, unpaired US presentations were followed by unpaired CS+ and CS- presentations. Group differences in cerebellar activation were analyzed for the contrasts CS+ > CS- and CS- > CS+. During acquisition, IBS patients revealed significantly enhanced cerebellar BOLD responses to pain-predictive (CS+) and safety (CS-) cues compared to controls (p CS- and CS- > CS+. Group differences were most prominent in the contrast CS- > CS+. During extinction and reinstatement, no significant group differences were found. During visceral pain-related fear conditioning, IBS patients showed increased activations in circumscribed areas of the medial, intermediate, and lateral cerebellum. These areas are involved in autonomic, somatosensory, and cognitive functions and likely contribute to the different aspects of pain-related fear. The cerebellum contributes to altered pain-related fear learning in IBS.
Pamplona, Fabrício Alano; Takahashi, Reinaldo Naoto
The memory deficits induced by cannabinoid agonists have been found in several behavioral paradigms. Nevertheless, there is evidence that not all types of memory are impaired after cannabinoid administration. The aim of this study was to investigate whether the cannabinoid agonist WIN 55212-2 (WIN) is able to influence the acquisition of fear conditioning using tone and contextual versions. For tone-fear conditioning, male Wistar rats were placed in the conditioning chamber and after 3 min, a sound (CS) was presented for 10s that terminated with a 1-s electric footshock (1.5 mA). For contextual-fear conditioning, a similar procedure was used but no sound was presented. Twenty-four hours after, the animals were re-exposed to the respective CS (tone or conditioning chamber) and the freezing behavior was registered. A subsequent experiment investigated a possible state-dependent effect of WIN by administering WIN or control solution 30 min before conditioning and before testing. WIN (2.5 and 5.0 mg/kg) administered i.p. 30 min before impaired contextual fear conditioning but did not modify the freezing behavior elicited by tone presentation. These animals did not show any state-dependent effects of WIN. Further, the impaired contextual conditioning was prevented by preadministration of SR141716A (1.0 mg/kg, i.p.) or SR147778 (1.0 mg/kg, i.p.), selective cannabinoid CB1 receptor antagonists. The present findings highlight that cannabinoid agonists effects are selective for the hippocampus-dependent aversive memories in rats. This effect appears to be related to the activation of CB1 cannabinoid receptors and confirms that cannabinoids might provide a novel approach for the treatment of unpleasant memories.
McDannald, Michael A
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. Copyright 2010 Elsevier B.V. All rights reserved.
Full Text Available A single electroconvulsive shock (ECS or a sham ECS was administered to male 3-4-month-old Wistar rats 1, 2, and 4 h before training in an inhibitory avoidance test and in cued classical fear conditioning (measured by means of freezing time in a new environment. ECS impaired inhibitory avoidance at all times and, at 1 or 2 h before training, reduced freezing time before and after re-presentation of the ECS. These results are interpreted as a transient conditioned stimulus (CS-induced anxiolytic or analgesic effect lasting about 2 h after a single treatment, in addition to the known amnesic effect of the stimulus. This suggests that the effect of anterograde learning impairment is demonstrated unequivocally only when the analgesic/anxiolytic effect is over (about 4 h after ECS administration and that this impairment of learning is selective, affecting inhibitory avoidance but not classical fear conditioning to a discrete stimulus.
Chang, Chun-hui; Maren, Stephen
It has been suggested that reduced infralimbic (IL) cortical activity contributes to impairments of fear extinction. We therefore explored whether pharmacological activation of the IL would facilitate extinction under conditions it normally fails (i.e., immediate extinction). Rats received auditory fear conditioning 1 h before extinction training.…
Kenney, Justin W; Raybuck, Jonathan D; Gould, Thomas J
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. Copyright © 2012 Wiley Periodicals, Inc.
Dibbets, Pauline; van den Broek, Anne; Evers, Elisabeth A T
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.
Full Text Available Traditionally , the analysis of extinction data in fear conditioning experiments has involved the use of standard linear models, mostly ANOVA of between-group differences of subjects that have undergone different extinction protocols, pharmacological manipulations or some other treatment. Although some studies report individual differences in quantities such as suppression rates or freezing percentages, these differences are not included in the statistical modeling. Withinsubject response patterns are then averaged using coarse-grain time windows which can overlook these individual performance dynamics. Here we illustrate an alternative analytical procedure consisting of 2 steps: the estimation of a trend for within-session data and analysis of group differences in trend as main outcome. This procedure is tested on real fear-conditioning extinction data, comparing trend estimates via Ordinary Least Squares (OLS and robust Least Median of Squares (LMS regression estimates, as well as comparing between-group differences and analyzing mean freezing percentage versus LMS slopes as outcomes
mechanism underlying the most successful treatment for PTSD, Prolonged Exposure. In animal models, sleep deprivation has been shown to impair extinction ...2. 3. 9 +Sleep and Extinction Learning Animal models show fear conditioning: Disrupts sleep Disrupted sleep, in turn Impairs extinction ...examining impact of total sleep deprivation (TSD) on extinction learning and recall Hypotheses TSD may impair extinction learning TSD will impair
Alexander, Jon C; McDermott, Carmel M; Tunur, Tumay; Rands, Vicky; Stelly, Claire; Karhson, Debra; Bowlby, Mark R; An, W Frank; Sweatt, J David; Schrader, Laura A
Potassium channel interacting proteins (KChIPs) are members of a family of calcium binding proteins that interact with Kv4 potassium (K(+)) channel primary subunits and also act as transcription factors. The Kv4 subunit is a primary K(+) channel pore-forming subunit, which contributes to the somatic and dendritic A-type currents throughout the nervous system. These A-type currents play a key role in the regulation of neuronal excitability and dendritic processing of incoming synaptic information. KChIP3 is also known as calsenilin and as the transcription factor, downstream regulatory element antagonist modulator (DREAM), which regulates a number of genes including prodynorphin. KChIP3 and Kv4 primary channel subunits are highly expressed in hippocampus, an area of the brain important for learning and memory. Through its various functions, KChIP3 may play a role in the regulation of synaptic plasticity and learning and memory. We evaluated the role of KChIP3 in a hippocampus-dependent memory task, contextual fear conditioning. Male KChIP3 knockout (KO) mice showed significantly enhanced memory 24 hours after training as measured by percent freezing. In addition, we found that membrane association and interaction with Kv4.2 of KChIP3 protein was significantly decreased and nuclear KChIP3 expression was increased six hours after the fear conditioning training paradigm with no significant change in KChIP3 mRNA. In addition, prodynorphin mRNA expression was significantly decreased six hours after fear conditioning training in wild-type (WT) but not in KO animals. These data suggest a role for regulation of gene expression by KChIP3/DREAM/calsenilin in consolidation of contextual fear conditioning memories.
performance task, and how analogous the effects of deprivation are to the homologues model in animals. These data helped validate the use of this...task to assesse sleep deprivation effects on cognitive performance using a cross-species task. These data suggest that this task may have...1 Award Number: W81XWH-11-2-0001 TITLE: Role of Sleep Deprivation in Fear Conditioning and Extinction: Implications for Treatment of PTSD
Effects of auditory and physical enrichment on 3 measurements of fear and stress (tonic immobility duration, heterophil to lymphocyte ratio, and fluctuating asymmetry) in several breeds of layer chicks.
Dávila, S G; Campo, J L; Gil, M G; Prieto, M T; Torres, O
The purpose of this study was to analyze the effect of auditory enrichment (by means of classical music) or physical enrichment (by means of hanging colored string bunches and barley grains on the floor) on tonic immobility duration, heterophil to lymphocyte ratio, and fluctuating asymmetry (FA) in chicks of several layer breeds. In experiment 1, 192 chicks from 8 Spanish breeds and 1 White Leghorn population were reared in cages with or without music auditory enrichment until 8 wk of age. The effect of music auditory enrichment was significant for heterophil to lymphocyte ratio (P music than in those reared with music, suggesting that auditory enrichment from classical music reduces stress in chicks. There were significant differences in morphological trait measurements (relative asymmetry of wing length, leg width, and combined asymmetry; P music. This result suggests that FA is a good indicator for stress level in chicks, given that it follows the same trend as that found for heterophil to lymphocyte ratio. There was a significant treatment by breed interaction (P stress in layer chicks. In conclusion, auditory enrichment by means of classical music is a reliable method for reducing stress levels in several breeds of layer chicks. However, music auditory enrichment was not effective in reducing fearfulness in any of the layer breeds. Physical enrichment by means of colored plastic string bunches and floor barley grains does not appear to be an effective method for reducing stress and fear in layer chicks.
Shuman, Tristan; Wood, Suzanne C.; Anagnostaras, Stephan G.
Modafinil has been shown to promote wakefulness and some studies suggest the drug can improve cognitive function. Because of many similarities, the mechanism of action may be comparable to classical psychostimulants, although the exact mechanisms of modafinil’s actions in wakefulness and cognitive enhancement are unknown. The current study aims to further examine the effects of modafinil as a cognitive enhancer on hippocampus-dependent memory in mice. A high dose of modafinil (75 mg/kg, i.p.) given before training improved acquisition on a Morris water maze. When given only before testing, modafinil did not affect water maze performance. We also examined modafinil (0.075 – 75 mg/kg) on Pavlovian fear conditioning. A low dose of pre-training modafinil (0.75 mg/kg) enhanced memory of contextual fear conditioning (tested off-drug one week later) while a high dose (75 mg/kg) disrupted memory. Pre-training modafinil did not affect cued conditioning at any dose tested, and immediate post-training modafinil had no effect on either cued or contextual fear. These results suggest that modafinil’s effects of memory are more selective than amphetamine or cocaine, and specific to hippocampus-dependent memory. PMID:19331449
Spitzer, Matthew W.; Bala, Avinash D. S.; Takahashi, Terry T.
In humans, directional hearing in reverberant conditions is characterized by a ``precedence effect,'' whereby directional information conveyed by leading sounds dominates perceived location, and listeners are relatively insensitive to directional information conveyed by lagging sounds. Behavioral studies provide evidence of precedence phenomena in a wide range of species. The present study employs a discrimination paradigm, based on habituation and recovery of the pupillary dilation response, to provide quantitative measures of precedence phenomena in the barn owl. As in humans, the owl's ability to discriminate changes in the location of lagging sources is impaired relative to that for single sources. Spatial discrimination of lead sources is also impaired, but to a lesser extent than discrimination of lagging sources. Results of a control experiment indicate that sensitivity to monaural cues cannot account for discrimination of lag source location. Thus, impairment of discrimination ability in the two-source conditions most likely reflects a reduction in sensitivity to binaural directional information. These results demonstrate a similarity of precedence effect phenomena in barn owls and humans, and provide a basis for quantitative comparison with neuronal data from the same species.
Herry, Cyril; Johansen, Joshua P
How sensory information is transformed by learning into adaptive behaviors is a fundamental question in neuroscience. Studies of auditory fear conditioning have revealed much about the formation and expression of emotional memories and have provided important insights into this question. Classical work focused on the amygdala as a central structure for fear conditioning. Recent advances, however, have identified new circuits and neural coding strategies mediating fear learning and the expression of fear behaviors. One area of research has identified key brain regions and neuronal coding mechanisms that regulate the formation, specificity and strength of fear memories. Other work has discovered critical circuits and neuronal dynamics by which fear memories are expressed through a medial prefrontal cortex pathway and coordinated activity across interconnected brain regions. Here we review these recent advances alongside prior work to provide a working model of the extended circuits and neuronal coding mechanisms mediating fear learning and memory.
Dylan C Barnes
Full Text Available 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
Full Text Available 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 a 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 autonomic (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.
Full Text Available 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.
Marin, Marie-France; Zsido, Rachel G; Song, Huijin; Lasko, Natasha B; Killgore, William D S; Rauch, Scott L; Simon, Naomi M; Milad, Mohammed R
The fear conditioning and extinction neurocircuitry has been extensively studied in healthy and clinical populations, with a particular focus on posttraumatic stress disorder. Despite significant overlap of symptoms between posttraumatic stress disorder and anxiety disorders, the latter has received less attention. Given that dysregulated fear levels characterize anxiety disorders, examining the neural correlates of fear and extinction learning may shed light on the pathogenesis of underlying anxiety disorders. To investigate the psychophysiological and neural correlates of fear conditioning and extinction recall in anxiety disorders and to document how these features differ as a function of multiple diagnoses or anxiety severity. This investigation was a cross-sectional, case-control, functional magnetic resonance imaging study at an academic medical center. Participants were healthy controls and individuals with at least 1 of the following anxiety disorders: generalized anxiety disorder, social anxiety disorder, specific phobia, and panic disorder. The study dates were between March 2013 and May 2015. Two-day fear conditioning and extinction paradigm. Skin conductance responses, blood oxygenation level-dependent responses, trait anxiety scores from the State Trait Anxiety Inventory-Trait Form, and functional connectivity. This study included 21 healthy controls (10 women) and 61 individuals with anxiety disorders (36 women). P values reported for the neuroimaging results are all familywise error corrected. Skin conductance responses during extinction recall did not differ between individuals with anxiety disorders and healthy controls (ηp2 = 0.001, P = .79), where ηp2 is partial eta squared. The anxiety group had lower activation of the ventromedial prefrontal cortex (vmPFC) during extinction recall (ηp2 = 0.178, P = .02). A similar hypoactive pattern was found during early conditioning (ηp2 = 0.106, P = .009). The vmPFC hypoactivation
Full Text Available We conducted a human fear conditioning experiment in which three different color cues were followed by an aversive electric shock on 0, 50, and 100% of the trials, and thus induced low (L, partial (P, and high (H shock expectancy, respectively. The cues differed with respect to the strength of their shock association (L < P < H and the uncertainty of their prediction (L < P > H. During conditioning we measured pupil dilation and ocular fixations to index differences in the attentional processing of the cues. After conditioning, the shock-associated colors were introduced as irrelevant distracters during visual search for a shape target while shocks were no longer administered and we analyzed the cues’ potential to capture and hold overt attention automatically. Our findings suggest that fear conditioning creates an automatic attention bias for the conditioned cues that depends on their correlation with the aversive outcome. This bias was exclusively linked to the strength of the cues’ shock association for the early attentional processing of cues in the visual periphery, but additionally was influenced by the uncertainty of the shock prediction after participants fixated on the cues. These findings are in accord with attentional learning theories that formalize how associative learning shapes automatic attention.
Acheson, Dean T.; Feifel, David; de Wilde, Sofieke; Mckinney, Rebecca; Lohr, James B.; Risbrough, Victoria B.
Rationale To improve outcomes for patients undergoing extinction-based therapies (e.g. exposure therapy) for anxiety disorders such as post-traumatic stress disorder, there has been interest in identifying pharmaceutical compounds which might facilitate fear extinction learning and recall. Oxytocin (OT) is a mammalian neuropeptide that modulates activation of fear extinction-based neural circuits and fear responses. Little is known however about the effects of OT treatment on conditioned fear responding and extinction in humans. Objectives The purpose of the present study was to assess the effects of OT in a fear-potentiated startle task of fear conditioning and extinction. Methods A double-blind, placebo-controlled study of 44 healthy human participants was conducted. Participants underwent a conditioned fear acquisition procedure, after which they were randomized to treatment group and delivered OT (24 IU) or placebo via intranasal spray. Forty-five min after treatment, participants underwent extinction training. Twenty-four hrs later subjects were tested for extinction recall. Results Relative to placebo, the OT group showed increased fear potentiated startle responding during the earliest stage of extinction training relative to placebo, however all treatment groups showed the same level of reduced responding by the end of extinction training. Twenty-four hours later the OT group showed significantly higher recall of extinction relative to placebo. Conclusions The current study provides preliminary evidence that OT may facilitate fear extinction recall in humans. These results support further study of OT as a potential adjunctive treatment for extinction-based therapies in fear-related disorders. PMID:23644911
Holmes, Nathan M; Cai, Stefanie Yuxuan; Lay, Belinda Po Pyn; Watts, Nicola R; Westbrook, R Frederick
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.
Bernier, Brian E; Lacagnina, Anthony F; Ayoub, Adam; Shue, Francis; Zemelman, Boris V; Krasne, Franklin B; Drew, Michael R
Dentate gyrus (DG) is widely thought to provide a teaching signal that enables hippocampal encoding of memories, but its role during retrieval is poorly understood. Some data and models suggest that DG plays no role in retrieval; others encourage the opposite conclusion. To resolve this controversy, we evaluated the effects of optogenetic inhibition of dorsal DG during context fear conditioning, recall, generalization, and extinction in male mice. We found that (1) inhibition during training impaired context fear acquisition; (2) inhibition during recall did not impair fear expression in the training context, unless mice had to distinguish between similar feared and neutral contexts; (3) inhibition increased generalization of fear to an unfamiliar context that was similar to a feared one and impaired fear expression in the conditioned context when it was similar to a neutral one; and (4) inhibition impaired fear extinction. These effects, as well as several seemingly contradictory published findings, could be reproduced by BACON (Bayesian Context Fear Algorithm), a physiologically realistic hippocampal model positing that acquisition and retrieval both involve coordinated activity in DG and CA3. Our findings thus suggest that DG contributes to retrieval and extinction, as well as to the initial establishment of context fear. SIGNIFICANCE STATEMENT Despite abundant evidence that the hippocampal dentate gyrus (DG) plays a critical role in memory, it remains unclear whether the role of DG relates to memory acquisition or retrieval. Using contextual fear conditioning and optogenetic inhibition, we show that DG contributes to both of these processes. Using computational simulations, we identify specific mechanisms through which the suppression of DG affects memory performance. Finally, we show that DG contributes to fear extinction learning, a process in which learned fear is attenuated through exposures to a fearful context in the absence of threat. Our data resolve a
Dawn H Loh
Full Text Available BACKGROUND: Circadian rhythms govern many aspects of physiology and behavior including cognitive processes. Components of neural circuits involved in learning and memory, e.g., the amygdala and the hippocampus, exhibit circadian rhythms in gene expression and signaling pathways. The functional significance of these rhythms is still not understood. In the present study, we sought to determine the impact of transiently disrupting the circadian system by shifting the light/dark (LD cycle. Such "jet lag" treatments alter daily rhythms of gene expression that underlie circadian oscillations as well as disrupt the synchrony between the multiple oscillators found within the body. METHODOLOGY/PRINCIPAL FINDINGS: We subjected adult male C57Bl/6 mice to a contextual fear conditioning protocol either before or after acute phase shifts of the LD cycle. As part of this study, we examined the impact of phase advances and phase delays, and the effects of different magnitudes of phase shifts. Under all conditions tested, we found that recall of fear conditioned behavior was specifically affected by the jet lag. We found that phase shifts potentiated the stress-evoked corticosterone response without altering baseline levels of this hormone. The jet lag treatment did not result in overall sleep deprivation, but altered the temporal distribution of sleep. Finally, we found that prior experience of jet lag helps to compensate for the reduced recall due to acute phase shifts. CONCLUSIONS/SIGNIFICANCE: Acute changes to the LD cycle affect the recall of fear-conditioned behavior. This suggests that a synchronized circadian system may be broadly important for normal cognition and that the consolidation of memories may be particularly sensitive to disruptions of circadian timing.
Full Text Available Social and echolocation vocalizations of bats contain different patterns of frequency modulations. An adult bat's ability to discriminate between various FM parameters, however, is not well established. Using changes in heart rate (HR as a quantitative measure of associative learning, we demonstrate that mustached bats (Pteronotus parnellii can be fear conditioned to linear frequency modulated (FM sweeps typically centered at their acoustic fovea (approximately 60 kHz. We also show that HR is sensitive to a change in the direction of the conditional frequency modulation keeping all other parameters constant. In addition, a change in either depth or duration co-varied with FM rate is reflected in the change in HR. Finally, HR increases linearly with FM rate incremented by 0.1 kHz/ms from a pure tone to a target rate of 1.0 kHz/ms of the conditional stimulus. Learning is relatively rapid, occurring after a single training session. We also observed that fear conditioning enhances local field potential activity within the basolateral amygdala. Neural response enhancement coinciding with rapid learning and a fine scale cortical representation of FM sweeps shown earlier make FMs prime candidates for discriminating between different call types and possibly communicating socially relevant information within species-specific sounds.
Hoffman, Ann N; Armstrong, Charles E; Hanna, Jeffery J; Conrad, Cheryl D
Chronic stress and estrogens alter many forebrain regions in female rats that affect cognition. In order to investigate how chronic stress and estrogens influence fear learning and memory, we ovariectomized (OVX) female Sprague-Dawley rats and repeatedly injected them (s.c.) with 17β-estradiol (E, 10 μg/250 g or sesame oil vehicle, VEH). Concurrently, rats were restrained for 6 h/d/21 d (STR) or left undisturbed (CON). Rats were then fear conditioned with 4 tone-footshock pairings and then after 1 h and 24 h delays, given 15 tone extinction trials. Regardless of E treatment, chronic stress (VEH, E) facilitated freezing to tone during acquisition and extinction following a 1h delay, but not during extinction after a 24 h delay. E did not influence freezing to tone during any phase of fear conditioning for either the control or chronically stressed rats, but did influence contextual conditioning that may have been carried predominately by the STR group. In the second experiment, we investigated "handling" influences on fear conditioning acquisition, given the disparate findings from the current study and previous work (Baran, Armstrong, Niren, & Conrad, 2010; Baran, Armstrong, Niren, Hanna, & Conrad, 2009). Female rats remained gonadally-intact since E did not influence tone fear conditioning. Indeed, brief daily handling (1-3 m/d/21 d) facilitated acquisition of fear conditioning in chronically stressed female rats, and either had no effect or slightly attenuated fear conditioning in controls. Thus, chronic stress impacts amygdala-mediated fear learning in both OVX- and gonadally-intact females as found previously in males, with handling significantly influencing these outcomes. Copyright © 2010 Elsevier Inc. All rights reserved.
Portugal, George S.; Wilkinson, Derek S.; Turner, Jill R.; Blendy, Julie A.; Gould, Thomas J.
Pre-adolescence and adolescence are developmental periods associated with increased vulnerability for tobacco addiction, and exposure to tobacco during these periods may lead to long-lasting changes in behavioral and neuronal plasticity. The present study examined the short- and long-term effects of nicotine and nicotine withdrawal on fear conditioning in pre-adolescent, adolescent, and adult mice, and potential underlying substrates that may mediate the developmental effects of nicotine, such as changes in nicotinic acetylcholine receptor (nAChR) binding, CREB expression, and nicotine metabolism. Age-related differences existed in sensitivity to the effects of acute nicotine, chronic nicotine and nicotine withdrawal on contextual fear conditioning (no changes in cued fear conditioning were seen); younger mice were more sensitive to the acute effects and less sensitive to the effects of nicotine withdrawal 24 hours post treatment cessation. Developmental differences in nAChR binding were associated with the effects of nicotine withdrawal on contextual learning. Developmental differences in nicotine metabolism and CREB expression were also observed, but were not related to the effects of nicotine withdrawal on contextual learning 24 hours post treatment. Chronic nicotine exposure during pre-adolescence or adolescence, however, produced long-lasting impairments in contextual learning that were observed during adulthood, whereas adult chronic nicotine exposure did not. These developmental effects could be related to changes in CREB. Overall, there is a developmental shift in the effects of nicotine on hippocampus-dependent learning and developmental exposure to nicotine results in adult cognitive deficits; these changes in cognition may play an important role in the development and maintenance of nicotine addiction. PMID:22521799
Morris, David Jackson; Steinmetzger, Kurt; Tøndering, John
The modulation of auditory event-related potentials (ERP) by attention generally results in larger amplitudes when stimuli are attended. We measured the P1-N1-P2 acoustic change complex elicited with synthetic overt (second formant, F2 = 1000 Hz) and subtle (F2 = 100 Hz) diphthongs, while subjects....... Multivariate analysis of ERP components from the rising F2 changes showed main effects of attention on P2 amplitude and latency, and N1-P2 amplitude. P2 amplitude decreased by 40% between the attend and ignore conditions, and by 60% between the attend and divert conditions. The effect of diphthong magnitude...
Knapska, Ewelina; Maren, Stephen
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.…
Hart, Genevra; Harris, Justin A.; Westbrook, R. Frederick
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…
Gaigg, Sebastian B; Bowler, Dermot M
Since the first descriptions of individuals with autism spectrum disorders (ASD), abnormalities in socio-emotional behaviours have been described as amongst the most characteristic clinical features of this condition. Current evidence in this area suggests that individuals with ASD experience difficulties in the perception and expression of emotions within the social domain. The causes for these emotional difficulties are, however, still poorly understood. At the developmental level, it is unclear whether emotional disturbances constitute a primary feature of the clinical presentation of ASD or whether they are secondary to abnormalities in other areas of cognition. At the neurobiological level, it is still debated to what extent abnormalities of the limbic system, in particular the amygdala, may be responsible for the emotional disturbances characterising ASD. Here we show that a group of individuals with Asperger's syndrome exhibit a pattern of abnormality in differentially acquiring fear, which suggests that their fear responses are atypically modulated by conditioned and non-conditioned stimuli. On the basis of these results and the existing literature we suggest that ASD may be characterised by atypicalities in the integration of physiological and cognitive aspects of emotional experiences which we argue arise because of poor connectivity between the amygdala and functionally associated cortical areas.
Auditory event-related potentials (ERP) and sensomotor reaction time (RT) were investigated in divers during decompression from hyperbaric trimix conditions in order to assess the auditory information processing of the divers. Two passive series, 30 low (800 Hz) and 30 high (1200 Hz) tones were presented as well as one simple reaction task (SRT) and one choice reaction task (CRT) series. In both task series, the subjects were instructed to press the button as quickly as possible with the right-hand thumb after a low tone was heard. The individual analyses of the decompression period ERPs and RT data were compared with the pre-diving results for the series. Despite the interindividual differences, the sensomotor reactions were retarded during the decompression period, most clearly in the CRT. A prolongation of the N2 and P3 latency in this series gives grounds to accept that a cognitive slowing takes part in the longer reaction times during decompression. The slowing of the auditory information processing during decompression manifests with task manipulation difficulties.
Full Text Available INTRODUCTION: Auditory conditioning consists of the pre-exposure to low levels of a potential harmful agent to protect against a subsequent harmful presentation. OBJECTIVE: To confirm if conditioning with an agent different from the used to cause the trauma can also be effective. METHOD: Experimental study with 17 guinea pigs divided as follows: group Som: exposed to 85 dB broadband noise centered at 4 kHz, 30 minutes a day for 10 consecutive days; group Cont: intramuscular administration of gentamicin 160 mg/kg a day for 10 consecutive days; group Expt: conditioned with noise similarly to group Som and, after each noise presentation, received gentamicin similarly to group Cont. The animals were evaluated by distortion product otoacoustic emissions (DPOAEs, brainstem auditory evoked potentials (BAEPs and scanning electron microscopy. RESULTS: The animals that were conditioned with noise did not show any protective effect compared to the ones that received only the ototoxic gentamicin administration. This lack of protection was observed functionally and morphologically. CONCLUSION: Conditioning with 85 dB broadband noise, 30 min a day for 10 consecutive days does not protect against an ototoxic gentamicin administration of 160 mg/kg a day for 10 consecutive days in the guinea pig.
Crosse, Michael J; Butler, John S; Lalor, Edmund C
Congruent audiovisual speech enhances our ability to comprehend a speaker, even in noise-free conditions. When incongruent auditory and visual information is presented concurrently, it can hinder a listener's perception and even cause him or her to perceive information that was not presented in either modality. Efforts to investigate the neural basis of these effects have often focused on the special case of discrete audiovisual syllables that are spatially and temporally congruent, with less work done on the case of natural, continuous speech. Recent electrophysiological studies have demonstrated that cortical response measures to continuous auditory speech can be easily obtained using multivariate analysis methods. Here, we apply such methods to the case of audiovisual speech and, importantly, present a novel framework for indexing multisensory integration in the context of continuous speech. Specifically, we examine how the temporal and contextual congruency of ongoing audiovisual speech affects the cortical encoding of the speech envelope in humans using electroencephalography. We demonstrate that the cortical representation of the speech envelope is enhanced by the presentation of congruent audiovisual speech in noise-free conditions. Furthermore, we show that this is likely attributable to the contribution of neural generators that are not particularly active during unimodal stimulation and that it is most prominent at the temporal scale corresponding to syllabic rate (2-6 Hz). Finally, our data suggest that neural entrainment to the speech envelope is inhibited when the auditory and visual streams are incongruent both temporally and contextually. Seeing a speaker's face as he or she talks can greatly help in understanding what the speaker is saying. This is because the speaker's facial movements relay information about what the speaker is saying, but also, importantly, when the speaker is saying it. Studying how the brain uses this timing relationship to
Rudy, Jerry W.; Matus-Amat, Patricia
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 enhances freezing normally supported by a weak footshock. This effect of DHPG was blocked when it was co-infused with either the general group 1 mGluR1 antagonist, (R,S)-1-aminoindan-1,5 dicarboxylic acid (AIDA), or with the selective mGluR5 antagonist, 2-methyl-6-(phenylethynyl)-pyridine (MPEP). These results support previous findings by Rodrigues and colleagues that mGluR5s in the lateral region of the amygdala make an import contribution to fear conditioning. More importantly, they support the general ideas embedded in the concept of metaplasticity, as per Abraham, and the synaptic-tagging hypothesis per Frey and Morris—that the processes that specify the content of experience can be experimentally separated from those needed to acquire the memory. PMID:19553379
Wood, Kimberly H; Ver Hoef, Lawrence W; Knight, David C
Recognizing cues that predict an aversive event allows one to react more effectively under threatening conditions, and minimizes the reaction to the threat itself. This is demonstrated during Pavlovian fear conditioning when the unconditioned response (UCR) to a predictable unconditioned stimulus (UCS) is diminished compared to the UCR to an unpredictable UCS. The present study investigated the functional magnetic resonance imaging (fMRI) signal response associated with Pavlovian conditioned UCR diminution to better understand the relationship between individual differences in behavior and the neural mechanisms of the threat-related emotional response. Healthy volunteers participated in a fear conditioning study in which trait anxiety, skin conductance response (SCR), UCS expectancy, and the fMRI signal were assessed. During acquisition trials, a tone (CS+) was paired with a white noise UCS and a second tone (CS-) was presented without the UCS. Test trials consisted of the CS+ paired with the UCS, CS- paired with the UCS, and presentations of the UCS alone to assess conditioned UCR diminution. UCR diminution was observed within the dorsolateral PFC, dorsomedial PFC, cingulate cortex, inferior parietal lobule (IPL), anterior insula, and amygdala. The threat-related activity within the dorsolateral PFC, dorsomedial PFC, posterior cingulate cortex, and IPL varied with individual differences in trait anxiety. In addition, anticipatory (i.e. CS elicited) activity within the PFC showed an inverse relationship with threat-related (i.e. UCS elicited) activity within the PFC, IPL, and amygdala. Further, the emotional response (indexed via SCR) elicited by the threat was closely linked to amygdala activity. These findings are consistent with the view that the amygdala and PFC support learning-related processes that influence the emotional response evoked by a threat. Copyright © 2011 Elsevier Inc. All rights reserved.
Przewłocka, B; Sumová, A; Lasoń, W
In this study the rats were repeatedly placed in a conditioning box, and 30 min later were subjected to a mild foot-shock. Anticipation of painful stimuli resulted in development of antinociception before a painful stimulus was applied. This conditioned fear-induced antinociception was antagonized by naloxone (1 mg/kg IP), as well as by ipsapirone (10 mg/kg IP), as measured by a tail-flick test. Stressed rats were hypersensitive to the analgesic action of morphine (1 mg/kg SC), but not to the specific kappa agonist U69,593 (0.1 mg/kg SC). In order to determine the involvement of the proopiomelanocortin and prodynorphin systems in stress we measured levels of their represenative peptides beta-endorphin and alpha-neoendorphin using selective RIAs. Biochemical data showed that conditioned stress evoked a marked decrease in the beta-endorphin level in the hypothalamus and both lobes of the pituitary, together with a three-fold increase in the peptide level in the plasma. In contrast, the level of alpha-neoendorphin in the hypothalamus, pituitary and spinal cord remained unchanged. Only in the plasma a decrease in that peptide content was found. Furthermore, in vitro studies showed that the spontaneous and K(+)-stimulated release of beta-endorphin from the hypothalamus of rats which had been exposed to a conditioned stimulus was enhanced, whereas the release of alpha-neoendorphin from that tissue was attenuated. These results suggest a major role of the proopiomelanocortin system and, to the lesser extent, of the prodynorphin one in the mechanism of a conditioned fear-induced stress.
Woods, Amanda M.; Bouton, Mark E.
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…
Wu, I-Tek; Tang, Tso-Hao; Ko, Meng-Chang; Chiu, Chen-Yu; Lu, Kwok-Tung
The involvement of glutamate in fear extinction is perhaps the most promising in terms of facilitating clinical interventions for posttraumatic stress disorder (PTSD). This study was aimed at elucidating the possible role of zif268 on the D-cycloserine (DCS) facilitation effect on extinction. We investigated the association between zif268 and the extinction of conditioned fear by using antisense oligodeoxynucleotide (ODN) of zif268 and the fear-potentiated startle paradigm. Male adult Wistar rats were injected DCS (15 mg/kg, IP) 15 min prior to the extinction training, administered with antisense or sense ODN (800 pmol) of zif268 and subjected for fear-potentiated startle paradigm (FPS) and Western blot. Either context exposure or cue exposure elevated the expression of zif268 in the basolateral nucleus of the amygdala (BLA) (p extinction of conditioned fear. Subsequent control experiments indicated that administration of vehicle or zif268 sense ODN did not alter the facilitation of DCS and that the blockage effect of zif268 antisense ODN was not due to lasting damage to the amygdala. Our results suggest that zif268 within the amygdala participates in the DCS facilitation effect on the extinction of conditioned fear.
Chrosniak, L.D.; Smith, L.N.; McDonald, C.G.; Jones, B.F.; Flinn, J.M.
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.
Ding, Abby Y.; Li, Qi; Zhou, Iris Y.; Ma, Samantha J.; Tong, Gehua; McAlonan, Grainne M.; Wu, Ed X.
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
Rabinak, Christine A; Mori, Shoko; Lyons, Maryssa; Milad, Mohammed R; Phan, K Luan
Fear-based disorders, like social anxiety disorder (SAD) and posttraumatic stress disorder (PTSD), are characterized by an exaggerated fear response and avoidance to trigger cues, suggesting a transdiagnostic mechanism of psychopathology. Current theories suggest that abnormalities in conditioned fear is a primary contributor to the pathophysiology of these disorders. The primary goal of this study was to compare acquisition of conditioned stimulus (CS) and aversive unconditioned stimulus (US) contingencies during fear learning and extinction in individuals with SAD and PTSD. In a standard Pavlovian fear conditioning-extinction paradigm we measured subjective US expectancy ratings to different CSs in patients with SAD (n=16) compared to patients with PTSD (n=13) and healthy controls (n=15) RESULTS: Both patient groups (SAD, PTSD) acquired differential conditioning between a CS that predicted US (CS+) and a CS that never predicted the US (CS-), however, both groups reported an increased expectancy that the US would occur following the CS-. Additionally, the PTSD group overestimated that the US would occur in general. Neither patient group showed evidence of successful extinction of the CS+-US contingency nor differentiated their expectation of US occurrence between the CS+ and CS- during extinction learning. Group sample sizes were small and we did not include a trauma-exposed group without PTSD CONCLUSIONS: Both SAD and PTSD generalize expectations of an aversive outcome across CSs, even when a CS never signals an aversive outcome and PTSD may tend to over-expect threat. Fear learning and extinction abnormalities may be a core feature underlying shared symptoms across fear-based disorders. Copyright © 2016 Elsevier B.V. All rights reserved.
Masoud Motalebi Kashani
Full Text Available Background and Aim: Sound conditioning is exposure to a non-traumatic, moderate level of sound which increases inner ear resistance against further severe noise. In this study, we aimed to survey the effect of sound conditioning on auditory brainstem response (ABR threshold shifts using click stimulus, and the effect of the frequency of conditioning on hearing protection.Methods: Fifteen guinea pigs were randomly divided into 3 groups. Two conditioned groups were exposed to 1 kHz, and 4 kHz octave band noise at 85 dB SPL, 6 hours per day for 5 days, respectively.On the sixth day, the animals were exposed to 4 kHz octave band noise at 105 dB SPL, for 4 hours.The control group was exposed to intense noise, 4 kHz at 105 Db SPL for 4 hours (withoutconditioning. After exposure, ABR thresholds using click were recorded an hour, and 7 days after noise exposure.Results: The results of the ABR with click stimulus showed less thresold shifts in conditioned groups than control (p≤0.001. Comparison of the results of conditioned groups, showed less threshold shift by 4 kHz conditioning, however, this difference was not statistically significant (p>0.05.Conclusion: Electrophysiological data of our study showed that sound conditioning has a protective effect against subsequent intensive noise exposure, and the frequency of conditioning does not havesignificant effect on ABR threshold shifts when using click stimulus.
DeLorey, T M; Lin, R C; McBrady, B; He, X; Cook, J M; Lameh, J; Loew, G H
Eight compounds that bind to the benzodiazepine binding site on the gamma-amino butyric acid(A) (GABA(A)) receptor were assessed for their influence on contextual memory, an aspect of memory affected in various cognitive disorders including Alzheimer's disease. Using a Pavlovian fear-conditioning paradigm, each ligand was evaluated in C57Bl/6 mice in regards to its direct affect on contextual memory and whether the ligand could attenuate scopolamine-induced contextual memory impairment. Of the eight ligands tested, one impaired contextual memory (agonist), six attenuated scopolamine-induced contextual memory impairment (inverse agonists), and one antagonized the ability of an inverse agonist to attenuate scopolamine-induced contextual memory impairment. Hence, further demonstrating the bi-directional influence benzodiazepine binding site ligands are able to exert on memory modulation. This study serves as an initial starting point in the development of pharmacological tools to be used in deciphering how GABA(A) receptors influence contextual memory.
Gao, Yu; Raine, Adrian; Venables, Peter H.; Dawson, Michael E.; Mednick, Sarnoff A.
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…
Lueken, U; Straube, B; Reinhardt, I; Maslowski, N I; Wittchen, H-U; Ströhle, A; Wittmann, A; Pfleiderer, B; Konrad, C; Ewert, A; Uhlmann, C; Arolt, V; Jansen, A; Kircher, T
Although several neurophysiological models have been proposed for panic disorder with agoraphobia (PD/AG), there is limited evidence from functional magnetic resonance imaging (fMRI) studies on key neural networks in PD/AG. Fear conditioning has been proposed to represent a central pathway for the development and maintenance of this disorder; however, its neural substrates remain elusive. The present study aimed to investigate the neural correlates of fear conditioning in PD/AG patients. The blood oxygen level-dependent (BOLD) response was measured using fMRI during a fear conditioning task. Indicators of differential conditioning, simple conditioning and safety signal processing were investigated in 60 PD/AG patients and 60 matched healthy controls. Differential conditioning was associated with enhanced activation of the bilateral dorsal inferior frontal gyrus (IFG) whereas simple conditioning and safety signal processing were related to increased midbrain activation in PD/AG patients versus controls. Anxiety sensitivity was associated positively with the magnitude of midbrain activation. The results suggest changes in top-down and bottom-up processes during fear conditioning in PD/AG that can be interpreted within a neural framework of defensive reactions mediating threat through distal (forebrain) versus proximal (midbrain) brain structures. Evidence is accumulating that this network plays a key role in the aetiopathogenesis of panic disorder.
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
Wessa, Michèle; Flor, Herta
Posttraumatic stress disorder (PTSD) is characterized by the re-experiencing of a traumatic event, although the trauma itself occurred in the past. The extinction of the traumatic response might be impeded if trauma reminders maintain fear responses by their association with the original trauma through second-order conditioning. A differential conditioning paradigm with a trauma-specific picture, used as an acquired unconditioned stimulus, and graphic representations, used as conditioned stimuli, were employed in 14 PTSD patients, 15 trauma-exposed subjects without PTSD, and 15 healthy comparison subjects. The authors used event-related potentials of electroencephalogram (EEG), self-report measures, skin conductance responses, heart rate, and startle modulation to assess the differential conditioned response among subjects. Trauma-exposed subjects with and without PTSD but not healthy comparison subjects showed successful differential conditioning to the trauma-relevant cue indicative of second-order conditioning. Only PTSD patients exhibited enhanced conditioned responses to the trauma reminder during acquisition and impaired extinction as evident in more negative evaluations of the conditioned stimuli associated with a trauma reminder as well as enhanced peripheral and brain responses. These findings suggest that PTSD may be maintained by second-order conditioning where trauma-relevant cues come to serve as unconditioned stimuli, thus generalizing enhanced emotional responses to many previously neutral cues and impeding extinction. The extinction deficit in PTSD patients observed in this study underlines the need for therapies focusing on the extinction of learned responses, such as behavioral treatment, with or without the addition of pharmacological substances that enhance the extinction of a learned response.
Provensi, Gustavo; Fabbri, Roberta; Munari, Leonardo; Costa, Alessia; Baldi, Elisabetta; Bucherelli, Corrado; Blandina, Patrizio
Abstract Background: The integrity of the brain histaminergic system is necessary for the unfolding of homeostatic and cognitive processes through the recruitment of alternative circuits with distinct temporal patterns. We recently demonstrated that the fat-sensing lipid mediator oleoylethanolamide indirectly activates histaminergic neurons to exerts its hypophagic effects. The present experiments investigated whether histaminergic neurotransmission is necessary also for the modulation of emotional memory induced by oleoylethanolamide in a contextual fear conditioning paradigm. Methods: We examined the acute effect of i.p. administration of oleoylethanolamide immediately posttraining in the contextual fear conditioning test. Retention test was performed 72 hours after training. To test the participation of the brain histaminergic system in the cognitive effect of oleoylethanolamide, we depleted rats of brain histamine with an i.c.v. injection of alpha-fluoromethylhistidine (a suicide inhibitor of histidine decarboxylase) or bilateral intra-amygdala infusions of histamine H1 or H2 receptor antagonists. We also examined the effect of oleoylethanolamide on histamine release in the amygdala using in vivo microdialysis. Results: Posttraining administration of oleoylethanolamide enhanced freezing time at retention. This effect was blocked by both i.c.v. infusions of alpha-fluoromethylhistidine or by intra-amygdala infusions of either pyrilamine or zolantidine (H1 and H2 receptor antagonists, respectively). Microdialysis experiments showed that oleoylethanolamide increased histamine release from the amygdala of freely moving rats. Conclusions: Our results suggest that activation of the histaminergic system in the amygdala has a “permissive” role on the memory-enhancing effects of oleoylethanolamide. Hence, targeting the H1 and H2 receptors may modify the expression of emotional memory and reduce dysfunctional aversive memories as found in phobias and posttraumatic
Full Text Available Subhadra Evans, Laura C Seidman, Kirsten C Lung, Lonnie K Zeltzer, Jennie C TsaoPediatric Pain Program, Department of Pediatrics, David Geffen School of Medicine at UCLA, Los Angeles, CA, USABackground: Parental behaviors, emotions, and cognitions are known to influence children's response to pain. However, prior work has not tested the association between maternal psychological factors and children's responses to a conditioned pain modulation (CPM task. CPM refers to the reduction in perceived pain intensity for a test stimulus following application of a conditioning stimulus to a remote area of the body, and is thought to reflect the descending inhibition of nociceptive signals.Methods: The present study examined sex differences in the association between maternal anxiety about pain and children's CPM responses in 133 healthy children aged 8–17 years. Maternal pain anxiety was assessed using the Pain Anxiety Symptoms Scale-20. In addition to the magnitude of CPM, children's anticipatory anxiety and pain-related fear of the CPM task were measured.Results: Sequential multiple linear regression revealed that even after controlling for child age and general maternal psychological distress, greater maternal pain anxiety was significantly related to greater CPM anticipatory anxiety and pain-related fear in girls, and to less CPM (ie, less pain inhibition in boys.Conclusion: The findings indicate sex-specific relationships between maternal pain anxiety and children's responses to a CPM task over and above that accounted for by the age of the child and the mother's general psychological distress.Keywords: diffuse noxious inhibitory controls, pediatric pain, mother-child relationship, cold pressor, pressure pain, laboratory pain
Hunter, Amy Silvestri
Both human and animal research indicate that rapid eye movement sleep (REM) plays an important role in the processing of emotional information. REM is altered after fear conditioning in rats, but this alteration can be mitigated by exposure to a naïve conspecific. In addition, both the housing condition (isolated vs paired) and the experiences of rats' cagemates can influence the response to aversive events. Based on this prior work, the present study sought to determine the effects of social housing on the previously demonstrated impairment in the extinction of conditioned fear responses produced by REM deprivation. Rats were assigned to one of three housing conditions: housed with a naïve rat, housed with another fear-conditioned rat, or housed alone. The results demonstrated that rats housed with either a naïve or a fear-conditioned conspecific exhibited an impairment in the acquisition of extinction as a consequence of REM deprivation, as observed in previous studies. However, rats in the isolated condition demonstrated a trend toward an impairment only after continued extinction training. These results indicate that the effects of social housing on REM deprivation-induced impairments in learning and memory are subtle, but may explain some conflicting findings in the literature.
Murawski, Nathen J; Asok, Arun
The precise contribution of visual information to contextual fear learning and discrimination has remained elusive. To better understand this contribution, we coupled the context pre-exposure facilitation effect (CPFE) fear conditioning paradigm with presentations of distinct visual scenes displayed on 4 LCD screens surrounding a conditioning chamber. Adult male Long-Evans rats received non-reinforced context pre-exposure on Day 1, an immediate 1.5mA foot shock on Day 2, and a non-reinforced context test on Day 3. Rats were pre-exposed to either digital Context (dCtx) A, dCtx B, a distinct Ctx C, or no context on Day 1. Digital context A and B were identical except for the visual image displayed on the LCD screens. Immediate shock and retention testing occurred in dCtx A. Rats pre-exposed dCtx A showed the CPFE with significantly higher levels of freezing compared to controls. Rats pre-exposed to Context B failed to show the CPFE, with freezing that did not highly differ from controls. These results suggest that visual information contributes to contextual fear learning and that visual components of the context can be manipulated via LCD screens. Our approach offers a simple modification to contextual fear conditioning paradigms whereby the visual features of a context can be manipulated to better understand the factors that contribute to contextual fear discrimination and generalization. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.
Feenstra, M. G.; Vogel, M.; Botterblom, M. H.; Joosten, R. N.; de Bruin, J. P.
We used bilateral microdialysis in the medial prefrontal cortex (PFC) of awake, freely moving rats to study aversive conditioning to an auditory cue in the controlled environment of the Skinner box. The presentation of the explicit conditioned stimuli (CS), previously associated with foot shocks,
Anne Albrecht; Oliver Stork
.... Evidence suggests that a circadian regulation mechanism allows for a timestamping of such fear memories and controlling memory salience during both their acquisition and their modification after retrieval...
Vanessa C Rossi
Full Text Available Numerous studies show that sleep deprivation (SD impacts negatively on cognitive processes, including learning and memory. Memory formation encompasses distinct phases of which acquisition, consolidation and retrieval are better known. Previous studies with pre-training SD induced by the platform method have shown impairment in fear conditioning tasks. Nonetheless, pre-training manipulations do not allow the distinction between effects on acquisition and/or consolidation, interfering, ultimately, on recall of/performance in the task. In the present study, animals were first trained in contextual and tone fear conditioning tasks and then submitted to SD with the purpose to evaluate the effect of this manipulation on different stages of the learning process, e.g. in the uptake of (new information during learning, its encoding and stabilization, and the recall of stored memories. Besides, we also investigated the effect of SD in the extinction of fear memory and a possible state-dependent learning induced by this manipulation. For each task (contextual or tone fear conditioning, animals were trained and then distributed into control, not sleep-deprived (CTL and SD groups, the latter being submitted to the modified multiple platform paradigm for 96 h. Subsets of eight rats in each group/experiment were submitted to the test of the tasks, either immediately or at different time intervals after SD. The results indicated that a pre-, but not post-training SD impaired recall in the contextual and tone fear conditioning; b this impairment was not state-dependent; c in the contextual fear conditioning, pre-test SD prevented extinction of the learned task. Overall, these results suggest that SD interferes with acquisition, recall and extinction, but not necessarily with consolidation of emotional memory.
Full Text Available 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 fearful 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 activations in repressors as compared to sensitizers in the ventromedial prefrontal cortex and the anterior cingulate cortex during fear conditioning. In addition, elevated activity to the CS+ in amygdala, insula, occipital, and orbitofrontal cortex as well as 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, and the orbitofrontal cortex, which is also mirrored in increased SCRs. The present results support recent assumptions about a two-process model of repression postulating a fast vigilant response to fearful stimuli, but also a second emotion down-regulating process.
Julie eBoulanger Bertolus
Full Text Available 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 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 post-natal 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.
Katz, Ira K; Lamprecht, Raphael
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. © 2014 International Society for Neurochemistry.
Benjamin N Greenwood
Full Text Available Repeated stressor exposure can sensitize physiological responses to novel stressors and facilitate the development of stress-related psychiatric disorders including anxiety. Disruptions in diurnal rhythms of sleep-wake behavior accompany stress-related psychiatric disorders and could contribute to their development. Complex stressors that include fear-eliciting stimuli can be a component of repeated stress experienced by humans, but whether exposure to repeated fear can prime the development of anxiety and sleep disturbances is unknown. In the current study, adult male F344 rats were exposed to either control conditions or repeated contextual fear conditioning for 22 days followed by exposure to either no, mild (10, or severe (100 acute uncontrollable tail shock stress. Exposure to acute stress produced anxiety-like behavior as measured by a reduction in juvenile social exploration and exaggerated shock-elicited freezing in a novel context. Prior exposure to repeated fear enhanced anxiety-like behavior as measured by shock-elicited freezing, but did not alter social exploratory behavior. The potentiation of anxiety produced by prior repeated fear was temporary; exaggerated fear was present 1 day but not 4 days following acute stress. Interestingly, exposure to acute stress reduced REM and NREM sleep during the hours immediately following acute stress. This initial reduction in sleep was followed by robust REM rebound and diurnal rhythm flattening of sleep / wake behavior. Prior repeated fear extended the acute stress-induced REM and NREM sleep loss, impaired REM rebound, and prolonged the flattening of the diurnal rhythm of NREM sleep following acute stressor exposure. These data suggest that impaired recovery of sleep / wake behavior following acute stress could contribute to the mechanisms by which a history of prior repeated stress increases vulnerability to subsequent novel stressors and stress-related disorders.
Animal acoustic communication commonly takes place under masked conditions. For instance, sound signals relevant for mating and survival are very often masked by background noise, which makes their detection and recognition by organisms difficult. Ambient noise (AN) varies in level and shape among different habitats, but also remarkable variations in time and space occurs within the same habitat. Variable AN conditions mask hearing thresholds of the receiver in complex and unpredictable ways, thereby causing distortions in sound perception. When communication takes place in a noisy environment, a highly sensitive system might confer no advantage to the receiver compared to a less sensitive one. The effects of noise masking on auditory thresholds and hearing-related functions are well known, and the potential role of AN in the evolution of the species' auditory sensitivity has been recognized by few authors. The mechanism of the underlying selection process has never been explored, however. Here I present a simple fitness model that seeks for the best sensitivity of a hearing system performing the detection and recognition of the sound under variable AN conditions. The model predicts higher sensitivity (i.e. lower hearing thresholds) as best strategy for species living in quiet habitats and lower sensitivity (i.e. higher hearing thresholds) as best strategy for those living in noisy habitats provided the cost of incorrect recognition is not low. The tradeoff between detection and recognition of acoustic signals appears to be a key factor determining the best level of hearing sensitivity of a species when acoustic communication is corrupted by noise. Copyright © 2015 Elsevier Ltd. All rights reserved.
Full Text Available 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.
Hatherall, Lauren; Sánchez, Connie; Morilak, David A
Stress is a risk factor for depression and anxiety disorders, disrupting neuronal processes leading to exaggerated fear and compromised coping behaviors. Current antidepressants are only partially effective. Vortioxetine, a novel multimodal antidepressant, is a serotonin transporter inhibitor; 5-HT3, 5-HT7, and 5-HT1D receptor antagonist; 5-HT1B partial agonist; and 5-HT1A agonist. We have shown that chronic dietary vortioxetine administration reversed stress-induced deficits in cognitive flexibility. In the present studies, we investigated the generality of vortioxetine's effects on other stress-related behavioral changes after different types of chronic stress. In experiment 1, rats were fear-conditioned by pairing a tone with footshock, then exposed to chronic plus acute prolonged stress. In experiment 2, rats were exposed to chronic unpredictable stress. In both experiments, beginning on day 4 of chronic stress, vortioxetine was given in the diet (24 mg/kg/d). In experiment 1, effects of vortioxetine were tested on stress-induced changes in retention and extinction of cue-conditioned fear, and in experiment 2, on coping behavior on the shock probe defensive burying test after chronic stress. Chronic stress exaggerated the expression of conditioned fear memory. Vortioxetine restored fear memory to control levels and rendered extinction in stressed rats comparable with that in controls. In experiment 2, chronic unpredictable stress caused a shift from active to passive coping behavior, and vortioxetine restored active coping. Vortioxetine reduced exaggerated expression of conditioned fear and restored adaptive coping behavior following 2 different types of chronic stress, adding to the evidence of its therapeutic potential in the management of depression and anxiety disorders.
Pavesi, Eloisa; Gooch, Allison; Lee, Elizabeth; Fletcher, Max L.
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…
Lommen, Miriam J.J.; Duta, Mihaela; Vanbrabant, Koen; De Jong, Rachel; Juechems, Keno; Ehlers, Anke
Anxiety disorders are the most common mental disorder worldwide. Although anxiety disorders differ in the nature of feared objects or situations, they share a common mechanism by which fear generalizes to related but innocuous objects, eliciting avoidance of objects and situations that pose no
Baker, Kathryn D.; McNally, Gavan P.; Richardson, Rick
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…
Kim, Hyung-Su; Cho, Hye-Yeon; Augustine, George J; Han, Jin-Hee
Evidence from rodent and human studies has identified the ventromedial prefrontal cortex, specifically the infralimbic cortex (IL), as a critical brain structure in the extinction of conditioned fear. However, how IL activity controls fear expression at the time of extinction memory retrieval is unclear and controversial. To address this issue, we used optogenetics to precisely manipulate the activity of genetically targeted cells and to examine the real-time contribution of IL activity to expression of auditory-conditioned fear extinction in mice. We found that inactivation of IL, but not prelimbic cortex, impaired extinction retrieval. Conversely, photostimulation of IL excitatory neurons robustly enhanced the inhibition of fear expression after extinction, but not before extinction. Moreover, this effect was specific to the conditioned stimulus (CS): IL activity had no effect on expression of fear in response to the conditioned context after auditory fear extinction. Thus, in contrast to the expectation from a generally held view, artificial activation of IL produced no significant effect on expression of non-extinguished conditioned fear. Therefore, our data provide compelling evidence that IL activity is critical for expression of fear extinction and establish a causal role for IL activity in controlling fear expression in a CS-specific manner after extinction. PMID:26354044
Quiñones-Laracuente, Kelvin; Hernández-Rodríguez, Marán Y; Bravo-Rivera, Christian; Melendez, Roberto I; Quirk, Gregory J
There is a high degree of comorbidity between alcohol use disorder and post-traumatic stress disorder (PTSD), but little is known about the interactions of ethanol with traumatic memories. Using auditory fear conditioning in rats, we asked if repeated exposure to ethanol could modify the retrieval of fear memories acquired prior to ethanol exposure. Following auditory fear conditioning, Sprague-Dawley rats were given daily injections of ethanol (1.5 g/kg) or saline over 5 days. Two days later, they were given 20 trials of extinction training and then tested for extinction memory the following day. In a separate experiment, conditioned rats were given repeated ethanol injections and processed for c-Fos immunohistochemistry following a fear retrieval session. Two days following the cessation of ethanol, the magnitude of conditioned fear responses (freezing and suppression of bar pressing) was significantly increased. This increase persisted the following day. Waiting 10 days following cessation of ethanol eliminated the effect on fear retrieval. In rats conditioned with low shock levels, repeated exposure to ethanol converted a sub-threshold fear memory into a supra-threshold fear memory. It also increased c-Fos expression in the prelimbic prefrontal cortex, paraventricular thalamus, and the central and basolateral nuclei of the amygdala, areas implicated in the retrieval of fear memories. These results suggest that repeated exposure to ethanol may exacerbate pre-existing traumatic memories.
Bredy, Timothy W.; Wu, Hao; Crego, Cortney; Zellhoefer, Jessica; Sun, Yi E.; Barad, Mark
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,…
Papesh, Melissa A.; Billings, Curtis J.; Baltzell, Lucas S.
Objective To use cortical auditory evoked potentials (CAEPs) to understand neural encoding in background noise and the conditions under which noise enhances CAEP responses. Methods CAEPs from 16 normal-hearing listeners were recorded using the speech syllable/ba/presented in quiet and speech-shaped noise at signal-to-noise ratios of 10 and 30 dB. The syllable was presented binaurally and monaurally at two presentation rates. Results The amplitudes of N1 and N2 peaks were often significantly enhanced in the presence of low-level background noise relative to quiet conditions, while P1 and P2 amplitudes were consistently reduced in noise. P1 and P2 amplitudes were significantly larger during binaural compared to monaural presentations, while N1 and N2 peaks were similar between binaural and monaural conditions. Conclusions Methodological choices impact CAEP peaks in very different ways. Negative peaks can be enhanced by background noise in certain conditions, while positive peaks are generally enhanced by binaural presentations. Significance Methodological choices significantly impact CAEPs acquired in quiet and in noise. If CAEPs are to be used as a tool to explore signal encoding in noise, scientists must be cognizant of how differences in acquisition and processing protocols selectively shape CAEP responses. PMID:25453611
Alexandra Kredlow, M; Pineles, Suzanne L; Inslicht, Sabra S; Marin, Marie-France; Milad, Mohammed R; Otto, Michael W; Orr, Scott P
Skin conductance (SC) is a psychophysiological measure of sympathetic nervous system activity that is commonly used in research to assess conditioned fear responses. A portion of individuals evidence very low or unmeasurable SC levels (SCL) and/or response (SCR) during fear conditioning, which precludes the use of their SC data. The reason that some individuals do not produce measurable SCL and/or SCR is not clear; some early research suggested that race may be an influencing factor. In the current article, archival data from five fear conditioning samples collected from four different laboratories were examined to explore SCL and SCR magnitude in African American (AA) and non-African American (non-AA) participants. Across studies, the aggregate group difference for exclusion due to unmeasurable SCL or no measurable SCR to an unconditioned stimulus reflected a significant medium effect size (d = 0.54). Furthermore, 24.3% (range: 0-48.3%) of AA participants met SC exclusion criteria versus 14.3% (range: 4.3-24.2%) of non-AA participants. AA participants also displayed significantly lower SCL during habituation (d = 0.58). The low SC levels and responses in AA individuals and the consequent exclusion of their contributions to fear conditioning study results impacts the generalizability of findings across races. Given higher rates of posttraumatic stress disorder (PTSD) and chronic anxiety in AA individuals, it is important that AA individuals not be excluded from fear conditioning research, which informs the treatment of anxiety and PTSD. Examination of the basis of very low SCL and/or SCR is a potentially informative direction for future research. © 2017 Society for Psychophysiological Research.
Cacciaglia, Raffaele; Nees, Frauke; Pohlack, Sebastian T; Ruttorf, Michaela; Winkelmann, Tobias; Witt, Stephanie H; Nieratschker, Vanessa; Rietschel, Marcella; Flor, Herta
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. Copyright © 2013 Elsevier B.V. All rights reserved.
Davis, Jennifer A; Gould, Thomas J
Previous research indicates that nicotine administration enhances hippocampus-dependent forms of learning, including contextual fear conditioning. This effect is blocked by mecamylamine, a noncompetitive, broad-spectrum nicotinic receptor antagonist. The present study extends previous research by further characterizing the nicotinic acetylcholinergic receptor (nAChR) subtypes through which nicotine acts to enhance contextual fear conditioning. C57BL/6J mice were trained with two conditioned stimulus (CS; 30 s, 85-dB white noise)-unconditioned stimulus (US; 2 s, 0.57-mA foot shock) pairings and tested 24 h later for contextual and cued fear conditioning. The effects of the alpha7 nAChR antagonist methyllycaconitine (MLA; 1.00, 10.00, and 20.00 mg/kg) and the effects of the alpha4beta2 nAChR antagonist dihydro-beta-erythroidine (DHBE; 1.00, 3.00, and 6.00 mg/kg) on cued and contextual fear conditioning and on the enhancement of contextual fear conditioning by nicotine (0.25 mg/kg) were examined. We demonstrate that DHBE (all doses) administration attenuates the enhancing effect of nicotine on contextual fear conditioning, and MLA administration has no significant effect on the enhancement of contextual fear conditioning by nicotine. The data suggest that non-alpha7 nAChRs (most likely alpha4beta2 nAChRs) underlie the enhancement of contextual fear conditioning by nicotine.
Full Text Available Adult neurogenesis replenishes olfactory bulb (OB interneurons throughout the life of most mammals, yet during this constant fl ux it remains unclear how the OB maintains a constant structure and function. In the mouse OB, we investigated the dynamics of turnover and its impact on olfactory function by ablating adult neurogenesis with an x-ray lesion to the subventricular zone (SVZ. Regardless of the magnitude of the lesion to the SVZ, we found no change in the survival of young adult born granule cells (GCs born after the lesion, and a gradual decrease in the population of GCs born before the lesion. After a lesion producing a 96% reduction of incoming adult born GCs to the OB, we found a diminished behavioral fear response to conditioned odor cues but not to audio cues. Interestingly, despite this behavioral defi cit and gradual anatomical changes, we found no electrophysiological changes in the GC population assayed in vivo through dendro-dendritic synaptic plasticity and odor-evoked local fi eld potential oscillations. These data indicate that turnover in the granule cell layer is generally decoupled from the rate of adult neurogenesis, and that OB adult neurogenesis plays a role in a wide behavioral system extending beyond the OB.
Kubota, Natsuko; Amemiya, Seiichiro; Yanagita, Shinya; Nishijima, Takeshi; Kita, Ichiro
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. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.
Schmidt, S D; Myskiw, J C; Furini, C R G; Schmidt, B E; Cavalcante, L E; Izquierdo, I
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. Copyright © 2014 Elsevier Inc. All rights reserved.
Ikegami, S; Harada, A; Hirokawa, N
Tau, one of the major neuronal microtubule-associated proteins (MAPs), is important for neuronal cell morphogenesis and axonal maintenance. Tau is also known to be a component of the paired helical filaments (PHFs) in Alzheimer's disease patients. Recently, mutations in the tau gene were found in a hereditary neurodegenerative disease called frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) which exhibits various neurological and neuropathological characteristics including PHF-like intracellular tau deposit formation. Currently, the phenotype of the disease is thought to be due to: (1) the toxicity of mutant tau molecules and and/or; (2) the loss of function of normal tau molecules in patients' brains. To test the latter hypothesis, we performed behavioral and neurological tests on tau-deficient mice. Tau-deficient mice showed muscle weakness in the wire-hanging test, hyperactivity in a novel environment, and impairment in the contextual fear conditioning. They also had a tendency to fall more easily in the rod-walking test. These phenotypes parallel some signs and symptoms of FTDP-17 patients. Our results show that the loss of tau protein may itself lead to some of the neurological characteristics observed in FTDP-17 patients.
Hunt, Pamela S.; Burk, Joshua A.; Barnet, Robert C.
Adolescence is a time of critical brain changes that pave the way for adult learning processes. However, the extent to which learning in adolescence is best characterized as a transitional linear progression from childhood to adulthood, or represents a period that differs from earlier and later developmental stages, remains unclear. Here we examine behavioral literature on associative fear conditioning and complex choice behavior with rodent models. Many aspects of fear conditioning are intact by adolescence and do not differ from adult patterns. Sufficient evidence, however, suggests that adolescent learning cannot be characterized simply as an immature precursor to adulthood. Across different paradigms assessing choice behavior, literature suggests that adolescent animals typically display more impulsive patterns of responding compared to adults. The extent to which the development of basic conditioning processes serves as a scaffold for later adult decision making is an additional research area that is important for theory, but also has widespread applications for numerous psychological conditions. PMID:27339692
Hardcastle, W. J.
Reports on the effects of oral anaesthesia and auditory masking on various aspects of speech articulation as objectively quantified by electropalatography and sound spectrography. The results show changes in speech production caused by altered tactile and auditory feedback. (Author/TL)
Chang, Chun-hui; Maren, Stephen
It has been suggested that reduced infralimbic (IL) cortical activity contributes to impairments of fear extinction. We therefore explored whether pharmacological activation of the IL would facilitate extinction under conditions it normally fails (i.e., immediate extinction). Rats received auditory fear conditioning 1 h before extinction training. Immediately prior to extinction, rats received microinfusions into the IL of the GABAA receptor antagonist, picrotoxin, or the NMDA receptor partia...
Broadwater, Margaret; Spear, Linda P
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. Copyright © 2013 Elsevier B.V. All rights reserved.
Broadwater, Margaret; Spear, Linda P.
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 minutes 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 24 hours 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 Exp1, 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. PMID:23810415
細羽, 竜也; 生和, 秀敏; 岩永, 誠
The preparedness theory of phobia holds that humans are biologically prepared to learn to fear ohjects and situations that threatened the human species throughout its evolutonary history (Seligman, 1971). Biological preparedness is postulated to be responsible for the rapid acquition of fear, a resistance to the influence of cognitive factors, resistance to extinction, and belongingness. Because of some difficulties, many reseachers suggest that preparedness effects may be produced by cogniti...
Cao, Bo; Ni, Huan-Yu; Li, Jun; Zhou, Ying; Bian, Xin-Lan; Tao, Yan; Cai, Cheng-Yun; Qin, Cheng; Wu, Hai-Yin; Chang, Lei; Luo, Chun-Xia; Zhu, Dong-Ya
Fear- and anxiety-related psychiatric disorders have been one of the major chronic diseases afflicting patients for decades, and new compounds for treating such disorders remain to be developed. (+)-Borneol, a bicyclic monoterpene found in several species of Artemisia and Dipterocarpaceae, is widely used for anxiety, pain and anesthesia in Chinese medicine. Meanwhile, it can potentiate GABA (γ-aminobutyric acid) activity directly in recombinant GABAA receptors. The present study was to investigate the effects of (+)-Borneol on both contextual and cued fear recall. Interestingly, microinjection of (+)-Borneol into the dorsal hippocampus inhibited 24 h and 7 d contextual fear, whereas its infusion into ventral hippocampus only reduced 24 h cued fear responses. Moreover, microinjection of (+)-Borneol into dorsal but not ventral hippocampus suppressed anxiety-like behaviors in the open field test, light/dark exploration and the elevated plus maze test. As selective GABA A receptor antagonist bicuculline reversed the effect of (+)-Borneol on contextual fear paradigm and the drug potentiated GABA-evoked currents in acute hippocampus slices, modulation of the GABAergic neurotransmission may explain the effects of (+)-Borneol. Our findings suggest that (+)-Borneol can serve as a new therapeutic in fear- and anxiety-related disorders. Copyright © 2017 Elsevier Inc. All rights reserved.
Conrad, Claudius; Konuk, Yusuf; Werner, Paul; Cao, Caroline G; Warshaw, Andrew; Rattner, David; Jones, Daniel B; Gee, Denise
Music and noise are frequent occurrences in the operating room. To date, the effects of these auditory conditions on the performance of laparoscopic surgery experts have not been evaluated. Eight internationally recognized experts were recruited for a crossover study. The experts were randomized to perform three simple tasks on a laparoscopic simulator, SurgicalSIM VR. The tasks were equal in difficulty and performed under the following conditions: silence, dichaotic music (auditory stress), classical music (auditory relaxation), and mental loading (mental arithmetic tasks). Permutations of the conditions were created to account for a learning effect. The tasks were performed twice to test for memory consolidation and to accommodate baseline variability. Time until task completion and task accuracy via instrument tip trajectory (path of the tip through space) were recorded. Performance was correlated with responses on the Brief Musical Experience Questionnaire (MEQ). The study demonstrated that dichaotic music has a negative impact on time until task completion but not on task accuracy. In addition, memory consolidation of accuracy is negatively influenced. Classical music has a variable effect on experts' time until task completion, yet all the experts performed the tasks more accurately. Classical music had no effect on recall of a procedure. Mental loading increased time until completion, but did not affect accuracy or recall. The experience of music varied among experts and influenced how each of the conditions affected their performance. The study demonstrated that, contrary to common belief, proficiency in surgery does not protect against stressful auditory influences or the influence of mental preoccupation. Interestingly, relaxing auditory influences such as classical music can even have a positive impact on the accuracy of experts. Previous musical experience could help to identify surgeons whose performance may be specifically affected by music or noise.
Beijer, L. J.; Rietveld, A. C. M.; van Stiphout, A. J. L.
Background: Web based speech training for dysarthric speakers, such as E-learning based Speech Therapy (EST), puts considerable demands on auditory discrimination abilities. Aims: To discuss the development and the evaluation of an auditory discrimination test (ADT) for the assessment of auditory speech discrimination skills in Dutch adult…
Fernandez, Brice; Leuchs, Laura; Sämann, Philipp G; Czisch, Michael; Spoormaker, Victor I
Standard T2(*) weighted functional magnetic resonance imaging (fMRI) performed with echo-planar imaging (EPI) suffers from signal loss in the ventromedial prefrontal cortex (vmPFC) due to macroscopic field inhomogeneity. However, this region is of special interest to affective neuroscience and psychiatry. The Multi-echo EPI (MEPI) approach has several advantages over EPI but its performance against EPI in the vmPFC has not yet been examined in a study with sufficient statistical power using a task specifically eliciting activity in this region. We used a fear conditioning task with MEPI to compare the performance of MEPI and EPI in vmPFC and control regions in 32 healthy young subjects. We analyzed activity associated with short (12ms), standard (29ms) and long (46ms) echo times, and a voxel-wise combination of these three echo times. Behavioral data revealed successful differentiation of the conditioned versus safety stimulus; activity in the vmPFC was shown by the contrast "safety stimulus > conditioned stimulus" as in previous research and proved significantly stronger with the combined MEPI than standard single-echo EPI. Then, we aimed to demonstrate that the additional cluster extent (ventral extension) detected in the vmPFC with MEPI reflects activation in a relevant cluster (i.e., not just non-neuronal noise). To do this, we used resting state data from the same subjects to show that the time-course of this region was both connected to bilateral amygdala and the default mode network. Overall, we demonstrate that MEPI (by means of the weighted sum combination approach) outperforms standard EPI in vmPFC; MEPI performs always at least as good as the best echo time for a given brain region but provides all necessary echo times for an optimal BOLD sensitivity for the whole brain. This is relevant for affective neuroscience and psychiatry given the critical role of the vmPFC in emotion regulation. Copyright © 2017 Elsevier Inc. All rights reserved.
Binaural interaction in the auditory brainstem response (ABR) represents the discrepancy between the binaural waveform and the sum of monaural ones. A typical ABR binaural interaction in humans is a reduction of the binaural amplitude compared to the monaural sum at the wave-V latency, i.e., the DN1 component. It has been considered that the DN1 is mainly elicited by high frequency components of stimuli whereas some studies have shown the contribution of low-to-middle frequency components to the DN1. To examine this issue, the present study compared the ABR binaural interaction elicited by tone pips (1 kHz, 10-ms duration) with the one by clicks (a rectangular wave, 0.1-ms duration) presented at 80 dB peak equivalent SPL and a fixed stimulus onset interval (180 ms). The DN1 due to tone pips was vulnerable compared to the click-evoked DN1. The pip-evoked DN1 was significantly detected under auditory attention whereas it failed to reach significance under visual attention. The click-evoked DN1 was robustly present for the two attention conditions. The current results might confirm the high frequency sound contribution to the DN1 elicitation. Copyright © 2015 Elsevier B.V. All rights reserved.
Seifert, A Ronald
Absence of memory or verbal recall for symptom acquisition in fear and trauma exposure, as well as absence of successful coping behavior for life events, is associated with a number of diagnoses, including traumatic brain injury, posttraumatic stress disorder, pain, and anxiety. The difficulty with diagnosis and treatment planning based on the absence of recall, memory, and successful coping behavior is threefold: (1) these assessments do not distinguish between disruption of behavior and lack of capacity, (2) the absence of verbal recall and memory complicates cognitive-based treatment, and (3) a confounding issue is the same absent behavior can be observed at different times and contexts. While memory of the specific details of the initial traumatic event(s) may not be available to verbal report, the existence of time- and context-dependent relationships for the initial as well as subsequent experiences is arguable. The absence of memory or lack of verbal recall does not rule out measurable physiological bodily responses for the initial trauma(s), nor does it help to establish the effects of subsequent experiences for symptom expression. Also, the absence of memory must include the prospect of fear-based learning that does not require or involve the cortex. It is posited that the literatures of fear conditioning and learned nonuse provide complementary illustrations of how the time and context of the initial trauma(s) and subsequent experiences affect behavior, which is not dependent on the effected individual being able to provide a memory-based verbal report. The replicated clinical application demonstrates that, without scientific demonstration, neither neuroanatomy nor verbal report can be assumed sufficient to predict overt behavior or physiologic responses. For example, while commonly assumed to be predictively so, autonomic nervous system innervation is insufficient to define the unique stimulus- and context-dependent physiological responses of an
Campbell-Smith, Emma J.; Holmes, Nathan M.; Lingawi, Nura W.; Panayi, Marios C.; Westbrook, R. Frederick
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…
Sarabdjitsingh, R Angela; Zhou, Ming; Yau, Joyce L W; Webster, Scott P; Walker, Brian R; Seckl, Jonathan R; Joëls, Marian; Krugers, Harm J
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. Copyright © 2014 Elsevier Ltd. All rights reserved.
Haufler, Darrell; Nagy, Frank Z.; Pare, Denis
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…
Bos, M.G.N.; Beckers, T.; Kindt, M.
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
Kindt, M.; Soeter, M.
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
Foilb, Allison R.; Bals, Julia; Sarlitto, Mary C.; Christianson, John P.
Distinguishing safety from danger is necessary for survival, but is aberrant in individuals with post-traumatic stress disorder (PTSD). While PTSD is more prevalent in women than men, research on sex differences in safety learning is limited. Here, female rats demonstrated greater fear discrimination than males in a CS+/CS- paradigm. To determine…
Luyten, Laura; Beckers, Tom
In 2009, Monfils and colleagues proposed a behavioral procedure that was said to result in a permanent attenuation of a previously established fear memory, thereby precluding a possible return of fear after extinction (Monfils, Cowansage, Klann, & LeDoux, 2009). By presenting a single retrieval trial one hour before standard extinction training, they found an enduring reduction of fear. The retrieval-extinction procedure holds great clinical potential, particularly for anxiety patients, but the findings are not undisputed, and several conceptual replications have failed to reproduce the effect. These failures have largely been attributed to small procedural differences. This preregistered study is the first endeavor to exactly replicate three key experiments of the original report by Monfils et al. (2009), thereby gauging the robustness of their seminal findings. Despite adhering to the original procedures as closely as possible, we did not find any evidence for reduced return of fear with the retrieval-extinction procedure relative to regular extinction training, as assessed through spontaneous recovery, reinstatement and renewal. Behavior of animals in the control condition (extinction only) was comparable to that in the original studies and provided an adequate baseline to reveal differences with the retrieval-extinction condition. Our null findings indicate that the effect sizes in the original paper may have been inflated and question the legitimacy of previously proposed moderators of the retrieval-extinction effect. We argue that direct experimental evaluation of purported moderators of the retrieval-extinction effect will be key to shed more light on its nature and prerequisites. Copyright © 2017 Elsevier Inc. All rights reserved.
Full Text Available The theory of memory reconsolidation argues that consolidated memory is not unchangeable. Once a memory is reactivated it may go back into an unstable state and need new protein synthesis to be consolidated again, which is called “memory reconsolidation”. Boundary studies have shown that interfering with reconsolidation through pharmacologic or behavioral intervention can lead to the updating of the initial memory, for example, erasing undesired memories. Behavioral procedures based on memory reconsolidation interference have been shown to be an effective way to inhibit fear memory relapse after extinction. However, the effectiveness of retrieval–extinction differs by subtle differences in the protocol of the reactivation session. This represents a challenge with regard to finding an optimal operational model to facilitate its clinical use for patients suffering from pathogenic memories such as those associated with post-traumatic stress disorder. Most of the laboratory models for fear learning have used a single conditioned stimulus (CS paired with an unconditioned stimulus (US. This has simplified the real situation of traumatic events to an excessive degree, and thus, limits the clinical application of the findings based on these models. Here, we used a basic visual compound CS model as the CS to ascertain whether partial repetition of the compound CSs in conditioning can reactivate memory into reconsolidation. The results showed that the no retrieval group or the 1/3 ratio retrieval group failed to open the memory reconsolidation time window. The 2/3 repetition retrieval group and the whole repetition retrieval group were able to prevent fear reinstatement, whereas only a 2/3 ratio repetition of the initial compound CS as a reminder could inhibit spontaneous recovery. We inferred that a retrieval–extinction paradigm was also effective in a more complex model of fear if a sufficient prediction error (PE could be generated in the
Quiñones, María M; Maldonado, Lizette; Velazquez, Bethzaly; Porter, James T
Patients with post-traumatic stress disorder (PTSD) tend to show signs of a relatively increased inflammatory state suggesting that activation of the immune system may contribute to the development of PTSD. In the present study, we tested whether activation of the innate immune system can disrupt acquisition or recall of auditory fear extinction using an animal model of PTSD. Male adolescent rats received auditory fear conditioning in context A. The next day, an intraperitoneal injection of lipopolysaccharide (LPS; 100 μg/kg) prior to auditory fear extinction in context B impaired acquisition and recall of extinction. LPS (100 μg/kg) given after extinction training did not impair extinction recall suggesting that LPS did not affect consolidation of extinction. In contrast to cued fear extinction, contextual fear extinction was not affected by prior injection of LPS (100 μg/kg). Although LPS also reduced locomotion, we could dissociate the effects of LPS on extinction and locomotion by using a lower dose of LPS (50 μg/kg) which impaired locomotion without affecting extinction. In addition, 15 h after an injection of 250 μg/kg LPS in adult rats, extinction learning and recall were impaired without affecting locomotion. A sub-chronic treatment with candesartan, an angiotensin II type 1 receptor blocker, prevented the LPS-induced impairment of extinction in adult rats. Our results demonstrate that activation of the innate immune system can disrupt auditory fear extinction in adolescent and adult animals. These findings also provide direction for clinical studies of novel treatments that modulate the innate immune system for stress-related disorders like PTSD. Copyright © 2015 Elsevier Inc. All rights reserved.
Jürgens, Tim; Brand, Thomas; Clark, Nicholas R; Meddis, Ray; Brown, Guy J
Different methods of extracting speech features from an auditory model were systematically investigated in terms of their robustness to different noises. The methods either computed the average firing rate within frequency channels (spectral features) or inter-spike-intervals (timing features) from the simulated auditory nerve response. When used as the front-end for an automatic speech recognizer, timing features outperformed spectral features in Gaussian noise. However, this advantage was lost in babble, because timing features extracted the spectro-temporal structure of babble noise, which is similar to the target speaker. This suggests that different feature extraction methods are optimal depending on the background noise.
Full Text Available Three days of fear conditioning that combines tactile stimulation of a row of facial vibrissae (conditioned stimulus, CS with a tail shock (unconditioned stimulus, UCS expands the representation of "trained" vibrissae, which can be demonstrated by labeling with 2-deoxyglucose in layer IV of the barrel cortex. We have also shown that functional reorganization of the primary somatosensory cortex (S1 increases GABAergic markers in the hollows of "trained" barrels of the adult mouse. This study investigated how whisker-shock conditioning (CS+UCS affected the expression of puncta of a high-affinity GABA plasma membrane transporter GAT-1 in the barrel cortex of mice 24 h after associative learning paradigm. We found that whisker-shock conditioning (CS+UCS led to increase expression of neuronal and astroglial GAT-1 puncta in the "trained" row compared to controls: Pseudoconditioned, CS-only, UCS-only and Naïve animals. These findings suggest that fear conditioning specifically induces activation of systems regulating cellular levels of the inhibitory neurotransmitter GABA.
Broadwater, Margaret; Spear, Linda P
An acute ethanol (EtOH) challenge prior to fear conditioning typically disrupts fear retention to contextual cues to a greater degree than fear retention to a discrete tone cue, and adolescent rats are less sensitive than adults to these EtOH-induced disruptions of context fear memory. Given that some research suggests that repeated EtOH exposure during adolescence may "lock-in" adolescent-typical EtOH sensitivity into adulthood, the purpose of this study was to determine whether adults exposed to EtOH as adolescents would be less sensitive to EtOH-induced disruptions of context fear. Male Sprague-Dawley rats were given 4 g/kg intragastric EtOH (25% v/v) or water every 48 hours for a total of 11 exposures during adolescence (postnatal day [P] 28 to 48) or adulthood (P70-90). After a 22-day non-EtOH period, animals were acutely challenged with 1 g/kg intraperitoneal EtOH or saline 10 minutes prior to tone or context (noncued) fear conditioning. Tone and context fear retention was subsequently examined. Regardless of age or exposure history, typical deficits in context fear retention were evident after EtOH challenge during conditioning. Similarly, tone fear retention was disrupted in all animals that were trained in the presence of EtOH, which was somewhat surprising given the relative resistance of tone fear retention to an acute EtOH challenge. These results do not support the notion of a "lock-in" of adolescent-typical EtOH sensitivity as there was no influence of exposure age on sensitivity to the disruptive effects of an acute EtOH challenge. Thus, it appears that not all adolescent-like EtOH sensitivities persist into adulthood after prior EtOH exposure during adolescence. Copyright © 2014 by the Research Society on Alcoholism.
Park, Chun Hui J; Ganella, Despina E; Kim, Jee Hyun
Anxiety disorders emerge early, and girls are significantly more likely to develop anxiety compared to boys. However, sex differences in fear during development are poorly understood. Therefore, we investigated juvenile male and female rats in the relapse behaviors following extinction of conditioned fear. In all experiments, 18-d-old rats first received three white-noise-footshock pairings on day 1. On day 2, extinction involved 60 white-noise alone trials. In experiment 1, we examined renewal by testing the rats in either the same or different context as extinction on day 3. Male rats did not show renewal, however, female rats showed renewal. Experiment 2 investigated reinstatement by giving rats either a mild reminder footshock or context exposure on day 3. When tested the next day, male rats did not show reinstatement, whereas female rats showed reinstatement. Experiment 3 investigated spontaneous recovery by testing the rats either 1 or 5 d following extinction. Male rats did not show any spontaneous recovery whereas female rats did. Taken together, fear regulation appear to be different in males versus females from early in development, which may explain why girls are more prone to suffer from anxiety disorders compared to boys. © 2017 Park et al.; Published by Cold Spring Harbor Laboratory Press.
van Reekum, C.M.; van den Berg, H.; Frijda, N.H.
A cross-modal paradigm was chosen to test the hypothesis that affective olfactory and auditory cues paired with neutral visual stimuli bearing no resemblance or logical connection to the affective cues can evoke preference shifts in those stimuli. Neutral visual stimuli of abstract paintings were
Osman, Homira; Sullivan, Jessica R.
Purpose: The objectives of this study were to determine (a) whether school-age children with typical hearing demonstrate poorer auditory working memory performance in multitalker babble at degraded signal-to-noise ratios than in quiet; and (b) whether the amount of cognitive demand of the task contributed to differences in performance in noise. It…
Souza, Rimenez R; Dal Bó, Silvia; de Kloet, E Ronald; Oitzl, Melly S; Carobrez, Antonio P
There is general agreement that the substantial modification in memory and motivational states exerted by corticosteroids after a traumatic experience is mediated in complementary manner by the mineralocorticoid (MR) and glucocorticoid (GR) receptors. Here we tested the hypothesis that pharmacological manipulation of MR activity would affect behavioral strategy and information storage in an olfactory fear conditioning (OFC) task. Male Wistar rats were submitted to the OFC with different training intensities. We observed that following high intensity OFC acquisition, a set of defensive coping strategies, which includes avoidance and risk assessment behaviors, was elicited when subjects were exposed to the conditioned stimulus (CS) 48 h later. In addition, following either OFC acquisition or retrieval (CS-I test) a profound corticosterone secretion was also detected. Systemic administration of the MR antagonist spironolactone altered the behavioral coping style irrespective the antagonist was administered 60 min prior to the acquisition or before the retrieval session. Surprisingly, the MR agonist fludrocortisone given 60 min prior to acquisition or retrieval of OFC had similar effects as the antagonist. In addition, post-training administration of fludrocortisone, following a weak training procedure, facilitated the consolidation of OFC. Fludrocortisone rather than spironolactone reduced serum corticosterone levels, suggesting that, at least in part, the effects of the MR agonist may derive from additional GR-mediated HPA-axis suppression. In conclusion, the present study suggests the involvement of the MR in the fine-tuning of behavioral adaptation necessary for optimal information storage and expression, as revealed by the marked alterations in the risk assessment behavior. Copyright © 2013 Elsevier Ltd. All rights reserved.
Zhang, Wei-Ning; Bast, Tobias; Xu, Yan; Feldon, Joram
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. Copyright © 2013 Elsevier B.V. All rights reserved.
Storsve, Andreas Berg; McNally, Gavan P; Richardson, Rick
Just as fear can be learned, it can also be inhibited. The most common way of reducing learned fear is through extinction, where the conditioned stimulus (CS) previously paired with an aversive unconditioned stimulus (US) is repeatedly presented on its own. Another, much less commonly studied, way to inhibit learned fear is by habituating, or devaluing, the US. In this procedure, fear responding to a CS is reduced by repeatedly presenting the US in the absence of the CS following the conditioning phase. The purpose of the present study was to directly compare the effects of US habituation and CS extinction on a learned fear response (freezing). Experiment 1 demonstrated that US habituation given either after (Experiment 1A) or before (Experiment 1B) fear conditioning reduced freezing to the CS at test. We then showed that the reduction in freezing resulting from either US habituation or CS extinction was context-specific (i.e., a change in context led to a renewal of the learned fear response; Experiment 2) and, furthermore, was attenuated when a pre-test shock was given (i.e., reinstatement of fear was observed in both cases; Experiment 3). Finally, Experiment 4 demonstrated that an injection of the NMDA antagonist MK-801 prior to US habituation impaired long-term retention of the learning that takes place during this procedure. Together, these results suggest that the decrement in conditioned fear responses produced by US habituation and CS extinction could rely on overlapping processes. Copyright 2010 Elsevier Inc. All rights reserved.
Musetto, Andrew P.
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)
Arias, Natalia; Méndez, Marta; Arias, Jorge L
The importance context has been broadly studied in the management of phobias and in the drug addiction literature. The way in which changes to a context influence behavior after the simple acquisition of a passive avoidance task remains unclear. The hippocampus has long been implicated in the contextual and spatial processing required for contextual fear, but its role in encoding the aversive component of a contextual fear memory is still inconclusive. Our work tries to elucidate whether a change in context, represented as differences in the load of the stimuli, is critical for learning about the context-shock association and whether this manipulation of the context could be linked to any change in metabolic brain activity requirements. For this purpose, we used an avoidance conditioning task. Animals were divided into three different experimental conditions. In one group, acquisition was performed in an enriched stimuli environment and retention was performed in a typically lit chamber (the PA-ACQ-CONTX group). In another group, acquisition was performed in the typically lit chamber and retention was undertaken in the highly enriched chamber (the PA-RET-CONTX group). Finally, for the control group, PA-CN-CONTX, acquisition, and retention were performed in the enriched stimuli environment. Our results showed that the PA-ACQ-CONTX group had longer escape latencies and poorer retention than the PA-RET-CONTX and PA-CN-CONTX groups after 24 h of acquisition under contextual changes. To study metabolic brain activity, histochemical labelling of cytochrome c-oxidase (CO) was performed. CO results suggested a neural circuit including the hippocampus, amygdala, thalamus, parahippocampal cortices, and mammillary nuclei that is involved in the learning and memory processes that enable context-dependent behavior. These results highlight how dysfunction in this network may be involved in the contextualization of fear associations that underlie several forms of psychopathology
Goode, Travis D; Holloway-Erickson, Crystal M; Maren, Stephen
Retrieving fear memories just prior to extinction has been reported to effectively erase fear memories and prevent fear relapse. The current study examined whether the type of retrieval procedure influences the ability of extinction to impair fear renewal, a form of relapse in which responding to a conditional stimulus (CS) returns outside of the extinction context. Rats first underwent Pavlovian fear conditioning with an auditory CS and footshock unconditional stimulus (US); freezing behavior served as the index of conditioned fear. Twenty-four hours later, the rats underwent a retrieval-extinction procedure. Specifically, 1h prior to extinction (45 CS-alone trials; 44 for rats receiving a CS reminder), fear memory was retrieved by either a single exposure to the CS alone, the US alone, a CS paired with the US, or exposure to the conditioning context itself. Over the next few days, conditional freezing to the extinguished CS was tested in the extinction and conditioning context in that order (i.e., an ABBA design). In the extinction context, rats that received a CS+US trial before extinction exhibited higher levels of conditional freezing than animals in all other groups, which did not differ from one another. In the renewal context, all groups showed renewal, and none of the reactivation procedures reduced renewal relative to a control group that did not receive a reactivation procedure prior to extinction. These data suggest retrieval-extinction procedures may have limited efficacy in preventing fear renewal. Copyright © 2017 Elsevier Inc. All rights reserved.
Butler, Christopher W.; Wilson, Yvette M.; Gunnersen, Jenny M.; Murphy, Mark
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…
Walker, David L.; Davis, Michael
Within the amygdala, most N-methyl-D-aspartic acid (NMDA) receptors consist of NR1 subunits in combination with either NR2A or NR2B subunits. Because the particular subunit composition greatly influences the receptors' properties, we investigated the contribution of both subtypes to fear conditioning and expression. To do so, we infused the…
Full Text Available As a fundamental learning process, fear conditioning promotes the formation of associations between predictive cues and biologically-significant signals. In its application to pain, conditioning may provide important insight into mechanisms underlying pain-related fear, although knowledge especially in interoceptive pain paradigms remains scarce. Furthermore, while the influence of contingency awareness on excitatory learning is subject of ongoing debate, its role in pain-related acquisition is poorly understood and essentially unknown regarding extinction as inhibitory learning. Therefore, we addressed the impact of contingency awareness on learned emotional responses to pain- and safety-predictive cues in a combined dataset of two pain-related conditioning studies.In total, 75 healthy participants underwent differential fear acquisition, during which rectal distensions as interoceptive unconditioned stimuli (US were repeatedly paired with a predictive visual cue (conditioned stimulus; CS+ while another cue (CS- was presented unpaired. During extinction, both CS were presented without US. CS valence, indicating learned emotional responses, and CS-US contingencies were assessed on visual analogue scales. Based on an integrative measure of contingency accuracy, a median-split was performed to compare groups with low versus high contingency accuracy regarding learned emotional responses. To investigate predictive value of contingency accuracy, regression analyses were conducted. Highly accurate individuals revealed more pronounced negative emotional responses to CS+ and increased positive responses to CS- when compared to participants with low contingency accuracy. Following extinction, highly accurate individuals had fully extinguished pain-predictive cue properties, while exhibiting persistent positive emotional responses to safety signals. In contrast, individuals with low accuracy revealed equally positive emotional responses to both, CS+ and
Li, Susan S Y; McNally, Gavan P
Two experiments used an associative blocking design to study the role of dopamine receptors in the nucleus accumbens shell (AcbSh) and core (AcbC) in fear prediction error. Rats in the experimental groups were trained to a visual fear-conditioned stimulus (conditional stimulus [CS]) A in Stage I, whereas rats in the control groups were not. In Stage II, all rats received compound fear conditioning of the visual CSA and an auditory CSB. Rats were later tested for their fear responses to CSB. All rats received microinjections of saline or the D1-D2 receptor antagonist cis-(z)-flupenthixol prior to Stage II. These microinjections targeted either the AcbSh (Experiment 1) or the AcbC (Experiment 2). In each experiment, Stage I fear conditioning of CSA blocked fear learning to CSB. Microinjection of cis-(z)-flupenthixol (10 or 20 μg) into the AcbSh (Experiment 1) had no effect on fear learning or associative blocking. In contrast, microinjection of cis-(z)-flupenthixol (10 or 20 μg) into the AcbC (Experiment 2) attenuated blocking and so enabled fear learning to CSB. These results identify the AcbC as the critical locus for dopamine receptor contributions to fear prediction error and the associative blocking of fear learning. (c) 2015 APA, all rights reserved).
Rabinak, Christine A.; Orsini, Caitlin A.; Zimmerman, Joshua M.; Maren, Stephen
The basolateral complex (BLA) and central nucleus (CEA) of the amygdala play critical roles in associative learning, including Pavlovian conditioning. However, the precise role for these structures in Pavlovian conditioning is not clear. Recent work in appetitive conditioning paradigms suggests that the amygdala, particularly the BLA, has an…
Bi, Qiang; Shi, Lijuan; Yang, Pingting; Wang, Jianing; Qin, Ling
Extinction of conditioned fear is an important brain function for animals to adapt to a new environment. Accumulating evidence suggests that innate immune cytokines are involved in the pathology of psychotic disorders. However, the involvement of cytokines in fear dysregulation remains less investigated. In the present study, we investigated how interferon (IFN)-α disrupts the extinction of conditioned fear and propose an approach to rescue IFN-α-induced neurologic impairment. We used a rat model of auditory fear conditioning to study the effect of IFN-α on the fear memory process. IFN-α was infused directly into the amygdala of rats and examined the rats' behavioral response (freezing) to fear-conditioned stimuli. Immunohistochemical staining was used to examine the glia activity status of glia in the amygdala. The levels of the proinflammatory cytokines interleukin (IL)-1β and tumor necrosis factor (TNF)-α in the amygdala were measured by enzyme-linked immunosorbent assay. We also administrated minocycline, a microglial activation inhibitor, before the IFN-α infusion to testify the possibility to reverse the IFN-α-induced effects. Infusing the amygdala with IFN-α impaired the extinction of conditioned fear in rats and activated microglia and astrocytes in the amygdala. Administering minocycline prevented IFN-α from impairing fear extinction. The immunohistochemical and biochemical results show that minocycline inhibited IFN-α-induced microglial activation and reduced IL-1β and TNF-α production. Our findings suggest that IFN-α disrupts the extinction of auditory fear by activating glia in the amygdala and provides direction for clinical studies of novel treatments to modulate the innate immune system in patients with psychotic disorders.
Poole, Rachel L; Braak, David; Gould, Thomas J
Chronic caffeine exerts negligible effects on learning and memory in normal adults, but it is unknown whether this is also true for children and adolescents. The hippocampus, a brain region important for learning and memory, undergoes extensive structural and functional modifications during pre-adolescence and adolescence. As a result, chronic caffeine may have differential effects on hippocampus-dependent learning in pre-adolescents and adolescents compared with adults. Here, we characterized the effects of chronic caffeine and withdrawal from chronic caffeine on hippocampus-dependent (contextual) and hippocampus-independent (cued) fear conditioning in pre-adolescent, adolescent, and adult mice. The results indicate that chronic exposure to caffeine during pre-adolescence and adolescence enhances or impairs contextual conditioning depending on concentration, yet has no effect on cued conditioning. In contrast, withdrawal from chronic caffeine impairs contextual conditioning in pre-adolescent mice only. No changes in learning were seen for adult mice for either the chronic caffeine or withdrawal conditions. These findings support the hypothesis that chronic exposure to caffeine during pre-adolescence and adolescence can alter learning and memory and as changes were only seen in hippocampus-dependent learning, which suggests that the developing hippocampus may be sensitive to the effects of caffeine. Copyright © 2015 Elsevier B.V. All rights reserved.
Brown, Rachel M; Palmer, Caroline
In two experiments, we investigated how auditory-motor learning influences performers' memory for music. Skilled pianists learned novel melodies in four conditions: auditory only (listening), motor only (performing without sound), strongly coupled auditory-motor (normal performance), and weakly coupled auditory-motor (performing along with auditory recordings). Pianists' recognition of the learned melodies was better following auditory-only or auditory-motor (weakly coupled and strongly coupled) learning than following motor-only learning, and better following strongly coupled auditory-motor learning than following auditory-only learning. Auditory and motor imagery abilities modulated the learning effects: Pianists with high auditory imagery scores had better recognition following motor-only learning, suggesting that auditory imagery compensated for missing auditory feedback at the learning stage. Experiment 2 replicated the findings of Experiment 1 with melodies that contained greater variation in acoustic features. Melodies that were slower and less variable in tempo and intensity were remembered better following weakly coupled auditory-motor learning. These findings suggest that motor learning can aid performers' auditory recognition of music beyond auditory learning alone, and that motor learning is influenced by individual abilities in mental imagery and by variation in acoustic features.
volume. The conference's topics include auditory exploration of data via sonification and audification; real time monitoring of multivariate date; sound in immersive interfaces and teleoperation; perceptual issues in auditory display; sound in generalized computer interfaces; technologies supporting...... auditory display creation; data handling for auditory display systems; applications of auditory display....
Full Text Available Stress during postnatal development is associated with an increased risk for depression, anxiety disorders, and substance abuse later in life, almost as if mental illness is able to be programed by early life stressors. Recent studies suggest that such "programmed" effects can be caused by epigenetic regulation. With respect to conditioned fear, previous studies have indicated that early life stress influences its development in adulthood, whereas no potential role of epigenetic regulation has been reported. Neurotensin (NTS is an endogenous neuropeptide that has receptors densely located in the amygdala and hippocampus. Recently, NTS systems have constituted an emerging target for the treatment of anxiety. The aim of the present work is to clarify whether the NTS system is involved in the disturbance of conditioned fear in rats stressed by maternal separation (MS. The results showed that MS enhanced freezing behaviors in fear-conditioned stress and reduced the gene expression of NTS receptor (NTSR 1 but not of NTS or NTSR2 in the amygdalas of adult rats. The microinjection of a NTSR1 antagonist into the amygdala increased the percentage of freezing in conditioned fear, whereas the microinjection of NTSR1 agonist decreased freezing. These results suggest that NTSR1 in the amygdala may play a role in the effects of MS on conditioned fear stress in adult rats. Moreover, MS increased DNA methylation in the promoter region of NTSR1 in the amygdala. Taken together, MS may leave epigenetic marks in the NTSR1 gene in the amygdala, which may enhance conditioned fear in adulthood. The MS-induced alternations of DNA methylation in the promoter region of NTSR1 in the amygdala may be associated with vulnerability to the development of anxiety disorders and depression in adulthood.
Sevenster, D.; Beckers, T.; Kindt, M.
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
Heimer-McGinn, Victoria R; Poeta, Devon L; Aghi, Krishan; Udawatta, Methma; Burwell, Rebecca D
The perirhinal cortex (PER) is known to process object information, whereas the rodent postrhinal cortex (POR), homolog to the parahippocampal cortex in primates, is thought to process spatial information. A number of studies, however, provide evidence that both areas are involved in processing contextual information. In this study, we tested the hypothesis that the rat POR relies on object information received from the PER to form complex representations of context. Using three fear-conditioning (FC) paradigms (signaled, unsignaled, and renewal) and two context-guided object recognition tasks (with 3D and 2D objects), we examined the effects of crossed excitotoxic lesions to the POR and the contralateral PER. Performance of rats with crossed lesions was compared with that of rats with ipsilateral POR plus PER lesions and sham-operated rats. We found that rats with contralateral PER-POR lesions were impaired in object-context recognition but not in contextual FC. Therefore, interaction between the POR and PER is necessary for context-guided exploratory behavior but not for associating fear with context. Our results provide evidence for the hypothesis that the POR relies on object and pattern information from the PER to encode representations of context. The association of fear with a context, however, may be supported by alternate cortical and/or subcortical pathways when PER-POR interaction is not available. Our results suggest that contextual FC may represent a special case of context-guided behavior.SIGNIFICANCE STATEMENT Representations of context are important for perception, memory, decision making, and other cognitive processes. Moreover, there is extensive evidence that the use of contextual representations to guide appropriate behavior is disrupted in neuropsychiatric and neurological disorders including developmental disorders, schizophrenia, affective disorders, and Alzheimer's disease. Many of these disorders are accompanied by changes in
Schultz, Douglas H; Helmstetter, Fred J
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
Song, Chenghui; Ehlers, Vanessa L.
Neuronal activity in medial prefrontal cortex (mPFC) is critical for the formation of trace fear memory, yet the cellular mechanisms underlying these memories remain unclear. One possibility involves the modulation of intrinsic excitability within mPFC neurons that project to the basolateral complex of amygdala (BLA). The current study used a combination of retrograde labeling and in vitro whole-cell patch-clamp recordings to examine the effect of trace fear conditioning on the intrinsic excitability of layer 5 mPFC–BLA projection neurons in adult rats. Trace fear conditioning significantly enhanced the intrinsic excitability of regular spiking infralimbic (IL) projection neurons, as evidenced by an increase in the number of action potentials after current injection. These changes were also associated with a reduction in spike threshold and an increase in h current. In contrast, trace fear conditioning reduced the excitability of regular spiking prelimbic (PL) projection neurons, through a learning-related decrease of input resistance. Interestingly, the amount of conditioned freezing was (1) positively correlated with excitability of IL-BLA projection neurons after conditioning and (2) negatively correlated with excitability of PL-BLA projection neurons after extinction. Trace fear conditioning also significantly enhanced the excitability of burst spiking PL-BLA projection neurons. In both regions, conditioning-induced plasticity was learning specific (observed in conditioned but not in pseudoconditioned rats), flexible (reversed by extinction), and transient (lasted conditioning. SIGNIFICANCE STATEMENT Frontal lobe-related function is vital for a variety of important behaviors, some of which decline during aging. This study involves a novel combination of electrophysiological recordings from fluorescently labeled mPFC-to-amygdala projection neurons in rats with acquisition and extinction of trace fear conditioning to determine how specific neurons change during
March, Amelia; Borchelt, David; Golde, Todd; Janus, Christopher
Fear-conditioning testing paradigms have been used to study differences in memory formation between inbred mouse strains, including numerous mouse models of human diseases. In this study, we characterized the conditioned fear memory of 3 inbred strains: C57BL/6NCrl, 129S2/SvPasCrl, and FVB/NCrl, obtained from Charles River Laboratories. We used 2 training paradigms: delay conditioning, in which an unconditional stimulus coterminates with the presentation of a conditional stimulus, and trace conditioning, in which the conditional and unconditional stimuli are separated by a trace interval. In each paradigm, we evaluated the recent (3 d) and remote (25 d) memory of the mice by using a longitudinal design. Our results showed that both C57BL/6NCrl and 129S2/SvPasCrl mice developed strong and long-lasting context and tone memories in both paradigms, but FVB/NCrl mice showed a weaker but nevertheless consistent tone memory after delay training. Tone memory in the FVB strain was stronger in male than female mice. The remote tone memory of 129S2/SvPasCrl mice diminished after delay training but was stable and stronger than that of C57BL/6NCrl mice after trace training. In conclusion, both C57BL/6NCrl and 129S2/SvPasCrl mice showed reliable and long-lasting fear memory after delay or trace training, with 129 mice showing particularly strong tone memory after trace conditioning. The FVB/NCrl strain, especially male mice, showed reliable tone fear memory after delay training. Our findings confirm that both C57BL/6NCrl and 129S2/SvPasCrl mice develop strong context and tone memory in delay and trace fear-conditioning paradigms.
Schipper, P.; Henckens, M.J.A.G.; Borghans, B.; Hiemstra, M.; Kozicz, T.; Homberg, J.R.
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
Flack, F; Gerlach, A L; Simons, L E; Zernikow, B; Hechler, T
To date, no German instrument exists to measure pain-related fear in paediatric pain populations. The objective of the current study was to determine the construct validity of the translated German fear of pain questionnaire for children (GFOPQ-C) in a sample of children with mixed chronic pain disorders by testing the underlying factor structure, and its psychometric properties. N = 241 children with mixed chronic pain disorders (aged 8-19 years) presenting to a specialized pain clinic completed the GFOPQ-C and several other pain, fear and disability measures. The two-factor structure of the FOPQ-C (fear, avoidance) was replicated. Internal consistency for the shortened German version was good for both subscales (Fear subscale: α = 0.89; avoidance subscale: α = 0.76). As expected, the fear subscale correlated highly with anxiety sensitivity (r = 0.63), pain catastrophizing (r = 0.62) and general anxiety (r = 0.54), while the avoidance subscale was more closely related to disability (r = 0.24) and school functioning (r = 0.28). Pain-related fear differed in children with chronic pain depending on their pain location with higher fear ratings in children with abdominal pain and musculoskeletal pain. The GFOPQ-C is a valid instrument that assesses two distinct dimensions of pain-related fear in children: fear and avoidance. Future research is needed to evaluate the impact of increased pain-related fear on outcomes over time as well as to examine pain-related fear among healthy children. This will enhance our knowledge of who might be particularly vulnerable to potentially dysfunctional trajectories, such as ongoing pain or anxiety symptoms. The current study validates the first tool to assess pain-related fear in German-speaking children with chronic pain. Findings support two distinct domains: fear and activity avoidance. © 2017 European Pain Federation - EFIC®.
VanElzakker, Michael B; Dahlgren, M. Kathryn; Davis, F. Caroline; Dubois, Stacey; Shin, Lisa M
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 ...
Morrison, Filomene G.; Dias, Brian G.; Ressler, Kerry J.
Olfactory cues may be paired with traumatic experiences in humans (e.g., the smell of a physical abuser), and subsequent exposure to the environmental odor cue may serve as a reminder of the traumatic event and trigger posttraumatic stress disorder symptoms. Very few studies have investigated the mechanisms accompanying the processing of emotional learning at the level of specific sensory modalities. The present study demonstrates that extinction specific to the conditioned odor acetophenone ...
Slouzkey, Ilana; Maroun, Mouna
The basolateral amygdala (BLA), medial prefrontal cortex (mPFC) circuit, plays a crucial role in acquisition and extinction of fear memory. Extinction of aversive memories is mediated, at least in part, by the phosphoinositide-3 kinase (PI3K)/Akt pathway in adult rats. There is recent interest in the neural mechanisms that mediate fear and extinction in juvenile animals and whether these mechanisms are distinctive from those in adult animals. In the present study, we examined (1) changes in phosphorylation of Akt in the BLA and mPFC after fear conditioning and extinction in juvenile and adult rats and (2) the effect of BLA and mPFC localized inhibition of the PI3K following acquisition and extinction of contextual fear memory. Our results show that Akt phosphorylation is increased following acquisition of contextual fear learning in the BLA but not in the mPFC in adult and juvenile rats. Extinction learning was not associated with changes in Akt phosphorylation. Although there were no differences in the pattern of phosphorylation of Akt either in adult or juvenile rats, microinjection of the PI3K inhibitor, LY294002, into the BLA or mPFC elicited differential effects on fear memory acquisition and extinction, depending on the site and timing of the microinjection, as well as on the age of the animal. These results suggest that PI3K/Akt has a differential role in formation, retrieval, and extinction of contextual fear memory in juvenile and adult animals, and point to developmental differences between adult and juvenile rats in mechanisms of extinction. © 2016 Slouzkey and Maroun; Published by Cold Spring Harbor Laboratory Press.
Koo, Ja Wook; Duman, Ronald S.
IL-1β is a proinflammatory cytokine that contributes to psychological stress responses and has been implicated in various psychiatric disorders most notably depression. Preclinical studies also demonstrate that IL-1β modulates anxiety- and fear-related behaviors, although these findings are difficult to assess because IL-1β infusions influence locomotor activity and nociception. Here we demonstrate that IL-1RI null mice exhibit a behavioral phenotype consistent with a decrease in anxiety-related behaviors. This includes significant effects in the elevated plus maze, light–dark, and novelty-induced hypophagia tests compared to wild-type mice, with no differences in locomotor activity. With regard to fear conditioning, IL-1RI null mice showed more freezing in auditory and contextual fear conditioning tests, and there was no effect on pain sensitivity. Taken together, the results indicate that the IL-1β/IL-1RI signaling pathway induces anxiety-related behaviors and impairs fear memory. PMID:19429130
Full Text Available Maternal immune activation during pregnancy is an environmental risk factor for psychiatric illnesses such as schizophrenia and autism in the offspring. Hence, changes in an array of behaviors, including behavioral flexibility, consistent with altered functioning of cortico-limbic circuits have been reported in rodent models of maternal immune activation. Surprisingly, previous studies have not examined the effect of maternal immune activation on the extinction of fear conditioning which depends on cortico-limbic circuits. Thus, we tested the effects of treating pregnant Long Evans rats with the viral mimetic polyI:C (gestational day 15; 4 mg/kg; i.v. on fear conditioning and extinction in the male offspring using two different tasks. In the first experiment, we observed no effect of polyI:C treatment on the acquisition or extinction of a classically conditioned fear memory in a non-discriminative auditory cue paradigm. However, polyI:C-treated offspring did increase contextual freezing during the recall of fear extinction in this non-discriminative paradigm. The second experiment utilized a recently developed task to explicitly test the ability of rats to discriminate among cues signifying fear, reward, and safety; a task that requires behavioral flexibility. To our surprise, polyI:C-treated rats acquired the task in a manner similar to saline-treated rats. However, upon subsequent extinction training, they showed significantly faster extinction of the freezing response to the fear cue. In contrast, during the extinction recall test, polyI:C-treated offspring showed enhanced freezing behavior before and after presentation of the fear cue, suggesting an impairment in their ability to regulate fear behavior. These behavioral results are integrated into the literature suggesting impairments in cortico-limbic brain function in the offspring of rats treated with polyI:C during pregnancy.
Do-Monte, Fabricio H.; Manzano-Nieves, Gabriela; Quiñones-Laracuente, Kelvin; Ramos-Medina, Liorimar; Quirk, Gregory J.
Previous rodent studies have implicated the infralimbic (IL) subregion of the medial prefrontal cortex in extinction of auditory fear conditioning. However, these studies used pharmacological inactivation or electrical stimulation techniques, which lack temporal precision and neuronal specificity. Here, we used an optogenetic approach to either activate (with channelrhodopsin) or silence (with halorhodopsin) glutamatergic IL neurons during conditioned tones delivered in one of two phases: ext...
Pedraza, Lizeth K; Sierra, Rodrigo O; Crestani, Ana P; Quillfeldt, Jorge A; de Oliveira Alvares, Lucas
Systems consolidation has been described as a time-dependent reorganization process involving the neocortical and hippocampal networks underlying memory storage and retrieval. Previous studies of our lab were able to demonstrate that systems consolidation is a dynamic process, rather than a merely passive, time-dependent phenomenon. Here, we studied the influence of sequential learning in contextual fear conditioning (CFC) with different training intensities in the time-course of hippocampal dependency and contextual specificity. We found that sequential learning with high-intensity shocks during CFC induces generalization of the first learning (context A) and maintains contextual specificity of the second learning (context B) 15 days after acquisition. Moreover, subsequent experiences reorganize brain structures involved in retrieval, accelerating the involvement of cortical structures and diminishing the hippocampal participation. Exposure to original context before novelty seems to only induce context specificity in hippocampal-dependent memories. We propose that systems consolidation could be considered a potential biological mechanism for reducing possible interferences between similar memory traces. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.
Jonathan E Ploski
Full Text Available The Neuronal PAS domain protein 4 (Npas4 is a neuronal activity-dependent immediate early gene that has recently been identified as a transcription factor which regulates the transcription of genes that control inhibitory synapse development and synaptic plasticity. The role Npas4 in learning and memory, however, is currently unknown. Here, we systematically examine the role of Npas4 in auditory Pavlovian fear conditioning, an amygdala-dependent form of emotional learning. In our first series of experiments, we show that Npas4 mRNA and protein are regulated in the rat lateral nucleus of the amygdala (LA in a learning-dependent manner. Further, knockdown of Npas4 protein in the LA via adeno-associated viral (AAV mediated gene delivery of RNAi was observed to impair fear memory formation, while innate fear and the expression of fear memory were not affected. In our second series of experiments, we show that Npas4 protein is regulated in the LA by retrieval of an auditory fear memory and that knockdown of Npas4 in the LA impairs retention of a reactivated, but not a non-reactivated, fear memory. Collectively, our findings provide the first comprehensive look at the functional role of Npas4 in learning and memory.
Kong, Ying-Yee; Mullangi, Ala; Ding, Nai
This study investigates how top-down attention modulates neural tracking of the speech envelope in different listening conditions. In the quiet conditions, a single speech stream was presented and the subjects paid attention to the speech stream (active listening) or watched a silent movie instead (passive listening). In the competing speaker (CS) conditions, two speakers of opposite genders were presented diotically. Ongoing electroencephalographic (EEG) responses were measured in each condition and cross-correlated with the speech envelope of each speaker at different time lags. In quiet, active and passive listening resulted in similar neural responses to the speech envelope. In the CS conditions, however, the shape of the cross-correlation function was remarkably different between the attended and unattended speech. The cross-correlation with the attended speech showed stronger N1 and P2 responses but a weaker P1 response compared to the cross-correlation with the unattended speech. Furthermore, the N1 response to the attended speech in the CS condition was enhanced and delayed compared with the active listening condition in quiet, while the P2 response to the unattended speaker in the CS condition was attenuated compared with the passive listening in quiet. Taken together, these results demonstrate that top-down attention differentially modulates envelope-tracking neural activity at different time lags and suggest that top-down attention can both enhance the neural responses to the attended sound stream and suppress the responses to the unattended sound stream. Copyright © 2014 Elsevier B.V. All rights reserved.
Wadhwa, S; Anand, P; Bhowmick, D
Morphological effects of prenatal sound attenuation and sound overstimulation by species specific and music sounds on the brainstem auditory nuclei of chick have been evaluated quantitatively. Changes in length, volume, neuron number, size of neuronal nuclei and glial numbers of second and third order auditory nuclei, n. magnocellularis (NM) and n. laminaris (NL), were determined from thionine-stained serial sections of control and experimental groups on posthatch day 1 using stereological methods. Significant increase in volume of both auditory nuclei attributable to increase in length of nucleus, number and size of neurons, number of glia as well as neuropil was observed in response to both species specific and music overstimulation given during the critical period of development. The enhanced development of auditory nuclei in response to enriched environment prenatally indicates a positive effect of activity on neurons which may have clinical implications in addition to providing explanation for preference to auditory cues in the postnatal life. Reduction in neuron number with a small increase in proportion of cell nuclei of large size as well as an increase in glial numbers was seen in both NM and NL of the prenatally sound attenuated chicks. The increase in size of some neuronal nuclei may probably be evidence of enhanced synthesis of proteins involved in cell death or an attempt at recovery. The dissociated response of neurons and glia under sound attenuated and auditory stimulated conditions suggests that they are independently regulated by activity-dependent signals with glia also being under influence of other signals for a role in removal of dead cell debris.
Rauhut, A S; McPhee, J E; Ayres, J J
The ability of a blocked or overshadowed conditioned stimulus (CS) to serve as (a) blocker or (b) a 2nd-order reinforcer in Pavlovian fear conditioning was tested in 152 albino rats. CS-evoked suppression of barpressing for food was the index of conditioned fear. Experiments 1 and 2 showed that an overshadowed CS was weakened in its ability to serve as a blocker. In Experiment 2, a blocked CS was similarly weakened. Experiment 3 showed that an overshadowed and blocked CS was weakened in its ability to serve as a 2nd-order reinforcer. Experiments 4 and 5 failed to restore the blocking ability of blocked (Experiment 4) or overshadowed (Experiment 5) CSs by extinguishing the CSs that had blocked or overshadowed them. Results favor a learning-deficit view of blocking and overshadowing.
Goksoy, Cuneyt; Demirtas, Serdar; Ates, Kahraman
Neurophysiological studies aiming to explore how the brain integrates information from different brain regions are increasing in the literature. The aim of the present study is to explore intramodal (binaural, binocular) and intermodal (audio-visual) interactions in the guinea pig brain through the observation of changes in evoked potentials by generalized continuous background activity. Seven chronically prepared animals were used in the study and the recordings were made as they were awake. Epidural electrodes were implanted to the skulls by using stereotaxic methods. Continuous light for retinal or continuous white noise for cochlear receptors were used as continuous conditioning stimuli for generalized stimulation. To evoke auditory or visual potentials, click or flash were used as transient imperative stimuli. The study data suggest that (a) white noise applied to one ear modifies the response to click in the contralateral ear which is a binaural interaction; (b) continuous light applied to one eye modifies the response to flash applied to the contralateral eye which is interpreted as a binocular interaction; (c) regardless of the application side, white noise similarly modified the response to flash applied to the either eye connoting a nonspecific effect of white noise on vision, independent from spatial hearing mechanisms; (d) on the other hand, continuous light, in either eye, did not affect the response to click applied to any ear, reminding a 'one-way' interaction that continuous aural stimulation affects visual response.
Jan 11, 2006 ... the fear circuits, d) fear memory, and e) fear extinction, the new learning that the harmless stimulus no longer forecasts a threat. We conclude with a few points regarding selected anxiety disorders and different therapeutic modalities. The neuroanatomy of fear and fear conditioning. The fear pathways have ...
Bakker, Mirte J; Tijssen, Marina A J; van der Meer, Johan N; Koelman, Johannes H T M; Boer, Frits
Background: Young patients with anxiety disorders are thought to have a hypersensitive fear system, including alterations of the early sensorimotor processing of threatening information. However, there is equivocal support in auditory blink response studies for an enlarged auditory startle reflex
A young man with chronic auditory hallucinations was treated according to the principle that increasing external auditory stimulation decreases the likelihood of auditory hallucinations. Listening to a radio through stereo headphones in conditions of low auditory stimulation eliminated the patient's hallucinations.
Tronson, Natalie C.; Wiseman, Shari L.; Neve, Rachael L.; Nestler, Eric J.; Olausson, Peter; Taylor, Jane R.
Cyclic AMP response element binding protein (CREB) plays a critical role in fear memory formation. Here we determined the role of CREB selectively within the amygdala in reconsolidation and extinction of auditory fear. Viral overexpression of the inducible cAMP early repressor (ICER) or the dominant-negative mCREB, specifically within the lateral amygdala disrupted reconsolidation of auditory fear memories. In contrast, manipulations of CREB in the amygdala did not modify extinction of fear. ...
DuPont, Caitlin M; Coppola, Jennifer J; Kaercher, Roxanne M; Lindquist, Derick H
Utilizing a rat model of fetal alcohol spectrum disorder (FASD), ethanol was administered over postnatal days (PD) 4 to 9. As adults, control and ethanol rats underwent trace fear conditioning (TFC), in which a tone conditioned stimulus (CS) and footshock unconditioned stimulus (US) were repeatedly paired, though the two stimuli never overlapped in time. Following training in Experiment 1, conditioned fear (freezing) to the tone CS was dose-dependently reduced in ethanol rats relative to controls. Experiment 2 was designed to test whether the TFC deficit varied based on the duration of the trace interval (TI; time from CS offset to US onset). Holding the time separating CS onset from US onset constant at 20 sec, control and ethanol rats were trained with a 5 or 15 sec tone CS, followed 15 or 5 sec later, respectively, by the US. Conditioned fear to the tone CS was significantly reduced in high dose ethanol rats trained with the 15 sec TI only. Acquisition and consolidation of trace fear memories relies on forebrain N-methyl-d-aspartate receptor (NMDAR) signaling, including the downstream phosphorylation of extracellular signal-regulated kinase 1/2 (pERK1/2). Separate rats were trained with the 5 or 15 sec TI and then sacrificed 1 hr later. Significant reductions in pERK1/2-positive neurons were seen in areas CA1 and CA3 of the dorsal hippocampus (DH) following training at both TIs in ethanol rats. The disruption of DH learning-dependent plasticity appears tied to freezing behavior in ethanol rats, but only when the training stimuli are separated by more than 5 sec.
Janik Vincent M
Full Text Available Abstract Background Autonomous reflexes enable animals to respond quickly to potential threats, prevent injury and mediate fight or flight responses. Intense acoustic stimuli with sudden onsets elicit a startle reflex while stimuli of similar intensity but with longer rise times only cause a cardiac defence response. In laboratory settings, habituation appears to affect all of these reflexes so that the response amplitude generally decreases with repeated exposure to the stimulus. The startle reflex has become a model system for the study of the neural basis of simple learning processes and emotional processing and is often used as a diagnostic tool in medical applications. However, previous studies did not allow animals to avoid the stimulus and the evolutionary function and long-term behavioural consequences of repeated startling remain speculative. In this study we investigate the follow-up behaviour associated with the startle reflex in wild-captured animals using an experimental setup that allows individuals to exhibit avoidance behaviour. Results We present evidence that repeated elicitation of the acoustic startle reflex leads to rapid and pronounced sensitisation of sustained spatial avoidance behaviour in grey seals (Halichoerus grypus. Animals developed rapid flight responses, left the exposure pool and showed clear signs of fear conditioning. Once sensitised, seals even avoided a known food source that was close to the sound source. In contrast, animals exposed to non-startling (long rise time stimuli of the same maximum sound pressure habituated and flight responses waned or were absent from the beginning. The startle threshold of grey seals expressed in units of sensation levels was comparable to thresholds reported for other mammals (93 dB. Conclusions Our results demonstrate that the acoustic startle reflex plays a crucial role in mediating flight responses and strongly influences the motivational state of an animal beyond a short
Bobeck, Erin N; Gomes, Ivone; Pena, Darlene; Cummings, Kirstie A; Clem, Roger L; Mezei, Mihaly; Devi, Lakshmi A
Studies show that neuropeptide-receptor systems in the basolateral amygdala (BLA) play an important role in the pathology of anxiety and other mood disorders. Since GPR171, a recently deorphanized receptor for the abundant neuropeptide BigLEN, is expressed in the BLA, we investigated its role in fear and anxiety-like behaviors. To carry out these studies we identified small molecule ligands using a homology model of GPR171 to virtually screen a library of compounds. One of the hits, MS0021570_1, was identified as a GPR171 antagonist based on its ability to block (i) BigLEN-mediated activation of GPR171 in heterologous cells, (ii) BigLEN-mediated hyperpolarization of BLA pyramidal neurons, and (iii) feeding induced by DREADD-mediated activation of BigLEN containing AgRP neurons in the arcuate nucleus. The role of GPR171 in anxiety-like behavior or fear conditioning was evaluated following systemic or intra-BLA administration of MS0021570_1, as well as following lentiviral-mediated knockdown of GPR171 in the BLA. We find that systemic administration of MS0021570_1 attenuates anxiety-like behavior while intra-BLA administration or knockdown of GPR171 in the BLA reduces anxiety-like behavior and fear conditioning. These results indicate that the BigLEN-GPR171 system plays an important role in these behaviors and could be a novel target to develop therapeutics to treat psychiatric disorders.
Slevc, L Robert; Shell, Alison R
Auditory agnosia refers to impairments in sound perception and identification despite intact hearing, cognitive functioning, and language abilities (reading, writing, and speaking). Auditory agnosia can be general, affecting all types of sound perception, or can be (relatively) specific to a particular domain. Verbal auditory agnosia (also known as (pure) word deafness) refers to deficits specific to speech processing, environmental sound agnosia refers to difficulties confined to non-speech environmental sounds, and amusia refers to deficits confined to music. These deficits can be apperceptive, affecting basic perceptual processes, or associative, affecting the relation of a perceived auditory object to its meaning. This chapter discusses what is known about the behavioral symptoms and lesion correlates of these different types of auditory agnosia (focusing especially on verbal auditory agnosia), evidence for the role of a rapid temporal processing deficit in some aspects of auditory agnosia, and the few attempts to treat the perceptual deficits associated with auditory agnosia. A clear picture of auditory agnosia has been slow to emerge, hampered by the considerable heterogeneity in behavioral deficits, associated brain damage, and variable assessments across cases. Despite this lack of clarity, these striking deficits in complex sound processing continue to inform our understanding of auditory perception and cognition. © 2015 Elsevier B.V. All rights reserved.
Saltuklaroglu, Tim; Kalinowski, Joseph; Robbins, Mary; Crawcour, Stephen; Bowers, Andrew
Background: Stuttering is prone to strike during speech initiation more so than at any other point in an utterance. The use of auditory feedback (AAF) has been found to produce robust decreases in the stuttering frequency by creating an electronic rendition of choral speech (i.e., speaking in unison). However, AAF requires users to self-initiate…
Full Text Available The paraventricular nucleus of the thalamus (PVT has generated interest because of its strong projections to areas of the brain associated with the regulation of emotional behaviors. The posterior aspect of the PVT (pPVT is notable for its projection to the central nucleus of the amygdala which is essential for the expression of a conditioned fear response. The present study was done to determine if the pPVT is involved in the expression of fear by examining the effect of post-conditioning lesions of the pPVT. Male rats were trained to bar press for food pellets on a variable ratio schedule. Fear conditioning was done using auditory tones (30 s that co-terminate with footschocks (0.65 mA, 1.0 s. Rats were anesthetized 24 hours later and small bilateral electrolytic lesions of the pPVT were made. Fear expression to the tone was assessed using suppression of bar-pressing and freezing after one week of recovery from the surgical procedure. Small bilateral lesions of the pPVT increased bar-pressing for food and decreased freezing during the presentation of the conditioned tone. Lesions of the pPVT had no effect on fear extinction, fear conditioning to a novel tone, or the motivation for food as assessed using a progressive ratio schedule. The results of the experiment support a role for the pPVT in fear expression. In contrast, the pPVT does not appear to be involved in fear learning or extinction nor does it appear to play a role in the motivation of rats to bar press for food.
Luke R Johnson
Full Text Available Pavlovian auditory fear conditioning crucially involves the integration of information about and acoustic conditioned stimulus (CS and an aversive unconditioned stimulus (US in the lateral nucleus of the amygdala (LA. The auditory CS reaches the LA subcortically via a direct connection from the auditory thalamus and also from the auditory association cortex itself. How neural modulators, especially those activated during stress, such as norepinephrine (NE, regulate synaptic transmission and plasticity in this network is poorly understood. Here we show that NE inhibits synaptic transmission in both the subcortical and cortical input pathway but that sensory processing is biased towards the subcortical pathway. In addition binding of NE to β-adrenergic receptors further dissociates sensory processing in the LA. These findings suggest a network mechanism that shifts sensory balance towards the faster but more primitive subcortical input.
Full Text Available An increasing body of evidence suggests that mechanisms related to the introduction and repair of DNA double strand breaks (DSBs may be associated with long-term memory (LTM processes. Previous studies from our group suggested that factors known to function in DNA recombination/repair machineries, such as DNA ligases, polymerases, and DNA endonucleases, play a role in LTM. Here we report data using C57BL/6 mice showing that the V(DJ recombination-activating gene 1 (RAG1, which encodes a factor that introduces DSBs in immunoglobulin and T-cell receptor genes, is induced in the amygdala, but not in the hippocampus, after context fear conditioning. Amygdalar induction of RAG1 mRNA, measured by real-time PCR, was not observed in context-only or shock-only controls, suggesting that the context fear conditioning response is related to associative learning processes. Furthermore, double immunofluorescence studies demonstrated the neuronal localization of RAG1 protein in amygdalar sections prepared after perfusion and fixation. In functional studies, intra-amygdalar injections of RAG1 gapmer antisense oligonucleotides, given 1 h prior to conditioning, resulted in amygdalar knockdown of RAG1 mRNA and a significant impairment in LTM, tested 24 h after training. Overall, these findings suggest that the V(DJ recombination-activating gene 1, RAG1, may play a role in LTM consolidation.
Lonsdorf, Tina B; Haaker, Jan; Schümann, Dirk; Sommer, Tobias; Bayer, Janine; Brassen, Stefanie; Bunzeck, Nico; Gamer, Matthias; Kalisch, Raffael
Anxiety disorders are more prevalent in women than in men. Despite this sexual dimorphism, most experimental studies are conducted in male participants and studies focusing on sex differences are sparse. In addition, the role of hormonal contraceptives and menstrual cycle phase in fear conditioning and extinction processes remain largely unknown. We investigated sex differences in context-dependent fear acquisition and extinction (day 1) and their retrieval/expression (day 2). Skin conductance responses (SCRs), fear and unconditioned stimulus expectancy ratings were obtained. We included 377 individuals (261 women) in our study. Robust sex differences were observed in all dependent measures. Women generally displayed higher subjective ratings but smaller SCRs than men and showed reduced excitatory/inhibitory conditioned stimulus (CS+/CS-) discrimination in all dependent measures. Furthermore, women using hormonal contraceptives showed reduced SCR CS discrimination on day 2 than men and free-cycling women, while menstrual cycle phase had no effect. Possible limitations include the simultaneous testing of up to 4 participants in cubicles, which might have introduced a social component, and not assessing postexperimental contingency awareness. The response pattern in women shows striking similarity to previously reported sex differences in patients with anxiety. Our results suggest that pronounced deficits in associative discrimination learning and subjective expression of safety information (CS- responses) might underlie higher prevalence and higher symptom rates seen in women with anxiety disorders. The data call for consideration of biological sex and hormonal contraceptive use in future studies and may suggest that targeting inhibitory learning during therapy might aid precision medicine.
Chia, Chester; Otto, Tim
Mounting evidence suggests that long-lasting, protein synthesis-dependent changes in synaptic strength accompany both the initial acquisition and subsequent recall of specific memories. Within brain areas thought to be important for learning and memory, including the hippocampus, learning-related plasticity is likely mediated in part by NMDA receptor activation and experience-dependent changes in gene expression. In the present study, we examined the role of activity-regulated cytoskeletal-associated protein (Arc/Arg3.1) expression in the acquisition, recall, and reconsolidation of memory in a trace fear conditioning paradigm. First, we show that the expression of Arc protein in ventral hippocampus (VH) is dramatically enhanced by memory recall 24h after the acquisition of trace fear conditioning, and that both memory recall and the associated recall-induced enhancement of Arc expression are blocked by pre-training administration of 2-amino-5-phosphonovaleric acid (APV). Next, we show that while infusion of Arc antisense oligodeoxynucleotides (ODNs) into VH prior to testing had little effect on memory recall, it significantly reduced both Arc protein expression and freezing behavior during subsequent testing sessions. Collectively, these results suggest that Arc/Arg3.1 protein plays an important functional role in both the initial acquisition of hippocampal-dependent memory and the reconsolidation of these memories after recall. Copyright © 2013 Elsevier Inc. All rights reserved.
Thomas F Giustino
Full Text Available The medial prefrontal cortex (mPFC plays a crucial role in emotional learning and memory in rodents and humans. While many studies suggest a differential role for the prelimbic (PL and infralimbic (IL subdivisions of mPFC, few have considered the relationship between neural activity in these two brain regions recorded simultaneously in behaving animals. Importantly, how concurrent PL and IL activity relate to conditioned freezing behavior is largely unknown. Here we used single-unit recordings targeting PL and IL in awake, behaving rats during the acquisition and expression of conditioned fear. On Day 1, rats received either signaled or unsignaled footshocks in the recording chamber; an auditory conditioned stimulus (CS preceded signaled footshocks. Twenty-four hours later, animals were returned to the recording chamber (modified to create a novel context where they received 5 CS-alone trials. After fear conditioning, both signaled and unsignaled rats exhibited high levels of post-shock freezing that was associated with an enduring suppression of mPFC spontaneous firing, particularly in the IL of signaled rats. Twenty-four hours later, CS presentation produced differential conditioned freezing in signaled and unsignaled rats: freezing increased in rats that had received signaled shocks, but decreased in animals in the unsignaled condition (i.e., external inhibition. This group difference in CS-evoked freezing was mirrored in the spontaneous firing rate of neurons in both PL and IL. Interestingly, differences in PL and IL firing rate highly correlated with freezing levels. In other words, in the signaled group IL spontaneous rates were suppressed relative to PL, perhaps limiting IL-mediated suppression of fear and allowing PL activity to dominate performance, resulting in high levels of freezing. This was not observed in the unsignaled group, which exhibited low freezing. These data reveal that the activity of mPFC neurons is modulated by both
Raber, Jacob; Weber, Sydney J.; Kronenberg, Amy; Turker, Mitchell S.
The space radiation environment includes energetic charged particles that may impact behavioral and cognitive performance. The relationship between the dose and the ionization density of the various types of charged particles (expressed as linear energy transfer or LET), and cognitive performance is complex. In our earlier work, whole body exposure to 28Si ions (263 MeV/n, LET = 78keV / μ m ; 1.6 Gy) affected contextual fear memory in C57BL/6J × DBA2/J F1 (B6D2F1) mice three months following irradiation but this was not the case following exposure to 48Ti ions (1 GeV/n, LET = 107keV / μ m ; 0.2 or 0.4 Gy). As an increased understanding of the impact of charged particle exposures is critical for assessment of risk to the CNS of astronauts during and following missions, in this study we used 40Ca ion beams (942 MeV/n, LET = 90keV / μm) to determine the behavioral and cognitive effects for the LET region between that of Si ions and Ti ions. 40Ca ion exposure reduced baseline activity in a novel environment in a dose-dependent manner, which suggests reduced motivation to explore and/or a diminished level of curiosity in a novel environment. In addition, exposure to 40Ca ions had sex-dependent effects on response to shock. 40Ca ion irradiation reduced the response to shock in female, but not male, mice. In contrast, 40Ca ion irradiation did not affect fear learning, memory, or extinction of fear memory for either gender at the doses employed in this study. Thus 40Ca ion irradiation affected behavioral, but not cognitive, performance. The effects of 40Ca ion irradiation on behavioral performance are relevant, as a combination of novelty and aversive environmental stimuli is pertinent to conditions experienced by astronauts during and following space missions.
Full Text Available Ras-GRF1 is a neuronal specific guanine exchange factor that, once activated by both ionotropic and metabotropic neurotransmitter receptors, can stimulate Ras proteins, leading to long-term phosphorylation of downstream signaling. The two available reports on the behavior of two independently generated Ras-GRF1 deficient mouse lines provide contrasting evidence on the role of Ras-GRF1 in spatial memory and contextual fear conditioning. These discrepancies may be due to the distinct alterations introduced in the mouse genome by gene targeting in the two lines that could differentially affect expression of nearby genes located in the imprinted region containing the Ras-grf1 locus. In order to determine the real contribution of Ras-GRF1 to spatial memory we compared in Morris Water Maze learning the Brambilla’s mice with a third mouse line (GENA53 in which a nonsense mutation was introduced in the Ras-GRF1 coding region without additional changes in the genome and we found that memory in this task is normal. Also, we measured both contextual and cued fear conditioning, which were previously reported to be affected in the Brambilla’s mice, and we confirmed that contextual learning but not cued conditioning is impaired in both mouse lines. In addition, we also tested both lines for the first time in conditioned place aversion in the Intellicage, an ecological and remotely controlled behavioral test, and we observed normal learning. Finally, based on previous reports of other mutant lines suggesting that Ras-GRF1 may control body weight, we also measured this non-cognitive phenotype and we confirmed that both Ras-GRF1 deficient mutants are smaller than their control littermates. In conclusion, we demonstrate that Ras-GRF1 has no unique role in spatial memory while its function in contextual fear conditioning is likely to be due not only to its involvement in amygdalar functions but possibly to some distinct hippocampal connections specific to
Hunt, Pamela S; Barnet, Robert C
Experience-produced deficits in trace conditioning and context conditioning have been useful tools for examining the role of the hippocampus in learning. It has also been suggested that learning in these tasks is especially vulnerable to neurotoxic effects of alcohol during key developmental periods such as adolescence. In five experiments we systematically examined the presence and source of age-dependent vulnerability to the memory-disrupting effects of acute ethanol in trace conditioning and contextual fear conditioning. In Experiment 1a pre-training ethanol disrupted trace conditioning more strongly in adolescent (postnatal day, PD30-35) than adult rats (PD65-75). In Experiment 1b when pre-training ethanol was accompanied by pre-test ethanol no deficit in trace conditioning was observed in adolescents, suggesting that state-dependent retrieval failure mediated ethanol's disruption of trace conditioning at this age. Experiment 2a and b examined the effect of ethanol pretreatment on context conditioning. Here, adult but not adolescent rats were impaired in conditioned freezing to context cues. Experiment 2c explored state-dependency of this effect. Pre-training ethanol continued to disrupt context conditioning in adults even when ethanol was also administered prior to test. Collectively these findings reveal clear age-dependent and task-dependent vulnerabilities in ethanol's disruptive effects on hippocampus-dependent memory. Adolescents were more disrupted by ethanol in trace conditioning than adults, and adults were more disrupted by ethanol in context conditioning than adolescents. We suggest that adolescents may be more susceptible to changes in internal state (state-dependent retrieval failure) than adults and that ethanol disrupted performance in trace and context conditioning through different mechanisms. Relevance of these findings to theories of hippocampus function is discussed. Copyright © 2015 Elsevier B.V. All rights reserved.
Thomas, Brian L.; Ayres, John J. B.
In four experiments using albino rats in an ABA fear renewal paradigm, we studied conditioned fear in the A test context following extinction in Context B. Conditioned suppression of operant responding was the index of fear. In Experiments 1-3, we found that extinguishing a feared cue in compound with a putative conditioned inhibitor of fear led…
An K Raes
Full Text Available Previous research showed that instructions about CS-US pairings can lead to fear of the CS even when the pairings are never presented. In the present study, we examined whether the experience of CS-US pairings adds to the effect of instructions by comparing instructed conditioning with and without actual CS-US pairings in a within-subject design. Thirty-two participants saw three fractals as CSs (CS(+1, CS(+2, CS(- and received electric shocks as USs. Before the start of a so-called training phase, participants were instructed that both CS(+1 and CS(+2 would be followed by the US, but only CS(+1 was actually paired with the US. The absence of the US after CS(+2 was explained in such a way that participants would not doubt the instructions about the CS(+2-US relation. After the training phase, a test phase was carried out. In this phase, participants expected the US after both CS(+s but none of the CS(+s was actually paired with the US. During test, self-reported fear was initially higher for CS(+1 than for CS(+2, which indicates that the experience of actual CS-US pairings adds to instructions about these pairings. On the other hand, the CS(+s elicited similar skin conductance responses and US expectancies. Theoretical and clinical implications are discussed.
Pannese, Alessia; Grandjean, Didier; Frühholz, Sascha
Discriminating between auditory signals of different affective value is critical to successful social interaction. It is commonly held that acoustic decoding of such signals occurs in the auditory system, whereas affective decoding occurs in the amygdala. However, given that the amygdala receives direct subcortical projections that bypass the auditory cortex, it is possible that some acoustic decoding occurs in the amygdala as well, when the acoustic features are relevant for affective discrimination. We tested this hypothesis by combining functional neuroimaging with the neurophysiological phenomena of repetition suppression (RS) and repetition enhancement (RE) in human listeners. Our results show that both amygdala and auditory cortex responded differentially to physical voice features, suggesting that the amygdala and auditory cortex decode the affective quality of the voice not only by processing the emotional content from previously processed acoustic features, but also by processing the acoustic features themselves, when these are relevant to the identification of the voice's affective value. Specifically, we found that the auditory cortex is sensitive to spectral high-frequency voice cues when discriminating vocal anger from vocal fear and joy, whereas the amygdala is sensitive to vocal pitch when discriminating between negative vocal emotions (i.e., anger and fear). Vocal pitch is an instantaneously recognized voice feature, which is potentially transferred to the amygdala by direct subcortical projections. These results together provide evidence that, besides the auditory cortex, the amygdala too processes acoustic information, when this is relevant to the discrimination of auditory emotions. Copyright Â© 2016 Elsevier Ltd. All rights reserved.
Fear, which can be expressed innately or after conditioning, is triggered when a danger or a stimulus predicting immediate danger is perceived. Its role is to prepare the body to face this danger. However, dysfunction in fear processing can lead to psychiatric disorders in which fear outweighs the danger or possibility of harm. Although recognized…
Henrich-Noack, Petra; Krautwald, Karla; Reymann, Klaus G; Wetzel, Wolfram
Transient global ischaemia induces cell death in the CA1 layer of the hippocampus. To evaluate the functional consequences, we performed context-dependent fear conditioning. Ischaemia was induced by 2-vessel-occlusion (2VO) in gerbils. On day 6 post ischaemia or sham procedures (in control group) gerbils were placed in a test chamber and after 3 min adaption time exposed to foot-shocks (training session). On the next day the animals were placed in the same test chamber without foot-shocks (test session). As a parameter for memory performance we used the standard method of measuring the total freezing time via a cumulative time-sampling procedure during the test session. We found a significant longer total freezing time in control animals than in ischaemic animals. In addition, however, we applied a more detailed analysis of (i) quantifying the number of freezing bouts, (ii) the average duration of single freezing bouts, (iii) the activity pattern during the training and test situation and (iv) we differentially evaluated all the single time segments of the experiment. These analyses revealed that although maintenance of freezing (duration of freezing bout) was significantly lower in ischaemic animals compared to controls, the initiation of freezing (number of freezing bouts) was not significantly different between the two groups during the test session. The activity scores of ischaemic and non-ischaemic gerbils were similar during the adaption time of the training session. The foot-shock, however, induced a significantly different pattern of behaviour in the ischaemic animals, which was selectively reproduced during the test session. In conclusion, ischaemic gerbils reacted to a fearsome thread with a behavioural pattern different from unlesioned animals and they revealed this specific foot-shock induced behaviour again during the test session. This indicated that CA1 hippocampal death did not interrupt memory performance but changed expression of fear. Therefore
Glenn, Daniel Erik
This dissertation is a two-paper investigation of the basic associative and arousal-based processes involved in reinstatement of conditional fear. Clarifying the factors involved in reinstatement of fear--a behavioral phenomenon in which the experience of an aversive event following fear extinction produces a return of fear--provides a better understanding of the factors that contribute to the waxing and waning of untreated fear and the return of fear following exposure treatment. Shedding li...
Bredy, Timothy W.; Barad, Mark
Mice communicate through visual, vocal, and olfactory cues that influence innate, nonassociative behavior. We here report that exposure to a recently fear-conditioned familiar mouse impairs acquisition of conditioned fear and facilitates fear extinction, effects mimicked by both an olfactory chemosignal emitted by a recently fear-conditioned…
Tanner, Daniel C; Githinji, Ann W; Young, Elizabeth A; Meiri, Karina; Savage, Daniel D; Perrone-Bizzozero, Nora I
The growth- and plasticity-associated protein GAP-43 plays a significant role in the establishment and remodeling of neuronal connections. We have previously shown that GAP-43 levels, protein kinase C (PKC) activity, and GAP-43 phosphorylation increase during contextual fear conditioning and that fetal alcohol exposure (FAE) decreases PKC activity and GAP-43 phosphorylation in the hippocampus of adult offspring. Drawing on these observations, we hypothesized that FAE manifests its cognitive impairment by disrupting PKC activation and membrane translocation, thereby decreasing GAP-43 phosphorylation and function. Three groups of pregnant rat dams (FAE and two control diet groups) were placed on different diet regimens. Offspring from each of these groups were placed into each of four test groups, a contextual fear conditioned (CFC) group, a naïve unhandled group, and two nonlearning stress control groups. Hippocampi were dissected, homogenized, and used to prepare a cytosolic and a membrane fraction. These fractions were probed for total GAP-43, PKC-phosphorylated GAP-43, and several PKC subtypes. PKC activity also was measured in total homogenates. Compared with both control diet groups, FAE animals showed a deficit in the activation of PKC in the hippocampus at 24 hr but not at 1.5 hr after CFC. Likewise, we found that the amount of GAP-43 and its phosphorylation were decreased 24 hr after CFC in FAE rats but not at early times after training. Analysis of the translocation of various PKC isoforms revealed that FAE animals had decreased levels of membrane-bound PKC beta2 and PKC epsilon 24 hr after CFC. Considering the role of PKC activation and GAP-43 phosphorylation in synaptic plasticity, our results suggest that deficient translocation of PKC beta2 and PKC epsilon in the hippocampus may mediate the electrophysiological and behavioral deficits observed in fetal alcohol exposed animals.
Full Text Available Corticotropin releasing factor (CRF dysregulation is implicated in mood and anxiety disorders such as posttraumatic stress disorder (PTSD. CRF is expressed in areas engaged in fear and anxiety processing including the central amygdala (CeA. Complicating our ability to study the contribution of CRF-containing neurons to fear and anxiety behavior is the wide variety of cell types in which CRF is expressed. To manipulate specific subpopulations of CRF containing neurons, our lab has developed a mouse with a Cre recombinase gene driven by a CRF promoter (CRFp3.0Cre (Martin et al., 2010. In these studies, mice that have the gene that encodes NR1 (Grin1 flanked by loxP sites (floxed were crossed with our previously developed CRFp3.0Cre mouse to selectively disrupt Grin1 within CRF containing neurons (Cre+/fGrin1+. We find that disruption of Grin1 in CRF neurons did not affect baseline levels of anxiety, locomotion, pain sensitivity or exploration of a novel object. However, baseline expression of Grin1 was decreased in Cre+/fGrin1+ mice as measured by RTPCR. Cre+/fGrin1+ mice showed enhanced auditory fear acquisition and retention without showing any significant effect on fear extinction. We measured Gria1, the gene that encodes AMPAR1 and the CREB activator Creb1 in the amygdala of Cre+/fGrin1+ mice after fear conditioning. Both Gria1 and Creb1 were enhanced in the amygdala after training. To determine if the Grin1-expressing CRF neurons within the CeA are responsible for the enhancement of fear memory in adults, we infused a lentivirus with Cre driven by a CRF promoter (LV pCRF-Cre/fGrin1+ into the CeA of floxed Grin1 mice. Cre driven deletion of Grin1 specifically within CRF expressing cells in the CeA also resulted in enhanced fear memory acquisition and retention. Altogether, these findings suggest that selective disruption of Grin1 within CeA CRF neurons strongly enhances fear memory.
Duvarci, Sevil; Pare, Denis
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
Ghosh, Supriya; Chattarji, Sumantra
Fear memories are crucial for survival. However, excessive generalization of such memories, characterized by a failure to discriminate dangerous from safe stimuli, is common in anxiety disorders. Neuronal encoding of the transition from cue-specific to generalized fear is poorly understood. We identified distinct neuronal populations in the lateral amygdala (LA) of rats that signaled generalized versus cue-specific associations and determined how their distributions switched during fear generalization. Notably, the same LA neurons that were cue specific before the behavioral shift to generalized fear lost their specificity afterwards, thereby tilting the balance of activity toward a greater proportion of generalizing neurons. Neuronal activity in the LA, but not the auditory cortex, was necessary for fear generalization. Furthermore, targeted activation of cAMP-PKA signaling in the LA increased neuronal excitability of LA neurons and led to generalized fear. These results provide a cellular basis in the amygdala for the alteration of emotional states from normal to pathological fear.
Ueno, Masaharu; Yamada, Kazuo; Ichitani, Yukio
Some individuals recover quickly from stressful events, while others do not; this suggests that there are individual differences in stress resilience. Previous studies in rats have shown that an animal's ability to extinguish conditioned fear can predict their stress resilience. In the present study, we investigated whether rats who are resilient or vulnerable to fear conditioning would consistently show resilient or vulnerable behaviors in other behavioral tests. Male Wistar-Imamichi rats were subjected to a series of behavioral tests, including open field, conditioned place-preference (CPP), forced swim and auditory fear conditioning. The subjects were assigned to one of two different groups: resilient or vulnerable, based on their level of freezing during fear extinction, and their other behavioral phenotypes were then compared. Rats in the resilient group showed faster extinction in the methamphetamine-induced CPP test than rats in the vulnerable group. The results suggest that resilience to stressful events is associated with drug-dependence and that individuals' abilities to recover from stressful situations and drug-dependence may share a common mechanism. Copyright © 2017 Elsevier Ireland Ltd and Japan Neuroscience Society. All rights reserved.
Pillai, Roshni; Yathiraj, Asha
The study evaluated whether there exists a difference/relation in the way four different memory skills (memory score, sequencing score, memory span, & sequencing span) are processed through the auditory modality, visual modality and combined modalities. Four memory skills were evaluated on 30 typically developing children aged 7 years and 8 years across three modality conditions (auditory, visual, & auditory-visual). Analogous auditory and visual stimuli were presented to evaluate the three modality conditions across the two age groups. The children obtained significantly higher memory scores through the auditory modality compared to the visual modality. Likewise, their memory scores were significantly higher through the auditory-visual modality condition than through the visual modality. However, no effect of modality was observed on the sequencing scores as well as for the memory and the sequencing span. A good agreement was seen between the different modality conditions that were studied (auditory, visual, & auditory-visual) for the different memory skills measures (memory scores, sequencing scores, memory span, & sequencing span). A relatively lower agreement was noted only between the auditory and visual modalities as well as between the visual and auditory-visual modality conditions for the memory scores, measured using Bland-Altman plots. The study highlights the efficacy of using analogous stimuli to assess the auditory, visual as well as combined modalities. The study supports the view that the performance of children on different memory skills was better through the auditory modality compared to the visual modality. Copyright © 2017 Elsevier B.V. All rights reserved.
Full Text Available Fear is a well-characterized biological response to threatening or stressful situations in humans and other social animals. Importantly, fearful stimuli in the natural environment are likely to be encountered concurrently by a group of animals. The modulation of fear acquisition and fear memory by a group as opposed to an individual experience, however, remains largely unknown. Here, we demonstrate a robust reduction in fear memory to an aversive event undertaken in a group despite similar fear learning between individually- and group-conditioned rats. This reduction persists outside the group confines, appears to be a direct outcome of group cognizance and is counteracted by loss of olfactory signaling among the group members. These results show that a group experience of fear can be protective and suggest that distinct neural pathways from those classically studied in individuals modulate collective fear memories.
Matsuda, Shingo; Matsuzawa, Daisuke; Ishii, Daisuke; Tomizawa, Haruna; Shimizu, Eiji
Fear extinction is a major task in our understanding of the biological mechanisms of exposure therapy, one of the most used treatments for stress-related disorders. It was recently reported that an extinction of 5 consecutive days prevents spontaneous recovery of fear memory. Memory age and the timing of fear extinction influence the effect of fear extinction. In this study, we used contextual fear extinction in adult male mice to examine whether memory age influences an extinction of 5 consecutive days and whether consecutiveness is necessary to prevent spontaneous recovery. Our results showed that, although fear memory was not affected by the passage of time, the old fear memory (28 days after fear conditioning) was more sensitive to fear extinction than the young fear memory (7 days after fear conditioning). Additionally, we demonstrated that consecutiveness of extinction sessions is not necessary to prevent spontaneous recovery. Instead, fear extinction sessions at spaced intervals were found to be more effective than consecutive extinction sessions for young fear memory. Our results suggest that taking memory age and the interval of fear extinction sessions into consideration would help to optimize exposure therapy. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.
Kraus, Kari Suzanne; Canlon, Barbara
Acoustic experience such as sound, noise, or absence of sound induces structural or functional changes in the central auditory system but can also affect limbic regions such as the amygdala and hippocampus. The amygdala is particularly sensitive to sound with valence or meaning, such as vocalizations, crying or music. The amygdala plays a central role in auditory fear conditioning, regulation of the acoustic startle response and can modulate auditory cortex plasticity. A stressful acoustic stimulus, such as noise, causes amygdala-mediated release of stress hormones via the HPA-axis, which may have negative effects on health, as well as on the central nervous system. On the contrary, short-term exposure to stress hormones elicits positive effects such as hearing protection. The hippocampus can affect auditory processing by adding a temporal dimension, as well as being able to mediate novelty detection via theta wave phase-locking. Noise exposure affects hippocampal neurogenesis and LTP in a manner that affects structural plasticity, learning and memory. Tinnitus, typically induced by hearing malfunctions, is associated with emotional stress, depression and anatomical changes of the hippocampus. In turn, the limbic system may play a role in the generation as well as the suppression of tinnitus indicating that the limbic system may be essential for tinnitus treatment. A further understanding of auditory-limbic interactions will contribute to future treatment strategies of tinnitus and noise trauma. Copyright © 2012 Elsevier B.V. All rights reserved.
Lisboa, Sabrina F; Gomes, Felipe V; Silva, Andréia L; Uliana, Daniela L; Camargo, Laura H A; Guimarães, Francisco S; Cunha, Fernando Q; Joca, Sâmia R L; Resstel, Leonardo B M
Inducible or neuronal nitric oxide synthase gene deletion increases or decreases anxiety-like behavior in mice, respectively. Since nitric oxide and endocannabinoids interact to modulate defensive behavior, the former effect could involve a compensatory increase in basal brain nitric oxide synthase activity and/or changes in the endocannabinoid system. Thus, we investigated the expression and extinction of contextual fear conditioning of inducible nitric oxide knockout mice and possible involvement of endocannabinoids in these responses. We evaluated the effects of a preferential neuronal nitric oxide synthase inhibitor, 7-nitroindazol, nitric oxide synthase activity, and mRNA changes of nitrergic and endocannabinoid systems components in the medial prefrontal cortex and hippocampus of wild-type and knockout mice. The effects of URB597, an inhibitor of the fatty acid amide hydrolase enzyme, which metabolizes the endocannabinoid anandamide, WIN55,212-2, a nonselective cannabinoid agonist, and AM281, a selective CB1 antagonist, on contextual fear conditioning were also evaluated. Contextual fear conditioning expression was similar in wild-type and knockout mice, but the latter presented extinction deficits and increased basal nitric oxide synthase activity in the medial prefrontal cortex. 7-Nitroindazol decreased fear expression and facilitated extinction in wild-type and knockout mice. URB597 decreased fear expression in wild-type and facilitated extinction in knockout mice, whereas WIN55,212-2 and AM281 increased it in wild-type mice. Nonconditioned knockout mice showed changes in the mRNA expression of nitrergic and endocannabinoid system components in the medial prefrontal cortex and hippocampus that were modified by fear conditioning. These data reinforce the involvement of the nitric oxide and endocannabinoids (anandamide) in stress-related disorders and point to a deregulation of the endocannabinoid system in situations where nitric oxide signaling is
Morey, R A; Dunsmoor, J E; Haswell, C C; Brown, V M; Vora, A; Weiner, J; Stjepanovic, D; Wagner, H R; Brancu, Mira; Marx, Christine E; Naylor, Jennifer C; Van Voorhees, Elizabeth; Taber, Katherine H; Beckham, Jean C; Calhoun, Patrick S; Fairbank, John A; Szabo, Steven T; LaBar, K S
Fear conditioning is an established model for investigating posttraumatic stress disorder (PTSD). However, symptom triggers may vaguely resemble the initial traumatic event, differing on a variety of sensory and affective dimensions. We extended the fear-conditioning model to assess generalization of conditioned fear on fear processing neurocircuitry in PTSD. Military veterans (n=67) consisting of PTSD (n=32) and trauma-exposed comparison (n=35) groups underwent functional magnetic resonance imaging during fear conditioning to a low fear-expressing face while a neutral face was explicitly unreinforced. Stimuli that varied along a neutral-to-fearful continuum were presented before conditioning to assess baseline responses, and after conditioning to assess experience-dependent changes in neural activity. Compared with trauma-exposed controls, PTSD patients exhibited greater post-study memory distortion of the fear-conditioned stimulus toward the stimulus expressing the highest fear intensity. PTSD patients exhibited biased neural activation toward high-intensity stimuli in fusiform gyrus (Pgeneralization in PTSD is biased toward stimuli with higher emotional intensity than the original conditioned-fear stimulus. Functional brain differences provide a putative neurobiological model for fear generalization whereby PTSD symptoms are triggered by threat cues that merely resemble the index trauma. PMID:26670285
The amygdala is essential for fear learning and expression. The central amygdala (CeA), once viewed as a passive relay between the amygdala complex and downstream fear effectors, has emerged as an active participant in fear conditioning. However, how the CeA contributes to the learning and expression of fear remains unclear. Our recent studies in mice indicate that fear conditioning induces robust plasticity of excitatory synapses onto inhibitory neurons in the lateral subdivision of CeA (CeL). In particular, this plasticity is cell-type specific and is required for the formation of fear memory. In addition, sensory cues that predict threat can cause activation of the somatostatin-positive CeL neurons, which is sufficient to drive freezing behavior. Here I will report our recent findings regarding the circuit and cellular mechanisms underlying CeL function in fear processing.
Theories and descriptions of various infant fear behaviors are presented in this paper. Five examples of fear are given: (1) learned fear, in which the infant associates some unpleasant action with an agent, (2) unlearned fear, in which the infant experiences an intense sensory phenomena such as a loud noise, (3) stranger anxiety, (4) fear caused…
Melissa Judith Sharpe
Full Text Available The prelimbic (PL cortex allows rodents to adapt their responding under changing experimental circumstances. In line with this, the PL cortex has been implicated in strategy set shifting, attentional set shifting, the resolution of response conflict, and the modulation of attention towards predictive stimuli. One interpretation of this research is that the PL cortex is involved in using information garnered from higher-order cues in the environment to modulate how an animal responds to environmental stimuli. However, data supporting this view of PL function in the aversive domain are lacking. In the following experiments, we attempted to answer two questions. Firstly, we wanted to investigate whether the role of the PL cortex in using higher-order cues to influence responding generalizes across appetitive and aversive domains. Secondly, as much of the research has focused on a role for the PL cortex in performance, we wanted to assess whether this region is also involved in the acquisition of hierarchal associations which facilitate an ability to use higher-order cues to modulate responding. In order to answer these questions, we assessed the impact of PL inactivation during both the acquisition and expression of a contextual bi-conditional discrimination. A contextual bi-conditional discrimination involves presenting two stimuli. In one context, one stimulus is paired with shock while the other is presented without shock. In another context, these contingencies are reversed. Thus, animals have to use the present contextual cues to disambiguate the significance of the stimulus and respond appropriately. We found that PL inactivation disrupted both the encoding and expression of these context-dependent associations. This supports a role for the PL cortex in allowing higher-order cues to modulate both learning about, and responding towards, different cues. We discuss these findings in the broader context of functioning in the medial prefrontal
Baker, Kathryn D.; Richardson, Rick
Fear inhibition is markedly impaired in adolescent rodents and humans. The present experiments investigated whether this impairment is critically determined by the animal's age at the time of fear learning or their age at fear extinction. Male rats (n = 170) were tested for extinction retention after conditioning and extinction at different ages.…
Jackson, Thomas E; Sandramouli, Soupramanien
Synesthesia is an unusual condition in which stimulation of one sensory modality causes an experience in another sensory modality or when a sensation in one sensory modality causes another sensation within the same modality. We describe a previously unreported association of auditory-olfactory synesthesia coexisting with auditory-visual synesthesia. Given that many types of synesthesias involve vision, it is important that the clinician provide these patients with the necessary information and support that is available.
Full Text Available In this review, the concepts of fear, phobia and aggression in dogs were precisely defined, as well as their underlying causes. The behavioural activities specific for these conditions were indicated. The accompanying symptoms were consistently explained. The causes that the development of pathological fear leads to aggression in dogs as well as the ex various therapy options depending on the clinical signs were presented.
... Videos for Educators Search English Español Fears and Phobias KidsHealth / For Teens / Fears and Phobias What's in ... might need help and support to overcome them. Phobias A phobia is an intense fear reaction to ...
Perai, A. H.; Kermanshahi, H.; Moghaddam, H. Nassiri; Zarban, A.
A total of 240 female broilers (42 days old) were randomly assigned to four groups with six replicates and fed either a basal diet (two control groups) or a basal diet supplemented with either 1,200 μg Cr+3 from chromium (Cr) methionine/kg (Cr group) or 1,200 μg Cr+3 from Cr methionine plus 800 mg vitamin C (Vit C)/kg of diet (Cr + Vit C group). After 7 days on the dietary treatment, all groups except one of the controls were transported for 3 h under the summer conditions. Performance parameters were not influenced by dietary treatments. The plasma concentrations of insulin, triiodothyronine, triglyceride, and the ratio of triiodothyronine/thyroxin were decreased and the ratio of glucose/insulin was increased due to transport process. Road transportation also increased the plasma concentrations of protein, cholesterol, aspartate aminotransferase, and creatine kinase and decreased the concentration of low-density lipoprotein cholesterol in the Cr + Vit C group. The pretransport concentrations of insulin and triiodothyronine were highest in the Cr + Vit C group. The concentration of phosphorous was lower in the Cr group than that in the other groups after transport. No significant effects of dietary treatments were observed on the other biochemical parameters. Transport increased malondialdehyde concentration in the control group and did not change plasma total antioxidant capacity and erythrocyte glutathione peroxidase activity. Either in combination or alone, Cr increased plasma total antioxidant capacity (before transport P ≤ 0.05, after transport P = 0.07) but did not affect the concentration of malondialdehyde and activity of glutathione peroxidase. The duration of tonic immobility (TI) was similar between nontransported control chicks and transported chicks without any supplements. Pretreatment with Cr + Vit C significantly reduced the duration of TI.
A minor feature of a Congressional energy bill is causing consternation for a number of propane-consuming chemical companies. The firms are fighting the bill`s inclusion of liquefied petroleum gas (LPG) on a list of alternative fuels that can be used to meet its urban fleet vehicles requirements. The firms fear that this added use would drive up the price of propane-an LPG-for homeowners, farmers, and themselves. Speaking for the Propane Consumers Coalition, a Dow Chemical spokesman says 7.7 million households use propane, as does agriculture, and current demand is such that December saw a 23-year low in US inventories. The US depends on imports of propane, he says, and about half the propane sold in the US is derived from the refining of oil, much of which is also imported. Adding demand for vehicle fuel would drive up imports and process, the spokesman says, thereby damaging all users, including the petrochemical industry.
Soeter, Marieke; Kindt, Merel
In addition to the extensive evidence in animals, we previously showed that disrupting reconsolidation by noradrenergic blockade produced amnesia for the original fear response in humans. Interestingly, the declarative memory for the fear association remained intact. These results asked for a solid replication. Moreover, given the constructive nature of memories, the intact recollection of the fear association could eventually 'rebuild' the fear memory, resulting in the spontaneous recovery of the fear response. Yet, perseverance of the amnesic effects would have substantial clinical implications, as even the most effective treatments for psychiatric disorders display high percentages of relapse. Using a differential fear conditioning procedure in humans, we replicated our previous findings by showing that administering propranolol (40mg) prior to memory reactivation eliminated the startle fear response 24h later. But most importantly, this effect persisted at one month follow-up. Notably, the propranolol manipulation not only left the declarative memory for the acquired contingency untouched, but also skin conductance discrimination. In addition, a close association between declarative knowledge and skin conductance responses was found. These findings are in line with the supposed double dissociation of fear conditioning and declarative knowledge relative to the amygdala and hippocampus in humans. They support the view that skin conductance conditioning primarily reflects contingency learning, whereas the startle response is a rather specific measure of fear. Furthermore, the results indicate the absence of a causal link between the actual knowledge of a fear association and its fear response, even though they often operate in parallel. Interventions targeting the amygdalar fear memory may be essential in specifically and persistently dampening the emotional impact of fear. From a clinical and ethical perspective, disrupting reconsolidation points to promising
Kakui, Nobukazu; Yokoyama, Fumikazu; Yamauchi, Miki; Kitamura, Koichi; Imanishi, Taiichiro; Inoue, Takeshi; Koyama, Tsukasa
Mirtazapine is an antidepressant with a unique mechanism of action and has been categorized as a Noradrenergic and Specific Serotonergic Antidepressant (NaSSA). Although numerous clinical trials suggested the usefulness of mirtazapine for not only major depressive disorders but also a variety of anxiety disorders, efficacy studies in animal anxiety models have been rarely reported. The present study investigated a potential anxiolytic-like profile of mirtazapine in rat conditioned fear stress model. A 5-hydroxytryptamine (5-HT) 1A receptor partial agonist, buspirone (1-5 mg/kg) exhibited a significant reduction in freezing time, and its maximal effect was reversed by a selective 5-HT(1A) antagonist, WAY-100635 (1 mg/kg). Mirtazapine (1-10 mg/kg) also reduced the freezing time in a dose-related fashion, a substantial proportion (approx. 50%) of which was likewise antagonized by WAY-100635 (1 mg/kg). Mianserin (1-30 mg/kg), a structural analogue for mirtazapine, was ineffective. Furthermore, co-administration of alpha1 adrenoceptor antagonist, prazosin (0.03 mg/kg) completely reversed mirtazapine (10 mg/kg)-induced reduction of freezing time. These findings represent the first demonstration that the anxiolytic-like action of mirtazapine involves activation of 5-HT(1A) receptor and alpha1 adrenoceptor to different extents, and are compatible with one aspect of mirtazapine's pharmacological profile as NaSSA.
Archer, T; Ogren, S O; Ross, S B
5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT), a serotonin (5-HT) agonist, fenfluramine and p-chloroamphetamine (PCA), which are 5-HT releasers, produce deficits in fear retention as indicated by a notable lack of the immobility resulting from inescapable shocks. Depletion of central 5-HT neurones after long-term PCA treatment (2 X 10 mg/kg) completely blocked the retention impairment resulting from acute PCA (2.5 mg/kg) and fenfluramine (5 mg/kg), and partially blocked the deficit produced by 5-MeO-DMT (4 mg/kg). 5-HT depletion after p-chlorophenylalanine (PCPA) treatment (200, 100, 100 mg/kg, 72, 48 and 24 h before) did not do so; this is in agreement with other findings which suggest the involvement of different 5-HT stores in the action of PCA and PCPA. These data further underline the importance of the ascending 5-HT pathway in aversive conditioning in the rat.
Hagewoud, Roelina; Whitcomb, Shamiso N.; Heeringa, Amarins N.; Havekes, Robbert; Koolhaas, Jaap M.; Meerlo, Peter
Study Objectives: Sleep deprivation negatively affects memory consolidation, especially in the case of hippocampus-dependent memories. Studies in rodents have shown that 5 hours of sleep deprivation immediately following footshock exposure selectively impairs the formation of a contextual fear
Slouzkey, Ilana; Maroun, Mouna
The basolateral amygdala (BLA), medial prefrontal cortex (mPFC) circuit, plays a crucial role in acquisition and extinction of fear memory. Extinction of aversive memories is mediated, at least in part, by the phosphoinositide-3 kinase (PI3K)/Akt pathway in adult rats. There is recent interest in the neural mechanisms that mediate fear and extinction in juvenile animals and whether these mechanisms are distinctive from those in adult animals. In the present study, we examined (1) changes in p...
Fear inhibition learning induces plasticity and remodeling of circuits within the amygdala. Most studies examine these changes in nondiscriminative fear conditioning paradigms. Using a discriminative fear, safety, and reward conditioning task, Sangha et al. (2013) have previously reported several neural microcircuits within the basal amygdala (BA) which discriminate among these cues, including a subpopulation of neurons responding selectively to a safety cue and not a fear cue. Here, the hypothesis that these “safety” neurons isolated during discriminative conditioning are biased to become fear cue responsive as a result of extinction, when fear behavior diminishes, was tested. Although 41% of “safety” neurons became fear cue responsive as a result of extinction, the data revealed that there was no bias for these neurons to become preferentially responsive during fear extinction compared to the other identified subgroups. In addition to the plasticity seen in the “safety” neurons, 44% of neurons unresponsive to either the fear cue or safety cue during discriminative conditioning became fear cue responsive during extinction. Together these emergent responses to the fear cue as a result of extinction support the hypothesis that new learning underlies extinction. In contrast, 47% of neurons responsive to the fear cue during discriminative conditioning became unresponsive to the fear cue during extinction. These findings are consistent with a suppression of neural responding mediated by inhibitory learning, or, potentially, by direct unlearning. Together, the data support extinction as an active process involving both gains and losses of responses to the fear cue and suggests the final output of the integrated BA circuit in influencing fear behavior is a balance of excitation and inhibition, and perhaps reversal of learning-induced changes. PMID:26733838
Nomura, Hiroshi; Hara, Kojiro; Abe, Reimi; Hitora-Imamura, Natsuko; Nakayama, Ryota; Sasaki, Takuya; Matsuki, Norio; Ikegaya, Yuji
Sensory stimuli not only activate specific populations of cortical neurons but can also silence other populations. However, it remains unclear whether neuronal silencing per se leads to memory formation and behavioral expression. Here we show that mice can report optogenetic inactivation of auditory neuron ensembles by exhibiting fear responses or seeking a reward. Mice receiving pairings of footshock and silencing of a neuronal ensemble exhibited a fear response selectively to the subsequent silencing of the same ensemble. The valence of the neuronal silencing was preserved for at least 30 d and was susceptible to extinction training. When we silenced an ensemble in one side of auditory cortex for conditioning, silencing of an ensemble in another side induced no fear response. We also found that mice can find a reward based on the presence or absence of the silencing. Neuronal silencing was stored as working memory. Taken together, we propose that neuronal silencing without explicit activation in the cerebral cortex is enough to elicit a cognitive behavior.
Vianna, Daniel M.L.; Graeff, Frederico G.; Landeira-Fernandez, Jesus; Brandão, Marcus L.
Previously-reported evidence showed that freezing to a context previously associated with footshock is impaired by lesion of the ventral periaqueductal gray (vPAG). It has also been shown that stepwise increase in the intensity of the electrical stimulation of the dorsal periaqueductal gray (dPAG) produces alertness, then freezing, and finally escape. These aversive responses are mimicked by microinjections of GABA receptor antagonists, such as bicuculline, or blockers of the glutamic acid decarboxylase (GAD), such as semicarbazide, into the dPAG. In this work, we examined whether the expression of these defensive responses could be the result of activation of ventral portion of the periaqueductal gray. Sham- or vPAG electrolytic–lesioned rats were implanted with an electrode in the dPAG for the determination of the thresholds of freezing and escape responses. The vPAG electrolytic lesions were behaviorally verified through a context-conditioned fear paradigm. Results indicated that lesion of the vPAG disrupted conditioned freezing response to contextual cues associated with footshocks but did not change the dPAG electrical stimulation for freezing and escape responses. In a second experiment, lesion of the vPAG also did not change the amount of freezing and escape behavior produced by microinjections of semicarbazide into the dPAG. These findings indicate that freezing and escape defensive responses induced by dPAG stimulation do not depend on the integrity of the vPAG. A discussion on different neural circuitries that might underlie different inhibitory and active defensive behavioral patterns that animals display during threatening situations is presented. PMID:11390636
Chen, Sufen; Sussman, Elyse S.
The purpose of the study was to test the hypothesis that sound context modulates the magnitude of auditory distraction, indexed by behavioral and electrophysiological measures. Participants were asked to identify tone duration, while irrelevant changes occurred in tone frequency, tone intensity, and harmonic structure. Frequency deviants were randomly intermixed with standards (Uni-Condition), with intensity deviants (Bi-Condition), and with both intensity and complex deviants (Tri-Condition). Only in the Tri-Condition did the auditory distraction effect reflect the magnitude difference among the frequency and intensity deviants. The mixture of the different types of deviants in the Tri-Condition modulated the perceived level of distraction, demonstrating that the sound context can modulate the effect of deviance level on processing irrelevant acoustic changes in the environment. These findings thus indicate that perceptual contrast plays a role in change detection processes that leads to auditory distraction. PMID:23886958
Kenney, Justin W.; Scott, Ian C.; Josselyn, Sheena A.; Frankland, Paul W.
Zebrafish are a genetically tractable vertebrate that hold considerable promise for elucidating the molecular basis of behavior. Although numerous recent advances have been made in the ability to precisely manipulate the zebrafish genome, much less is known about many aspects of learning and memory in adult fish. Here, we describe the development…
Huang, Chiung-Chun; Chou, Dylan; Yeh, Che-Ming; Hsu, Kuei-Sen
Fear memory-encoding thalamic input synapses to the lateral amygdala (T-LA) exhibit dynamic efficacy changes that are tightly correlated with fear memory strength. Previous studies have shown that auditory fear conditioning involves strengthening of synaptic strength, and conversely, fear extinction training leads to T-LA synaptic weakening and occlusion of long-term depression (LTD) induction. These findings suggest that the mechanisms governing LTD at T-LA synapses may determine the behavioral outcomes of extinction training. Here, we explored this hypothesis by implementing food deprivation (FD) stress in mice to determine its effects on fear extinction and LTD induction at T-LA synapses. We found that FD increased plasma acylated ghrelin levels and enhanced fear extinction and its retention. Augmentation of fear extinction by FD was blocked by pretreatment with growth hormone secretagogue receptor type-1a antagonist D-Lys(3)-GHRP-6, suggesting an involvement of ghrelin signaling. Confirming previous findings, two distinct forms of LTD coexist at thalamic inputs to LA pyramidal neurons that can be induced by low-frequency stimulation (LFS) or paired-pulse LFS (PP-LFS) paired with postsynaptic depolarization, respectively. Unexpectedly, we found that FD impaired the induction of PP-LFS- and group I metabotropic glutamate receptor agonist (S)-3,5-dihydroxyphenylglycine (DHPG)-induced LTD, but not LFS-induced LTD. Ghrelin mimicked the effects of FD to impair the induction of PP-LFS- and DHPG-induced LTD at T-LA synapses, which were blocked by co-application of D-Lys(3)-GHRP-6. The sensitivity of synaptic transmission to 1-naphthyl acetyl spermine was not altered by either FD or ghrelin treatment. These results highlight distinct features of fear extinction and LTD at T-LA synapses. Copyright © 2015 Elsevier Ltd. All rights reserved.
Sanjuán Juaristi, Julio; Sanjuán Martínez-Conde, Mar
Given the relevance of possible hearing losses due to sound overloads and the short list of references of objective procedures for their study, we provide a technique that gives precise data about the audiometric profile and recruitment factor. Our objectives were to determine peripheral fatigue, through the cochlear microphonic response to sound pressure overload stimuli, as well as to measure recovery time, establishing parameters for differentiation with regard to current psychoacoustic and clinical studies. We used specific instruments for the study of cochlear microphonic response, plus a function generator that provided us with stimuli of different intensities and harmonic components. In Wistar rats, we first measured the normal microphonic response and then the effect of auditory fatigue on it. Using a 60dB pure tone acoustic stimulation, we obtained a microphonic response at 20dB. We then caused fatigue with 100dB of the same frequency, reaching a loss of approximately 11dB after 15minutes; after that, the deterioration slowed and did not exceed 15dB. By means of complex random tone maskers or white noise, no fatigue was caused to the sensory receptors, not even at levels of 100dB and over an hour of overstimulation. No fatigue was observed in terms of sensory receptors. Deterioration of peripheral perception through intense overstimulation may be due to biochemical changes of desensitisation due to exhaustion. Auditory fatigue in subjective clinical trials presumably affects supracochlear sections. The auditory fatigue tests found are not in line with those obtained subjectively in clinical and psychoacoustic trials. Copyright © 2013 Elsevier España, S.L.U. y Sociedad Española de Otorrinolaringología y Patología Cérvico-Facial. All rights reserved.
Do Monte, Fabricio H.; Quirk, Gregory J.; Li, Bo; Penzo, Mario A.
Fear conditioning researches have led to a comprehensive picture of the neuronal circuit underlying the formation of fear memories. In contrast, knowledge about the retrieval of fear memories is much more limited. This disparity may stem from the fact that fear memories are not rigid, but reorganize over time. To bring clarity and raise awareness on the time-dependent dynamics of retrieval circuits, we review current evidence on the neuronal circuitry participating in fear memory retrieval at both early and late time points after conditioning. We focus on the temporal recruitment of the paraventricular nucleus of the thalamus, and its BDNFergic efferents to the central nucleus of the amygdala, for the retrieval and maintenance of fear memories. Finally, we speculate as to why retrieval circuits change across time, and the functional benefits of recruiting structures such as the paraventricular nucleus into the retrieval circuit. PMID:27217148
Full Text Available Auditory Hallucination or Paracusia is a form of hallucination that involves perceiving sounds without auditory stimulus. A common is hearing one or more talking voices which is associated with psychotic disorders such as schizophrenia or mania. Hallucination, itself, is the most common feature of perceiving the wrong stimulus or to the better word perception of the absence stimulus. Here we will discuss four definitions of hallucinations:1.Perceiving of a stimulus without the presence of any subject; 2. hallucination proper which are the wrong perceptions that are not the falsification of real perception, Although manifest as a new subject and happen along with and synchronously with a real perception;3. hallucination is an out-of-body perception which has no accordance with a real subjectIn a stricter sense, hallucinations are defined as perceptions in a conscious and awake state in the absence of external stimuli which have qualities of real perception, in that they are vivid, substantial, and located in external objective space. We are going to discuss it in details here.
Full Text Available Auditory dysfunction is a common clinical symptom that can induce profound effects on the quality of life of those affected. Cerebrovascular disease (CVD is the most prevalent neurological disorder today, but it has generally been considered a rare cause of auditory dysfunction. However, a substantial proportion of patients with stroke might have auditory dysfunction that has been underestimated due to difficulties with evaluation. The present study reviews relationships between auditory dysfunction and types of CVD including cerebral infarction, intracerebral hemorrhage, subarachnoid hemorrhage, cerebrovascular malformation, moyamoya disease, and superficial siderosis. Recent advances in the etiology, anatomy, and strategies to diagnose and treat these conditions are described. The numbers of patients with CVD accompanied by auditory dysfunction will increase as the population ages. Cerebrovascular diseases often include the auditory system, resulting in various types of auditory dysfunctions, such as unilateral or bilateral deafness, cortical deafness, pure word deafness, auditory agnosia, and auditory hallucinations, some of which are subtle and can only be detected by precise psychoacoustic and electrophysiological testing. The contribution of CVD to auditory dysfunction needs to be understood because CVD can be fatal if overlooked.
Tronson, Natalie C.; Wiseman, Shari L.; Neve, Rachael L.; Nestler, Eric J.; Olausson, Peter; Taylor, Jane R.
Cyclic AMP response element binding protein (CREB) plays a critical role in fear memory formation. Here we determined the role of CREB selectively within the amygdala in reconsolidation and extinction of auditory fear. Viral overexpression of the inducible cAMP early repressor (ICER) or the dominant-negative mCREB, specifically within the lateral…
Daliri, Ayoub; Max, Ludo
Auditory modulation during speech movement planning is limited in adults who stutter (AWS), but the functional relevance of the phenomenon itself remains unknown. We investigated for AWS and adults who do not stutter (AWNS) (a) a potential relationship between pre-speech auditory modulation and auditory feedback contributions to speech motor learning and (b) the effect on pre-speech auditory modulation of real-time versus delayed auditory feedback. Experiment I used a sensorimotor adaptation paradigm to estimate auditory-motor speech learning. Using acoustic speech recordings, we quantified subjects' formant frequency adjustments across trials when continually exposed to formant-shifted auditory feedback. In Experiment II, we used electroencephalography to determine the same subjects' extent of pre-speech auditory modulation (reductions in auditory evoked potential N1 amplitude) when probe tones were delivered prior to speaking versus not speaking. To manipulate subjects' ability to monitor real-time feedback, we included speaking conditions with non-altered auditory feedback (NAF) and delayed auditory feedback (DAF). Experiment I showed that auditory-motor learning was limited for AWS versus AWNS, and the extent of learning was negatively correlated with stuttering frequency. Experiment II yielded several key findings: (a) our prior finding of limited pre-speech auditory modulation in AWS was replicated; (b) DAF caused a decrease in auditory modulation for most AWNS but an increase for most AWS; and (c) for AWS, the amount of auditory modulation when speaking with DAF was positively correlated with stuttering frequency. Lastly, AWNS showed no correlation between pre-speech auditory modulation (Experiment II) and extent of auditory-motor learning (Experiment I) whereas AWS showed a negative correlation between these measures. Thus, findings suggest that AWS show deficits in both pre-speech auditory modulation and auditory-motor learning; however, limited pre
Kuriyama, Kenichi; Honma, Motoyasu; Yoshiike, Takuya; Kim, Yoshiharu
Sleep deprivation immediately following an aversive event reduces fear by preventing memory consolidation during homeostatic sleep. This suggests that acute insomnia might act prophylactically against the development of posttraumatic stress disorder (PTSD) even though it is also a possible risk factor for PTSD. We examined total sleep deprivation and memory suppression to evaluate the effects of these interventions on subsequent aversive memory formation and fear conditioning. Active suppression of aversive memory impaired retention of event memory. However, although the remembered fear was more reduced in sleep-deprived than sleep-control subjects, suppressed fear increased, and seemed to abandon the sleep-dependent plasticity of fear. Active memory suppression, which provides a psychological model for Freud's ego defense mechanism, enhances fear and casts doubt on the potential of acute insomnia as a prophylactic measure against PTSD. Our findings bring into question the role of sleep in aversive-memory consolidation in clinical PTSD pathophysiology.
Browne, Caroline A.; Hanke, Joachim; Rose, Claudia; Walsh, Irene; Foley, Tara; Clarke, Gerard; Schwegler, Herbert; Cryan, John F.; Yilmazer-Hanke, Deniz
Stress-induced changes in plasma corticosterone and central monoamine levels were examined in mouse strains that differ in fear-related behaviors. Two DxH recombinant inbred mouse strains with a DBA/2J background, which were originally bred for a high (H-FSS) and low fear-sensitized acoustic startle reflex (L-FSS), were used. Levels of noradrenaline, dopamine, and serotonin and their metabolites (DOPAC), homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5-HIAA) were studied in the amygdala, hippocampus, medial prefrontal cortex, striatum, hypothalamus, and brainstem. H-FSS mice exhibited increased fear levels and a deficit in fear extinction (within-session) in the auditory fear-conditioning test, and depressive-like behavior in the acute forced swim stress test. They had higher tissue noradrenaline and serotonin levels and lower dopamine and serotonin turnover under basal conditions, although they were largely insensitive to stress-induced changes in neurotransmitter metabolism. In contrast, acute swim stress increased monoamine levels but decreased turnover in the less fearful L-FSS mice. L-FSS mice also showed a trend toward higher basal and stress-induced corticosterone levels and an increase in noradrenaline and serotonin in the hypothalamus and brainstem 30 minutes after stress compared to H-FSS mice. Moreover, the dopaminergic system was activated differentially in the medial prefrontal cortex and striatum of the two strains by acute stress. Thus, H-FSS mice showed increased basal noradrenaline tissue levels compatible with a fear phenotype or chronic stressed condition. Low corticosterone levels and the poor monoamine response to stress in H-FSS mice may point to mechanisms similar to those found in principal fear disorders or posttraumatic stress disorder. PMID:25117886
Slouzkey, Ilana; Maroun, Mouna
The basolateral amygdala (BLA), medial prefrontal cortex (mPFC) circuit, plays a crucial role in acquisition and extinction of fear memory. Extinction of aversive memories is mediated, at least in part, by the phosphoinositide-3 kinase (P[subscript 3]K)/Akt pathway in adult rats. There is recent interest in the neural mechanisms that mediate fear…
Gilmartin, Marieke R.; Kwapis, Janine L.; Helmstetter, Fred J.
Activation of "N"-methyl-D-aspartate receptors (NMDAR) in the prelimbic medial prefrontal cortex (PL mPFC) is necessary for the acquisition of both trace and contextual fear memories, but it is not known how specific NR2 subunits support each association. The NR2B subunit confers unique properties to the NMDAR and may differentially…
Andy M Kazama
Full Text Available Recent studies in monkeys have demonstrated that damage to the lateral subfields of orbital frontal cortex (OFC areas 11/13 yields profound changes in flexible modulation of goal-directed behaviors and a lack in fear regulation. Yet, little consideration has been placed on its role in emotional and social development throughout life. The current study investigated the effects of neonatal lesions of the OFC on the flexible modulation of goal-directed behaviors and fear responses in monkeys. Infant monkeys received neonatal lesions of OFC areas 11/13 or sham-lesions during the first post-natal week. Modulation of goal-directed behaviors was measured with a devaluation task at 3-4 years and 6-7 years. Modulation of fear reactivity by safety signals was assessed with the AX+/BX- potentiated-startle paradigm at 6-7 years. Similar to adult-onset OFC lesions, selective neonatal lesions of OFC areas 11/13 yielded a failure to modulate behavioral responses guided by changes in reward value, but spared the ability to modulate fear responses in the presence of safety signals. These results suggest that these areas play a critical role in the development of behavioral adaptation during goal-directed behaviors, but not, or less so, in the development of the ability to process emotionally salient stimuli and to modulate emotional reactivity using environmental contexts, which could be supported by other OFC subfields, such as the most ventromedial subfields (i.e. areas 14/25. Given similar impaired decision-making abilities and spared modulation of fear followed both neonatal lesions of either OFC areas 11 and 13 or amygdala (Kazama et al., 2012; Kazama & Bachevalier, 2013, the present results suggest that interactions between these two neural structures play a critical role in the development of behavioral adaptation; an ability essential for the self-regulation of emotion and behavior that assures the maintenance of successful social relationships.
Voulo, Meagan E.; Parsons, Ryan G.
Fear conditioning studies in rodents allow us to assess vulnerability factors which might underlie fear-based psychopathology such as post-traumatic stress disorder (PTSD). Despite PTSD being more prevalent in females than males, very few fear conditioning studies in rodents have tested females. Our study assessed fear conditioning and extinction…
Holmes, Nathan M.; Leung, Hiu T.; Westbrook, R. Frederick
This series of experiments used rats to compare counterconditioning and extinction of conditioned fear responses (freezing) with respect to the effects of a context shift. In each experiment, a stimulus was paired with shock in context A, extinguished or counterconditioned through pairings with sucrose in context B, and then tested for renewal…
Brown, Rachel M.; Palmer, Caroline
Skilled performers such as athletes or musicians can improve their performance by imagining the actions or sensory outcomes associated with their skill. Performers vary widely in their auditory and motor imagery abilities, and these individual differences influence sensorimotor learning. It is unknown whether imagery abilities influence both memory encoding and retrieval. We examined how auditory and motor imagery abilities influence musicians' encoding (during Learning, as they practiced novel melodies), and retrieval (during Recall of those melodies). Pianists learned melodies by listening without performing (auditory learning) or performing without sound (motor learning); following Learning, pianists performed the melodies from memory with auditory feedback (Recall). During either Learning (Experiment 1) or Recall (Experiment 2), pianists experienced either auditory interference, motor interference, or no interference. Pitch accuracy (percentage of correct pitches produced) and temporal regularity (variability of quarter-note interonset intervals) were measured at Recall. Independent tests measured auditory and motor imagery skills. Pianists' pitch accuracy was higher following auditory learning than following motor learning and lower in motor interference conditions (Experiments 1 and 2). Both auditory and motor imagery skills improved pitch accuracy overall. Auditory imagery skills modulated pitch accuracy encoding (Experiment 1): Higher auditory imagery skill corresponded to higher pitch accuracy following auditory learning with auditory or motor interference, and following motor learning with motor or no interference. These findings suggest that auditory imagery abilities decrease vulnerability to interference and compensate for missing auditory feedback at encoding. Auditory imagery skills also influenced temporal regularity at retrieval (Experiment 2): Higher auditory imagery skill predicted greater temporal regularity during Recall in the presence of
Brown, Rachel M; Palmer, Caroline
Skilled performers such as athletes or musicians can improve their performance by imagining the actions or sensory outcomes associated with their skill. Performers vary widely in their auditory and motor imagery abilities, and these individual differences influence sensorimotor learning. It is unknown whether imagery abilities influence both memory encoding and retrieval. We examined how auditory and motor imagery abilities influence musicians' encoding (during Learning, as they practiced novel melodies), and retrieval (during Recall of those melodies). Pianists learned melodies by listening without performing (auditory learning) or performing without sound (motor learning); following Learning, pianists performed the melodies from memory with auditory feedback (Recall). During either Learning (Experiment 1) or Recall (Experiment 2), pianists experienced either auditory interference, motor interference, or no interference. Pitch accuracy (percentage of correct pitches produced) and temporal regularity (variability of quarter-note interonset intervals) were measured at Recall. Independent tests measured auditory and motor imagery skills. Pianists' pitch accuracy was higher following auditory learning than following motor learning and lower in motor interference conditions (Experiments 1 and 2). Both auditory and motor imagery skills improved pitch accuracy overall. Auditory imagery skills modulated pitch accuracy encoding (Experiment 1): Higher auditory imagery skill corresponded to higher pitch accuracy following auditory learning with auditory or motor interference, and following motor learning with motor or no interference. These findings suggest that auditory imagery abilities decrease vulnerability to interference and compensate for missing auditory feedback at encoding. Auditory imagery skills also influenced temporal regularity at retrieval (Experiment 2): Higher auditory imagery skill predicted greater temporal regularity during Recall in the presence of
Wu, Zhong-Min; Yang, Li-Hua; Cui, Rong; Ni, Gui-Lian; Wu, Feng-Tian; Liang, Yong
One of the hypotheses about the pathogenesis of posttraumatic stress disorder (PTSD) is the dysfunction of serotonin (5-HT) neurotransmission. While certain 5-HT receptor subtypes are likely critical for the symptoms of PTSD, few studies have examined the role of 5-HT3 receptor in the development of PTSD, even though 5-HT3 receptor is critical for contextual fear extinction and anxiety-like behavior. Therefore, we hypothesized that stimulation of 5-HT3 receptor in the dorsal hippocampus (DH) could prevent hippocampal autophagy and the development of PTSD-like behavior in animals. To this end, we infused SR57227, selective 5-HT3 agonist, into the DH after a single prolonged stress (SPS) treatment in rats. Three weeks later, we evaluated the effects of this pharmacological treatment on anxiety-related behaviors and extinction of contextual fear memory. We also accessed hippocampal autophagy and the expression of 5-HT3A subunit, Beclin-1, LC3-I, and LC3-II in the DH. We found that SPS treatment did not alter anxiety-related behaviors but prolonged the extinction of contextual fear memory, and such a behavioral phenomenon was correlated with increased hippocampal autophagy, decreased 5-HT3A expression, and increased expression of Beclin-1 and LC3-II/LC3-I ratio in the DH. Furthermore, intraDH infusions of SR57227 dose-dependently promoted the extinction of contextual fear memory, prevented hippocampal autophagy, and decreased expression of Beclin-1 and LC3-II/LC3-I ratio in the DH. These results indicated that 5-HT3 receptor in the hippocampus may play a critical role in the pathogenesis of hippocampal autophagy, and is likely involved in the pathophysiology of PTSD.
Garner, Tom Alexander; Grimshaw, Mark Nicholas
This paper proposes a framework that incorporates fear, acoustics, thought processing and digital game sound theory; with the potential to not only improve understanding of our relationship with fear, but also generate a foundation for reliable and significant manipulation of the fear experience....... A brief literature review provides the context for a discussion of fear and sound in virtual worlds before the framework is described; concluding remarks point to future empirical work testing and refining the framework....
Mulig, Joanne C.; And Others
Research has reported relationships between fear of success and fear of failure and between fear of success and various sex-role identity factors. These relationships were examined for undergraduates (N=154) using the Fear of Success Scale (FOSS) to measure fear of success, the Debilitating Anxiety Scale (DAS) to measure fear of failure, and the…
Baker, Kathryn D.; Richardson, Rick
Fear inhibition is markedly impaired in adolescent rodents and humans. The present experiments investigated whether this impairment is critically determined by the animal's age at the time of fear learning or their age at fear extinction. Male rats (n = 170) were tested for extinction retention after conditioning and extinction at different ages. We examined neural correlates of impaired extinction retention by detection of phosphorylated mitogen-activated protein kinase immunoreactivity (pMA...
Keller, Samantha M; Schreiber, William B; Stanfield, Briana R; Knox, Dayan
Using the single prolonged stress (SPS) animal model of post-traumatic stress disorder (PTSD), previous studies suggest that enhanced glucocorticoid receptor (GR) expression leads to cued fear extinction retention deficits. However, it is unknown how the endogenous ligand of GRs, corticosterone (CORT), may contribute to extinction retention deficits in the SPS model. Given that CORT synthesis during fear learning is critical for fear memory consolidation and SPS enhances GR expression, CORT synthesis during fear memory formation could strengthen fear memory in SPS rats by enhancing GR activation during fear learning. In turn, this could lead to cued fear extinction retention deficits. We tested the hypothesis that CORT synthesis during fear learning leads to cued fear extinction retention deficits in SPS rats by administering the CORT synthesis inhibitor metyrapone to SPS and control rats prior to fear conditioning, and observed the effect this had on extinction memory. Inhibiting CORT synthesis during fear memory formation in control rats tended to decrease cued freezing, though this effect never reached statistical significance. Contrary to our hypothesis, inhibiting CORT synthesis during fear memory formation disrupted extinction retention in SPS rats. This finding suggests that even though SPS exposure leads to cued fear extinction memory deficits, CORT synthesis during fear memory formation enhances extinction retention in SPS rats. This suggests that stress-induced CORT synthesis in previously stressed rats can be beneficial. Copyright © 2015 Elsevier B.V. All rights reserved.
Full Text Available The receptor for advanced glycation end-products (RAGE is a multi-ligand receptor that belongs to the immunoglobulin superfamily of cell surface receptors. In diabetes and Alzheimer's disease, pathological progression is accelerated by activation of RAGE. However, how RAGE influences gross behavioral activity patterns in basal condition has not been addressed to date. In search for a functional role of RAGE in normal mice, a series of standard behavioral tests were performed on adult RAGE knockout (KO mice. We observed a solid increase of home cage activity in RAGE KO. In addition, auditory startle response assessment resulted in a higher sensitivity to auditory signal and increased prepulse inhibition in KO mice. There were no significant differences between KO and wild types in behavioral tests for spatial memory and anxiety, as tested by Morris water maze, classical fear conditioning, and elevated plus maze. Our results raise a possibility that systemic therapeutic treatments to occlude RAGE activation may have adverse effects on general activity levels or sensitivity to auditory stimuli.
Full Text Available Peri-personal space (PPS is defined as the space immediately surrounding our bodies, which is critical in the adaptation of our social behavior. As a space of interaction with the external world, PPS is involved in the control of motor action as well as in the protection of the body. The boundaries of this PPS are known to be flexible but so far, little is known about how PPS boundaries are influenced by unreasonable fear. We hypothesized that unreasonable fear extends the neural representation of the multisensory space immediately surrounding the body in the presence of a feared object, with the aim of expanding the space of protection around the body. To test this hypothesis, we explored the impact of unreasonable fear on the size of PPS in two groups of non-clinical participants: dog-fearful and non-fearful participants. The sensitivity to cynophobia was assessed with a questionnaire. We measured participants’ PPS extent in the presence of threatening (dog growling and non-threatening (sheep bleating auditory stimuli. The sound stimuli were processed through binaural rendering so that the virtual sound sources were looming towards participants from their rear hemi-field. We found that, when in the presence of the auditory dog stimulus, the PPS of dog-fearful participants is larger than that of non-fearful participants. Our results demonstrate that PPS size is adaptively modulated by cynophobia and suggest that anxiety tailors PPS boundaries when exposed to fear-relevant features. Anxiety, with the exception of social phobia, has rarely been studied as a disorder of social interaction. These findings could help develop new treatment strategies for anxious disorders, by involving the link between space and interpersonal interaction in the approach of the disorder.
Herschbach, Peter; Dinkel, Andreas
Fear of progression (or fear of recurrence) is an appropriate, rational response to the real threat of cancer and cancer treatments. However, elevated levels of fear of progression can become dysfunctional, affecting well-being, quality of life, and social functioning. Research has shown that fear of progression is one of the most frequent distress symptoms of patients with cancer and with other chronic diseases. As a clear consensus concerning clinically relevant states of fear of progression is currently lacking, it is difficult to provide a valid estimate of the rate of cancer patients who clearly suffer from fear of progression. However, recent systematic reviews suggest that probably 50 % of cancer patients experience moderate to severe fear of progression. Furthermore, many patients express unmet needs in dealing with the fear of cancer spreading. These results underline the necessity to provide effective psychological treatments for clinical levels of fear of progression. A few psychosocial interventions for treating fear of progression have been developed so far. Our own, targeted intervention study showed that dysfunctional fear of progression can be effectively treated with a brief group therapy.
Hagewoud, Roelina; Whitcomb, Shamiso N; Heeringa, Amarins N; Havekes, Robbert; Koolhaas, Jaap M; Meerlo, Peter
Sleep deprivation negatively affects memory consolidation, especially in the case of hippocampus-dependent memories. Studies in rodents have shown that 5 hours of sleep deprivation immediately following footshock exposure selectively impairs the formation of a contextual fear memory. In these studies, both acquisition and subsequent sleep deprivation were performed in the animals' main resting phase. However, in everyday life, subjects most often learn during their active phase. Here we examined the effects of sleep deprivation on memory consolidation for contextual fear in rats when the task was performed at different times of the day, particularly, at the beginning of the resting phase or right before the onset of the active phase. Results show that sleep deprivation immediately following training affects consolidation of contextual fear, independent of time of training. However, in the resting phase memory consolidation was impaired by 6 hours of posttraining sleep deprivation, whereas, in the active phase, the impairment was only seen after 12 hours of sleep deprivation. Since rats sleep at least twice as much during the resting phase compared with the active phase, these data suggest that the effect of sleep deprivation depends on the amount of sleep that was lost. Also, control experiments show that effects of sleep deprivation were not related to the amount of stimulation the animals received and were therefore not likely an indirect effect of the sleep-deprivation method. These results support the notion that sleep immediately following acquisition, independent of time of day, promotes memory consolidation and that sleep deprivation may disrupt this process depending on the amount of sleep that is lost.
Glenn, Catherine R; Lieberman, Lynne; Hajcak, Greg
The potency of an unconditioned stimulus (UCS) can impact the degree of fear learning. One of the most common and effective UCSs is an electric shock, which is inappropriate for certain populations (e.g., children). To address this need, a novel fear learning paradigm was recently developed that uses a fearful female face and scream as the UCS. The present study directly compared the efficacy of the screaming female UCS and a traditional shock UCS in two fear learning paradigms. Thirty-six young adults completed two fear learning tasks and a measure of trait anxiety; fear learning was indexed with fear-potentiated startle (FPS) and self-reported fear ratings. Results indicated comparable FPS across the two tasks. However, larger overall startle responses were exhibited in the shock task, and participants rated the shock UCS and overall task as more aversive than the screaming female. In addition, trait anxiety was only related to FPS in the fear learning task that employed a shock as the UCS. Taken together, results indicate that, although both UCS paradigms can be used for fear conditioning (i.e., to produce differences between CS+ and CS-), the shock UCS paradigm is more aversive and potentially more sensitive to individual differences in anxiety. Copyright © 2012 Elsevier B.V. All rights reserved.
Wellman, Laurie L; Fitzpatrick, Mairen E; Hallum, Olga Y; Sutton, Amy M; Williams, Brook L; Sanford, Larry D
To examine the REM sleep response to stress and fearful memories as a potential marker of stress resilience and vulnerability and to assess the role of the basolateral amygdala (BLA) in mediating the effects of fear memory on sleep. Outbred Wistar rats were surgically implanted with electrodes for recording EEG and EMG and with bilateral guide cannulae directed at the BLA. Data loggers were placed intraperitoneally to record core body temperature. After recovery from surgery, the rats received shock training (ST: 20 footshocks, 0.8 mA, 0.5-s duration, 60-s interstimulus interval) and afterwards received microinjections of the GABAA agonist muscimol (MUS; 1.0 μM) to inactivate BLA or microinjections of vehicle (VEH) alone. Subsequently, the rats were separated into 4 groups (VEH-vulnerable (VEH-Vul; n = 14), VEH-resilient (VEH-Res; n = 13), MUS-vulnerable (MUS-Vul; n = 8), and MUS-resilient (MUS-Res; n = 11) based on whether or not REM was decreased, compared to baseline, during the first 4 h following ST. We then compared sleep, freezing, and the stress response (stress-induced hyperthermia, SIH) across groups to determine the effects of ST and fearful context re-exposure alone (CTX). REM was significantly reduced on the ST day in both VEH-Vul and MUS-Vul rats; however, post-ST MUS blocked the reduction in REM on the CTX day in the MUS-Vul group. The VEH-Res and MUS-Res rats showed similar levels of REM on both ST and CTX days. The effects of post-ST inactivation of BLA on freezing and SIH were minimal. Outbred Wistar rats can show significant individual differences in the effects of stress on REM that are mediated by BLA. These differences in REM can be independent of behavioral fear and the peripheral stress response, and may be an important biomarker of stress resilience and vulnerability. © 2016 Associated Professional Sleep Societies, LLC.
Keilmann, A; Läßig, A K; Nospes, S
The definition of an auditory processing disorder (APD) is based on impairments of auditory functions. APDs are disturbances in processes central to hearing that cannot be explained by comorbidities such as attention deficit or language comprehension disorders. Symptoms include difficulties in differentiation and identification of changes in time, structure, frequency and intensity of sounds; problems with sound localization and lateralization, as well as poor speech comprehension in adverse listening environments and dichotic situations. According to the German definition of APD (as opposed to central auditory processing disorder, CAPD), peripheral hearing loss or cognitive impairment also exclude APD. The diagnostic methodology comprises auditory function tests and the required diagnosis of exclusion. APD is diagnosed if a patient's performance is two standard deviations below the normal mean in at least two areas of auditory processing. The treatment approach for an APD depends on the patient's particular deficits. Training, compensatory strategies and improvement of the listening conditions can all be effective.
Mertens, Gaëtan; Kuhn, Manuel; Raes, An K; Kalisch, Raffael; De Houwer, Jan; Lonsdorf, Tina B
Prior research showed that mere instructions about the contingency between a conditioned stimulus (CS) and an unconditioned stimulus (US) can generate fear reactions to the CS. Little is known, however, about the extent to which actual CS-US contingency experience adds anything beyond the effect of contingency instructions. Our results extend previous studies on this topic in that it included fear potentiated startle as an additional dependent variable and examined return of fear (ROF) following reinstatement. We observed that CS-US pairings can enhance fear reactions beyond the effect of contingency instructions. Moreover, for all measures of fear, instructions elicited immediate fear reactions that could not be completely overridden by subsequent situational safety information. Finally, ROF following reinstatement for instructed CS+s was unaffected by actual experience. In summary, our results demonstrate the power of contingency instructions and reveal the additional impact of actual experience of CS-US pairings.
Full Text Available The present study evaluated the long-lasting effects of neonatal handling (H; administered during the first 21 days of life on unlearned and learned anxiety-related responses in inbred Roman High- (RHA-I and Low-avoidance (RLA-I rats. To this aim, untreated and neonatally-handled RHA-I and RLA-I rats of both sexes were tested in the following tests/tasks in baseline acoustic startle (BAS test, a context-conditioned fear (CCF test and the acquisition of two-way active –shuttle box- avoidance (SHAV. RLA-I rats showed higher unconditioned (NOE, ZM, BAS and conditioned (CCF, SHAV anxiety. H treatment increased exploration of the novel object in the NOE test as well as exploration of the open sections of the ZM test in both rat strains and sexes, although the effects were relatively more marked in the (high anxious RLA-I strain and in females. Neonatal handling did not affect BAS, but reduced context-conditioned fear in both strains and sexes, and improved shuttle box avoidance acquisition especially in RLA-I (and particularly in females and in female RHA-I rats. These are completely novel findings, and may suggest that H-induced changes in hippocampal function, which is enhanced in RLA-Is vs RHA-I rats, could be a candidate mechanism underlying the observed long-lasting benefits of neonatal handling on known hippocampal-dependent responses/tasks.
Full Text Available Abstract Calcium-calmodulin dependent protein kinase IV (CaMKIV is a protein kinase that activates the transcription factor CREB. Our previous work demonstrated that mice lacking CaMKIV had a defect in fear memory while behavioral responses to noxious stimuli were unchanged. Here, we measured ultrasonic vocalizations (USVs before and after fear conditioning and in response to a noxious injection of capsaicin to measure behavioral responses to emotional stimuli. Consistent with previous findings, behavioral nociceptive responses to capsaicin were undistinguishable between wild-type and CaMKIV-/- mice. Wild-type animals showed a selective increase in 50 kHz USVs in response to capsaicin while such an increase was absent in CaMKIV-/- mice. The foot shock given during fear conditioning caused an increase in 30 kHz USVs in both wild-type and CaMKIV-/- mice. When returned to the context one hour later, USVs from the wild-type were significantly decreased. Additionally, the onset of a tone, which had previously been paired with the foot shock, caused a significant decrease in USVs during auditory conditioning. CaMKIV-/- mice showed significantly less reduction in USVs when placed in the same context three days after receiving the shock, consistent with the decrease in freezing reported previously. Our results provide a new approach for investigating the molecular mechanism for emotional vocalization in mice and suggest that CaMKIV dependent signaling pathways play an important role in the emotional response to pain and fear.
Christiansen, Steen Ledet
movies work to dispel fear by producing potency and bolstering resolve. We can thus understand action movies as participating in the biopolitical effects of contemporary warfare. Affect is globalized and intensified through action movies’ aesthetics, with the aim of producing a kind of drone subject....... Robin James significantly posits a drone atmosphere where our perceptual limit reconfigures through ‘droning’ – the creation of an affective timbre [James, R., 2013. Drones, sound, and super-panoptic surveillance. Cyborgology]. As James argues, ‘[d]roning rivets you to material conditions, affects......, and sensations that compel you to behave in specific ways, and not in others’ (n.p.). So while drones currently work overseas to target morale, action movies work on the home front to target our potency and resolve and so engender a mode of sensation that also functions as action. Affect works as a translator...
Sehlmeyer, C; Dannlowski, U; Schöning, S; Kugel, H; Pyka, M; Pfleiderer, B; Zwitserlood, P; Schiffbauer, H; Heindel, W; Arolt, V; Konrad, C
Fear conditioning involves the amygdala as the main neural structure for learning fear responses whereas fear extinction mainly activates the inhibitory prefrontal cortex (PFC). In this study we investigated whether individual differences in trait anxiety affect amygdala and dorsal anterior cingulate cortex (dACC) activation during fear conditioning and extinction. Thirty-two healthy subjects were investigated by functional magnetic resonance imaging (fMRI) at 3 T while performing a cued fear-conditioning task. All participants completed the trait version of the State-Trait Anxiety Inventory (STAI-T). Activations of the amygdala and the dACC were examined with respect to the effects of trait anxiety. Analysis of the fMRI data demonstrated enhanced activation in fear-related brain areas, such as the insula and the ACC, during both fear conditioning and extinction. Activation of the amygdala appeared only during the late acquisition phase whereas deactivation was observed during extinction. Regression analyses revealed that highly trait-anxious subjects exhibited sustained amygdala activation and reduced dACC involvement during the extinction of conditioned responses. This study reveals that high levels of trait anxiety are associated with both increased amygdala activation and reduced dACC recruitment during the extinction of conditioned fear. This hyper-responsivity of the amygdala and the deficient cognitive control during the extinction of conditioned fear in anxious subjects reflect an increased resistance to extinct fear responses and may thereby enhance the vulnerability to developing anxiety disorders.
Bergstrom, Hadley C
Memories of threatening, fear-evoking events can persist even over a lifetime. While fear memory is widely considered to be a highly persistent and durable form of memory, its circuits are not. This article reviews the dynamic temporal representation of remote fear memory in the brain, at the level of local circuits and distributed networks. Data from the study of Pavlovian cued fear conditioning suggests memory retrieval remains amygdala-dependent, even over protracted time scales, all the while interconnected cortical and subcortical circuits are newly recruited and progressively reorganized. A deeper understanding into how the neurocircuitry of cued fear memory reorganizes with the passage of time will advance our ongoing search for the elusive physical changes representing fear memories in the brain. Considering that persistent, pathological fear memories are a hallmark feature of post-traumatic stress disorder (PTSD), the behavioral and circuit-level study of remote cued fear memory retrieval adds a key element towards a systems understanding of PTSD. Copyright Â© 2016 Elsevier Ltd. All rights reserved.
Rachel M. Brown
Full Text Available Skilled performers such as athletes or musicians can improve their performance by imagining the actions or sensory outcomes associated with their skill. Performers vary widely in their auditory and motor imagery abilities, and these individual differences influence sensorimotor learning. It is unknown whether imagery abilities influence both memory encoding and retrieval. We examined how auditory and motor imagery abilities influence musicians’ encoding (during Learning, as they practiced novel melodies, and retrieval (during Recall of those melodies. Pianists learned melodies by listening without performing (auditory learning or performing without sound (motor learning; following Learning, pianists performed the melodies from memory with auditory feedback (Recall. During either Learning (Experiment 1 or Recall (Experiment 2, pianists experienced either auditory interference, motor interference, or no interference. Pitch accuracy (percentage of correct pitches produced and temporal regularity (variability of quarter-note interonset intervals were measured at Recall. Independent tests measured auditory and motor imagery skills. Pianists’ pitch accuracy was higher following auditory learning than following motor learning and lower in motor interference conditions (Experiments 1 and 2. Both auditory and motor imagery skills improved pitch accuracy overall. Auditory imagery skills modulated pitch accuracy encoding (Experiment 1: Higher auditory imagery skill corresponded to higher pitch accuracy following auditory learning with auditory or motor interference, and following motor learning with motor or no interference. These findings suggest that auditory imagery abilities decrease vulnerability to interference and compensate for missing auditory feedback at encoding. Auditory imagery skills also influenced temporal regularity at retrieval (Experiment 2: Higher auditory imagery skill predicted greater temporal regularity during Recall in the
A driving simulator was used to compare the effectiveness of increasing intensity (looming) auditory warning signals with other types of auditory warnings. Auditory warnings have been shown to speed driver reaction time in rear-end collision situations; however, it is not clear which type of signal is the most effective. Although verbal and symbolic (e.g., a car horn) warnings have faster response times than abstract warnings, they often lead to more response errors. Participants (N=20) experienced four nonlooming auditory warnings (constant intensity, pulsed, ramped, and car horn), three looming auditory warnings ("veridical," "early," and "late"), and a no-warning condition. In 80% of the trials, warnings were activated when a critical response was required, and in 20% of the trials, the warnings were false alarms. For the early (late) looming warnings, the rate of change of intensity signaled a time to collision (TTC) that was shorter (longer) than the actual TTC. Veridical looming and car horn warnings had significantly faster brake reaction times (BRT) compared with the other nonlooming warnings (by 80 to 160 ms). However, the number of braking responses in false alarm conditions was significantly greater for the car horn. BRT increased significantly and systematically as the TTC signaled by the looming warning was changed from early to veridical to late. Looming auditory warnings produce the best combination of response speed and accuracy. The results indicate that looming auditory warnings can be used to effectively warn a driver about an impending collision.
Gori, Monica; Vercillo, Tiziana; Sandini, Giulio; Burr, David
Our recent studies suggest that congenitally blind adults have severely impaired thresholds in an auditory spatial bisection task, pointing to the importance of vision in constructing complex auditory spatial maps (Gori et al., 2014). To explore strategies that may improve the auditory spatial sense in visually impaired people, we investigated the impact of tactile feedback on spatial auditory localization in 48 blindfolded sighted subjects. We measured auditory spatial bisection thresholds before and after training, either with tactile feedback, verbal feedback, or no feedback. Audio thresholds were first measured with a spatial bisection task: subjects judged whether the second sound of a three sound sequence was spatially closer to the first or the third sound. The tactile feedback group underwent two audio-tactile feedback sessions of 100 trials, where each auditory trial was followed by the same spatial sequence played on the subject's forearm; auditory spatial bisection thresholds were evaluated after each session. In the verbal feedback condition, the positions of the sounds were verbally reported to the subject after each feedback trial. The no feedback group did the same sequence of trials, with no feedback. Performance improved significantly only after audio-tactile feedback. The results suggest that direct tactile feedback interacts with the auditory spatial localization system, possibly by a process of cross-sensory recalibration. Control tests with the subject rotated suggested that this effect occurs only when the tactile and acoustic sequences are spatially congruent. Our results suggest that the tactile system can be used to recalibrate the auditory sense of space. These results encourage the possibility of designing rehabilitation programs to help blind persons establish a robust auditory sense of space, through training with the tactile modality.
Full Text Available Attentional control (AC and fear extinction learning are known to be involved in pathological anxiety. In this study we explored whether individual differences in non-emotional AC were associated with individual differences in the magnitude and gradient of fear extinction (learning and recall. In 50 individuals with fear of spiders, we collected measures of non-emotional AC by means of self-report and by assessing the functioning of the major attention networks (executive control, orienting, and alerting. The participants then underwent a paradigm assessing fear extinction learning and extinction recall. The two components of the orienting network functioning (costs and benefits were significantly associated with fear extinction gradient over and above the effects of trait anxiety. Specifically, participants with enhanced orienting costs (i.e., difficulties in disengaging attention from cues not relevant for the task showed faster extinction learning, while those with enhanced orienting benefits (i.e., attention facilitated by valid cues exhibited faster extinction recall as measured by fear-potentiated startle and Unconditioned Stimulus expectancies, respectively. Our findings suggest that, in non-emotional conditions, the orienting component of attention may be predictive of fear extinction. They also show that the use of fear extinction gradients and the exploration of individual differences in non-emotional AC (using performance-based measures of attentional network functioning can provide a better understanding of individual differences in fear learning. Our findings also may help to understand differences in exposure therapy outcomes.
Forcadell, Eduard; Torrents-Rodas, David; Treen, Devi; Fullana, Miquel A.; Tortella-Feliu, Miquel
Attentional control (AC) and fear extinction learning are known to be involved in pathological anxiety. In this study we explored whether individual differences in non-emotional AC were associated with individual differences in the magnitude and gradient of fear extinction (learning and recall). In 50 individuals with fear of spiders, we collected measures of non-emotional AC by means of self-report and by assessing the functioning of the major attention networks (executive control, orienting, and alerting). The participants then underwent a paradigm assessing fear extinction learning and extinction recall. The two components of the orienting network functioning (costs and benefits) were significantly associated with fear extinction gradient over and above the effects of trait anxiety. Specifically, participants with enhanced orienting costs (i.e., difficulties in disengaging attention from cues not relevant for the task) showed faster extinction learning, while those with enhanced orienting benefits (i.e., attention facilitated by valid cues) exhibited faster extinction recall as measured by fear-potentiated startle and Unconditioned Stimulus expectancies, respectively. Our findings suggest that, in non-emotional conditions, the orienting component of attention may be predictive of fear extinction. They also show that the use of fear extinction gradients and the exploration of individual differences in non-emotional AC (using performance-based measures of attentional network functioning) can provide a better understanding of individual differences in fear learning. Our findings also may help to understand differences in exposure therapy outcomes. PMID:29018384
Norrholm, S.D.; Vervliet, B.; Jovanovic, T.; Boshoven, W.; Myers, K.M.; Davis, M.; Rothbaum, B.O.; Duncan, E.J.
Fear extinction is a reduction in conditioned fear following repeated exposure to the feared cue in the absence of any aversive event. Extinguished fear often reappears after extinction through spontaneous recovery. Animal studies suggest that spontaneous recovery can be abolished if extinction
Carter, Ava Elizabeth; Carter, Geoff; Boschen, Mark; AlShwaimi, Emad; George, Roy
The aim of this article was to analyze the theories underpinning dental fear, anxiety and phobias. To be included, articles must have been published between the years of 1949 and 2013 concerning fears and phobias within dentistry and/or psychiatry. Of 200 articles originally under review, 140 were included and reviewed by the authors.Five specific pathways relating to dental fear and anxiety were identified; Cognitive Conditioning, Informative, Visual Vicarious, Verbal Threat, and Parental. Eight currently accepted management techniques across all dental disciplines for dental fear and anxiety were identified. Further research is required to identify clinical diagnosis and treatment for fears originating from different pathways.
Carter, Ava Elizabeth; Carter, Geoff; Boschen, Mark; AlShwaimi, Emad; George, Roy
The aim of this article was to analyze the theories underpinning dental fear, anxiety and phobias. To be included, articles must have been published between the years of 1949 and 2013 concerning fears and phobias within dentistry and/or psychiatry. Of 200 articles originally under review, 140 were included and reviewed by the authors.Five specific pathways relating to dental fear and anxiety were identified; Cognitive Conditioning, Informative, Visual Vicarious, Verbal Threat, and Parental. Eight currently accepted management techniques across all dental disciplines for dental fear and anxiety were identified. Further research is required to identify clinical diagnosis and treatment for fears originating from different pathways. PMID:25405187
Harmatz, Elia S; Stone, Lauren; Lim, Seh Hong; Lee, Graham; McGrath, Anna; Gisabella, Barbara; Peng, Xiaoyu; Kosoy, Eliza; Yao, Junmei; Liu, Elizabeth; Machado, Nuno J; Weiner, Veronica S; Slocum, Warren; Cunha, Rodrigo A; Goosens, Ki A
There are many contradictory findings about the role of the hormone ghrelin in aversive processing, with studies suggesting that ghrelin signaling can both inhibit and enhance aversion. Here, we characterize and reconcile the paradoxical role of ghrelin in the acquisition of fearful memories. We used enzyme-linked immunosorbent assay to measure endogenous acyl-ghrelin and corticosterone at time points surrounding auditory fear learning. We used pharmacological (systemic and intra-amygdala) manipulations of ghrelin signaling and examined several aversive and appetitive behaviors. We also used biotin-labeled ghrelin to visualize ghrelin binding sites in coronal brain sections of amygdala. All work was performed in rats. In unstressed rodents, endogenous peripheral acyl-ghrelin robustly inhibits fear memory consolidation through actions in the amygdala and accounts for virtually all interindividual variability in long-term fear memory strength. Higher levels of endogenous ghrelin after fear learning were associated with weaker long-term fear memories, and pharmacological agonism of the ghrelin receptor during the memory consolidation period reduced fear memory strength. These fear-inhibitory effects cannot be explained by changes in appetitive behavior. In contrast, we show that chronic stress, which increases both circulating endogenous acyl-ghrelin and fear memory formation, promotes profound loss of ghrelin binding sites in the amygdala and behavioral insensitivity to ghrelin receptor agonism. These studies provide a new link between stress, a novel type of metabolic resistance, and vulnerability to excessive fear memory formation and reveal that ghrelin can regulate negative emotionality in unstressed animals without altering appetite. Copyright © 2016 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
Fear of success in a group of high school students (N=127) was studied, with research findings supporting the following generalizations: (1) high school students with an intermediate level of self-esteem have greater fear of success than those with high and low levels of self-esteem; (2) high school students with BSRI (Bem Sex Role Inventory)…
Hjøllund, Niels-Peder Osmundsen
I plan to take departure in the Freudian concept of the uncanny and unfold how this also plays on aesthetics of pleasure. The way we cope with fear is often related to pleasure, for example how children often laugh when frightened. This will lead me to a discussion of how fear and pleasure...
Brink, Dennis Meyhoff
The article examines the history of the fear of religious satire in modern Europe. The article argues that this fear primarily concerns the potential dissolution of 'the social bond of society' or 'the moral and social order'. From the 17th Century until today, censorship measures and blasphemy...
... What Comes Next After Finishing Treatment Coping With Fear of Recurrence Having a Baby After Cancer: Pregnancy ... treatment and preparing for the future. Coping With Fear of Recurrence Learn ways to manage the fear ...
Each of us has felt afraid, and we can all recognize fear in many animal species. Yet there is no consensus in the scientific study of fear. Some argue that “fear” is a psychological construct rather than discoverable through scientific investigation. Others argue that the term “fear” cannot properly be applied to animals because we cannot know whether they feel afraid. Studies in rodents show that there are highly specific brain circuits for fear, whereas findings from human neuroimaging seem to make the opposite claim. Here I review the field and urge three approaches that could reconcile the debates. For one, we need a broadly comparative approach that would identify core components of fear conserved across phylogeny. This also pushes us towards the second point of emphasis: an ecological theory of fear that is essentially functional. Finally, we should aim even to incorporate the conscious experience of being afraid, reinvigorating the study of feelings across species. PMID:23347946
Fattahi, Fariba; Geshani, Ahmad; Jafari, Zahra; Jalaie, Shohreh; Salman Mahini, Mona
Chess is a game that involves many aspects of high level cognition such as memory, attention, focus and problem solving. Long term practice of chess can improve cognition performances and behavioral skills. Auditory memory, as a kind of memory, can be influenced by strengthening processes following long term chess playing like other behavioral skills because of common processing pathways in the brain. The purpose of this study was to evaluate the auditory memory function of expert chess players using the Persian version of dichotic auditory-verbal memory test. The Persian version of dichotic auditory-verbal memory test was performed for 30 expert chess players aged 20-35 years and 30 non chess players who were matched by different conditions; the participants in both groups were randomly selected. The performance of the two groups was compared by independent samples t-test using SPSS version 21. The mean score of dichotic auditory-verbal memory test between the two groups, expert chess players and non-chess players, revealed a significant difference (p≤ 0.001). The difference between the ears scores for expert chess players (p= 0.023) and non-chess players (p= 0.013) was significant. Gender had no effect on the test results. Auditory memory function in expert chess players was significantly better compared to non-chess players. It seems that increased auditory memory function is related to strengthening cognitive performances due to playing chess for a long time.
Gondra, José María; Sánchez de Miguel, Manuel
In the late 1930s, the Institute of Human Relations of Yale University developed a research program on conflict and anxiety as an outcome of Clark Hull's informal seminar on the integration of Freud's and Pavlov's theories. The program was launched at the 1937 Annual Meeting of the APA in a session chaired by Clark L. Hull, and the experiments continued through 1941, when the United States entered the Second World War. In an effort to apply the findings from animal experiments to the war situation, John Dollard and Neal E. Miller decided to study soldiers' fear reactions in combat. As a first step, they arranged interviews with a few veterans of the Abraham Lincoln Brigade. Taking these interviews as a point of departure, Dollard devised a questionnaire to which 300 former Lincoln brigaders responded. The present paper analyzes the main outcomes of the questionnaire, together with the war experiences reported in the interview transcripts. Our purpose was to evaluate a project which was initially investigated by the FBI because of the communists among the Lincoln ranks, but eventually supported by the American Army, and which exerted great influence on the military psychology of the time.
Bogert, Brigitte; Numminen-Kontti, Taru; Gold, Benjamin; Sams, Mikko; Numminen, Jussi; Burunat, Iballa; Lampinen, Jouko; Brattico, Elvira
Music is often used to regulate emotions and mood. Typically, music conveys and induces emotions even when one does not attend to them. Studies on the neural substrates of musical emotions have, however, only examined brain activity when subjects have focused on the emotional content of the music. Here we address with functional magnetic resonance imaging (fMRI) the neural processing of happy, sad, and fearful music with a paradigm in which 56 subjects were instructed to either classify the emotions (explicit condition) or pay attention to the number of instruments playing (implicit condition) in 4-s music clips. In the implicit vs. explicit condition, stimuli activated bilaterally the inferior parietal lobule, premotor cortex, caudate, and ventromedial frontal areas. The cortical dorsomedial prefrontal and occipital areas activated during explicit processing were those previously shown to be associated with the cognitive processing of music and emotion recognition and regulation. Moreover, happiness in music was associated with activity in the bilateral auditory cortex, left parahippocampal gyrus, and supplementary motor area, whereas the negative emotions of sadness and fear corresponded with activation of the left anterior cingulate and middle frontal gyrus and down-regulation of the orbitofrontal cortex. Our study demonstrates for the first time in healthy subjects the neural underpinnings of the implicit processing of brief musical emotions, particularly in frontoparietal, dorsolateral prefrontal, and striatal areas of the brain. Copyright © 2016 Elsevier Ltd. All rights reserved.
Orcutt, Holly K.; Hannan, Susan M.; Seligowski, Antonia V.; Jovanovic, Tanja; Norrholm, Seth D.; Ressler, Kerry J.; McCanne, Thomas
Posttraumatic stress disorder (PTSD) is a common psychological disorder that affects a substantial minority of individuals. Previous research has suggested that PTSD can be partially explained as a disorder of impaired fear inhibition. The current study utilized a previously validated fear acquisition and extinction paradigm in a sample of 75 undergraduate women who were exposed to a campus mass shooting that occurred in 2008. We used a protocol in which conditioned fear was first acquired through the presentation of one colored shape (reinforced conditioned stimulus, CS+) that was paired with an aversive airblast to the larynx (unconditioned stimulus, US) and a different colored shape that was not paired with the airblast (non-reinforced conditioned stimulus, CS-). Fear was extinguished 10 min later through repeated presentations of the CSs without reinforcement. Number of clinically significant posttraumatic stress symptoms (PTSS) immediately following the mass shooting were positively associated with fear-potentiated startle (FPS) to the CS+ and CS- during late periods of acquisition. During early periods of fear extinction, PTSS was positively associated with FPS to the CS+. Results from the current study suggest that PTSS is related to altered fear inhibition and extinction during an FPS paradigm. In line with similar research, women with greater PTSS demonstrated a greater “fear load,” suggesting that these women experienced elevated fear to the CS+ during extinction after conditioned fear was acquired. PMID:28111559
Orcutt, Holly K; Hannan, Susan M; Seligowski, Antonia V; Jovanovic, Tanja; Norrholm, Seth D; Ressler, Kerry J; McCanne, Thomas
Posttraumatic stress disorder (PTSD) is a common psychological disorder that affects a substantial minority of individuals. Previous research has suggested that PTSD can be partially explained as a disorder of impaired fear inhibition. The current study utilized a previously validated fear acquisition and extinction paradigm in a sample of 75 undergraduate women who were exposed to a campus mass shooting that occurred in 2008. We used a protocol in which conditioned fear was first acquired through the presentation of one colored shape (reinforced conditioned stimulus, CS+) that was paired with an aversive airblast to the larynx (unconditioned stimulus, US) and a different colored shape that was not paired with the airblast (non-reinforced conditioned stimulus, CS-). Fear was extinguished 10 min later through repeated presentations of the CSs without reinforcement. Number of clinically significant posttraumatic stress symptoms (PTSS) immediately following the mass shooting were positively associated with fear-potentiated startle (FPS) to the CS+ and CS- during late periods of acquisition. During early periods of fear extinction, PTSS was positively associated with FPS to the CS+. Results from the current study suggest that PTSS is related to altered fear inhibition and extinction during an FPS paradigm. In line with similar research, women with greater PTSS demonstrated a greater "fear load," suggesting that these women experienced elevated fear to the CS+ during extinction after conditioned fear was acquired.
... auditory potentials; Brainstem auditory evoked potentials; Evoked response audiometry; Auditory brainstem response; ABR; BAEP ... Normal results vary. Results will depend on the person and the instruments used to perform the test.
... role. Auditory cohesion problems: This is when higher-level listening tasks are difficult. Auditory cohesion skills — drawing inferences from conversations, understanding riddles, or comprehending verbal math problems — require heightened auditory processing and language levels. ...
Edwards, Sarah; Salkovskis, Paul M
It has been suggested that disgust, rather than anxiety, may be important in some phobias. Correlational studies have been ambiguous, indicating either that disgust increases phobic anxiety or that phobic anxiety potentiates disgust. In the experimental study reported here, disgust and phobic anxiety were manipulated in the context of habituation to phobic stimuli. Spider fearful participants were randomly allocated to conditions in which neutral, disgusting, and phobic anxiety provoking stimuli were introduced into a video-based spider phobic habituation sequence. Exposure to the phobic stimulus resulted in a return of self-reported fear and disgust levels. However, exposure to disgusting stimulus increased disgust levels, but not anxiety levels. Results are most consistent with the hypothesis that fear enhances the disgust response in phobias, but that disgust alone does not enhance the fear response. Previously observed links between disgust and spider phobia may be a consequence of fear enhancing disgust.
Full Text Available The functional auditory system extends from the ears to the frontal lobes with successively more complex functions occurring as one ascends the hierarchy of the nervous system. Several areas of the frontal lobe receive afferents from both early and late auditory processing regions within the temporal lobe. Afferents from the early part of the cortical auditory system, the auditory belt cortex, which are presumed to carry information regarding auditory features of sounds, project to only a few prefrontal regions and are most dense in the ventrolateral prefrontal cortex (VLPFC. In contrast, projections from the parabelt and the rostral superior temporal gyrus (STG most likely convey more complex information and target a larger, widespread region of the prefrontal cortex. Neuronal responses reflect these anatomical projections as some prefrontal neurons exhibit responses to features in acoustic stimuli, while other neurons display task-related responses. For example, recording studies in non-human primates indicate that VLPFC is responsive to complex sounds including vocalizations and that VLPFC neurons in area 12/47 respond to sounds with similar acoustic morphology. In contrast, neuronal responses during auditory working memory involve a wider region of the prefrontal cortex. In humans, the frontal lobe is involved in auditory detection, discrimination, and working memory. Past research suggests that dorsal and ventral subregions of the prefrontal cortex process different types of information with dorsal cortex processing spatial/visual information and ventral cortex processing non-spatial/auditory information. While this is apparent in the non-human primate and in some neuroimaging studies, most research in humans indicates that specific task conditions, stimuli or previous experience may bias the recruitment of specific prefrontal regions, suggesting a more flexible role for the frontal lobe during auditory cognition.
Plakke, Bethany; Romanski, Lizabeth M.
The functional auditory system extends from the ears to the frontal lobes with successively more complex functions occurring as one ascends the hierarchy of the nervous system. Several areas of the frontal lobe receive afferents from both early and late auditory processing regions within the temporal lobe. Afferents from the early part of the cortical auditory system, the auditory belt cortex, which are presumed to carry information regarding auditory features of sounds, project to only a few prefrontal regions and are most dense in the ventrolateral prefrontal cortex (VLPFC). In contrast, projections from the parabelt and the rostral superior temporal gyrus (STG) most likely convey more complex information and target a larger, widespread region of the prefrontal cortex. Neuronal responses reflect these anatomical projections as some prefrontal neurons exhibit responses to features in acoustic stimuli, while other neurons display task-related responses. For example, recording studies in non-human primates indicate that VLPFC is responsive to complex sounds including vocalizations and that VLPFC neurons in area 12/47 respond to sounds with similar acoustic morphology. In contrast, neuronal responses during auditory working memory involve a wider region of the prefrontal cortex. In humans, the frontal lobe is involved in auditory detection, discrimination, and working memory. Past research suggests that dorsal and ventral subregions of the prefrontal cortex process different types of information with dorsal cortex processing spatial/visual information and ventral cortex processing non-spatial/auditory information. While this is apparent in the non-human primate and in some neuroimaging studies, most research in humans indicates that specific task conditions, stimuli or previous experience may bias the recruitment of specific prefrontal regions, suggesting a more flexible role for the frontal lobe during auditory cognition. PMID:25100931
Hermans, E.J.; Kanen, J.W.; Tambini, A.; Fernandez, G.; Davachi, L.; Phelps, E.A.
After encoding, memories undergo a process of consolidation that determines long-term retention. For conditioned fear, animal models postulate that consolidation involves reactivations of neuronal assemblies supporting fear learning during postlearning "offline" periods. However, no human studies to
Thompson, Brittany M.; Baratta, Michael V.; Biedenkapp, Joseph C.; Rudy, Jerry W.; Watkins, Linda R.; Maier, Steven F.
Activation of the infralimbic region (IL) of the medial prefrontal cortex (mPFC) reduces conditioned fear in a variety of situations, and the IL is thought to play an important role in the extinction of conditioned fear. Here we report a series of experiments using contextual fear conditioning in which the IL is activated with the GABAa antagonist…
In recent years, questions have been raised regarding the dimensionality of existing measures of fear of fear. This is an important issue that needs to be addressed if the dimensions(s) of any scale purporting to assess fear of fear are to guide theory and research. One of the most widely used
Dunsmoor, Joseph E.; White, Allison J.; LaBar, Kevin S.
We tested the hypothesis that conceptual similarity promotes generalization of conditioned fear. Using a sensory preconditioning procedure, three groups of subjects learned an association between two cues that were conceptually similar, unrelated, or mismatched. Next, one of the cues was paired with a shock. The other cue was then reintroduced to test for fear generalization, as measured by the skin conductance response. Results showed enhanced fear generalization that correlated with trait anxiety levels in the group that learned an association between conceptually similar stimuli. These findings suggest that conceptual representations of conditional stimuli influence human fear learning processes. PMID:21330378
Heard through the ears of the Canadian composer and music teacher R. Murray Schafer the ideal auditory community had the shape of a village. Schafer’s work with the World Soundscape Project in the 70s represent an attempt to interpret contemporary environments through musical and auditory...
Crease, Robert P.
In 1988 the science historian Spencer Weart published a groundbreaking book called Nuclear Fear: A History of Images, which examined visions of radiation damage and nuclear disaster in newspapers, television, film, literature, advertisements and popular culture.
Dagnino-Subiabre, A; Terreros, G; Carmona-Fontaine, C; Zepeda, R; Orellana, J A; Díaz-Véliz, G; Mora, S; Aboitiz, F
Chronic stress affects brain areas involved in learning and emotional responses. These alterations have been related with the development of cognitive deficits in major depression. The aim of this study was to determine the effect of chronic immobilization stress on the auditory and visual mesencephalic regions in the rat brain. We analyzed in Golgi preparations whether stress impairs the neuronal morphology of the inferior (auditory processing) and superior colliculi (visual processing). Afterward, we examined the effect of stress on acoustic and visual conditioning using an avoidance conditioning test. We found that stress induced dendritic atrophy in inferior colliculus neurons and did not affect neuronal morphology in the superior colliculus. Furthermore, stressed rats showed a stronger impairment in acoustic conditioning than in visual conditioning. Fifteen days post-stress the inferior colliculus neurons completely restored their dendritic structure, showing a high level of neural plasticity that is correlated with an improvement in acoustic learning. These results suggest that chronic stress has more deleterious effects in the subcortical auditory system than in the visual system and may affect the aversive system and fear-like behaviors. Our study opens a new approach to understand the pathophysiology of stress and stress-related disorders such as major depression.
Do-Monte, Fabricio H; Manzano-Nieves, Gabriela; Quiñones-Laracuente, Kelvin; Ramos-Medina, Liorimar; Quirk, Gregory J
Previous rodent studies have implicated the infralimbic (IL) subregion of the medial prefrontal cortex in extinction of auditory fear conditioning. However, these studies used pharmacological inactivation or electrical stimulation techniques, which lack temporal precision and neuronal specificity. Here, we used an optogenetic approach to either activate (with channelrhodopsin) or silence (with halorhodopsin) glutamatergic IL neurons during conditioned tones delivered in one of two phases: extinction training or extinction retrieval. Activating IL neurons during extinction training reduced fear expression and strengthened extinction memory the following day. Silencing IL neurons during extinction training had no effect on within-session extinction, but impaired the retrieval of extinction the following day, indicating that IL activity during extinction tones is necessary for the formation of extinction memory. Surprisingly, however, silencing IL neurons optogenetically or pharmacologically during the retrieval of extinction 1 day or 1 week following extinction training had no effect. Our findings suggest that IL activity during extinction training likely facilitates storage of extinction in target structures, but contrary to current models, IL activity does not appear to be necessary for retrieval of extinction memory. Copyright © 2015 the authors 0270-6474/15/353607-09$15.00/0.
Dahlen, Hannah Grace; Caplice, Shea
There is evidence that a significant number of women are fearful about birth but less is known about the fears of maternity health providers and how their fear may impact on the women they care for. The aim of this study was to determine the top fears midwives in Australia and New Zealand hold when it comes to caring for childbearing women. From 2009 to 2011, 17 workshops were held in Australia and New Zealand supporting over 700 midwives develop skills to keep birth normal. During the workshop midwives were asked to write their top fear on a piece of paper and return it to the presenters. Similar concepts were grouped together to form 8 major categories. In total 739 fears were reported and these were death of a baby (n=177), missing something that causes harm (n=176), obstetric emergencies (n=114), maternal death (n=83), being watched (n=68), being the cause of a negative birth experience (n=52), dealing with the unknown (n=36) and losing passion and confidence around normal birth (n=32). Student midwives were more concerned about knowing what to do, while homebirth midwives were mostly concerned with being blamed if something went wrong. There was consistency between the 17 groups of midwives regarding top fears held. Supporting midwives with workshops such as dealing with grief and loss and managing fear could help reduce their anxiety. Obstetric emergency skills workshops may help midwives feel more confident, especially those dealing with shoulder dystocia and PPH as they were most commonly recorded. Copyright © 2014 Australian College of Midwives. Published by Elsevier Ltd. All rights reserved.
Wiemer, S. A.; Kratochwill, T. R.
Examination of the number, content, and intensity of fears of 42 visually impaired children, aged 5-18, found more fears of potentially physically dangerous situations than of psychologically harmful ones and little difference between the number of mild and severe fears. Counselors' estimations of children's fears generally disagreed with the…
Civier, Oren; Tasko, Stephen M.; Guenther, Frank H.
This paper investigates the hypothesis that stuttering may result in part from impaired readout of feedforward control of speech, which forces persons who stutter (PWS) to produce speech with a motor strategy that is weighted too much toward auditory feedback control. Over-reliance on feedback control leads to production errors which, if they grow large enough, can cause the motor system to “reset” and repeat the current syllable. This hypothesis is investigated using computer simulations of a “neurally impaired” version of the DIVA model, a neural network model of speech acquisition and production. The model’s outputs are compared to published acoustic data from PWS’ fluent speech, and to combined acoustic and articulatory movement data collected from the dysfluent speech of one PWS. The simulations mimic the errors observed in the PWS subject’s speech, as well as the repairs of these errors. Additional simulations were able to account for enhancements of fluency gained by slowed/prolonged speech and masking noise. Together these results support the hypothesis that many dysfluencies in stuttering are due to a bias away from feedforward control and toward feedback control. PMID:20831971
Greco, John A; Liberzon, Israel
Fear conditioning has been commonly used as a model of emotional learning in animals and, with the introduction of functional neuroimaging techniques, has proven useful in establishing the neurocircuitry of emotional learning in humans. Studies of fear acquisition suggest that regions such as amygdala, insula, anterior cingulate cortex, and hippocampus play an important role in acquisition of fear, whereas studies of fear extinction suggest that the amygdala is also crucial for safety learning. Extinction retention testing points to the ventromedial prefrontal cortex as an essential region in the recall of the safety trace, and explicit learning of fear and safety associations recruits additional cortical and subcortical regions. Importantly, many of these findings have implications in our understanding of the pathophysiology of psychiatric disease. Recent studies using clinical populations have lent insight into the changes in regional activity in specific disorders, and treatment studies have shown how pharmaceutical and other therapeutic interventions modulate brain activation during emotional learning. Finally, research investigating individual differences in neurotransmitter receptor genotypes has highlighted the contribution of these systems in fear-associated learning. PMID:26294108
Frey, Aline; Aramaki, Mitsuko; Besson, Mireille
Two experiments were conducted using both behavioral and Event-Related brain Potentials methods to examine conceptual priming effects for realistic auditory scenes and for auditory words. Prime and target sounds were presented in four stimulus combinations: Sound-Sound, Word-Sound, Sound-Word and Word-Word. Within each combination, targets were conceptually related to the prime, unrelated or ambiguous. In Experiment 1, participants were asked to judge whether the primes and targets fit together (explicit task) and in Experiment 2 they had to decide whether the target was typical or ambiguous (implicit task). In both experiments and in the four stimulus combinations, reaction times and/or error rates were longer/higher and the N400 component was larger to ambiguous targets than to conceptually related targets, thereby pointing to a common conceptual system for processing auditory scenes and linguistic stimuli in both explicit and implicit tasks. However, fine-grained analyses also revealed some differences between experiments and conditions in scalp topography and duration of the priming effects possibly reflecting differences in the integration of perceptual and cognitive attributes of linguistic and nonlinguistic sounds. These results have clear implications for the building-up of virtual environments that need to convey meaning without words. Copyright © 2013 Elsevier Inc. All rights reserved.
Cohen, Michael A; Horowitz, Todd S; Wolfe, Jeremy M
Visual memory for scenes is surprisingly robust. We wished to examine whether an analogous ability exists in the auditory domain. Participants listened to a variety of sound clips and were tested on their ability to distinguish old from new clips. Stimuli ranged from complex auditory scenes (e.g., talking in a pool hall) to isolated auditory objects (e.g., a dog barking) to music. In some conditions, additional information was provided to help participants with encoding. In every situation, however, auditory memory proved to be systematically inferior to visual memory. This suggests that there exists either a fundamental difference between auditory and visual stimuli, or, more plausibly, an asymmetry between auditory and visual processing.
Jarome, Timothy J.; Kwapis, Janine L.; Werner, Craig T.; Parsons, Ryan G.; Gafford, Georgette M.; Helmstetter, Fred J.
Numerous studies have indicated that maintaining a fear memory after retrieval requires de novo protein synthesis. However, no study to date has examined how the temporal dynamics of repeated retrieval events affect this protein synthesis requirement. The present study varied the timing of a second retrieval of an established auditory fear memory…
Orcutt, Holly K.; Hannan, Susan M.; Seligowski, Antonia V.; Jovanovic, Tanja; Norrholm, Seth D.; Ressler, Kerry J.; McCanne, Thomas
Posttraumatic stress disorder (PTSD) is a common psychological disorder that affects a substantial minority of individuals. Previous research has suggested that PTSD can be partially explained as a disorder of impaired fear inhibition. The current study utilized a previously validated fear acquisition and extinction paradigm in a sample of 75 undergraduate women who were exposed to a campus mass shooting that occurred in 2008. We used a protocol in which conditioned fear was first acquired th...
Steinfurth, Elisa C. K.; Kanen, Jonathan W.; Raio, Candace M.; Clem, Roger L.; Huganir, Richard L.; Phelps, Elizabeth A.
Extinction training during reconsolidation has been shown to persistently diminish conditioned fear responses across species. We investigated in humans if older fear memories can benefit similarly. Using a Pavlovian fear conditioning paradigm we compared standard extinction and extinction after memory reactivation 1 d or 7 d following acquisition.…
Monti, Roque I. Ferrer; Alfei, Joaquin M.; Mugnaini, Matias; Bueno, Adrian M.; Beckers, Tom; Urcelay, Gonzalo P.; Molina, Victor A.
Two experiments using rats in a contextual fear memory preparation compared two approaches to reduce conditioned fear: (1) pharmacological reconsolidation blockade and (2) reactivation-plus-extinction training. In Experiment 1, we explored different combinations of reactivation-plus-extinction parameters to reduce conditioned fear and attenuate…
Sevenster, D.; Beckers, T.; Kindt, M.
Instructed extinction after fear conditioning is relatively effective in attenuating electrodermal responding. Testing the single-process account of fear learning, we examined whether this manipulation similarly affects the startle response. Skin conductance responses (SCRs), startle responses, and
Full Text Available Auditory integration training (AIT is a hearing enhancement training process for sensory input anomalies found in individuals with autism, attention deficit hyperactive disorder, dyslexia, hyperactivity, learning disability, language impairments, pervasive developmental disorder, central auditory processing disorder, attention deficit disorder, depressin, and hyperacute hearing. AIT, recently introduced in the United States, and has received much notice of late following the release of The Sound of a Moracle, by Annabel Stehli. In her book, Mrs. Stehli describes before and after auditory integration training experiences with her daughter, who was diagnosed at age four as having autism.
Full Text Available Auditory integration training (AIT is a hearing enhancement training process for sensory input anomalies found in individuals with autism, attention deficit hyperactive disorder, dyslexia, hyperactivity, learning disability, language impairments, pervasive developmental disorder, central auditory processing disorder, attention deficit disorder, depression, and hyper acute hearing. AIT, recently introduced in the United States, and has received much notice of late following the release of the sound of a miracle, by Annabel Stehli. In her book, Mrs. Stehli describes before and after auditory integration training experiences with her daughter, who was diagnosed at age four as having autism.
Soeter, Marieke; Kindt, Merel
Disrupting reconsolidation may be promising in the treatment of anxiety disorders but the fear-reducing effects are thus far solely demonstrated in the average organism. A relevant question is whether disrupting fear memory reconsolidation is less effective in individuals who are vulnerable to develop an anxiety disorder. By collapsing data from six previous human fear conditioning studies we tested whether trait anxiety was related to the fear-reducing effects of a pharmacological agent targeting the process of memory reconsolidation - n = 107. Testing included different phases across three consecutive days each separated by 24 h. Fear responding was measured by the eye-blink startle reflex. Disrupting the process of fear memory reconsolidation was manipulated by administering the β-adrenergic receptor antagonist propranolol HCl either before or after memory retrieval. Trait anxiety uniquely predicted the fear-reducing effects of disrupting memory reconsolidation: the higher the trait anxiety, the less fear reduction. Vulnerable individuals with the propensity to develop anxiety disorders may need higher dosages of propranolol HCl or more retrieval trials for targeting and changing fear memory. Our finding clearly demonstrates that we cannot simply translate observations from fundamental research on fear reduction in the average organism to clinical practice. PMID:24260096
Full Text Available Disrupting reconsolidation may be promising in the treatment of anxiety disorders but the fear-reducing effects are thus far solely demonstrated in the average organism. A relevant question is whether disrupting fear memory reconsolidation is less effective in individuals who are vulnerable to develop an anxiety disorder. By collapsing data from six previous human fear conditioning studies we tested whether trait anxiety was related to the fear-reducing effects of a pharmacological agent targeting the process of memory reconsolidation--n = 107. Testing included different phases across three consecutive days each separated by 24 h. Fear responding was measured by the eye-blink startle reflex. Disrupting the process of fear memory reconsolidation was manipulated by administering the β-adrenergic receptor antagonist propranolol HCl either before or after memory retrieval. Trait anxiety uniquely predicted the fear-reducing effects of disrupting memory reconsolidation: the higher the trait anxiety, the less fear reduction. Vulnerable individuals with the propensity to develop anxiety disorders may need higher dosages of propranolol HCl or more retrieval trials for targeting and changing fear memory. Our finding clearly demonstrates that we cannot simply translate observations from fundamental research on fear reduction in the average organism to clinical practice.
Keifer, Orion P.; Hurt, Robert C.; Ressler, Kerry J.
The historically understood role of the central amygdala (CeA) in fear learning is to serve as a passive output station for processing and plasticity that occurs elsewhere in the brain. However, recent research has suggested that the CeA may play a more dynamic role in fear learning. In particular, there is growing evidence that the CeA is a site of plasticity and memory formation, and that its activity is subject to tight regulation. The following review examines the evidence for these three main roles of the CeA as they relate to fear learning. The classical role of the CeA as a routing station to fear effector brain structures like the periaqueductal gray, the lateral hypothalamus, and paraventricular nucleus of the hypothalamus will be briefly reviewed, but specific emphasis is placed on recent literature suggesting that the CeA 1) has an important role in the plasticity underlying fear learning, 2) is involved in regulation of other amygdala subnuclei, and 3) is itself regulated by intra- and extra-amygdalar input. Finally, we discuss the parallels of human and mouse CeA involvement in fear disorders and fear conditioning, respectively. PMID:26328883
van Well, S.; Visser, R.M.; Scholte, H.S.; Kindt, M.
To provide insight into individual differences in fear learning, we examined the emotional and cognitive expressions of discriminative fear conditioning in direct relation to its neural substrates. Contrary to previous behavioral-neural (fMRI) research on fear learning—in which the emotional
Thrasher, Cat; LoBue, Vanessa
In the current research, we sought to measure infants' physiological responses to snakes-one of the world's most widely feared stimuli-to examine whether they find snakes aversive or merely attention grabbing. Using a similar method to DeLoache and LoBue (Developmental Science, 2009, Vol. 12, pp. 201-207), 6- to 9-month-olds watched a series of multimodal (both auditory and visual) stimuli: a video of a snake (fear-relevant) or an elephant (non-fear-relevant) paired with either a fearful or happy auditory track. We measured physiological responses to the pairs of stimuli, including startle magnitude, latency to startle, and heart rate. Results suggest that snakes capture infants' attention; infants showed the fastest startle responses and lowest average heart rate to the snakes, especially when paired with a fearful voice. Unexpectedly, they also showed significantly reduced startle magnitude during this same snake video plus fearful voice combination. The results are discussed with respect to theoretical perspectives on fear acquisition. Copyright © 2015 Elsevier Inc. All rights reserved.
The roles of the nucleus accumbens core, dorsomedial striatum, and dorsolateral striatum in learning: performance and extinction of Pavlovian fear-conditioned responses and instrumental avoidance responses.
Wendler, Etieli; Gaspar, Jessica C C; Ferreira, Tatiana L; Barbiero, Janaína K; Andreatini, Roberto; Vital, Maria A B F; Blaha, Charles D; Winn, Philip; Da Cunha, Claudio
This study examined the effects of bilateral excitotoxic lesions of the nucleus accumbens core (NAc-co), dorsomedial striatum (DMS) or dorsolateral striatum (DLS) of rats on the learning and extinction of Pavlovian and instrumental components of conditioned avoidance responses (CARs). None of the lesions caused sensorimotor deficits that could affect locomotion. Lesions of the NAc-co, but not DMS or DLS, decreased unconditioned and conditioned freezing. The NAc-co and DLS lesioned rats learned the 2-way active avoidance task more slowly. These results suggest: (i) CARs depend on both Pavlovian and instrumental learning; (ii) learning the Pavlovian component of CARs depends on the NAc-co; learning the instrumental component