Bupropion Dose-Dependently Reverses Nicotine Withdrawal Deficits in Contextual Fear Conditioning

PubMed Central

Portugal, George S.; Gould, Thomas J.

2007-01-01

Bupropion, a norepinephrine and dopamine reuptake inhibitor and nicotinic acetylcholine receptor antagonist, facilitates smoking cessation and reduces some symptoms of nicotine withdrawal. However, the effects of bupropion on nicotine withdrawal-associated deficits in learning remain unclear. The present study investigated whether bupropion has effects on contextual and cued fear conditioning following withdrawal from chronic nicotine or when administered alone. Bupropion was administered alone for a range of doses (2.5, 5, 10, 20 or 40 mg/kg), and dose-dependent impairments in contextual and cued fear conditioning were observed (20 or 40 mg/kg). Follow-up studies investigated if bupropion disrupted acquisition or expression of fear conditioning. Bupropion (40 mg/kg) administration on training day only produced deficits in contextual fear conditioning. Alternatively, bupropion (20 or 40 mg/kg) administration during testing dose-dependently produced deficits in contextual and cued fear conditioning. To test the effect of bupropion on nicotine withdrawal, mice were withdrawn from 12 days of chronic nicotine (6.3 mg/kg/day) or saline treatment. Withdrawal from chronic nicotine disrupted contextual fear conditioning; however, 5 mg/kg bupropion reversed this deficit. Overall, these results indicate that a low dose of bupropion can reverse nicotine withdrawal deficits in contextual fear conditioning, but that high doses of bupropion produce deficits in fear conditioning. PMID:17868796

Contextual and Auditory Fear Conditioning Continue to Emerge during the Periweaning Period in Rats

PubMed Central

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

2014-01-01

Anxiety disorders often emerge during childhood. Rodent models using classical fear conditioning have shown that different types of fear depend upon different neural structures and may emerge at different stages of development. For example, some work has suggested that contextual fear conditioning generally emerges later in development (postnatal day 23–24) than explicitly cued fear conditioning (postnatal day 15–17) in rats. This has been attributed to an inability of younger subjects to form a representation of the context due to an immature hippocampus. However, evidence that contextual fear can be observed in postnatal day 17 subjects and that cued fear conditioning continues to emerge past this age raises questions about the nature of this deficit. The current studies examine this question using both the context pre-exposure facilitation effect for immediate single-shock contextual fear conditioning and traditional cued fear conditioning using Sprague-Dawley rats. The data suggest that both cued and contextual fear conditioning are continuing to develop between PD 17 and 24, consistent with development occurring the in essential fear conditioning circuit. PMID:24977415

Effect of ablated hippocampal neurogenesis on the formation and extinction of contextual fear memory

PubMed Central

Ko, Hyoung-Gon; Jang, Deok-Jin; Son, Junehee; Kwak, Chuljung; Choi, Jun-Hyeok; Ji, Young-Hoon; Lee, Yun-Sil; Son, Hyeon; Kaang, Bong-Kiun

2009-01-01

Newborn neurons in the subgranular zone (SGZ) of the hippocampus incorporate into the dentate gyrus and mature. Numerous studies have focused on hippocampal neurogenesis because of its importance in learning and memory. However, it is largely unknown whether hippocampal neurogenesis is involved in memory extinction per se. Here, we sought to examine the possibility that hippocampal neurogenesis may play a critical role in the formation and extinction of hippocampus-dependent contextual fear memory. By methylazoxymethanol acetate (MAM) or gamma-ray irradiation, hippocampal neurogenesis was impaired in adult mice. Under our experimental conditions, only a severe impairment of hippocampal neurogenesis inhibited the formation of contextual fear memory. However, the extinction of contextual fear memory was not affected. These results suggest that although adult newborn neurons contribute to contextual fear memory, they may not be involved in the extinction or erasure of hippocampus-dependent contextual fear memory. PMID:19138433

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

PubMed

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

2015-10-01

Eph receptors regulate glutamate receptors functions, neuronal morphology and synaptic plasticity, cellular events believed to be involved in memory formation. In this study we aim to explore the roles of Eph receptors in learning and memory. Toward that end, we examined the roles of EphB2 and EphA4 receptors, key regulators of synaptic functions, in fear conditioning memory formation. We show that mice lacking EphB2 (EphB2(-/-)) are impaired in short- and long-term contextual fear conditioning memory. Mice that express a carboxy-terminally truncated form of EphB2 that lacks forward signaling, instead of the full EphB2, are impaired in long-term, but not short-term, contextual fear conditioning memory. Long-term contextual fear conditioning memory is attenuated in CaMKII-cre;EphA4(lx/-) mice where EphA4 is removed from all pyramidal neurons of the forebrain. Mutant mice with targeted kinase-dead EphA4 (EphA4(KD)) exhibit intact long-term contextual fear conditioning memory showing that EphA4 kinase-mediated forward signaling is not needed for contextual fear memory formation. The ability to form long-term conditioned taste aversion (CTA) memory is not impaired in the EphB2(-/-) and CaMKII-cre;EphA4(lx/-) mice. We conclude that EphB2 forward signaling is required for long-term contextual fear conditioning memory formation. In contrast, EphB2 mediates short-term contextual fear conditioning memory formation in a forward signaling-independent manner. EphA4 mediates long-term contextual fear conditioning memory formation in a kinase-independent manner. Copyright © 2015 Elsevier Inc. All rights reserved.

Evidence for Hippocampus-Dependent Contextual Learning at Postnatal Day 17 in the Rat

ERIC Educational Resources Information Center

Foster, Jennifer A.; Burman, Michael A.

2010-01-01

Long-term memory for fear of an environment (contextual fear conditioning) emerges later in development (postnatal day; PD 23) than long-term memory for fear of discrete stimuli (PD 17). As contextual, but not explicit cue, fear conditioning relies on the hippocampus; this has been interpreted as evidence that the hippocampus is not fully…

Increased Contextual Fear Conditioning in iNOS Knockout Mice: Additional Evidence for the Involvement of Nitric Oxide in Stress-Related Disorders and Contribution of the Endocannabinoid System

PubMed Central

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.

2015-01-01

Background: 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. Methods: 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. Results: 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. Conclusion: 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 increased. PMID:25618404

Estrogen modulates sexually dimorphic contextual fear extinction in rats through estrogen receptor beta.

PubMed

Chang, Yao-Ju; Yang, Chih-Hao; Liang, Ying-Ching; Yeh, Che-Ming; Huang, Chiung-Chun; Hsu, Kuei-Sen

2009-11-01

Females and males are different in brain and behavior. These sex differences occur early during development due to a combination of genetic and hormonal factors and continue throughout the lifespan. Previous studies revealed that male rats exhibited significantly higher levels of contextual fear memory than female rats. However, it remains unknown whether a sex difference exists in the contextual fear extinction. To address this issue, male, normally cycling female, and ovariectomized (OVX) female Sprague-Dawley rats were subjected to contextual fear conditioning and extinction trials. Here we report that although male rats exhibited higher levels of freezing than cycling female rats after contextual fear conditioning, female rats subjected to conditioning in the proestrus and estrus stage exhibited an enhancement of fear extinction than male rats. An estrogen receptor (ER) beta agonist diarylpropionitrile but not an ERalpha agonist propyl-pyrazole-triol administration also enhanced extinction of contextual fear in OVX female rats, suggesting that estrogen-mediated facilitation of extinction involves the activation of ERbeta. Intrahippocampal injection of estradiol or diarylpropionitrile before extinction training in OVX female rats remarkably reduced the levels of freezing response during extinction trials. In addition, the locomotion or anxiety state of female rats does not vary across the ovarian cycle. These results reveal a crucial role for estrogen in mediating sexually dimorphic contextual fear extinction, and that estrogen-mediated enhancement of fear extinction involves the activation of ERbeta.

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

PubMed

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

2015-01-01

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

Testing conditions in shock-based contextual fear conditioning influence both the behavioral responses and the activation of circuits potentially involved in contextual avoidance.

PubMed

Viellard, Juliette; Baldo, Marcus Vinicius C; Canteras, Newton Sabino

2016-12-15

Previous studies from our group have shown that risk assessment behaviors are the primary contextual fear responses to predatory and social threats, whereas freezing is the main contextual fear response to physically harmful events. To test contextual fear responses to a predator or aggressive conspecific threat, we developed a model that involves placing the animal in an apparatus where it can avoid the threat-associated environment. Conversely, in studies that use shock-based fear conditioning, the animals are usually confined inside the conditioning chamber during the contextual fear test. In the present study, we tested shock-based contextual fear responses using two different behavioral testing conditions: confining the animal in the conditioning chamber or placing the animal in an apparatus with free access to the conditioning compartment. Our results showed that during the contextual fear test, the animals confined to the shock chamber exhibited significantly more freezing. In contrast, the animals that could avoid the conditioning compartment displayed almost no freezing and exhibited risk assessment responses (i.e., crouch-sniff and stretch postures) and burying behavior. In addition, the animals that were able to avoid the shock chamber had increased Fos expression in the juxtadorsomedial lateral hypothalamic area, the dorsomedial part of the dorsal premammillary nucleus and the lateral and dorsomedial parts of the periaqueductal gray, which are elements of a septo/hippocampal-hypothalamic-brainstem circuit that is putatively involved in mediating contextual avoidance. Overall, the present findings show that testing conditions significantly influence both behavioral responses and the activation of circuits involved in contextual avoidance. Copyright © 2016 Elsevier B.V. All rights reserved.

Hypobaric hypoxia impairs cued and contextual fear memory in rats.

PubMed

Kumari, Punita; Kauser, Hina; Wadhwa, Meetu; Roy, Koustav; Alam, Shahnawaz; Sahu, Surajit; Kishore, Krishna; Ray, Koushik; Panjwani, Usha

2018-04-26

Fear memory is essential for survival, and its dysregulation leads to disorders. High altitude hypobaric hypoxia (HH) is known to induce cognitive decline. However, its effect on fear memory is still an enigma. We aimed to investigate the temporal effect of HH on fear conditioning and the underlying mechanism. Adult male Sprague-Dawley rats were trained for fear conditioning and exposed to simulated HH equivalent to 25,000 ft for different durations (1, 3, 7, 14 and 21 days). Subsequently, rats were tested for cued and contextual fear conditioning. Neuronal morphology, apoptosis and DNA fragmentation were studied in the medial prefrontal cortex (mPFC), hippocampus and basolateral amygdala (BLA). We observed significant deficit in cued and contextual fear acquisition (at 1, 3 and 7 days) and consolidation (cued at 1 and 3 days and contextual fear at 1, 3 and 7 days) under HH. HH exposure with retraining showed the earlier restoration of contextual fear memory. Further, we found a gradual increase in the number of pyknotic and apoptotic neurons together with the increase in DNA fragmentation in mPFC, hippocampus, and BLA up to 7 days of HH exposure. The present study concludes that HH exposure equivalent to 25000 ft induced cued and contextual fear memory deficit (acquisition and consolidation) which is found to be correlated with the neurodegenerative changes in the limbic brain regions. Copyright © 2018. Published by Elsevier B.V.

A dissociation between renewal and contextual fear conditioning in juvenile rats.

PubMed

Park, Chun Hui J; Ganella, Despina E; Kim, Jee Hyun

2017-05-01

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.

Chronic nicotine differentially alters spontaneous recovery of contextual fear in male and female mice.

PubMed

Tumolo, Jessica M; Kutlu, Munir Gunes; Gould, Thomas J

2018-04-02

Post-traumatic stress disorder (PTSD) is a devastating disorder with symptoms such as flashbacks, hyperarousal, and avoidance of reminders of the traumatic event. Exposure therapy, which attempts to extinguish fear responses, is a commonly used treatment for PTSD but relapse following successful exposure therapy is a frequent problem. In rodents, spontaneous recovery (SR), where extinguished fear responses resurface following extinction treatment, is used as a model of fear relapse. Previous studies from our lab showed that chronic nicotine impaired fear extinction and acute nicotine enhanced SR of contextual fear in adult male mice. In addition, we showed that acute nicotine's effects were specific to SR as acute nicotine did not affect recall of contextual fear conditioning in the absence of extinction. However, effects of chronic nicotine administration on SR are not known. Therefore, in the present study, we investigated if chronic nicotine administration altered SR or recall of contextual fear in adult male and female C57BL/6J mice. Our results showed that chronic nicotine significantly enhanced SR in female mice and significantly decreased SR in males. Chronic nicotine had no effect on recall of contextual fear in males or females. Female sham mice also had significantly less baseline SR than male sham mice. Overall, these results demonstrate sex differences in SR of fear memories and that chronic nicotine modulates these effects on SR but nicotine does not alter recall of contextual fear. Copyright © 2018 Elsevier B.V. All rights reserved.

Stability of Recent and Remote Contextual Fear Memory

ERIC Educational Resources Information Center

Frankland, Paul W.; Ding, Hoi-Ki; Takahashi, Eiki; Suzuki, Akinobu; Kida, Satoshi; Silva, Alcino J.

2006-01-01

Following initial encoding, memories undergo a prolonged period of reorganization. While such reorganization may occur in many different memory systems, its purpose is not clear. Previously, we have shown that recall of recent contextual fear memories engages the dorsal hippocampus (dHPC). In contrast, recall of remote contextual fear memories…

Differential Involvement of the Medial Prefrontal Cortex across Variants of Contextual Fear Conditioning

ERIC Educational Resources Information Center

Heroux, Nicholas A.; Robinson-Drummer, Patrese A.; Sanders, Hollie R.; Rosen, Jeffrey B.; Stanton, Mark E.

2017-01-01

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…

Systems Reconsolidation Reveals a Selective Role for the Anterior Cingulate Cortex in Generalized Contextual Fear Memory Expression

PubMed Central

Einarsson, Einar Ö; Pors, Jennifer; Nader, Karim

2015-01-01

After acquisition, hippocampus-dependent memories undergo a systems consolidation process, during which they become independent of the hippocampus and dependent on the anterior cingulate cortex (ACC) for memory expression. However, consolidated remote memories can become transiently hippocampus-dependent again following memory reactivation. How this systems reconsolidation affects the role of the ACC in remote memory expression is not known. Using contextual fear conditioning, we show that the expression of 30-day-old remote memory can transiently be supported by either the ACC or the dorsal hippocampus following memory reactivation, and that the ACC specifically mediates expression of remote generalized contextual fear memory. We found that suppression of neural activity in the ACC with the AMPA/kainate receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) impaired the expression of remote, but not recent, contextual fear memory. Fear expression was not affected by this treatment if preceded by memory reactivation 6 h earlier, nor was it affected by suppression of neural activity in the dorsal hippocampus with the GABA-receptor agonist muscimol. However, simultaneous targeting of both the ACC and the dorsal hippocampus 6 h after memory reactivation disrupted contextual fear memory expression. Second, we observed that expression of a 30-day-old generalized contextual fear memory in a novel context was not affected by memory reactivation 6 h earlier. However, intra-ACC CNQX infusion before testing impaired contextual fear expression in the novel context, but not the original training context. Together, these data suggest that although the dorsal hippocampus may be recruited during systems reconsolidation, the ACC remains necessary for the expression of generalized contextual fear memory. PMID:25091528

Systems reconsolidation reveals a selective role for the anterior cingulate cortex in generalized contextual fear memory expression.

PubMed

Einarsson, Einar Ö; Pors, Jennifer; Nader, Karim

2015-01-01

After acquisition, hippocampus-dependent memories undergo a systems consolidation process, during which they become independent of the hippocampus and dependent on the anterior cingulate cortex (ACC) for memory expression. However, consolidated remote memories can become transiently hippocampus-dependent again following memory reactivation. How this systems reconsolidation affects the role of the ACC in remote memory expression is not known. Using contextual fear conditioning, we show that the expression of 30-day-old remote memory can transiently be supported by either the ACC or the dorsal hippocampus following memory reactivation, and that the ACC specifically mediates expression of remote generalized contextual fear memory. We found that suppression of neural activity in the ACC with the AMPA/kainate receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) impaired the expression of remote, but not recent, contextual fear memory. Fear expression was not affected by this treatment if preceded by memory reactivation 6 h earlier, nor was it affected by suppression of neural activity in the dorsal hippocampus with the GABA-receptor agonist muscimol. However, simultaneous targeting of both the ACC and the dorsal hippocampus 6 h after memory reactivation disrupted contextual fear memory expression. Second, we observed that expression of a 30-day-old generalized contextual fear memory in a novel context was not affected by memory reactivation 6 h earlier. However, intra-ACC CNQX infusion before testing impaired contextual fear expression in the novel context, but not the original training context. Together, these data suggest that although the dorsal hippocampus may be recruited during systems reconsolidation, the ACC remains necessary for the expression of generalized contextual fear memory.

Impairment of contextual fear extinction by chronic nicotine and withdrawal from chronic nicotine is associated with hippocampal nAChR upregulation

PubMed Central

Kutlu, Munir Gunes; Oliver, Chicora; Huang, Peng; Liu-Chen, Lee-Yuan; Gould, Thomas J.

2017-01-01

Chronic nicotine and withdrawal from chronic nicotine have been shown to be major modulators of fear learning behavior. Moreover, recent studies from our laboratory have shown that acute nicotine impaired fear extinction and safety learning in mice. However, the effects of chronic nicotine and withdrawal on fear extinction are unknown. Therefore, the current experiments were conducted to investigate the effects of chronic nicotine as well as withdrawal from chronic nicotine on contextual fear extinction in mice. C57BL6/J mice were given contextual fear conditioning training and retention testing during chronic nicotine administration. Mice then received contextual fear extinction either during chronic nicotine or during withdrawal from chronic nicotine. Our results showed that contextual fear extinction was impaired both during chronic nicotine administration and subsequent withdrawal. However, it was also observed that the effects of prior chronic nicotine disappeared after 72 h in withdrawal, a timeline that closely matches with the timing of the chronic nicotine-induced upregulation of hippocampal nicotinic acetylcholine receptor (nAChR) density. Additional experiments found that 4 days, but not 1 day, of continuous nicotine administration upregulated hippocampal nAChRs and impaired contextual fear extinction. These effects disappeared following 72 h withdrawal. Overall, these experiments provide a potential link between nicotine-induced upregulation of hippocampal nAChRs and fear extinction deficits observed in patients with anxiety disorders, which may lead to advancements in the pharmacological treatment methods for this disorder. PMID:27378334

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

PubMed

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

2012-03-17

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

Unilateral hippocampal inactivation or lesion selectively impairs remote contextual fear memory.

PubMed

Zhou, Heng; Zhou, Qixin; Xu, Lin

2016-10-01

Contextual fear memory depends on the hippocampus, but the role of unilateral hippocampus in this type of memory remains unclear. Herein, pharmacological inactivation or excitotoxic lesions were used to study the role of unilateral hippocampus in the stages of contextual fear memory. The pharmacological experiments revealed that compared with the control groups, unilateral hippocampal blockade did not impair 1-day recent memory following learning, whereas bilateral hippocampal blockade significantly impaired this memory. The lesion experiments showed that compared with the control groups, the formed contextual fear memory was retained for 7 days and that 30-day remote memory was markedly reduced in unilateral hippocampal lesion groups. These results indicate that an intact bilateral hippocampus is required for the formation of remote memory and that unilateral hippocampus is sufficient for recent contextual fear memory.

Effects of Long-Term Ayahuasca Administration on Memory and Anxiety in Rats

PubMed Central

Favaro, Vanessa Manchim; Yonamine, Maurício; Soares, Juliana Carlota Kramer; Oliveira, Maria Gabriela Menezes

2015-01-01

Ayahuasca is a hallucinogenic beverage that combines the action of the 5-HT2A/2C agonist N,N-dimethyltryptamine (DMT) from Psychotria viridis with the monoamine oxidase inhibitors (MAOIs) induced by beta-carbonyls from Banisteriopsis caapi. Previous investigations have highlighted the involvement of ayahuasca with the activation of brain regions known to be involved with episodic memory, contextual associations and emotional processing after ayahuasca ingestion. Moreover long term users show better performance in neuropsychological tests when tested in off-drug condition. This study evaluated the effects of long-term administration of ayahuasca on Morris water maze (MWM), fear conditioning and elevated plus maze (EPM) performance in rats. Behavior tests started 48h after the end of treatment. Freeze-dried ayahuasca doses of 120, 240 and 480 mg/kg were used, with water as the control. Long-term administration consisted of a daily oral dose for 30 days by gavage. The behavioral data indicated that long-term ayahuasca administration did not affect the performance of animals in MWM and EPM tasks. However the dose of 120 mg/kg increased the contextual conditioned fear response for both background and foreground fear conditioning. The tone conditioned response was not affected after long-term administration. In addition, the increase in the contextual fear response was maintained during the repeated sessions several weeks after training. Taken together, these data showed that long-term ayahuasca administration in rats can interfere with the contextual association of emotional events, which is in agreement with the fact that the beverage activates brain areas related to these processes. PMID:26716991

Effects of Long-Term Ayahuasca Administration on Memory and Anxiety in Rats.

PubMed

Favaro, Vanessa Manchim; Yonamine, Maurício; Soares, Juliana Carlota Kramer; Oliveira, Maria Gabriela Menezes

2015-01-01

Ayahuasca is a hallucinogenic beverage that combines the action of the 5-HT2A/2C agonist N,N-dimethyltryptamine (DMT) from Psychotria viridis with the monoamine oxidase inhibitors (MAOIs) induced by beta-carbonyls from Banisteriopsis caapi. Previous investigations have highlighted the involvement of ayahuasca with the activation of brain regions known to be involved with episodic memory, contextual associations and emotional processing after ayahuasca ingestion. Moreover long term users show better performance in neuropsychological tests when tested in off-drug condition. This study evaluated the effects of long-term administration of ayahuasca on Morris water maze (MWM), fear conditioning and elevated plus maze (EPM) performance in rats. Behavior tests started 48h after the end of treatment. Freeze-dried ayahuasca doses of 120, 240 and 480 mg/kg were used, with water as the control. Long-term administration consisted of a daily oral dose for 30 days by gavage. The behavioral data indicated that long-term ayahuasca administration did not affect the performance of animals in MWM and EPM tasks. However the dose of 120 mg/kg increased the contextual conditioned fear response for both background and foreground fear conditioning. The tone conditioned response was not affected after long-term administration. In addition, the increase in the contextual fear response was maintained during the repeated sessions several weeks after training. Taken together, these data showed that long-term ayahuasca administration in rats can interfere with the contextual association of emotional events, which is in agreement with the fact that the beverage activates brain areas related to these processes.

Effects of 7-nitroindazole, a selective neural nitric oxide synthase inhibitor, on context-shock associative learning in a two-process contextual fear conditioning paradigm.

PubMed

Chen, Weihai; Yan, Minmin; Wang, Yan; Wang, Xiaqing; Yuan, Jiajin; Li, Ming

2016-10-01

Nitric oxide (NO) is an important retrograde neuronal intracellular messenger which plays an important role in synaptic plasticity and is involved in learning and memory. However, evidence that NO is particularly important for the acquisition of contextual fear conditioning is mixed. Also, little is known about at which stages of the contextual fear conditioning does NO make its contribution. In the present study, we used 7-nitroindazole to temporarily inhibit neural nitric oxide synthase at either the pre-exposure stage or conditioning stage in a two-process paradigm and examined the potential contribution that NO makes to the contextually conditioned fear. Results showed that the expression of contextual fear memory was significantly impaired in rats treated with 7-nitroindazole (30mg/kg, i.p.) prior to the pairing of context-shock (p=0.034, n=8), but not after the conditioning phase (p=0.846, n=8). In addition, the expression of contextual fear memory and reconsolidation was not significantly impaired by 7-nitroindazole administered prior to the context pre-exposure stage or prior to another context-shock learning. These findings suggest that NO is specifically involved in the acquisition but not the consolidation, retrieval or reconsolidation of contextual fear memory. Copyright © 2016 Elsevier Inc. All rights reserved.

Repeated Recall and PKM? Maintain Fear Memories in Juvenile Rats

ERIC Educational Resources Information Center

Oliver, Chicora F.; Kabitzke, Patricia; Serrano, Peter; Egan, Laura J.; Barr, Gordon A.; Shair, Harry N.; Wiedenmayer, Christoph

2016-01-01

We examined the neural substrates of fear memory formation and maintenance when repeated recall was used to prevent forgetting in young animals. In contrast to adult rats, juveniles failed to show contextual fear responses at 4 d post-fear conditioning. Reconsolidation sessions 3 and 6 d after conditioning restored contextual fear responses in…

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

ERIC Educational Resources Information Center

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

2013-01-01

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

Post-Training Unilateral Amygdala Lesions Selectively Impair Contextual Fear Memories

ERIC Educational Resources Information Center

Flavell, Charlotte R.; Lee, Jonathan L. C.

2012-01-01

The basolateral amygdala (BLA) and the dorsal hippocampus (dHPC) are both structures with key roles in contextual fear conditioning. During fear conditioning, it is postulated that contextual representations of the environment are formed in the hippocampus, which are then associated with foot shock in the amygdala. However, it is not known to what…

Threatening social context facilitates pain-related fear learning.

PubMed

Karos, Kai; Meulders, Ann; Vlaeyen, Johan W S

2015-03-01

This study investigated the effects of a threatening and a safe social context on learning pain-related fear, a key factor in the development and maintenance of chronic pain. We measured self-reported pain intensity, pain expectancy, pain-related fear (verbal ratings and eyeblink startle responses), and behavioral measures of avoidance (movement-onset latency and duration) using an established differential voluntary movement fear conditioning paradigm. Participants (N = 42) performed different movements with a joystick: during fear acquisition, movement in one direction (CS+) was followed by a painful stimulus (pain-US) whereas movement in another direction (CS-) was not. For participants in the threat group, an angry face was continuously presented in the background during the task, whereas in the safe group, a happy face was presented. During the extinction phase the pain-US was omitted. As compared to the safe social context, a threatening social context led to increased contextual fear and facilitated differentiation between CS+ and CS- movements regarding self-reported pain expectancy, fear of pain, eyeblink startle responses, and movement-onset latency. In contrast, self-reported pain intensity was not affected by social context. These data support the modulation of pain-related fear by social context. A threatening social context leads to stronger acquisition of (pain-related) fear and simultaneous contextual fear but does not affect pain intensity ratings. This knowledge may aid in the prevention of chronic pain and anxiety disorders and shows that social context might modulate pain-related fear without immediately affecting pain intensity itself. Copyright © 2015 American Pain Society. Published by Elsevier Inc. All rights reserved.

Impairment of contextual fear extinction by chronic nicotine and withdrawal from chronic nicotine is associated with hippocampal nAChR upregulation.

PubMed

Kutlu, Munir Gunes; Oliver, Chicora; Huang, Peng; Liu-Chen, Lee-Yuan; Gould, Thomas J

2016-10-01

Chronic nicotine and withdrawal from chronic nicotine have been shown to be major modulators of fear learning behavior. Moreover, recent studies from our laboratory have shown that acute nicotine impaired fear extinction and safety learning in mice. However, the effects of chronic nicotine and withdrawal on fear extinction are unknown. Therefore, the current experiments were conducted to investigate the effects of chronic nicotine as well as withdrawal from chronic nicotine on contextual fear extinction in mice. C57BL6/J mice were given contextual fear conditioning training and retention testing during chronic nicotine administration. Mice then received contextual fear extinction either during chronic nicotine or during withdrawal from chronic nicotine. Our results showed that contextual fear extinction was impaired both during chronic nicotine administration and subsequent withdrawal. However, it was also observed that the effects of prior chronic nicotine disappeared after 72 h in withdrawal, a timeline that closely matches with the timing of the chronic nicotine-induced upregulation of hippocampal nicotinic acetylcholine receptor (nAChR) density. Additional experiments found that 4 days, but not 1 day, of continuous nicotine administration upregulated hippocampal nAChRs and impaired contextual fear extinction. These effects disappeared following 72 h withdrawal. Overall, these experiments provide a potential link between nicotine-induced upregulation of hippocampal nAChRs and fear extinction deficits observed in patients with anxiety disorders, which may lead to advancements in the pharmacological treatment methods for this disorder. Copyright © 2016 Elsevier Ltd. All rights reserved.

Extinction of Contextual Fear with Timed Exposure to Enriched Environment: A Differential Effect

PubMed Central

Hegde, Preethi; O'Mara, Shane; Laxmi, Thenkanidiyoor Rao

2017-01-01

Background Extinction of fear memory depends on the environmental and emotional cues. Furthermore, consolidation of extinction is also dependent on the environmental exposure. But, the relationship of the time of the exposure to a variety of environmental cues is not well known. The important region involved in facilitation of extinction of fear memory is through diversion of the flow of information leaving the lateral nucleus of amygdala. Purpose The study aimed to address a question to explain how these brain regions react to environmental stimulation during the retention and extinction of fear memory. Methods An enriched environment (EE) is assumed to mediate extinction of fear memory, we examined the apparent discrepancy between the effects of defensive response, the freezing behavior induced by Pavlovian classical fear conditioning by subjecting them to variance in the timing to EE. The different timing of EE exposure was 10 days of EE either before fear conditioning and/or after extinction training to the rats. The local field potentials was recorded from CA1 hippocampus, lateral nucleus of amygdala and infralimbic region of medial prefrontal cortex (mPFC) during the fear learning and extinction from the control rats and rats exposed to EE before and after fear conditioning. Results Exposure to EE before the fear conditioning and after extinction training was more effective in the extinction fear memory. In addition, we also found switching from exploratory locomotion to freezing during retention of contextual fear memory which was associated with decreased theta power and reduced synchronized theta oscillations in CA1-hippocampus, lateral nucleus of amygdala, and infralimbic region of mPFC. Conclusion Thus, we propose that the timing of exposure to EE play a key role in the extinction of fear memory. PMID:28588364

Modulation of contextual fear conditioning by chronic stress in rats is related to individual differences in behavioral reactivity to novelty.

PubMed

Cordero, M Isabel; Kruyt, Nyika D; Sandi, Carmen

2003-04-25

We investigated whether contextual fear conditioning could be related to the behavioral trait of locomotor reactivity to novelty in undisturbed and chronically stressed rats. Fear conditioning was found to be specifically enhanced in low reactive-stressed animals, as compared to low reactive-undisturbed rats. The results suggest that individuals that display low reactivity to novelty are more susceptible to be influenced by stress exposure to subsequently exhibit potentiated contextual fear conditioning.

Social appraisal influences recognition of emotions.

PubMed

Mumenthaler, Christian; Sander, David

2012-06-01

The notion of social appraisal emphasizes the importance of a social dimension in appraisal theories of emotion by proposing that the way an individual appraises an event is influenced by the way other individuals appraise and feel about the same event. This study directly tested this proposal by asking participants to recognize dynamic facial expressions of emotion (fear, happiness, or anger in Experiment 1; fear, happiness, anger, or neutral in Experiment 2) in a target face presented at the center of a screen while a contextual face, which appeared simultaneously in the periphery of the screen, expressed an emotion (fear, happiness, anger) or not (neutral) and either looked at the target face or not. We manipulated gaze direction to be able to distinguish between a mere contextual effect (gaze away from both the target face and the participant) and a specific social appraisal effect (gaze toward the target face). Results of both experiments provided evidence for a social appraisal effect in emotion recognition, which differed from the mere effect of contextual information: Whereas facial expressions were identical in both conditions, the direction of the gaze of the contextual face influenced emotion recognition. Social appraisal facilitated the recognition of anger, happiness, and fear when the contextual face expressed the same emotion. This facilitation was stronger than the mere contextual effect. Social appraisal also allowed better recognition of fear when the contextual face expressed anger and better recognition of anger when the contextual face expressed fear. 2012 APA, all rights reserved

Gadd45b knockout mice exhibit selective deficits in hippocampus-dependent long-term memory

PubMed Central

Leach, Prescott T.; Poplawski, Shane G.; Kenney, Justin W.; Hoffman, Barbara; Liebermann, Dan A.; Abel, Ted; Gould, Thomas J.

2012-01-01

Growth arrest and DNA damage-inducible β (Gadd45b) has been shown to be involved in DNA demethylation and may be important for cognitive processes. Gadd45b is abnormally expressed in subjects with autism and psychosis, two disorders associated with cognitive deficits. Furthermore, several high-throughput screens have identified Gadd45b as a candidate plasticity-related gene. However, a direct demonstration of a link between Gadd45b and memory has not been established. The current studies first determined whether expression of the Gadd45 family of genes was affected by contextual fear conditioning. Gadd45b, and to a lesser extent Gadd45g, were up-regulated in the hippocampus following contextual fear conditioning, whereas Gadd45a was not. Next, Gadd45b knockout mice were tested for contextual and cued fear conditioning. Gadd45b knockout mice exhibited a significant deficit in long-term contextual fear conditioning; however, they displayed normal levels of short-term contextual fear conditioning. No differences between Gadd45b knockout and wild-type mice were observed in cued fear conditioning. Because cued fear conditioning is hippocampus independent, while contextual fear conditioning is hippocampus dependent, the current studies suggest that Gadd45b may be important for long-term hippocampus-dependent memory storage. Therefore, Gadd45b may be a novel therapeutic target for the cognitive deficits associated with many neurodevelopmental, neurological, and psychiatric disorders. PMID:22802593

Tyrosine receptor kinase B receptor activation reverses the impairing effects of acute nicotine on contextual fear extinction.

PubMed

Kutlu, Munir Gunes; Cole, Robert D; Connor, David A; Natwora, Brendan; Gould, Thomas J

2018-03-01

Anxiety and stress disorders have been linked to deficits in fear extinction. Our laboratory and others have demonstrated that acute nicotine impairs contextual fear extinction, suggesting that nicotine exposure may have negative effects on anxiety and stress disorder symptomatology. However, the neurobiological mechanisms underlying the acute nicotine-induced impairment of contextual fear extinction are unknown. Therefore, based on the previous studies showing that brain-derived neurotrophic factor is central for fear extinction learning and acute nicotine dysregulates brain-derived neurotrophic factor signaling, we hypothesized that the nicotine-induced impairment of contextual fear extinction may involve changes in tyrosine receptor kinase B signaling. To test this hypothesis, we systemically, intraperitoneally, injected C57BL/6J mice sub-threshold doses (2.5 and 4.0 mg/kg) of 7,8-dihydroxyflavone, a small-molecule tyrosine receptor kinase B agonist that fully mimics the effects of brain-derived neurotrophic factor, or vehicle an hour before each contextual fear extinction session. Mice also received injections, intraperitoneally, of acute nicotine (0.18 mg/kg) or saline 2-4 min before extinction sessions. While the animals that received only 7,8-dihydroxyflavone did not show any changes in contextual fear extinction, 4.0 mg/kg of 7,8-dihydroxyflavone ameliorated the extinction deficits in mice administered acute nicotine. Overall, these results suggest that acute nicotine-induced impairment of context extinction may be related to a disrupted brain-derived neurotrophic factor signaling.

Acute nicotine disrupts consolidation of contextual fear extinction and alters long-term memory-associated hippocampal kinase activity.

PubMed

Kutlu, Munir Gunes; Garrett, Brendan; Gadiwalla, Sana; Tumolo, Jessica M; Gould, Thomas J

2017-11-01

Previous research has shown that acute nicotine, an agonist of nAChRs, impaired fear extinction. However, the effects of acute nicotine on consolidation of contextual fear extinction memories and associated cell signaling cascades are unknown. Therefore, we examined the effects of acute nicotine injections before (pre-extinction) and after (post-extinction) contextual fear extinction on behavior and the phosphorylation of dorsal and ventral hippocampal ERK1/2 and JNK1 and protein levels on the 1st and 3rd day of extinction. Our results showed that acute nicotine administered prior to extinction sessions downregulated the phosphorylated forms of ERK1/2 in the ventral hippocampus, but not dorsal hippocampus, and JNK1 in both dorsal and ventral hippocampus on the 3rd extinction day. These effects were absent on the 1st day of extinction. We also showed that acute nicotine administered immediately and 30 min, but not 6 h, following extinction impaired contextual fear extinction suggesting that acute nicotine disrupts consolidation of contextual fear extinction memories. Finally, acute nicotine injections immediately after extinction sessions upregulated the phosphorylated forms of ERK1/2 in the ventral hippocampus, but did not affect JNK1. These results show that acute nicotine impairs contextual fear extinction potentially by altering molecular processes responsible for the consolidation of extinction memories. Copyright © 2017 Elsevier Inc. All rights reserved.

Involvement of the prelimbic cortex in contextual fear conditioning with temporal and spatial discontinuity.

PubMed

Santos, Thays Brenner; Kramer-Soares, Juliana Carlota; Favaro, Vanessa Manchim; Oliveira, Maria Gabriela Menezes

2017-10-01

Time plays an important role in conditioning, it is not only possible to associate stimuli with events that overlap, as in delay fear conditioning, but it is also possible to associate stimuli that are discontinuous in time, as shown in trace conditioning for a discrete stimuli. The environment itself can be a powerful conditioned stimulus (CS) and be associated to unconditioned stimulus (US). Thus, the aim of the present study was to determine the parameters in which contextual fear conditioning occurs by the maintenance of a contextual representation over short and long time intervals. The results showed that a contextual representation can be maintained and associated after 5s, even in the absence of a 15s re-exposure to the training context before US delivery. The same effect was not observed with a 24h interval of discontinuity. Furthermore, optimal conditioned response with a 5s interval is produced only when the contexts (of pre-exposure and shock) match. As the pre-limbic cortex (PL) is necessary for the maintenance of a continuous representation of a stimulus, the involvement of the PL in this temporal and contextual processing was investigated. The reversible inactivation of the PL by muscimol infusion impaired the acquisition of contextual fear conditioning with a 5s interval, but not with a 24h interval, and did not impair delay fear conditioning. The data provided evidence that short and long intervals of discontinuity have different mechanisms, thus contributing to a better understanding of PL involvement in contextual fear conditioning and providing a model that considers both temporal and contextual factors in fear conditioning. Copyright © 2017 Elsevier Inc. All rights reserved.

Hippocampal GABAB(1a) Receptors Constrain Generalized Contextual Fear

PubMed Central

Lynch, Joseph F; Winiecki, Patrick; Gilman, T Lee; Adkins, Jordan M; Jasnow, Aaron M

2017-01-01

Many anxiety disorders are characterized by generalization of fear responses to neutral or ambiguous stimuli. Therefore, a comprehensive understanding of the mechanisms contributing to generalized fear is essential for formulating successful treatments for anxiety disorders. Previous research shows that GABA-mediated presynaptic inhibition has a critical role in cued fear generalization, as animals with genetically deleted presynaptic GABAB(1a) receptors cannot discriminate between CS+ and CS− tones. Work from our laboratory has further identified that GABAB(1a) receptors are necessary for maintaining contextual memory precision, thereby constraining generalized contextual fear. We previously found that GABAB(1a) KO mice show generalized fear to a neutral context 24 h after training, but not 2 h after training. A similar pattern was observed with object location and recognition, suggesting that this receptor subtype affects consolidation and/or retrieval of precise contextual and spatial memories. Here we sought to specifically examine the involvement of GABAB(1a) receptors in consolidation or retrieval of a precise fear memory. To do so, we infused a selective GABAB(1a) receptor antagonist, CGP 36216, intracerebroventricularly (ICV), or locally into the dorsal hippocampus, ventral hippocampus, or anterior cingulate cortex (ACC), during consolidation and retrieval of context fear training. Blockade of GABAB(1a) receptors through ICV, dorsal hippocampal, or ventral hippocampal infusions ‘after' training (consolidation) resulted in fear generalization to the neutral context when mice were tested 24, but not 6 h after training. Post-training infusions of CGP into the ACC, however, did not promote generalized fear. In addition, ICV, dorsal hippocampal, ventral hippocampal, or ACC infusions immediately ‘before' testing (retrieval) did not result in context fear generalization. These data suggest that GABA-mediated presynaptic inhibition is not critical for retrieval of precise contextual memory, but rather has an important role in the long-term consolidation of precise contextual memories and constrains generalized fear responses. PMID:27834391

TBI-Induced Formation of Toxic Tau and Its Biochemical Similarities to Tau in AD Brains

DTIC Science & Technology

2016-10-01

onto wild-type mice markedly reduces 1) memory including contextual fear memory and spatial memory, and 2) long-term potentiation, a type of...TERMS Tau, contextual fear memory, spatial memory, synaptic plasticity, traumatic brain injury, Alzheimer’s disease 16. SECURITY CLASSIFICATION OF: 17...mechanism leading to TBI and AD. 2 KEYWORDS Tau, contextual fear memory, spatial memory, synaptic plasticity, traumatic brain injury, Alzheimer’s

Novel cage stress alters remote contextual fear extinction and regional T2 magnetic resonance relaxation times in TASTPM mice overexpressing amyloid.

PubMed

Rattray, Ivan; Pitiot, Alain; Lowe, James; Auer, Dorothee P; Lima, Sarah-Jane; Schubert, Mirjam I; Prior, Malcolm J W; Marsden, Charles A; Diaz, Fernando Pérez; Kendall, David A; Pardon, Marie-Christine

2010-01-01

We have previously shown that repeated exposure to mild novel cage stress prevents the onset of recent contextual fear memory deficits and attenuated amyloid deposition in the TASTPM mouse model of Alzheimer's disease. Here, we extended this investigation to remote contextual fear memory and extinction. TASTPM and wild-type mice acquired contextual fear at 4 months of age. Retention and extinction of contextual fear were assessed at 5.5 months prior to in vivo MRI assessment of regional T2 relaxation times and brain volumes followed by immunostaining to determine amyloid plaque load. Remote contextual fear memory was preserved in TASTPM mice regardless of the stress condition. Stress impaired extinction in wild-type mice but facilitated this process in TASTPM mice. Genotype-dependent effects of stress were observed on regional T2 times which were prolonged in the subiculum and thalamus of stressed TASTPM, possibly reflecting reduced amyloid pathology. Amyloid plaque load was particularly decreased in the retrosplenial cortex of stressed TASTPM mice, which also showed an overall reduction in the number of diffuse plaques. These findings support the hypothesis that repeated mild levels of stress induced by novel activities can delay the progression of pathological changes relevant to Alzheimer's disease.

A Key Role for Nectin-1 in the Ventral Hippocampus in Contextual Fear Memory

PubMed Central

Grosse, Jocelyn; Krummenacher, Claude; Sandi, Carmen

2013-01-01

Nectins are cell adhesion molecules that are widely expressed in the brain. Nectin expression shows a dynamic spatiotemporal regulation, playing a role in neural migratory processes during development. Nectin-1 and nectin-3 and their heterophilic trans-interactions are important for the proper formation of synapses. In the hippocampus, nectin-1 and nectin-3 localize at puncta adherentia junctions and may play a role in synaptic plasticity, a mechanism essential for memory and learning. We evaluated the potential involvement of nectin-1 and nectin-3 in memory consolidation using an emotional learning paradigm. Rats trained for contextual fear conditioning showed transient nectin-1—but not nectin-3—protein upregulation in synapse-enriched hippocampal fractions at about 2 h posttraining. The upregulation of nectin-1 was found exclusively in the ventral hippocampus and was apparent in the synaptoneurosomal fraction. This upregulation was induced by contextual fear conditioning but not by exposure to context or shock alone. When an antibody against nectin-1, R165, was infused in the ventral-hippocampus immediately after training, contextual fear memory was impaired. However, treatment with the antibody in the dorsal hippocampus had no effect in contextual fear memory formation. Similarly, treatment with the antibody in the ventral hippocampus did not interfere with acoustic memory formation. Further control experiments indicated that the effects of ventral hippocampal infusion of the nectin-1 antibody in contextual fear memory cannot be ascribed to memory non-specific effects such as changes in anxiety-like behavior or locomotor behavior. Therefore, we conclude that nectin-1 recruitment to the perisynaptic environment in the ventral hippocampus plays an important role in the formation of contextual fear memories. Our results suggest that these mechanisms could be involved in the connection of emotional and contextual information processed in the amygdala and dorsal hippocampus, respectively, thus opening new venues for the development of treatments to psychopathological alterations linked to impaired contextualization of emotions. PMID:23418609

Effects of the beta-blocker propranolol on cued and contextual fear conditioning in humans.

PubMed

Grillon, Christian; Cordova, Jeremy; Morgan, Charles Andrew; Charney, Dennis S; Davis, Michael

2004-09-01

Beta-adrenergic receptors are involved in the consolidation of emotional memories. Yet, a number of studies using Pavlovian cued fear conditioning have been unable to demonstrate an effect of beta-adrenergic blockade on acquisition or retention of fear conditioning. Evidence for the involvement of beta-adrenergic receptors in emotional memories comes mostly from studies using fear inhibitory avoidance in rodents. It is possible that fear inhibitory avoidance is more akin to contextual conditioning than to cued fear conditioning, suggesting that context conditioning may be disrupted by beta-adrenergic blockade. This study investigated the effects of the beta-adrenergic blocker propranolol on cued and contextual fear conditioning in humans. Subjects were given either placebo (n=15) or 40 mg propranolol (n=15) prior to differential cued conditioning. A week later, they were tested for retention of context and cued fear conditioning using physiological (startle reflex and electrodermal activity) and subjective measures of emotional arousal. The results were consistent with the hypothesis. The skin conductance level (SCL) and the subjective measure of arousal suggested reduced emotional arousal upon returning to the conditioning context in the propranolol group, compared to the placebo group. The acquisition and retention of cued fear conditioning were not affected by propranolol. These results suggest that beta-adrenergic receptors are involved in contextual fear conditioning.

Impaired contextual fear extinction and hippocampal synaptic plasticity in adult rats induced by prenatal morphine exposure.

PubMed

Tan, Ji-Wei; Duan, Ting-Ting; Zhou, Qi-Xin; Ding, Ze-Yang; Jing, Liang; Cao, Jun; Wang, Li-Ping; Mao, Rong-Rong; Xu, Lin

2015-07-01

Prenatal opiate exposure causes a series of neurobehavioral disturbances by affecting brain development. However, the question of whether prenatal opiate exposure increases vulnerability to memory-related neuropsychiatric disorders in adult offspring remains largely unknown. Here, we found that rats prenatally exposed to morphine (PM) showed impaired acquisition but enhanced maintenance of contextual fear memory compared with control animals that were prenatally exposed to saline (PS). The impairment of acquisition was rescued by increasing the intensity of footshocks (1.2 mA rather than 0.8 mA). Meanwhile, we also found that PM rats exhibited impaired extinction of contextual fear, which is associated with enhanced maintenance of fear memory. The impaired extinction lasted for 1 week following extinction training. Furthermore, PM rats exhibited reduced anxiety-like behavior in the elevated plus-maze and light/dark box test without differences in locomotor activity. These alterations in PM rats were mirrored by abnormalities in synaptic plasticity in the Schaffer collateral-CA1 synapses of the hippocampus in vivo. PS rats showed blocked long-term potentiation and enabled long-term depression in CA1 synapses following contextual fear conditioning, while prenatal morphine exposure restricted synaptic plasticity in CA1 synapses. The smaller long-term potentiation in PM rats was not further blocked by contextual fear conditioning, and the long-term depression enabled by contextual fear conditioning was abolished. Taken together, our results provide the first evidence suggesting that prenatal morphine exposure may increase vulnerability to fear memory-related neuropsychiatric disorders in adulthood. © 2014 Society for the Study of Addiction.

The Central Nucleus of the Amygdala and Corticotropin-Releasing Factor: Insights into Contextual Fear Memory

PubMed Central

Pitts, Matthew W.; Todorovic, Cedomir; Blank, Thomas; Takahashi, Lorey K.

2009-01-01

The central nucleus of the amygdala (CeA) has been traditionally viewed in fear conditioning to serve as an output neural center that transfers conditioned information formed in the basolateral amygdala to brain structures that generate emotional responses. Recent studies suggest that the CeA may also be involved in fear memory consolidation. In addition, corticotropin-releasing factor systems were shown to facilitate memory consolidation in the amygdala, which contains a high density of CRF immunoreactive cell bodies and fibers in the lateral part of the CeA (CeAl). However, the involvement of CeA CRF in contextual fear conditioning remains poorly understood. Therefore, we first conducted a series of studies using fiber-sparing lesion and reversible inactivation methods to assess the general role of the CeA in contextual fear. We then used identical training and testing procedures to compare and evaluate the specific function of CeA CRF using CRF antisense oligonucleotides (CRF ASO). Rats microinjected with ibotenic acid, muscimol, or a CRF ASO into the CeA prior to contextual fear conditioning showed typical levels of freezing during acquisition training but exhibited significant reductions in contextual freezing in a retention test 48 h later. Furthermore, CeA inactivation induced by either muscimol or CRF ASO administration immediately prior to retention testing did not impair freezing, suggesting that the previously observed retention deficits were due to inhibition of consolidation rather than fear expression. Collectively, our results suggest CeA involvement in the consolidation of contextual fear memory and specifically implicate CeA CRF as an important mediator. PMID:19494159

Lifelong disturbance of serotonin transporter functioning results in fear learning deficits: Reversal by blockade of CRF1 receptors.

PubMed

Bijlsma, Elisabeth Y; Hendriksen, Hendrikus; Baas, Johanna M P; Millan, Mark J; Groenink, Lucianne

2015-10-01

The inability to associate aversive events with relevant cues (i.e. fear learning) may lead to maladaptive anxiety. To further study the role of the serotonin transporter (SERT) in fear learning, classical fear conditioning was studied in SERT knockout rats (SERT(-/-)) using fear potentiation of the startle reflex. Next, fear acquisition and concomitant development of contextual conditioned fear were monitored during training. To differentiate between developmental and direct effects of reduced SERT functioning, effects of acute and chronic SSRI treatment were studied in adult rats. Considering the known interactions between serotonin and corticotropin-releasing factor (CRF), we studied the effect of the CRFR1 antagonist CP154,526 on behavioral changes observed and determined CRF1 receptor levels in SERT(-/-) rats. SERT(-/-) showed blunted fear potentiation and enhanced contextual fear, which resulted from a deficit in fear acquisition. Paroxetine treatment did not affect acquisition or expression of fear-potentiated startle, suggesting that disturbed fear learning in SERT(-/-) results from developmental changes and not from reduced SERT functioning. Although CRF1 receptor levels did not differ significantly between genotypes, CP154,526 treatment normalized both cue- and contextual fear in SERT(-/-) during acquisition, but not expression of fear-potentiated startle. The disrupted fear acquisition and concomitant increase in contextual conditioned fear-potentiated startle fear in SERT(-/-) resembles the associative learning deficit seen in patients with panic disorder and suggests that normal SERT functioning is crucial for the development of an adequate fear neuro-circuitry. Moreover, the normalization of fear acquisition by CP154,526 suggests a role for central CRF signaling in the generalization of fear. Copyright © 2015 Elsevier B.V. and ECNP. All rights reserved.

Nicotinic Receptors in the Dorsal and Ventral Hippocampus Differentially Modulate Contextual Fear Conditioning

PubMed Central

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

2012-01-01

Nicotine administration alters various forms of hippocampus-dependent learning and memory. Increasing work has found that the dorsal and ventral hippocampus differentially contribute to multiple behaviors. Thus, the present study examined whether the effects of nicotine in the dorsal and ventral hippocampus have distinct influences on contextual fear learning in male C57BL/6J mice. Direct infusion of nicotine into the dorsal hippocampus resulted in an enhancement of contextual fear learning, whereas nicotine infused into the ventral hippocampus resulted in deficits. Nicotine infusions into the ventral hippocampus did not alter hippocampus-independent cued fear conditioning or time spent in the open arm of the elevated plus maze, a measure of anxiety, suggesting 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. PMID:22271264

Combined effects of complex magnetic fields and agmatine for contextual fear learning deficits in rats.

PubMed

McKay, B E; Persinger, M A

2003-04-18

Acute post-training exposures to weak intensity theta-burst stimulation (TBS) patterned complex magnetic fields attenuated the magnitude of conditioned fear learning for contextual stimuli. A similar learning impairment was evoked in a linear and dose-dependent manner by pre-conditioning injections of the polyamine agmatine. The present study examined the hypothesis that whole-body applications of the TBS complex magnetic field pattern when co-administered with systemic agmatine treatment may combine to evoke impairments in contextual fear learning. Within minutes of 4 mg/kg agmatine injections, male Wistar rats were fear conditioned to contextual stimuli and immediately exposed for 30 min to the TBS patterned complex magnetic field or to sham conditions. TBS patterned complex magnetic field treatment was found to linearly summate with the contextual fear learning impairment evoked by agmatine treatment alone. Furthermore, we report for sham-treated rats, but not rats exposed to the synthetic magnetic field pattern, that the magnitude of learned fear decreased and the amount of variability in learning increased, as the K-index (a measure of change in intensity of the time-varying ambient geomagnetic field) increased during the 3-hr intervals over which conditioning and testing sessions were conducted.

Short-Term Total Sleep-Deprivation Impairs Contextual Fear Memory, and Contextual Fear-Conditioning Reduces REM Sleep in Moderately Anxious Swiss Mice

PubMed Central

Qureshi, Munazah F.; Jha, Sushil K.

2017-01-01

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. PMID:29238297

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

ERIC Educational Resources Information Center

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

2015-01-01

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

Infralimbic Neurotrophin-3 Infusion Rescues Fear Extinction Impairment in a Mouse Model of Pathological Fear.

PubMed

D'Amico, Davide; Gener, Thomas; de Lagrán, Maria Martínez; Sanchez-Vives, Maria V; Santos, Mónica; Dierssen, Mara

2017-01-01

The inability to properly extinguish fear memories constitutes the foundation of several anxiety disorders, including panic disorder. Recent findings show that boosting prefrontal cortex synaptic plasticity potentiates fear extinction, suggesting that therapies that augment synaptic plasticity could prove useful in rescue of fear extinction impairments in this group of disorders. Previously, we reported that mice with selective deregulation of neurotrophic tyrosine kinase receptor, type 3 expression (TgNTRK3) exhibit increased fear memories accompanied by impaired extinction, congruent with an altered activation pattern of the amygdala-hippocampus-medial prefrontal cortex fear circuit. Here we explore the specific role of neurotrophin 3 and its cognate receptor in the medial prefrontal cortex, and its involvement in fear extinction in a pathological context. In this study we combined molecular, behavioral, in vivo pharmacology and ex vivo electrophysiological recordings in TgNTRK3 animals during contextual fear extinction processes. We show that neurotrophin 3 protein levels are increased upon contextual fear extinction in wild-type animals but not in TgNTRK3 mice, which present deficits in infralimbic long-term potentiation. Importantly, infusion of neurotrophin 3 to the medial prefrontal cortex of TgNTRK3 mice rescues contextual fear extinction and ex vivo local application improves medial prefrontal cortex synaptic plasticity. This effect is blocked by inhibition of extracellular signal-regulated kinase phosphorylation through peripheral administration of SL327, suggesting that rescue occurs via this pathway. Our results suggest that stimulating neurotrophin 3-dependent medial prefrontal cortex plasticity could restore contextual fear extinction deficit in pathological fear and could constitute an effective treatment for fear-related disorders.

The Role Of Basal Forebrain Cholinergic Neurons In Fear and Extinction Memory

PubMed Central

Knox, Dayan

2016-01-01

Cholinergic input to the neocortex, dorsal hippocampus (dHipp), and basolateral amygdala (BLA) is critical for neural function and synaptic plasticity in these brain regions. Synaptic plasticity in the neocortex, dHipp, ventral Hipp (vHipp), and BLA has also been implicated in fear and extinction memory. This finding raises the possibility that basal forebrain (BF) cholinergic neurons, the predominant source of acetylcholine in these brain regions, have an important role in mediating fear and extinction memory. While empirical studies support this hypothesis, there are interesting inconsistencies among these studies that raise questions about how best to define the role of BF cholinergic neurons in fear and extinction memory. Nucleus basalis magnocellularis (NBM) cholinergic neurons that project to the BLA are critical for fear memory and contextual fear extinction memory. NBM cholinergic neurons that project to the neocortex are critical for cued and contextual fear conditioned suppression, but are not critical for fear memory in other behavioral paradigms and in the inhibitory avoidance paradigm may even inhibit contextual fear memory formation. Medial septum and diagonal band of Broca cholinergic neurons are critical for contextual fear memory and acquisition of cued fear extinction. Thus, even though the results of previous studies suggest BF cholinergic neurons modulate fear and extinction memory, inconsistent findings among these studies necessitates more research to better define the neural circuits and molecular processes through which BF cholinergic neurons modulate fear and extinction memory. Furthermore, studies determining if BF cholinergic neurons can be manipulated in such a manner so as to treat excessive fear in anxiety disorders are needed. PMID:27264248

Prefrontocortical dopamine loss in rats delays long-term extinction of contextual conditioned fear, and reduces social interaction without affecting short-term social interaction memory.

PubMed

Fernandez Espejo, Emilio

2003-03-01

Prefrontal dopamine loss delays extinction of cued fear conditioning responses, but its role in contextual fear conditioning has not been explored. Medial prefrontal lesions also enhance social interaction in rats, but the role of prefrontal dopamine loss on social interaction memory is not known. Besides, a role for subcortical accumbal dopamine on mnesic changes after prefrontal dopamine manipulation has been proposed but not explored. The objective was to study the involvement of dopaminergic neurotransmission in the medial prefrontal cortex (mPFC) and nucleus accumbens in two mnesic tasks: contextual fear conditioning and social interaction memory. For contextual fear conditioning, short- and long-term freezing responses after an electric shock were studied, as well as extinction retention. Regarding social interaction memory, the recognition of a juvenile, a very sensitive short-term memory test, was used. Dopamine loss was carried out by injection of 6-hydroxydopamine, and postmortem catecholamine levels were analyzed by high-performance liquid chromatography. Prefrontocortical dopamine loss (>76%) led to a reactive enhancement of accumbal dopamine content (p<0.01), supporting the hypothesis that a hyperdopaminergic tone emerges in the nucleus accumbens after prefrontocortical dopamine loss. In lesioned rats, long-term extinction of contextual fear conditioning was significantly delayed and extinction retention was impaired without changes in acquisition and short-term contextual fear conditioning and, on the other hand, acquisition and short-term social interaction memory were not affected, although time spent on social interaction was significantly reduced. Added dopamine loss in the nucleus accumbens (>76%) did not alter these behavioral changes. In summary, the results of the present study indicate that the dopaminergic network in the mPFC (but not in the nucleus accumbens) coordinates the normal long-term extinction of contextual fear conditioning responses without affecting their acquisition, and it is involved in time spent on social interaction, but not acquisition and short-term social interaction memory.

Interference effects of transcranial direct current stimulation over the right frontal cortex and adrenergic system on conditioned fear.

PubMed

Nasehi, Mohammad; Soltanpour, Reyhaneh; Ebrahimi-Ghiri, Mohaddeseh; Zarrabian, Shahram; Zarrindast, Mohammad-Reza

2017-11-01

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.

Inhibition of projections from the basolateral amygdala to the entorhinal cortex disrupts the acquisition of contextual fear

PubMed Central

Sparta, Dennis R.; Smithuis, Jim; Stamatakis, Alice M.; Jennings, Joshua H.; Kantak, Pranish A.; Ung, Randall L.; Stuber, Garret D.

2014-01-01

The development of excessive fear and/or stress responses to environmental cues such as contexts associated with a traumatic event is a hallmark of post-traumatic stress disorder (PTSD). The basolateral amygdala (BLA) has been implicated as a key structure mediating contextual fear conditioning. In addition, the hippocampus has an integral role in the encoding and processing of contexts associated with strong, salient stimuli such as fear. Given that both the BLA and hippocampus play an important role in the regulation of contextual fear conditioning, examining the functional connectivity between these two structures may elucidate a role for this pathway in the development of PTSD. Here, we used optogenetic strategies to demonstrate that the BLA sends a strong glutamatergic projection to the hippocampal formation through the entorhinal cortex (EC). Next, we photoinhibited glutamatergic fibers from the BLA terminating in the EC during the acquisition or expression of contextual fear conditioning. In mice that received optical inhibition of the BLA-to-EC pathway during the acquisition session, we observed a significant decrease in freezing behavior in a context re-exposure session. In contrast, we observed no differences in freezing behavior in mice that were only photoinhibited during the context re-exposure session. These data demonstrate an important role for the BLA-to-EC glutamatergic pathway in the acquisition of contextual fear conditioning. PMID:24834031

Overexpression of SIRT6 in the hippocampal CA1 impairs the formation of long-term contextual fear memory

PubMed Central

Yin, Xi; Gao, Yuan; Shi, Hai-Shui; Song, Li; Wang, Jie-Chao; Shao, Juan; Geng, Xu-Hong; Xue, Gai; Li, Jian-Li; Hou, Yan-Ning

2016-01-01

Histone modifications have been implicated in learning and memory. Our previous transcriptome data showed that expression of sirtuins 6 (SIRT6), a member of Histone deacetylases (HDACs) family in the hippocampal cornu ammonis 1 (CA1) was decreased after contextual fear conditioning. However, the role of SIRT6 in the formation of memory is still elusive. In the present study, we found that contextual fear conditioning inhibited translational expression of SIRT6 in the CA1. Microinfusion of lentiviral vector-expressing SIRT6 into theCA1 region selectively enhanced the expression of SIRT6 and impaired the formation of long-term contextual fear memory without affecting short-term fear memory. The overexpression of SIRT6 in the CA1 had no effect on anxiety-like behaviors or locomotor activity. Also, we also found that SIRT6 overexpression significantly inhibited the expression of insulin-like factor 2 (IGF2) and amounts of proteins and/or phosphoproteins (e.g. Akt, pAkt, mTOR and p-mTOR) related to the IGF2 signal pathway in the CA1. These results demonstrate that the overexpression of SIRT6 in the CA1 impaired the formation of long-term fear memory, and SIRT6 in the CA1 may negatively modulate the formation of contextual fear memory via inhibiting the IGF signaling pathway. PMID:26732053

The impact of cue learning, trait anxiety and genetic variation in the serotonin 1A receptor on contextual fear.

PubMed

Baas, Johanna M P; Heitland, Ivo

2015-12-01

In everyday life, aversive events are usually associated with certain predictive cues. Normally, the acquisition of these contingencies enables organisms to appropriately respond to threat. Presence of a threat cue clearly signals 'danger', whereas absence of such cues signals a period of 'safety'. Failure to identify threat cues may lead to chronic states of anxious apprehension in the context in which the threat has been imminent, which may be instrumental in the pathogenesis of anxiety disorders. In this study, existing data from 150 healthy volunteers in a cue and context virtual reality fear conditioning paradigm were reanalyzed. The aim was to further characterize the impact of cue acquisition and trait anxiety, and of a single nucleotide polymorphism in the serotonin 1A receptor gene (5-HTR1A, rs6295), on cued fear and contextual anxiety before and after fear contingencies were explicitly introduced. Fear conditioned responding was quantified with fear potentiation of the eyeblink startle reflex and subjective fear ratings. First, we replicated previous findings that the inability to identify danger cues during acquisition leads to heightened anxious apprehension in the threat context. Second, in subjects who did not identify the danger cue initially, contextual fear was associated with trait anxiety after the contingencies were explicitly instructed. Third, genetic variability within 5-HTR1A (rs6295) was associated with contextual fear independent of awareness or trait anxiety. These findings confirm that failure to acquire cue contingencies impacts contextual fear responding, in association with trait anxiety. The observed 5-HTR1A effect is in line with models of anxiety, but needs further replication. Copyright © 2014 Elsevier B.V. All rights reserved.

Adiponectin regulates contextual fear extinction and intrinsic excitability of dentate gyrus granule neurons through AdipoR2 receptors

PubMed Central

Zhang, D; Wang, X; Wang, B; Garza, J C; Fang, X; Wang, J; Scherer, P E; Brenner, R; Zhang, W; Lu, X-Y

2017-01-01

Post-traumatic stress disorder (PTSD) is characterized by exaggerated fear expression and impaired fear extinction. The underlying molecular and cellular mechanisms of PTSD are largely unknown. The current pharmacological and non-pharmacological treatments for PTSD are either ineffective or temporary with high relapse rates. Here we report that adiponectin-deficient mice exhibited normal contextual fear conditioning but displayed slower extinction learning. Infusions of adiponectin into the dentate gyrus (DG) of the hippocampus in fear-conditioned mice facilitated extinction of contextual fear. Whole-cell patch-clamp recordings in brain slices revealed that intrinsic excitability of DG granule neurons was enhanced by adiponectin deficiency and suppressed after treatment with the adiponectin mimetic AdipoRon, which were associated with increased input resistance and hyperpolarized resting membrane potential, respectively. Moreover, deletion of AdipoR2, but not AdipoR1 in the DG, resulted in augmented fear expression and reduced extinction, accompanied by intrinsic hyperexcitability of DG granule neurons. Adiponectin and AdipoRon failed to induce facilitation of fear extinction and elicit inhibition of intrinsic excitability of DG neurons in AdipoR2 knockout mice. These results indicated that adiponectin action via AdipoR2 was both necessary and sufficient for extinction of contextual fear and intrinsic excitability of DG granule neurons, implying that enhancing or dampening DG neuronal excitability may cause resistance to or facilitation of extinction. Therefore, our findings provide a functional link between adiponectin/AdipoR2 activation, DG neuronal excitability and contextual fear extinction, and suggest that targeting adiponectin/AdipoR2 may be used to strengthen extinction-based exposure therapies for PTSD. PMID:27137743

Adiponectin regulates contextual fear extinction and intrinsic excitability of dentate gyrus granule neurons through AdipoR2 receptors.

PubMed

Zhang, D; Wang, X; Wang, B; Garza, J C; Fang, X; Wang, J; Scherer, P E; Brenner, R; Zhang, W; Lu, X-Y

2017-07-01

Post-traumatic stress disorder (PTSD) is characterized by exaggerated fear expression and impaired fear extinction. The underlying molecular and cellular mechanisms of PTSD are largely unknown. The current pharmacological and non-pharmacological treatments for PTSD are either ineffective or temporary with high relapse rates. Here we report that adiponectin-deficient mice exhibited normal contextual fear conditioning but displayed slower extinction learning. Infusions of adiponectin into the dentate gyrus (DG) of the hippocampus in fear-conditioned mice facilitated extinction of contextual fear. Whole-cell patch-clamp recordings in brain slices revealed that intrinsic excitability of DG granule neurons was enhanced by adiponectin deficiency and suppressed after treatment with the adiponectin mimetic AdipoRon, which were associated with increased input resistance and hyperpolarized resting membrane potential, respectively. Moreover, deletion of AdipoR2, but not AdipoR1 in the DG, resulted in augmented fear expression and reduced extinction, accompanied by intrinsic hyperexcitability of DG granule neurons. Adiponectin and AdipoRon failed to induce facilitation of fear extinction and elicit inhibition of intrinsic excitability of DG neurons in AdipoR2 knockout mice. These results indicated that adiponectin action via AdipoR2 was both necessary and sufficient for extinction of contextual fear and intrinsic excitability of DG granule neurons, implying that enhancing or dampening DG neuronal excitability may cause resistance to or facilitation of extinction. Therefore, our findings provide a functional link between adiponectin/AdipoR2 activation, DG neuronal excitability and contextual fear extinction, and suggest that targeting adiponectin/AdipoR2 may be used to strengthen extinction-based exposure therapies for PTSD.

Non-Suicidal Self-Injury in Adolescence: The Role of Shame, Self-Criticism and Fear of Self-Compassion

ERIC Educational Resources Information Center

Xavier, Ana; Pinto Gouveia, José; Cunha, Marina

2016-01-01

Background: Non-suicidal self-injury (NSSI) is a serious and relatively prevalent problem in adolescence. Although several studies have identified risk factors for the aetiology and maintenance of NSSI, little is known about the impact of individual and contextual variables in such pervasive behaviors among adolescents. Objective: This paper aims…

Automatic integration of social information in emotion recognition.

PubMed

Mumenthaler, Christian; Sander, David

2015-04-01

This study investigated the automaticity of the influence of social inference on emotion recognition. Participants were asked to recognize dynamic facial expressions of emotion (fear or anger in Experiment 1 and blends of fear and surprise or of anger and disgust in Experiment 2) in a target face presented at the center of a screen while a subliminal contextual face appearing in the periphery expressed an emotion (fear or anger) or not (neutral) and either looked at the target face or not. Results of Experiment 1 revealed that recognition of the target emotion of fear was improved when a subliminal angry contextual face gazed toward-rather than away from-the fearful face. We replicated this effect in Experiment 2, in which facial expression blends of fear and surprise were more often and more rapidly categorized as expressing fear when the subliminal contextual face expressed anger and gazed toward-rather than away from-the target face. With the contextual face appearing for 30 ms in total, including only 10 ms of emotion expression, and being immediately masked, our data provide the first evidence that social influence on emotion recognition can occur automatically. (c) 2015 APA, all rights reserved).

Prediction of individual differences in fear response by novelty seeking, and disruption of contextual fear memory reconsolidation by ketamine

PubMed Central

Duclot, Florian; Perez-Taboada, Iara; Wright, Katherine N.; Kabbaj, Mohamed

2016-01-01

Only a portion of the population exposed to trauma will develop persistent emotional alterations characteristic of posttraumatic stress disorder (PTSD), which illustrates the necessity for identifying vulnerability factors and novel pharmacotherapeutic alternatives. Interestingly, clinical evidence suggests that novelty seeking is a good predictor for vulnerability to the development of excessive and persistent fear. Here, we first tested this hypothesis by analyzing contextual and cued fear responses of rats selected for their high (high responders, HR) or low (low responders, LR) exploration of a novel environment, indicator of novelty seeking. While HR and LR rats exhibited similar sensitivity to the shock and cued fear memory retention, fewer extinction sessions were required in HR than LR animals to reach extinction, indicating faster contextual and cued memory extinction. In a second part, we found an effective disruption of contextual fear reconsolidation by the N-methyl-D-aspartate receptor antagonist ketamine, associated with a down-regulation of early growth response 1 (Egr1) in the hippocampal CA1 area, and up-regulation of brain-derived neurotrophic factor (Bdnf) mRNA levels in the prelimbic and infralimbic cortices. Altogether, these data demonstrate a link between novelty seeking and conditioned fear extinction, and highlight a promising novel role of ketamine in affecting established fear memory. PMID:27343386

Developing and Validating Trace Fear Conditioning Protocols in C57BL/6 Mice

PubMed Central

Burman, Michael A; Simmons, Cassandra A; Hughes, Miles; Lei, Lei

2013-01-01

Background Classical fear conditioning is commonly used to study the biology of fear, anxiety and memory. Previous research demonstrated that delay conditioning requires a neural circuit involving the amygdala, but not usually the hippocampus. Trace and contextual fear conditioning require the amygdala and hippocampus. While these paradigms were developed primarily using rat models, they are increasingly being used in mice. New Method The current studies develop trace fear conditioning and control paradigms to allow for the assessment of trace and delay fear conditioning in C57BL/6N mice. Our initial protocol yielded clear delay and contextual conditioning. However, trace conditioning failed to differentiate from an unpaired group and was not hippocampus-dependent. These results suggested that the protocol needed to be modified to specifically accommodate trace conditioning the mice. In order to reduce unconditioned freezing and increase learning, the final protocol was developed by decreasing the intensity of the tone and by increasing the inter-trial interval. Results Our final protocol produced trace conditioned freezing that was significantly greater than that followed unpaired stimulus exposure and was disrupted by hippocampus lesions. Comparison with Existing Methods A review of the literature produced 90 articles using trace conditioning in mice. Few of those articles used any kind of behavioral control group, which is required to rule out non-associative factors causing fearful behavior. Fewer used unpaired groups involving tones and shocks within a session, which is the optimal control group. Conclusions Our final trace conditioning protocol can be used in future studies examining genetically modified C57BL/6N mice. PMID:24269252

Double Dissociation of Amygdala and Hippocampal Contributions to Trace and Delay Fear Conditioning

PubMed Central

Raybuck, Jonathan D.; Lattal, K. Matthew

2011-01-01

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

Post-Session Administration of USP Methylene Blue Facilitates the Retention of Pathological Fear Extinction and Contextual Memory in Phobic Adults

PubMed Central

Telch, Michael J.; Bruchey, Aleksandra K.; Rosenfield, David; Cobb, Adam R.; Smits, Jasper; Pahl, Sandra; Gonzalez-Lima, F.

2015-01-01

Objective Preclinical studies have shown that low-dose USP methylene blue increases mitochondrial cytochrome oxidase activity in the brain and improves memory retention after learning tasks, including fear extinction. We report on the first controlled experiment to examine the memory-enhancing effects of post-training methylene blue administration on retention of fear extinction and contextual memory following fear extinction training. Method Adults (N = 42) displaying marked claustrophobic fear were randomized to double-blind administration of 260 mg of methylene blue versus placebo immediately following six five-minute extinction trials to an enclosed chamber. Retesting occurred one month later to assess fear renewal as indexed by peak fear during exposure to a non-trained enclosed chamber with the prediction that methylene blue's effects would vary as a function of fear reduction achieved during extinction training. Incidental contextual memory was assessed 1 and 30 days after training to assess the cognitive enhancing effects of methylene blue independent of its effects on fear attenuation. Results Consistent with predictions, participants displaying low end fear at post-training showed significantly less fear at follow-up if they received methylene blue post-training relative to placebo. In contrast, participants displaying moderate to high levels of post-training fear tended to fare worse at follow-up relative to placebo. Methylene blue's enhancement of contextual memory was unrelated to initial or post-training claustrophobic fear. Conclusions Methylene blue enhances memory and the retention of fear extinction when administered after a successful exposure session, but may have a deleterious effect on extinction when administered after an unsuccessful exposure session. PMID:25018057

Infralimbic Neurotrophin-3 Infusion Rescues Fear Extinction Impairment in a Mouse Model of Pathological Fear

PubMed Central

D'Amico, Davide; Gener, Thomas; de Lagrán, Maria Martínez; Sanchez-Vives, Maria V; Santos, Mónica; Dierssen, Mara

2017-01-01

The inability to properly extinguish fear memories constitutes the foundation of several anxiety disorders, including panic disorder. Recent findings show that boosting prefrontal cortex synaptic plasticity potentiates fear extinction, suggesting that therapies that augment synaptic plasticity could prove useful in rescue of fear extinction impairments in this group of disorders. Previously, we reported that mice with selective deregulation of neurotrophic tyrosine kinase receptor, type 3 expression (TgNTRK3) exhibit increased fear memories accompanied by impaired extinction, congruent with an altered activation pattern of the amygdala—hippocampus—medial prefrontal cortex fear circuit. Here we explore the specific role of neurotrophin 3 and its cognate receptor in the medial prefrontal cortex, and its involvement in fear extinction in a pathological context. In this study we combined molecular, behavioral, in vivo pharmacology and ex vivo electrophysiological recordings in TgNTRK3 animals during contextual fear extinction processes. We show that neurotrophin 3 protein levels are increased upon contextual fear extinction in wild-type animals but not in TgNTRK3 mice, which present deficits in infralimbic long-term potentiation. Importantly, infusion of neurotrophin 3 to the medial prefrontal cortex of TgNTRK3 mice rescues contextual fear extinction and ex vivo local application improves medial prefrontal cortex synaptic plasticity. This effect is blocked by inhibition of extracellular signal-regulated kinase phosphorylation through peripheral administration of SL327, suggesting that rescue occurs via this pathway. Our results suggest that stimulating neurotrophin 3-dependent medial prefrontal cortex plasticity could restore contextual fear extinction deficit in pathological fear and could constitute an effective treatment for fear-related disorders. PMID:27534266

The role of basal forebrain cholinergic neurons in fear and extinction memory.

PubMed

Knox, Dayan

2016-09-01

Cholinergic input to the neocortex, dorsal hippocampus (dHipp), and basolateral amygdala (BLA) is critical for neural function and synaptic plasticity in these brain regions. Synaptic plasticity in the neocortex, dHipp, ventral Hipp (vHipp), and BLA has also been implicated in fear and extinction memory. This finding raises the possibility that basal forebrain (BF) cholinergic neurons, the predominant source of acetylcholine in these brain regions, have an important role in mediating fear and extinction memory. While empirical studies support this hypothesis, there are interesting inconsistencies among these studies that raise questions about how best to define the role of BF cholinergic neurons in fear and extinction memory. Nucleus basalis magnocellularis (NBM) cholinergic neurons that project to the BLA are critical for fear memory and contextual fear extinction memory. NBM cholinergic neurons that project to the neocortex are critical for cued and contextual fear conditioned suppression, but are not critical for fear memory in other behavioral paradigms and in the inhibitory avoidance paradigm may even inhibit contextual fear memory formation. Medial septum and diagonal band of Broca cholinergic neurons are critical for contextual fear memory and acquisition of cued fear extinction. Thus, even though the results of previous studies suggest BF cholinergic neurons modulate fear and extinction memory, inconsistent findings among these studies necessitates more research to better define the neural circuits and molecular processes through which BF cholinergic neurons modulate fear and extinction memory. Furthermore, studies determining if BF cholinergic neurons can be manipulated in such a manner so as to treat excessive fear in anxiety disorders are needed. Copyright © 2016 Elsevier Inc. All rights reserved.

Effects of post-session administration of methylene blue on fear extinction and contextual memory in adults with claustrophobia.

PubMed

Telch, Michael J; Bruchey, Aleksandra K; Rosenfield, David; Cobb, Adam R; Smits, Jasper; Pahl, Sandra; Gonzalez-Lima, F

2014-10-01

Preclinical studies have shown that low-dose methylene blue increases mitochondrial cytochrome oxidase activity in the brain and improves memory retention after learning tasks, including fear extinction. The authors report on the first controlled experiment to examine the memory-enhancing effects of posttraining methylene blue administration on retention of fear extinction and contextual memory following fear extinction training. Adult participants displaying marked claustrophobic fear were randomly assigned to double-blind administration of 260 mg of methylene blue (N=23) or administration of placebo (N=19) immediately following six 5-minute extinction trials in an enclosed chamber. Retesting occurred 1 month later to assess fear renewal as indexed by peak fear during exposure to a nontraining chamber, with the prediction that the effects of methylene blue would vary as a function of fear reduction achieved during extinction training. Incidental contextual memory was assessed 1 and 30 days after training to assess the cognitive-enhancing effects of methylene blue independent of its effects on fear attenuation. Consistent with predictions, participants displaying low end fear posttraining showed significantly less fear at the 1-month follow-up if they received methylene blue posttraining compared with placebo. In contrast, participants displaying moderate to high levels of posttraining fear tended to fare worse at the follow-up if they received methylene blue posttraining. Methylene blue's enhancement of contextual memory was unrelated to initial or posttraining claustrophobic fear. Methylene blue enhances memory and the retention of fear extinction when administered after a successful exposure session but may have a deleterious effect on extinction when administered after an unsuccessful exposure session.

Memory retrieval after contextual fear conditioning induces c-Fos and JunB expression in CA1 hippocampus.

PubMed

Strekalova, T; Zörner, B; Zacher, C; Sadovska, G; Herdegen, T; Gass, P

2003-02-01

Using specific polyclonal antisera against c-Fos, JunB, c-Jun and JunD, we tried to identify the candidate transcription factors of the immediate early gene family which may contribute to the molecular processes during contextual memory reconsolidation. For that purpose we analyzed the expression of these proteins in the hippocampus after contextual memory retrieval in a mouse model of fear conditioning. A single exposure to a foot shock of 0.8 mA was sufficient to induce robust contextual fear conditioning in C57BI/6N mice. In these mice context dependent memory retrieval evoked a marked induction of c-Fos and JunB, but not of c-Jun and JunD, in pyramidal CA1 neurons of the dorsal hippocampus. In contrast, mice exposed and re-exposed only to the context, without foot shock, did not show behavioral signs of contextual fear conditioning and exhibited significantly less expression of c-Fos and JunB in CA1 neurons. Mice which received a foot shock but were not re-exposed to the context revealed no immediate early gene induction. These results demonstrate that contextual memory retrieval is associated with de novo synthesis of specific members of the Fos/Jun transcription factor family. Therefore we suggest that these genes may contribute to plasticity and reconsolidation accompanying the retrieval process. The specific activation of CA1 neurons during the retrieval of contextual fear associations supports the postulated concept of a mnemonic role of this hippocampal subsector during the retrieval of contextual informations.

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

PubMed Central

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

2009-01-01

Contextual fear conditioning was tested in infant, adolescent, and adult rats in terms of Pavlovian conditioned suppression. When a discrete auditory conditioned stimulus (CS) was paired with footshock (unconditioned stimulus, US) within the largely olfactory context, infants and adolescents conditioned to the context with substantial effectiveness but adult rats did not. When unpaired presentations of the CS and US occurred within the context, contextual fear conditioning was strong for adults, weak for infants, but about as strong for adolescents as when pairings of CS and US occurred in the context. Nonreinforced presentations of either the CS or context markedly reduced contextual fear conditioning in infants, but, in adolescents, CS extinction had no effect on contextual fear conditioning, although context extinction significantly reduced it. Neither CS extinction nor context extinction affected responding to the CS-context compound in infants, suggesting striking discrimination between the compound and its components. Female adolescents showed the same lack of effect of component extinction on response to the compound as infants, but CS extinction reduced responding to the compound in adolescent males, a sex difference seen also in adults. Theoretical implications are discussed for the development of perceptual-cognitive processing and hippocampus role. PMID:18343048

Context-Dependent Encoding of Fear and Extinction Memories in a Large-Scale Network Model of the Basal Amygdala

PubMed Central

Vlachos, Ioannis; Herry, Cyril; Lüthi, Andreas; Aertsen, Ad; Kumar, Arvind

2011-01-01

The basal nucleus of the amygdala (BA) is involved in the formation of context-dependent conditioned fear and extinction memories. To understand the underlying neural mechanisms we developed a large-scale neuron network model of the BA, composed of excitatory and inhibitory leaky-integrate-and-fire neurons. Excitatory BA neurons received conditioned stimulus (CS)-related input from the adjacent lateral nucleus (LA) and contextual input from the hippocampus or medial prefrontal cortex (mPFC). We implemented a plasticity mechanism according to which CS and contextual synapses were potentiated if CS and contextual inputs temporally coincided on the afferents of the excitatory neurons. Our simulations revealed a differential recruitment of two distinct subpopulations of BA neurons during conditioning and extinction, mimicking the activation of experimentally observed cell populations. We propose that these two subgroups encode contextual specificity of fear and extinction memories, respectively. Mutual competition between them, mediated by feedback inhibition and driven by contextual inputs, regulates the activity in the central amygdala (CEA) thereby controlling amygdala output and fear behavior. The model makes multiple testable predictions that may advance our understanding of fear and extinction memories. PMID:21437238

Short-term inhibition of 11β-hydroxysteroid dehydrogenase type 1 reversibly improves spatial memory but persistently impairs contextual fear memory in aged mice

PubMed Central

Wheelan, Nicola; Webster, Scott P.; Kenyon, Christopher J.; Caughey, Sarah; Walker, Brian R.; Holmes, Megan C.; Seckl, Jonathan R.; Yau, Joyce L.W.

2015-01-01

High glucocorticoid levels induced by stress enhance the memory of fearful events and may contribute to the development of anxiety and posttraumatic stress disorder. In contrast, elevated glucocorticoids associated with ageing impair spatial memory. We have previously shown that pharmacological inhibition of the intracellular glucocorticoid-amplifying enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) improves spatial memory in aged mice. However, it is not known whether inhibition of 11β-HSD1 will have any beneficial effects on contextual fear memories in aged mice. Here, we examined the effects of UE2316, a selective 11β-HSD1 inhibitor which accesses the brain, on both spatial and contextual fear memories in aged mice using a vehicle-controlled crossover study design. Short-term UE2316 treatment improved spatial memory in aged mice, an effect which was reversed when UE2316 was substituted with vehicle. In contrast, contextual fear memory induced by foot-shock conditioning was significantly reduced by UE2316 in a non-reversible manner. When the order of treatment was reversed following extinction of the original fear memory, and a second foot-shock conditioning was given in a novel context, UE2316 treated aged mice (previously on vehicle) now showed increased fear memory compared to vehicle-treated aged mice (previously on UE2316). Renewal of the original extinguished fear memory triggered by exposure to a new environmental context may explain these effects. Thus 11β-HSD1 inhibition reverses spatial memory impairments with ageing while reducing the strength and persistence of new contextual fear memories. Potentially this could help prevent anxiety-related disorders in vulnerable elderly individuals. PMID:25497454

Short-term inhibition of 11β-hydroxysteroid dehydrogenase type 1 reversibly improves spatial memory but persistently impairs contextual fear memory in aged mice.

PubMed

Wheelan, Nicola; Webster, Scott P; Kenyon, Christopher J; Caughey, Sarah; Walker, Brian R; Holmes, Megan C; Seckl, Jonathan R; Yau, Joyce L W

2015-04-01

High glucocorticoid levels induced by stress enhance the memory of fearful events and may contribute to the development of anxiety and posttraumatic stress disorder. In contrast, elevated glucocorticoids associated with ageing impair spatial memory. We have previously shown that pharmacological inhibition of the intracellular glucocorticoid-amplifying enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) improves spatial memory in aged mice. However, it is not known whether inhibition of 11β-HSD1 will have any beneficial effects on contextual fear memories in aged mice. Here, we examined the effects of UE2316, a selective 11β-HSD1 inhibitor which accesses the brain, on both spatial and contextual fear memories in aged mice using a vehicle-controlled crossover study design. Short-term UE2316 treatment improved spatial memory in aged mice, an effect which was reversed when UE2316 was substituted with vehicle. In contrast, contextual fear memory induced by foot-shock conditioning was significantly reduced by UE2316 in a non-reversible manner. When the order of treatment was reversed following extinction of the original fear memory, and a second foot-shock conditioning was given in a novel context, UE2316 treated aged mice (previously on vehicle) now showed increased fear memory compared to vehicle-treated aged mice (previously on UE2316). Renewal of the original extinguished fear memory triggered by exposure to a new environmental context may explain these effects. Thus 11β-HSD1 inhibition reverses spatial memory impairments with ageing while reducing the strength and persistence of new contextual fear memories. Potentially this could help prevent anxiety-related disorders in vulnerable elderly individuals. Copyright © 2014 Elsevier Ltd. All rights reserved.

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

PubMed

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

2016-03-01

The noradrenergic system plays a critical role in the modulation of emotional state, primarily related to anxiety, arousal, and stress. Growing evidence suggests that the endocannabinoid system mediates stress responses and emotional homeostasis, in part, by targeting noradrenergic circuits. In addition, there is an interaction between the cannabinoid and noradrenergic system that has significant functional and behavioral implications. Considering the importance of these systems in forming memories for fearful events, we have investigated the involvement of basolateral amygdala (BLA) α2-adrenoceptors on ACPA (as selective cannabinoid CB1 agonist)-induced inhibition of the acquisition of contextual and auditory conditioned fear. A contextual and auditory fear conditioning apparatus for assess fear memory in adult male NMRI mice was used. Pre-training, intraperitoneal administration of ACPA decreased the percentage freezing time in contextual (at doses of 0.05 and 0.1mg/kg) and auditory (at dose of 0.1 mg/kg) in the fear conditioning task, indicating memory acquisition deficit. The same result was observed with intra-BLA microinjection of clonidine (0.001-0.5 μg/mouse, for both memories), as α2-adrenoceptor agonist and yohimbine (at doses of 0.005 and 0.05 for contextual and at dose of 0.05 μg/mouse for auditory fear memory), as α2-adrenoceptor antagonist. In addition, intra-BLA microinjection of clonidine (0.0005 μg/mouse) did not alter ACPA response in both conditions, while the same dose of yohimbine potentiated ACPA response at the lower dose on contextual fear memory. It is concluded that BLA α2-adrenergic receptors may be involved in context- but not tone-dependent fear memory impairment induced by activation of CB1 receptors. Copyright © 2015. Published by Elsevier B.V.

Orexin receptor-1 in the locus coeruleus plays an important role in cue-dependent fear memory consolidation.

PubMed

Soya, Shingo; Shoji, Hirotaka; Hasegawa, Emi; Hondo, Mari; Miyakawa, Tsuyoshi; Yanagisawa, Masashi; Mieda, Michihiro; Sakurai, Takeshi

2013-09-04

The noradrenergic (NA) projections arising from the locus ceruleus (LC) to the amygdala and bed nucleus of the stria terminalis have been implicated in the formation of emotional memory. Since NA neurons in the LC (LC-NA neurons) abundantly express orexin receptor-1 (OX1R) and receive prominent innervation by orexin-producing neurons, we hypothesized that an OX1R-mediated pathway is involved in the physiological fear learning process via regulation of LC-NA neurons. To evaluate this hypothesis, we examined the phenotype of Ox1r(-/-) mice in the classic cued and contextual fear-conditioning test. We found that Ox1r(-/-) mice showed impaired freezing responses in both cued and contextual fear-conditioning paradigms. In contrast, Ox2r(-/-) mice showed normal freezing behavior in the cued fear-conditioning test, while they exhibited shorter freezing time in the contextual fear-conditioning test. Double immunolabeling of Fos and tyrosine hydroxylase showed that double-positive LC-NA neurons after test sessions of both cued and contextual stimuli were significantly fewer in Ox1r(-/-) mice. AAV-mediated expression of OX1R in LC-NA neurons in Ox1r(-/-) mice restored the freezing behavior to the auditory cue to a comparable level to that in wild-type mice in the test session. Decreased freezing time during the contextual fear test was not affected by restoring OX1R expression in LC-NA neurons. These observations support the hypothesis that the orexin system modulates the formation and expression of fear memory via OX1R in multiple pathways. Especially, OX1R in LC-NA neurons plays an important role in cue-dependent fear memory formation and/or retrieval.

Maternal inexperience as a risk factor of innate fear and PTSD-like symptoms in mice.

PubMed

Siegmund, Anja; Dahlhoff, Maik; Habersetzer, Ursula; Mederer, Anna; Wolf, Eckhard; Holsboer, Florian; Wotjak, Carsten T

2009-09-01

In laboratory rats and mice, differences in maternal care during the first week of life have been shown to exert long-lasting consequences on cognitive functioning and stress processing of the offspring. Such epigenetic programming is also assumed to play an important role in the transgenerational transmission of PTSD in humans. Here we studied whether even subtle within-subject differences in maternal care - caused by increasing mothering experience from the first to the second litter - can determine subsequent vulnerability for PTSD-like behaviour. To assess the influence of maternal experience on different components of fear, we analysed the adult male offspring of two subsequent litters (offspring 1, 2) from the same parental C57BL/6NCrl (B6N) and C57BL/6JOla (B6JOla) mice for (i) their innate anxiety behaviour on a modified hole board and (ii) their vulnerability to develop long-lasting PTSD-like fear symptoms ("hyperarousal", contextually conditioned fear) following perception of an inescapable foot shock. Increasing maternal experience reduced the animals' innate fear on the modified hole board (more exploration, less inhibition), the acute stress reaction to the shock and - one month after trauma - the levels of hyperarousal-like behaviour in the PTSD-prone B6N strain. In contrast, both acquisition and extinction of contextually conditioned fear were increased in the second offspring, representing cognitive flexibility. A factor analysis showed that innate fear, "hyperarousal" and conditioned fear represent independent behavioural dimensions. In conclusion, the present study identifies maternal inexperience as a risk factor for the development of PTSD-like symptoms. This effect - occurring in inbred mice on an almost identical genetic background - emphasizes the impact of epigenetic factors in PTSD-like behaviour.

NMDA receptor antagonism disrupts the acquisition and retention of the Context Preexposure Facilitation Effect in adolescent rats

PubMed Central

Heroux, Nicholas A.; Robinson-Drummer, Patrese A.; Rosen, Jeffrey B.; Stanton, Mark E.

2016-01-01

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. The current study investigated the involvement of NMDA receptors in contextual fear acquisition, retention, and expression across all phases of the CPFE in adolescent rats. In Experiment 1 systemic injections of 0.1 mg/kg MK-801, a non-competitive NMDA receptor antagonist, given before multiple context preexposure disrupted the acquisition of a context representation. In Experiment 2, pre-training MK-801 disrupted both immediate acquisition of contextual fear measured by postshock freezing, as well as retention test freezing 24 hours later. Experiment 3 showed that expression of contextual fear via a 24hr retention freezing test does not depend on NMDA receptors, indicating that MK-801 disrupts learning rather than performance of freezing behavior. In Experiment 4, consolidation of contextual information was partially disrupted by post-preexposure MK-801 whereas consolidation of contextual fear was not disrupted by post-training MK-801. Finally, Experiment 5 employed a dose-response design and found that a pre-training dose of 0.1 mg/kg MK-801 disrupted both postshock and retention test freezing while lower pre-training doses of MK-801 (0.025 or 0.05 mg/kg) only disrupted retention freezing. This is the first study to distinguish the role of NMDA receptors in acquisition (post-shock freezing), retention, expression, and consolidation of context vs. context-shock learning using the CPFE paradigm in adolescent rats. The findings provide a foundation for similar developmental studies examining these effects from early ontogeny through adulthood. PMID:26711910

Corticotropin Releasing Factor (CRF) Modulates Fear-Induced Alterations in Sleep in Mice

PubMed Central

Yang, Linghui; Tang, Xiangdong; Wellman, Laurie L.; Liu, Xianling; Sanford, Larry D.

2009-01-01

Contextual fear significantly reduces rapid eye movement sleep (REM) during post-exposure sleep in mice and rats. Corticotropin releasing factor (CRF) plays a major role in CNS responses to stressors. We examined the influence of CRF and astressin (AST), a non-specific CRF antagonist, on sleep after contextual fear in BALB/c mice. Male mice were implanted with transmitters for recording sleep via telemetry and with a guide cannula aimed into the lateral ventricle. Recordings for vehicle and handling control were obtained after ICV microinjection of saline (SAL) followed by exposure to a novel chamber. Afterwards, the mice were subjected to shock training (20 trials, 0.5 mA, 0.5 s duration) for 2 sessions. After training, separate groups of mice received ICV microinjections of SAL (0.2 microl, n=9), CRF (0.4 microg, n=8), or AST (1.0 microg, n=8) prior to exposure to the shock context alone. Sleep was then recorded for 20 hours (8-hour light and 12-hour dark period). Compared to handling control, contextual fear significantly decreased REM during the 8-h light period in mice receiving SAL and in mice receiving CRF, but not in the mice receiving AST. Mice receiving CRF exhibited reductions in REM during the 12-h dark period after contextual fear, whereas mice receiving SAL or AST did not. CRF also reduced non-REM (NREM) delta (slow wave) amplitude in the EEG. Only mice receiving SAL prior to contextual fear exhibited significant reductions in NREM and total sleep. These findings demonstrate a role for the central CRF system in regulating alterations in sleep induced by contextual fear. PMID:19376095

Selective early-acquired fear memories undergo temporary suppression during adolescence

PubMed Central

Pattwell, Siobhan S.; Bath, Kevin G.; Casey, B. J.; Ninan, Ipe; Lee, Francis S.

2011-01-01

Highly conserved neural circuitry between rodents and humans has allowed for in-depth characterization of behavioral and molecular processes associated with emotional learning and memory. Despite increased prevalence of affective disorders in adolescent humans, few studies have characterized how associative-emotional learning changes during the transition through adolescence or identified mechanisms underlying such changes. By examining fear conditioning in mice, as they transitioned into and out of adolescence, we found that a suppression of contextual fear occurs during adolescence. Although contextual fear memories were not expressed during early adolescence, they could be retrieved and expressed as the mice transitioned out of adolescence. This temporary suppression of contextual fear was associated with blunted synaptic activity in the basal amygdala and decreased PI3K and MAPK signaling in the hippocampus. These findings reveal a unique form of brain plasticity in fear learning during early adolescence and may prove informative for understanding endogenous mechanisms to suppress unwanted fear memories. PMID:21220344

TRPC3 channels critically regulate hippocampal excitability and contextual fear memory.

PubMed

Neuner, Sarah M; Wilmott, Lynda A; Hope, Kevin A; Hoffmann, Brian; Chong, Jayhong A; Abramowitz, Joel; Birnbaumer, Lutz; O'Connell, Kristen M; Tryba, Andrew K; Greene, Andrew S; Savio Chan, C; Kaczorowski, Catherine C

2015-03-15

Memory formation requires de novo protein synthesis, and memory disorders may result from misregulated synthesis of critical proteins that remain largely unidentified. Plasma membrane ion channels and receptors are likely candidates given their role in regulating neuron excitability, a candidate memory mechanism. Here we conduct targeted molecular monitoring and quantitation of hippocampal plasma membrane proteins from mice with intact or impaired contextual fear memory to identify putative candidates. Here we report contextual fear memory deficits correspond to increased Trpc3 gene and protein expression, and demonstrate TRPC3 regulates hippocampal neuron excitability associated with memory function. These data provide a mechanistic explanation for enhanced contextual fear memory reported herein following knockdown of TRPC3 in hippocampus. Collectively, TRPC3 modulates memory and may be a feasible target to enhance memory and treat memory disorders. Copyright © 2014 The Authors. Published by Elsevier B.V. All rights reserved.

Switching from Contextual to Tone Fear Conditioning and Vice Versa: The Key Role of the Glutamatergic Hippocampal-Lateral Septal Neurotransmission

ERIC Educational Resources Information Center

Calandreau, Ludovic; Desgranges, Bertrand; Jaffard, Robert; Desmedt, Aline

2010-01-01

The aim of the present experiment was to directly assess the role of the glutamatergic hippocampal-lateral septal (HPC-LS) neurotransmission in tone and contextual fear conditioning. We found that pretraining infusion of glutamatergic acid into the lateral septum promotes tone conditioning and concomitantly disrupts contextual conditioning.…

Enhanced extinction of contextual fear conditioning in ClockΔ19 mutant mice.

PubMed

Bernardi, Rick E; Spanagel, Rainer

2014-08-01

Clock genes have been implicated in several disorders, such as schizophrenia, bipolar disorder, autism spectrum disorders, and drug dependence. However, few studies to date have examined the role of clock genes in fear-related behaviors. The authors used mice with the ClockΔ19 mutation to assess the involvement of this gene in contextual fear conditioning. Male wild-type (WT) and ClockΔ19 mutant mice underwent a single session of contextual fear conditioning (12 min, 4 unsignaled shocks), followed by daily 12-min retention trials. There were no differences between mutant and WT mice in the acquisition of contextual fear, and WT and mutant mice demonstrated similar freezing during the first retention session. However, extinction of contextual fear was accelerated in mutant mice across the remaining retention sessions, as compared to WT mice, suggesting a role for Clock in extinction following aversive learning. Because the ClockΔ19 mutation has previously been demonstrated to result in an increase in dopamine signaling, the authors confirmed the role of dopamine in extinction learning using preretention session administration of a low dose of the dopamine transport reuptake inhibitor modafinil (0.75 mg/kg), which resulted in decreased freezing across retention sessions. These findings are consistent with an emerging portrayal of the importance of Clock genes in noncircadian functions, as well as the important role of dopamine in extinction learning.

Intranasal Cotinine Plus Krill Oil Facilitates Fear Extinction, Decreases Depressive-Like Behavior, and Increases Hippocampal Calcineurin A Levels in Mice.

PubMed

Alvarez-Ricartes, Nathalie; Oliveros-Matus, Patricia; Mendoza, Cristhian; Perez-Urrutia, Nelson; Echeverria, Florencia; Iarkov, Alexandre; Barreto, George E; Echeverria, Valentina

2018-02-27

Failure in fear extinction is one of the more troublesome characteristics of posttraumatic stress disorder (PTSD). Cotinine facilitates fear memory extinction and reduces depressive-like behavior when administered 24 h after fear conditioning in mice. In this study, it was investigated the behavioral and molecular effects of cotinine, and other antidepressant preparations infused intranasally. Intranasal (IN) cotinine, IN krill oil, IN cotinine plus krill oil, and oral sertraline were evaluated on depressive-like behavior and fear retention and extinction after fear conditioning in C57BL/6 mice. Since calcineurin A has been involved in facilitating fear extinction in rodents, we also investigated changes of calcineurin in the hippocampus, a region key on contextual fear extinction. Short-term treatment with cotinine formulations was superior to krill oil and oral sertraline in reducing depressive-like behavior and fear consolidation and enhancing contextual fear memory extinction in mice. IN krill oil slowed the extinction of fear. IN cotinine preparations increased the levels of calcineurin A in the hippocampus of conditioned mice. In the light of the results, the future investigation of the use of IN cotinine preparations for the extinction of contextual fear memory and treatment of treatment-resistant depression (TRD) in PTSD is discussed.

A role for the anteromedial thalamic nucleus in the acquisition of contextual fear memory to predatory threats.

PubMed

de Lima, Miguel Antonio Xavier; Baldo, Marcus Vinicius C; Canteras, Newton Sabino

2017-01-01

Previous studies from our group have shown that cytotoxic lesions in the ventral portion of the anteromedial thalamic nucleus (AMv), one of the main targets of the hypothalamic predator-responsive circuit, strongly impairs contextual fear responses to an environment previously associated with a predator. The AMv is in a position to convey information to cortico-hippocampal-amygdalar circuits involved in the processing of fear memory. However, it remains to be determined whether the nucleus is involved in the acquisition or subsequent expression of contextual fear. In the present investigation, we addressed this question by inactivating the rat AMv with muscimol either prior to cat exposure or prior to exposure to the cat-related context. Accordingly, AMv pharmacological inactivation prior to cat exposure did not interfere with innate fear responses, but it drastically reduced contextual conditioning to the predator-associated environment. On the other hand, AMv inactivation prior to exposure to the environment associated with the predator threat did not affect contextual fear responses. The behavioral results were further supported by the demonstration that AMv inactivation prior to cat exposure also blocked the activation of sites critically involved in the expression of anti-predatory contextual defensive responses (i.e., the dorsal premammillary nucleus and the dorsolateral periaqueductal gray) in animals exposed to the predator-associated context. The AMv projections were also examined, and the results of this investigation outline important paths that can influence hippocampal circuitry and raise new ideas for anterior thalamic-hippocampal paths involved in emotional learning.

Differential Effects of Cannabinoid Receptor Agonist on Social Discrimination and Contextual Fear in Amygdala and Hippocampus

ERIC Educational Resources Information Center

Segev, Amir; Akirav, Irit

2011-01-01

We examined whether the cannabinoid receptor agonist WIN55,212-2 (WIN; 5 [mu]g/side) microinjected into the hippocampus or the amygdala would differentially affect memory processes in a neutral vs. an aversive task. In the aversive contextual fear task, WIN into the basolateral amygdala impaired fear acquisition/consolidation, but not retrieval.…

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

ERIC Educational Resources Information Center

Wilson, Yvette M.; Murphy, Mark

2009-01-01

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

G protein-gated K+ channel ablation in forebrain pyramidal neurons selectively impairs fear learning

PubMed Central

Victoria, Nicole C.; de Velasco, Ezequiel Marron Fernandez; Ostrovskaya, Olga; Metzger, Stefania; Xia, Zhilian; Kotecki, Lydia; Benneyworth, Michael A.; Zink, Anastasia N.; Martemyanov, Kirill A.; Wickman, Kevin

2015-01-01

Background Cognitive dysfunction occurs in many debilitating conditions including Alzheimer’s disease, Down syndrome, schizophrenia, and mood disorders. The dorsal hippocampus is a critical locus of cognitive processes linked to spatial and contextual learning. G protein-gated inwardly rectifying K+ (GIRK/Kir3) channels, which mediate the postsynaptic inhibitory effect of many neurotransmitters, have been implicated in hippocampal-dependent cognition. Available evidence, however, derives primarily from constitutive gain-of-function models that lack cellular specificity. Methods We used constitutive and neuron-specific gene ablation models targeting an integral subunit of neuronal GIRK channels (GIRK2) to probe the impact of GIRK channels on associative learning and memory. Results Constitutive Girk2−/− mice exhibited a striking deficit in hippocampal-dependent (contextual) and hippocampal-independent (cue) fear conditioning. Mice lacking GIRK2 in GABA neurons (GAD-Cre:Girk2flox/flox mice) exhibited a clear deficit in GIRK-dependent signaling in dorsal hippocampal GABA neurons, but no evident behavioral phenotype. Mice lacking GIRK2 in forebrain pyramidal neurons (CaMKII-Cre(+):Girk2flox/flox mice) exhibited diminished GIRK-dependent signaling in dorsal, but not ventral, hippocampal pyramidal neurons. CaMKII-Cre(+):Girk2flox/flox mice also displayed a selective impairment in contextual fear conditioning, as both cue-fear and spatial learning were intact in these mice. Finally, loss of GIRK2 in forebrain pyramidal neurons correlated with enhanced long-term depression and blunted depotentiation of long-term potentiation at the Schaffer collateral/CA1 synapse in the dorsal hippocampus. Conclusions Our data suggest that GIRK channels in dorsal hippocampal pyramidal neurons are necessary for normal learning involving aversive stimuli, and support the contention that dysregulation of GIRK-dependent signaling may underlie cognitive dysfunction in some disorders. PMID:26612516

The Effect of Midazolam and Propranolol on Fear Memory Reconsolidation in Ethanol-Withdrawn Rats: Influence of D-Cycloserine

PubMed Central

Ortiz, Vanesa; Giachero, Marcelo; Espejo, Pablo Javier; Molina, Víctor Alejandro

2015-01-01

Background: Withdrawal from chronic ethanol facilitates the formation of contextual fear memory and delays the onset to extinction, with its retrieval promoting an increase in ethanol consumption. Consequently, manipulations aimed to reduce these aversive memories, may be beneficial in the treatment of alcohol discontinuation symptoms. Related to this, pharmacological memory reconsolidation blockade has received greater attention due to its therapeutic potential. Methods: Here, we examined the effect of post-reactivation amnestic treatments such as Midazolam (MDZ, 3 mg/kg i.p) and Propranolol (PROP, 5 mg/kg i.p) on contextual fear memory reconsolidation in ethanol- withdrawn (ETOH) rats. Next, we examined whether the activation of N-methyl-D-aspartate (NMDA) receptors induced by d-cycloserine (DCS, 5 mg/kg i.p., a NMDA partial agonist) before memory reactivation can facilitate the disruptive effect of PROP and MDZ on fear memory in ETOH rats. Results: We observed a resistance to the disruptive effect of both MDZ and PROP following memory reactivation. Although intra-basolateral amygdala (BLA; 1.25 ug/side) and systemic PROP administration attenuated fear memory in DCS pre-treated ETOH rats, DCS/MDZ treatment did not affect memory in these animals. Finally, a decrease of both total and surface protein expression of the α1 GABAA receptor (GABAA-R) subunit in BLA was found in the ETOH rats. Conclusions: Ethanol withdrawal facilitated the formation of fear memory resistant to labilization post-reactivation. DCS administration promoted the disruptive effect of PROP on memory reconsolidation in ETOH rats. The resistance to MDZ’s disruptive effect on fear memory reconsolidation may be, at least in part, associated with changes in the GABAA-R composition induced by chronic ethanol administration/withdrawal. PMID:25617327

Context Preexposure Prevents Forgetting of a Contextual Fear Memory: Implication for Regional Changes in Brain Activation Patterns Associated with Recent and Remote Memory Tests

ERIC Educational Resources Information Center

Biedenkapp, Joseph C.; Rudy, Jerry W.

2007-01-01

Contextual fear conditioning was maintained over a 15-day retention interval suggesting no forgetting of the conditioning experience. However, a more subtle generalization test revealed that, as the retention interval increased, rats showed enhanced generalized fear to an altered context. Preexposure to the training context prior to conditioning,…

Impaired contextual modulation of memories in PTSD: an fMRI and psychophysiological study of extinction retention and fear renewal.

PubMed

Garfinkel, Sarah N; Abelson, James L; King, Anthony P; Sripada, Rebecca K; Wang, Xin; Gaines, Laura M; Liberzon, Israel

2014-10-01

Post-traumatic stress disorder (PTSD) patients display pervasive fear memories, expressed indiscriminately. Proposed mechanisms include enhanced fear learning and impaired extinction or extinction recall. Documented extinction recall deficits and failure to use safety signals could result from general failure to use contextual information, a hippocampus-dependent process. This can be probed by adding a renewal phase to standard conditioning and extinction paradigms. Human subjects with PTSD and combat controls were conditioned (skin conductance response), extinguished, and tested for extinction retention and renewal in a scanner (fMRI). Fear conditioning (light paired with shock) occurred in one context, followed by extinction in another, to create danger and safety contexts. The next day, the extinguished conditioned stimulus (CS+E) was re-presented to assess extinction recall (safety context) and fear renewal (danger context). PTSD patients showed impaired extinction recall, with increased skin conductance and heightened amygdala activity to the extinguished CS+ in the safety context. However, they also showed impaired fear renewal; in the danger context, they had less skin conductance response to CS+E and lower activity in amygdala and ventral-medial prefrontal cortex compared with combat controls. Control subjects displayed appropriate contextual modulation of memory recall, with extinction (safety) memory prevailing in the safety context, and fear memory prevailing in the danger context. PTSD patients could not use safety context to sustain suppression of extinguished fear memory, but they also less effectively used danger context to enhance fear. They did not display globally enhanced fear expression, but rather showed a globally diminished capacity to use contextual information to modulate fear expression. Copyright © 2014 the authors 0270-6474/14/3413435-09$15.00/0.

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

PubMed

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

2013-11-01

The underlying neuronal mechanisms of learning and memory have been heavily explored using associative learning paradigms. Two of the more commonly employed learning paradigms have been contextual and delay fear conditioning. In fear conditioning, a subject learns to associate a neutral stimulus (conditioned stimulus; CS), such as a tone or the context of the room, with a fear provoking stimulus (unconditioned stimulus; US), such as a mild footshock. Utilizing these two paradigms, various analyses have elegantly demonstrated that the amygdala plays a role in both fear-related associative learning paradigms. However, the amygdala's involvement in trace fear conditioning, a forebrain-dependent fear associative learning paradigm that has been suggested to tap into higher cognitive processes, has not been closely investigated. Furthermore, to our knowledge, the specific amygdala nuclei involved with trace fear conditioning has not been examined. The present study used Arc expression as an activity marker to determine the amygdala's involvement in trace fear associative learning and to further explore involvement of specific amygdalar nuclei. Arc is an immediate early gene that has been shown to be associated with neuronal activation and is believed to be necessary for neuronal plasticity. Findings from the present study demonstrated that trace-conditioned mice, compared to backward-conditioned (stimulation-control), delay-conditioned and naïve mice, exhibited elevated amygdalar Arc expression in the basolateral (BLA) but not the central (CeA) or the lateral amygdala (LA). These findings are consistent with previous reports demonstrating that the amygdala plays a critical role in trace conditioning. Furthermore, these findings parallel studies demonstrating hippocampal-BLA activation following contextual fear conditioning, suggesting that trace fear conditioning and contextual fear conditioning may involve similar amygdala nuclei. Together, findings from this study demonstrate similarities in the pathway for trace and contextual fear conditioning, and further suggest possible underlying mechanisms for acquisition and consolidation of these two types of fear-related learning. Copyright © 2013 Elsevier Inc. All rights reserved.

Early-life exposure to fibroblast growth factor-2 facilitates context-dependent long-term memory in developing rats.

PubMed

Graham, Bronwyn M; Richardson, Rick

2010-06-01

Fibroblast growth factor-2 (FGF2) is a potent neurotrophic factor that is involved in brain development and the formation of long-term memory. It has recently been shown that acute FGF2, administered at the time of learning, enhances long-term memory for contextual fear conditioning as well as extinction of conditioned fear in developing rats. As other research has shown that administering FGF2 on the first day of life leads to long-term morphological changes in the hippocampus, in the present study we investigated whether early life exposure to FGF2 affects contextual fear conditioning, and renewal following extinction, later in life. Experiment 1 demonstrated that a single injection of FGF2 on Postnatal Day (PND) 1 did not lead to any detectable changes in contextual fear conditioning in PND 16 or PND 23 rats. Experiments 2 and 3 demonstrated that 5 days of injections of FGF2 (from PND 1-5) facilitated contextual fear conditioning in PND 16 and PND 23 rats. Experiment 4 demonstrated that the observed facilitation of memory was not due to FGF2 increasing rats' sensitivity to foot shock. Experiment 5 showed that early life exposure to FGF2 did not affect learning about a discrete conditioned stimulus, but did allow PND 16 rats to use contextual information in more complex ways, leading to context-dependent extinction of conditioned fear. These results further implicate FGF2 as a critical signal involved in the development of learning and memory.

Understanding the contributions of visual stimuli to contextual fear conditioning: A proof-of-concept study using LCD screens.

PubMed

Murawski, Nathen J; Asok, Arun

2017-01-10

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.

The hippocampus integrates context and shock into a configural memory in contextual fear conditioning.

PubMed

Chang, Shih-Dar; Liang, K C

2017-02-01

Contextual fear conditioning involves forming a representation for the context and associating it with a shock, which were attributed by the prevailing view to functions of the hippocampus and amygdala, respectively. Yet our recent evidence suggested that both processes require integrity of the dorsal hippocampus (DH). In view of the DH involvement in uniting multiple stimuli into a configuration, this study examined whether the DH would integrate context and shock into a shocked-context representation. Male Wistar rats were trained on a two-phase training paradigm of contextual fear conditioning. They explored a novel context on the first day to acquire a contextual representation, and received a shock in that context on the second day to form the context-shock memory. Tests of conditioned freezing given on the following days revealed two properties of configural memory-direct and mediated pattern completion: First, the contextual fear memory was retrieved in a novel context by a cue embedded in the configural set-a shock that did not elicit significant freezing on its own. Second, freezing was also elicited in a novel context by a transportation chamber that was not directly paired with the shock but could activate the fear memory inferentially. The effects were specific to the cue and not due to context generalization. Infusion of lidocaine into the DH, but not the amygdala, immediately after context-shock training impaired conditioned freezing elicited through either type of pattern completion. Our data suggest that the DH in contextual fear conditioning associates context and shock in parallel with the amygdala by incorporating the shock into an otherwise neutral context representation and turning it into a shocked-context representation. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Oxytocin receptor antagonist atosiban impairs consolidation, but not reconsolidation of contextual fear memory in rats.

PubMed

Abdullahi, Payman Rasise; Eskandarian, Sharaf; Ghanbari, Ali; Rashidy-Pour, Ali

2018-05-23

There is increasing evidence that oxytocin is involved in learning and memory process. This study investigated the effects of blockade of oxytocin receptors using the selective oxytocin receptor antagonist atosiban (ATO) on contextual fear memory consolidation and reconsolidation in male rats. Post-training injections of different doses of ATO (1, 10, 100 or 1000 µg/kg) impaired the 48 h retention performance in a dose-dependent manner. The same doses of ATO following memory reactivation did not impair subsequent expression of contextual fear memories which formed under low or high shock intensities and tested 24 h or one week following memory reactivation. Also, no effect was found when ATO was administrated in the absence of memory reactivation. Our finding is the first report that indicates endogenous oxytocin released during training play an important role in the consolidation, but not reconsolidation of contextual fear memory in rats. Copyright © 2018. Published by Elsevier B.V.

Activation of alpha2 adrenergic receptors suppresses fear conditioning: expression of c-Fos and phosphorylated CREB in mouse amygdala.

PubMed

Davies, M Frances; Tsui, Janet; Flannery, Judy A; Li, Xiangqi; DeLorey, Timothy M; Hoffman, Brian B

2004-02-01

alpha(2) adrenergic agonists such as dexmedetomidine generally suppress noradrenergic transmission and have sedative, analgesic, and antihypertensive properties. Considering the importance of the neurotransmitter norepinephrine in forming memories for fearful events, we have investigated the acute and chronic effects of dexmedetomidine on discrete cue and contextual fear conditioning in mice. When administered before training, dexmedetomidine (10-20 microg/kg, i.p.) selectively suppressed discrete cue fear conditioning without affecting contextual memory. This behavioral change was associated with a decrease in memory retrieval-induced expression of c-Fos and P-CREB in the lateral, basolateral, and central nuclei of the amygdala. Dexmedetomidine's action on discrete cue memory did not occur in alpha(2A) adrenoceptor knockout (KO) mice. When dexmedetomidine was administered after training, it suppressed contextual memory, an effect that did not occur in alpha(2A) adrenoceptor KO mice. We conclude that dexmedetomidine, acting at alpha(2A) adrenoceptors, must be present during the encoding process to decrease discrete cue fear memory; however, its ability to suppress contextual memory is likely the result of blocking the consolidation process. The ability of alpha(2) agonists to suppress fear memory may be a valuable property clinically in order to suppress the formation of memories during stressful situations.

Glycyrrhizin Treatment Facilitates Extinction of Conditioned Fear Responses After a Single Prolonged Stress Exposure in Rats.

PubMed

Lai, Shuhua; Wu, Gangwei; Jiang, Zhixian

2018-01-01

Impaired fear memory extinction is widely considered a key mechanism of post-traumatic stress disorder (PTSD). Recent studies have suggested that neuroinflammation after a single prolonged stress (SPS) exposure may play a critical role in the impaired fear memory extinction. Studies have shown that high mobility group box chromosomal protein 1 (HMGB-1) is critically involved in neuroinflammation. However, the role of HMGB-1 underlying the development of impairment of fear memory extinction is still not known. Thus, we examined the levels of HMGB-1 in the basolateral amygdala (BLA) following SPS using Western blot and evaluated the levels of microglia and astrocytes activation in the BLA after SPS using immunohistochemical staining. We then examined the effects of pre-SPS intra-BLA administration of glycyrrhizin, an HMGB1 inhibitor, or LPS-RS, a competitive TLR4 antagonist, on subsequent post-SPS fear extinction. We found that SPS treatment prolonged the extinction of contextual fear memory after the SPS. The impairment of SPS-induced extinction of contextual fear memory was associated with increased HMGB1 and Toll-like receptor 4 (TLR4) levels in the BLA. Additionally, the impairment of SPS-induced extinction of contextual fear memory was associated with increased activation of microglia and astrocyte in the BLA. Intra-BLA administrations of glycyrrhizin (HMGB-1 inhibitor) or LPS-RS (TLR4 antagonist) can prevent the development of SPS-induced fear extinction impairment. Taken together, these results suggested that SPS treatment may not only produce short term effects on the HMGB1/TLR4-mediated pro-inflammation, but alter the response of microglia and astrocytes to the exposure to fear associated contextual stimuli. © 2018 The Author(s). Published by S. Karger AG, Basel.

Impaired right inferior frontal gyrus response to contextual cues in male veterans with PTSD during response inhibition

PubMed Central

van Rooij, Sanne J.H.; Rademaker, Arthur R.; Kennis, Mitzy; Vink, Matthijs; Kahn, René S.; Geuze, Elbert

2014-01-01

Background Posttraumatic stress disorder (PTSD) is often associated with impaired fear inhibition and decreased safety cue processing; however, studies capturing the cognitive aspect of inhibition and contextual cue processing are limited. In this fMRI study, the role of contextual cues in response inhibition was investigated. Methods Male medication-naive war veterans with PTSD, male control veterans (combat controls) and healthy nonmilitary men (healthy controls) underwent fMRI while performing the stop-signal anticipation task (SSAT). The SSAT evokes 2 forms of response inhibition: reactive inhibition (outright stopping) and proactive inhibition (anticipation of stopping based on contextual cues). Results We enrolled 28 veterans with PTSD, 26 combat controls and 25 healthy controls in our study. Reduced reactive inhibition was observed in all veterans, both with and without PTSD, but not in nonmilitary controls, whereas decreased inhibition of the left pre/postcentral gyrus appeared to be specifically associated with PTSD. Impaired behavioural proactive inhibition was also specific to PTSD. Furthermore, the PTSD group showed a reduced right inferior frontal gyrus response during proactive inhibition compared with the combat control group. Limitations Most patients with PTSD had comorbid psychiatric disorders, but such comorbidity is common in patients with PTSD. Also, the education level (estimate of intelligence) of participants, but not of their parents, differed among the groups. Conclusion Our findings of reduced proactive inhibition imply that patients with PTSD show reduced contextual cue processing. These results complement previous findings on fear inhibition and demonstrate that contextual cue processing in patients with PTSD is also reduced during cognitive processes, indicating a more general deficit. PMID:24886789

Prior exposure to a single stress session facilitates subsequent contextual fear conditioning in rats. Evidence for a role of corticosterone.

PubMed

Cordero, M Isabel; Venero, Cesar; Kruyt, Nyika D; Sandi, Carmen

2003-11-01

Previous studies showed that exposure of rats to chronic restraint stress for 21 days enhances subsequent contextual fear conditioning. Since recent evidence suggest that this effect is not dependent on stress-induced neurodegenerative processes, but to elevated training-elicited glucocorticoid release in chronically stressed animals, we aimed to explore here whether a single exposure to restraint stress, which is not expected to induce neuronal damage, would also affect contextual fear conditioning. We also questioned whether post-training corticosterone levels might be associated with any potential effect of stress on fear conditioning. Adult male Wistar rats were exposed to acute restraint stress for 2 h and, two days later, trained in the contextual fear conditioning task, under training conditions involving either moderate (0.4 mA shock) or high (1 mA shock) stress levels. The results showed that acute stress enhanced conditioned freezing at both training conditions, although data from the 1 mA shock intensity experiment only approached significance. Stressed animals were shown to display higher post-training corticosterone levels. Furthermore, the facilitating effect of prior stress was not evident when animals were trained in the hippocampal-independent auditory-cued conditioning task. Therefore, these findings support the idea that stress experiences preceding exposure to new types of stressors facilitate the development of contextual fear conditioning. They also indicate that not only repeated, but also a single exposure to aversive stimulation is sufficient to facilitate context-dependent fear conditioning, and suggest that increased glucocorticoid release at training might be implicated in the mechanisms mediating the memory facilitating effects induced by prior stress experiences.

Medial prefrontal cortex serotonergic and GABAergic mechanisms modulate the expression of contextual fear: intratelencephalic pathways and differential involvement of cortical subregions.

PubMed

Almada, R C; Coimbra, N C; Brandão, M L

2015-01-22

Several lines of evidence indicate that the dorsal hippocampus (dH) and medial prefrontal cortex (mPFC) regulate contextual fear conditioning. The prelimbic (PrL), infralimbic (IL) and the anterior cingulate cortex (ACC) subregions of the mPFC likely play distinct roles in the expression of fear. Moreover, studies have highlighted the role of serotonin (5-hydroxytryptamine, 5-HT)- and γ-aminobutyric acid (GABA)-mediated mechanisms in the modulation of innate fear in the mPFC. The present study characterized dH-mPFC pathways and investigated the role of serotonergic and GABAergic mechanisms of the PrL, IL and ACC-area 1 (Cg1) in the elaboration of contextual fear conditioning using fear-potentiated startle (FPS) and freezing behavior in Rattus norvegicus. The results of neurotracing with microinjections of biotinylated dextran amine into the dH revealed a neural link of the dH with the PrL and ACC. Intra-PrL injections of the 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) and the GABAA receptor-selective agonist muscimol reduced contextual FPS and freezing responses. Intra-Cg1 injections of muscimol but not 8-OH-DPAT decreased FPS and freezing responses. However, neither intra-IL injections of a 5-HT1A agonist nor of a GABAA agonist affected these defensive responses. Labeled neuronal fibers from the dH reached the superficial layers of the PrL cortex and spread to the inner layers of PrL and Cg1 cortices, supporting the pharmacological findings. The present results confirmed the involvement of PrL and Cg1 in the expression of FPS and freezing responses to aversive conditions. In addition, PrL serotoninergic mechanisms play a key role in contextual fear conditioning. This study suggests that PrL, IL and Cg1 distinctively contribute to the modulation of contextual fear conditioning. Copyright © 2014 IBRO. Published by Elsevier Ltd. All rights reserved.

Activity of the anterior cingulate cortex and ventral hippocampus underlie increases in contextual fear generalization.

PubMed

Cullen, Patrick K; Gilman, T Lee; Winiecki, Patrick; Riccio, David C; Jasnow, Aaron M

2015-10-01

Memories for context become less specific with time resulting in animals generalizing fear from training contexts to novel contexts. Though much attention has been given to the neural structures that underlie the long-term consolidation of a context fear memory, very little is known about the mechanisms responsible for the increase in fear generalization that occurs as the memory ages. Here, we examine the neural pattern of activation underlying the expression of a generalized context fear memory in male C57BL/6J mice. Animals were context fear conditioned and tested for fear in either the training context or a novel context at recent and remote time points. Animals were sacrificed and fluorescent in situ hybridization was performed to assay neural activation. Our results demonstrate activity of the prelimbic, infralimbic, and anterior cingulate (ACC) cortices as well as the ventral hippocampus (vHPC) underlie expression of a generalized fear memory. To verify the involvement of the ACC and vHPC in the expression of a generalized fear memory, animals were context fear conditioned and infused with 4% lidocaine into the ACC, dHPC, or vHPC prior to retrieval to temporarily inactivate these structures. The results demonstrate that activity of the ACC and vHPC is required for the expression of a generalized fear memory, as inactivation of these regions returned the memory to a contextually precise form. Current theories of time-dependent generalization of contextual memories do not predict involvement of the vHPC. Our data suggest a novel role of this region in generalized memory, which should be incorporated into current theories of time-dependent memory generalization. We also show that the dorsal hippocampus plays a prolonged role in contextually precise memories. Our findings suggest a possible interaction between the ACC and vHPC controls the expression of fear generalization. Copyright © 2015 Elsevier Inc. All rights reserved.

Fear-Conditioning Mechanisms Associated with Trait Vulnerability to Anxiety in Humans

PubMed Central

Indovina, Iole; Robbins, Trevor W.; Núñez-Elizalde, Anwar O.; Dunn, Barnaby D.; Bishop, Sonia J.

2011-01-01

Summary Investigations of fear conditioning in rodents and humans have illuminated the neural mechanisms underlying cued and contextual fear. A critical question is how personality dimensions such as trait anxiety act through these mechanisms to confer vulnerability to anxiety disorders, and whether humans' ability to overcome acquired fears depends on regulatory skills not characterized in animal models. In a neuroimaging study of fear conditioning in humans, we found evidence for two independent dimensions of neurocognitive function associated with trait vulnerability to anxiety. The first entailed increased amygdala responsivity to phasic fear cues. The second involved impoverished ventral prefrontal cortical (vPFC) recruitment to downregulate both cued and contextual fear prior to omission (extinction) of the aversive unconditioned stimulus. These two dimensions may contribute to symptomatology differences across anxiety disorders; the amygdala mechanism affecting the development of phobic fear and the frontal mechanism influencing the maintenance of both specific fears and generalized anxiety. PMID:21315265

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

PubMed

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

2017-07-01

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

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

PubMed Central

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

2017-01-01

There is evidence that pain can impact cognitive function in people. The present study evaluated whether Pavlovian fear conditioning in rats would be reduced if conditioning were followed by persistent inflammatory pain induced by a subcutaneous injection of dilute formalin or complete Freund's adjuvant (CFA) on the dorsal lumbar surface of the back. Formalin-induced pain specifically impaired contextual fear conditioning but not auditory cue conditioning (Experiment 1A). Moreover, formalin pain only impaired contextual fear conditioning if it was initiated within 1 h of conditioning and did not have a significant effect if initiated 2, 8 or 32 h after (Experiments 1A and 1B). Experiment 2 showed that formalin pain initiated after a session of context pre-exposure reduced the ability of that pre-exposure to facilitate contextual fear when the rat was limited to a brief exposure to the context during conditioning. Similar impairments in context- but not CS-fear conditioning were also observed if the rats received an immediate post-conditioning injection with CFA (Experiment 3). Finally, we confirmed that formalin and CFA injected s.c. on the back induced pain-indicative behaviours, hyperalgesia and allodynia with a similar timecourse to intraplantar injections (Experiment 4). These results suggest that persistent pain impairs learning in a hippocampus-dependent task, and may disrupt processes that encode experiences into long-term memory. PMID:21920390

Fear Conditioning is Disrupted by Damage to the Postsubiculum

PubMed Central

Robinson, Siobhan; Bucci, David J.

2011-01-01

The hippocampus plays a central role in spatial and contextual learning and memory, however relatively little is known about the specific contributions of parahippocampal structures that interface with the hippocampus. The postsubiculum (PoSub) is reciprocally connected with a number of hippocampal, parahippocampal and subcortical structures that are involved in spatial learning and memory. In addition, behavioral data suggest that PoSub is needed for optimal performance during tests of spatial memory. Together, these data suggest that PoSub plays a prominent role in spatial navigation. Currently it is unknown whether the PoSub is needed for other forms of learning and memory that also require the formation of associations among multiple environmental stimuli. To address this gap in the literature we investigated the role of PoSub in Pavlovian fear conditioning. In Experiment 1 male rats received either lesions of PoSub or Sham surgery prior to training in a classical fear conditioning procedure. On the training day a tone was paired with foot shock three times. Conditioned fear to the training context was evaluated 24 hr later by placing rats back into the conditioning chamber without presenting any tones or shocks. Auditory fear was assessed on the third day by presenting the auditory stimulus in a novel environment (no shock). PoSub-lesioned rats exhibited impaired acquisition of the conditioned fear response as well as impaired expression of contextual and auditory fear conditioning. In Experiment 2, PoSub lesions were made 1 day after training to specifically assess the role of PoSub in fear memory. No deficits in the expression of contextual fear were observed, but freezing to the tone was significantly reduced in PoSub-lesioned rats compared to shams. Together, these results indicate that PoSub is necessary for normal acquisition of conditioned fear, and that PoSub contributes to the expression of auditory but not contextual fear memory. PMID:22076971

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

PubMed

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

2012-05-01

Epigenetic regulation of chromatin structure is an essential molecular mechanism that contributes to the formation of synaptic plasticity and long-term memory (LTM). An important regulatory process of chromatin structure is acetylation and deacetylation of histone proteins. Inhibition of histone deacetylase (HDAC) increases acetylation of histone proteins and facilitate learning and memory. Nitric oxide (NO) signaling pathway has a role in synaptic plasticity, LTM and regulation of histone acetylation. We have previously shown that NO signaling pathway is required for contextual fear conditioning. The present study investigated the effects of systemic administration of the HDAC inhibitor sodium butyrate (NaB) on fear conditioning in neuronal nitric oxide synthase (nNOS) knockout (KO) and wild type (WT) mice. The effect of single administration of NaB on total H3 and H4 histone acetylation in hippocampus and amygdala was also investigated. A single administration of NaB prior to fear conditioning (a) rescued contextual fear conditioning of nNOS KO mice and (b) had long-term (weeks) facilitatory effect on the extinction of cued fear memory of WT mice. The facilitatory effect of NaB on extinction of cued fear memory of WT mice was confirmed in a study whereupon NaB was administered during extinction. Results suggest that (a) the rescue of contextual fear conditioning in nNOS KO mice is associated with NaB-induced increase in H3 histone acetylation and (b) the accelerated extinction of cued fear memory in WT mice is associated with NaB-induced increase in H4 histone acetylation. Hence, a single administration of HDAC inhibitor may rescue NO-dependent cognitive deficits and afford a long-term accelerating effect on extinction of fear memory of WT mice. Copyright © 2012 Elsevier Inc. All rights reserved.

The effect of ketamine on the consolidation and extinction of contextual fear memory

PubMed Central

Thomas, Kerrie L; Hall, Jeremy

2018-01-01

Ketamine, principally an antagonist of N-methyl-ᴅ-aspartate receptors, induces schizophrenia-like symptoms in adult humans, warranting its use in the investigation of psychosis-related phenotypes in animal models. Genomic studies further implicate N-methyl-ᴅ-aspartate receptor-mediated processes in schizophrenia pathology, together with more broadly-defined synaptic plasticity and associative learning processes. Strong pathophysiological links have been demonstrated between fear learning and psychiatric disorders such as schizophrenia. To further investigate the impact of ketamine on associative fear learning, we studied the effects of pre- and post-training ketamine on the consolidation and extinction of contextual fear memory in rats. Administration of 25 mg/kg ketamine prior to fear conditioning did not affect consolidation when potentially confounding effects of state dependency were controlled for. Pre-training ketamine (25 mg/kg) impaired the extinction of the conditioned fear response, which was mirrored with the use of a lower dose (8 mg/kg). Post-training ketamine (25 mg/kg) had no effect on the consolidation or extinction of conditioned fear. These observations implicate processes relating to the extinction of contextual fear memory in the manifestation of ketamine-induced phenotypes, and are consistent with existing hypotheses surrounding abnormal associative learning in schizophrenia. PMID:29338491

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

PubMed

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

2014-12-01

Hippocampus-dependent learning is known to induce changes in gene expression, but information on gene expression differences between different learning paradigms that require the hippocampus is limited. The bulk of studies investigating RNA expression after learning use the contextual fear conditioning task, which couples a novel environment with a footshock. Although contextual fear conditioning has been useful in discovering gene targets, gene expression after spatial memory tasks has received less attention. In this study, we used the object-location memory task and studied gene expression at two time points after learning in a high-throughput manner using a microfluidic qPCR approach. We found that expression of the classic immediate-early genes changes after object-location training in a fashion similar to that observed after contextual fear conditioning. However, the temporal dynamics of gene expression are different between the two tasks, with object-location memory producing gene expression changes that last at least 2 hours. Our findings indicate that different training paradigms may give rise to distinct temporal dynamics of gene expression after learning. Copyright © 2014 Elsevier Inc. All rights reserved.

Object-Location Training Elicits an Overlapping but Temporally Distinct Transcriptional Profile from Contextual Fear Conditioning

PubMed Central

Wimmer, Mathieu; Hawk, Joshua D.; Walsh, Jennifer L.; Giese, Karl P.; Abel, Ted

2014-01-01

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

Post-training gamma irradiation-enhanced contextual fear memory associated with reduced neuronal activation of the infralimbic cortex.

PubMed

Kugelman, Tara; Zuloaga, Damian G; Weber, Sydney; Raber, Jacob

2016-02-01

The brain might be exposed to irradiation under a variety of situations, including clinical treatments, nuclear accidents, dirty bomb scenarios, and military and space missions. Correctly recalling tasks learned prior to irradiation is important but little is known about post-learning effects of irradiation. It is not clear whether exposure to X-ray irradiation during memory consolidation, a few hours following training, is associated with altered contextual fear conditioning 24h after irradiation and which brain region(s) might be involved in these effects. Brain immunoreactivity patterns of the immediately early gene c-Fos, a marker of cellular activity was used to determine which brain areas might be altered in post-training irradiation memory retention tasks. In this study, we show that post-training gamma irradiation exposure (1 Gy) enhanced contextual fear memory 24h later and is associated with reduced cellular activation in the infralimbic cortex. Reduced GABA-ergic neurotransmission in parvalbumin-positive cells in the infralimbic cortex might play a role in this post-training radiation-enhanced contextual fear memory. Copyright © 2015 Elsevier B.V. All rights reserved.

Post-training gamma irradiation-enhanced contextual fear memory associated with reduced neuronal activation of the infralimbic cortex

PubMed Central

Kugelman, Tara; Zuloaga, Damian G.; Weber, Sydney; Raber, Jacob

2015-01-01

The brain might be exposed to irradiation under a variety of situations, including clinical treatments, nuclear accidents, dirty bomb scenarios, and military and space missions. Correctly recalling tasks learned prior to irradiation is important but little is known about post-learning effects of irradiation. It is not clear whether exposure to X-ray irradiation during memory consolidation, a few hours following training, is associated with altered contextual fear conditioning 24 hours after irradiation and which brain region(s) might be involved in these effects. Brain immunoreactivity patterns of the immediately early gene c-Fos, a marker of cellular activity was used to determine which brain areas might be altered in post-training irradiation memory retention tasks. In this study, we show that post-training gamma irradiation exposure (1 Gy) enhanced contextual fear memory 24 hours later and is associated with reduced cellular activation in the infralimbic cortex. Reduced GABA-ergic neurotransmission in parvalbumin-positive cells in the infralimbic cortex might play a role in this post-training radiation-enhanced contextual fear memory. PMID:26522840

Elevation of Hippocampal Neurogenesis Induces a Temporally Graded Pattern of Forgetting of Contextual Fear Memories.

PubMed

Gao, Aijing; Xia, Frances; Guskjolen, Axel J; Ramsaran, Adam I; Santoro, Adam; Josselyn, Sheena A; Frankland, Paul W

2018-03-28

Throughout life neurons are continuously generated in the subgranular zone of the hippocampus. The subsequent integration of newly generated neurons alters patterns of dentate gyrus input and output connectivity, potentially rendering memories already stored in those circuits harder to access. Consistent with this prediction, we previously showed that increasing hippocampal neurogenesis after training induces forgetting of hippocampus-dependent memories, including contextual fear memory. However, the brain regions supporting contextual fear memories change with time, and this time-dependent memory reorganization might regulate the sensitivity of contextual fear memories to fluctuations in hippocampal neurogenesis. By virally expressing the inhibitory designer receptor exclusively activated by designer drugs, hM4Di, we first confirmed that chemogenetic inhibition of dorsal hippocampal neurons impairs retrieval of recent (day-old) but not remote (month-old) contextual fear memories in male mice. We then contrasted the effects of increasing hippocampal neurogenesis at recent versus remote time points after contextual fear conditioning in male and female mice. Increasing hippocampal neurogenesis immediately following training reduced conditioned freezing when mice were replaced in the context 1 month later. In contrast, when hippocampal neurogenesis was increased time points remote to training, conditioned freezing levels were unaltered when mice were subsequently tested. These temporally graded forgetting effects were observed using both environmental and genetic interventions to increase hippocampal neurogenesis. Our experiments identify memory age as a boundary condition for neurogenesis-mediated forgetting and suggest that, as contextual fear memories mature, they become less sensitive to changes in hippocampal neurogenesis levels because they no longer depend on the hippocampus for their expression. SIGNIFICANCE STATEMENT New neurons are generated in the hippocampus throughout life. As they integrate into the hippocampus, they remodel neural circuitry, potentially making information stored in those circuits harder to access. Consistent with this, increasing hippocampal neurogenesis after learning induces forgetting of the learnt information. The current study in mice asks whether these forgetting effects depend on the age of the memory. We found that post-training increases in hippocampal neurogenesis only impacted recently acquired, and not remotely acquired, hippocampal memories. These experiments identify memory age as a boundary condition for neurogenesis-mediated forgetting, and suggest remote memories are less sensitive to changes in hippocampal neurogenesis levels because they no longer depend critically on the hippocampus for their expression. Copyright © 2018 the authors 0270-6474/18/383190-09$15.00/0.

BDNF-TrkB signaling through Erk1/2MAPK phosphorylation mediates the enhancement of fear memory induced by glucocorticoids

PubMed Central

Revest, J-M; Le Roux, A; Roullot-Lacarrière, V; Kaouane, N; Vallée, M; Kasanetz, F; Rougé-Pont, F; Tronche, F; Desmedt, A; Piazza, P V

2014-01-01

Activation of glucocorticoid receptors (GR) by glucocorticoid hormones (GC) enhances contextual fear memories through the activation of the Erk1/2MAPK signaling pathway. However, the molecular mechanism mediating this effect of GC remains unknown. Here we used complementary molecular and behavioral approaches in mice and rats and in genetically modified mice in which the GR was conditionally deleted (GRNesCre). We identified the tPA-BDNF-TrkB signaling pathway as the upstream molecular effectors of GR-mediated phosphorylation of Erk1/2MAPK responsible for the enhancement of contextual fear memory. These findings complete our knowledge of the molecular cascade through which GC enhance contextual fear memory and highlight the role of tPA-BDNF-TrkB-Erk1/2MAPK signaling pathways as one of the core effectors of stress-related effects of GC. PMID:24126929

Contextual Fear Memories Formed in the Absence of the Dorsal Hippocampus Decay Across Time

PubMed Central

Zelikowsky, Moriel; Bissiere, Stephanie; Fanselow, Michael S.

2012-01-01

Mammals suffering damage to the hippocampus display a dramatic loss of explicit, recently formed memories (retrograde amnesia). In contrast, deficits in the ability to form new memories following hippocampal damage (anterograde amnesia) can be overcome with sufficient training. By combining contextual fear conditioning with lesions of the dorsal hippocampus in rats, we discovered that while animals can form long-term contextual fear memories in the absence of the hippocampus, these memories decay with time, lacking the permanence that is a hallmark characteristic of normal fear memories. These findings indicate that while it is initially possible to acquire explicit memories when the hippocampus is compromised, these memories cannot transfer from a recent to remote state. This suggests that memories formed outside the hippocampus may nevertheless require the hippocampus to undergo systems consolidation, which has important clinical implications for the treatment of memory disorders. PMID:22399761

On the transition from reconsolidation to extinction of contextual fear memories

PubMed Central

Flavell, Charlotte R.; Lee, Jonathan L.C.

2017-01-01

Retrieval of an associative memory can lead to different phenomena. Brief reexposure sessions tend to trigger reconsolidation, whereas more extended ones trigger extinction. In appetitive and fear cued Pavlovian memories, an intermediate “null point” period has been observed where neither process seems to be engaged. Here we investigated whether this phenomenon extends to contextual fear memory. Adult rats were subjected to a contextual fear conditioning paradigm, reexposed to the context 2 d later for 3, 5, 10, 20, or 30 min, with immediate injections of MK-801 or saline following reexposure, and tested on the following day. We observed a significant effect of MK-801 with the 3- and 30-min sessions, impairing reconsolidation and extinction, respectively. However, it did not have significant effects with 5-, 10-, or 20-min sessions, even though freezing decreased from reexposure to test. Further analyses indicated that this is not likely to be due to a variable transition point at the population level. In conclusion, the results show that in contextual fear memories there is a genuine “null point” between the parameters that induce reconsolidation and extinction, as defined by the effects of MK-801, although NMDA receptor-independent decreases in freezing can still occur in these conditions. PMID:28814464

Allopregnanolone induces state-dependent fear via the bed nucleus of the stria terminalis

PubMed Central

Acca, Gillian M.; Mathew, Abel S.; Jin, Jingji; Maren, Stephen; Nagaya, Naomi

2017-01-01

Gonadal steroids and their metabolites have been shown to be important modulators of emotional behavior. Allopregnanolone (ALLO), for example, is a metabolite of progesterone that has been linked to anxiety-related disorders such as posttraumatic stress disorder. In rodents, it has been shown to reduce anxiety in a number of behavioral paradigms including Pavlovian fear conditioning. We have recently found that expression of conditioned contextual (but not auditory) freezing in rats can be suppressed by infusion of ALLO into the bed nucleus of the stria terminalis (BNST). To further explore the nature of this effect, we infused ALLO into the BNST of male rats prior to both conditioning and testing. We found that suppression of contextual fear occurred when the hormone was present during either conditioning or testing but not during both procedures, suggesting that ALLO acts in a state-dependent manner within the BNST. A shift in interoceptive context during testing for animals conditioned under ALLO provided further support for this mechanism of hormonal action on contextual fear. Interestingly, infusions of ALLO into the basolateral amygdala produced a state-independent suppression of both conditioned contextual and auditory freezing. Altogether, these results suggest that ALLO can influence the acquisition and expression of fear memories by both state-dependent and state-independent mechanisms. PMID:28104355

Inhaled Lavandula angustifolia essential oil inhibits consolidation of contextual- but not tone-fear conditioning in rats.

PubMed

Coelho, Laura Segismundo; Correa-Netto, Nelson Francisco; Masukawa, Marcia Yuriko; Lima, Ariadiny Caetano; Maluf, Samia; Linardi, Alessandra; Santos-Junior, Jair Guilherme

2018-04-06

Although the current treatment for anxiety is effective, it promotes a number of adverse reactions and medical interactions. Inhaled essential oils have a prominent action on the central nervous system, with minimal systemic effects, primarily because of reduced systemic bioavailability. The effects of drugs on the consolidation of fear conditioning reflects its clinical efficacy in preventing a vicious cycle of anticipatory anxiety leading to fearful cognition and anxiety symptoms. In this study, we investigated the effects of inhaled Lavandula angustifolia essential oil on the consolidation of aversive memories and its influence on c-Fos expression. Adult male Wistar rats were subjected to a fear conditioning protocol. Immediately after the training session, the rats were exposed to vaporized water or essential oil (1%, 2.5% and 5% solutions) for 4h. The next day, the rats underwent contextual- or tone-fear tests and 90min after the test they were euthanized and their brains processed for c-Fos immunohistochemistry. In the contextual-fear test, essential oil at 2.5% and 5% (but not 1%) reduced the freezing response and its respective c-Fos expression in the ventral hippocampus and amygdala. In the tone-fear test, essential oil did not reduce the freezing response during tone presentation. However, rats that inhaled essential oil at 2.5% and 5% (but not 1%) showed decreased freezing in the three minutes after tone presentation, as well as reduced c-Fos expression in the prefrontal cortex and amygdala. These results show that the inhalation of L. angustifolia essential oil inhibited the consolidation of contextual- but not tone-fear conditioning and had an anxiolytic effect in a conditioned animal model of anxiety. Copyright © 2018 Elsevier B.V. All rights reserved.

Sexual behavior modulates contextual fear memory through dopamine D1/D5 receptors.

PubMed

Bai, Hua-Yi; Cao, Jun; Liu, Na; Xu, Lin; Luo, Jian-Hong

2009-03-01

Traumatic events always lead to aversive emotional memory, i.e., fear memory. In contrast, positive events in daily life such as sex experiences seem to reduce aversive memory after aversive events. Thus, we hypothesized that post-traumatic pleasurable experiences, especially instinctive behaviors such as sex, might modulate traumatic memory through a memory competition mechanism. Here, we first report that male rats persistently expressed much lower fear responses when exposed to females, but not when exposed to males, for 24 h immediately after contextual fear conditioning. Remarkably, this effect of sexual behavior was blocked by either systemic or intrahippocampal injection of the dopamine D1/D5 receptor antagonist R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (SCH23390) and was mimicked by systemic but not intrahippocampal injection of the D1/D5 receptor agonist R(+)-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7,8-diol hydrochloride (SKF39393). Furthermore, as a candidate mechanism underlying contextual fear memory, the impaired induction of hippocampal long-term potentiation (LTP) elicited by conditioned fear was rescued in male rats immediately exposed to female but not male rats for 24 h. Systemic injection of the dopamine D1/D5 receptor antagonist SCH23390 or agonist SKF38393 prevented or mimicked the effect of sexual behavior on the impaired induction of hippocampal LTP. Thus, our finding suggests that dopaminergic functions may, at least partially, govern competition between contextual fear and enjoyable memories through the modulation of hippocampal LTP.

Hippocampal and extrahippocampal systems compete for control of contextual fear: Role of ventral subiculum and amygdala

PubMed Central

Biedenkapp, Joseph C.; Rudy, Jerry W.

2009-01-01

Two neural systems, a hippocampal system and an extrahippocampal system compete for control over contextual fear, and the hippocampal system normally dominates. Our experiments reveal that output provided by the ventral subiculum is critical for the hippocampal system to win this competition. Bilateral electrolytic lesions of the ventral subiculum after conditioning, but not before conditioning, impaired contextual fear conditioning. Reversibly inactivating this region by bilateral injections of muscimol produced the same results—no impairment when the injection occurred prior to conditioning but a significant impairment when this region was inactivated after conditioning. Thus, the extrahippocampal system can support contextual fear conditioning if the ventral subiculum is disabled before conditioning but not if it is disabled after conditioning. Our experiments also reveal that the basolateral region of the amygdala (BLA) is where the two systems compete for associative control of the fear system. To test this hypothesis we reasoned that the extrahippocampal system would also acquire associative control over the fear system, even if the hippocampal system were functional, if the basal level of plasticity potential in the BLA could be increased. We did this by injecting the D1 dopamine agonist, SKF82958, into the BLA just prior to conditioning. This treatment resulted in a significant increase in freezing when the ventral subiculum was disabled prior to the test. These results are discussed in relationship to the idea that D1 agonists increase plasticity potential by increasing the pool of available extrasynaptic GluR1 receptors in the population of neurons supporting acquired fear. PMID:19117915

No effect of glucose administration in a novel contextual fear generalization protocol in rats

PubMed Central

Luyten, L; Schroyens, N; Luyck, K; Fanselow, M S; Beckers, T

2016-01-01

The excessive transfer of fear acquired for one particular context to similar situations has been implicated in the development and maintenance of anxiety disorders, such as post-traumatic stress disorder. Recent evidence suggests that glucose ingestion improves the retention of context conditioning. It has been speculated that glucose might exert that effect by ameliorating hippocampal functioning, and may hold promise as a therapeutic add-on in traumatized patients because improved retention of contextual fear could help to restrict its generalization. However, direct data regarding the effect of glucose on contextual generalization are lacking. Here, we introduce a new behavioral protocol to study such contextual fear generalization in rats. In adult Wistar rats, our procedure yields a gradient of generalization, with progressively less freezing when going from the original training context, over a perceptually similar generalization context, to a markedly dissimilar context. Moreover, we find a flattening of the gradient when the training-test interval is prolonged with 1 week. We next examine the effect of systemic glucose administration on contextual generalization with this novel procedure. Our data do not sustain generalization-reducing effects of glucose and question its applicability in traumatic situations. In summary, we have developed a replicable contextual generalization procedure for rats and demonstrate how it is a valuable tool to examine the neurobiological correlates and test pharmacological interventions pertaining to an important mechanism in the etiology of pathological anxiety. PMID:27676444

Disruption of medial septum and diagonal bands of Broca cholinergic projections to the ventral hippocampus disrupt auditory fear memory.

PubMed

Staib, Jennifer M; Della Valle, Rebecca; Knox, Dayan K

2018-07-01

In classical fear conditioning, a neutral conditioned stimulus (CS) is paired with an aversive unconditioned stimulus (US), which leads to a fear memory. If the CS is repeatedly presented without the US after fear conditioning, the formation of an extinction memory occurs, which inhibits fear memory expression. A previous study has demonstrated that selective cholinergic lesions in the medial septum and vertical limb of the diagonal bands of Broca (MS/vDBB) prior to fear and extinction learning disrupt contextual fear memory discrimination and acquisition of extinction memory. MS/vDBB cholinergic neurons project to a number of substrates that are critical for fear and extinction memory. However, it is currently unknown which of these efferent projections are critical for contextual fear memory discrimination and extinction memory. To address this, we induced cholinergic lesions in efferent targets of MS/vDBB cholinergic neurons. These included the dorsal hippocampus (dHipp), ventral hippocampus (vHipp), medial prefrontal cortex (mPFC), and in the mPFC and dHipp combined. None of these lesion groups exhibited deficits in contextual fear memory discrimination or extinction memory. However, vHipp cholinergic lesions disrupted auditory fear memory. Because MS/vDBB cholinergic neurons are the sole source of acetylcholine in the vHipp, these results suggest that MS/vDBB cholinergic input to the vHipp is critical for auditory fear memory. Taken together with previous findings, the results of this study suggest that MS/vDBB cholinergic neurons are critical for fear and extinction memory, though further research is needed to elucidate the role of MS/vDBB cholinergic neurons in these types of emotional memory. Copyright © 2018 Elsevier Inc. All rights reserved.

Fear-conditioning mechanisms associated with trait vulnerability to anxiety in humans.

PubMed

Indovina, Iole; Robbins, Trevor W; Núñez-Elizalde, Anwar O; Dunn, Barnaby D; Bishop, Sonia J

2011-02-10

Investigations of fear conditioning in rodents and humans have illuminated the neural mechanisms underlying cued and contextual fear. A critical question is how personality dimensions such as trait anxiety act through these mechanisms to confer vulnerability to anxiety disorders, and whether humans' ability to overcome acquired fears depends on regulatory skills not characterized in animal models. In a neuroimaging study of fear conditioning in humans, we found evidence for two independent dimensions of neurocognitive function associated with trait vulnerability to anxiety. The first entailed increased amygdala responsivity to phasic fear cues. The second involved impoverished ventral prefrontal cortical (vPFC) recruitment to downregulate both cued and contextual fear prior to omission (extinction) of the aversive unconditioned stimulus. These two dimensions may contribute to symptomatology differences across anxiety disorders; the amygdala mechanism affecting the development of phobic fear and the frontal mechanism influencing the maintenance of both specific fears and generalized anxiety. Copyright © 2011 Elsevier Inc. All rights reserved.

(+)-Borneol suppresses conditioned fear recall and anxiety-like behaviors in mice.

PubMed

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

2018-01-08

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.

Aniracetam improves contextual fear conditioning and increases hippocampal gamma-PKC activation in DBA/2J mice.

PubMed

Smith, Amy M; Wehner, Jeanne M

2002-01-01

DBA/2J (D2) mice display poor contextual learning and have less membrane-bound hippocampal protein kinase C (PKC) compared with C57BL/6 (B6) mice. Aniracetam and oxiracetam were previously shown to improve contextual learning in D2 mice and increase PKC activity. This study investigated a possible mechanism for learning enhancement by examining the effects of aniracetam on contextual fear conditioning and activation of the y isoform of PKC (gamma-PKC) in male D2 mice. In comparison to animals treated with vehicle only (10% 2-hydroxypropyl-beta-cyclodextrin), mice treated with aniracetam (100 mg/kg) 30 min prior to fear conditioning training demonstrated significantly improved contextual learning when tested 30 min and 24 h after training. This corresponded with a significant increase in activated, membrane-bound hippocampal gamma-PKC 30 min after training. No increase in learning or gamma-PKC was found 5 min after training. These results suggest an altered time course of activation of gamma-PKC in response to treatment with aniracetam, which improves learning in D2 mice.

The prelimbic cortex directs attention toward predictive cues during fear learning.

PubMed

Sharpe, Melissa J; Killcross, Simon

2015-06-01

The prelimbic cortex is argued to promote conditioned fear expression, at odds with appetitive research implicating this region in attentional processing. Consistent with an attentional account, we report that the effect of prelimbic lesions on fear expression depends on the degree of competition between contextual and discrete cues. Further, when competition from contextual cues is low, we found that PL inactivation resulted in animals expressing fear toward irrelevant discrete cues; an effect selective to inactivation during the learning phase and not during retrieval. These data demonstrate that the prelimbic cortex modulates attention toward cues to preferentially direct fear responding on the basis of their predictive value. © 2015 Sharpe and Killcross; Published by Cold Spring Harbor Laboratory Press.

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

PubMed

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

2009-10-01

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

Involvement of the Anterior Cingulate Cortex in Formation, Consolidation, and Reconsolidation of Recent and Remote Contextual Fear Memory

ERIC Educational Resources Information Center

Einarsson, Einar O.; Nader, Karim

2012-01-01

It has been suggested that memories become more stable and less susceptible to the disruption of reconsolidation over weeks after learning. Here, we test this by targeting the anterior cingulate cortex (ACC) and test its involvement in the formation, consolidation, and reconsolidation of recent and remote contextual fear memory. We found that…

Glucocorticoids interact with the hippocampal endocannabinoid system in impairing retrieval of contextual fear memory

PubMed Central

Atsak, Piray; Hauer, Daniela; Campolongo, Patrizia; Schelling, Gustav; McGaugh, James L.; Roozendaal, Benno

2012-01-01

There is extensive evidence that glucocorticoid hormones impair the retrieval of memory of emotionally arousing experiences. Although it is known that glucocorticoid effects on memory retrieval impairment depend on rapid interactions with arousal-induced noradrenergic activity, the exact mechanism underlying this presumably nongenomically mediated glucocorticoid action remains to be elucidated. Here, we show that the hippocampal endocannabinoid system, a rapidly activated retrograde messenger system, is involved in mediating glucocorticoid effects on retrieval of contextual fear memory. Systemic administration of corticosterone (0.3–3 mg/kg) to male Sprague–Dawley rats 1 h before retention testing impaired the retrieval of contextual fear memory without impairing the retrieval of auditory fear memory or directly affecting the expression of freezing behavior. Importantly, a blockade of hippocampal CB1 receptors with AM251 prevented the impairing effect of corticosterone on retrieval of contextual fear memory, whereas the same impairing dose of corticosterone increased hippocampal levels of the endocannabinoid 2-arachidonoylglycerol. We also found that antagonism of hippocampal β-adrenoceptor activity with local infusions of propranolol blocked the memory retrieval impairment induced by the CB receptor agonist WIN55,212–2. Thus, these findings strongly suggest that the endocannabinoid system plays an intermediary role in regulating rapid glucocorticoid effects on noradrenergic activity in impairing memory retrieval of emotionally arousing experiences. PMID:22331883

Allopregnanolone induces state-dependent fear via the bed nucleus of the stria terminalis.

PubMed

Acca, Gillian M; Mathew, Abel S; Jin, Jingji; Maren, Stephen; Nagaya, Naomi

2017-03-01

Gonadal steroids and their metabolites have been shown to be important modulators of emotional behavior. Allopregnanolone (ALLO), for example, is a metabolite of progesterone that has been linked to anxiety-related disorders such as posttraumatic stress disorder. In rodents, it has been shown to reduce anxiety in a number of behavioral paradigms including Pavlovian fear conditioning. We have recently found that expression of conditioned contextual (but not auditory) freezing in rats can be suppressed by infusion of ALLO into the bed nucleus of the stria terminalis (BNST). To further explore the nature of this effect, we infused ALLO into the BNST of male rats prior to both conditioning and testing. We found that suppression of contextual fear occurred when the hormone was present during either conditioning or testing but not during both procedures, suggesting that ALLO acts in a state-dependent manner within the BNST. A shift in interoceptive context during testing for animals conditioned under ALLO provided further support for this mechanism of hormonal action on contextual fear. Interestingly, infusions of ALLO into the basolateral amygdala produced a state-independent suppression of both conditioned contextual and auditory freezing. Altogether, these results suggest that ALLO can influence the acquisition and expression of fear memories by both state-dependent and state-independent mechanisms. Copyright © 2017 Elsevier Inc. All rights reserved.

Long-term stabilization of place cell remapping produced by a fearful experience

PubMed Central

Wang, Melissa E.; Wann, Ellen G.; Yuan, Robin K.; Ramos Álvarez, Manuel M.; Stead, Squire M.; Muzzio, Isabel A.

2012-01-01

Fear is an emotional response to danger that is highly conserved throughout evolution because it is critical for survival. Accordingly, episodic memory for fearful locations is widely studied using contextual fear conditioning, a hippocampus-dependent task (Kim and Fanselow, 1992; Phillips and LeDoux, 1992). The hippocampus has been implicated in episodic emotional memory and is thought to integrate emotional stimuli within a spatial framework. Physiological evidence supporting the role of the hippocampus in contextual fear indicates that pyramidal cells in this region, which fire in specific locations as an animal moves through an environment, shift their preferred firing locations shortly after the presentation of an aversive stimulus (Moita et al., 2004). However, the long-term physiological mechanisms through which emotional memories are encoded by the hippocampus are unknown. Here we show that during and directly after a fearful experience, new hippocampal representations are established and persist in the long term. We recorded from the same place cells in mouse hippocampal area CA1 over several days during predator odor contextual fear conditioning and found that a subset of cells changed their preferred firing locations in response to the fearful stimulus. Furthermore, the newly formed representations of the fearful context stabilized in the long term. Our results demonstrate that place cells respond to the presence of an aversive stimulus, modify their firing patterns during emotional learning, and stabilize a long-term spatial representation in response to a fearful encounter. The persistent nature of these representations may contribute to the enduring quality of emotional memories. PMID:23136419

The prelimbic cortex uses contextual cues to modulate responding towards predictive stimuli during fear renewal.

PubMed

Sharpe, Melissa; Killcross, Simon

2015-02-01

Previous research suggests the prelimbic (PL) cortex is involved in expression of conditioned fear (Burgos-Robles, Vidal-Gonzalez, & Quirk, 2009; Corcoran & Quirk, 2007). However, there is a long history of research in the appetitive domain which implicates this region in using higher-order cues to modulate a behavioural response (Birrell & Brown, 2000; Floresco, Block, & Tse, 2008; Marquis, Killcross, & Haddon, 2007; Sharpe & Killcross, 2014). For example, the PL cortex is necessary to allow animals to use contextual cues to disambiguate response conflict in ambiguous circumstances (Marquis et al., 2007). Using an ABA fear renewal procedure, we assessed the role of the PL cortex in using contextual cues to modulate a response towards a conditioned stimulus (CS) in an aversive setting. We found that pre-training lesions of the PL cortex did not impact on the expression or extinction of conditioned fear. Rather, they selectively abolished renewal. Functional inactivation of the PL cortex during extinction did not disrupt the subsequent renewal of conditioned fear or the ability of animals to exhibit fear towards a CS during the extinction session. However, PL inactivation during the renewal test session disrupted the ability of animals to demonstrate a reinstatement of responding in the renewal context. An analysis of orienting responses showed that renewal deficits were accompanied by a lack of change in attentional responding towards the CS. These data suggest the PL cortex uses contextual cues to modulate both a behavioural and an attentional response during aversive procedures. We argue that the role of the PL cortex in the expression of conditioned fear is to use higher-order information to modulate responding towards predictive cues in ambiguous circumstance. Copyright © 2014 Elsevier Inc. All rights reserved.

Roles of the anterior basolateral amygdalar nucleus during exposure to a live predator and to a predator-associated context.

PubMed

Bindi, Ricardo Passoni; Baldo, Marcus Vinicius C; Canteras, Newton Sabino

2018-04-16

The basolateral amygdala complex, which includes the lateral, basolateral and basomedial nuclei, has been implicated in innate and contextual fear responses to predator threats. In the basolateral complex, the lateral and posterior basomedial nuclei are able to process predator odor information, and they project to the predator-responsive hypothalamic circuit; lesions in these amygdalar sites reduce innate responses and practically abolish contextual fear responses to predatory threats. In contrast to the lateral and posterior basomedial nuclei, the basolateral nucleus does not receive direct information from predator olfactory cues and has no direct link to the predator-responsive hypothalamic circuit. No attempt has previously been made to determine the specific role of the basolateral nucleus in fear responses to predatory threats, and we currently addressed this question by making bilateral N-methyl-D-aspartate lesions in the anterior basolateral nucleus of the amygdala (BLAa), which is often regarded as being contiguous with the lateral amygdalar nucleus, and tested both innate and contextual fear in response to cat exposure. Accordingly, BLAa lesions decreased both innate and contextual fear responses to predator exposure. Considering the targets of the BLAa, the nucleus accumbens appears to be a potential candidate to influence innate defensive responses to predator threats. The present findings also suggest that the BLAa has a role in fear memory of predator threat. The BLAa is likely involved in memory consolidation, which could potentially engage BLAa projection targets, opening interesting possibilities in the investigation of how these targets could be involved in the consolidation of predator-related fear memory. Copyright © 2018 Elsevier B.V. All rights reserved.

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

PubMed

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

2010-07-29

Long-lasting memories of aversive or stressful events have been associated with the noradrenergic system activation. Alpha-1-adrenergic antagonist prazosin has successfully been used in the last years to treat anxiety disorders related to aversive memories recurrence in humans. Contextual conditioned fear extinction paradigm in rats has been used to better understand the mechanisms involved in the attenuation of defensive behaviour after a traumatic situation. Here we investigated the effects of systemic administration of prazosin in the fear extinction processes. Rats were previously paired in a contextual fear conditioning box (1 footshock, 1 mA, 2s duration), further returning to the same box during three consecutive days receiving an intraperitoneal injection of vehicle or prazosin 30 min before (acquisition of extinction; 0.1 or 0.5mg/kg) or immediately after (consolidation of extinction, 0.5 or 1.5mg/kg) each extinction session (10 min). On the last day, all animals were re-exposed undrugged to the apparatus. Since the medial prefrontal cortex (mPFC) has been described as a key structure in the modulation of conditioned fear extinction, the effects of intra-mPFC microinjection (0.2 microl per side) of vehicle (PBS) or prazosin (0.75 or 2.5 nmol) in the acquisition of fear extinction (10 min before extinction session 1) were further evaluated. Subjects were drug-free re-exposed to the same box in the next day (extinction session 2). The percentage of freezing time was used as the memory retention parameter. The results showed that either systemic or intra-mPFC-alpha-1-adrenergic blockade increased the freezing time in the last extinction sessions, suggesting impairment of the extinction of contextual conditioned fear in rats. Copyright 2010 Elsevier B.V. All rights reserved.

Acute Ethanol Withdrawal Impairs Contextual Learning and Enhances Cued Learning

PubMed Central

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

2014-01-01

Background Alcohol affects many of the brain regions and neural processes that support learning and memory, and these effects are thought to underlie, at least in part, the development of addiction. Although much work has been done regarding the effects of alcohol intoxication on learning and memory, little is known about the effects of acute withdrawal from a single alcohol exposure. Methods We assess the effects of acute ethanol withdrawal (6 h post-injection with 4 g/kg ethanol) on two forms of fear conditioning (delay and trace fear conditioning) in C57BL/6J and DBA/2J mice. The influence of a number of experimental parameters (pre- and post-training withdrawal exposure; foreground/background processing; training strength; non-associative effects) is also investigated. Results Acute ethanol withdrawal during training had a bidirectional effect on fear conditioned responses, decreasing contextual responses and increasing cued responses. These effects were apparent for both trace and delay conditioning in DBA/2J mice and for trace conditioning in C57BL/6J mice; however, C57BL/6J mice were selectively resistant to the effects of acute withdrawal on delay cued responses. Conclusions Our results show that acute withdrawal from a single, initial ethanol exposure is sufficient to alter long-term learning in mice. In addition, the differences between the strains and conditioning paradigms used suggest that specific learning processes can be differentially affected by acute withdrawal in a manner that is distinct from the reported effects of both alcohol intoxication and withdrawal following chronic alcohol exposure. Thus, our results suggest a unique effect of acute alcohol withdrawal on learning and memory processes. PMID:25684050

Differential effects of cannabinoid receptor agonist on social discrimination and contextual fear in amygdala and hippocampus.

PubMed

Segev, Amir; Akirav, Irit

2011-04-01

We examined whether the cannabinoid receptor agonist WIN55,212-2 (WIN; 5 µg/side) microinjected into the hippocampus or the amygdala would differentially affect memory processes in a neutral vs. an aversive task. In the aversive contextual fear task, WIN into the basolateral amygdala impaired fear acquisition/consolidation, but not retrieval. In the ventral subiculum (vSub), WIN impaired fear retrieval. In the neutral social discrimination task, WIN into the vSub impaired both acquisition/consolidation and retrieval, whereas in the medial amygdala WIN impaired acquisition. The results suggest that cannabinoid signaling differentially affects memory in a task-, region-, and memory stage-dependent manner.

Activation of Metabotropic Glutamate Receptor Type 2/3 Supports the Involvement of the Hippocampal Mossy Fiber Pathway on Contextual Fear Memory Consolidation

ERIC Educational Resources Information Center

Daumas, Stephanie; Ceccom, Johnatan; Halley, Helene; Frances, Bernard; Lassalle, Jean-Michel

2009-01-01

Elucidating the functional properties of the dentate gyrus (DG), CA3, and CA1 areas is critical for understanding the role of the dorsal hippocampus in contextual fear memory processing. In order to specifically disrupt various hippocampal inputs, we used region-specific infusions of DCG-IV, the metabotropic glutamate receptor agonist, which…

Not all stressors are equal: behavioral and endocrine evidence for development of contextual fear conditioning after a single session of footshocks but not of immobilization.

PubMed

Daviu, Núria; Delgado-Morales, Raúl; Nadal, Roser; Armario, Antonio

2012-01-01

Exposure of animals to footshocks (FS) in absence of any specific cue results in the development of fear to the compartment where shocks were given (contextual fear conditioning), and this is usually evaluated by time spent freezing. However, the extent to which contextual fear conditioning always develops when animals are exposed to other stressors is not known. In the present work we firstly demonstrated, using freezing, that exposure of adult rats to a single session of FS resulted in short-term and long-term contextual fear conditioning (freezing) that was paralleled by increased hypothalamic-pituitary-adrenal (HPA) activation. In contrast, using a similar design, no HPA or behavioral evidence for such conditioning was found after exposure to immobilization on boards (IMO), despite this stressor being of similar severity as FS on the basis of standard physiological measures of stress, including HPA activation. In a final experiment we directly compared the exposure to the two stressors in the same type of context and tested for the development of conditioning to the context and to a specific cue for IMO (the board). We observed the expected high levels of freezing and the conditioned HPA activation after FS, but not after IMO, regardless of the presence of the board during testing. Therefore, it can be concluded that development of fear conditioning to context or particular cues, as evaluated by either behavioral or endocrine measures, appears to be dependent on the nature of the aversive stimuli, likely to be related to biologically preparedness to establish specific associations.

Propranolol–induced Impairment of Contextual Fear Memory Reconsolidation in Rats: A similar Effect on Weak and Strong Recent and Remote Memories

PubMed Central

Taherian, Fatemeh; Vafaei, Abbas Ali; Vaezi, Gholam Hassan; Eskandarian, Sharaf; Kashef, Adel; Rashidy-Pour, Ali

2014-01-01

Introduction Previous studies have demonstrated that the β-adrenergic receptor antagonist propranolol impairs fear memory reconsolidation in experimental animals. There are experimental parameters such as the age and the strength of memory that can interact with pharmacological manipulations of memory reconsolidation. In this study, we investigated the ability of the age and the strength of memory to influence the disrupting effects of propranolol on fear memory reconsolidation in rats. Methods The rats were trained in a contextual fear conditioning using two (weak training) or five (strong training) footshocks (1mA). Propranolol (10mg/kg) injection was immediately followed retrieval of either a one-day recent (weak or strong) or 36-day remote (weak or strong) contextual fear memories. Results We found that propranolol induced a long-lasting impairment of subsequent expression of recent and remote memories with either weak or strong strength. We also found no memory recovery after a weak reminder shock. Furthermore, no significant differences were found on the amount of memory deficit induced by propranolol among memories with different age and strength. Discussion Our data suggest that the efficacy of propranolol in impairing fear memory reconsolidation is not limited to the age or strength of the memory. PMID:25337385

A Comparison of Behavioral and Pharmacological Interventions to Attenuate Reactivated Fear Memories

ERIC Educational Resources Information Center

Monti, Roque I. Ferrer; Alfei, Joaquin M.; Mugnaini, Matias; Bueno, Adrian M.; Beckers, Tom; Urcelay, Gonzalo P.; Molina, Victor A.

2017-01-01

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…

Cholinergic effects on fear conditioning I: the degraded contingency effect is disrupted by atropine but reinstated by physostigmine.

PubMed

Carnicella, Sebastien; Pain, Laure; Oberling, Philippe

2005-04-01

The cholinergic system has been shown to modulate contextual fear conditioning. However, with the exception of trace conditioning studies, most of the available data have focussed on independent context, i.e., context that do not compete with the conditioned stimulus to control for the conditioned response (interactive context). In the present series of experiments, the effects of the muscarinic antagonist, atropine, were assessed when contextual fear memory interacts with cued fear memory to regulate conditioned response, using a Pavlovian degraded contingency preparation in rats. This preparation not only afforded an insight into simple Pavlovian associations but also enabled us to test for the processes of competition that made use of these associations to make an appropriate response to a stimulus [degraded contingency effect (DCE)]. In experiment 1, three doses of atropine [2.5, 5.0, and 10.0 mg/kg, intraperitoneally (i.p.)] were evaluated on male Sprague-Dawley rats. In experiment 2, physostigmine (0.037-0.3 mg/kg, i.p.) was injected after the administration of 5 mg/kg of atropine. Experiment 1A and its partial replication (experiment 1B) showed that at asymptotic level of training, atropine did not alter contextual and cued fear memories when the subjects were directly tested for them, whereas it suppressed the DCE for a 5 mg/kg dose. Indeed, atropine-induced suppression of the DCE was found to be an inverted U-shaped dose-response curve. Experiment 2 showed that physostigmine caused a dose-dependent reversal of the atropine-induced alleviation of the DCE, without altering the expression of simple cued and contextual fear memories. These results evidence at asymptotic level of training a cholinergic modulation of the processing of interactive context, but not of independent ones. They are discussed in the framework of the mechanisms that are involved in both types of contextual processing.

Selective neuronal degeneration in the retrosplenial cortex impairs the recall of contextual fear memory.

PubMed

Sigwald, Eric L; Genoud, Manuel E; Giachero, Marcelo; de Olmos, Soledad; Molina, Víctor A; Lorenzo, Alfredo

2016-05-01

The retrosplenial cortex (RSC) is one of the largest cortical areas in rodents, and is subdivided in two main regions, A29 and A30, according to their cytoarchitectural organization and connectivities. However, very little is known about the functional activity of each RSC subdivision during the execution of complex cognitive tasks. Here, we used a well-established fear learning protocol that induced long-lasting contextual fear memory and showed that during evocation of the fear memory, the expression of early growth response gene 1 was up-regulated in A30, and in other brain areas implicated in fear and spatial memory, however, was down-regulated in A29, including layers IV and V. To search for the participation of A29 on fear memory, we triggered selective degeneration of neurons within cortical layers IV and V of A29 by using a non-invasive protocol that takes advantage of the vulnerability that these neurons have MK801-toxicity and the modulation of this neurodegeneration by testosterone. Application of 5 mg/kg MK801 in intact males induced negligible neuronal degeneration of A29 neurons and had no impact on fear memory retrieval. However, in orchiectomized rats, 5 mg/kg MK801 induced overt degeneration of layers IV-V neurons of A29, significantly impairing fear memory recall. Degeneration of A29 neurons did not affect exploratory or anxiety-related behavior nor altered unconditioned freezing. Importantly, protecting A29 neurons from MK801-toxicity by testosterone preserved fear memory recall in orchiectomized rats. Thus, neurons within cortical layers IV-V of A29 are critically required for efficient retrieval of contextual fear memory.

Contextual Information Drives the Reconsolidation-Dependent Updating of Retrieved Fear Memories

PubMed Central

Jarome, Timothy J; Ferrara, Nicole C; Kwapis, Janine L; Helmstetter, Fred J

2015-01-01

Stored memories enter a temporary state of vulnerability following retrieval known as ‘reconsolidation', a process that can allow memories to be modified to incorporate new information. Although reconsolidation has become an attractive target for treatment of memories related to traumatic past experiences, we still do not know what new information triggers the updating of retrieved memories. Here, we used biochemical markers of synaptic plasticity in combination with a novel behavioral procedure to determine what was learned during memory reconsolidation under normal retrieval conditions. We eliminated new information during retrieval by manipulating animals' training experience and measured changes in proteasome activity and GluR2 expression in the amygdala, two established markers of fear memory lability and reconsolidation. We found that eliminating new contextual information during the retrieval of memories for predictable and unpredictable fear associations prevented changes in proteasome activity and glutamate receptor expression in the amygdala, indicating that this new information drives the reconsolidation of both predictable and unpredictable fear associations on retrieval. Consistent with this, eliminating new contextual information prior to retrieval prevented the memory-impairing effects of protein synthesis inhibitors following retrieval. These results indicate that under normal conditions, reconsolidation updates memories by incorporating new contextual information into the memory trace. Collectively, these results suggest that controlling contextual information present during retrieval may be a useful strategy for improving reconsolidation-based treatments of traumatic memories associated with anxiety disorders such as post-traumatic stress disorder. PMID:26062788

Effect of Dorsal and Ventral Hippocampal Lesions on Contextual Fear Conditioning and Unconditioned Defensive Behavior Induced by Electrical Stimulation of the Dorsal Periaqueductal Gray

PubMed Central

Ballesteros, Carolina Irurita; de Oliveira Galvão, Bruno; Maisonette, Silvia; Landeira-Fernandez, J.

2014-01-01

The dorsal (DH) and ventral (VH) subregions of the hippocampus are involved in contextual fear conditioning. However, it is still unknown whether these two brain areas also play a role in defensive behavior induced by electrical stimulation of the dorsal periaqueductal gray (dPAG). In the present study, rats were implanted with electrodes into the dPAG to determine freezing and escape response thresholds after sham or bilateral electrolytic lesions of the DH or VH. The duration of freezing behavior that outlasted electrical stimulation of the dPAG was also measured. The next day, these animals were subjected to contextual fear conditioning using footshock as an unconditioned stimulus. Electrolytic lesions of the DH and VH impaired contextual fear conditioning. Only VH lesions disrupted conditioned freezing immediately after footshock and increased the thresholds of aversive freezing and escape responses to dPAG electrical stimulation. Neither DH nor VH lesions disrupted post-dPAG stimulation freezing. These results indicate that the VH but not DH plays an important role in aversively defensive behavior induced by dPAG electrical stimulation. Interpretations of these findings should be made with caution because of the fact that a non-fiber-sparing lesion method was employed. PMID:24404134

Selective inhibition of miR-92 in hippocampal neurons alters contextual fear memory.

PubMed

Vetere, Gisella; Barbato, Christian; Pezzola, Silvia; Frisone, Paola; Aceti, Massimiliano; Ciotti, MariaTeresa; Cogoni, Carlo; Ammassari-Teule, Martine; Ruberti, Francesca

2014-12-01

Post-transcriptional gene regulation mediated by microRNAs (miRNAs) is implicated in memory formation; however, the function of miR-92 in this regulation is uncharacterized. The present study shows that training mice in contextual fear conditioning produces a transient increase in miR-92 levels in the hippocampus and decreases several miR-92 gene targets, including: (i) the neuronal Cl(-) extruding K(+) Cl(-) co-transporter 2 (KCC2) protein; (ii) the cytoplasmic polyadenylation protein (CPEB3), an RNA-binding protein regulator of protein synthesis in neurons; and (iii) the transcription factor myocyte enhancer factor 2D (MEF2D), one of the MEF2 genes which negatively regulates memory-induced structural plasticity. Selective inhibition of endogenous miR-92 in CA1 hippocampal neurons, by a sponge lentiviral vector expressing multiple sequences imperfectly complementary to mature miR-92 under the control of the neuronal specific synapsin promoter, leads to up-regulation of KCC2, CPEB3 and MEF2D, impairs contextual fear conditioning, and prevents a memory-induced increase in the spine density. Taken together, the results indicate that neuronal-expressed miR-92 is an endogenous fine regulator of contextual fear memory in mice. © 2014 Wiley Periodicals, Inc.

A proteomic analysis of contextual fear conditioned rats reveals dynamic modifications in neuron and oligodendrocyte protein expression in the dentate gyrus.

PubMed

Houyoux, Nicolas; Wattiez, Ruddy; Ris, Laurence

2017-09-01

Contextual memory is an intricate process involving synaptic plasticity and network rearrangement. Both are governed by many molecular processes including phosphorylation and modulation of protein expression. However, little is known about the molecules involved in it. Here, we exploited the advantages of a quantitative proteomic approach to identify a great number of molecules in the rat dentate gyrus after a contextual fear conditioning session. Our results allowed us to highlight protein expression patterns, not only related to neuroplasticity, but also to myelin structure, such as myelin basic protein and myelin proteolipid protein showing a decrease in expression. Validation of the modification in protein expression reveals a dynamic profile during the 48 h following the fear conditioning session. The expression of proteins involved in neurite outgrowth, such as BASP-1 and calcineurin B1, and in synaptic structure and function, VAMP2 and RAB3C, was increased in the dentate gyrus of rats submitted to fear conditioning compared to controls. We showed that the increase in BASP-1 protein was specific to fear conditioning learning as it was not present in immediate-shock rats, neither in rats exposed to a novel environment without being shocked. As myelin is known to stabilise synaptic network, the decrease in myelin proteins suggests a neuroglia interactive process taking place in the dentate gyrus in the 24 h following contextual fear learning, which has never been demonstrated before. These results therefore open the way to the study of new plasticity mechanisms underlying learning and memory. © 2017 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

Not all stressors are equal: behavioral and endocrine evidence for development of contextual fear conditioning after a single session of footshocks but not of immobilization

PubMed Central

Daviu, Núria; Delgado-Morales, Raúl; Nadal, Roser; Armario, Antonio

2012-01-01

Exposure of animals to footshocks (FS) in absence of any specific cue results in the development of fear to the compartment where shocks were given (contextual fear conditioning), and this is usually evaluated by time spent freezing. However, the extent to which contextual fear conditioning always develops when animals are exposed to other stressors is not known. In the present work we firstly demonstrated, using freezing, that exposure of adult rats to a single session of FS resulted in short-term and long-term contextual fear conditioning (freezing) that was paralleled by increased hypothalamic-pituitary-adrenal (HPA) activation. In contrast, using a similar design, no HPA or behavioral evidence for such conditioning was found after exposure to immobilization on boards (IMO), despite this stressor being of similar severity as FS on the basis of standard physiological measures of stress, including HPA activation. In a final experiment we directly compared the exposure to the two stressors in the same type of context and tested for the development of conditioning to the context and to a specific cue for IMO (the board). We observed the expected high levels of freezing and the conditioned HPA activation after FS, but not after IMO, regardless of the presence of the board during testing. Therefore, it can be concluded that development of fear conditioning to context or particular cues, as evaluated by either behavioral or endocrine measures, appears to be dependent on the nature of the aversive stimuli, likely to be related to biologically preparedness to establish specific associations. PMID:23112767

Acute exercise enhances the consolidation of fear extinction memory and reduces conditioned fear relapse in a sex-dependent manner.

PubMed

Bouchet, Courtney A; Lloyd, Brian A; Loetz, Esteban C; Farmer, Caroline E; Ostrovskyy, Mykola; Haddad, Natalie; Foright, Rebecca M; Greenwood, Benjamin N

2017-08-01

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 enhance the acquisition and consolidation of fear extinction in male rats, but the effects of exercise on relapse of fear after extinction are not well understood. Here, we characterized the effects of 2 h of voluntary exercise during the consolidation phase of contextual or auditory fear extinction learning on long-term fear extinction memory and renewal in adult, male and female, Long-Evans rats. Results indicate that exercise enhances consolidation of fear extinction memory and reduces fear relapse after extinction in a sex-dependent manner. These data suggest that brief bouts of exercise could be used as an augmentation strategy for exposure therapy, even in previously sedentary subjects. Fear memories of discrete cues, rather than of contextual ones, may be most susceptible to exercise-augmented extinction, especially in males. Additionally, exercise seems to have the biggest impact on fear relapse phenomena, even if fear extinction memories themselves are only minimally enhanced. © 2017 Bouchet et al.; Published by Cold Spring Harbor Laboratory Press.

Trauma exposure and aggression toward partners and children: Contextual influences of fear and anger.

PubMed

Marshall, Amy D; Roettger, Michael E; Mattern, Alexandra C; Feinberg, Mark E; Jones, Damon E

2018-05-07

Trauma exposure is a consistent correlate of intimate partner aggression (IPA) and parent-to-child aggression (PCA) perpetration, and difficulties with emotions (particularly fear and anger) are hypothesized to underlie these relations. However, the absence of knowledge of the immediate, contextual influence of emotions on aggression renders existing conclusions tenuous. This study illustrates a new method for studying contextual influences on aggressive behavior. Quarterly for 1 year, 94 men and 109 women with children age 2.5 years at study commencement were interviewed to measure the sequence of behaviors during aggressive incidents as well as the intensity of their emotions immediately prior to initiation of aggression. Within aggressive incidents, the number of acts of men's PCA was predicted by men's greater fear, anger, and trauma exposure, and the positive association between men's trauma exposure and PCA perpetration was especially strong under conditions of high fear and anger. In contrast, men's IPA was predicted by greater fear and anger, but not trauma exposure. Men with low trauma exposure engaged in more IPA under conditions of high fear; among men with high trauma exposure, fear inhibited their IPA persistence. Trauma exposure and fear interacted in the same manner to predict women's IPA, but many other findings among men did not generalize to women's aggression. This study illuminates the utility of simultaneously examining aggression across genders and family dyads, and serves as a foundation for refining theories of trauma and family aggression to account for emotion as a factor that can both motivate and inhibit aggression. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

NR2A- and NR2B-Containing NMDA Receptors in the Prelimbic Medial Prefrontal Cortex Differentially Mediate Trace, Delay, and Contextual Fear Conditioning

ERIC Educational Resources Information Center

Gilmartin, Marieke R.; Kwapis, Janine L.; Helmstetter, Fred J.

2013-01-01

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…

Enhanced discrimination between threatening and safe contexts in high-anxious individuals

PubMed Central

Glotzbach-Schoon, Evelyn; Tadda, Regina; Andreatta, Marta; Tröger, Christian; Ewald, Heike; Grillon, Christian; Pauli, Paul; Mühlberger, Andreas

2014-01-01

Trait anxiety, a stable personality trait associated with increased fear responses to threat, is regarded as a risk factor for the development and maintenance of anxiety disorders. Although the effect of trait anxiety has been examined with regard to explicit threat cues, little is known about the effect of trait anxiety on contextual threat learning. To assess this issue, extreme groups of low and high trait anxiety underwent a contextual fear conditioning protocol using virtual reality. Two virtual office rooms served as the conditioned contexts. One virtual office room (CXT+) was paired with unpredictable electrical stimuli. In the other virtual office room, no electrical stimuli were delivered (CXT−). High-anxious participants tended to show faster acquisition of startle potentiation in the CXT+ versus the CXT− than low-anxious participants. This enhanced contextual fear learning might function as a risk factor for anxiety disorders that are characterized by sustained anxiety. PMID:23384512

Medial prefrontal pathways for the contextual regulation of extinguished fear in humans

PubMed Central

Åhs, Fredrik; Kragel, Philip A.; Zielinski, David J.; Brady, Rachael; LaBar, Kevin S.

2015-01-01

The maintenance of anxiety disorders is thought to depend, in part, on deficits in extinction memory, possibly due to reduced contextual control of extinction that leads to fear renewal. Animal studies suggest that the neural circuitry responsible fear renewal includes the hippocampus, amygdala, and dorsomedial (dmPFC) and ventromedial (vmPFC) prefrontal cortex. However, the neural mechanisms of context-dependent fear renewal in humans remain poorly understood. We used functional magnetic resonance imaging (fMRI), combined with psychophysiology and immersive virtual reality, to elucidate how the hippocampus, amygdala, and dmPFC and vmPFC interact to drive the context-dependent renewal of extinguished fear. Healthy human participants encountered dynamic fear-relevant conditioned stimuli (CSs) while navigating through 3-D virtual reality environments in the MRI scanner. Conditioning and extinction were performed in two different virtual contexts. Twenty-four hours later, participants were exposed to the CSs without reinforcement while navigating through both contexts in the MRI scanner. Participants showed enhanced skin conductance responses (SCRs) to the previously-reinforced CS+ in the acquisition context on Day 2, consistent with fear renewal, and sustained responses in the dmPFC. In contrast, participants showed low SCRs to the CSs in the extinction context on Day 2, consistent with extinction recall, and enhanced vmPFC activation to the non-reinforced CS−. Structural equation modeling revealed that the dmPFC fully mediated the effect of the hippocampus on right amygdala activity during fear renewal, whereas the vmPFC partially mediated the effect of the hippocampus on right amygdala activity during extinction recall. These results indicate dissociable contextual influences of the hippocampus on prefrontal pathways, which, in turn, determine the level of reactivation of fear associations. PMID:26220745

How Administration of the Beta-Blocker Propranolol Before Extinction can Prevent the Return of Fear

PubMed Central

Kroes, Marijn C W; Tona, Klodiana-Daphne; den Ouden, Hanneke E M; Vogel, Susanne; van Wingen, Guido A; Fernández, Guillén

2016-01-01

Combining beta-blockers with exposure therapy has been advocated to reduce fear, yet experimental studies combining beta-blockers with memory reactivation have had contradictory results. We explored how beta-blockade might affect the course of safety learning and the subsequent return of fear in a double-blind placebo-controlled functional magnetic resonance imaging study in humans (N=46). A single dose of propranolol before extinction learning caused a loss of conditioned fear responses, and prevented the subsequent return of fear and decreased explicit memory for the fearful events in the absence of drug. Fear-related neural responses were persistently attenuated in the dorsal medial prefrontal cortex (dmPFC), increased in the hippocampus 24 h later, and correlated with individual behavioral indices of fear. Prediction error-related responses in the ventral striatum persisted during beta-blockade. We suggest that this pattern of results is most consistent with a model where beta-blockade can prevent the return of fear by (i) reducing retrieval of fear memory, via the dmPFC and (ii) increasing contextual safety learning, via the hippocampus. Our findings suggest that retrieval of fear memory and contextual safety learning form potential mnemonic target mechanisms to optimize exposure-based therapy with beta-blockers. PMID:26462618

Increased Contextual Fear Conditioning in iNOS Knockout Mice: Additional Evidence for the Involvement of Nitric Oxide in Stress-Related Disorders and Contribution of the Endocannabinoid System.

PubMed

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

2015-01-24

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 increased. © The Author 2015. Published by Oxford University Press on behalf of CINP.

Conditioning- and Time-Dependent Increases in Context Fear and Generalization

ERIC Educational Resources Information Center

Poulos, Andrew M.; Mehta, Nehali; Lu, Bryan; Amir, Dorsa; Livingston, Briana; Santarelli, Anthony; Zhuravka, Irina; Fanselow, Michael S.

2016-01-01

A prominent feature of fear memories and anxiety disorders is that they endure across extended periods of time. Here, we examine how the severity of the initial fear experience influences incubation, generalization, and sensitization of contextual fear memories across time. Adult rats were presented with either five, two, one, or zero shocks (1.2…

Epinephrine increases contextual learning through activation of peripheral β2-adrenoceptors.

PubMed

Alves, Ester; Lukoyanov, Nikolay; Serrão, Paula; Moura, Daniel; Moreira-Rodrigues, Mónica

2016-06-01

Phenylethanolamine-N-methyltransferase knockout (Pnmt-KO) mice are unable to synthesize epinephrine and display reduced contextual fear. However, the precise mechanism responsible for impaired contextual fear learning in these mice is unknown. Our aim was to study the mechanism of epinephrine-dependent contextual learning. Wild-type (WT) or Pnmt-KO (129x1/SvJ) mice were submitted to a fear conditioning test either in the absence or in the presence of epinephrine, isoprenaline (non-selective β-adrenoceptor agonist), fenoterol (selective β2-adrenoceptor agonist), epinephrine plus sotalol (non-selective β-adrenoceptor antagonist), and dobutamine (selective β1-adrenoceptor agonist). Catecholamines were separated by reverse-phase HPLC and quantified by electrochemical detection. Blood glucose was measured by coulometry. Re-exposure to shock context induced higher freezing in WT and Pnmt-KO mice treated with epinephrine and fenoterol than in mice treated with vehicle. In addition, freezing response in Pnmt-KO mice was much lower than in WT mice. Freezing induced by epinephrine was blocked by sotalol in Pnmt-KO mice. Epinephrine and fenoterol treatment restored glycemic response in Pnmt-KO mice. Re-exposure to shock context did not induce a significant difference in freezing in Pnmt-KO mice treated with dobutamine and vehicle. Aversive memories are best retained if moderately high plasma epinephrine concentrations occur at the same moment as the aversive stimulus. In addition, epinephrine increases context fear learning by acting on peripheral β2-adrenoceptors, which may induce high levels of blood glucose. Since glucose crosses the blood-brain barrier, it may enhance hippocampal-dependent contextual learning.

Hippocampal Mek/Erk signaling mediates extinction of contextual freezing behavior.

PubMed

Fischer, Andre; Radulovic, Marko; Schrick, Christina; Sananbenesi, Farahnaz; Godovac-Zimmermann, Jasminka; Radulovic, Jelena

2007-01-01

Fear memories elicit multiple behavioral responses, encompassing avoidance, or behavioral inhibition in response to threatening contexts. Context-specific freezing, reflecting fear-induced behavioral inhibition, has been proposed as one of the main risks factors for the development of anxiety disorders. We attempted to define the key hippocampal mediators of extinction in a mouse model of context-dependent freezing. Nine-week-old male C57BL/6J mice were trained and tested for contextual fear conditioning and extinction. Freezing behavior scored by unbiased sampling, was used as an index of fear. Proteomic, immunoblot, and immunohistochemical approaches were employed to identify, verify, and analyze the alterations of the hippocampal extracellular signal-regulated kinases 1 and 2 (Erk-1/2). Targeted pharmacological inhibition of the Erk-1/2 activating kinase, the mitogen activated and extracellular signal-regulated kinase (Mek), served to establish the role of Mek/Erk signaling in extinction. When compared to acquisition, extinction of contextual freezing triggered a rapid activation of Erk-1/2 showing a distinctive time-course, nuclear localization, and subcellular isoform distribution. These differences suggested that the upstream regulation and downstream effects of this pathway might be specific for each process. Dorsohippocampal injections of the Mek inhibitors U0126 (0.5 microg/site) and PD98059 (1.5 microg/site) immediately after the nonreinforced trials prevented Erk-1/2 activation and significantly impaired extinction. This effect was dissociable from potential actions on memory retrieval or reconsolidation. On the basis of these findings, we propose that hippocampal Mek/Erk signaling might serve as one of the key mediators of contextual fear extinction.

16Oxygen irradiation enhances cued fear memory in B6D2F1 mice

NASA Astrophysics Data System (ADS)

Raber, Jacob; Marzulla, Tessa; Kronenberg, Amy; Turker, Mitchell S.

2015-11-01

The space radiation environment includes energetic charged particles that may impact cognitive performance. We assessed the effects of 16O ion irradiation on cognitive performance of C57BL/6J × DBA/2J F1 (B6D2F1) mice at OHSU (Portland, OR) one month following irradiation at Brookhaven National Laboratory (BNL, Upton, NY). Hippocampus-dependent contextual fear memory and hippocampus-independent cued fear memory of B6D2F1 mice were tested. 16O ion exposure enhanced cued fear memory. This effect showed a bell-shaped dose response curve. Cued fear memory was significantly stronger in mice irradiated with 16O ions at a dose of 0.4 or 0.8 Gy than in sham-irradiated mice or following irradiation at 1.6 Gy. In contrast to cued fear memory, contextual fear memory was not affected following 16O ion irradiation at the doses used in this study. These data indicate that the amygdala might be particularly susceptible to effects of 16O ion exposure.

Changes in heart rate variability are associated with expression of short-term and long-term contextual and cued fear memories.

PubMed

Liu, Jun; Wei, Wei; Kuang, Hui; Zhao, Fang; Tsien, Joe Z

2013-01-01

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

Hippocampus-based contextual memory alters the morphological characteristics of astrocytes in the dentate gyrus.

PubMed

Choi, Moonseok; Ahn, Sangzin; Yang, Eun-Jeong; Kim, Hyunju; Chong, Young Hae; Kim, Hye-Sun

2016-07-26

Astrocytes have been reported to exist in two states, the resting and the reactive states. Morphological changes in the reactive state of astrocytes include an increase in thickness and number of processes, and an increase in the size of the cell body. Molecular changes also occur, such as an increase in the expression of glial fibrillary acidic protein (GFAP). However, the morphological and molecular changes during the process of learning and memory have not been elucidated. In the current study, we subjected Fvb/n mice to contextual fear conditioning, and checked for morphological and molecular changes in astrocytes. 1 h after fear conditioning, type II and type III astrocytes exhibited a unique status with an increased number of processes and decreased GFAP expression which differed from the typical resting or reactive state. In addition, the protein level of excitatory excitatory amino acid transporter 2 (EAAT2) was increased 1 h to 24 h after contextual fear conditioning while EAAT1 did not show any alterations. Connexin 43 (Cx43) protein was found to be increased at 24 h after fear conditioning. These data suggest that hippocampus-based contextual memory process induces changes in the status of astrocytes towards a novel status different from typical resting or reactive states. These morphological and molecular changes may be in line with functional changes.

Validating a human model for anxiety using startle potentiated by cue and context: the effects of alprazolam, pregabalin, and diphenhydramine

PubMed Central

Mol, N.; Kenemans, J. L.; Prinssen, E. P.; Niklson, I.; Xia-Chen, C.; Broeyer, F.; van Gerven, J.

2009-01-01

Background Fear-potentiated startle has been suggested as a translational model for evaluating efficacy of anxiolytic compounds in humans. Several known anxiolytic compounds have been tested as well as several putative anxiolytics. Because results of these studies have been equivocal, the aim of the present study was to examine another pharmacological permutation of the human potentiated startle model by comparing two anxiolytic agents to a non-anxiolytic sedative and placebo. Methods Twenty healthy volunteers participated in a double-blind, placebo-controlled, cross-over study with four sessions in which they received single doses of the anxiolytics alprazolam (1 mg) and pregabalin (200 mg), as well as diphenhydramine (50 mg) as a non-anxiolytic sedative control and placebo. The design included a cued shock condition that presumably evokes fear and an unpredictable shock context condition presumably evoking anxiety. Results None of the treatments reliably reduced either fear- or anxiety-potentiated startle. Alprazolam and diphenhydramine reduced overall baseline startle. Alprazolam was found to only affect contextual anxiety in a statistical significant way after two subjects who failed to show a contextual anxiety effect in the placebo condition were excluded from the analysis. Pregabalin did not significantly affect any of the physiological measures. Discussion The negative findings from this study are discussed in terms of methodological differences between designs and in variability of startle both between and within study participants. Conclusion Even though fear-potentiated startle may be used to translate preclinical evidence to human populations, methodological issues still hamper the application of this model to early screening of putative anxiolytic drugs. PMID:19415242

Encoding, consolidation, and retrieval of contextual memory: differential involvement of dorsal CA3 and CA1 hippocampal subregions.

PubMed

Daumas, Stéphanie; Halley, Hélène; Francés, Bernard; Lassalle, Jean-Michel

2005-01-01

Studies on human and animals shed light on the unique hippocampus contributions to relational memory. However, the particular role of each hippocampal subregion in memory processing is still not clear. Hippocampal computational models and theories have emphasized a unique function in memory for each hippocampal subregion, with the CA3 area acting as an autoassociative memory network and the CA1 area as a critical output structure. In order to understand the respective roles of the CA3- and CA1-hippocampal areas in the formation of contextual memory, we studied the effects of the reversible inactivation by lidocaine of the CA3 or CA1 areas of the dorsal hippocampus on acquisition, consolidation, and retrieval of a contextual fear conditioning. Whereas infusions of lidocaine never impaired elementary tone conditioning, their effects on contextual conditioning provided interesting clues about the role of these two hippocampal regions. They demonstrated first that the CA3 area is necessary for the rapid elaboration of a unified representation of the context. Secondly, they suggested that the CA1 area is rather involved in the consolidation process of contextual memory. Third, they showed that CA1 or CA3 inactivation during retention test has no effect on contextual fear retrieval when a recognition memory procedure is used. In conclusion, our findings point as evidence that CA1 and CA3 subregions of the dorsal hippocampus play important and different roles in the acquisition and consolidation of contextual fear memory, whereas they are not required for context recognition.

AMPA Receptors Control Fear Extinction through an Arc-Dependent Mechanism

ERIC Educational Resources Information Center

Trent, Simon; Barnes, Philip; Hall, Jeremy; Thomas, Kerrie L.

2017-01-01

Activity-regulated cytoskeleton-associated protein (Arc) supports fear memory through synaptic plasticity events requiring actin cytoskeleton rearrangements. We have previously shown that reducing hippocampal Arc levels through antisense knockdown leads to the premature extinction of contextual fear. Here we show that the AMPA receptor antagonist…

Behavioral Mechanisms of Context Fear Generalization in Mice

ERIC Educational Resources Information Center

Huckleberry, Kylie A.; Ferguson, Laura B.; Drew, Michael R.

2016-01-01

There is growing interest in generalization of learned contextual fear, driven in part by the hypothesis that mood and anxiety disorders stem from impaired hippocampal mechanisms of fear generalization and discrimination. However, there has been relatively little investigation of the behavioral and procedural mechanisms that might control…

The effects of varying contextual demands on age-related positive gaze preferences.

PubMed

Noh, Soo Rim; Isaacowitz, Derek M

2015-06-01

Despite many studies on the age-related positivity effect and its role in visual attention, discrepancies remain regarding whether full attention is required for age-related differences to emerge. The present study took a new approach to this question by varying the contextual demands of emotion processing. This was done by adding perceptual distractions, such as visual and auditory noise, that could disrupt attentional control. Younger and older participants viewed pairs of happy-neutral and fearful-neutral faces while their eye movements were recorded. Facial stimuli were shown either without noise, embedded in a background of visual noise (low, medium, or high), or with simultaneous auditory babble. Older adults showed positive gaze preferences, looking toward happy faces and away from fearful faces; however, their gaze preferences tended to be influenced by the level of visual noise. Specifically, the tendency to look away from fearful faces was not present in conditions with low and medium levels of visual noise but was present when there were high levels of visual noise. It is important to note, however, that in the high-visual-noise condition, external cues were present to facilitate the processing of emotional information. In addition, older adults' positive gaze preferences disappeared or were reduced when they first viewed emotional faces within a distracting context. The current results indicate that positive gaze preferences may be less likely to occur in distracting contexts that disrupt control of visual attention. (c) 2015 APA, all rights reserved.

Effects of the swimming exercise on the consolidation and persistence of auditory and contextual fear memory.

PubMed

Faria, Rodolfo Souza; Gutierres, Luís Felipe Soares; Sobrinho, Fernando César Faria; Miranda, Iris do Vale; Reis, Júlia Dos; Dias, Elayne Vieira; Sartori, Cesar Renato; Moreira, Dalmo Antonio Ribeiro

2016-08-15

Exposure to negative environmental events triggers defensive behavior and leads to the formation of aversive associative memory. Cellular and molecular changes in the central nervous system underlie this memory formation, as well as the associated behavioral changes. In general, memory process is established in distinct phases such as acquisition, consolidation, evocation, persistence, and extinction of the acquired information. After exposure to a particular event, early changes in involved neural circuits support the memory consolidation, which corresponds to the short-term memory. Re-exposure to previously memorized events evokes the original memory, a process that is considered essential for the reactivation and consequent persistence of memory, ensuring that long-term memory is established. Different environmental stimuli may modulate the memory formation process, as well as their distinct phases. Among the different environmental stimuli able of modulating memory formation is the physical exercise which is a potent modulator of neuronal activity. There are many studies showing that physical exercise modulates learning and memory processes, mainly in the consolidation phase of the explicit memory. However, there are few reports in the literature regarding the role of physical exercise in implicit aversive associative memory, especially at the persistence phase. Thus, the present study aimed to investigate the relationship between swimming exercise and the consolidation and persistence of contextual and auditory-cued fear memory. Male Wistar rats were submitted to sessions of swimming exercise five times a week, over six weeks. After that, the rats were submitted to classical aversive conditioning training by a pairing tone/foot shock paradigm. Finally, rats were evaluated for consolidation and persistence of fear memory to both auditory and contextual cues. Our results demonstrate that classical aversive conditioning with tone/foot shock pairing induced consolidation as well as persistence of conditioned fear memory. In addition, rats submitted to swimming exercise over six weeks showed an improved performance in the test of auditory-cued fear memory persistence, but not in the test of contextual fear memory persistence. Moreover, no significant effect from swimming exercise was observed on consolidation of both contextual and auditory fear memory. So, our study, revealing the effect of the swimming exercise on different stages of implicit memory of tone/foot shock conditioning, contributes to and complements the current knowledge about the environmental modulation of memory process. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

PI3-kinase cascade has a differential role in acquisition and extinction of conditioned fear memory in juvenile and adult rats.

PubMed

Slouzkey, Ilana; Maroun, Mouna

2016-12-01

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.

Allopregnanolone in the bed nucleus of the stria terminalis modulates contextual fear in rats

PubMed Central

Nagaya, Naomi; Acca, Gillian M.; Maren, Stephen

2015-01-01

Trauma- and stress-related disorders are among the most common types of mental illness affecting the U.S. population. For many of these disorders, there is a striking sex difference in lifetime prevalence; for instance, women are twice as likely as men to be affected by posttraumatic stress disorder (PTSD). Gonadal steroids and their metabolites have been implicated in sex differences in fear and anxiety. One example, allopregnanolone (ALLO), is a neuroactive metabolite of progesterone that allosterically enhances GABAA receptor activity and has anxiolytic effects. Like other ovarian hormones, it not only occurs at different levels in males and females but also fluctuates over the female reproductive cycle. One brain structure that may be involved in neuroactive steroid regulation of fear and anxiety is the bed nucleus of the stria terminalis (BNST). To explore this question, we examined the consequences of augmenting or reducing ALLO activity in the BNST on the expression of Pavlovian fear conditioning in rats. In Experiment 1, intra-BNST infusions of ALLO in male rats suppressed freezing behavior (a fear response) to the conditioned context, but did not influence freezing to a discrete tone conditioned stimulus (CS). In Experiment 2, intra-BNST infusion of either finasteride (FIN), an inhibitor of ALLO synthesis, or 17-phenyl-(3α,5α)-androst-16-en-3-ol, an ALLO antagonist, in female rats enhanced contextual freezing; neither treatment affected freezing to the tone CS. These findings support a role for ALLO in modulating contextual fear via the BNST and suggest that sex differences in fear and anxiety could arise from differential steroid regulation of BNST function. The susceptibility of women to disorders such as PTSD may be linked to cyclic declines in neuroactive steroid activity within fear circuitry. PMID:26300750

Early life stress in rats sex-dependently affects remote endocrine rather than behavioral consequences of adult exposure to contextual fear conditioning.

PubMed

Fuentes, Sílvia; Daviu, Núria; Gagliano, Humberto; Belda, Xavier; Armario, Antonio; Nadal, Roser

2018-05-30

Exposure to electric foot-shocks can induce in rodents contextual fear conditioning, generalization of fear to other contexts and sensitization of the hypothalamic-pituitary-adrenal (HPA) axis to further stressors. All these aspects are relevant for the study of post-traumatic stress disorder. In the present work we evaluated in rats the sex differences and the role of early life stress (ELS) in fear memories, generalization and sensitization. During the first postnatal days subjects were exposed to restriction of nesting material along with exposure to a "substitute" mother. In the adulthood they were exposed to (i) a contextual fear conditioning to evaluate long-term memory and extinction and (ii) to a novel environment to study cognitive fear generalization and HPA axis heterotypic sensitization. ELS did not alter acquisition, expression or extinction of context fear conditioned behavior (freezing) in either sex, but reduced activity in novel environments only in males. Fear conditioning associated hypoactivity in novel environments (cognitive generalization) was greater in males than females but was not specifically affected by ELS. Although overall females showed greater basal and stress-induced levels of ACTH and corticosterone, an interaction between ELS, shock exposure and sex was found regarding HPA hormones. In males, ELS did not affect ACTH response in any situation, whereas in females, ELS reduced both shock-induced sensitization of ACTH and its conditioned response to the shock context. Also, shock-induced sensitization of corticosterone was only observed in males and ELS specifically reduced corticosterone response to stressors in males but not females. In conclusion, ELS seems to have only a minor impact on shock-induced behavioral conditioning, while affecting the unconditioned and conditioned responses of HPA hormones in a sex-dependent manner. Copyright © 2018. Published by Elsevier Inc.

The effects of midazolam and D-cycloserine on the release of glutamate and GABA in the basolateral amygdala of low and high anxiety rats during extinction trial of a conditioned fear test.

PubMed

Lehner, Małgorzata; Wisłowska-Stanek, Aleksandra; Taracha, Ewa; Maciejak, Piotr; Szyndler, Janusz; Skórzewska, Anna; Turzyńska, Danuta; Sobolewska, Alicja; Hamed, Adam; Bidziński, Andrzej; Płaźnik, Adam

2010-11-01

In this study, we investigated how midazolam and d-cycloserine regulate the tonic activity and/or phasic reactivity of brain neurotransmitter systems to fear-evoking stimuli in rats with varying intensities of a fear response. We used a new animal model composed of high (HR) and low (LR) anxiety rats, selected according to their behaviour in the contextual fear test (i.e., the duration of a freezing response was used as a discriminating variable). In these rats, we examined the effects of both drugs on the release of glutamate and GABA in the basolateral amygdala (BLA) during the first extinction trial of a conditioned fear test. The results showed that administration of d-cycloserine (15 mg/kg, i.p.) significantly enhanced the inhibition of an aversive context-induced freezing response observed during the extinction session in HR and LR rats. In contrast, midazolam (0.75 mg/kg, i.p.) accelerated the attenuation of fear responses only in HR rats. The less anxious behaviour of LR animals given saline was accompanied by elevated basal levels of glutamate in the BLA, in comparison with HR rats, and a stronger elevation of GABA in response to contextual fear. In HR animals, the pretreatment of rats with d-cycloserine and midazolam significantly increased the local concentration of GABA and inhibited the expression of contextual fear. These findings suggest that animals more vulnerable to stress have innate deficits in brain systems that control the activity of the BLA mediating the central effect of stress. These results contribute to our understanding of observed individual differences in the effects of anxiolytic drugs among patients with anxiety disorders. Copyright © 2010. Published by Elsevier Inc.

Allopregnanolone in the bed nucleus of the stria terminalis modulates contextual fear in rats.

PubMed

Nagaya, Naomi; Acca, Gillian M; Maren, Stephen

2015-01-01

Trauma- and stress-related disorders are among the most common types of mental illness affecting the U.S. population. For many of these disorders, there is a striking sex difference in lifetime prevalence; for instance, women are twice as likely as men to be affected by posttraumatic stress disorder (PTSD). Gonadal steroids and their metabolites have been implicated in sex differences in fear and anxiety. One example, allopregnanolone (ALLO), is a neuroactive metabolite of progesterone that allosterically enhances GABAA receptor activity and has anxiolytic effects. Like other ovarian hormones, it not only occurs at different levels in males and females but also fluctuates over the female reproductive cycle. One brain structure that may be involved in neuroactive steroid regulation of fear and anxiety is the bed nucleus of the stria terminalis (BNST). To explore this question, we examined the consequences of augmenting or reducing ALLO activity in the BNST on the expression of Pavlovian fear conditioning in rats. In Experiment 1, intra-BNST infusions of ALLO in male rats suppressed freezing behavior (a fear response) to the conditioned context, but did not influence freezing to a discrete tone conditioned stimulus (CS). In Experiment 2, intra-BNST infusion of either finasteride (FIN), an inhibitor of ALLO synthesis, or 17-phenyl-(3α,5α)-androst-16-en-3-ol, an ALLO antagonist, in female rats enhanced contextual freezing; neither treatment affected freezing to the tone CS. These findings support a role for ALLO in modulating contextual fear via the BNST and suggest that sex differences in fear and anxiety could arise from differential steroid regulation of BNST function. The susceptibility of women to disorders such as PTSD may be linked to cyclic declines in neuroactive steroid activity within fear circuitry.

Activation of the Infralimbic Cortex in a Fear Context Enhances Extinction Learning

ERIC Educational Resources Information Center

Thompson, Brittany M.; Baratta, Michael V.; Biedenkapp, Joseph C.; Rudy, Jerry W.; Watkins, Linda R.; Maier, Steven F.

2010-01-01

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…

Time-dependent effects of cortisol on the contextualization of emotional memories.

PubMed

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

2013-12-01

The inability to store fearful memories into their original encoding context is considered to be an important vulnerability factor for the development of anxiety disorders like posttraumatic stress disorder. Altered memory contextualization most likely involves effects of the stress hormone cortisol, acting via receptors located in the memory neurocircuitry. Cortisol via these receptors induces rapid nongenomic effects followed by slower genomic effects, which are thought to modulate cognitive function in opposite, complementary ways. Here, we targeted these time-dependent effects of cortisol during memory encoding and tested subsequent contextualization of emotional and neutral memories. In a double-blind, placebo-controlled design, 64 men were randomly assigned to one of three groups: 1) received 10 mg hydrocortisone 30 minutes (rapid cortisol effects) before a memory encoding task; 2) received 10 mg hydrocortisone 210 minutes (slow cortisol) before a memory encoding task; or 3) received placebo at both times. During encoding, participants were presented with neutral and emotional words in unique background pictures. Approximately 24 hours later, context dependency of their memories was assessed. Recognition data revealed that cortisol's rapid effects impair emotional memory contextualization, while cortisol's slow effects enhance it. Neutral memory contextualization remained unaltered by cortisol, irrespective of the timing of the drug. This study shows distinct time-dependent effects of cortisol on the contextualization of specifically emotional memories. The results suggest that rapid effects of cortisol may lead to impaired emotional memory contextualization, while slow effects of cortisol may confer protection against emotional memory generalization. © 2013 Society of Biological Psychiatry.

Methylphenidate Enhances Extinction of Contextual Fear

ERIC Educational Resources Information Center

Abraham, Antony D.; Cunningham, Christopher L.; Lattal, K. Matthew

2012-01-01

Methylphenidate (MPH, Ritalin) is a norepinephrine and dopamine transporter blocker that is widely used in humans for treatment of attention deficit disorder and narcolepsy. Although there is some evidence that targeted microinjections of MPH may enhance fear acquisition, little is known about the effect of MPH on fear extinction. Here, we show…

Administration of riluzole to the basolateral amygdala facilitates fear extinction in rats.

PubMed

Sugiyama, Azusa; Yamada, Misa; Saitoh, Akiyoshi; Oka, Jun-Ichiro; Yamada, Mitsuhiko

2018-01-15

A general understanding exists that inhibition of glutamatergic neurotransmission in the basolateral amygdala (BLA) impairs fear extinction in rodents. Surprisingly, we recently found that systemic administration of riluzole, which has been shown to inhibit the glutamatergic system, facilitates extinction learning in rats with a preconditioned contextual fear response. However, the mechanisms underlying this paradoxical effect of riluzole remain unclear. In this study, adult male Wistar rats were bilaterally cannulated in the BLA to examine the effects of intra-BLA administration of riluzole. We also compared the effects of riluzole with those of d-cycloserine, a partial agonist at the glycine-binding region of the N-methyl-d-aspartate (NMDA) receptor. In this study, intra-BLA administration of either riluzole or d-cycloserine facilitated extinction learning of contextual fear in conditioned rats. In addition, both riluzole and d-cycloserine enhanced the acquisition of recognition memory in the same model. However, intra-BLA injections of riluzole, but not d-cycloserine, had a potent anxiolytic-like effect when investigated using an elevated plus-maze test. Our findings suggest that riluzole-induced facilitation of extinction learning in rats with a preconditioned contextual fear reflects an indirect effect, resulting from the intra-BLA administration of the drug, and might not be directly related to inhibition of glutamatergic signaling. Further research is needed to clarify the mechanisms underlying the paradoxical effect of riluzole on fear extinction learning observed in this study. Copyright © 2017 Elsevier B.V. All rights reserved.

Prostaglandins are necessary and sufficient to induce contextual fear learning impairments after interleukin-1 beta injections into the dorsal hippocampus

PubMed Central

Hein, A.M.; Stutzman, D.L.; Bland, S.T.; Barrientos, R.M.; Watkins, L.R.; Rudy, J.W.; Maier, S.F.

2008-01-01

The intra-hippocampal administration of interleukin-1β (IL-1β) as well as the induction of elevated but physiological levels of IL-1β within the hippocampus interferes with the formation of long-term memory. There is evidence suggesting that the induction of prostaglandin (PG) formation by IL-1β is involved in impairments in working and spatial memory following IL-1β. The present experiments extend these findings by showing that PGs are responsible for memory deficits in contextual fear conditioning that occur following IL-1β injection into the dorsal hippocampus. Cyclooxygenase (COX) inhibition blocked the disruption in contextual fear conditioning produced by IL-1β and COX inhibition alone also disrupted contextual memory, suggesting an inverted U-shaped relationship between PG levels and memory. In addition to demonstrating the necessity of PGs in IL-1β mediated memory deficits, we also show that PGs injected directly into the dorsal hippocampus are sufficient to impair context memory and significantly reduce post-conditioning levels of BDNF within the hippocampus, suggesting a possible mechanism for the memory-impairing effects of PGs. PMID:18035502

PEGylated carbon nanotubes impair retrieval of contextual fear memory and alter oxidative stress parameters in the rat hippocampus.

PubMed

Dal Bosco, Lidiane; Weber, Gisele E B; Parfitt, Gustavo M; Paese, Karina; Gonçalves, Carla O F; Serodre, Tiago M; Furtado, Clascídia A; Santos, Adelina P; Monserrat, José M; Barros, Daniela M

2015-01-01

Carbon nanotubes (CNT) are promising materials for biomedical applications, especially in the field of neuroscience; therefore, it is essential to evaluate the neurotoxicity of these nanomaterials. The present work assessed the effects of single-walled CNT functionalized with polyethylene glycol (SWCNT-PEG) on the consolidation and retrieval of contextual fear memory in rats and on oxidative stress parameters in the hippocampus. SWCNT-PEG were dispersed in water at concentrations of 0.5, 1.0, and 2.1 mg/mL and infused into the rat hippocampus. The infusion was completed immediately after training and 30 min before testing of a contextual fear conditioning task, resulting in exposure times of 24 h and 30 min, respectively. The results showed that a short exposure to SWCNT-PEG impaired fear memory retrieval and caused lipid peroxidation in the hippocampus. This response was transient and overcome by the mobilization of antioxidant defenses at 24 h. These effects occurred at low and intermediate but not high concentration of SWCNT-PEG, suggesting that the observed biological response may be related to the concentration-dependent increase in particle size in SWCNT-PEG dispersions.

PEGylated Carbon Nanotubes Impair Retrieval of Contextual Fear Memory and Alter Oxidative Stress Parameters in the Rat Hippocampus

PubMed Central

Dal Bosco, Lidiane; Weber, Gisele E. B.; Parfitt, Gustavo M.; Paese, Karina; Gonçalves, Carla O. F.; Serodre, Tiago M.; Furtado, Clascídia A.; Santos, Adelina P.; Monserrat, José M.; Barros, Daniela M.

2015-01-01

Carbon nanotubes (CNT) are promising materials for biomedical applications, especially in the field of neuroscience; therefore, it is essential to evaluate the neurotoxicity of these nanomaterials. The present work assessed the effects of single-walled CNT functionalized with polyethylene glycol (SWCNT-PEG) on the consolidation and retrieval of contextual fear memory in rats and on oxidative stress parameters in the hippocampus. SWCNT-PEG were dispersed in water at concentrations of 0.5, 1.0, and 2.1 mg/mL and infused into the rat hippocampus. The infusion was completed immediately after training and 30 min before testing of a contextual fear conditioning task, resulting in exposure times of 24 h and 30 min, respectively. The results showed that a short exposure to SWCNT-PEG impaired fear memory retrieval and caused lipid peroxidation in the hippocampus. This response was transient and overcome by the mobilization of antioxidant defenses at 24 h. These effects occurred at low and intermediate but not high concentration of SWCNT-PEG, suggesting that the observed biological response may be related to the concentration-dependent increase in particle size in SWCNT-PEG dispersions. PMID:25738149

The Duration of Nicotine Withdrawal-Associated Deficits in Contextual Fear Conditioning Parallels Changes in Hippocampal High Affinity Nicotinic Acetylcholine Receptor Upregulation

PubMed Central

Gould, Thomas J.; Portugal, George S.; André, Jessica M.; Tadman, Matthew P.; Marks, Michael J.; Kenney, Justin W.; Yildirim, Emre; Adoff, Michael

2012-01-01

A predominant symptom of nicotine withdrawal is cognitive deficits, yet understanding of the neural basis for these deficits is limited. Withdrawal from chronic nicotine disrupts contextual learning in mice and this deficit is mediated by direct effects of nicotine in the hippocampus. Chronic nicotine treatment upregulates nicotinic acetylcholine receptors (nAChR); however, it is unknown whether upregulation is related to the observed withdawal-induced cognitive deficits. If a relationship between altered learning and nAChR levels exists, changes in nAChR levels after cessation of nicotine treatment should match the duration of learning deficits. To test this hypothesis, mice were chronically administered 6.3 mg/kg/day (freebase) nicotine for 12 days and trained in contextual fear conditioning on day 11 or between 1 to 16 days after withdrawal of treatment. Changes in [125I]-epibatidine binding at cytisine-sensitive and cytisine-resistant nAChRs and chronic nicotine-related changes in α4, α7, and β2 nAChR subunit mRNA expression were assessed. Chronic nicotine had no behavioral effect but withdrawal produced deficits in contextual fear conditioning that lasted 4 days. Nicotine withdrawal did not disrupt cued fear conditioning. Chronic nicotine upregulated hippocampal cytisine-sensitive nAChR binding; upregulation continued after cessation of nicotine administration and the duration of upregulation during withdrawal paralleled the duration of behavioral changes. Changes in binding in cortex and cerebellum did not match behavioral changes. No changes in α4, α7, and β2 subunit mRNA expression were seen with chronic nicotine. Thus, nicotine withdrawal-related deficits in contextual learning are time-limited changes that are associated with temporal changes in upregulation of high-affinity nAChR binding. PMID:22285742

Early life programming of innate fear and fear learning in adult female rats.

PubMed

Stevenson, Carl W; Meredith, John P; Spicer, Clare H; Mason, Rob; Marsden, Charles A

2009-03-02

The early rearing environment can impact on emotional reactivity and learning later in life. In this study the effects of neonatal maternal separation (MS) on innate fear and fear learning were assessed in the adult female rat. Pups were subjected to MS (360 min), brief handling (H; 15 min), or animal facility rearing (AFR) on post-natal days 2-14. In the first experiment, innate fear was tested in the open field. No differences between the early rearing groups were observed in unconditioned fear. In the second experiment, separate cohorts were used in a 3-day fear learning paradigm which tested the acquisition (Day 1), expression and extinction (both Day 2) of conditioning to an auditory cue; extinction recall was determined as well (Day 3). Contextual fear conditioning was also assessed prior to cue presentations on Days 2 and 3. Whereas MS attenuated the acquisition and expression of fear conditioning to the cue, H potentiated extinction learning. Cue-induced fear was reduced on Day 3, compared to Day 2, indicating that the recall of extinction learning was evident; however, no early rearing group differences in extinction recall were observed. Similarly, while contextual fear was decreased on Day 3, compared to Day 2, there were no differences between the early rearing groups on either day tested. The present findings of altered cue-conditioned fear learning, in the absence of innate fear changes, lend further support for the important role of the early rearing environment in mediating cognition in adulthood.

Early life programming of fear conditioning and extinction in adult male rats.

PubMed

Stevenson, Carl W; Spicer, Clare H; Mason, Rob; Marsden, Charles A

2009-12-28

The early rearing environment programs corticolimbic function and neuroendocrine stress reactivity in adulthood. Although early environmental programming of innate fear has been previously examined, its impact on fear learning and memory later in life remains poorly understood. Here we examined the role of the early rearing environment in programming fear conditioning and extinction in adult male rats. Pups were subjected to maternal separation (MS; 360 min), brief handling (H; 15 min), or animal facility rearing (AFR) on post-natal days 2-14. As adults, animals were tested in a 3-day fear learning and memory paradigm which assessed the acquisition, expression and extinction of fear conditioning to an auditory cue; the recall of extinction was also assessed. In addition, contextual fear was assessed prior to cued extinction and its recall. We found that the acquisition of fear conditioning to the cue was modestly impaired by MS. However, no early rearing group differences were observed in cue-induced fear expression. In contrast, both the rate of extinction and extinction recall were attenuated by H. Finally, although contextual fear was reduced after extinction to the cue, no differences in context-induced fear were observed between the early rearing groups. These results add to a growing body of evidence supporting an important role for early environmental programming of fear conditioning and extinction. They also indicate that different early rearing conditions can program varying effects on distinct fear learning and memory processes in adulthood.

Effects of Mineralocorticoid Receptor Overexpression on Anxiety and Memory after Early Life Stress in Female Mice

PubMed Central

Kanatsou, Sofia; Ter Horst, Judith P.; Harris, Anjanette P.; Seckl, Jonathan R.; Krugers, Harmen J.; Joëls, Marian

2016-01-01

Early-life stress (ELS) is a risk factor for the development of psychopathology, particularly in women. Human studies have shown that certain haplotypes of NR3C2, encoding the mineralocorticoid receptor (MR), that result in gain of function, may protect against the consequences of stress exposure, including childhood trauma. Here, we tested the hypothesis that forebrain-specific overexpression of MR in female mice would ameliorate the effects of ELS on anxiety and memory in adulthood. We found that ELS increased anxiety, did not alter spatial discrimination and reduced contextual fear memory in adult female mice. Transgenic overexpression of MR did not alter anxiety but affected spatial memory performance and enhanced contextual fear memory formation. The effects of ELS on anxiety and contextual fear were not affected by transgenic overexpression of MR. Thus, MR overexpression in the forebrain does not represent a major resilience factor to early life adversity in female mice. PMID:26858618

Spine growth in the anterior cingulate cortex is necessary for the consolidation of contextual fear memory

PubMed Central

Vetere, Gisella; Restivo, Leonardo; Cole, Christina J.; Ross, P. Joel; Ammassari-Teule, Martine; Josselyn, Sheena A.; Frankland, Paul W.

2011-01-01

Remodeling of cortical connectivity is thought to allow initially hippocampus-dependent memories to be expressed independently of the hippocampus at remote time points. Consistent with this, consolidation of a contextual fear memory is associated with dendritic spine growth in neurons of the anterior cingulate cortex (aCC). To directly test whether such cortical structural remodeling is necessary for memory consolidation, we disrupted spine growth in the aCC at different times following contextual fear conditioning in mice. We took advantage of previous studies showing that the transcription factor myocyte enhancer factor 2 (MEF2) negatively regulates spinogenesis both in vitro and in vivo. We found that increasing MEF2-dependent transcription in the aCC during a critical posttraining window (but not at later time points) blocked both the consolidation-associated dendritic spine growth and subsequent memory expression. Together, these data strengthen the causal link between cortical structural remodeling and memory consolidation and, further, identify MEF2 as a key regulator of these processes. PMID:21531906

Contribution of Hippocampal 5-HT3 Receptors in Hippocampal Autophagy and Extinction of Conditioned Fear Responses after a Single Prolonged Stress Exposure in Rats.

PubMed

Wu, Zhong-Min; Yang, Li-Hua; Cui, Rong; Ni, Gui-Lian; Wu, Feng-Tian; Liang, Yong

2017-05-01

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-HT 3 receptor in the development of PTSD, even though 5-HT 3 receptor is critical for contextual fear extinction and anxiety-like behavior. Therefore, we hypothesized that stimulation of 5-HT 3 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-HT 3 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-HT 3A 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-HT 3A 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-HT 3 receptor in the hippocampus may play a critical role in the pathogenesis of hippocampal autophagy, and is likely involved in the pathophysiology of PTSD.

Selective post-training time window for memory consolidation interference of cannabidiol into the prefrontal cortex: Reduced dopaminergic modulation and immediate gene expression in limbic circuits.

PubMed

Rossignoli, Matheus Teixeira; Lopes-Aguiar, Cleiton; Ruggiero, Rafael Naime; Do Val da Silva, Raquel Araujo; Bueno-Junior, Lezio Soares; Kandratavicius, Ludmyla; Peixoto-Santos, José Eduardo; Crippa, José Alexandre; Cecilio Hallak, Jaime Eduardo; Zuardi, Antonio Waldo; Szawka, Raphael Escorsim; Anselmo-Franci, Janete; Leite, João Pereira; Romcy-Pereira, Rodrigo Neves

2017-05-14

The prefrontal cortex (PFC), amygdala and hippocampus display a coordinated activity during acquisition of associative fear memories. Evidence indicates that PFC engagement in aversive memory formation does not progress linearly as previously thought. Instead, it seems to be recruited at specific time windows after memory acquisition, which has implications for the treatment of post-traumatic stress disorders. Cannabidiol (CBD), the major non-psychotomimetic phytocannabinoid of the Cannabis sativa plant, is known to modulate contextual fear memory acquisition in rodents. However, it is still not clear how CBD interferes with PFC-dependent processes during post-training memory consolidation. Here, we tested whether intra-PFC infusions of CBD immediately after or 5h following contextual fear conditioning was able to interfere with memory consolidation. Neurochemical and cellular correlates of the CBD treatment were evaluated by the quantification of extracellular levels of dopamine (DA), serotonin, and their metabolites in the PFC and by measuring the cellular expression of activity-dependent transcription factors in cortical and limbic regions. Our results indicate that bilateral intra-PFC CBD infusion impaired contextual fear memory consolidation when applied 5h after conditioning, but had no effect when applied immediately after it. This effect was associated with a reduction in DA turnover in the PFC following retrieval 5days after training. We also observed that post-conditioning infusion of CBD reduced c-fos and zif-268 protein expression in the hippocampus, PFC, and thalamus. Our findings support that CBD interferes with contextual fear memory consolidation by reducing PFC influence on cortico-limbic circuits. Copyright © 2017 IBRO. Published by Elsevier Ltd. All rights reserved.

Impairments in Fear Conditioning in Mice Lacking the nNOS Gene

ERIC Educational Resources Information Center

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

2009-01-01

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

The Prelimbic Cortex Directs Attention toward Predictive Cues during Fear Learning

ERIC Educational Resources Information Center

Sharpe, Melissa J.; Killcross, Simon

2015-01-01

The prelimbic cortex is argued to promote conditioned fear expression, at odds with appetitive research implicating this region in attentional processing. Consistent with an attentional account, we report that the effect of prelimbic lesions on fear expression depends on the degree of competition between contextual and discrete cues. Further, when…

Facilitation of Contextual Fear Extinction by Orexin-1 Receptor Antagonism Is Associated with the Activation of Specific Amygdala Cell Subpopulations.

PubMed

Flores, África; Herry, Cyril; Maldonado, Rafael; Berrendero, Fernando

2017-08-01

Orexins are hypothalamic neuropeptides recently involved in the regulation of emotional memory. The basolateral amygdala, an area orchestrating fear memory processes, appears to be modulated by orexin transmission during fear extinction. However, the neuronal types within the basolateral amygdala involved in this modulation remain to be elucidated. We used retrograde tracing combined with immunofluorescence techniques in mice to identify basolateral amygdala projection neurons and cell subpopulations in this brain region influenced by orexin transmission during contextual fear extinction consolidation. Treatment with the orexin-1 receptor antagonist SB334867 increased the activity of basolateral amygdala neurons projecting to infralimbic medial prefrontal cortex during fear extinction. GABAergic interneurons expressing calbindin, but not parvalbumin, were also activated by orexin-1 receptor antagonism in the basolateral amygdala. These data identify neuronal circuits and cell populations of the amygdala associated with the facilitation of fear extinction consolidation induced by the orexin-1 receptor antagonist SB334867. © The Author 2017. Published by Oxford University Press on behalf of CINP.

Hippocampal neurogenesis enhancers promote forgetting of remote fear memory after hippocampal reactivation by retrieval

PubMed Central

Ishikawa, Rie; Fukushima, Hotaka; Frankland, Paul W; Kida, Satoshi

2016-01-01

Forgetting of recent fear memory is promoted by treatment with memantine (MEM), which increases hippocampal neurogenesis. The approaches for treatment of post-traumatic stress disorder (PTSD) using rodent models have focused on the extinction and reconsolidation of recent, but not remote, memories. Here we show that, following prolonged re-exposure to the conditioning context, enhancers of hippocampal neurogenesis, including MEM, promote forgetting of remote contextual fear memory. However, these interventions are ineffective following shorter re-exposures. Importantly, we find that long, but not short re-exposures activate gene expression in the hippocampus and induce hippocampus-dependent reconsolidation of remote contextual fear memory. Furthermore, remote memory retrieval becomes hippocampus-dependent after the long-time recall, suggesting that remote fear memory returns to a hippocampus dependent state after the long-time recall, thereby allowing enhanced forgetting by increased hippocampal neurogenesis. Forgetting of traumatic memory may contribute to the development of PTSD treatment. DOI: http://dx.doi.org/10.7554/eLife.17464.001 PMID:27669409

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

PubMed

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

2014-04-01

Studies in rats, involving hippocampal lesions and hippocampal drug infusions, have implicated the hippocampus in the modulation of anxiety-related behaviors and conditioned fear. The ventral hippocampus is considered to be more important for anxiety- and fear-related behaviors than the dorsal hippocampus. In the present study, we compared the role of dorsal and ventral hippocampus in innate anxiety and classical fear conditioning in Wistar rats, examining the effects of temporary pharmacological inhibition by the GABA-A agonist muscimol (0.5 ug/0.5 ul/side) in the elevated plus maze and on fear conditioning to a tone and the conditioning context. In the elevated plus maze, dorsal and ventral hippocampal muscimol caused distinct behavioral changes. The effects of ventral hippocampal muscimol were consistent with suppression of locomotion, possibly accompanied by anxiolytic effects, whereas the pattern of changes caused by dorsal hippocampal muscimol was consistent with anxiogenic effects. In contrast, dorsal and ventral hippocampal muscimol caused similar effects in the fear conditioning experiments, disrupting contextual, but not tone, fear conditioning. Copyright © 2013 Elsevier B.V. All rights reserved.

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

PubMed Central

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

2016-01-01

The anterior cingulate cortex (AC) component of the medial prefrontal cortex (mPFC) has been implicated in attention and working memory as measured by trace conditioning. Since dopamine (DA) is a key modulator of mPFC function, the present study evaluated the role of DA receptor agents in rat AC, using trace fear conditioning. A conditioned stimulus (CS, noise) was followed by an unconditioned stimulus (US, shock) with or without a 10 s trace interval interposed between these events in a between-subjects design. Conditioned suppression of drinking was assessed in response to presentation of the CS or an experimental background stimulus (flashing lights, previously presented for the duration of the conditioning session). The selective D1 agonist SKF81297 (0.05 μg/side) or D1 antagonist SCH23390 (0.5 μg/side) was administered by intra-cerebral microinfusion directly into AC. It was predicted that either of these manipulations should be sufficient to impair trace (but not delay) conditioning. Counter to expectation, there was no effect of DA D1 modulation on trace conditioning as measured by suppression to the noise CS. However, rats infused with SKF81297 acquired stronger conditioned suppression to the experimental background stimulus than those infused with SCH23390 or saline. Thus, the DA D1 agonist SKF81297 increased conditioned suppression to the contextual background light stimulus but was otherwise without effect on fear conditioning. PMID:26343307

Midazolam treatment before re-exposure to contextual fear reduces freezing behavior and amygdala activity differentially in high- and low-anxiety rats.

PubMed

Skórzewska, Anna; Lehner, Małgorzata; Wisłowska-Stanek, Aleksandra; Turzyńska, Danuta; Sobolewska, Alicja; Krząścik, Paweł; Płaźnik, Adam

2015-02-01

The aim of this study was to examine the effects of benzodiazepine (midazolam) administration on rat conditioned fear responses and on local brain activity (c-Fos and CRF expressions) of low- (LR) and high- (HR)anxiety rats after the first and second contextual fear test sessions. The animals were divided into LR and HR groups based on the duration of their conditioned freezing response in the first contextual fear test. The fear-re-conditioned LR and HR animals (28 days later) had increased freezing durations compared with those durations during the first conditioned fear test. These behavioral effects were accompanied by increased c-Fos expression in the medial amygdala (MeA), the basolateral amygdala (BLA), and the paraventricular hypothalamic nuclei and elevated CRF expression in the MeA. All these behavioral and immunochemical effects of fear re-conditioning were stronger in the LR group compared with the effects in the HR group. Moreover, in the LR rats, the re-conditioning led to decreased CRF expression in the primary motor cortex (M1) and to increased CRF expression in the BLA. The pretreatment of rats with midazolam before the second exposure to the aversive context significantly attenuated the conditioned fear response, lowered the serum corticosterone concentration, decreased c-Fos and CRF expressions in the MeA and in the BLA, and increased CRF complex density in M1 area only in the LR group. These studies have demonstrated that LR rats are more sensitive to re-exposure to fear stimuli and that midazolam pretreatment was associated with modified brain activity in the amygdala and in the prefrontal cortex in this group of animals. The current data may facilitate a better understanding of the neurobiological mechanisms responsible for individual differences in the psychopathological processes accompanying some anxiety disorders characterized by stronger reactivity to re-exposure to stressful challenges, e.g., posttraumatic stress disorder. Copyright © 2013 Elsevier Inc. All rights reserved.

The effect of left frontal transcranial direct-current stimulation on propranolol-induced fear memory acquisition and consolidation deficits.

PubMed

Nasehi, Mohammad; Khani-Abyaneh, Mozhgan; Ebrahimi-Ghiri, Mohaddeseh; Zarrindast, Mohammad-Reza

2017-07-28

Accumulating evidence supports the efficacy of transcranial direct current stimulation (tDCS) in modulating numerous cognitive functions. Despite the fact that tDCS has been used for the enhancement of memory and cognition, very few animal studies have addressed its impact on the modulation of fear memory. This study was designed to determine whether pre/post-training frontal tDCS application would alter fear memory acquisition and/or consolidation deficits induced by propranolol in NMRI mice. Results indicated that administration of β1-adrenoceptor blocker propranolol (0.1mg/kg) impaired fear memory retrieval. Pre/post-training application of anodal tDCS when propranolol was administered prior to training reversed contextual memory retrieval whereas only the anodal application prior to training could induce the same result in the auditory test. Meanwhile, anodal stimulation had no effect on fear memories by itself. Moreover, regardless of when cathode was applied and propranolol administered, their combination restored contextual memory retrieval, while only cathodal stimulation prior to training facilitated the contextual memory retrieval. Also, auditory memory retrieval was restored when cathodal stimulation and propranolol occurred prior to training but it was abolished when stimulation occurred after training and propranolol was administered prior to training. Collectively, our findings show that tDCS applied on the left frontal cortex of mice affects fear memory performance. This alteration seems to be task-dependent and varies depending on the nature and timing of the stimulation. In certain conditions, tDCS reverses the effect of propranolol. These results provide initial evidence to support the timely use of tDCS for the modulation of fear-related memories. Copyright © 2017 Elsevier B.V. All rights reserved.

AMPK Signaling in the Dorsal Hippocampus Negatively Regulates Contextual Fear Memory Formation

PubMed Central

Han, Ying; Luo, Yixiao; Sun, Jia; Ding, Zengbo; Liu, Jianfeng; Yan, Wei; Jian, Min; Xue, Yanxue; Shi, Jie; Wang, Ji-Shi; Lu, Lin

2016-01-01

Both the formation of long-term memory (LTM) and dendritic spine growth that serves as a physical basis for the long-term storage of information require de novo protein synthesis. Memory formation also critically depends on transcription. Adenosine monophosphate-activated protein kinase (AMPK) is a transcriptional regulator that has emerged as a major energy sensor that maintains cellular energy homeostasis. However, still unknown is its role in memory formation. In the present study, we found that AMPK is primarily expressed in neurons in the hippocampus, and then we demonstrated a time-dependent decrease in AMPK activity and increase in mammalian target of rapamycin complex 1 (mTORC1) activity after contextual fear conditioning in the CA1 but not CA3 area of the dorsal hippocampus. Using pharmacological methods and adenovirus gene transfer to bidirectionally regulate AMPK activity, we found that increasing AMPK activity in the CA1 impaired the formation of long-term fear memory, and decreasing AMPK activity enhanced fear memory formation. These findings were associated with changes in the phosphorylation of AMPK and p70s6 kinase (p70s6k) and expression of BDNF and membrane GluR1 and GluR2 in the CA1. Furthermore, the prior administration of an mTORC1 inhibitor blocked the enhancing effect of AMPK inhibition on fear memory formation, suggesting that this negative regulation of contextual fear memory by AMPK in the CA1 depends on the mTORC1 signaling pathway. Finally, we found that AMPK activity regulated hippocampal spine growth associated with memory formation. In summary, our results indicate that AMPK is a key negative regulator of plasticity and fear memory formation. PMID:26647974

Strain-dependent Effects of Acute, Chronic, and Withdrawal from Chronic Nicotine on Fear Conditioning

PubMed Central

Portugal, George S.; Wilkinson, Derek S.; Kenney, Justin W.; Sullivan, Colleen

2013-01-01

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

Role of the 5HT3 Receptor in Alcohol Drinking and Aggression Using a Transgenic Mouse Model

DTIC Science & Technology

2006-09-01

Dissociations in hippocampal 5-hydroxytryptamine release in the rat following Pavlovian aversive conditioning to discrete and contextual stimuli. Eur J...P < 0.05]. B6SJL/F2-OE and C57Bl/6J-OE mice display improved contextual fear conditioning , whereas DBA/2J-OE mice do not. Fear conditioning to...None of the IS groups differed in freezing behavior and are not reported here. Transgene presence improved conditioning on B6SJL/F2 and C57Bl/6J

Activity in Prelimbic Cortex Subserves Fear Memory Reconsolidation over Time

ERIC Educational Resources Information Center

Stern, Cristina A. J.; Gazarini, Lucas; Vanvossen, Ana C.; Hames, Mayara S.; Bertoglio, Leandro J.

2014-01-01

The prelimbic cortex has been implicated in the consolidation of previously learned fear. Herein, we report that temporarily inactivating this medial prefrontal cortex subregion with the GABA [subscript A] agonist muscimol (4.0 nmol in 0.2 µL per hemisphere) was able to equally disrupt 1-, 7-, and 21-d-old contextual fear memories after their…

The Ventromedial Prefrontal Cortex in a Model of Traumatic Stress: Fear Inhibition or Contextual Processing?

ERIC Educational Resources Information Center

Pennington, Zachary T.; Anderson, Austin S.; Fanselow, Michael S.

2017-01-01

The ventromedial prefrontal cortex (vmPFC) has consistently appeared altered in post-traumatic stress disorder (PTSD). Although the vmPFC is thought to support the extinction of learned fear responses, several findings support a broader role for this structure in the regulation of fear. To further characterize the relationship between vmPFC…

Contextual Fear Conditioning in Humans: Cortical-Hippocampal and Amygdala Contributions

PubMed Central

Alvarez, Ruben P.; Biggs, Arter; Chen, Gang; Pine, Daniel S.; Grillon, Christian

2008-01-01

Functional imaging studies of cued fear conditioning in humans have largely confirmed findings in animals, but it is unclear whether the brain mechanisms that underlie contextual fear conditioning in animals are also preserved in humans. We investigated this issue using fMRI and virtual reality contexts. Subjects underwent differential context conditioning in which they were repeatedly exposed to two contexts (CXT+ and CXT-) in semi-random order, with contexts counterbalanced across participants. An un-signaled footshock was consistently paired with the CXT+, and no shock was ever delivered in the CXT-. Evidence for context conditioning was established using skin conductance and anxiety ratings. Consistent with animal models centrally implicating the hippocampus and amygdala in a network supporting context conditioning, CXT+ compared to CXT- significantly activated right anterior hippocampus and bilateral amygdala. In addition, context conditioning was associated with activation in posterior orbitofrontal cortex, medial dorsal thalamus, anterior insula, subgenual anterior cingulate, and parahippocampal, inferior frontal and parietal cortices. Structural equation modeling was used to assess interactions among the core brain regions mediating context conditioning. The derived model indicated that medial amygdala was the source of key efferent and afferent connections including input from orbitofrontal cortex. These results provide evidence that similar brain mechanisms may underlie contextual fear conditioning across species. PMID:18550763

Developmental Effects of Acute, Chronic, and Withdrawal from Chronic Nicotine on Fear Conditioning

PubMed Central

Portugal, George S.; Wilkinson, Derek S.; Turner, Jill R.; Blendy, Julie A.; Gould, Thomas J.

2012-01-01

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

Effects of lentivirus-mediated CREB expression in the dorsolateral striatum: memory enhancement and evidence for competitive and cooperative interactions with the hippocampus.

PubMed

Kathirvelu, Balachandar; Colombo, Paul J

2013-11-01

Neural systems specialized for memory may interact during memory formation or recall, and the results of interactions are important determinants of how systems control behavioral output. In two experiments, we used lentivirus-mediated expression of the transcription factor CREB (LV-CREB) to test if localized manipulations of cellular plasticity influence interactions between the hippocampus and dorsolateral striatum. In Experiment 1, we tested the hypothesis that infusion of LV-CREB in the dorsolateral striatum facilitates memory for response learning, and impairs memory for place learning. LV-CREB in the dorsolateral striatum had no effect on response learning, but impaired place memory; a finding consistent with competition between the striatum and hippocampus. In Experiment 2, we tested the hypothesis that infusion of LV-CREB in the dorsolateral striatum facilitates memory for cue learning, and impairs memory for contextual fear conditioning. LV-CREB in the dorsolateral striatum enhanced memory for cue learning and, in contrast to our prediction, also enhanced memory for contextual fear conditioning, consistent with a cooperative interaction between the striatum and hippocampus. Overall, the current experiments demonstrate that infusion of LV-CREB in the dorsolateral striatum (1) increases levels of CREB protein locally, (2) does not alter acquisition of place, response, cue, or contextual fear conditioning, (3) facilitates memory for cue learning and contextual fear conditioning, and (4) impairs memory for place learning. Taken together, the present results provide evidence that LV-CREB in the dorsolateral striatum can enhance memory formation and cause both competitive and cooperative interactions with the hippocampus. Copyright © 2013 Wiley Periodicals, Inc.

Low-dose systemic scopolamine disrupts context conditioning in rats.

PubMed

Luyten, Laura; Nuyts, Shauni; Beckers, Tom

2017-06-01

Cholinergic neurotransmission plays a key role in learning and memory. Prior research with rats indicated that a low dose of pre-training scopolamine (0.1 mg/kg), a cholinergic receptor antagonist, did not affect cued fear conditioning, but did block renewal when injected before extinguishing a conditioned tone, opening up opportunities to pharmacologically improve exposure therapy for anxiety patients. Before translating these findings to the clinic, it is important to carefully examine how scopolamine affects contextual fear memories. Here, we investigated the effects of scopolamine on encoding of contextual anxiety and its generalization in male Wistar rats. We found a profound disruption of context conditioning, suggesting that, even at a low dose, systemic scopolamine may influence contextual encoding in the hippocampus, particularly when the context is the best predictor for the presence of shocks.

Hippocampal Administration of Levothyroxine Impairs Contextual Fear Memory Consolidation in Rats.

PubMed

Yu, Dafu; Zhou, Heng; Zou, Lin; Jiang, Yong; Wu, Xiaoqun; Jiang, Lizhu; Zhou, Qixin; Yang, Yuexiong; Xu, Lin; Mao, Rongrong

2017-01-01

Thyroid hormone (TH) receptors are highly distributed in the hippocampus, which plays a vital role in memory processes. However, how THs are involved in the different stages of memory process is little known. Herein, we used hippocampus dependent contextual fear conditioning to address the effects of hippocampal THs on the different stages of fear memory. First, we found that a single systemic levothyroxine (LT 4 ) administration increased the level of free triiodothyronine (FT 3 ) and free tetraiodothyroxine (FT 4 ) not only in serum but also in hippocampus. In addition, a single systemic LT 4 administration immediately after fear conditioning significantly impaired fear memory. These results indicated the important role of hippocampal THs in fear memory process. To further confirm the effects of hippocampal THs on the different stages of fear memory, LT 4 (0.4 μg/μl, 1 μl/side) was injected bilaterally into hippocampus. Rats given LT 4 into hippocampus before training or tests had no effect on the acquisition or retrieval of fear memory, however rats given LT 4 into hippocampus either immediately or 2 h after training showed being significantly impaired fear memory, which demonstrated LT 4 administration into hippocampus impairs the consolidation but has no effect on the acquisition and retrieval of fear memory. Furthermore, hippocampal injection of LT 4 did not affect rats' locomotor activity, thigmotaxis and THs level in prefrontal cortex (PFC) and serum. These findings may have important implications for understanding mechanisms underlying contribution of THs to memory disorders.

Hippocampal Administration of Levothyroxine Impairs Contextual Fear Memory Consolidation in Rats

PubMed Central

Yu, Dafu; Zhou, Heng; Zou, Lin; Jiang, Yong; Wu, Xiaoqun; Jiang, Lizhu; Zhou, Qixin; Yang, Yuexiong; Xu, Lin; Mao, Rongrong

2017-01-01

Thyroid hormone (TH) receptors are highly distributed in the hippocampus, which plays a vital role in memory processes. However, how THs are involved in the different stages of memory process is little known. Herein, we used hippocampus dependent contextual fear conditioning to address the effects of hippocampal THs on the different stages of fear memory. First, we found that a single systemic levothyroxine (LT4) administration increased the level of free triiodothyronine (FT3) and free tetraiodothyroxine (FT4) not only in serum but also in hippocampus. In addition, a single systemic LT4 administration immediately after fear conditioning significantly impaired fear memory. These results indicated the important role of hippocampal THs in fear memory process. To further confirm the effects of hippocampal THs on the different stages of fear memory, LT4 (0.4 μg/μl, 1 μl/side) was injected bilaterally into hippocampus. Rats given LT4 into hippocampus before training or tests had no effect on the acquisition or retrieval of fear memory, however rats given LT4 into hippocampus either immediately or 2 h after training showed being significantly impaired fear memory, which demonstrated LT4 administration into hippocampus impairs the consolidation but has no effect on the acquisition and retrieval of fear memory. Furthermore, hippocampal injection of LT4 did not affect rats’ locomotor activity, thigmotaxis and THs level in prefrontal cortex (PFC) and serum. These findings may have important implications for understanding mechanisms underlying contribution of THs to memory disorders. PMID:28824379

Acute Nicotine Enhances Spontaneous Recovery of Contextual Fear and Changes "c-fos" Early Gene Expression in Infralimbic Cortex, Hippocampus, and Amygdala

ERIC Educational Resources Information Center

Kutlu, Munir G.; Tumolo, Jessica M.; Holliday, Erica; Garrett, Brendan; Gould, Thomas J.

2016-01-01

Exposure therapy, which focuses on extinguishing fear-triggering cues and contexts, is widely used to treat post-traumatic stress disorder (PTSD). Yet, PTSD patients who received successful exposure therapy are vulnerable to relapse of fear response after a period of time, a phenomenon known as spontaneous recovery (SR). Increasing evidence…

Contextual-Specificity of Short-Delay Extinction in Humans: Renewal of Fear-Potentiated Startle in a Virtual Environment

ERIC Educational Resources Information Center

Alvarez, Ruben P.; Johnson, Linda; Grillon, Christian

2007-01-01

A recent fear-potentiated startle study in rodents suggested that extinction was not context dependent when extinction was conducted after a short delay following acquisition, suggesting that extinction can lead to erasure of fear learning in some circumstances. The main objective of this study was to attempt to replicate these findings in humans…

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

ERIC Educational Resources Information Center

Graham, Bronwyn M.; Richardson, Rick

2016-01-01

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

The Melatonergic System in Anxiety Disorders and the Role of Melatonin in Conditional Fear.

PubMed

Huang, F; Yang, Z; Li, C-Q

2017-01-01

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.

Suppression of Neurotoxic Lesion-Induced Seizure Activity: Evidence for a Permanent Role for the Hippocampus in Contextual Memory

PubMed Central

Sparks, Fraser T.; Lehmann, Hugo; Hernandez, Khadaryna; Sutherland, Robert J.

2011-01-01

Damage to the hippocampus (HPC) using the excitotoxin N-methyl-D-aspartate (NMDA) can cause retrograde amnesia for contextual fear memory. This amnesia is typically attributed to loss of cells in the HPC. However, NMDA is also known to cause intense neuronal discharge (seizure activity) during the hours that follow its injection. These seizures may have detrimental effects on retrieval of memories. Here we evaluate the possibility that retrograde amnesia is due to NMDA-induced seizure activity or cell damage per se. To assess the effects of NMDA induced activity on contextual memory, we developed a lesion technique that utilizes the neurotoxic effects of NMDA while at the same time suppressing possible associated seizure activity. NMDA and tetrodotoxin (TTX), a sodium channel blocker, are simultaneously infused into the rat HPC, resulting in extensive bilateral damage to the HPC. TTX, co-infused with NMDA, suppresses propagation of seizure activity. Rats received pairings of a novel context with foot shock, after which they received NMDA-induced, TTX+NMDA-induced, or no damage to the HPC at a recent (24 hours) or remote (5 weeks) time point. After recovery, the rats were placed into the shock context and freezing was scored as an index of fear memory. Rats with an intact HPC exhibited robust memory for the aversive context at both time points, whereas rats that received NMDA or NMDA+TTX lesions showed a significant reduction in learned fear of equal magnitude at both the recent and remote time points. Therefore, it is unlikely that observed retrograde amnesia in contextual fear conditioning are due to disruption of non-HPC networks by propagated seizure activity. Moreover, the memory deficit observed at both time points offers additional evidence supporting the proposition that the HPC has a continuing role in maintaining contextual memories. PMID:22110648

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

PubMed

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

2009-03-01

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

Impaired contextual fear-conditioning in MAM rodent model of schizophrenia.

PubMed

Gill, Kathryn M; Miller, Sarah A; Grace, Anthony A

2018-05-01

The methylazoxymethanol acetate (MAM) rodent neurodevelopmental model of schizophrenia exhibits aberrant dopamine system activation attributed to hippocampal dysfunction. Context discrimination is a component of numerous behavioral and cognitive functions and relies on intact hippocampal processing. The present study explored context processing behaviors, along with dopamine system activation, during fear learning in the MAM model. Male offspring of dams treated with MAM (20mg/kg, i.p.) or saline on gestational day 17 were used for electrophysiological and behavioral experiments. Animals were tested on the immediate shock fear conditioning paradigm, with either different pre-conditioning contexts or varying amounts of context pre-exposure (0-10 sessions). Amphetamine-induced locomotor activity and dopamine neural activity was measured 1-week after fear conditioning. Saline, but not MAM animals, demonstrated enhanced fear responses following a single context pre-exposure in the conditioning context. One week following fear learning, saline rats with 2 or 7min of context pre-exposure prior to fear conditioning also demonstrated enhanced amphetamine-induced locomotor response relative to MAM animals. Dopamine neuron recordings showed fear learning-induced reductions in spontaneous dopamine neural activity in MAM rats that was further reduced by amphetamine. Apomorphine administration confirmed that reductions in dopamine neuron activity in MAM animals resulted from over excitation, or depolarization block. These data show a behavioral insensitivity to contextual stimuli in MAM rats that coincide with a less dynamic dopamine response after fear learning. Copyright © 2017 Elsevier B.V. All rights reserved.

COCAINE AND PAVLOVIAN FEAR CONDITIONING: DOSE-EFFECT ANALYSIS

PubMed Central

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

2007-01-01

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

Cocaine and Pavlovian fear conditioning: dose-effect analysis.

PubMed

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

2007-01-25

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.

Both mineralocorticoid and glucocorticoid receptors regulate emotional memory in mice.

PubMed

Zhou, Ming; Bakker, Eveline H M; Velzing, Els H; Berger, Stefan; Oitzl, Melly; Joëls, Marian; Krugers, Harm J

2010-11-01

Corticosteroid hormones are thought to promote optimal behavioral adaptation under fearful conditions, primarily via glucocorticoid receptors (GRs). Here, we examined - using pharmacological and genetic approaches in mice - if mineralocorticoid receptors (MRs) also play a role in fearful memory formation. As expected, administration of the GR-antagonist RU38486 prior to training in a fear conditioning paradigm impaired contextual memory when tested 24 (but not when tested 3) h after training. Tone-cue memory was enhanced by RU38486 when tested at 4 (but not 25) h after training. Interestingly, pre (but not post)-training administration of MR antagonist spironolactone impaired contextual memory, both at 3 and 24h after training. Similar effects were also found in forebrain-specific MR knockout mice. Spironolactone also impaired tone-cue memory, but only at 4h after training. These results reveal that - in addition to GRs - MRs also play a critical role in establishing fear memories, particularly in the early phase of memory formation. Copyright © 2010 Elsevier Inc. All rights reserved.

D-Cycloserine Does Not Facilitate Fear Extinction by Reducing Conditioned Stimulus Processing or Promoting Conditioned Inhibition to Contextual Cues

ERIC Educational Resources Information Center

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

2012-01-01

The NMDA receptor partial agonist d-cycloserine (DCS) enhances the extinction of learned fear in rats and exposure therapy in humans with anxiety disorders. Despite these benefits, little is known about the mechanisms by which DCS promotes the loss of fear. The present study examined whether DCS augments extinction retention (1) through reductions…

Low-dose systemic scopolamine disrupts context conditioning in rats

PubMed Central

Luyten, Laura; Nuyts, Shauni; Beckers, Tom

2017-01-01

Cholinergic neurotransmission plays a key role in learning and memory. Prior research with rats indicated that a low dose of pre-training scopolamine (0.1 mg/kg), a cholinergic receptor antagonist, did not affect cued fear conditioning, but did block renewal when injected before extinguishing a conditioned tone, opening up opportunities to pharmacologically improve exposure therapy for anxiety patients. Before translating these findings to the clinic, it is important to carefully examine how scopolamine affects contextual fear memories. Here, we investigated the effects of scopolamine on encoding of contextual anxiety and its generalization in male Wistar rats. We found a profound disruption of context conditioning, suggesting that, even at a low dose, systemic scopolamine may influence contextual encoding in the hippocampus, particularly when the context is the best predictor for the presence of shocks. PMID:28417664

A Bayesian context fear learning algorithm/automaton

PubMed Central

Krasne, Franklin B.; Cushman, Jesse D.; Fanselow, Michael S.

2015-01-01

Contextual fear conditioning is thought to involve the synaptic plasticity-dependent establishment in hippocampus of representations of to-be-conditioned contexts which can then become associated with USs in the amygdala. A conceptual and computational model of this process is proposed in which contextual attributes are assumed to be sampled serially and randomly during contextual exposures. Given this assumption, moment-to-moment information about such attributes will often be quite different from one exposure to another and, in particular, between exposures during which representations are created, exposures during which conditioning occurs, and during recall sessions. This presents challenges to current conceptual models of hippocampal function. In order to meet these challenges, our model's hippocampus was made to operate in different modes during representation creation and recall, and non-hippocampal machinery was constructed that controlled these hippocampal modes. This machinery uses a comparison between contextual information currently observed and information associated with existing hippocampal representations of familiar contexts to compute the Bayesian Weight of Evidence that the current context is (or is not) a known one, and it uses this value to assess the appropriateness of creation or recall modes. The model predicts a number of known phenomena such as the immediate shock deficit, spurious fear conditioning to contexts that are absent but similar to actually present ones, and modulation of conditioning by pre-familiarization with contexts. It also predicts a number of as yet unknown phenomena. PMID:26074792

Neonatal Handling Increases Cardiovascular Reactivity to Contextual Fear Conditioning in Borderline Hypertensive Rats (BHR)

PubMed Central

Sanders, Brian J.; Knoepfler, Jonathan

2008-01-01

Much research has demonstrated that events occurring in early life can have a profound influence on future biobehavioral responses to stressful and emotion provoking situations. The purpose of these studies was to determine the effects of an early environmental manipulation, handling (HAN) on cardiovascular (CV) reactivity, freezing behavior and corticosterone (CORT) responses to contextual fear conditioning in the borderline hypertensive rat (BHR), which is susceptible to environmental stressors. HAN subjects were separated from the nest for 15 min/day on post-natal days 1–14, while non-handled (NON-HAN) controls remained in the home cage. Adult subjects were exposed to the contextual fear conditioning procedure and returned to the chamber 24 h later for a 10 min test period. HAN subjects displayed significantly more freezing behavior compared to NON-HAN(92%±2.2 vs 80.7%±5.7, p < .05). Although resting MAP did not differ between groups, HAN subjects had increased MAP reactivity when re-exposed to the chamber. In addition, HAN subjects had significantly lower CORT levels at the end of the 10 min test period (174.2±9 ng/ml vs 237.2±12.9 ng/ml, p < .05). In the second experiment, CORT responses to 60 min of restraint stress and recovery following return to the home cage were assessed in separate groups of HAN and NON-HAN subjects. HAN subjects showed reduced CORT levels in response to acute restraint stress. These results indicate that neonatal handling can modulate biobehavioral responses to contextual fear conditioning in BHR and may suggest a useful model with which to study emotionality and susceptibility to CV disease. PMID:18538802

Nicotine Ameliorates NMDA Receptor Antagonist-Induced Deficits in Contextual Fear Conditioning through High Affinity Nicotinic Acetylcholine Receptors in the Hippocampus

PubMed Central

André, Jessica M.; Leach, Prescott T.; Gould, Thomas J.

2011-01-01

NMDA glutamate receptors (NMDARs) and nicotinic acetylcholine receptors (nAChRs) are both involved in learning and synaptic plasticity. Increasing evidence suggests processes mediated by these receptors may interact to modulate learning; however, little is known about the neural substrates involved in these interactive processes. The present studies investigated the effects of nicotine on MK-801 hydrogen maleate (MK-801) and DL-2-Amino-5-phosphonovaleric acid (APV) induced disruption of contextual fear conditioning in male C57BL/6J mice, using direct drug infusion and selective nAChR antagonists to define the brain regions and the nAChR subtypes involved. Mice treated with MK-801 showed a deficit in contextual fear conditioning that was ameliorated by nicotine. Direct drug infusion demonstrated that the NMDAR antagonists disrupted hippocampal function and that nicotine acted in the dorsal hippocampus to ameliorate the deficit in learning. The high-affinity nAChR antagonist Dihydro-β-erythroidine hydrobromide (DhβE) blocked the effects of nicotine on MK-801-induced deficits while the α7 nAChR antagonist methyllycaconitine citrate salt hydrate (MLA) did not. These results suggest that NMDARs and nAChRs may mediate similar hippocampal processes involved in contextual fear conditioning. Furthermore, these results may have implications for developing effective therapeutics for the cognitive deficits associated with schizophrenia because a large subset of patients with schizophrenia exhibit cognitive deficits that may be related to NMDAR dysfunction and smoke at much higher rates than the healthy population, which may be an attempt to ameliorate cognitive deficits. PMID:21167848

Converging evidence for an impact of a functional NOS gene variation on anxiety-related processes

PubMed Central

Haaker, Jan; Glotzbach-Schoon, Evelyn; Schümann, Dirk; Andreatta, Marta; Mechias, Marie-Luise; Raczka, Karolina; Gartmann, Nina; Büchel, Christian; Mühlberger, Andreas; Pauli, Paul; Reif, Andreas; Kalisch, Raffael; Lonsdorf, Tina B.

2016-01-01

Abstract Being a complex phenotype with substantial heritability, anxiety and related phenotypes are characterized by a complex polygenic basis. Thereby, one candidate pathway is neuronal nitric oxide (NO) signaling, and accordingly, rodent studies have identified NO synthase (NOS-I), encoded by NOS1, as a strong molecular candidate for modulating anxiety and hippocampus-dependent learning processes. Using a multi-dimensional and -methodological replication approach, we investigated the impact of a functional promoter polymorphism (NOS1-ex1f-VNTR) on human anxiety-related phenotypes in a total of 1019 healthy controls in five different studies. Homozygous carriers of the NOS1-ex1f short-allele displayed enhanced trait anxiety, worrying and depression scores. Furthermore, short-allele carriers were characterized by increased anxious apprehension during contextual fear conditioning. While autonomous measures (fear-potentiated startle) provided only suggestive evidence for a modulatory role of NOS1-ex1f-VNTR on (contextual) fear conditioning processes, neural activation at the amygdala/anterior hippocampus junction was significantly increased in short-allele carriers during context conditioning. Notably, this could not be attributed to morphological differences. In accordance with data from a plethora of rodent studies, we here provide converging evidence from behavioral, subjective, psychophysiological and neuroimaging studies in large human cohorts that NOS-I plays an important role in anxious apprehension but provide only limited evidence for a role in (contextual) fear conditioning. PMID:26746182

The hippocampo-amygdala control of contextual fear expression is affected in a model of intellectual disability.

PubMed

Zhang, Chun-Lei; Houbaert, Xander; Lepleux, Marilyn; Deshors, Melissa; Normand, Elisabeth; Gambino, Frédéric; Herzog, Etienne; Humeau, Yann

2015-11-01

The process of learning mainly depends on the ability to store new information, while the ability to retrieve this information and express appropriate behaviors are also crucial for the adaptation of individuals to environmental cues. Thereby, all three components contribute to the cognitive fitness of an individual. While a lack of behavioral adaptation is a recurrent trait of intellectually disabled patients, discriminating between memory formation, memory retrieval or behavioral expression deficits is not easy to establish. Here, we report some deficits in contextual fear behavior in knockout mice for the intellectual disability gene Il1rapl1. Functional in vivo experiments revealed that the lack of conditioned response resulted from a local inhibitory to excitatory (I/E) imbalance in basolateral amygdala (BLA) consecutive to a loss of excitatory drive onto BLA principal cells by caudal hippocampus axonal projections. A normalization of the fear behavior was obtained in adult mutant mice following opsin-based in vivo synaptic priming of hippocampo-BLA synapses in adult il1rapl1 knockout mice, indicating that synaptic efficacy at hippocampo-BLA projections is crucial for contextual fear memory expression. Importantly, because this restoration was obtained after the learning phase, our results suggest that some of the genetically encoded cognitive deficits in humans may originate from a lack of restitution of genuinely formed memories rather than an exclusive inability to store new memories.

Female-dependent impaired fear memory of adult rats induced by maternal separation, and screening of possible related genes in the hippocampal CA1.

PubMed

Sun, Xiu-Min; Tu, Wen-Qiang; Shi, Yan-Wei; Xue, Li; Zhao, Hu

2014-07-01

Early life stress is one of the major susceptible factors for stress-related pathologies like posttraumatic stress disorder (PTSD). Recent studies in rats suggest that rather than being overall unfavorable, early life stress may prepare the organism to perform optimally to stressful environments later in life. In this study, severely adverse early life stress was conducted by six consecutive hours of maternal separation (MS), from PND1 to PND21, and contextual fear conditioning model was used on PND90 to mimic the second stress in adulthood and the re-experiencing symptom of PTSD. It was observed that in this investigation pups experienced MS showed decreased sensibility to contextual fear conditioning in adulthood, and there sex plays an important role. For example, female rats suffered MS had much lower freezing than males and controls. Meanwhile, Morris water maze test indicated that MS did not impair rat's performance of spatial learning and memory. Furthermore, suppression subtractive hybridization (SSH) was used to screen the related genes of fear memory, by examining the changes of mRNA expression in CA1 area between female MS and control rats after contextual fear conditioning. Finally, nine up-regulated and one down-regulated genes, including β2-MG, MAF, Nd1-L, TorsinA and MACF1 gene were found in this study. It is assumed that the TorsinA, MACF1 and Nd1-L gene may contribute to the decreased sensitivity of PTSD induced by MS. Copyright © 2014 Elsevier B.V. All rights reserved.

Multilevel analysis of facial expressions of emotion and script: self-report (arousal and valence) and psychophysiological correlates

PubMed Central

2014-01-01

Background The paper explored emotion comprehension in children with regard to facial expression of emotion. The effect of valence and arousal evaluation, of context and of psychophysiological measures was monitored. Indeed subjective evaluation of valence (positive vs. negative) and arousal (high vs. low), and contextual (facial expression vs. facial expression and script) variables were supposed to modulate the psychophysiological responses. Methods Self-report measures (in terms of correct recognition, arousal and valence attribution) and psychophysiological correlates (facial electromyography, EMG, skin conductance response, SCR, and heart rate, HR) were observed when children (N = 26; mean age = 8.75 y; range 6-11 y) looked at six facial expressions of emotions (happiness, anger, fear, sadness, surprise, and disgust) and six emotional scripts (contextualized facial expressions). The competencies about the recognition, the evaluation on valence and arousal was tested in concomitance with psychophysiological variations. Specifically, we tested for the congruence of these multiple measures. Results Log-linear analysis and repeated measure ANOVAs showed different representations across the subjects, as a function of emotion. Specifically, children’ recognition and attribution were well developed for some emotions (such as anger, fear, surprise and happiness), whereas some other emotions (mainly disgust and sadness) were less clearly represented. SCR, HR and EMG measures were modulated by the evaluation based on valence and arousal, with increased psychophysiological values mainly in response to anger, fear and happiness. Conclusions As shown by multiple regression analysis, a significant consonance was found between self-report measures and psychophysiological behavior, mainly for emotions rated as more arousing and negative in valence. The multilevel measures were discussed at light of dimensional attribution model. PMID:25261242

Calcineurin inhibition blocks within-, but not between-session fear extinction in mice

PubMed Central

Moulin, Thiago C.; Carneiro, Clarissa F. D.; Gonçalves, Marina M. C.; Junqueira, Lara S.; Amaral, Olavo B.

2015-01-01

Memory extinction involves the formation of a new associative memory that inhibits a previously conditioned association. Nonetheless, it could also depend on weakening of the original memory trace if extinction is assumed to have multiple components. The phosphatase calcineurin (CaN) has been described as being involved in extinction but not in the initial consolidation of fear learning. With this in mind, we set to study whether CaN could have different roles in distinct components of extinction. Systemic treatment with the CaN inhibitors cyclosporin A (CsA) or FK-506, as well as i.c.v. administration of CsA, blocked within-session, but not between-session extinction or initial learning of contextual fear conditioning. Similar effects were found in multiple-session extinction of contextual fear conditioning and in auditory fear conditioning, indicating that CaN is involved in different types of short-term extinction. Meanwhile, inhibition of protein synthesis by cycloheximide (CHX) treatment did not affect within-session extinction, but disrupted fear acquisition and slightly impaired between-session extinction. Our results point to a dissociation of within- and between-session extinction of fear conditioning, with the former being more dependent on CaN activity and the latter on protein synthesis. Moreover, the modulation of within-session extinction did not affect between-session extinction, suggesting that these components are at least partially independent. PMID:25691516

Trace and contextual fear conditioning require neural activity and NMDA receptor-dependent transmission in the medial prefrontal cortex

PubMed Central

Gilmartin, Marieke R.; Helmstetter, Fred J.

2010-01-01

The contribution of the medial prefrontal cortex (mPFC) to the formation of memory is a subject of considerable recent interest. Notably, the mechanisms supporting memory acquisition in this structure are poorly understood. The mPFC has been implicated in the acquisition of trace fear conditioning, a task that requires the association of a conditional stimulus (CS) and an aversive unconditional stimulus (UCS) across a temporal gap. In both rat and human subjects, frontal regions show increased activity during the trace interval separating the CS and UCS. We investigated the contribution of prefrontal neural activity in the rat to the acquisition of trace fear conditioning using microinfusions of the γ-aminobutyric acid type A (GABAA) receptor agonist muscimol. We also investigated the role of prefrontal N-methyl-d-aspartate (NMDA) receptor-mediated signaling in trace fear conditioning using the NMDA receptor antagonist 2-amino-5-phosphonovaleric acid (APV). Temporary inactivation of prefrontal activity with muscimol or blockade of NMDA receptor-dependent transmission in mPFC impaired the acquisition of trace, but not delay, conditional fear responses. Simultaneously acquired contextual fear responses were also impaired in drug-treated rats exposed to trace or delay, but not unpaired, training protocols. Our results support the idea that synaptic plasticity within the mPFC is critical for the long-term storage of memory in trace fear conditioning. PMID:20504949

Pharmacological Enhancement of mGluR5 Facilitates Contextual Fear Memory Extinction

ERIC Educational Resources Information Center

Sethna, Ferzin; Wang, Hongbing

2014-01-01

Behavioral exposure therapy, which involves extinction of the previously acquired fear, has been used to treat anxiety-related symptoms such as post-traumatic stress disorder. It has been hypothesized that proextinction pharmacotherapeutics may enhance the efficacy of exposure therapy. Systemic administration of the metabotropic glutamate receptor…

Potent Attenuation of Context Fear by Extinction Training Contiguous with Acquisition

ERIC Educational Resources Information Center

Bernier, Brian E.; Lacagnina, Anthony F.; Drew, Michael R.

2015-01-01

Studies on the behavioral mechanisms underlying contextual fear conditioning (CFC) have demonstrated the importance of preshock context exposure in the formation of aversive context memories. However, there has been comparatively little investigation of the effects of context exposure immediately after the shock. Some models predict that…

On the Transition from Reconsolidation to Extinction of Contextual Fear Memories

ERIC Educational Resources Information Center

Cassini, Lindsey F.; Flavell, Charlotte R.; Amaral, Olavo B.; Lee, Jonathan L. C.

2017-01-01

Retrieval of an associative memory can lead to different phenomena. Brief reexposure sessions tend to trigger reconsolidation, whereas more extended ones trigger extinction. In appetitive and fear cued Pavlovian memories, an intermediate "null point" period has been observed where neither process seems to be engaged. Here we investigated…

Post-Retrieval Late Process Contributes to Persistence of Reactivated Fear Memory

ERIC Educational Resources Information Center

Nakayama, Daisuke; Yamasaki, Yoshiko; Matsuki, Norio; Nomura, Hiroshi

2013-01-01

Several studies have demonstrated the mechanisms involved in memory persistence after learning. However, little is known about memory persistence after retrieval. In this study, a protein synthesis inhibitor, anisomycin, was infused into the basolateral amygdala of mice 9.5 h after retrieval of contextual conditioned fear. Anisomycin attenuated…

Extinction of Learned Fear Induces Hippocampal Place Cell Remapping

PubMed Central

Wang, Melissa E.; Yuan, Robin K.; Keinath, Alexander T.; Ramos Álvarez, Manuel M.

2015-01-01

The extinction of learned fear is a hippocampus-dependent process thought to embody new learning rather than erasure of the original fear memory, although it is unknown how these competing contextual memories are represented in the hippocampus. We previously demonstrated that contextual fear conditioning results in hippocampal place cell remapping and long-term stabilization of novel representations. Here we report that extinction learning also induces place cell remapping in C57BL/6 mice. Specifically, we observed cells that preferentially remapped during different stages of learning. While some cells remapped in both fear conditioning and extinction, others responded predominantly during extinction, which may serve to modify previous representations as well as encode new safe associations. Additionally, we found cells that remapped primarily during fear conditioning, which could facilitate reacquisition of the original fear association. Moreover, we also observed cells that were stable throughout learning, which may serve to encode the static aspects of the environment. The short-term remapping observed during extinction was not found in animals that did not undergo fear conditioning, or when extinction was conducted outside of the conditioning context. Finally, conditioning and extinction produced an increase in spike phase locking to the theta and gamma frequencies. However, the degree of remapping seen during conditioning and extinction only correlated with gamma synchronization. Our results suggest that the extinction learning is a complex process that involves both modification of pre-existing memories and formation of new ones, and these traces coexist within the same hippocampal representation. PMID:26085635

Behavioural, neurochemical and neuroendocrine effects of the endogenous β-carboline harmane in fear-conditioned rats.

PubMed

Smith, Karen L; Ford, Gemma K; Jessop, David S; Finn, David P

2013-02-01

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

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

PubMed

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

2014-11-01

In recent years, special attention is being paid to sex differences in susceptibility to disease. In this regard, there is evidence that male rats present higher levels of both cued and contextual fear conditioning than females. However, little is known about the concomitant hypothalamic-pituitary-adrenal (HPA) axis response to those situations which are critical in emotional memories. Here, we studied the behavioural and HPA responses of male and female Wistar rats to context fear conditioning using electric footshock as the aversive stimulus. Fear-conditioned rats showed a much greater ACTH and corticosterone response than those merely exposed to the fear conditioning chamber without receiving shocks. Moreover, males presented higher levels of freezing whereas HPA axis response was greater in females. Accordingly, during the fear extinction tests, female rats consistently showed less freezing and higher extinction rate, but greater HPA activation than males. Exposure to an open-field resulted in lower activity/exploration in fear-conditioned males, but not in females, suggesting greater conditioned cognitive generalization in males than females. It can be concluded that important sex differences in fear conditioning are observed in both freezing and HPA activation, but the two sets of variables are affected in the opposite direction: enhanced behavioural impact in males, but enhanced HPA responsiveness in females. Thus, the role of sex differences on fear-related stimuli may depend on the variables chosen to evaluate it, the greater responsiveness of the HPA axis in females perhaps being an important factor to be further explored. Copyright © 2014 Elsevier Inc. All rights reserved.

Vorinostat ameliorates impaired fear extinction possibly via the hippocampal NMDA-CaMKII pathway in an animal model of posttraumatic stress disorder.

PubMed

Matsumoto, Yasutaka; Morinobu, Shigeru; Yamamoto, Shigeto; Matsumoto, Tomoya; Takei, Shiro; Fujita, Yosuke; Yamawaki, Shigeto

2013-09-01

Given that impairment of fear extinction plays a pivotal role in the pathophysiology of posttraumatic stress disorder (PTSD), drugs that facilitate fear extinction may be useful as novel treatments for PTSD. Histone deacetylase (HDAC) inhibitors have recently been shown to enhance fear extinction in animal studies. Using a single prolonged stress (SPS) paradigm, an animal model of PTSD, we examined whether the HDAC inhibitor vorinostat can facilitate fear extinction in rats, and elucidated the mechanism by which vorinostat enhanced fear extinction, focusing on the N-methyl-D-aspartate (NMDA) receptor signals in the hippocampus. Seven days after SPS, rats received contextual fear conditioning, followed by 2-day extinction training. Vorinostat was intraperitoneally injected immediately after second extinction training session. Contextual fear response was assessed 24 h after vorinostat injection. Hippocampal tissues were dissected 2 h after vorinostat injection. The levels of mRNA and protein tested were measured by RT-PCR or western blotting, respectively. Systemic administration of vorinostat with extinction training significantly enhanced fear extinction in SPS rats as compared with the controls. Furthermore, vorinostat enhanced the hippocampal levels of NR2B and calcium/calmodulin kinase II (CaMKII) α and β proteins, accompanied by increases in the levels of acetylated histone H3 and H4. These findings suggest that vorinostat ameliorated the impaired fear extinction in SPS rats, and this effect was associated with an increase in histone acetylation and thereby enhancement of NR2B and CaMKII in the hippocampus. Our results may provide new insight into the molecular and therapeutic mechanisms of PTSD.

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

PubMed Central

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

2016-01-01

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

Activation of LVGCCs and CB1 Receptors Required for Destabilization of Reactivated Contextual Fear Memories

ERIC Educational Resources Information Center

Suzuki, Akinobu; Mukawa, Takuya; Tsukagoshi, Akinori; Frankland, Paul W.; Kida, Satoshi

2008-01-01

Previous studies have shown that inhibiting protein synthesis shortly after reactivation impairs the subsequent expression of a previously consolidated fear memory. This has suggested that reactivation returns a memory to a labile state and that protein synthesis is required for the subsequent restabilization of memory. While the molecular…

The role of calsenilin/DREAM/KChIP3 in contextual fear conditioning.

PubMed

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

2009-03-01

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.

Reconsolidation or extinction: transcription factor switch in the determination of memory course after retrieval.

PubMed

de la Fuente, Verónica; Freudenthal, Ramiro; Romano, Arturo

2011-04-13

In fear conditioning, aversive stimuli are readily associated with contextual features. A brief reexposure to the training context causes fear memory reconsolidation, whereas a prolonged reexposure induces memory extinction. The regulation of hippocampal gene expression plays a key role in contextual memory consolidation and reconsolidation. However, the mechanisms that determine whether memory will reconsolidate or extinguish are not known. Here, we demonstrate opposing roles for two evolutionarily related transcription factors in the mouse hippocampus. We found that nuclear factor-κB (NF-κB) is required for fear memory reconsolidation. Conversely, calcineurin phosphatase inhibited NF-κB and induced nuclear factor of activated T-cells (NFAT) nuclear translocation in the transition between reconsolidation and extinction. Accordingly, the hippocampal inhibition of both calcineurin and NFAT independently impaired memory extinction, whereas inhibition of NF-κB enhanced memory extinction. These findings represent the first insight into the molecular mechanisms that determine memory reprocessing after retrieval, supporting a transcriptional switch that directs memory toward reconsolidation or extinction. The precise molecular characterization of postretrieval processes has potential importance to the development of therapeutic strategies for fear memory disorders.

Converging evidence for an impact of a functional NOS gene variation on anxiety-related processes.

PubMed

Kuhn, Manuel; Haaker, Jan; Glotzbach-Schoon, Evelyn; Schümann, Dirk; Andreatta, Marta; Mechias, Marie-Luise; Raczka, Karolina; Gartmann, Nina; Büchel, Christian; Mühlberger, Andreas; Pauli, Paul; Reif, Andreas; Kalisch, Raffael; Lonsdorf, Tina B

2016-05-01

Being a complex phenotype with substantial heritability, anxiety and related phenotypes are characterized by a complex polygenic basis. Thereby, one candidate pathway is neuronal nitric oxide (NO) signaling, and accordingly, rodent studies have identified NO synthase (NOS-I), encoded by NOS1, as a strong molecular candidate for modulating anxiety and hippocampus-dependent learning processes. Using a multi-dimensional and -methodological replication approach, we investigated the impact of a functional promoter polymorphism (NOS1-ex1f-VNTR) on human anxiety-related phenotypes in a total of 1019 healthy controls in five different studies. Homozygous carriers of the NOS1-ex1f short-allele displayed enhanced trait anxiety, worrying and depression scores. Furthermore, short-allele carriers were characterized by increased anxious apprehension during contextual fear conditioning. While autonomous measures (fear-potentiated startle) provided only suggestive evidence for a modulatory role of NOS1-ex1f-VNTR on (contextual) fear conditioning processes, neural activation at the amygdala/anterior hippocampus junction was significantly increased in short-allele carriers during context conditioning. Notably, this could not be attributed to morphological differences. In accordance with data from a plethora of rodent studies, we here provide converging evidence from behavioral, subjective, psychophysiological and neuroimaging studies in large human cohorts that NOS-I plays an important role in anxious apprehension but provide only limited evidence for a role in (contextual) fear conditioning. © The Author (2016). Published by Oxford University Press. For Permissions, please email: journals.permissions@oup.com.

Disconnection of the Perirhinal and Postrhinal Cortices Impairs Recognition of Objects in Context But Not Contextual Fear Conditioning

PubMed Central

2017-01-01

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 parahippocampal and hippocampal structures. Understanding how context is represented in the brain and how parahippocampal structures are involved will enhance our understanding and treatment of the cognitive and behavioral symptoms associated with neurological disorders and neuropsychiatric disease. PMID:28411272

Disconnection of the Perirhinal and Postrhinal Cortices Impairs Recognition of Objects in Context But Not Contextual Fear Conditioning.

PubMed

Heimer-McGinn, Victoria R; Poeta, Devon L; Aghi, Krishan; Udawatta, Methma; Burwell, Rebecca D

2017-05-03

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 parahippocampal and hippocampal structures. Understanding how context is represented in the brain and how parahippocampal structures are involved will enhance our understanding and treatment of the cognitive and behavioral symptoms associated with neurological disorders and neuropsychiatric disease. Copyright © 2017 the authors 0270-6474/17/374819-11$15.00/0.

Extinction after retrieval: effects on the associative and nonassociative components of remote contextual fear memory.

PubMed

Costanzi, Marco; Cannas, Sara; Saraulli, Daniele; Rossi-Arnaud, Clelia; Cestari, Vincenzo

2011-01-01

Long-lasting memories of adverse experiences are essential for individuals' survival but are also involved, in the form of recurrent recollections of the traumatic experience, in the aetiology of anxiety diseases (e.g., post-traumatic stress disorder [PTSD]). Extinction-based erasure of fear memories has long been pursued as a behavioral way to treat anxiety disorders; yet, such a procedure turns out to be transient, context-dependent, and ineffective unless it is applied immediately after trauma. Recent evidence indicates that, in both rats and humans, extinction training can prevent the return of fear if administered within the reconsolidation window, when memories become temporarily labile and susceptible of being updated. Here, we show that the reconsolidation-extinction procedure fails to prevent the spontaneous recovery of a remote contextual fear memory in a mouse model of PTSD, as well as the long-lasting behavioral abnormalities induced by traumatic experience on anxiety and in both social and cognitive domains (i.e., social withdrawal and spatial learning deficits). Such a failure appears to be related to the ineffectiveness of the reconsolidation-extinction procedure in targeting the pathogenic process of fear sensitization, a nonassociative component of traumatic memory that causes animals to react aberrantly to harmless stimuli. This indicates fear sensitization as a major target for treatments aimed at mitigating anxiety and the behavioral outcomes of traumatic experiences.

Contextual-specificity of short-delay extinction in humans: Renewal of fear-potentiated startle in a virtual environment

PubMed Central

Alvarez, Ruben P.; Johnson, Linda; Grillon, Christian

2007-01-01

A recent fear-potentiated startle study in rodents suggested that extinction was not context dependent when extinction was conducted after a short delay following acquisition, suggesting that extinction can lead to erasure of fear learning in some circumstances. The main objective of this study was to attempt to replicate these findings in humans by examining the context specificity of short-delay extinction in an ABA renewal procedure using virtual reality environments. A second objective was to examine whether renewal, if any, would be influenced by context conditioning. Subjects underwent differential aversive conditioning in virtual context A, which was immediately followed by extinction in virtual context B. Extinction was followed by tests of renewal in context A and B, with the order counterbalanced across subjects. Results showed that extinction was context dependent. Evidence for renewal was established using fear-potentiated startle as well as skin conductance and fear ratings. In addition, although contextual anxiety was greater in the acquisition context than in the extinction context during renewal, as assessed with startle, context conditioning did not influence the renewal effect. These data do not support the view that extinction conducted shortly after acquisition is context independent. Hence, they do not provide evidence that extinction can lead to erasure of a fear memory established via Pavlovian conditioning. PMID:17412963

Influence of different estrogens on neuroplasticity and cognition in the hippocampus.

PubMed

Barha, Cindy K; Galea, Liisa A M

2010-10-01

Estrogens modulate the morphology and function of the hippocampus. Recent studies have focused on the effects of different types of estrogens on neuroplasticity in the hippocampus and cognition. There are three main forms of estrogens found in mammals: estradiol, estrone, and estriol. The vast majority of studies have used estradiol to investigate the effects of estrogens on the brain. This review focuses on the effects of different estrogens on adult hippocampal neurogenesis, synaptic plasticity in the hippocampus, and cognition in female rats. Different forms of estrogens modulate neuroplasticity and cognition in complex and intriguing ways. Specifically, estrogens upregulate adult hippocampal neurogenesis (via cell proliferation) and synaptic protein levels in the hippocampus in a time- and dose-dependent manner. Low levels of estradiol facilitate spatial working memory and contextual fear conditioning while high levels of estradiol impair spatial working, spatial reference memory and contextual fear conditioning. In addition, estrone impairs contextual fear conditioning. Advances in our knowledge of how estrogens exert their effects on the brain may ultimately lead to refinements in targeted therapies for cognitive impairments at all stages of life. However caution should be taken in interpreting current research and in conducting future studies as estrogens likely work differently in males than in females. Copyright © 2010 Elsevier B.V. All rights reserved.

Hippocampus and Medial Prefrontal Cortex Contributions to Trace and Contextual Fear Memory Expression over Time

ERIC Educational Resources Information Center

Beeman, Christopher L.; Bauer, Philip S.; Pierson, Jamie L.; Quinn, Jennifer J.

2013-01-01

Previous work has shown that damage to the dorsal hippocampus (DH) occurring at recent, but not remote, timepoints following acquisition produces a deficit in trace conditioned fear memory expression. The opposite pattern has been observed with lesions to the medial prefrontal cortex (mPFC). The present studies address: (1) whether these lesion…

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

ERIC Educational Resources Information Center

Rogers, Jason L.; Kesner, Raymond P.

2004-01-01

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

p300/CBP Histone Acetyltransferase Activity Is Required for Newly Acquired and Reactivated Fear Memories in the Lateral Amygdala

ERIC Educational Resources Information Center

Maddox, Stephanie A.; Watts, Casey S.; Schafe, Glenn E.

2013-01-01

Modifications in chromatin structure have been widely implicated in memory and cognition, most notably using hippocampal-dependent memory paradigms including object recognition, spatial memory, and contextual fear memory. Relatively little is known, however, about the role of chromatin-modifying enzymes in amygdala-dependent memory formation.…

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

ERIC Educational Resources Information Center

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

2005-01-01

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

The Effects of Varying Contextual Demands on Age-related Positive Gaze Preferences

PubMed Central

Noh, Soo Rim; Isaacowitz, Derek M.

2015-01-01

Despite many studies on the age-related positivity effect and its role in visual attention, discrepancies remain regarding whether one’s full attention is required for age-related differences to emerge. The present study took a new approach to this question by varying the contextual demands of emotion processing. This was done by adding perceptual distractions, such as visual and auditory noise, that could disrupt attentional control. Younger and older participants viewed pairs of happy–neutral and fearful–neutral faces while their eye movements were recorded. Facial stimuli were shown either without noise, embedded in a background of visual noise (low, medium, or high), or with simultaneous auditory babble. Older adults showed positive gaze preferences, looking toward happy faces and away from fearful faces; however, their gaze preferences tended to be influenced by the level of visual noise. Specifically, the tendency to look away from fearful faces was not present in conditions with low and medium levels of visual noise, but was present where there were high levels of visual noise. It is important to note, however, that in the high-visual-noise condition, external cues were present to facilitate the processing of emotional information. In addition, older adults’ positive gaze preferences disappeared or were reduced when they first viewed emotional faces within a distracting context. The current results indicate that positive gaze preferences may be less likely to occur in distracting contexts that disrupt control of visual attention. PMID:26030774

Chronic Nicotine Treatment During Adolescence Attenuates the Effects of Acute Nicotine in Adult Contextual Fear Learning.

PubMed

Holliday, Erica D; Gould, Thomas J

2017-01-01

Adolescent onset of nicotine abuse is correlated with worse chances at successful abstinence in adulthood. One reason for this may be due to enduring learning deficits resulting from nicotine use during adolescence. Previous work has indicated that chronic nicotine administration beginning in late adolescence (PND38) caused learning deficits in contextual fear when tested in adulthood. The purpose of this study was to determine if chronic nicotine treatment during adolescence would alter sensitivity to nicotine's cognitive enhancing properties in adulthood. C57BL/6J mice received saline or chronic nicotine (12.6mg/kg/day) during adolescence (postnatal day 38) or adulthood (postnatal day 54) for a period of 12 days. Following a 30-day protracted abstinence, mice received either an acute injection of saline or nicotine (0.045, 0.18, and 0.36mg/kg) prior to training and testing a mouse model of contextual fear. It was found that chronic nicotine administration in adult mice did not alter sensitivity to acute nicotine following a protracted abstinence. In adolescent mice, chronic nicotine administration disrupted adult learning and decreased sensitivity to acute nicotine in adulthood as only the highest dose tested (0.36mg/kg) was able to enhance contextual fear learning. These results suggest that adolescent nicotine exposure impairs learning in adulthood, which could increase the risk for continued nicotine use in adulthood by requiring administration of higher doses of nicotine to reverse learning impairments caused by adolescent nicotine exposure. Results from this study add to the growing body of literature suggesting chronic nicotine exposure during adolescence leads to impaired learning in adulthood and demonstrates that nicotine exposure during adolescence attenuates the cognitive enhancing effects of acute nicotine in adulthood, which suggests altered cholinergic function. © The Author 2016. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Comprehensive behavioral analysis of the Cdkl5 knockout mice revealed significant enhancement in anxiety- and fear-related behaviors and impairment in both acquisition and long-term retention of spatial reference memory

PubMed Central

Okuda, Kosuke; Takao, Keizo; Watanabe, Aya; Miyakawa, Tsuyoshi; Mizuguchi, Masashi

2018-01-01

Mutations in the Cyclin-dependent kinase-like 5 (CDKL5) gene cause severe neurodevelopmental disorders. Recently we have generated Cdkl5 KO mice by targeting exon 2 on the C57BL/6N background, and demonstrated postsynaptic overaccumulation of GluN2B-containing N-methyl-D-aspartate (NMDA) receptors in the hippocampus. In the current study, we subjected the Cdkl5 KO mice to a battery of comprehensive behavioral tests, aiming to reveal the effects of loss of CDKL5 in a whole perspective of motor, emotional, social, and cognition/memory functions, and to identify its undetermined roles. The neurological screen, rotarod, hot plate, prepulse inhibition, light/dark transition, open field, elevated plus maze, Porsolt forced swim, tail suspension, one-chamber and three-chamber social interaction, 24-h home cage monitoring, contextual and cued fear conditioning, Barnes maze, and T-maze tests were applied on adult Cdkl5 -/Y and +/Y mice. Cdkl5 -/Y mice showed a mild alteration in the gait. Analyses of emotional behaviors revealed significantly enhanced anxiety-like behaviors of Cdkl5 -/Y mice. Depressive-like behaviors and social interaction of Cdkl5 -/Y mice were uniquely altered. The contextual and cued fear conditioning of Cdkl5 -/Y mice were comparable to control mice; however, Cdkl5 -/Y mice showed a significantly increased freezing time and a significantly decreased distance traveled during the pretone period in the altered context. Both acquisition and long-term retention of spatial reference memory were significantly impaired. The morphometric analysis of hippocampal CA1 pyramidal neurons revealed impaired dendritic arborization and immature spine development in Cdkl5 -/Y mice. These results indicate that CDKL5 plays significant roles in regulating emotional behaviors especially on anxiety- and fear-related responses, and in both acquisition and long-term retention of spatial reference memory, which suggests that focus and special attention should be paid to the specific mechanisms of these deficits in the CDKL5 deficiency disorder. PMID:29702698

Comprehensive behavioral analysis of the Cdkl5 knockout mice revealed significant enhancement in anxiety- and fear-related behaviors and impairment in both acquisition and long-term retention of spatial reference memory.

PubMed

Okuda, Kosuke; Takao, Keizo; Watanabe, Aya; Miyakawa, Tsuyoshi; Mizuguchi, Masashi; Tanaka, Teruyuki

2018-01-01

Mutations in the Cyclin-dependent kinase-like 5 (CDKL5) gene cause severe neurodevelopmental disorders. Recently we have generated Cdkl5 KO mice by targeting exon 2 on the C57BL/6N background, and demonstrated postsynaptic overaccumulation of GluN2B-containing N-methyl-D-aspartate (NMDA) receptors in the hippocampus. In the current study, we subjected the Cdkl5 KO mice to a battery of comprehensive behavioral tests, aiming to reveal the effects of loss of CDKL5 in a whole perspective of motor, emotional, social, and cognition/memory functions, and to identify its undetermined roles. The neurological screen, rotarod, hot plate, prepulse inhibition, light/dark transition, open field, elevated plus maze, Porsolt forced swim, tail suspension, one-chamber and three-chamber social interaction, 24-h home cage monitoring, contextual and cued fear conditioning, Barnes maze, and T-maze tests were applied on adult Cdkl5 -/Y and +/Y mice. Cdkl5 -/Y mice showed a mild alteration in the gait. Analyses of emotional behaviors revealed significantly enhanced anxiety-like behaviors of Cdkl5 -/Y mice. Depressive-like behaviors and social interaction of Cdkl5 -/Y mice were uniquely altered. The contextual and cued fear conditioning of Cdkl5 -/Y mice were comparable to control mice; however, Cdkl5 -/Y mice showed a significantly increased freezing time and a significantly decreased distance traveled during the pretone period in the altered context. Both acquisition and long-term retention of spatial reference memory were significantly impaired. The morphometric analysis of hippocampal CA1 pyramidal neurons revealed impaired dendritic arborization and immature spine development in Cdkl5 -/Y mice. These results indicate that CDKL5 plays significant roles in regulating emotional behaviors especially on anxiety- and fear-related responses, and in both acquisition and long-term retention of spatial reference memory, which suggests that focus and special attention should be paid to the specific mechanisms of these deficits in the CDKL5 deficiency disorder.

Deficient inhibitory processing in trait anxiety: Evidence from context-dependent fear learning, extinction recall and renewal.

PubMed

Haaker, J; Lonsdorf, T B; Schümann, D; Menz, M; Brassen, S; Bunzeck, N; Gamer, M; Kalisch, R

2015-10-01

Impaired fear inhibition has been described as a hallmark of pathological anxiety. We aimed at further characterizing the relation between fear inhibition and anxiety by extending previous work to contextual safety stimuli as well as to dimensional scores of trait anxiety in a large sample. We employed a validated paradigm for context-dependent fear acquisition/extinction (day 1) and retrieval/expression (day 2) in 377 healthy individuals. This large sample size allowed the employment of a dimensional rather than binary approach with respect to individual differences in trait anxiety. We observed a positive correlation on day 1 between trait anxiety with all CSs that possess an inherent inhibitory component, conveyed either by reliable non-reinforcement of a specific CS in a dangerous context (safe cue) or by the context itself (i.e., safe context). No correlation however was observed for a CS that possesses excitatory (threatening) properties only. These results were observed during fear learning (day 1) for US expectancy and fear ratings but not for SCRs. No such pattern was evident during fear and extinction retrieval/expression (day 2). We provide further evidence that high trait anxiety is associated with the inability to take immediate advantage of environmental safety cues (cued and contextual), which might represent a promising trans-diagnostic marker for different anxiety disorders. Consequently, the incorporation of methods to optimize inhibitory learning in current cognitive behavioral therapy (CBT) treatments might open up a promising avenue for precision medicine in anxiety disorders. We did not include patients diagnosed with anxiety disorders. Copyright © 2015. Published by Elsevier B.V.

Developing and validating trace fear conditioning protocols in C57BL/6 mice.

PubMed

Burman, Michael A; Simmons, Cassandra A; Hughes, Miles; Lei, Lei

2014-01-30

Classical fear conditioning is commonly used to study the biology of fear, anxiety and memory. Previous research demonstrated that delay conditioning requires a neural circuit involving the amygdala, but not usually the hippocampus. Trace and contextual fear conditioning require the amygdala and hippocampus. While these paradigms were developed primarily using rat models, they are increasingly being used in mice. The current studies develop trace fear conditioning and control paradigms to allow for the assessment of trace and delay fear conditioning in C57BL/6N mice. Our initial protocol yielded clear delay and contextual conditioning. However, trace conditioning failed to differentiate from an unpaired group and was not hippocampus-dependent. These results suggested that the protocol needed to be modified to specifically accommodate trace conditioning the mice. In order to reduce unconditioned freezing and increase learning, the final protocol was developed by decreasing the intensity of the tone and by increasing the inter-trial interval. Our final protocol produced trace conditioned freezing that was significantly greater than that followed unpaired stimulus exposure and was disrupted by hippocampus lesions. A review of the literature produced 90 articles using trace conditioning in mice. Few of those articles used any kind of behavioral control group, which is required to rule out non-associative factors causing fearful behavior. Fewer used unpaired groups involving tones and shocks within a session, which is the optimal control group. Our final trace conditioning protocol can be used in future studies examining genetically modified C57BL/6N mice. Copyright © 2013 Elsevier B.V. All rights reserved.

Ca2+ -stimulated adenylyl cyclases regulate ERK-dependent activation of MSK1 during fear conditioning.

PubMed

Sindreu, Carlos Balet; Scheiner, Zachary S; Storm, Daniel R

2007-01-04

The cAMP and ERK/MAP kinase (MAPK) signal transduction pathways are critical for hippocampus-dependent memory, a process that depends on CREB-mediated transcription. However, the extent of crosstalk between these pathways and the downstream CREB kinase activated during memory formation has not been elucidated. Here we report that PKA, MAPK, and MSK1, a CREB kinase, are coactivated in a subset of hippocampal CA1 pyramidal neurons following contextual fear conditioning. Activation of PKA, MAPK, MSK1, and CREB is absolutely dependent on Ca(2+)-stimulated adenylyl cyclase activity. We conclude that adenylyl cyclase activity supports the activation of MAPK, and that MSK1 is the major CREB kinase activated during training for contextual memory.

Ca2+-Stimulated Adenylyl Cyclases Regulate ERK-Dependent Activation of MSK1 During Fear Conditioning

PubMed Central

Sindreu, Carlos Balet; Scheiner, Zachary S.; Storm, Daniel R.

2007-01-01

The cAMP and ERK/MAP kinase (MAPK) signal transduction pathways are critical for hippocampus-dependent memory, a process that depends on CREB-mediated transcription. However, the extent of crosstalk between these pathways and the downstream CREB kinase activated during memory formation have not been elucidated. Here we report that PKA, MAPK, and MSK1, a CREB kinase, are co-activated in a subset of hippocampal CA1 pyramidal neurons following contextual fear conditioning. Activation of PKA, MAPK, MSK1, and CREB is absolutely dependent on Ca2+-stimulated adenylyl cyclase activity. We conclude that adenylyl cyclase activity supports the activation of MAPK, and that MSK1 is the major CREB kinase activated during training for contextual memory. PMID:17196532

Neuronal Correlates of Fear Conditioning in the Bed Nucleus of the Stria Terminalis

ERIC Educational Resources Information Center

Haufler, Darrell; Nagy, Frank Z.; Pare, Denis

2013-01-01

Lesion and inactivation studies indicate that the central amygdala (CeA) participates in the expression of cued and contextual fear, whereas the bed nucleus of the stria terminalis (BNST) is only involved in the latter. The basis for this functional dissociation is unclear because CeA and BNST form similar connections with the amygdala and…

An Appetitive Experience after Fear Memory Destabilization Attenuates Fear Retention: Involvement GluN2B-NMDA Receptors in the Basolateral Amygdala Complex

ERIC Educational Resources Information Center

Ferrer Monti, Roque I.; Giachero, Marcelo; Alfei, Joaquín M.; Bueno, Adrián M.; Cuadra, Gabriel; Molina, Victor A.

2016-01-01

It is known that a consolidated memory can return to a labile state and become transiently malleable following reactivation. This instability is followed by a restabilization phase termed reconsolidation. In this work, we explored whether an unrelated appetitive experience (voluntary consumption of diluted sucrose) can affect a contextual fear…

Hippocampal Erk Mechanisms Linking Prediction Error to Fear Extinction: Roles of Shock Expectancy and Contextual Aversive Valence

ERIC Educational Resources Information Center

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

2009-01-01

Extinction of fear requires learning that anticipated aversive events no longer occur. Animal models reveal that sustained phosphorylation of the extracellular signal-regulated kinase (Erk) in hippocampal CA1 neurons plays an important role in this process. However, the key signals triggering and regulating the activity of Erk are not known. By…

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

ERIC Educational Resources Information Center

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

2010-01-01

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

Extinction after Retrieval: Effects on the Associative and Nonassociative Components of Remote Contextual Fear Memory

ERIC Educational Resources Information Center

Costanzi, Marco; Cannas, Sara; Saraulli, Daniele; Rossi-Arnaud, Clelia; Cestari, Vincenzo

2011-01-01

Long-lasting memories of adverse experiences are essential for individuals' survival but are also involved, in the form of recurrent recollections of the traumatic experience, in the aetiology of anxiety diseases (e.g., post-traumatic stress disorder [PTSD]). Extinction-based erasure of fear memories has long been pursued as a behavioral way to…

Effects of medial prefrontal cortex lesions in rats on the what-where-when memory of a fear conditioning event.

PubMed

Li, Jay-Shake; Hsiao, Kun-Yuan; Chen, Wei-Min

2011-03-17

Previous animal studies have defined the ability to remember the details of what, where, and when of an event as an episodic-like memory to be used to model episodic memory in humans. Numerous findings indicate that the hippocampal-frontal cortical circuitry plays a major part in its neural mechanism. Researchers have intensively studied roles of diverse hippocampus sub-regions using animal models. By contrast, the impact of prefrontal cortex lesions on episodic-like memory in animals is still unknown. Here we show that Wistar rats with bilateral medial prefrontal cortex lesions failed to use the temporal-contextual information to retrieve memory of a fear-conditioning event, indicating impairments in their episodic-like memory. Subsequent experiments excluded alternative interpretations that the manipulation impaired the fear-conditioning per se, or interfered with the sensory preconditioning process. We concluded that damages in this area might impair temporal information processing, or interfere with integrating temporal and contextual elements of fear-conditioning events to form a conjunctive entity. These findings can help understand how the medial prefrontal cortex contributes to episodic-like memory. Copyright © 2010 Elsevier B.V. All rights reserved.

Matrix Metalloproteinase (MMP) 9 Transcription in Mouse Brain Induced by Fear Learning*

PubMed Central

Ganguly, Krishnendu; Rejmak, Emilia; Mikosz, Marta; Nikolaev, Evgeni; Knapska, Ewelina; Kaczmarek, Leszek

2013-01-01

Memory formation requires learning-based molecular and structural changes in neurons, whereas matrix metalloproteinase (MMP) 9 is involved in the synaptic plasticity by cleaving extracellular matrix proteins and, thus, is associated with learning processes in the mammalian brain. Because the mechanisms of MMP-9 transcription in the brain are poorly understood, this study aimed to elucidate regulation of MMP-9 gene expression in the mouse brain after fear learning. We show here that contextual fear conditioning markedly increases MMP-9 transcription, followed by enhanced enzymatic levels in the three major brain structures implicated in fear learning, i.e. the amygdala, hippocampus, and prefrontal cortex. To reveal the role of AP-1 transcription factor in MMP-9 gene expression, we have used reporter gene constructs with specifically mutated AP-1 gene promoter sites. The constructs were introduced into the medial prefrontal cortex of neonatal mouse pups by electroporation, and the regulation of MMP-9 transcription was studied after contextual fear conditioning in the adult animals. Specifically, −42/-50- and −478/-486-bp AP-1 binding motifs of the mouse MMP-9 promoter sequence have been found to play a major role in MMP-9 gene activation. Furthermore, increases in MMP-9 gene promoter binding by the AP-1 transcription factor proteins c-Fos and c-Jun have been demonstrated in all three brain structures under investigation. Hence, our results suggest that AP-1 acts as a positive regulator of MMP-9 transcription in the brain following fear learning. PMID:23720741

Matrix metalloproteinase (MMP) 9 transcription in mouse brain induced by fear learning.

PubMed

Ganguly, Krishnendu; Rejmak, Emilia; Mikosz, Marta; Nikolaev, Evgeni; Knapska, Ewelina; Kaczmarek, Leszek

2013-07-19

Memory formation requires learning-based molecular and structural changes in neurons, whereas matrix metalloproteinase (MMP) 9 is involved in the synaptic plasticity by cleaving extracellular matrix proteins and, thus, is associated with learning processes in the mammalian brain. Because the mechanisms of MMP-9 transcription in the brain are poorly understood, this study aimed to elucidate regulation of MMP-9 gene expression in the mouse brain after fear learning. We show here that contextual fear conditioning markedly increases MMP-9 transcription, followed by enhanced enzymatic levels in the three major brain structures implicated in fear learning, i.e. the amygdala, hippocampus, and prefrontal cortex. To reveal the role of AP-1 transcription factor in MMP-9 gene expression, we have used reporter gene constructs with specifically mutated AP-1 gene promoter sites. The constructs were introduced into the medial prefrontal cortex of neonatal mouse pups by electroporation, and the regulation of MMP-9 transcription was studied after contextual fear conditioning in the adult animals. Specifically, -42/-50- and -478/-486-bp AP-1 binding motifs of the mouse MMP-9 promoter sequence have been found to play a major role in MMP-9 gene activation. Furthermore, increases in MMP-9 gene promoter binding by the AP-1 transcription factor proteins c-Fos and c-Jun have been demonstrated in all three brain structures under investigation. Hence, our results suggest that AP-1 acts as a positive regulator of MMP-9 transcription in the brain following fear learning.

Fearful, but not angry, expressions diffuse attention to peripheral targets in an attentional blink paradigm.

PubMed

Taylor, James M; Whalen, Paul J

2014-06-01

We previously demonstrated that fearful facial expressions implicitly facilitate memory for contextual events whereas angry facial expressions do not. The current study sought to more directly address the implicit effect of fearful expressions on attention for contextual events within a classic attentional paradigm (i.e., the attentional blink) in which memory is tested on a trial-by-trial basis, thereby providing subjects with a clear, explicit attentional strategy. Neutral faces of a single gender were presented via rapid serial visual presentation (RSVP) while bordered by four gray pound signs. Participants were told to watch for a gender change within the sequence (T1). It is critical to note that the T1 face displayed a neutral, fearful, or angry expression. Subjects were then told to detect a color change (i.e., gray to green; T2) at one of the four peripheral pound sign locations appearing after T1. This T2 color change could appear at one of six temporal positions. Complementing previous attentional blink paradigms, participants were told to respond via button press immediately when a T2 target was detected. We found that, compared with the neutral T1 faces, fearful faces significantly increased target detection ability at four of the six temporal locations (all ps < .05) whereas angry expressions did not. The results of this study demonstrate that fearful facial expressions can uniquely and implicitly enhance environmental monitoring above and beyond explicit attentional effects related to task instructions.

Fear extinction causes target-specific remodeling of perisomatic inhibitory synapses

PubMed Central

Trouche, Stéphanie; Sasaki, Jennifer M.; Tu, Tiffany; Reijmers, Leon G.

2013-01-01

SUMMARY A more complete understanding of how fear extinction alters neuronal activity and connectivity within fear circuits may aid in the development of strategies to treat human fear disorders. Using a c-fos based transgenic mouse, we found that contextual fear extinction silenced basal amygdala (BA) excitatory neurons that had been previously activated during fear conditioning. We hypothesized that the silencing of BA fear neurons was caused by an action of extinction on BA inhibitory synapses. In support of this hypothesis, we found extinction-induced target-specific remodeling of BA perisomatic inhibitory synapses originating from parvalbumin and cholecystokinin-positive interneurons. Interestingly, the predicted changes in the balance of perisomatic inhibition matched the silent and active states of the target BA fear neurons. These observations suggest that target-specific changes in perisomatic inhibitory synapses represent a mechanism through which experience can sculpt the activation patterns within a neural circuit. PMID:24183705

Fear extinction causes target-specific remodeling of perisomatic inhibitory synapses.

PubMed

Trouche, Stéphanie; Sasaki, Jennifer M; Tu, Tiffany; Reijmers, Leon G

2013-11-20

A more complete understanding of how fear extinction alters neuronal activity and connectivity within fear circuits may aid in the development of strategies to treat human fear disorders. Using a c-fos-based transgenic mouse, we found that contextual fear extinction silenced basal amygdala (BA) excitatory neurons that had been previously activated during fear conditioning. We hypothesized that the silencing of BA fear neurons was caused by an action of extinction on BA inhibitory synapses. In support of this hypothesis, we found extinction-induced target-specific remodeling of BA perisomatic inhibitory synapses originating from parvalbumin and cholecystokinin-positive interneurons. Interestingly, the predicted changes in the balance of perisomatic inhibition matched the silent and active states of the target BA fear neurons. These observations suggest that target-specific changes in perisomatic inhibitory synapses represent a mechanism through which experience can sculpt the activation patterns within a neural circuit. Copyright © 2013 Elsevier Inc. All rights reserved.

Post-retrieval late process contributes to persistence of reactivated fear memory.

PubMed

Nakayama, Daisuke; Yamasaki, Yoshiko; Matsuki, Norio; Nomura, Hiroshi

2013-05-16

Several studies have demonstrated the mechanisms involved in memory persistence after learning. However, little is known about memory persistence after retrieval. In this study, a protein synthesis inhibitor, anisomycin, was infused into the basolateral amygdala of mice 9.5 h after retrieval of contextual conditioned fear. Anisomycin attenuated fear memory after 7 d, but not after 2 d. In contrast, infusion of anisomycin 5- or 24-h post-retrieval was ineffective. These findings indicate that anisomycin attenuates the persistence of reactivated fear memory in a time-dependent manner. We propose that late protein synthesis is required for memory persistence after retrieval.

Sodium nitroprusside is effective in preventing and/or reversing the development of schizophrenia-related behaviors in an animal model: The SHR strain.

PubMed

Diana, Mariana C; Peres, Fernanda F; Justi, Veronica; Bressan, Rodrigo A; Lacerda, Acioly L T; Crippa, José Alexandre; Hallak, Jaime E C; Abilio, Vanesssa Costhek

2018-04-14

The treatment of schizophrenia with antipsychotics is still unsatisfactory. Therefore, the search for new treatments and prevention is crucial, and animal models are fundamental tools for this objective. Preclinical and clinical data evidence the antipsychotic profile of sodium nitroprusside (SNP), a nitric oxide (NO) donor. We aimed to investigate SNP in treating and/or preventing the schizophrenia-related behaviors presented by the spontaneously hypertensive rats (SHR) strain. Wistar rats (WR) and SHRs were submitted to two schemes of treatment: (i) a single injection of SNP or vehicle in adulthood; (ii) a long-term early treatment from 30 to 60 postnatal day with SNP or vehicle. The following behaviors were evaluated 24 hours after the acute treatment or 30 days after the long-term treatment: locomotion, social interaction, and contextual fear conditioning. Spontaneously hypertensive rats presented hyperlocomotion, decreased social interaction, and impaired contextual fear conditioning. Single injection of SNP decreased social interaction in both strains and induced a deficit in contextual fear conditioning in WR. Oppositely, early treatment with SNP prevented the behavioral abnormalities in adult SHRs without promoting any effects in WR. Our preclinical data point to SNP as a preventive and safe strategy with a broad range of effectiveness to the positive, negative, and cognitive symptoms of schizophrenia. © 2018 John Wiley & Sons Ltd.

ApoE isoform-dependent deficits in extinction of contextual fear conditioning.

PubMed

Olsen, R H J; Agam, M; Davis, M J; Raber, J

2012-10-01

The three major human apoE isoforms (apoE2, apoE3 and apoE4) are encoded by distinct alleles (ϵ2, ϵ3 and ϵ4). Compared with ϵ3, ϵ4 is associated with increased risk to develop Alzheimer's disease (AD), cognitive impairments in Parkinson's disease (PD), and other conditions. In contrast, a recent study indicated an increased susceptibility to the recurring and re-experiencing symptom cluster of Post-Traumatic Stress Disorder (PTSD), as well as related memory impairments, in patients carrying at least one ϵ2 allele. Contextual fear conditioning and extinction are used in human and animal models to study this symptom cluster. In this study, acquisition (day 1, training), consolidation (day 2, first day of re-exposure) and extinction (days 2-5) of conditioned contextual fear in human apoE2, apoE3 and apoE4 targeted replacement and C57BL/6J wild-type (WT) mice was investigated. Male and female apoE2 showed acquisition and retrieval of conditioned fear, but failed to exhibit extinction. In contrast, WT, apoE3 and apoE4 mice showed extinction. While apoE2 mice exhibited lower freezing in response to the context on day 2 than apoE3 and apoE4 mice, this cannot explain their extinction deficit as WT mice exhibited similar freezing levels as apoE2 mice on day 2 but still exhibited extinction. Elevating freezing through extended training preserved extinction in controls, but failed to ameliorate extinction deficits in apoE2 animals. These data along with clinical data showing an association of apoE2 with susceptibility to specific symptom clusters in PTSD supports an important role for apoE isoform in the extinction of conditioned fear. © 2012 The Authors. Genes, Brain and Behavior © 2012 Blackwell Publishing Ltd and International Behavioural and Neural Genetics Society.

Impaired right inferior frontal gyrus response to contextual cues in male veterans with PTSD during response inhibition.

PubMed

van Rooij, Sanne J H; Rademaker, Arthur R; Kennis, Mitzy; Vink, Matthijs; Kahn, René S; Geuze, Elbert

2014-09-01

Posttraumatic stress disorder (PTSD) is often associated with impaired fear inhibition and decreased safety cue processing; however, studies capturing the cognitive aspect of inhibition and contextual cue processing are limited. In this fMRI study, the role of contextual cues in response inhibition was investigated. Male medication-naive war veterans with PTSD, male control veterans (combat controls) and healthy nonmilitary men (healthy controls) underwent fMRI while performing the stop-signal anticipation task (SSAT). The SSAT evokes 2 forms of response inhibition: reactive inhibition (outright stopping) and proactive inhibition (anticipation of stopping based on contextual cues). We enrolled 28 veterans with PTSD, 26 combat controls and 25 healthy controls in our study. Reduced reactive inhibition was observed in all veterans, both with and without PTSD, but not in nonmilitary controls, whereas decreased inhibition of the left pre/postcentral gyrus appeared to be specifically associated with PTSD. Impaired behavioural proactive inhibition was also specific to PTSD. Furthermore, the PTSD group showed a reduced right inferior frontal gyrus response during proactive inhibition compared with the combat control group. Most patients with PTSD had comorbid psychiatric disorders, but such comorbidity is common in patients with PTSD. Also, the education level (estimate of intelligence) of participants, but not of their parents, differed among the groups. Our findings of reduced proactive inhibition imply that patients with PTSD show reduced contextual cue processing. These results complement previous findings on fear inhibition and demonstrate that contextual cue processing in patients with PTSD is also reduced during cognitive processes, indicating a more general deficit.

Type 1 Adenylyl Cyclase is Essential for Maintenance of Remote Contextual Fear Memory

PubMed Central

Shan, Qiang; Chan, Guy C.-K.; Storm, Daniel R.

2008-01-01

Although molecular mechanisms for hippocampus-dependent memory have been extensively studied, much less is known about signaling events important for remote memory. Here we report that mice lacking type 1 adenylyl cyclase (AC1) are able to establish and retrieve remote contextual memory but unable to sustain it as long as wild type mice. Interestingly, mice over-expressing AC1 show superior remote contextual memory even though they exhibit normal hippocampus-dependent contextual memory. These data illustrate that calcium coupling to cAMP contributes to the stability of remote memory and identifies AC1 as a potential drug target site to improve long-term remote memory. PMID:19036980

The Cannabinoid System in the Retrosplenial Cortex Modulates Fear Memory Consolidation, Reconsolidation, and Extinction

ERIC Educational Resources Information Center

Sachser, Ricardo Marcelo; Crestani, Ana Paula; Quillfeldt, Jorge Alberto; e Souza, Tadeu Mello; de Oliveira Alvares, Lucas

2015-01-01

Despite the fact that the cannabinoid receptor type 1 (CB1R) plays a pivotal role in emotional memory processing in different regions of the brain, its function in the retrosplenial cortex (RSC) remains unknown. Here, using contextual fear conditioning in rats, we showed that a post-training intra-RSC infusion of the CB1R antagonist AM251…

Trace and Contextual Fear Conditioning Require Neural Activity and NMDA Receptor-Dependent Transmission in the Medial Prefrontal Cortex

ERIC Educational Resources Information Center

Gilmartin, Marieke R.; Helmstetter, Fred J.

2010-01-01

The contribution of the medial prefrontal cortex (mPFC) to the formation of memory is a subject of considerable recent interest. Notably, the mechanisms supporting memory acquisition in this structure are poorly understood. The mPFC has been implicated in the acquisition of trace fear conditioning, a task that requires the association of a…

Standardised extract of Bacopa monniera (CDRI-08) improves contextual fear memory by differentially regulating the activity of histone acetylation and protein phosphatases (PP1α, PP2A) in hippocampus.

PubMed

Preethi, Jayakumar; Singh, Hemant K; Venkataraman, Jois Shreyas; Rajan, Koilmani Emmanuvel

2014-05-01

Contextual fear conditioning is a paradigm for investigating cellular mechanisms involved in hippocampus-dependent memory. Earlier, we showed that standardised extract of Bacopa monniera (CDRI-08) improves hippocampus-dependent learning in postnatal rats by elevating the level of serotonin (5-hydroxytryptamine, 5-HT), activate 5-HT3A receptors, and cyclic adenosine monophosphate (cAMP) response element binding (CREB) protein. In this study, we have further examined the molecular mechanism of CDRI-08 in hippocampus-dependent memory and compared to the histone deacetylase (HDACs) inhibitor sodium butyrate (NaB). To assess the hippocampus-dependent memory, wistar rat pups were subjected to contextual fear conditioning (CFC) following daily (postnatal days 15-29) administration of vehicle solution (0.5 % gum acacia + 0.9 % saline)/CDRI-08 (80 mg/kg, p.o.)/NaB (1.2 g/kg in PBS, i.p.). CDRI-08/NaB treated group showed enhanced freezing behavior compared to control group when re-exposed to the same context. Administration of CDRI-08/NaB resulted in activation of extracellular signal-regulated kinase ERK/CREB signaling cascade and up-regulation of p300, Ac-H3 and Ac-H4 levels, and down-regulation of HDACs (1, 2) and protein phosphatases (PP1α, PP2A) in hippocampus following CFC. This would subsequently result in an increased brain-derived neurotrophic factor (Bdnf) (exon IV) mRNA in hippocampus. Altogether, our results indicate that CDRI-08 enhances hippocampus-dependent contextual memory by differentially regulating histone acetylation and protein phosphatases in hippocampus.

Phencyclidine and Scopolamine for Modeling Amnesia in Rodents: Direct Comparison with the Use of Barnes Maze Test and Contextual Fear Conditioning Test in Mice.

PubMed

Malikowska-Racia, Natalia; Podkowa, Adrian; Sałat, Kinga

2018-04-21

Nowadays cognitive impairments are a growing unresolved medical issue which may accompany many diseases and therapies, furthermore, numerous researchers investigate various neurobiological aspects of human memory to find possible ways to improve it. Until any other method is discovered, in vivo studies remain the only available tool for memory evaluation. At first, researchers need to choose a model of amnesia which may strongly influence observed results. Thereby a deeper insight into a model itself may increase the quality and reliability of results. The most common method to impair memory in rodents is the pretreatment with drugs that disrupt learning and memory. Taking this into consideration, we compared the activity of agents commonly used for this purpose. We investigated effects of phencyclidine (PCP), a non-competitive NMDA receptor antagonist, and scopolamine (SCOP), an antagonist of muscarinic receptors, on short-term spatial memory and classical fear conditioning in mice. PCP (3 mg/kg) and SCOP (1 mg/kg) were administrated intraperitoneally 30 min before behavioral paradigms. To assess the influence of PCP and SCOP on short-term spatial memory, the Barnes maze test in C57BL/J6 mice was used. Effects on classical conditioning were evaluated using contextual fear conditioning test. Additionally, spontaneous locomotor activity of mice was measured. These two tests were performed in CD-1 mice. Our study reports that both tested agents disturbed short-term spatial memory in the Barnes maze test, however, SCOP revealed a higher activity. Surprisingly, learning in contextual fear conditioning test was impaired only by SCOP. Graphical Abstract ᅟ.

Change of Rin1 and Stathmin in the Animal Model of Traumatic Stresses

PubMed Central

Han, Fang; Jiang, Jingzhi; Ding, Jinlan; Liu, Hong; Xiao, Bing; Shi, Yuxiu

2017-01-01

The molecular mechanism of fear memory is poorly understood. Therefore, the pathogenesis of post-traumatic stress disorder (PTSD), whose symptom presentation can enhance fear memory, remains largely unclear. Recent studies with knockout animals have reported that Rin1 and stathmin regulate fear memory. Rin1 inhibits acquisition and promotes memory extinction, whereas stathmin regulates innate and basal fear. The aim of our study was to examine changes in the expression of Rin1 and stathmin in different animal models of stress, particluarly traumatic stress. We used three animal traumatic stresses: single prolonged stress (SPS, which is a rodent model of PTSD), an immobilization-stress (IM) and a Loud sound stress (LSS), to examine the change and uniqueness in Rin1/stathmin expression. Behavioral tests of SPS rats demonstrated increased anxiety and contextual fear-conditioning. They showed decreased long-term potentiation (LTP), as well as decreased stathmin and increased Rin1 expression in the hippocampus and the amygdala. Expression of the stathmin effector, tubulin, and downstream molecules Rin1, Rab5, and Abl, appeared to increase. Rin1 and EphA4 were endogenously coexpressed in primary neurons after SPS stimulation. IM rats exhibited increased anxiety behavior and enhanced fear-conditioning to contextual and auditory stimuli. Similar changes in expression of Rin1/stathmin were observed in IM rats whereas no changes were observed in rats exposed to a loud sound. These data suggest that changes in expression of the Rin1 and stathmin genes may be involved in rodents with SPS and IM stresses, which provide valuable insight into fear memories under abnormal conditions, particularly in PTSD. PMID:28491025

Disruption of hippocampal CA3 network: effects on episodic-like memory processing in C57BL/6J mice.

PubMed

Daumas, Stéphanie; Halley, Hélène; Lassalle, Jean-Michel

2004-07-01

Lesion studies have demonstrated the prominent role of the hippocampus in spatial and contextual learning. To better understand how contextual information is processed in the CA3 region during learning, we focused on the CA3 autoassociative network hypothesis. We took advantage of a particularity of the mossy fibre (MF) synapses, i.e. their high zinc concentration, to reversibly disrupt the afferent MF pathway by microinfusions of an intracellular (DEDTC) or an extracellular (CaEDTA) zinc chelator into the CA3 area of the dorsal hippocampus of mice. Disruption of the CA3 network significantly impaired the acquisition and the consolidation of contextual fear conditioning, whereas contextual retrieval was unaffected. These results also suggest a heterogeneity between the cognitive processes underlying spatial and contextual memory that might be linked to the specific involvement of free zinc in contextual information processing.

Concentration- and age-dependent effects of chronic caffeine on contextual fear conditioning in C57BL/6J mice

PubMed Central

Poole, Rachel L.; Braak, David; Gould, Thomas J.

2015-01-01

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, this suggests that the developing hippocampus may be sensitive to the effects of caffeine. PMID:25827925

Dental fear among children and adolescents in a multicultural population--a cross-sectional study.

PubMed

Fägerstad, Anida; Lundgren, Jesper; Arnrup, Kristina

2015-01-01

The aim of this study was to explore dental fear in a multicultural population of child and adolescent dental patients, with background, gender, age, and socioeconomic status taken into account. A specific aim was to investigate whether the level of DF differed between patients with a non- Swedish background and patients with a Swedish background. In conjunction with a routine visit to the dental clinic, 301 patients (8-19 years old) assessed their dental fear on the Children's Fear Survey Schedule - Dental Subscale, using self-ratings. Following an interview protocol, patients' and their parents' country of birth, and parents' education and occupation/employment were registered. An interpreter was present when needed. Self-rated dental fear was almost equal among patients coming from a non-Swedish background and patients with a Swedish background. Girls scored higher than boys and younger children scored slightly higher compared to older children, but the pattern of dental fear variation was inconsistent. Socioeconomic status differed between the groups with a non-Swedish vs. a Swedish background, but no impact on dental fear was revealed. When children and adolescents with a non-Swedish vs. a Swedish background were modelled separately, female gender and younger age had an impact on dental fear only in the group with a Swedish background. No differences in dental fear were found between children and adolescents from non-Swedish vs. Swedish backgrounds. Dental fear variations according to gender and age were more pronounced in the group with a Swedish background compared to the group with a non-Swedish background. No impact of socioeconomic status could be revealed.

Using Retrieval Cues to Attenuate Return of Fear in Individuals With Public Speaking Anxiety.

PubMed

Shin, Ki Eun; Newman, Michelle G

2018-03-01

Even after successful exposure, relapse is not uncommon. Based on the retrieval model of fear extinction (e.g., Vervliet, Craske, & Hermans, 2013), return of fear can occur after exposure due to an elapse of time (spontaneous recovery) or change in context (contextual renewal). The use of external salient stimuli presented throughout extinction (i.e., retrieval cues [RCs]) has been suggested as a potential solution to this problem (Bouton, 2002). The current study examined whether RCs attenuated return of fear in individuals with public speaking anxiety. Sixty-five participants completed a brief exposure while presented with two RC stimuli aimed at a variety of senses (visual, tactile, olfactory, and auditory). Later, half the participants were tested for return of fear in a context different from the exposure context, and the other half in the same context. Half of each context group were presented with the same cues as in exposure, while the other half were not. Return of fear due to an elapse of time, change in context, and effects of RCs were evaluated on subjective, behavioral, and physiological measures of anxiety. Although contextual renewal was not observed, results supported effects of RCs in reducing spontaneous recovery on behavioral and physiological measures of anxiety. There was also evidence that participants who were reminded of feeling anxious during exposure by the RCs benefited more from using them at follow-up, whereas those who perceived the cues as comforting (safety signals) benefited less. Clinical implications of the findings are discussed. Copyright © 2017. Published by Elsevier Ltd.

"Fearful of the Written Word": White Fear, Black Writing, and Lorraine Hansberry's "A Raisin in the Sun" Screenplay

ERIC Educational Resources Information Center

Lipari, Lisbeth

2004-01-01

In 1959, Lorraine Hansberry was hired by Columbia Pictures to write a screenplay for her award-winning Broadway play, "A Raisin in the Sun". By the time the film was released in 1961, over one-third of the original screenplay had been cut. In this paper I undertake a rhetorical analysis of a particular historically contextualized instance of the…

Enduring deficits in contextual and auditory fear conditioning after adolescent, not adult, social instability stress in male rats.

PubMed

Morrissey, Mark D; Mathews, Iva Z; McCormick, Cheryl M

2011-01-01

Adolescence is a time of developmental changes and reorganization in the brain and stress systems, thus, adolescents may be more vulnerable than adults to the effects of chronic mild stressors. Most studies, however, have not directly compared stress experienced in adolescence to the same stress experience in adulthood. In the present study, adolescent (n=46) and adult (n=48) male rats underwent 16 days of social instability stress (daily 1h isolation and change of cage partners) or were non-stress controls. Rats were then tested on the strength of acquired contextual and cued fear conditioning, as well as extinction learning, beginning either the day after the stress procedure or 3 weeks later. No difference was found among the groups during the Training Phase of conditioning. Irrespective of the time between the social stress experience and fear conditioning, rats stressed in adolescence had decreased context and cue memory, and cue generalization compared to control rats, as measured by the percentage of time spent freezing in tests. Social instability stress in adulthood had no effect on any measure of fear conditioning. The results support the hypothesis that adolescence is a time of heightened vulnerability to stressors. Copyright © 2010 Elsevier Inc. All rights reserved.

Differential expression of the immediate early genes c-Fos, Arc, Egr-1, and Npas4 during long-term memory formation in the context preexposure facilitation effect (CPFE).

PubMed

Heroux, Nicholas A; Osborne, Brittany F; Miller, Lauren A; Kawan, Malak; Buban, Katelyn N; Rosen, Jeffrey B; Stanton, Mark E

2018-01-01

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 (context preexposure, immediate-shock training, and retention). The current study examined changes in the expression of plasticity-associated immediate early genes (IEGs) during context and contextual fear memory formation on the preexposure and training days of the CPFE, respectively. Using adolescent Long-Evans rats, preexposure and training day expression of the IEGs c-Fos, Arc, Egr-1, and Npas4 in the medial prefrontal cortex (mPFC), dorsal hippocampus (dHPC), and basolateral amygdala (BLA) was analyzed using qPCR as an extension of previous studies from our lab examining Egr-1 via in situ hybridization (Asok, Schreiber, Jablonski, Rosen, & Stanton, 2013; Schreiber, Asok, Jablonski, Rosen, & Stanton, 2014). In Expt. 1, context preexposure induced expression of c-Fos, Arc, Egr-1 and Npas4 significantly above that of home-cage (HC) controls in all three regions. In Expt. 2, immediate-shock was followed by a post-shock freezing test, resulting in increased mPFC c-Fos expression in a group preexposed to the training context but not a control group preexposed to an alternate context, indicating expression related to associative learning. This was not seen with other IEGs in mPFC or with any IEG in dHPC or BLA. Finally, when the post-shock freezing test was omitted in Expt. 3, training-related increases were observed in prefrontal c-Fos, Arc, Egr-1, and Npas4, hippocampal c-Fos, and amygdalar Egr-1 expression. These results indicate that context exposure in a post-shock freezing test re-engages IEG expression that may obscure associatively-induced expression during contextual fear conditioning. Additionally, these studies suggest a key role for long-term synaptic plasticity in the mPFC in supporting the CPFE. Copyright © 2017. Published by Elsevier Inc.

Lentiviral silencing of GSK-3β in adult dentate gyrus impairs contextual fear memory and synaptic plasticity

PubMed Central

Chew, Benjamin; Ryu, Jae Ryun; Ng, Teclise; Ma, Dongliang; Dasgupta, Ananya; Neo, Sin Hui; Zhao, Jing; Zhong, Zhong; Bichler, Zoë; Sajikumar, Sreedharan; Goh, Eyleen L. K.

2015-01-01

Attempts have been made to use glycogen synthase kinase-3 beta (GSK3β) inhibitors for prophylactic treatment of neurocognitive conditions. However the use of lithium, a non-specific inhibitor of GSK3β results in mild cognitive impairment in humans. The effects of global GSK3β inhibition or knockout on learning and memory in healthy adult mice are also inconclusive. Our study aims to better understand the role of GSK3β in learning and memory through a more regionally, targeted approach, specifically performing lentiviral-mediated knockdown of GSK3β within the dentate gyrus (DG). DG-GSK3β-silenced mice showed impaired contextual fear memory retrieval. However, cue fear memory, spatial memory, locomotor activity and anxiety levels were similar to control. These GSK3β-silenced mice also showed increased induction and maintenance of DG long-term potentiation (DG-LTP) compared to control animals. Thus, this region-specific, targeted knockdown of GSK3β in the DG provides better understanding on the role of GSK3β in learning and memory. PMID:26157370

Dissociation of the Role of Infralimbic Cortex in Learning and Consolidation of Extinction of Recent and Remote Aversion Memory

PubMed Central

Awad, Walaa; Ferreira, Guillaume; Maroun, Mouna

2015-01-01

Medial prefrontal circuits have been reported to undergo a major reorganization over time and gradually take a more important role for remote emotional memories such as contextual fear memory or food aversion memory. The medial prefrontal cortex, and specifically its ventral subregion, the infralimbic cortex (IL), was also reported to be critical for recent memory extinction of contextual fear conditioning and conditioned odor aversion. However, its exact role in the extinction of remotely acquired information is still not clear. Using postretrieval blockade of protein synthesis or inactivation of the IL, we showed that the IL is similarly required for extinction consolidation of recent and remote fear memory. However, in odor aversion memory, the IL was only involved in extinction consolidation of recent, but not remote, memory. In contrast, only remote retrieval of aversion memory induced c-Fos activation in the IL and preretrieval inactivation of the IL with lidocaine impaired subsequent extinction of remote but not recent memory, indicating IL is necessary for extinction learning of remote aversion memory. In contrast to the effects in odor aversion, our data show that the involvement of the IL in the consolidation of fear extinction does not depend on the memory age. More importantly, our data indicate that the IL is implicated in the extinction of fear and nonfear-based associations and suggest dissociation in the engagement of the IL in the learning and consolidation of food aversion extinction over time. PMID:25872918

The effects of acute nicotine on contextual safety discrimination.

PubMed

Kutlu, Munir G; Oliver, Chicora; Gould, Thomas J

2014-11-01

Anxiety disorders, such as post-traumatic stress disorder (PTSD), may be related to an inability to distinguish safe versus threatening environments and to extinguish fear memories. Given the high rate of cigarette smoking in patients with PTSD, as well as the recent finding that an acute dose of nicotine impairs extinction of contextual fear memory, we conducted a series of experiments to investigate the effect of acute nicotine in an animal model of contextual safety discrimination. Following saline or nicotine (at 0.0275, 0.045, 0.09 and 0.18 mg/kg) administration, C57BL/6J mice were trained in a contextual discrimination paradigm, in which the subjects received presentations of conditioned stimuli (CS) that co-terminated with a foot-shock in one context (context A (CXA)) and only CS presentations without foot-shock in a different context (context B (CXB)). Therefore, CXA was designated as the 'dangerous context', whereas CXB was designated as the 'safe context'. Our results suggested that saline-treated animals showed a strong discrimination between dangerous and safe contexts, while acute nicotine dose-dependently impaired contextual safety discrimination (Experiment 1). Furthermore, our results demonstrate that nicotine-induced impairment of contextual safety discrimination learning was not a result of increased generalized freezing (Experiment 2) or contingent on the common CS presentations in both contexts (Experiment 3). Finally, our results show that increasing the temporal gap between CXA and CXB during training abolished the impairing effects of nicotine (Experiment 4). The findings of this study may help link nicotine exposure to the safety learning deficits seen in anxiety disorder and PTSD patients. © The Author(s) 2014.

In Search for Boundary Conditions of Reconsolidation: A Failure of Fear Memory Interference

PubMed Central

Schroyens, Natalie; Beckers, Tom; Kindt, Merel

2017-01-01

The presentation of a fear memory cue can result in mere memory retrieval, destabilization of the reactivated memory trace, or the formation of an extinction memory. The interaction between the degree of novelty during reactivation and previous learning conditions is thought to determine the outcome of a reactivation session. This study aimed to evaluate whether contextual novelty can prevent cue-induced destabilization and disruption of a fear memory acquired by non-asymptotic learning. To this end, fear memory was reactivated in a novel context or in the original context of learning, and fear memory reactivation was followed by the administration of propranolol, an amnestic drug. Remarkably, fear memory was not impaired by post-reactivation propranolol administration or extinction training under the usual conditions used in our lab, irrespective of the reactivation context. These unexpected findings are discussed in the light of our current experimental parameters and alleged boundary conditions on memory destabilization. PMID:28469565

Fast neutron irradiation deteriorates hippocampus-related memory ability in adult mice.

PubMed

Yang, Miyoung; Kim, Hwanseong; Kim, Juhwan; Kim, Sung-Ho; Kim, Jong-Choon; Bae, Chun-Sik; Kim, Joong-Sun; Shin, Taekyun; Moon, Changjong

2012-03-01

Object recognition memory and contextual fear conditioning task performance in adult C57BL/6 mice exposed to cranial fast neutron irradiation (0.8 Gy) were examined to evaluate hippocampus-related behavioral dysfunction following acute exposure to relatively low doses of fast neutrons. In addition, hippocampal neurogenesis changes in adult murine brain after cranial irradiation were analyzed using the neurogenesis immunohistochemical markers Ki-67 and doublecortin (DCX). In the object recognition memory test and contextual fear conditioning, mice trained 1 and 7 days after irradiation displayed significant memory deficits compared to the sham-irradiated controls. The number of Ki-67- and DCX-positive cells decreased significantly 24 h post-irradiation. These results indicate that acute exposure of the adult mouse brain to a relatively low dose of fast neutrons interrupts hippocampal functions, including learning and memory, possibly by inhibiting neurogenesis.

Nucleus reuniens of the thalamus controls fear memory intensity, specificity and long-term maintenance during consolidation.

PubMed

Troyner, Fernanda; Bicca, Maira A; Bertoglio, Leandro J

2018-05-10

The thalamic nucleus reuniens (NR) has been shown to support bidirectional medial prefrontal cortex-hippocampus communication and synchronization relevant for cognitive processing. Using non-selective or prolonged inactivation of the NR, previous studies reported its activity positively modulates aversive memory consolidation. Here we examined the NR's role in consolidating contextual fear memories with varied strength, at both recent and more remote time points, using muscimol-induced temporary inactivation in rats. Results indicate the NR negatively modulates fear memory intensity, specificity and long-term maintenance. The more intense, generalized and enduring fear memory induced by NR inactivation during consolidation was also less prone to behavioral suppression by extinction or reconsolidation disruption induced by clonidine, an alpha-2 adrenergic receptor agonist. Lastly, we used immunohistochemistry for Arc protein, which is involved in synaptic modifications underlying aversive memory consolidation, to investigate whether treatment condition and/or conditioning status could change its levels in the NR, the hippocampus (dorsal and ventral CA1 subregions) and the medial prefrontal cortex (anterior cingulate, prelimbic and infralimbic subregions). Results indicate a significant imbalance in the number of Arc-expressing neurons in the brain areas investigated in muscimol fear conditioned animals when compared with controls. Collectively, present results provide convergent evidence for the NR's role as a hub regulating quantitative and qualitative aspects of a contextual fear memory during its consolidation that seem to influence the subsequent susceptibility to experimental interventions aiming at attenuating its expression. They also indicate the selectivity and duration of a given inactivation approach may influence its outcomes. This article is protected by copyright. All rights reserved. © 2018 Wiley Periodicals, Inc.

Education for sustainable development at the university level: Interactions of the need for community, fear of indoctrination, and the demands of work

NASA Astrophysics Data System (ADS)

Qablan, Ahmad

The goal of this study was to describe the factors that influence education for sustainable development (ESD) in American universities. Cultural Historical Activity Theory (CHAT) was employed as the theoretical lens to analyze the activity of ESD (Engestrom & Miettinen 1999). Data were collected by focusing on two university professors through a series of interviews, classroom observations, and artifacts. The findings of the study demonstrated that both professors encountered serious contradictions in their activity of ESD. These contradictions were both contextual and personal in origin and caused the professors to reshape the object of their teaching activity. The contextual contradictions originated from rules of the professors' institution, their inner and outer communities, and the division of labor in their work environment. The thematic analysis of the data revealed that the contextual contradictions included demanding work responsibilities, emphasis on research over teaching, and lack of community to consider teaching in general and specifically for ESD. The personal contradictions arose from the professors' personal philosophies, perspectives, and visions of sustainable development. Again the thematic analysis revealed the personal contradictions arose from the professors' conceptions of teaching and learning, fear of indoctrination, and again lack of community to support the consideration of teaching. Due to these contradictions in their activity systems, both professors narrowed their sustainability objects to address only one side of sustainability paradigm (the science component), changing the outcomes of their teaching activity to that of preparing environmentally informed citizens. While one professor focused on his new object of delivering environmental knowledge, the other professor adopted a mitigation strategy of focusing on the dual object of sustainability and delivering environmental knowledge. The study offers several strategies to resolve the personal and contextual contradictions identified in this study. Specifically addressed are strategies to alleviate their fear of indoctrination and to access surrounding teaching communities. It also offers strategies focusing on contextual contradictions: establishing ESD communities inside the university and changing faculty incentive and reward structures within the university.

Hippocampus-driven feed-forward inhibition of the prefrontal cortex mediates relapse of extinguished fear.

PubMed

Marek, Roger; Jin, Jingji; Goode, Travis D; Giustino, Thomas F; Wang, Qian; Acca, Gillian M; Holehonnur, Roopashri; Ploski, Jonathan E; Fitzgerald, Paul J; Lynagh, Timothy; Lynch, Joseph W; Maren, Stephen; Sah, Pankaj

2018-03-01

The medial prefrontal cortex (mPFC) has been implicated in the extinction of emotional memories, including conditioned fear. We found that ventral hippocampal (vHPC) projections to the infralimbic (IL) cortex recruited parvalbumin-expressing interneurons to counter the expression of extinguished fear and promote fear relapse. Whole-cell recordings ex vivo revealed that optogenetic activation of vHPC input to amygdala-projecting pyramidal neurons in the IL was dominated by feed-forward inhibition. Selectively silencing parvalbumin-expressing, but not somatostatin-expressing, interneurons in the IL eliminated vHPC-mediated inhibition. In behaving rats, pharmacogenetic activation of vHPC→IL projections impaired extinction recall, whereas silencing IL projectors diminished fear renewal. Intra-IL infusion of GABA receptor agonists or antagonists, respectively, reproduced these effects. Together, our findings describe a previously unknown circuit mechanism for the contextual control of fear, and indicate that vHPC-mediated inhibition of IL is an essential neural substrate for fear relapse.

Oxytocin Reduces Background Anxiety in a Fear-Potentiated Startle Paradigm: Peripheral vs Central Administration

PubMed Central

Ayers, Luke W; Missig, Galen; Schulkin, Jay; Rosen, Jeffrey B

2011-01-01

Oxytocin is known to have anti-anxiety and anti-stress effects. Using a fear-potentiated startle paradigm in rats, we previously demonstrated that subcutaneously administered oxytocin suppressed acoustic startle following fear conditioning compared with startle before fear conditioning (termed background anxiety), but did not have an effect on cue-specific fear-potentiated startle. The findings suggest oxytocin reduces background anxiety, an anxious state not directly related to cue-specific fear, but sustained beyond the immediate threat. The goal of the present study was to compare the effects of centrally and peripherally administered oxytocin on background anxiety and cue-specific fear. Male rats were given oxytocin either subcutaneously (SC) or intracerebroventricularly (ICV) into the lateral ventricles before fear-potentiated startle testing. Oxytocin doses of 0.01 and 0.1 μg/kg SC reduced background anxiety. ICV administration of oxytocin at doses from 0.002 to 20 μg oxytocin had no effect on background anxiety or cue-specific fear-potentiated startle. The 20 μg ICV dose of oxytocin did reduce acoustic startle in non-fear conditioned rats. These studies indicate that oxytocin is potent and effective in reducing background anxiety when delivered peripherally, but not when delivered into the cerebroventricular system. Oxytocin given systemically may have anti-anxiety properties that are particularly germane to the hypervigilance and exaggerated startle typically seen in many anxiety and mental health disorder patients. PMID:21796104

Intact renewal after extinction of conditioned suppression with lesions of either the retrosplenial cortex or dorsal hippocampus.

PubMed

Todd, Travis P; Jiang, Matthew Y; DeAngeli, Nicole E; Bucci, David J

2017-03-01

Extinction of fear to a Pavlovian conditioned stimulus (CS) is known to be context-specific. When the CS is tested outside the context of extinction, fear returns, or renews. Several studies have demonstrated that renewal depends upon the hippocampus, although there are also studies where renewal was not impacted by hippocampal damage, suggesting that under some conditions context encoding and/or retrieval of extinction depends upon other regions. One candidate region is the retrosplenial cortex (RSC), which is known to contribute to contextual and spatial learning and memory. Using a conditioned-suppression paradigm, Experiment 1 tested the impact of pre-training RSC lesions on renewal of extinguished fear. Consistent with previous studies, lesions of the RSC did not impact acquisition or extinction of conditioned fear to the CS. Further, there was no evidence that RSC lesions impaired renewal, indicating that contextual encoding and/or retrieval of extinction does not depend upon the RSC. In Experiment 2, post-extinction lesions of either the RSC or dorsal hippocampus (DH) also had no impact on renewal. However, in Experiment 3, both RSC and DH lesions did impair performance in an object-in-place procedure, an index of place memory. RSC and DH contributions to extinction and renewal are discussed. Copyright © 2016 Elsevier B.V. All rights reserved.

Mirtazapine exerts an anxiolytic-like effect through activation of the median raphe nucleus-dorsal hippocampal 5-HT pathway in contextual fear conditioning in rats.

PubMed

An, Yan; Chen, Chong; Inoue, Takeshi; Nakagawa, Shin; Kitaichi, Yuji; Wang, Ce; Izumi, Takeshi; Kusumi, Ichiro

2016-10-03

The functional role of serotonergic projections from the median raphe nucleus (MRN) to the dorsal hippocampus (DH) in anxiety remains understood poorly. The purpose of the present research was to examine the functional role of this pathway, using the contextual fear conditioning (CFC) model of anxiety. We show that intra-MRN microinjection of mirtazapine, a noradrenergic and specific serotonergic antidepressant, reduced freezing in CFC without affecting general motor activity dose-dependently, suggesting an anxiolytic-like effect. In addition, intra-MRN microinjection of mirtazapine dose-dependently increased extracellular concentrations of serotonin (5-HT) but not dopamine in the DH. Importantly, intra-DH pre-microinjection of WAY-100635, a 5-HT1A antagonist, significantly attenuated the effect of mirtazapine on freezing. These results, for the first time, suggest that activation of the MRN-DH 5-HT1A pathway exerts an anxiolytic-like effect in CFC. This is consistent with the literature that the hippocampus is essential for retrieval of contextual memory and that 5-HT1A receptor activation in the hippocampus primarily exerts an inhibitory effect on the neuronal activity. Copyright © 2016 Elsevier Inc. All rights reserved.

Disturbed Processing of Contextual Information in HCN3 Channel Deficient Mice

PubMed Central

Stieglitz, Marc S.; Fenske, Stefanie; Hammelmann, Verena; Becirovic, Elvir; Schöttle, Verena; Delorme, James E.; Schöll-Weidinger, Martha; Mader, Robert; Deussing, Jan; Wolfer, David P.; Seeliger, Mathias W.; Albrecht, Urs; Wotjak, Carsten T.; Biel, Martin; Michalakis, Stylianos; Wahl-Schott, Christian

2018-01-01

Hyperpolarization-activated cyclic nucleotide-gated channels (HCNs) in the nervous system are implicated in a variety of neuronal functions including learning and memory, regulation of vigilance states and pain. Dysfunctions or genetic loss of these channels have been shown to cause human diseases such as epilepsy, depression, schizophrenia, and Parkinson's disease. The physiological functions of HCN1 and HCN2 channels in the nervous system have been analyzed using genetic knockout mouse models. By contrast, there are no such genetic studies for HCN3 channels so far. Here, we use a HCN3-deficient (HCN3−/−) mouse line, which has been previously generated in our group to examine the expression and function of this channel in the CNS. Specifically, we investigate the role of HCN3 channels for the regulation of circadian rhythm and for the determination of behavior. Contrary to previous suggestions we find that HCN3−/− mice show normal visual, photic, and non-photic circadian function. In addition, HCN3−/− mice are impaired in processing contextual information, which is characterized by attenuated long-term extinction of contextual fear and increased fear to a neutral context upon repeated exposure. PMID:29375299

The prefrontal cortical endocannabinoid system modulates fear-pain interactions in a subregion-specific manner.

PubMed

Rea, Kieran; McGowan, Fiona; Corcoran, Louise; Roche, Michelle; Finn, David P

2018-05-30

The emotional processing and coordination of top-down responses to noxious and conditioned aversive stimuli involves the medial prefrontal cortex (mPFC). Evidence suggests that subregions of the mPFC, (infralimbic (IL), prelimbic (PrL), anterior cingulate (ACC) cortices), differentially alter the expression of contextually-induced fear and nociceptive behaviour. We investigated the role of the endocannabinoid system in the IL, PrL and ACC in formalin-evoked nociceptive behaviour, fear-conditioned analgesia (FCA) and conditioned fear in the presence of nociceptive tone. FCA was modelled in male Lister-hooded rats by assessing formalin-evoked nociceptive behaviour in an arena previously paired with footshock. The effects of intra-mPFC administration of AM251 (CB 1 receptor antagonist/inverse agonist), URB597 (fatty acid amide hydrolase inhibitor) or URB597 + AM251 on FCA and freezing behaviour were assessed. AM251 attenuated FCA when injected into the IL or PrL and reduced contextually induced freezing behaviour when injected intra-IL, but not intra-PrL or intra-ACC. Intra-ACC administration of AM251 alone or in combination with URB597 had no effect on FCA or freezing. URB597 attenuated FCA and freezing behaviour when injected intra-IL, prolonged the expression of FCA when injected intra-PrL and had no effect on these behaviours when injected intra-ACC. These results suggest important and differential roles for FAAH substrates or CB 1 receptors in the PrL, IL and ACC in the expression of FCA and conditioned fear in the presence of nociceptive tone. This article is protected by copyright. All rights reserved.

Behavioural endophenotypes in mice lacking the auxiliary GABAB receptor subunit KCTD16.

PubMed

Cathomas, Flurin; Sigrist, Hannes; Schmid, Luca; Seifritz, Erich; Gassmann, Martin; Bettler, Bernhard; Pryce, Christopher R

2017-01-15

Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the brain and is implicated in the pathophysiology of a number of neuropsychiatric disorders. The GABA B receptors are G-protein coupled receptors consisting of principle subunits and auxiliary potassium channel tetramerization domain (KCTD) subunits. The KCTD subunits 8, 12, 12b and 16 are cytosolic proteins that determine the kinetics of the GABA B receptor response. Previously, we demonstrated that Kctd12 null mutant mice (Kctd12 -/- ) exhibit increased auditory fear learning and that Kctd12 +/- mice show altered circadian activity, as well as increased intrinsic excitability in hippocampal pyramidal neurons. KCTD16 has been demonstrated to influence neuronal excitability by regulating GABA B receptor-mediated gating of postsynaptic ion channels. In the present study we investigated for behavioural endophenotypes in Kctd16 -/- and Kctd16 +/- mice. Compared with wild-type (WT) littermates, auditory and contextual fear conditioning were normal in both Kctd16 -/- and Kctd16 +/- mice. When fear memory was tested on the following day, Kctd16 -/- mice exhibited less extinction of auditory fear memory relative to WT and Kctd16 +/- mice, as well as more contextual fear memory relative to WT and, in particular, Kctd16 +/- mice. Relative to WT, both Kctd16 +/- and Kctd16 -/- mice exhibited normal circadian activity. This study adds to the evidence that auxillary KCTD subunits of GABA B receptors contribute to the regulation of behaviours that could constitute endophenotypes for hyper-reactivity to aversive stimuli in neuropsychiatric disorders. Copyright © 2016 Elsevier B.V. All rights reserved.

Cannabinoids and traumatic stress modulation of contextual fear extinction and GR expression in the amygdala-hippocampal-prefrontal circuit.

PubMed

Ganon-Elazar, Eti; Akirav, Irit

2013-09-01

Considerable evidence suggests that cannabinoids modulate the behavioral and physiological response to stressful events. We have recently shown that activating the cannabinoid system using the CB1/CB2 receptor agonist WIN55,212-2 (WIN) in proximity to exposure to single-prolonged stress (SPS), a rat model of emotional trauma, prevented the stress-induced enhancement of acoustic startle response, the impairment in avoidance extinction and the enhanced negative feedback on the hypothalamic-pituitary-adrenal (HPA) axis (Ganon-Elazar and Akirav, 2012). Some of the effects were found to be mediated by CB1 receptors in the basolateral amygdala (BLA). Here we examined whether cannabinoid receptor activation in a putative brain circuit that includes the BLA, hippocampus and prefrontal cortex (PFC), could prevent the effects of traumatic stress on contextual fear extinction and alterations in glucocorticoid receptor (GR) protein levels. We found that: (i) SPS impaired contextual fear extinction tested one week after trauma exposure and that WIN prevented the stress-induced impairment of extinction when microinjected immediately after trauma exposure into the BLA or hippocampus (5 μg), but not when microinjected into the PFC, (ii) the ameliorating effects of WIN on contextual extinction were prevented by blocking GRs in the BLA and hippocampus, and (iii) SPS up regulated GRs in the BLA, PFC and hippocampus and systemic WIN administration (0.5 mg/kg) after trauma exposure normalized GR levels in the BLA and hippocampus, but not in the PFC. Cannabinoid receptor activation in the aftermath of trauma exposure may regulate the emotional response to the trauma and prevent stress-induced impairment of extinction and GR up regulation through the mediation of CB1 receptors in the BLA and hippocampus. Taken together, the findings suggest that the interaction between the cannabinoid and glucocorticoid systems is crucial in the modulation of emotional trauma. Copyright © 2013 Elsevier Ltd. All rights reserved.

Bidirectional switch of the valence associated with a hippocampal contextual memory engram.

PubMed

Redondo, Roger L; Kim, Joshua; Arons, Autumn L; Ramirez, Steve; Liu, Xu; Tonegawa, Susumu

2014-09-18

The valence of memories is malleable because of their intrinsic reconstructive property. This property of memory has been used clinically to treat maladaptive behaviours. However, the neuronal mechanisms and brain circuits that enable the switching of the valence of memories remain largely unknown. Here we investigated these mechanisms by applying the recently developed memory engram cell- manipulation technique. We labelled with channelrhodopsin-2 (ChR2) a population of cells in either the dorsal dentate gyrus (DG) of the hippocampus or the basolateral complex of the amygdala (BLA) that were specifically activated during contextual fear or reward conditioning. Both groups of fear-conditioned mice displayed aversive light-dependent responses in an optogenetic place avoidance test, whereas both DG- and BLA-labelled mice that underwent reward conditioning exhibited an appetitive response in an optogenetic place preference test. Next, in an attempt to reverse the valence of memory within a subject, mice whose DG or BLA engram had initially been labelled by contextual fear or reward conditioning were subjected to a second conditioning of the opposite valence while their original DG or BLA engram was reactivated by blue light. Subsequent optogenetic place avoidance and preference tests revealed that although the DG-engram group displayed a response indicating a switch of the memory valence, the BLA-engram group did not. This switch was also evident at the cellular level by a change in functional connectivity between DG engram-bearing cells and BLA engram-bearing cells. Thus, we found that in the DG, the neurons carrying the memory engram of a given neutral context have plasticity such that the valence of a conditioned response evoked by their reactivation can be reversed by re-associating this contextual memory engram with a new unconditioned stimulus of an opposite valence. Our present work provides new insight into the functional neural circuits underlying the malleability of emotional memory.

Bidirectional switch of the valence associated with a hippocampal contextual memory engram

PubMed Central

Redondo, Roger L; Kim, Joshua; Arons, Autumn L; Ramirez, Steve; Liu, Xu; Tonegawa, Susumu

2014-01-01

The valence of memories is malleable because of their intrinsic reconstructive property1. This property of memory has been used clinically to treat maladaptive behaviours2. However, the neuronal mechanisms and brain circuits that enable the switching of the valence of memories remain largely unknown. Here, we investigated these mechanisms by applying the recently developed memory engram cell-labelling and -manipulation technique 3,4. We labelled, with Channelrhodopsin-2 (ChR2), a population of cells in either the dorsal dentate gyrus (DG) of the hippocampus or the basolateral complex of the amygdala (BLA) that were specifically activated during contextual fear or reward conditioning. Both groups of fear-conditioned mice displayed aversive light-dependent responses in an optogenetic place avoidance test, whereas both DG- and BLA-labelled mice that underwent reward conditioning exhibited an appetitive response in an optogenetic place preference test. Next, in an attempt to reverse the valence of memory within a subject, mice whose DG or BLA engram had initially been labelled by contextual fear or reward conditioning were subjected to a second conditioning of the opposite valence while their original DG or BLA engram was reactivated by blue light. Subsequent optogenetic place avoidance and preference tests revealed that while the DG-engram group displayed a response indicating a switch of the memory valence, the BLA-engram group did not. This switch was also evident at the cellular level by a change in functional connectivity between DG engram-bearing cells and BLA engram-bearing cells. Thus, we found that in the DG, the neurons carrying the memory engram of a given neutral context have plasticity such that the valence of a conditioned response evoked by their reactivation can be reversed by re-associating this contextual memory engram with a new US of an opposite valence. Our present work provides new insight into the functional neural circuit underlying the malleability of emotional memory. PMID:25162525

A specific role for hippocampal mossy fiber's zinc in rapid storage of emotional memories

PubMed Central

Ceccom, Johnatan; Halley, Hélène; Daumas, Stéphanie; Lassalle, Jean Michel

2014-01-01

We investigated the specific role of zinc present in large amounts in the synaptic vesicles of mossy fibers and coreleased with glutamate in the CA3 region. In previous studies, we have shown that blockade of zinc after release has no effect on the consolidation of spatial learning, while zinc is required for the consolidation of contextual fear conditioning. Although both are hippocampo-dependent processes, fear conditioning to the context implies a strong emotional burden. To verify the hypothesis that zinc could play a specific role in enabling sustainable memorization of a single event with a strong emotional component, we used a neuropharmacological approach combining a glutamate receptor antagonist with different zinc chelators. Results show that zinc is mandatory to allow the consolidation of one-shot memory, thus being the key element allowing the hippocampus submitted to a strong emotional charge to switch from the cognitive mode to a flashbulb memory mode. Individual differences in learning abilities have been known for a long time to be totally or partially compensated by distributed learning practice. Here we show that contextual fear conditioning impairments due to zinc blockade can be efficiently reduced by distributed learning practice. PMID:24741109

Synaptic consolidation as a temporally variable process: Uncovering the parameters modulating its time-course.

PubMed

Casagrande, Mirelle A; Haubrich, Josué; Pedraza, Lizeth K; Popik, Bruno; Quillfeldt, Jorge A; de Oliveira Alvares, Lucas

2018-04-01

Memories are not instantly created in the brain, requiring a gradual stabilization process called consolidation to be stored and persist in a long-lasting manner. However, little is known whether this time-dependent process is dynamic or static, and the factors that might modulate it. Here, we hypothesized that the time-course of consolidation could be affected by specific learning parameters, changing the time window where memory is susceptible to retroactive interference. In the rodent contextual fear conditioning paradigm, we compared weak and strong training protocols and found that in the latter memory is susceptible to post-training hippocampal inactivation for a shorter period of time. The accelerated consolidation process triggered by the strong training was mediated by glucocorticoids, since this effect was blocked by pre-training administration of metyrapone. In addition, we found that pre-exposure to the training context also accelerates fear memory consolidation. Hence, our results demonstrate that the time window in which memory is susceptible to post-training interferences varies depending on fear conditioning intensity and contextual familiarity. We propose that the time-course of memory consolidation is dynamic, being directly affected by attributes of the learning experiences. Copyright © 2018 Elsevier Inc. All rights reserved.

Long-lasting behavioral effects in neonatal mice with multiple exposures to ketamine-xylazine anesthesia

PubMed Central

Huang, Lianyan; Hayes, Scott; Yang, Guang

2016-01-01

Anesthetic agents are often administered in the neonatal period, a time of rapid brain development and synaptogenesis. Mounting evidence suggests that anesthetics can disrupt neurocognitive development, particularly in cases of multiple or prolonged anesthetic exposure. Previous studies have shown that administering multiple doses of ketamine-xylazine (KX) anesthesia to neonatal mice can induce long-term changes to synaptic plasticity in the cortex, but the effect on neurocognitive function remains unclear. In this study, we exposed neonatal mice to single dose and multiple doses of KX anesthesia in the neonatal period (postnatal days 7, 9, 11), and conducted a series of behavioral tests in young adulthood (1 month of age). Mice receiving multiple doses of KX anesthesia showed deficits in novel object recognition, sociability, preference for social novelty and contextual fear response, but no effect on auditory-cued fear response. Single dose of KX anesthesia had no effect on these behaviors except for contextual fear response. We also observed that multiple exposures to KX anesthesia were associated with decreased CaMKII phosphorylation, which is known to play a role in synapse development and long-term potentiation, likely contributing to learning impairment. PMID:27622724

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

PubMed

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

2017-05-01

The influence of brain interleukin-1 (IL-1ß) on memory processes includes both detrimental and beneficial effects. To further explore the dynamics of brain IL-1ß in mediating learning and memory during acute sickness, we injected species-homologous rat IL-1ß (100ng/5μl) or vehicle (0.1% bovine serum albumin, 5μl) directly into the cisterna magna (i.c.m.) of male Sprague-Dawley rats. We measured, in parallel, body temperature, food intake, body mass, cage activity, as well as learning and memory using contextual fear conditioning. To investigate the effects of IL-1ß on learning and memory processes we used: (1) a retrograde experiment that involved injecting rats i.c.m. with IL-1ß immediately after training in the novel context, and (2) an anterograde experiment that involved injecting rats i.c.m. with IL-1ß two hours before training in the novel context. In addition, hypothalamic and hippocampal concentrations of IL-1β were measured at several time points following injection. Administration of IL-1ß induced fever, lethargy and anorexia for∼two-to-three days and increased the concentration of IL-1ß in the hippocampus and hypothalamus for at least eight hours. Training in the context immediately before IL-1ß administration (retrograde experiment), did not impair contextual and auditory fear memory. However, when training in the context occurred concurrently with elevated hippocampal IL-1ß levels, two hours after IL-1ß administration (anterograde experiment), contextual, but not auditory, fear memory was impaired. Our results show that there are instances where memory consolidation can occur concurrently with elevated levels of IL-1ß in the hippocampus, fever, anorexia and lethargy during acute short-term sickness. Copyright © 2017 Elsevier B.V. All rights reserved.

Autophagy Enhances Memory Erasure through Synaptic Destabilization.

PubMed

Shehata, Mohammad; Abdou, Kareem; Choko, Kiriko; Matsuo, Mina; Nishizono, Hirofumi; Inokuchi, Kaoru

2018-04-11

There is substantial interest in memory reconsolidation as a target for the treatment of anxiety disorders, such as post-traumatic stress disorder. However, its applicability is restricted by reconsolidation-resistant boundary conditions that constrain the initial memory destabilization. In this study, we investigated whether the induction of synaptic protein degradation through autophagy modulation, a major protein degradation pathway, can enhance memory destabilization upon retrieval and whether it can be used to overcome these conditions. Here, using male mice in an auditory fear reconsolidation model, we showed that autophagy contributes to memory destabilization and its induction can be used to enhance erasure of a reconsolidation-resistant auditory fear memory that depended on AMPAR endocytosis. Using male mice in a contextual fear reconsolidation model, autophagy induction in the amygdala or in the hippocampus enhanced fear or contextual memory destabilization, respectively. The latter correlated with AMPAR degradation in the spines of the contextual memory-ensemble cells. Using male rats in an in vivo LTP reconsolidation model, autophagy induction enhanced synaptic destabilization in an NMDAR-dependent manner. These data indicate that induction of synaptic protein degradation can enhance both synaptic and memory destabilization upon reactivation and that autophagy inducers have the potential to be used as a therapeutic tool in the treatment of anxiety disorders. SIGNIFICANCE STATEMENT It has been reported that inhibiting synaptic protein degradation prevents memory destabilization. However, whether the reverse relation is true and whether it can be used to enhance memory destabilization are still unknown. Here we addressed this question on the behavioral, molecular, and synaptic levels, and showed that induction of autophagy, a major protein degradation pathway, can enhance memory and synaptic destabilization upon reactivation. We also show that autophagy induction can be used to overcome a reconsolidation-resistant memory, suggesting autophagy inducers as a potential therapeutic tool in the treatment of anxiety disorders. Copyright © 2018 the authors 0270-6474/18/383809-14$15.00/0.

Hippocampal calpain is required for the consolidation and reconsolidation but not extinction of contextual fear memory.

PubMed

Nagayoshi, Taikai; Isoda, Kiichiro; Mamiya, Nori; Kida, Satoshi

2017-12-19

Memory consolidation, reconsolidation, and extinction have been shown to share similar molecular signatures, including new gene expression. Calpain is a Ca 2+ -dependent protease that exerts its effects through the proteolytic cleavage of target proteins. Neuron-specific conditional deletions of calpain 1 and 2 impair long-term potentiation in the hippocampus and spatial learning. Moreover, recent studies have suggested distinct roles of calpain 1 and 2 in synaptic plasticity. However, the role of hippocampal calpain in memory processes, especially memory consolidation, reconsolidation, and extinction, is still unclear. In the current study, we demonstrated the critical roles of hippocampal calpain in the consolidation, reconsolidation, and extinction of contextual fear memory in mice. We examined the effects of pharmacological inhibition of calpain in the hippocampus on these memory processes, using the N-Acetyl-Leu-Leu-norleucinal (ALLN; calpain 1 and 2 inhibitor). Microinfusion of ALLN into the dorsal hippocampus impaired long-term memory (24 h memory) without affecting short-term memory (2 h memory). Similarly, this pharmacological blockade of calpain in the dorsal hippocampus also disrupted reactivated memory but did not affect memory extinction. Importantly, the systemic administration of ALLN inhibited the induction of c-fos in the hippocampus, which is observed when memory is consolidated. Our observations showed that hippocampal calpain is required for the consolidation and reconsolidation of contextual fear memory. Further, the results suggested that calpain contributes to the regulation of new gene expression that is necessary for these memory processes as a regulator of Ca 2+ -signal transduction pathway.

Extinction of fear is facilitated by social presence: Synergism with prefrontal oxytocin.

PubMed

Brill-Maoz, Naama; Maroun, Mouna

2016-04-01

This study addressed the question of whether extinction in pairs would have a beneficial effect on extinction of fear conditioning. To that end, we established an experimental setting for extinction in which we trained animals to extinguish contextual fear memory in pairs. Taking advantage of the role of oxytocin (OT) in the medial prefrontal cortex (mPFC) in the mediation of memory extinction and social interaction, we also sought to study its role in social interaction-induced effects on extinction. Our results clearly show that the social presence of another animal in the extinction context facilitates extinction, and that this facilitation is mediated through mPFC-OT. Our results suggest that social interaction may be a positive regulator of fear inhibition, implying that social interaction may be an easy, accessible therapeutic tool for the treatment of fear-associated disorders. Copyright © 2016. Published by Elsevier Ltd.

Prefrontal dopamine regulates fear reinstatement through the downregulation of extinction circuits

PubMed Central

Hitora-Imamura, Natsuko; Miura, Yuki; Teshirogi, Chie; Ikegaya, Yuji; Matsuki, Norio; Nomura, Hiroshi

2015-01-01

Prevention of relapses is a major challenge in treating anxiety disorders. Fear reinstatement can cause relapse in spite of successful fear reduction through extinction-based exposure therapy. By utilising a contextual fear-conditioning task in mice, we found that reinstatement was accompanied by decreased c-Fos expression in the infralimbic cortex (IL) with reduction of synaptic input and enhanced c-Fos expression in the medial subdivision of the central nucleus of the amygdala (CeM). Moreover, we found that IL dopamine plays a key role in reinstatement. A reinstatement-inducing reminder shock induced c-Fos expression in the IL-projecting dopaminergic neurons in the ventral tegmental area, and the blocking of IL D1 signalling prevented reduction of synaptic input, CeM c-Fos expression, and fear reinstatement. These findings demonstrate that a dopamine-dependent inactivation of extinction circuits underlies fear reinstatement and may explain the comorbidity of substance use disorders and anxiety disorders. DOI: http://dx.doi.org/10.7554/eLife.08274.001 PMID:26226637

Authentic Assessment: Reducing the Fear and Trembling.

ERIC Educational Resources Information Center

Terry, C. Ann; Pantle, Tonya T.

1994-01-01

This discussion of authentic assessment stresses that such assessment should be contextual (based on the context of meaning), collaborative (involves learners), and constructive (supports risk-taking). It compares tools designed for formative assessment including criteria checklists, "kidwatching," profiles, conferences, and portfolios. (DB)

Flexible attention deployment in threatening contexts: an instructed fear conditioning study.

PubMed

Shechner, Tomer; Pelc, Tatiana; Pine, Daniel S; Fox, Nathan A; Bar-Haim, Yair

2012-10-01

Factors leading humans to shift attention away from danger cues remain poorly understood. Two laboratory experiments reported here show that context interacts with learning experiences to shape attention avoidance of mild danger cues. The first experiment exposed 18 participants to contextual threat of electric shock. Attention allocation to mild danger cues was then assessed with the dot-probe task. Results showed that contextual threat caused subjects to avert attention from danger cues. In the second experiment, 36 participants were conditioned to the same contextual threat used in Experiment 1. These subjects then were randomly assigned to either an experimental group, trained to shift attention toward danger cues, or a placebo group exposed to the same stimuli without the training component. As in Experiment 1, contextual threat again caused attention allocation away from danger in the control group. However, this did not occur in the experimental group. These experiments show that acute contextual threat and learning experiences interact to shape the deployment of attention away from danger cues.

Islamic Headdress Influences How Emotion is Recognized from the Eyes

PubMed Central

Kret, Mariska Esther; de Gelder, Beatrice

2012-01-01

Previous research has shown a negative bias in the perception of whole facial expressions from out-group members. Whether or not emotion recognition from the eyes is already sensitive to contextual information is presently a matter of debate. In three experiments we tested whether emotions can be recognized when just the eyes are visible and whether this recognition is affected by context cues, such as various Islamic headdresses vs. a cap or a scarf. Our results indicate that fear is still well recognized from a briefly flashed (100 ms) image of a women wearing a burqa with less than 20% transparency of the eye region. Moreover, the type of headdress influences how emotions are recognized. In a group of participants from non-Islamic background, fear was recognized better from women wearing a niqāb than from women wearing a cap and a shawl, whereas the opposite was observed for happy and sad expressions. The response patterns showed that fearful and anger labels were more often attributed to women with a niqāb vs. a cap and a shawl and again, an opposite pattern was observed for the happy response. However, there was no general response bias: both correct and incorrect responses were influenced by the facial expression as well. Anxiety levels and/or explicit negative associations with the Islam as measured via questionnaires did not mediate the effects. Consistent with the face literature, we conclude that the recognition of emotions from the eyes is also influenced by context. PMID:22557983

Factors Impacting the Child with Behavioral Inhibition

ERIC Educational Resources Information Center

Hornbuckle, Suzanne R.

2010-01-01

Various factors influence the developmental course of the behaviorally inhibited child. These factors include reciprocating, contextual factors, such as the child's own traits, the environment, the maternal characteristics, and the environment. Behaviorally inhibited children show physiological and behavioral signs of fear and anxiety when…

Overexpression of Protein Kinase Mζ in the Hippocampus Enhances Long-Term Potentiation and Long-Term Contextual But Not Cued Fear Memory in Rats.

PubMed

Schuette, Sven R M; Fernández-Fernández, Diego; Lamla, Thorsten; Rosenbrock, Holger; Hobson, Scott

2016-04-13

The persistently active protein kinase Mζ (PKMζ) has been found to be involved in the formation and maintenance of long-term memory. Most of the studies investigating PKMζ, however, have used either putatively unselective inhibitors or conventional knock-out animal models in which compensatory mechanisms may occur. Here, we overexpressed an active form of PKMζ in rat hippocampus, a structure highly involved in memory formation, and embedded in several neural networks. We investigated PKMζ's influence on synaptic plasticity using electrophysiological recordings of basal transmission, paired pulse facilitation, and LTP and combined this with behavioral cognitive experiments addressing formation and retention of both contextual memory during aversive conditioning and spatial memory during spontaneous exploration. We demonstrate that hippocampal slices overexpressing PKMζ show enhanced basal transmission, suggesting a potential role of PKMζ in postsynaptic AMPAR trafficking. Moreover, the PKMζ-overexpressing slices augmented LTP and this effect was not abolished by protein-synthesis blockers, indicating that PKMζ induces enhanced LTP formation in a protein-synthesis-independent manner. In addition, we found selectively enhanced long-term memory for contextual but not cued fear memory, underlining the theory of the hippocampus' involvement in the contextual aspect of aversive reinforced tasks. Memory for spatial orientation during spontaneous exploration remained unaltered, suggesting that PKMζ may not affect the neural circuits underlying spontaneous tasks that are different from aversive tasks. In this study, using an overexpression strategy as opposed to an inhibitor-based approach, we demonstrate an important modulatory role of PKMζ in synaptic plasticity and selective memory processing. Most of the literature investigating protein kinase Mζ (PKMζ) used inhibitors with selectivity that has been called into question or conventional knock-out animal models in which compensatory mechanisms may occur. To avoid these issues, some studies have been done using viral overexpression of PKMζ in different brain structures to show cognitive enhancement. However, electrophysiological experiments were exclusively done in knock-out models or inhibitory studies to show depletion of LTP. There was no study showing the effect of PKMζ overexpression in the hippocampus on behavior and LTP experiments. To our knowledge, this is the first study to combine these aspects with the result of enhanced memory for contextual fear memory and to show enhanced LTP in hippocampal slices overexpressing PKMζ. Copyright © 2016 Schuette et al.

Severe and protracted sleep disruptions in mouse model of post-traumatic stress disorder.

PubMed

Sharma, Rishi; Sahota, Pradeep; Thakkar, Mahesh M

2018-03-01

Increasing evidences suggest that the predator threat model is a valid animal model of post-traumatic stress disorder (PTSD). However, sleep has never been examined in this model. Since sleep disturbances, including insomnia and excessive daytime sleepiness, are severe and protracted symptoms of PTSD, we hypothesized that mice exposed to predator odor trauma (POT) will display contextual fear conditioning along with severe and protracted sleep disruptions. Adult male C57BL/6J mice, instrumented with wire electrodes (to record hippocampal local field potentials [LFP] and nuchal muscle [electromyogram, EMG] activity), were exposed to contextual conditioning using soiled cat litter as unconditional stimulus (US). On day 1, fear memory acquisition (FMA) training was performed by exposing mice to contextual cage (conditional stimulus; CS) for 30 min followed by exposure to CS + US for 90 min. On day 5, fear memory recall (FMR) testing was performed by exposing mice to CS (without US) for 120 min. LFP and EMG were recorded continuously for 5 days. Mice exposed to POT displayed as follows: (1) hyperarousal coupled with electrophysiological indicators of memory acquisition and retrieval (increased hippocampal θ and γ power) during FMA and FMR; (2) increased nonrapid eye movement (NREM) δ and rapid eye movement θ power during sleep post FMA, indicating memory consolidation; (3) protracted sleep disturbances as evident by increased wakefulness, reduced NREM sleep and NREM δ power, increased NREM β power during light (sleep) period, and increased sleep during dark (active) period. Based on these results, we suggest that mice exposed to POT display severe and protracted sleep disturbances mimicking sleep disturbance observed in human PTSD.

Interleukin-6 trans-signaling in the senescent mouse brain is involved in infection-related deficits in contextual fear conditioning.

PubMed

Burton, Michael D; Johnson, Rodney W

2012-07-01

Excessive production of pro-inflammatory cytokines in the senescent brain in response to peripheral immune stimulation is thought to induce behavioral pathology, however, few studies have examined if the increase in pro-inflammatory cytokines is accompanied by an increase in cytokine signaling. Here, we focused on IL-6 as a prototypic pro-inflammatory cytokine and used phosphorylated STAT3 as a marker of IL-6 signaling. In an initial study, IL-6 mRNA and the magnitude and duration of STAT3 activation were increased in the hippocampus of senescent mice compared to adults after i.p. injection of LPS. The LPS-induced increase in STAT3 activity was ablated in aged IL-6(-/-) mice, suggesting IL-6 is a key driver of STAT3 activity in the aged brain. To determine if IL-6 activated the classical or trans-signaling pathway, before receiving LPS i.p., aged mice were injected ICV with sgp130, an antagonist of the trans-signaling pathway. Importantly, the LPS-induced increases in both IL-6 and STAT3 activity in the hippocampus were inhibited by sgp130. To assess hippocampal function, aged mice were injected ICV with sgp130 and i.p. with LPS immediately after the acquisition phase of contextual fear conditioning, and immobility was assessed in the retention phase 48h later. LPS reduced immobility in aged mice, indicating immune activation interfered with memory consolidation. However, sgp130 blocked the deficits in contextual fear conditioning caused by LPS. Taken together, the results suggest IL-6 trans-signaling is increased in the senescent brain following peripheral LPS challenge and that sgp130 may protect against infection-related neuroinflammation and cognitive dysfunction in the aged. Copyright © 2011 Elsevier Inc. All rights reserved.

Neonatal alcohol exposure disrupts hippocampal neurogenesis and contextual fear conditioning in adult rats

PubMed Central

Hamilton, G.F.; Murawski, N.J.; St. Cyr, S.A.; Jablonski, S.A.; Schiffino, F.L.; Stanton, M.E.; Klintsova, A.Y.

2011-01-01

Developmental alcohol exposure can permanently alter brain structures and produce functional impairments in many aspects of behavior, including learning and memory. This study evaluates the effect of neonatal alcohol exposure on adult neurogenesis in the dentate gyrus of the hippocampus and the implications of such exposure for hippocampus-dependent contextual fear conditioning. Alcohol-exposed rats (AE) received 5.25 g/kg/day of alcohol on postnatal days (PD) 4-9 (third trimester in humans), in a binge-like manner. Two control groups were included: sham-intubated (SI) and suckle-control (SC). Animals were housed in social cages (3/cage) after weaning. On PD80, animals were injected with 200 mg/kg BrdU. Half of the animals were sacrificed two hours later. The remainder were sacrificed on PD114 to evaluate cell survival; separate AE, SI, and SC rats not injected with BrdU were tested for the context preexposure facilitation effect (CPFE; ∼PD117). There was no difference in the number of BrdU+ cells in AE, SI and SC groups on PD80. On PD114, cell survival was significantly decreased in AE rats, demonstrating that developmental alcohol exposure damages new cells' ability to incorporate into the network and survive. Behaviorally tested SC and SI groups preexposed to the training context 24h prior to receiving a 1.5mA 2s footshock froze significantly more during the context test than their counterparts preexposed to an alternate context. AE rats failed to show the CPFE. The current study shows the detrimental, long-lasting effects of developmental alcohol exposure on hippocampal adult neurogenesis and contextual fear conditioning. PMID:21816390

Memory accuracy predicts hippocampal mTOR pathway activation following retrieval of contextual fear memory.

PubMed

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

2013-09-01

Prior work suggests that hippocampus-dependent memory undergoes a systems consolidation process such that recent memories are stored in the hippocampus, while older memories are independent of the hippocampus and instead dependent on cortical areas. One problem with interpreting these studies is that memory for the contextual stimuli weakens as time passes between the training event and testing and older memories are often less detailed, making it difficult to determine if memory storage in the hippocampus is related to the age or to the accuracy of the memory. Activity of the mammalian target of rapamycin (mTOR) signaling pathway is known to be important for controlling protein translation necessary for both memory consolidation after initial learning and for the reconsolidation of memory after retrieval. We tested whether p70s6 kinase (p70s6K), a key component of the mTOR signaling pathway, is activated following retrieval of context fear memory in the dorsal hippocampus (DH) and anterior cingulate cortex (ACC) at 1, 10, or 36 days after context fear conditioning. We also tested whether strengthening memory for the contextual stimuli changed p70s6K phosphorylation in these structures 36 days after training. We show that under standard training conditions retrieval of a recently formed memory is initially precise and involves the DH. Over time it loses detail, becomes independent of the DH and depends on the ACC. In a subsequent experiment, we preserved the accuracy of older memories through pre-exposure to the training context. We show that remote memory still involved the DH in animals given pre-exposure. These data support the notion that detailed memories depend on the DH regardless of their age. Copyright © 2013 Wiley Periodicals, Inc.

Early experience of a novel-environment in isolation primes a fearful phenotype characterized by persistent amygdala activation.

PubMed

Daskalakis, Nikolaos P; Diamantopoulou, Anastasia; Claessens, Sanne E F; Remmers, Elisa; Tjälve, Marika; Oitzl, Melly S; Champagne, Danielle L; de Kloet, E Ronald

2014-01-01

Prolonged maternal separation (MS) activates the neonate's hypothalamus-pituitary-adrenal axis causing elevated basal and stress-induced corticosterone levels that may initiate amygdala-dependent fear learning. Here we test the hypothesis that the adult fearful phenotype is programmed by the pup's stressful experience during prolonged MS rather than by prolonged maternal absence per se. For this purpose, Wistar rat pups were exposed, on postnatal-day (pnd) 3, to: (i) repeated-MS in home-environment (HOME-SEP), 8h-MS daily for three days with the pups remaining together in the home-cage; (ii) repeated-MS in a novel-environment (NOVEL-SEP), with the same separation procedure, but now the pups were individually housed in a novel-environment during the 8h dam's absence; (iii) repeated handling, which consisted of daily brief (15 min instead of 8h) MS in the home-altogether or in a novel-environment individually (HOME-HAN and NOVEL-HAN, respectively); (iv) no-separation/no-handling (NON-SEP/NON-HAN) control condition, in which pups were left undisturbed in their home-cage. Compared to HOME-SEP rats, the NOVEL-SEP rats showed one day after the last MS enhanced stress-induced amygdala c-Fos expression and ACTH-release, despite of reduced adrenal corticosterone secretion. The higher amygdala c-Fos expression, ACTH-release and reduced corticosterone output observed postnatally, persisted into adulthood of the NOVEL-SEP animals. Behaviorally, NOVEL-SEP juvenile rats displayed deficits in social play, had intact spatial memory in the peri-pubertal period and showed more contextual fear memory compared to HOME-SEP in adulthood. Finally, NOVEL-HAN, compared to HOME-HAN, displayed increased stress-induced corticosterone output, no deficits in social play and reduced contextual fear. In conclusion, programming of an adult fearful phenotype linked to amygdala priming develops if pups are repeatedly isolated from peers in a novel-environment, while away from the dam for a prolonged period of time. Copyright © 2013 Elsevier Ltd. All rights reserved.

Pigeons exhibit contextual cueing to both simple and complex backgrounds.

PubMed

Wasserman, Edward A; Teng, Yuejia; Castro, Leyre

2014-05-01

Repeated pairings of a particular visual context with a specific location of a target stimulus facilitate target search in humans. We explored an animal model of this contextual cueing effect using a novel Cueing-Miscueing design. Pigeons had to peck a target which could appear in one of four possible locations on four possible color backgrounds or four possible color photographs of real-world scenes. On 80% of the trials, each of the contexts was uniquely paired with one of the target locations; on the other 20% of the trials, each of the contexts was randomly paired with the remaining target locations. Pigeons came to exhibit robust contextual cueing when the context preceded the target by 2s, with reaction times to the target being shorter on correctly-cued trials than on incorrectly-cued trials. Contextual cueing proved to be more robust with photographic backgrounds than with uniformly colored backgrounds. In addition, during the context-target delay, pigeons predominately pecked toward the location of the upcoming target, suggesting that attentional guidance contributes to contextual cueing. These findings confirm the effectiveness of animal models of contextual cueing and underscore the important part played by associative learning in producing the effect. This article is part of a Special Issue entitled: SQAB 2013: Contextual Con. Copyright © 2014 Elsevier B.V. All rights reserved.

Interactive effects between gaze direction and facial expression on attentional resources deployment: the task instruction and context matter

PubMed Central

Ricciardelli, Paola; Lugli, Luisa; Pellicano, Antonello; Iani, Cristina; Nicoletti, Roberto

2016-01-01

In three experiments, we tested whether the amount of attentional resources needed to process a face displaying neutral/angry/fearful facial expressions with direct or averted gaze depends on task instructions, and face presentation. To this end, we used a Rapid Serial Visual Presentation paradigm in which participants in Experiment 1 were first explicitly asked to discriminate whether the expression of a target face (T1) with direct or averted gaze was angry or neutral, and then to judge the orientation of a landscape (T2). Experiment 2 was identical to Experiment 1 except that participants had to discriminate the gender of the face of T1 and fearful faces were also presented randomly inter-mixed within each block of trials. Experiment 3 differed from Experiment 2 only because angry and fearful faces were never presented within the same block. The findings indicated that the presence of the attentional blink (AB) for face stimuli depends on specific combinations of gaze direction and emotional facial expressions and crucially revealed that the contextual factors (e.g., explicit instruction to process the facial expression and the presence of other emotional faces) can modify and even reverse the AB, suggesting a flexible and more contextualized deployment of attentional resources in face processing. PMID:26898473

DREAM (Downstream Regulatory Element Antagonist Modulator) contributes to synaptic depression and contextual fear memory

PubMed Central

2010-01-01

The downstream regulatory element antagonist modulator (DREAM), a multifunctional Ca2+-binding protein, binds specifically to DNA and several nucleoproteins regulating gene expression and with proteins outside the nucleus to regulate membrane excitability or calcium homeostasis. DREAM is highly expressed in the central nervous system including the hippocampus and cortex; however, the roles of DREAM in hippocampal synaptic transmission and plasticity have not been investigated. Taking advantage of transgenic mice overexpressing a Ca2+-insensitive DREAM mutant (TgDREAM), we used integrative methods including electrophysiology, biochemistry, immunostaining, and behavior tests to study the function of DREAM in synaptic transmission, long-term plasticity and fear memory in hippocampal CA1 region. We found that NMDA receptor but not AMPA receptor-mediated current was decreased in TgDREAM mice. Moreover, synaptic plasticity, such as long-term depression (LTD) but not long-term potentiation (LTP), was impaired in TgDREAM mice. Biochemical experiments found that DREAM interacts with PSD-95 and may inhibit NMDA receptor function through this interaction. Contextual fear memory was significantly impaired in TgDREAM mice. By contrast, sensory responses to noxious stimuli were not affected. Our results demonstrate that DREAM plays a novel role in postsynaptic modulation of the NMDA receptor, and contributes to synaptic plasticity and behavioral memory. PMID:20205763

The AMPA receptor-associated protein Shisa7 regulates hippocampal synaptic function and contextual memory

PubMed Central

Zamri, Azra Elia; Stroeder, Jasper; Rao-Ruiz, Priyanka; Lodder, Johannes C; van der Loo, Rolinka J

2017-01-01

Glutamatergic synapses rely on AMPA receptors (AMPARs) for fast synaptic transmission and plasticity. AMPAR auxiliary proteins regulate receptor trafficking, and modulate receptor mobility and its biophysical properties. The AMPAR auxiliary protein Shisa7 (CKAMP59) has been shown to interact with AMPARs in artificial expression systems, but it is unknown whether Shisa7 has a functional role in glutamatergic synapses. We show that Shisa7 physically interacts with synaptic AMPARs in mouse hippocampus. Shisa7 gene deletion resulted in faster AMPAR currents in CA1 synapses, without affecting its synaptic expression. Shisa7 KO mice showed reduced initiation and maintenance of long-term potentiation of glutamatergic synapses. In line with this, Shisa7 KO mice showed a specific deficit in contextual fear memory, both short-term and long-term after conditioning, whereas auditory fear memory and anxiety-related behavior were normal. Thus, Shisa7 is a bona-fide AMPAR modulatory protein affecting channel kinetics of AMPARs, necessary for synaptic hippocampal plasticity, and memory recall. PMID:29199957

Parvalbumin-positive interneurons mediate neocortical-hippocampal interactions that are necessary for memory consolidation

PubMed Central

Xia, Frances; Richards, Blake A; Tran, Matthew M; Josselyn, Sheena A

2017-01-01

Following learning, increased coupling between spindle oscillations in the medial prefrontal cortex (mPFC) and ripple oscillations in the hippocampus is thought to underlie memory consolidation. However, whether learning-induced increases in ripple-spindle coupling are necessary for successful memory consolidation has not been tested directly. In order to decouple ripple-spindle oscillations, here we chemogenetically inhibited parvalbumin-positive (PV+) interneurons, since their activity is important for regulating the timing of spiking activity during oscillations. We found that contextual fear conditioning increased ripple-spindle coupling in mice. However, inhibition of PV+ cells in either CA1 or mPFC eliminated this learning-induced increase in ripple-spindle coupling without affecting ripple or spindle incidence. Consistent with the hypothesized importance of ripple-spindle coupling in memory consolidation, post-training inhibition of PV+ cells disrupted contextual fear memory consolidation. These results indicate that successful memory consolidation requires coherent hippocampal-neocortical communication mediated by PV+ cells. PMID:28960176

Extinction learning, which consists of the inhibition of retrieval, can be learned without retrieval.

PubMed

de Carvalho Myskiw, Jociane; Furini, Cristiane Regina Guerino; Schmidt, Bianca; Ferreira, Flávia; Izquierdo, Ivan

2015-01-13

In the present study we test the hypothesis that extinction is not a consequence of retrieval in unreinforced conditioned stimulus (CS) presentation but the mere perception of the CS in the absence of a conditioned response. Animals with cannulae implanted in the CA1 region of hippocampus were subjected to extinction of contextual fear conditioning. Muscimol infused intra-CA1 before an extinction training session of contextual fear conditioning (CFC) blocks retrieval but not consolidation of extinction measured 24 h later. Additionally, this inhibition of retrieval does not affect early persistence of extinction when tested 7 d later or its spontaneous recovery after 2 wk. Furthermore, both anisomycin, an inhibitor of ribosomal protein synthesis, and rapamycin, an inhibitor of extraribosomal protein synthesis, given into the CA1, impair extinction of CFC regardless of whether its retrieval was blocked by muscimol. Therefore, retrieval performance in the first unreinforced session is not necessary for the installation, maintenance, or spontaneous recovery of extinction of CFC.

Molecular mechanisms of D-cycloserine in facilitating fear extinction: insights from RNAseq.

PubMed

Malan-Müller, Stefanie; Fairbairn, Lorren; Daniels, Willie M U; Dashti, Mahjoubeh Jalali Sefid; Oakeley, Edward J; Altorfer, Marc; Kidd, Martin; Seedat, Soraya; Gamieldien, Junaid; Hemmings, Sîan Megan Joanna

2016-02-01

D-cycloserine (DCS) has been shown to be effective in facilitating fear extinction in animal and human studies, however the precise mechanisms whereby the co-administration of DCS and behavioural fear extinction reduce fear are still unclear. This study investigated the molecular mechanisms of intrahippocampally administered D-cycloserine in facilitating fear extinction in a contextual fear conditioning animal model. Male Sprague Dawley rats (n = 120) were grouped into four experimental groups (n = 30) based on fear conditioning and intrahippocampal administration of either DCS or saline. The light/dark avoidance test was used to differentiate maladapted (MA) (anxious) from well-adapted (WA) (not anxious) subgroups. RNA extracted from the left dorsal hippocampus was used for RNA sequencing and gene expression data was compared between six fear-conditioned + saline MA (FEAR + SALINE MA) and six fear-conditioned + DCS WA (FEAR + DCS WA) animals. Of the 424 significantly downregulated and 25 significantly upregulated genes identified in the FEAR + DCS WA group compared to the FEAR + SALINE MA group, 121 downregulated and nine upregulated genes were predicted to be relevant to fear conditioning and anxiety and stress-related disorders. The majority of downregulated genes transcribed immune, proinflammatory and oxidative stress systems molecules. These molecules mediate neuroinflammation and cause neuronal damage. DCS also regulated genes involved in learning and memory processes, and genes associated with anxiety, stress-related disorders and co-occurring diseases (e.g., cardiovascular diseases, digestive system diseases and nervous system diseases). Identifying the molecular underpinnings of DCS-mediated fear extinction brings us closer to understanding the process of fear extinction.

Social Capital and Fear of Crime in Adolescence: A Multilevel Study.

PubMed

Vieno, Alessio; Lenzi, Michela; Roccato, Michele; Russo, Silvia; Monaci, Maria Grazia; Scacchi, Luca

2016-09-01

Hierarchical linear modeling was used to examine the relationships between social capital (at the individual, the neighborhood, and the regional levels) and adolescents' fear of crime, while controlling for the main individual (sociodemographics, television viewing, and bullying victimization), neighborhood (neighborhood size and aggregated victimization), and regional (crime rate and level of urbanization) variables. Data were analyzed using a three-level model based on 22,639 15.7-year-old (SD = 0.67) students nested within 1081 neighborhoods and 19 Italian regions. The findings revealed that individual and contextual measures of social capital, modeled at the individual, neighborhood, and regional levels simultaneously, showed negative associations with adolescents' fear of crime. Males and participants with higher family affluence were less likely to feel fear of crime, whereas victimization, both at the individual and neighborhood levels, had a positive association with fear of crime. Strengths, limitations, and potential applications of the study are discussed. © Society for Community Research and Action 2016.

Brief fear preexposure facilitates subsequent fear conditioning.

PubMed

Iwasaki, Satoshi; Sakaguchi, Tetsuya; Ikegaya, Yuji

2015-06-01

Post-traumatic stress disorder (PTSD) is an anxiety disorder that occurs following an unexpected exposure to a severe psychological event. A history of a brief trauma is reported to affect a risk for future PTSD development; however, little is known about the mechanisms by which a previous trauma exposure drives the sensitivity to a late-coming trauma. Using a mouse PTSD model, we found that a prior foot shock enhances contextual fear conditioning. This shock-induced facilitation of fear conditioning (i.e., priming effect) persisted for 7 days and was prevented by MK801, an N-methyl-D-aspartate receptor antagonist. Other types of trauma, such as forced swimming or tail pinch, did not induce a priming effect on fear conditioning. Thus, a trauma is unlikely generalized to modify the sensitivity to other traumatic experiences. The behavioral procedure employed in this study may be a useful tool to elucidate the etiology of PTSD. Copyright © 2015 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.

5-HT2C receptors in the BNST are necessary for the enhancement of fear learning by selective serotonin reuptake inhibitors.

PubMed

Pelrine, Eliza; Pasik, Sara Diana; Bayat, Leyla; Goldschmiedt, Debora; Bauer, Elizabeth P

2016-12-01

Selective serotonin reuptake inhibitors (SSRIs) are widely prescribed to treat anxiety and depression, yet they paradoxically increase anxiety during initial treatment. Acute administration of these drugs prior to learning can also enhance Pavlovian cued fear conditioning. This potentiation has been previously reported to depend upon the bed nucleus of the stria terminalis (BNST). Here, using temporary inactivation, we confirmed that the BNST is not necessary for the acquisition of cued or contextual fear memory. Systemic administration of the SSRI citalopram prior to fear conditioning led to an upregulation of the immediate early gene Arc (activity-regulated cytoskeleton-associated protein) in the oval nucleus of the BNST, and a majority of these neurons expressed the 5-HT2C receptor. Finally, local infusions of a 5-HT2C receptor antagonist directly into the oval nucleus of the BNST prevented the fear memory-enhancing effects of citalopram. These findings highlight the ability of the BNST circuitry to be recruited into gating fear and anxiety-like behaviors. Copyright © 2016 Elsevier Inc. All rights reserved.

Age and adolescent social stress effects on fear extinction in female rats.

PubMed

McCormick, C M; Mongillo, D L; Simone, J J

2013-11-01

We previously observed that social instability stress (SS: daily 1 h isolation and change of cage partners for 16 days) in adolescence, but not in adulthood, decreased context and cue memory after fear conditioning in male rats. Effects of stress are typically sex-specific, and so here we investigated adolescent and adult SS effects in females on the strength of acquired contextual and cued fear conditioning, as well as extinction learning, beginning either the day after the stress procedure or four weeks later. For SS in adolescence, SS females spent more time freezing (fear measure) during extinction than did controls, whereas SS in adulthood had no effect on any measure of fear conditioning. The results also indicated an effect of age: females in late adolescence show more rapid extinction of cue and better memory of extinction of context compared to adult females, which may indicate resilience to acute footshock in adolescence. Thus fear circuitry continues to mature into late adolescence, which may underlie the heightened plasticity in response to chronic stressors of adolescents compared to adults.

Nucleus accumbens carbachol disrupts olfactory and contextual fear-potentiated startle and attenuates baseline startle reactivity.

PubMed

Cousens, Graham A; Skrobacz, Cheryl G; Blumenthal, Anna

2011-01-20

Although the nucleus accumbens (NAc) typically is not considered a primary component of the circuitry underlying either the acquisition or retrieval of conditioned fear, evidence suggests that this region may play some role in modulating fear-related behaviors. The goal of the present study was to explore a potential role for NAc cholinergic receptors in the expression of fear-potentiated startle (FPS) and baseline startle reactivity. Intra-NAc infusion of the broad-acting cholinergic receptor agonist, carbachol, suppressed FPS elicited by re-exposure to both a discrete odor previously paired with footshock and the conditioning context. Although carbachol elevated spontaneous motor activity, activity bouts did not account for startle suppression in carbachol-treated Ss. In addition, intra-NAc carbachol suppressed baseline startle over a range of acoustic pulse intensities in the absence of explicit fear conditioning. Collectively, these findings suggest that NAc cholinergic receptors play a role in the modulation of baseline startle reactivity, rather than in the retrieval of learned fear, and that this role is independent of overt motor activity. Copyright © 2010 Elsevier B.V. All rights reserved.

Beyond scene gist: Objects guide search more than scene background.

PubMed

Koehler, Kathryn; Eckstein, Miguel P

2017-06-01

Although the facilitation of visual search by contextual information is well established, there is little understanding of the independent contributions of different types of contextual cues in scenes. Here we manipulated 3 types of contextual information: object co-occurrence, multiple object configurations, and background category. We isolated the benefits of each contextual cue to target detectability, its impact on decision bias, confidence, and the guidance of eye movements. We find that object-based information guides eye movements and facilitates perceptual judgments more than scene background. The degree of guidance and facilitation of each contextual cue can be related to its inherent informativeness about the target spatial location as measured by human explicit judgments about likely target locations. Our results improve the understanding of the contributions of distinct contextual scene components to search and suggest that the brain's utilization of cues to guide eye movements is linked to the cue's informativeness about the target's location. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

Pigeons Exhibit Contextual Cueing to Both Simple and Complex Backgrounds

PubMed Central

Wasserman, Edward A.; Teng, Yuejia; Castro, Leyre

2014-01-01

Repeated pairings of a particular visual context with a specific location of a target stimulus facilitate target search in humans. We explored an animal model of this contextual cueing effect using a novel Cueing-Miscueing design. Pigeons had to peck a target which could appear in one of four possible locations on four possible color backgrounds or four possible color photographs of real-world scenes. On 80% of the trials, each of the contexts was uniquely paired with one of the target locations; on the other 20% of the trials, each of the contexts was randomly paired with the remaining target locations. Pigeons came to exhibit robust contextual cueing when the context preceded the target by 2 s, with reaction times to the target being shorter on correctly-cued trials than on incorrectly-cued trials. Contextual cueing proved to be more robust with photographic backgrounds than with uniformly colored backgrounds. In addition, during the context-target delay, pigeons predominately pecked toward the location of the upcoming target, suggesting that attentional guidance contributes to contextual cueing. These findings confirm the effectiveness of animal models of contextual cueing and underscore the important part played by associative learning in producing the effect. PMID:24491468

AMPA receptors control fear extinction through an Arc-dependent mechanism.

PubMed

Trent, Simon; Barnes, Philip; Hall, Jeremy; Thomas, Kerrie L

2017-08-01

Activity-regulated cytoskeleton-associated protein (Arc) supports fear memory through synaptic plasticity events requiring actin cytoskeleton rearrangements. We have previously shown that reducing hippocampal Arc levels through antisense knockdown leads to the premature extinction of contextual fear. Here we show that the AMPA receptor antagonist CNQX elevates hippocampal Arc levels during extinction and blocks extinction that can be rescued by reducing Arc. Increasing Arc levels with CNQX also overcomes the actin-destabilizing properties of cytochalasin D and promotes extinction. Therefore, extinction is dependent on AMPA-mediated reductions of Arc via a mechanism consistent with a role for Arc in stabilizing the actin cytoskeleton to constrain extinction. © 2017 Trent et al.; Published by Cold Spring Harbor Laboratory Press.

Effects of oxytocin on background anxiety in rats with high or low baseline startle

PubMed Central

Ayers, Luke; Agostini, Andrew; Schulkin, Jay; Rosen, Jeffrey B.

2016-01-01

Rationale Oxytocin has antianxiety properties in humans and rodents. However, the antianxiety effects have been variable. Objectives To reduce variability and strengthen to the antianxiety effect of oxytocin in fear-potentiated startle, two experiments were performed. First, different amounts of light-shock pairings were given to determine the optimal levels of cue-specific fear conditioning and non-predictable startle (background anxiety). Second, the antianxiety effects of oxytocin were examined in rats with high and low pre-fear conditioning baseline startle to determine if oxytocin differentially affects high and low trait anxiety rats. Methods Baseline pre-fear conditioning startle responses were first measured. Rats then received 1, 5 or 10 light-shock pairings. Fear-potentiated startle was then tested with two trial types: light-cued startle and non-cued startle trials. In the second experiment, rats fear conditioned with 10 light-shock pairings were administered either saline or oxytocin before a fear-potentiated startle test. Rats were categorized as low or high startlers by their pre-fear conditioning startle amplitude. Results Ten shock-pairings produced the largest non-cued startle responses (background anxiety), without increasing cue-specific fear-potentiated startle compared to 1 and 5 light-shock pairings. Cue-specific fear-potentiated startle was unaffected by oxytocin. Oxytocin reduced background anxiety only in rats with low pre-fear startle responses. Conclusions Oxytocin has population selective antianxiety effects on non-cued unpredictable threat, but only in rats with low pre-fear baseline startle responses. The low startle responses are reminiscent of humans with low startle responses and high trait anxiety. PMID:27004789

Post-training administration of a synthetic peptide ligand of the neural cell adhesion molecule, C3d, attenuates long-term expression of contextual fear conditioning.

PubMed

Cambon, K; Venero, C; Berezin, V; Bock, E; Sandi, C

2003-01-01

The neural cell adhesion molecule (NCAM) plays a key role in synaptic plasticity and memory formation. We have recently developed a synthetic peptide, termed C3d, which, through the binding to the first, N-terminal immunoglobulin-like (Ig) module in the extracellular portion of NCAM, has been shown to promote neurite outgrowth and synapse formation in vitro, and to interfere with passive avoidance memory in rats in vivo. In this study, we investigated whether the i.c.v. administration of C3d, either 5.5 h after or 2 days before training, could be effective to modulate the strength at which emotional memory for aversive situations is established into a long-term memory. The effects of the peptide were evaluated in adult male Wistar rats trained in the contextual fear conditioning task. The results indicated that C3d significantly reduced the subsequent long-term retention of the conditioned fear response when administered 5.5 h post-training, as indicated by retention tests performed 2-3 and 7 days post-training. However, this treatment failed to influence conditioning for this task when injected 2 days pre-training. Additional experiments showed that C3d did not influence the emotional or locomotor behaviour of the animals, when tested in the open field task. Furthermore, hippocampal levels of microtubule-associated protein 2 (MAP2), Synaptophysin and NCAM were found unchanged when evaluated by enzyme-linked immunosorbent assay in crude synaptosomal preparations 2 days after peptide i.c.v. injection. Therefore, post-training injection of this synthetic peptide was efficient to attenuate the strength at which memory for contextual fear conditioning was enduringly stored, whilst it did not affect the acquisition of new memories. In addition to further support the view that NCAM is critically involved in memory consolidation, the current findings suggest that the NCAM IgI module is a potential target for the development of therapeutic drugs capable to reduce the cognitive impact induced by exposure to intensive stress experiences.

An appetitive experience after fear memory destabilization attenuates fear retention: involvement GluN2B-NMDA receptors in the Basolateral Amygdala Complex

PubMed Central

Ferrer Monti, Roque I.; Giachero, Marcelo; Alfei, Joaquín M.; Bueno, Adrián M.; Cuadra, Gabriel

2016-01-01

It is known that a consolidated memory can return to a labile state and become transiently malleable following reactivation. This instability is followed by a restabilization phase termed reconsolidation. In this work, we explored whether an unrelated appetitive experience (voluntary consumption of diluted sucrose) can affect a contextual fear memory in rats during the reactivation-induced destabilization phase. Our findings show that exposure to an appetitive experience following reactivation can diminish fear retention. This effect persisted after 1 wk. Importantly, it was achieved only under conditions that induced fear memory destabilization. This result could not be explained as a potentiated extinction, because sucrose was unable to promote extinction. Since GluN2B-containing NMDA receptors in the basolateral amygdala complex (BLA) have been implicated in triggering fear memory destabilization, we decided to block pharmacologically these receptors to explore the neurobiological bases of the observed effect. Intra-BLA infusion with ifenprodil, a GluN2B-NMDA antagonist, prevented the fear reduction caused by the appetitive experience. In sum, these results suggest that the expression of a fear memory can be dampened by an unrelated appetitive experience, as long as memory destabilization is achieved during reactivation. Possible mechanisms behind this effect and its clinical implications are discussed. PMID:27531837

Contextual Influences on Concordance between Maternal Report and Laboratory Observation of Toddler Fear

PubMed Central

Kiel, Elizabeth J.; Hummel, Alexandra C.

2016-01-01

Emotion and temperament researchers have faced an enduring issue of how to best measure children’s tendencies to express specific emotions. Inconsistencies between laboratory observation and parental report have made it challenging for researchers to determine the utility of these different forms of measurement. The current study examined the effect of laboratory episode characteristics (i.e., threat-level of the episode, maternal involvement) on concordance between maternal report and laboratory observation of toddler fear. The sample included 111 mother-toddler dyads who participated in a laboratory assessment when toddlers were approximately 24-months-old. Toddler fear was assessed both via maternal report and observation from a number of laboratory episodes that varied in their level of threat and whether mothers were free or constrained in their involvement in the task. Results indicated that maternal report related to the observed fear composites for low-threat, but not high-threat episodes. On the other hand, maternal involvement in the laboratory episodes did not moderate the relation between maternal report and laboratory observation of fear. These results suggest that the threat-level of laboratory episodes designed to elicit fear, but not maternal involvement in these episodes, may be important to take into consideration when assessing their relation to maternal report of fear and fearful temperament. PMID:27606826

Perspectives on fear generalization and its implications for emotional disorders.

PubMed

Jasnow, Aaron M; Lynch, Joseph F; Gilman, T Lee; Riccio, David C

2017-03-01

Although generalization to conditioned stimuli is not a new phenomenon, renewed interest in understanding its biological underpinning has stemmed from its association with a number of anxiety disorders. Generalization as it relates to fear processing is a temporally dynamic process in which animals, including humans, display fear in response to similar yet distinct cues or contexts as the time between training and testing increases. This Review surveys the literature on contextual fear generalization and its relation to several views of memory, including systems consolidation, forgetting, and transformation hypothesis, which differentially implicate roles of the hippocampus and neocortex in memory consolidation and retrieval. We discuss recent evidence on the neurobiological mechanisms contributing to the increase in fear generalization over time and how generalized responding may be modulated by acquisition, consolidation, and retrieval mechanisms. Whereas clinical perspectives of generalization emphasize a lack of fear inhibition to CS - cues or fear toward intermediate CS cues, the time-dependent nature of generalization and its relation to traditional views on memory consolidation and retrieval are often overlooked. Understanding the time-dependent increase in fear generalization has important implications not only for understanding how generalization contributes to anxiety disorders but also for understanding basic long-term memory function. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Periodical reactivation under the effect of caffeine attenuates fear memory expression in rats.

PubMed

Pedraza, Lizeth K; Sierra, Rodrigo O; Lotz, Fernanda N; Alvares, Lucas de Oliveira

2018-05-08

In the last decade, several studies have shown that fear memories can be attenuated by interfering with reconsolidation. However, most of the pharmacological agents used in preclinical studies cannot be administered to humans. Caffeine is one of the world's most popular psychoactive drugs and its effects on cognitive and mood states are well documented. Nevertheless, the influence of caffeine administration on fear memory processing is not as clear. We employed contextual fear conditioning in rats and acute caffeine administration under a standard memory reconsolidation protocol or periodical memory reactivation. Additionally, potential rewarding/aversion and anxiety effects induced by caffeine were evaluated by conditioning place preference or open field, respectively. Caffeine administration was able to attenuate weak fear memories in a standard memory reconsolidation protocol; however, periodical memory reactivation under caffeine effect was necessary to attenuate strong and remote memories. Moreover, caffeine promoted conditioned place preference and anxiolytic-like behavior, suggesting that caffeine weakens the initial learning during reactivation through counterconditioning mechanisms. Thus, our study shows that rewarding and anxiolytic effects of caffeine during fear reactivation can change the emotional valence of fear memory. It brings a new promising pharmacological approach based on drugs widely used such as caffeine to treat fear-related disorders.

Negative Life Events Vary by Neighborhood and Mediate the Relation Between Neighborhood Context and Psychological Well-Being

EPA Science Inventory

Although a considerable amount of neighborhood research has addressed how fear of negative events may activate stress responses, few studies have noted the potentially embedded nature of negative life events within spatial riskscapes. Co-occurring contextual social and physical h...

ERK/MAPK Regulates Hippocampal Histone Phosphorylation Following Contextual Fear Conditioning

ERIC Educational Resources Information Center

Levenson, Jonathan M.; Sweatt, J. David; Chwang, Wilson B.; O'Riordan, Kenneth J.

2006-01-01

Long-term memory formation is regulated by many distinct molecular mechanisms that control gene expression. An emerging model for effecting a stable, coordinated pattern of gene transcription involves epigenetic tagging through modifications of histones or DNA. In this study, we investigated the regulation of histone phosphorylation in the…

Contextual Fear Conditioning in Zebrafish

ERIC Educational Resources Information Center

Kenney, Justin W.; Scott, Ian C.; Josselyn, Sheena A.; Frankland, Paul W.

2017-01-01

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…

The Exclusive Induction of Extinction Is Gated by BDNF

ERIC Educational Resources Information Center

Kirtley, Anne; Thomas, Kerrie L.

2010-01-01

We have previously reported that the reconsolidation and extinction of hippocampal-dependent contextual fear memory can be initiated by a single context conditioned stimulus (CS) presentation of either short or long duration, and that both processes require protein synthesis in this brain region. Furthermore, reconsolidation depends on Zif268…

Ion mobility-enhanced MS(E)-based label-free analysis reveals effects of low-dose radiation post contextual fear conditioning training on the mouse hippocampal proteome.

PubMed

Huang, Lin; Wickramasekara, Samanthi I; Akinyeke, Tunde; Stewart, Blair S; Jiang, Yuan; Raber, Jacob; Maier, Claudia S

2016-05-17

Recent advances in the field of biodosimetry have shown that the response of biological systems to ionizing radiation is complex and depends on the type and dose of radiation, the tissue(s) exposed, and the time lapsed after exposure. The biological effects of low dose radiation on learning and memory are not well understood. An ion mobility-enhanced data-independent acquisition (MS(E)) approach in conjunction with the ISOQuant software tool was utilized for label-free quantification of hippocampal proteins with the goal of determining protein alteration associated with low-dose whole body ionizing radiation (X-rays, 1Gy) of 5.5-month-old male C57BL/6J mice post contextual fear conditioning training. Global proteome analysis revealed deregulation of 73 proteins (out of 399 proteins). Deregulated proteins indicated adverse effects of irradiation on myelination and perturbation of energy metabolism pathways involving a shift from the TCA cycle to glutamate oxidation. Our findings also indicate that proteins associated with synaptic activity, including vesicle recycling and neurotransmission, were altered in the irradiated mice. The elevated LTP and decreased LTD suggest improved synaptic transmission and enhanced efficiency of neurotransmitter release which would be consistent with the observed comparable contextual fear memory performance of the mice following post-training whole body or sham-irradiation. This study is significant because the biological consequences of low dose radiation on learning and memory are complex and not yet well understood. We conducted a IMS-enhanced MS(E)-based label-free quantitative proteomic analysis of hippocampal tissue with the goal of determining protein alteration associated with low-dose whole body ionizing radiation (X-ray, 1Gy) of 5.5-month-old male C57BL/6J mice post contextual fear conditioning training. The IMS-enhanced MS(E) approach in conjunction with ISOQuant software was robust and accurate with low median CV values of 0.99% for the technical replicates of samples from both the sham and irradiated group. The biological variance was as low as 1.61% for the sham group and 1.31% for the irradiated group. The applied data generation and processing workflow allowed the quantitative evaluation of 399 proteins. The current proteomic analysis indicates that myelination is sensitive to low dose radiation. The observed protein level changes imply modulation of energy metabolism pathways in the radiation exposed group, specifically changes in protein abundance levels suggest a shift from TCA cycle to glutamate oxidation to satisfy energy demands. Most significantly, our study reveals deregulation of proteins involved in processes that govern synaptic activity including enhanced synaptic vesicle cycling, and altered long-term potentiation (LTP) and depression (LTD). An elevated LTP and decreased LTD suggest improved synaptic transmission and enhanced efficiency of neurotransmitter release which is consistent with the observed comparable contextual fear memory performance of the mice following post-training whole body or sham-irradiation. Overall, our results underscore the importance of low dose radiation experiments for illuminating the sensitivity of biochemical pathways to radiation, and the modulation of potential repair and compensatory response mechanisms. This kind of studies and associated findings may ultimately lead to the design of strategies for ameliorating hippocampal and CNS injury following radiation exposure as part of medical therapies or as a consequence of occupational hazards. Copyright © 2016 Elsevier B.V. All rights reserved.

The Type 3 Adenylyl Cyclase is Required for Novel Object Learning and Extinction of Contextual Memory: Role of cAMP Signaling in Primary Cilia

PubMed Central

Wang, Zhenshan; Phan, Trongha; Storm, Daniel R.

2011-01-01

Although primary cilia are found on neurons throughout the brain, their physiological function remains elusive. Human ciliopathies are associated with cognition defects and transgenic mice lacking proteins expressed in primary cilia exhibit defects in learning and memory. Recently, it was reported that mice lacking the G-protein coupling receptor somatostatin receptor-3 (SSTR3), a protein expressed predominately in the primary cilia of neurons, have defective memory for novel object recognition and lower cAMP levels in the brain. Since SSTR3 is coupled to regulation of adenylyl cyclase this suggests that adenylyl cyclase activity in primary cilia of CNS neurons may be critical for some forms of learning and memory. Because the type 3 adenylyl cyclase (AC3) is expressed in primary cilia of hippocampal neurons, we examined AC3−/− mice for several forms of learning and memory. Here, we report that AC3−/− mice show no short-term memory for novel objects and fail to exhibit extinction of contextual fear conditioning. They also show impaired learning and memory for temporally dissociated passive avoidance (TDPA). Since AC3 is exclusively expressed in primary cilia we conclude that cAMP signals generated within primary cilia contribute to some forms of learning and memory including extinction of contextual fear conditioning. PMID:21490195

The type 3 adenylyl cyclase is required for novel object learning and extinction of contextual memory: role of cAMP signaling in primary cilia.

PubMed

Wang, Zhenshan; Phan, Trongha; Storm, Daniel R

2011-04-13

Although primary cilia are found on neurons throughout the brain, their physiological function remains elusive. Human ciliopathies are associated with cognition defects, and transgenic mice lacking proteins expressed in primary cilia exhibit defects in learning and memory. Recently, it was reported that mice lacking the G-protein-coupling receptor somatostatin receptor-3 (SSTR3), a protein expressed predominately in the primary cilia of neurons, have defective memory for novel object recognition and lower cAMP levels in the brain. Since SSTR3 is coupled to regulation of adenylyl cyclase, this suggests that adenylyl cyclase activity in primary cilia of CNS neurons may be critical for some forms of learning and memory. Because the type 3 adenylyl cyclase (AC3) is expressed in primary cilia of hippocampal neurons, we examined AC3(-/-) mice for several forms of learning and memory. Here, we report that AC3(-/-) mice show no short-term memory for novel objects and fail to exhibit extinction of contextual fear conditioning. They also show impaired learning and memory for temporally dissociative passive avoidance. Since AC3 is exclusively expressed in primary cilia, we conclude that cAMP signals generated within primary cilia contribute to some forms of learning and memory, including extinction of contextual fear conditioning.

An Additional Prior Retrieval Alters the Effects of a Retrieval-Extinction Procedure on Recent and Remote Fear Memory

PubMed Central

An, Xianli; Yang, Ping; Chen, Siguang; Zhang, Fenfen; Yu, Duonan

2018-01-01

Several studies have shown that the isolated retrieval of a consolidated fear memory can induce a labile phase, during which extinction training can prevent the reinstatement, a form of relapse in which fear response to a fear-provoking context returns when a mild shock is presented. However, fear memory retrieval may also have another opposing result: the enhancement of fear memory. This implies that the fear memory trace can be modified by a brief retrieval. Unclear is whether the fear-impairing effect of retrieval-extinction (RE) is altered by a prior brief retrieval. The present study investigated the responses of recent and remote fear memories to the RE procedure after the presentation of an additional prior retrieval (priRet). We found that a single RE procedure effectively blocked the reinstatement of 2-day recent contextual fear memory. The memory-impairing effect of the RE procedure on recent fear was not observed when priRet was presented 6 or 24 h before the RE procedure. In contrast to the 2-day recent memory, the RE procedure failed to block the reinstatement of 36-day remote fear memory but successfully disrupted the return of remote fear memory after priRet. This memory-disruptive effect on remote memory did not occur when priRet was performed in a novel context. Nimodipine administration revealed that the blockade of priRet-induced processes recovered the effects of the RE procedure on both recent and remote fear memories. Our findings suggest that the susceptibility of recent and remote fear memories to RE procedures can be altered by an additional retrieval. PMID:29358910

An Additional Prior Retrieval Alters the Effects of a Retrieval-Extinction Procedure on Recent and Remote Fear Memory.

PubMed

An, Xianli; Yang, Ping; Chen, Siguang; Zhang, Fenfen; Yu, Duonan

2017-01-01

Several studies have shown that the isolated retrieval of a consolidated fear memory can induce a labile phase, during which extinction training can prevent the reinstatement, a form of relapse in which fear response to a fear-provoking context returns when a mild shock is presented. However, fear memory retrieval may also have another opposing result: the enhancement of fear memory. This implies that the fear memory trace can be modified by a brief retrieval. Unclear is whether the fear-impairing effect of retrieval-extinction (RE) is altered by a prior brief retrieval. The present study investigated the responses of recent and remote fear memories to the RE procedure after the presentation of an additional prior retrieval (priRet). We found that a single RE procedure effectively blocked the reinstatement of 2-day recent contextual fear memory. The memory-impairing effect of the RE procedure on recent fear was not observed when priRet was presented 6 or 24 h before the RE procedure. In contrast to the 2-day recent memory, the RE procedure failed to block the reinstatement of 36-day remote fear memory but successfully disrupted the return of remote fear memory after priRet. This memory-disruptive effect on remote memory did not occur when priRet was performed in a novel context. Nimodipine administration revealed that the blockade of priRet-induced processes recovered the effects of the RE procedure on both recent and remote fear memories. Our findings suggest that the susceptibility of recent and remote fear memories to RE procedures can be altered by an additional retrieval.

Contextual view of building, with building #12 in right background ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

Contextual view of building, with building #12 in right background and building #11 in right foreground. Camera facing east-southeast - Naval Supply Center, Broadway Complex, Administration Storehouse, 911 West Broadway, San Diego, San Diego County, CA

Two roles of the context in Pavlovian fear conditioning.

PubMed

Urcelay, Gonzalo P; Miller, Ralph R

2010-04-01

At both empirical and theoretical levels, multiple functional roles of contextual information upon memory performance have been proposed without a clear dissociation of these roles. Some theories have assumed that contexts are functionally similar to cues, whereas other views emphasize the retrieval facilitating properties of contextual information. In Experiment 1, we observed that one critical parameter, the spacing of trials, could determine whether the context would function as a conditioned stimulus or as a retrieval cue for memories trained in different phases. Experiments 2 and 3 doubly dissociated these functions by selectively disrupting one role but not the other, and vice versa. Overall, these observations identify one determinant of different functions of contextual information and pose a major challenge to theories of learning that assume exclusively one or the other function of the context. Moreover, these data emphasize the importance of parametric variations on behavioral control, which has critical implications for studies designed to understand the role of the hippocampus in processing of contextual attributes.

A role for anterior thalamic nuclei in affective cognition: interaction with environmental conditions.

PubMed

Dupire, Alexandra; Kant, Patricia; Mons, Nicole; Marchand, Alain R; Coutureau, Etienne; Dalrymple-Alford, John; Wolff, Mathieu

2013-05-01

Damage to anterior thalamic nuclei (ATN) is a well-known cause of diencephalic pathology that produces a range of cognitive deficits reminiscent of a hippocampal syndrome. Anatomical connections of the ATN also extend to cerebral areas that support affective cognition. Enriched environments promote recovery of declarative/relational memory after ATN lesions and are known to downregulate emotional behaviors. Hence, the performance of standard-housed and enriched ATN rats in a range of behavioral tasks engaging affective cognition was compared. ATN rats exhibited reduced anxiety responses in the elevated plus maze, increased activity and reduced corticosterone responses when exploring an open field, and delayed acquisition of a conditioned contextual fear response. ATN rats also exhibited reduced c-Fos and phosphorylated cAMP response element-binding protein (pCREB) immunoreactivity in the hippocampal formation and the amygdala after completion of the contextual fear test. Marked c-Fos hypoactivity and reduced pCREB levels were also evident in the granular retrosplenial cortex and, to a lesser extent, in the anterior cingulate cortex. Unlike standard-housed ATN rats, enriched ATN rats expressed virtually no fear of the conditioned context. These results show that the ATN regulate affective cognition and that damage to this region may produce markedly different behavioral effects as a function of environmental housing conditions. Copyright © 2013 Wiley Periodicals, Inc.

Influence of perceptual cues and conceptual information on the activation and reduction of claustrophobic fear.

PubMed

Shiban, Youssef; Peperkorn, Henrik; Alpers, Georg W; Pauli, Paul; Mühlberger, Andreas

2016-06-01

Fear reactions in phobic patients can be activated by specific perceptual cues (C) or by conceptual fear-related information (I). An earlier study with spider phobic participants documented that perceptual stimuli are particularly potent to trigger fear responses. Because fear of spiders is activated by very circumscribed stimuli, we set out to investigate whether another phobia with more contextual fear-elicitation (i.e., a situational phobia) would yield similar patterns. Thus, we investigate the two paths of fear activation (cues vs. information) and fear reduction during exposure in claustrophobic patients. Forty-eight claustrophobic patients and 48 healthy control participants were randomly assigned to one of three virtual reality exposure conditions: C, I, or a combination of both (CI). Exposure lasted 5 min and was repeated 4 times. Self-report and physiological reactions were assessed. Claustrophobic patients experienced more initial self-reported fear when confronted with fear-relevant perceptual cues than conceptual information, when the perceptual cues were combined with conceptual information there was no significant enhancement. Furthermore, fear habituated more in the perceptual condition. For the physiological parameters, groups differed and in claustrophobic patients heart rate decreased differently in the conditions. Longer exposure duration and long-term effects of the manipulation were not investigated. We found similar patterns in a situational phobia as compared to a specific-cue related phobia (animal type). Thus, once more this highlights the central role of visual cues in phobic fear and the potential of virtual reality for conducting exposure therapy. Copyright © 2015 Elsevier Ltd. All rights reserved.

Fear Extinction Memory Consolidation Requires Potentiation of Pontine-Wave Activity during REM Sleep

PubMed Central

Datta, Subimal; O'Malley, Matthew W .

2013-01-01

Sleep plays an important role in memory consolidation within multiple memory systems including contextual fear extinction memory, but little is known about the mechanisms that underlie this process. Here, we show that fear extinction training in rats, which extinguished conditioned fear, increased both slow-wave sleep and rapid-eye movement (REM) sleep. Surprisingly, 24 h later, during memory testing, only 57% of the fear-extinguished animals retained fear extinction memory. We found that these animals exhibited an increase in phasic pontine-wave (P-wave) activity during post-training REM sleep, which was absent in the 43% of animals that failed to retain fear extinction memory. The results of this study provide evidence that brainstem activation, specifically potentiation of phasic P-wave activity, during post-training REM sleep is critical for consolidation of fear extinction memory. The results of this study also suggest that, contrary to the popular hypothesis of sleep and memory, increased sleep after training alone does not guarantee consolidation and/or retention of fear extinction memory. Rather, the potentiation of specific sleep-dependent physiological events may be a more accurate predictor for successful consolidation of fear extinction memory. Identification of this unique mechanism will significantly improve our present understanding of the cellular and molecular mechanisms that underlie the sleep-dependent regulation of emotional memory. Additionally, this discovery may also initiate development of a new, more targeted treatment method for clinical disorders of fear and anxiety in humans that is more efficacious than existing methods such as exposure therapy that incorporate only fear extinction. PMID:23467372

Contextual view showing H1 on left and H270 in background; ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

Contextual view showing H1 on left and H270 in background; camera facing north. - Mare Island Naval Shipyard, Hospital Headquarters, Johnson Lane, west side at intersection of Johnson Lane & Cossey Street, Vallejo, Solano County, CA

Inception of a false memory by optogenetic manipulation of a hippocampal memory engram.

PubMed

Liu, Xu; Ramirez, Steve; Tonegawa, Susumu

2014-01-05

Memories can be easily distorted, and a lack of relevant animal models has largely hindered our understanding of false-memory formation. Here, we first identified a population of cells in the dentate gyrus (DG) of the hippocampus that bear the engrams for a specific context; these cells were naturally activated during the encoding phase of fear conditioning and their artificial reactivation using optogenetics in an unrelated context was sufficient for inducing the fear memory specific to the conditioned context. In a further study, DG or CA1 neurons activated by exposure to a particular context were labelled with channelrhodopsin-2 (ChR2). These neurons were later optically reactivated during fear conditioning in a different context. The DG experimental group showed increased freezing in the original context in which a foot shock was never delivered. The recall of this false memory was context specific, activated similar downstream regions engaged during natural fear-memory recall, and was also capable of driving an active fear response. Together, our data demonstrate that by substituting a natural conditioned stimulus with optogenetically reactivated DG cells that bear contextual memory engrams, it is possible to incept an internally and behaviourally represented false fear memory.

Inception of a false memory by optogenetic manipulation of a hippocampal memory engram

PubMed Central

Liu, Xu; Ramirez, Steve; Tonegawa, Susumu

2014-01-01

Memories can be easily distorted, and a lack of relevant animal models has largely hindered our understanding of false-memory formation. Here, we first identified a population of cells in the dentate gyrus (DG) of the hippocampus that bear the engrams for a specific context; these cells were naturally activated during the encoding phase of fear conditioning and their artificial reactivation using optogenetics in an unrelated context was sufficient for inducing the fear memory specific to the conditioned context. In a further study, DG or CA1 neurons activated by exposure to a particular context were labelled with channelrhodopsin-2 (ChR2). These neurons were later optically reactivated during fear conditioning in a different context. The DG experimental group showed increased freezing in the original context in which a foot shock was never delivered. The recall of this false memory was context specific, activated similar downstream regions engaged during natural fear-memory recall, and was also capable of driving an active fear response. Together, our data demonstrate that by substituting a natural conditioned stimulus with optogenetically reactivated DG cells that bear contextual memory engrams, it is possible to incept an internally and behaviourally represented false fear memory. PMID:24298144

A microRNA negative feedback loop downregulates vesicle transport and inhibits fear memory

PubMed Central

Mathew, Rebecca S; Tatarakis, Antonis; Rudenko, Andrii; Johnson-Venkatesh, Erin M; Yang, Yawei J; Murphy, Elisabeth A; Todd, Travis P; Schepers, Scott T; Siuti, Nertila; Martorell, Anthony J; Falls, William A; Hammack, Sayamwong E; Walsh, Christopher A; Tsai, Li-Huei; Umemori, Hisashi; Bouton, Mark E; Moazed, Danesh

2016-01-01

The SNARE-mediated vesicular transport pathway plays major roles in synaptic remodeling associated with formation of long-term memories, but the mechanisms that regulate this pathway during memory acquisition are not fully understood. Here we identify miRNAs that are up-regulated in the rodent hippocampus upon contextual fear-conditioning and identify the vesicular transport and synaptogenesis pathways as the major targets of the fear-induced miRNAs. We demonstrate that miR-153, a member of this group, inhibits the expression of key components of the vesicular transport machinery, and down-regulates Glutamate receptor A1 trafficking and neurotransmitter release. MiR-153 expression is specifically induced during LTP induction in hippocampal slices and its knockdown in the hippocampus of adult mice results in enhanced fear memory. Our results suggest that miR-153, and possibly other fear-induced miRNAs, act as components of a negative feedback loop that blocks neuronal hyperactivity at least partly through the inhibition of the vesicular transport pathway. DOI: http://dx.doi.org/10.7554/eLife.22467.001 PMID:28001126

Long-term memory deficits in Pavlovian fear conditioning in Ca2+/calmodulin kinase kinase alpha-deficient mice.

PubMed

Blaeser, Frank; Sanders, Matthew J; Truong, Nga; Ko, Shanelle; Wu, Long Jun; Wozniak, David F; Fanselow, Michael S; Zhuo, Min; Chatila, Talal A

2006-12-01

Signaling by the Ca(2+)/calmodulin kinase (CaMK) cascade has been implicated in neuronal gene transcription, synaptic plasticity, and long-term memory consolidation. The CaM kinase kinase alpha (CaMKKalpha) isoform is an upstream component of the CaMK cascade whose function in different behavioral and learning and memory paradigms was analyzed by targeted gene disruption in mice. CaMKKalpha mutants exhibited normal long-term spatial memory formation and cued fear conditioning but showed deficits in context fear during both conditioning and long-term follow-up testing. They also exhibited impaired activation of the downstream kinase CaMKIV/Gr and its substrate, the transcription factor cyclic AMP-responsive element binding protein (CREB) upon fear conditioning. Unlike CaMKIV/Gr-deficient mice, the CaMKKalpha mutants exhibited normal long-term potentiation and normal levels of anxiety-like behavior. These results demonstrate a selective role for CaMKKalpha in contextual fear memory and suggest that different combinations of upstream and downstream components of the CaMK cascade may serve distinct physiological functions.

Synaptic plasticity associated with a memory engram in the basolateral amygdala.

PubMed

Nonaka, Ayako; Toyoda, Takeshi; Miura, Yuki; Hitora-Imamura, Natsuko; Naka, Masamitsu; Eguchi, Megumi; Yamaguchi, Shun; Ikegaya, Yuji; Matsuki, Norio; Nomura, Hiroshi

2014-07-09

Synaptic plasticity is a cellular mechanism putatively underlying learning and memory. However, it is unclear whether learning induces synaptic modification globally or only in a subset of neurons in associated brain regions. In this study, we genetically identified neurons activated during contextual fear learning and separately recorded synaptic efficacy from recruited and nonrecruited neurons in the mouse basolateral amygdala (BLA). We found that the fear learning induces presynaptic potentiation, which was reflected by an increase in the miniature EPSC frequency and by a decrease in the paired-pulse ratio. Changes occurred only in the cortical synapses targeting the BLA neurons that were recruited into the fear memory trace. Furthermore, we found that fear learning reorganizes the neuronal ensemble responsive to the conditioning context in conjunction with the synaptic plasticity. In particular, the neuronal activity during learning was associated with the neuronal recruitment into the context-responsive ensemble. These findings suggest that synaptic plasticity in a subset of BLA neurons contributes to fear memory expression through ensemble reorganization. Copyright © 2014 the authors 0270-6474/14/349305-05$15.00/0.

Aversive Memory Reactivation Engages in the Amygdala Only Some Neurotransmitters Involved in Consolidation

ERIC Educational Resources Information Center

Bucherelli, Corrado; Baldi, Elisabetta; Mariottini, Chiara; Passani, Maria Beatrice; Blandina, Patrizio

2006-01-01

Consolidation refers to item stabilization in long-term memory. Retrieval renders a consolidated memory sensitive, and a "reconsolidation" process has been hypothesized to keep the original memory persistent. Some authors could not detect this phenomenon. Here we show that retrieved contextual fear memory is vulnerable to amnesic treatments and…

Extinction Partially Reverts Structural Changes Associated with Remote Fear Memory

ERIC Educational Resources Information Center

Vetere, Gisella; Restivo, Leonardo; Novembre, Giovanni; Aceti, Massimiliano; Lumaca, Massimo; Ammassari-Teule, Martine

2011-01-01

Structural synaptic changes occur in medial prefrontal cortex circuits during remote memory formation. Whether extinction reverts or further reshapes these circuits is, however, unknown. Here we show that the number and the size of spines were enhanced in anterior cingulate (aCC) and infralimbic (ILC) cortices 36 d following contextual fear…

Repeatedly Reactivated Memories Become More Resistant to Hippocampal Damage

ERIC Educational Resources Information Center

Lehmann, Hugo; McNamara, Kathryn C.

2011-01-01

We examined whether repeated reactivations of a context memory would prevent the typical amnesic effects of post-training damage to the hippocampus (HPC). Rats were given a single contextual fear-conditioning session followed by 10 reactivations, involving a brief return to the conditioning context (no shock). Subsequently, the rats received sham…

Emotional Representation in Facial Expression and Script: A Comparison between Normal and Autistic Children

ERIC Educational Resources Information Center

Balconi, Michela; Carrera, Alba

2007-01-01

The paper explored conceptual and lexical skills with regard to emotional correlates of facial stimuli and scripts. In two different experimental phases normal and autistic children observed six facial expressions of emotions (happiness, anger, fear, sadness, surprise, and disgust) and six emotional scripts (contextualized facial expressions). In…

Context Memory Formation Requires Activity-Dependent Protein Degradation in the Hippocampus

ERIC Educational Resources Information Center

Cullen, Patrick K.; Ferrara, Nicole C.; Pullins, Shane E.; Helmstetter, Fred J.

2017-01-01

Numerous studies have indicated that the consolidation of contextual fear memories supported by an aversive outcome like footshock requires de novo protein synthesis as well as protein degradation mediated by the ubiquitin-proteasome system (UPS). Context memory formed in the absence of an aversive stimulus by simple exposure to a novel…

Genetic disruption of the core circadian clock impairs hippocampus-dependent memory.

PubMed

Wardlaw, Sarah M; Phan, Trongha X; Saraf, Amit; Chen, Xuanmao; Storm, Daniel R

2014-08-01

Perturbing the circadian system by electrolytically lesioning the suprachiasmatic nucleus (SCN) or varying the environmental light:dark schedule impairs memory, suggesting that memory depends on the circadian system. We used a genetic approach to evaluate the role of the molecular clock in memory. Bmal1-/- mice, which are arrhythmic under constant conditions, were examined for hippocampus-dependent memory, LTP at the Schaffer-collateral synapse, and signal transduction activity in the hippocampus. Bmal1-/- mice exhibit impaired contextual fear and spatial memory. Furthermore, LTP in hippocampal slices from Bmal1-/- mice is also significantly decreased relative to that from wild-type mice. Activation of Erk1,2 MAP kinase (MAPK) during training for contextual fear memory and diurnal oscillation of MAPK activity and cAMP in the hippocampus is also lost in Bmal1-/- mice, suggesting that the memory defects are due to reduction of the memory consolidation pathway in the hippocampus. We conclude that critical signaling events in the hippocampus required for memory depend on BMAL1. © 2014 Wardlaw et al.; Published by Cold Spring Harbor Laboratory Press.

Improvement of memory recall by quercetin in rodent contextual fear conditioning and human early-stage Alzheimer's disease patients.

PubMed

Nakagawa, Toshiyuki; Itoh, Masanori; Ohta, Kazunori; Hayashi, Yuichi; Hayakawa, Miki; Yamada, Yasushi; Akanabe, Hiroshi; Chikaishi, Tokio; Nakagawa, Kiyomi; Itoh, Yoshinori; Muro, Takato; Yanagida, Daisuke; Nakabayashi, Ryo; Mori, Tetsuya; Saito, Kazuki; Ohzawa, Kaori; Suzuki, Chihiro; Li, Shimo; Ueda, Masashi; Wang, Miao-Xing; Nishida, Emika; Islam, Saiful; Tana; Kobori, Masuko; Inuzuka, Takashi

2016-06-15

Patients with Alzheimer's disease (AD) experience a wide array of cognitive deficits, which typically include the impairment of explicit memory. In previous studies, the authors reported that a flavonoid, quercetin, reduces the expression of ATF4 and delays memory deterioration in an early-stage AD mouse model. In the present study, the effects of long-term quercetin intake on memory recall were assessed using contextual fear conditioning in aged wild-type mice. In addition, the present study examined whether memory recall was affected by the intake of quercetin-rich onion (a new cultivar of hybrid onion 'Quergold') powder in early-stage AD patients. In-vivo analysis indicated that memory recall was enhanced in aged mice fed a quercetin-containing diet. Memory recall in early-stage AD patients, determined using the Revised Hasegawa Dementia Scale, was significantly improved by the intake of quercetin-rich onion (Quergold) powder for 4 weeks compared with the intake of control onion ('Mashiro' white onion) powder. These results indicate that quercetin might influence memory recall.

A single footshock causes long-lasting hypoactivity in unknown environments that is dependent on the development of contextual fear conditioning.

PubMed

Daviu, Núria; Fuentes, Silvia; Nadal, Roser; Armario, Antonio

2010-09-01

Exposure to a single session of footshocks induces long-lasting inhibition of activity in unknown environments that markedly differ from the shock context. Interestingly, these effects are not necessarily associated to an enhanced anxiety and interpretation of this hypoactivity remains unclear. In the present experiment we further studied this phenomenon in male Sprague-Dawley rats. In a first experiment, a session of three shocks resulted in hypoactivity during exposure, 6-12days later, to three different unknown environments. This altered behaviour was not accompanied by a greater hypothalamic-pituitary-adrenal (HPA) activation, although greater HPA activation paralleling higher levels of freezing was observed in the shock context. In a second experiment we used a single shock and two procedures, one with pre-exposure to the context before the shock and another with immediate shock that did not induce contextual fear conditioning. Hypoactivity and a certain level of generalization of fear (freezing) to the unknown environments only appeared in the group that developed fear conditioning, but no evidence for enhanced anxiety in the elevated plus-maze was found in any group. The results suggest that if animals are able to associate an aversive experience with a distinct unknown environment, they would display more cautious behaviour in any unknown environment and such strategy persists despite repeated experience with different environments. This long-lasting cautious behaviour was not associated to greater HPA response to the unknown environment that was however observed in the shock context. The present findings raised some concerns about interpretation of long-lasting behavioural changes caused by brief stressors. Copyright 2010 Elsevier Inc. All rights reserved.

Neural circuits involved in the renewal of extinguished fear.

PubMed

Chen, Weihai; Wang, Yan; Wang, Xiaqing; Li, Hong

2017-07-01

The last 10 years have witnessed a substantial progress in understanding the neural mechanisms for the renewal of the extinguished fear memory. Based on the theory of fear extinction, exposure therapy has been developed as a typical cognitive behavioral therapy for posttraumatic stress disorder. Although the fear memory can be extinguished by repeated presentation of conditioned stimulus without unconditioned stimulus, the fear memory is not erased and tends to relapse outside of extinction context, which is referred to as renewal. Therefore, the renewal is regarded as a great obstruction interfering with the effect of exposure therapy. In recent years, there has been a great deal of studies in understanding the neurobiological underpinnings of fear renewal. These offer a foundation upon which novel therapeutic interventions for the renewal may be built. This review focuses on behavioral, anatomical and electrophysiological studies that interpret roles of the hippocampus, prelimbic cortex and amygdala as well as the connections between them for the renewal of the extinguished fear. Additionally, this review suggests the possible pathways for the renewal: (1) the prelimbic cortex may integrate contextual information from hippocampal inputs and project to the basolateral amygdala to mediate the renewal of extinguished fear memory; the ventral hippocampus may innervate the activities of the basolateral amygdala or the central amygdala directly for the renewal. © 2017 IUBMB Life, 69(7):470-478, 2017. © 2017 International Union of Biochemistry and Molecular Biology.

Modulation of cannabinoid signaling by hippocampal 5-HT4 serotonergic system in fear conditioning.

PubMed

Nasehi, Mohammad; Farrahizadeh, Maryam; Ebrahimi-Ghiri, Mohaddeseh; Zarrindast, Mohammad-Reza

2016-09-01

Behavioral studies have suggested a key role for the cannabinoid system in the modulation of conditioned fear memory. Likewise, much of the literature has revealed that the serotonergic system affects Pavlovian fear conditioning and extinction. A high level of functional overlap between the serotonin and cannabinoid systems has also been reported. To clarify the interaction between the hippocampal serotonin (5-HT4) receptor and the cannabinoid CB1 receptor in the acquisition of fear memory, the effects of 5-HT4 agents, arachidonylcyclopropylamide (ACPA; CB1 receptor agonist), and the combined use of these drugs on fear learning were studied in a fear conditioning task in adult male NMRI mice. Pre-training intraperitoneal administration of ACPA (0.1 mg/kg) decreased the percentage of freezing time in both context- and tone-dependent fear conditions, suggesting impairment of the acquisition of fear memory. Pre-training, intra-hippocampal (CA1) microinjection of RS67333, a 5-HT4 receptor agonist, at doses of 0.1 and 0.2 or 0.2 µg/mouse impaired contextual and tone fear memory, respectively. A subthreshold dose of RS67333 (0.005 µg/mouse) did not alter the ACPA response in either condition. Moreover, intra-CA1 microinjection of RS23597 as a 5-HT4 receptor antagonist did not alter context-dependent fear memory acquisition, but it did impair tone-dependent fear memory acquisition. However, a subthreshold dose of the RS23597 (0.01 µg/mouse) potentiated ACPA-induced fear memory impairment in both conditions. Therefore, we suggest that the blockade of hippocampal 5-HT4 serotonergic system modulates cannabinoid signaling induced by the activation of CB1 receptors in conditioned fear. © The Author(s) 2016.

HDAC7 Ubiquitination by the E3 Ligase CBX4 Is Involved in Contextual Fear Conditioning Memory Formation.

PubMed

Jing, Xu; Sui, Wen-Hai; Wang, Shuai; Xu, Xu-Feng; Yuan, Rong-Rong; Chen, Xiao-Rong; Ma, Hui-Xian; Zhu, Ying-Xiao; Sun, Jin-Kai; Yi, Fan; Chen, Zhe-Yu; Wang, Yue

2017-04-05

Histone acetylation, an epigenetic modification, plays an important role in long-term memory formation. Recently, histone deacetylase (HDAC) inhibitors were demonstrated to promote memory formation, which raises the intriguing possibility that they may be used to rescue memory deficits. However, additional research is necessary to clarify the roles of individual HDACs in memory. In this study, we demonstrated that HDAC7, within the dorsal hippocampus of C57BL6J mice, had a late and persistent decrease after contextual fear conditioning (CFC) training (4-24 h), which was involved in long-term CFC memory formation. We also showed that HDAC7 decreased via ubiquitin-dependent degradation. CBX4 was one of the HDAC7 E3 ligases involved in this process. Nur77, as one of the target genes of HDAC7, increased 6-24 h after CFC training and, accordingly, modulated the formation of CFC memory. Finally, HDAC7 was involved in the formation of other hippocampal-dependent memories, including the Morris water maze and object location test. The current findings facilitate an understanding of the molecular and cellular mechanisms of HDAC7 in the regulation of hippocampal-dependent memory. SIGNIFICANCE STATEMENT The current findings demonstrated the effects of histone deacetylase 7 (HDAC7) on hippocampal-dependent memories. Moreover, we determined the mechanism of decreased HDAC7 in contextual fear conditioning (CFC) through ubiquitin-dependent protein degradation. We also verified that CBX4 was one of the HDAC7 E3 ligases. Finally, we demonstrated that Nur77, as one of the important targets for HDAC7, was involved in CFC memory formation. All of these proteins, including HDAC7, CBX4, and Nur77, could be potential therapeutic targets for preventing memory deficits in aging and neurological diseases. Copyright © 2017 the authors 0270-6474/17/373848-16$15.00/0.

SAD-B kinase regulates pre-synaptic vesicular dynamics at hippocampal Schaffer collateral synapses and affects contextual fear memory.

PubMed

Watabe, Ayako M; Nagase, Masashi; Hagiwara, Akari; Hida, Yamato; Tsuji, Megumi; Ochiai, Toshitaka; Kato, Fusao; Ohtsuka, Toshihisa

2016-01-01

Synapses of amphids defective (SAD)-A/B kinases control various steps in neuronal development and differentiation, such as axon specifications and maturation in central and peripheral nervous systems. At mature pre-synaptic terminals, SAD-B is associated with synaptic vesicles and the active zone cytomatrix; however, how SAD-B regulates neurotransmission and synaptic plasticity in vivo remains unclear. Thus, we used SAD-B knockout (KO) mice to study the function of this pre-synaptic kinase in the brain. We found that the paired-pulse ratio was significantly enhanced at Shaffer collateral synapses in the hippocampal CA1 region in SAD-B KO mice compared with wild-type littermates. We also found that the frequency of the miniature excitatory post-synaptic current was decreased in SAD-B KO mice. Moreover, synaptic depression following prolonged low-frequency synaptic stimulation was significantly enhanced in SAD-B KO mice. These results suggest that SAD-B kinase regulates vesicular release probability at pre-synaptic terminals and is involved in vesicular trafficking and/or regulation of the readily releasable pool size. Finally, we found that hippocampus-dependent contextual fear learning was significantly impaired in SAD-B KO mice. These observations suggest that SAD-B kinase plays pivotal roles in controlling vesicular release properties and regulating hippocampal function in the mature brain. Synapses of amphids defective (SAD)-A/B kinases control various steps in neuronal development and differentiation, but their roles in mature brains were only partially known. Here, we demonstrated, at mature pre-synaptic terminals, that SAD-B regulates vesicular release probability and synaptic plasticity. Moreover, hippocampus-dependent contextual fear learning was significantly impaired in SAD-B KO mice, suggesting that SAD-B kinase plays pivotal roles in controlling vesicular release properties and regulating hippocampal function in the mature brain. © 2015 International Society for Neurochemistry.

Galectin-3 Negatively Regulates Hippocampus-Dependent Memory Formation through Inhibition of Integrin Signaling and Galectin-3 Phosphorylation

PubMed Central

Chen, Yan-Chu; Ma, Yun-Li; Lin, Cheng-Hsiung; Cheng, Sin-Jhong; Hsu, Wei-Lun; Lee, Eminy H.-Y.

2017-01-01

Galectin-3, a member of the galectin protein family, has been found to regulate cell proliferation, inhibit apoptosis and promote inflammatory responses. Galectin-3 is also expressed in the adult rat hippocampus, but its role in learning and memory function is not known. Here, we found that contextual fear-conditioning training, spatial training or injection of NMDA into the rat CA1 area each dramatically decreased the level of endogenous galectin-3 expression. Overexpression of galectin-3 impaired fear memory, whereas galectin-3 knockout (KO) enhanced fear retention, spatial memory and hippocampal long-term potentiation. Galectin-3 was further found to associate with integrin α3, an association that was decreased after fear-conditioning training. Transfection of the rat CA1 area with small interfering RNA against galectin-3 facilitated fear memory and increased phosphorylated focal adhesion kinase (FAK) levels, effects that were blocked by co-transfection of the FAK phosphorylation-defective mutant Flag-FAKY397F. Notably, levels of serine-phosphorylated galectin-3 were decreased by fear conditioning training. In addition, blockade of galectin-3 phosphorylation at Ser-6 facilitated fear memory, whereas constitutive activation of galectin-3 at Ser-6 impaired fear memory. Interestingly galectin-1 plays a role in fear-memory formation similar to that of galectin-3. Collectively, our data provide the first demonstration that galectin-3 is a novel negative regulator of memory formation that exerts its effects through both extracellular and intracellular mechanisms. PMID:28744198

Pharmacological modulation of metabotropic glutamate receptor subtype 5 and 7 impairs extinction of social fear in a time-point-dependent manner.

PubMed

Slattery, David A; Neumann, Inga D; Flor, Peter J; Zoicas, Iulia

2017-06-15

Pharmacological modulation of metabotropic glutamate receptor subtype 5 (mGluR5) and 7 (mGluR7) was shown to attenuate the acquisition and to facilitate the extinction of cued and contextual, non-social, fear. Using the allosteric mGluR5 antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP) and the allosteric mGluR7 agonist N,N'-dibenzyhydryl-ethane-1,2-diamine dihydrochloride (AMN082), we aimed to study how pharmacological blockade of mGluR5 and activation of mGluR7 influence acquisition and extinction of social fear in mice. We could show that when administered before social fear conditioning, neither MPEP nor AMN082 affected acquisition and extinction of social fear, suggesting that mGluR5 inactivation and mGluR7 activation do not alter social fear. However, when administered before social fear extinction, both MPEP and AMN082 impaired social fear extinction and extinction recall. These findings suggest that mGluR5 inactivation and mGluR7 activation are unlikely to prevent the formation of traumatic social memories. Furthermore, medication strategies aimed at augmenting exposure-based therapies for psychiatric disorders associated with social deficits via modulation of mGluR5 and mGluR7 must be pursued cautiously because of their potential to delay social fear extinction processes. Copyright © 2017 Elsevier B.V. All rights reserved.

Postreactivation glucocorticoids impair recall of established fear memory.

PubMed

Cai, Wen-Hui; Blundell, Jacqueline; Han, Jie; Greene, Robert W; Powell, Craig M

2006-09-13

Pavlovian fear conditioning provides one of the best rodent models of acquired anxiety disorders, including posttraumatic stress disorder. Injection of a variety of drugs after training in fear-conditioning paradigms can impair consolidation of fear memories. Indeed, early clinical trials suggest that immediate administration of such drugs after a traumatic event may decrease the risk of developing posttraumatic stress disorder in humans (Pitman et al., 2002; Vaiva et al., 2003). The use of such a treatment is limited by the difficulty of treating every patient at risk and by the difficulty in predicting which patients will experience chronic adverse consequences. Recent clinical trials suggest that administration of glucocorticoids may have a beneficial effect on established posttraumatic stress disorder (Aerni et al., 2004) and specific phobia (Soravia et al., 2006). Conversely, glucocorticoid administration after training is known to enhance memory consolidation (McGaugh and Roozendaal, 2002; Roozendaal, 2002). From a clinical perspective, enhancement of a fear memory or a reactivated fear memory would not be desirable. We report here that when glucocorticoids are administered immediately after reactivation of a contextual fear memory, subsequent recall is significantly diminished. Additional experiments support the interpretation that glucocorticoids not only decrease fear memory retrieval but, in addition, augment consolidation of fear memory extinction rather than decreasing reconsolidation. These findings provide a rodent model for a potential treatment of established acquired anxiety disorders in humans, as suggested by others (Aerni et al., 2004; Schelling et al., 2004), based on a mechanism of enhanced extinction.

Temporal and Region-Specific Requirements of αCaMKII in Spatial and Contextual Learning

PubMed Central

Achterberg, Katharina G.; Buitendijk, Gabriëlle H.S.; Kool, Martijn J.; Goorden, Susanna M.I.; Post, Laura; Slump, Denise E.; Silva, Alcino J.; van Woerden, Geeske M.

2014-01-01

The α isoform of the calcium/calmodulin-dependent protein kinase II (αCaMKII) has been implicated extensively in molecular and cellular mechanisms underlying spatial and contextual learning in a wide variety of species. Germline deletion of Camk2a leads to severe deficits in spatial and contextual learning in mice. However, the temporal and region-specific requirements for αCaMKII have remained largely unexplored. Here, we generated conditional Camk2a mutants to examine the influence of spatially restricted and temporally controlled expression of αCaMKII. Forebrain-specific deletion of the Camk2a gene resulted in severe deficits in water maze and contextual fear learning, whereas mice with deletion restricted to the cerebellum learned normally. Furthermore, we found that temporally controlled deletion of the Camk2a gene in adult mice is as detrimental as germline deletion for learning and synaptic plasticity. Together, we confirm the requirement for αCaMKII in the forebrain, but not the cerebellum, in spatial and contextual learning. Moreover, we highlight the absolute requirement for intact αCaMKII expression at the time of learning. PMID:25143599

Behavioural memory reconsolidation of food and fear memories

PubMed Central

Flavell, Charlotte R.; Barber, David J.; Lee, Jonathan L. C.

2012-01-01

The reactivation of a memory through retrieval can render it subject to disruption or modification through the process of memory reconsolidation. In both humans and rodents, briefly reactivating a fear memory results in effective erasure by subsequent extinction training. Here we show that a similar strategy is equally effective in the disruption of appetitive pavlovian cue–food memories. However, systemic administration of the NMDA receptor partial agonist D-cycloserine under the same behavioural conditions did not potentiate appetitive memory extinction, suggesting that reactivation does not enhance subsequent extinction learning. To confirm that reactivation followed by extinction reflects a behavioural analog of memory reconsolidation, we show that prevention of contextual fear memory reactivation by the LVGCC blocker nimodipine interferes with the amnestic outcome. Therefore, the reconsolidation process can be manipulated behaviourally to disrupt both aversive and appetitive memories. PMID:22009036

Contextual behavior and neural circuits

PubMed Central

Lee, Inah; Lee, Choong-Hee

2013-01-01

Animals including humans engage in goal-directed behavior flexibly in response to items and their background, which is called contextual behavior in this review. Although the concept of context has long been studied, there are differences among researchers in defining and experimenting with the concept. The current review aims to provide a categorical framework within which not only the neural mechanisms of contextual information processing but also the contextual behavior can be studied in more concrete ways. For this purpose, we categorize contextual behavior into three subcategories as follows by considering the types of interactions among context, item, and response: contextual response selection, contextual item selection, and contextual item–response selection. Contextual response selection refers to the animal emitting different types of responses to the same item depending on the context in the background. Contextual item selection occurs when there are multiple items that need to be chosen in a contextual manner. Finally, when multiple items and multiple contexts are involved, contextual item–response selection takes place whereby the animal either chooses an item or inhibits such a response depending on item–context paired association. The literature suggests that the rhinal cortical regions and the hippocampal formation play key roles in mnemonically categorizing and recognizing contextual representations and the associated items. In addition, it appears that the fronto-striatal cortical loops in connection with the contextual information-processing areas critically control the flexible deployment of adaptive action sets and motor responses for maximizing goals. We suggest that contextual information processing should be investigated in experimental settings where contextual stimuli and resulting behaviors are clearly defined and measurable, considering the dynamic top-down and bottom-up interactions among the neural systems for contextual behavior. PMID:23675321

The transfer of Cfunc contextual control through equivalence relations.

PubMed

Perez, William F; Fidalgo, Adriana P; Kovac, Roberta; Nico, Yara C

2015-05-01

Derived relational responding is affected by contextual stimuli (Cfunc) that select specific stimulus functions. The present study investigated the transfer of Cfunc contextual control through equivalence relations by evaluating both (a) the maintenance of Cfunc contextual control after the expansion of a relational network, and (b) the establishment of novel contextual stimuli by the transfer of Cfunc contextual control through equivalence relations. Initially, equivalence relations were established and contingencies were arranged so that colors functioned as Cfunc stimuli controlling participants' key-pressing responses in the presence of any stimulus from a three-member equivalence network. To investigate the first research question, the three-member equivalence relations were expanded to five members and the novel members were presented with the Cfunc stimuli in the key-pressing task. To address the second goal of this study, the colors (Cfunc) were established as equivalent to certain line patterns. The transfer of contextual cue function (Cfunc) was tested replacing the colored backgrounds with line patterns in the key-pressing task. Results suggest that the Cfunc contextual control was transferred to novel stimuli that were added to the relational network. In addition, the line patterns indirectly acquired the contextual cue function (Cfunc) initially established for the colored backgrounds. The conceptual and applied implications of Cfunc contextual control are discussed. © Society for the Experimental Analysis of Behavior.

A shared neural ensemble links distinct contextual memories encoded close in time

NASA Astrophysics Data System (ADS)

Cai, Denise J.; Aharoni, Daniel; Shuman, Tristan; Shobe, Justin; Biane, Jeremy; Song, Weilin; Wei, Brandon; Veshkini, Michael; La-Vu, Mimi; Lou, Jerry; Flores, Sergio E.; Kim, Isaac; Sano, Yoshitake; Zhou, Miou; Baumgaertel, Karsten; Lavi, Ayal; Kamata, Masakazu; Tuszynski, Mark; Mayford, Mark; Golshani, Peyman; Silva, Alcino J.

2016-06-01

Recent studies suggest that a shared neural ensemble may link distinct memories encoded close in time. According to the memory allocation hypothesis, learning triggers a temporary increase in neuronal excitability that biases the representation of a subsequent memory to the neuronal ensemble encoding the first memory, such that recall of one memory increases the likelihood of recalling the other memory. Here we show in mice that the overlap between the hippocampal CA1 ensembles activated by two distinct contexts acquired within a day is higher than when they are separated by a week. Several findings indicate that this overlap of neuronal ensembles links two contextual memories. First, fear paired with one context is transferred to a neutral context when the two contexts are acquired within a day but not across a week. Second, the first memory strengthens the second memory within a day but not across a week. Older mice, known to have lower CA1 excitability, do not show the overlap between ensembles, the transfer of fear between contexts, or the strengthening of the second memory. Finally, in aged mice, increasing cellular excitability and activating a common ensemble of CA1 neurons during two distinct context exposures rescued the deficit in linking memories. Taken together, these findings demonstrate that contextual memories encoded close in time are linked by directing storage into overlapping ensembles. Alteration of these processes by ageing could affect the temporal structure of memories, thus impairing efficient recall of related information.

Reduced Contextual Discrimination following Alcohol Consumption or MDMA Administration in Mice.

PubMed

Johansson, Emily M; García-Gutiérrez, María S; Moscoso-Castro, María; Manzanares, Jorge; Valverde, Olga

2015-01-01

The recreational drugs, alcohol and 3,4-Methylenedioxymethamphetamine (MDMA, "Ecstasy") have both been shown to cause immune activation in vivo, and they are linked to cognitive impairment and anxiety-like behaviors in rodents. The neuronal effects of these drugs in the hippocampal area, an area that has been a focus of studies aiming to explain the mechanisms underlying anxiety related-disorders, remains poorly understood. Therefore we investigated the specific inflammatory impact of alcohol and MDMA on this area of the brain and on a hippocampal-related behavioral task. We centered our study on two inflammatory factors linked to anxiety-related disorders, namely Interleukin-1β (IL-1β) and brain-derived neurotrophic factor (BDNF). We subjected drug-consuming mice to a battery of behavioral tests to evaluate general activity, anxiety-like and depressive-live behaviors. We then introduced them to a contextual fear discrimination task and immune-related effects were examined by immunohistochemical and biochemical studies. Our results suggest that there is a relationship between the induction of immune activated pathways by voluntary alcohol consumption and a high-dose MDMA. Furthermore, the ability of mice to perform a contextual fear discrimination task was impaired by drug consumption and we report long term inflammatory alterations in the hippocampus even several weeks after drug intake. This information will be helpful for discovering new selective drug targets, and to develop treatments and preventive approaches for patients with anxiety-related disorders.

Reduced Contextual Discrimination following Alcohol Consumption or MDMA Administration in Mice

PubMed Central

Johansson, Emily M.; García-Gutiérrez, María S.; Moscoso-Castro, María; Manzanares, Jorge; Valverde, Olga

2015-01-01

The recreational drugs, alcohol and 3,4-Methylenedioxymethamphetamine (MDMA, “Ecstasy”) have both been shown to cause immune activation in vivo, and they are linked to cognitive impairment and anxiety-like behaviors in rodents. The neuronal effects of these drugs in the hippocampal area, an area that has been a focus of studies aiming to explain the mechanisms underlying anxiety related-disorders, remains poorly understood. Therefore we investigated the specific inflammatory impact of alcohol and MDMA on this area of the brain and on a hippocampal-related behavioral task. We centered our study on two inflammatory factors linked to anxiety-related disorders, namely Interleukin-1β (IL-1β) and brain-derived neurotrophic factor (BDNF). We subjected drug-consuming mice to a battery of behavioral tests to evaluate general activity, anxiety-like and depressive-live behaviors. We then introduced them to a contextual fear discrimination task and immune-related effects were examined by immunohistochemical and biochemical studies. Our results suggest that there is a relationship between the induction of immune activated pathways by voluntary alcohol consumption and a high-dose MDMA. Furthermore, the ability of mice to perform a contextual fear discrimination task was impaired by drug consumption and we report long term inflammatory alterations in the hippocampus even several weeks after drug intake. This information will be helpful for discovering new selective drug targets, and to develop treatments and preventive approaches for patients with anxiety-related disorders. PMID:26566284

Early-life inflammation with LPS delays fear extinction in adult rodents.

PubMed

Doenni, V M; Song, C M; Hill, M N; Pittman, Q J

2017-07-01

A large body of evidence has been brought forward connecting developmental immune activation to abnormal fear and anxiety levels. Anxiety disorders have extremely high lifetime prevalence, yet susceptibility factors that contribute to their emergence are poorly understood. In this research we investigated whether an inflammatory insult early in life can alter the response to fear conditioning in adulthood. Fear learning and extinction are important and adaptive behaviors, mediated largely by the amygdala and its interconnectivity with cortico-limbic circuits. Male and female rat pups were given LPS (100μg/kg i.p.) or saline at postnatal day 14; LPS activated cFos expression in the central amygdala 2.5h after exposure, but not the basal or lateral nuclei. When tested in adulthood, acquisition of an auditory cued or contextual learned fear memory was largely unaffected as was the extinction of fear to a conditioned context. However, we detected a deficit in auditory fear extinction in male and female rats that experienced early-life inflammation, such that there is a significant delay in fear extinction processes resulting in more sustained fear behaviors in response to a conditioned cue. This response was specific to extinction training and did not persist into extinction recall. The effect could not be explained by differences in pain threshold (unaltered) or in baseline anxiety, which was elevated in adolescent females only and unaltered in adolescent males and adult males and females. This research provides further evidence for the involvement of the immune system during development in the shaping of fear and anxiety related behaviors. Copyright © 2016 Elsevier Inc. All rights reserved.

Hippocampal Overexpression of Mutant CREB Blocks Long-Term, but Not Short-Term Memory for a Socially Transmitted Food Preference

ERIC Educational Resources Information Center

Brightwell, Jennifer J.; Countryman, Renee A.; Neve, Rachael L.; Colombo, Paul J.; Smith, Clayton A.

2005-01-01

Phosphorylation of the transcription factor CREB on Ser133 is implicated in the establishment of long-term memory for hippocampus-dependent tasks, including spatial learning and contextual fear conditioning. We reported previously that training on a hippocampus-dependent social transmission of food preference (STFP) task increases CREB…

Ontogeny of Contextual Fear Memory Formation, Specificity, and Persistence in Mice

ERIC Educational Resources Information Center

Akers, Katherine G.; Arruda-Carvalho, Maithe; Josselyn, Sheena A.; Frankland, Paul W.

2012-01-01

Pinpointing the precise age when young animals begin to form memories of aversive events is valuable for understanding the onset of anxiety and mood disorders and for detecting early cognitive impairment in models of childhood-onset disorders. Although these disorders are most commonly modeled in mice, we know little regarding the development of…

Memory Deficits Are Associated with Impaired Ability to Modulate Neuronal Excitability in Middle-Aged Mice

ERIC Educational Resources Information Center

Kaczorowski, Catherine C.; Disterhoft, John F.

2009-01-01

Normal aging disrupts hippocampal neuroplasticity and learning and memory. Aging deficits were exposed in a subset (30%) of middle-aged mice that performed below criterion on a hippocampal-dependent contextual fear conditioning task. Basal neuronal excitability was comparable in middle-aged and young mice, but learning-related modulation of the…

Retrosplenial Cortex Is Required for the Retrieval of Remote Memory for Auditory Cues

ERIC Educational Resources Information Center

Todd, Travis P.; Mehlman, Max L.; Keene, Christopher S.; DeAngeli, Nicole E.; Bucci, David J.

2016-01-01

The retrosplenial cortex (RSC) has a well-established role in contextual and spatial learning and memory, consistent with its known connectivity with visuo-spatial association areas. In contrast, RSC appears to have little involvement with delay fear conditioning to an auditory cue. However, all previous studies have examined the contribution of…

Changes in Context-Specificity during Memory Reconsolidation: Selective Effects of Hippocampal Lesions

ERIC Educational Resources Information Center

Winocur, Gordon; Frankland, Paul W.; Sekeres, Melanie; Fogel, Stuart; Moscovitch, Morris

2009-01-01

After acquisition, memories associated with contextual fear conditioning pass through a labile phase, in which they are vulnerable to hippocampal lesions, to a more stable state, via consolidation, in which they engage extrahippocampal structures and are resistant to such disruption. The process is accompanied by changes in the form of the memory…

NMDA receptor blockade and hippocampal neuronal loss impair fear conditioning and position habit reversal in C57Bl/6 mice.

PubMed

Bardgett, Mark E; Boeckman, Ryan; Krochmal, Daniel; Fernando, Hiran; Ahrens, Rebecca; Csernansky, John G

2003-04-15

The interpretation of learning and memory deficits in transgenic mice has largely involved theories of NMDA receptor and/or hippocampal function. However, there is little empirical data that describes what NMDA receptors or the hippocampus do in mice. This research assessed the effects of different doses of the NMDA receptor antagonist, MK-801, or different-sized hippocampal lesions on several behavioral parameters in adult male C57Bl/6 mice. In the first set of experiments, different doses of MK-801 (0.05-0.3mg/kg, s.c.) were assayed in fear conditioning, shock sensitivity, locomotion, anxiety, and position habit reversal tests. Contextual and cued fear conditioning, and position habit reversal were impaired in a dose-dependent manner. Locomotor activity was increased immediately after injection of the highest dose of MK-801. A second set of experiments determined the behavioral effects of a moderate and large excitotoxic hippocampal lesion. Both lesions impaired contextual conditioning, while the larger lesion interfered with cued conditioning. Reversal learning was significantly diminished by the large lesion, while the moderate lesion had a detrimental effect at a trend level (P<0.10). These results provide important reference data for studies involving genetic manipulations of NMDA receptor or hippocampal function in mice. Furthermore, they serve as a basis for a non-transgenic mouse model of the NMDA receptor or hippocampal dysfunction hypothesized to occur in human cognitive disorders.

Dentate Gyrus Contributes to Retrieval as well as Encoding: Evidence from Context Fear Conditioning, Recall, and Extinction

PubMed Central

Krasne, Franklin B.

2017-01-01

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 long-standing question about the role of DG in memory and provide insight into how disorders affecting DG, including aging, stress, and depression, influence cognitive processes. PMID:28546308

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

PubMed

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

2014-09-01

Exposure therapy is widely used to treat anxiety disorders, including posttraumatic stress disorder (PTSD). However, preventing the return of fear is still a major challenge after this behavioral treatment. An increasing number of studies suggest that high-dose glucocorticoid treatment immediately after trauma can alleviate the symptoms of PTSD in humans. Unknown is whether high-dose glucocorticoid treatment following fear conditioning suppresses the return of fear. In the present study, a typical fear renewal paradigm (AAB) was used, in which the fear response to an auditory cue can be restored in a novel context (context B) when both training and extinction occur in the same context (context A). We trained rats for auditory fear conditioning and administered corticosterone (CORT; 5 and 25mg/kg, i.p.) or vehicle with different delays (1 and 24h). Forty-eight hours after drug injection, extinction was conducted with no drug in the training context, followed by a test of tone-induced freezing behavior in the same (AAA) or a shifted (AAB) context. Both immediate and delayed administration of high-dose CORT after fear conditioning reduced fear renewal. To examine the anxiolytic effect of CORT, independent rats were trained for cued or contextual fear conditioning, followed by an injection of CORT (5 and 25mg/kg, i.p.) or vehicle at a 1 or 24h delay. One week later, anxiety-like behavior was assessed in the elevated plus maze (EPM) before and after fear expression. We found that high-dose CORT decreased anxiety-like behavior without changing tone- or context-induced freezing. These findings indicate that a single high-dose CORT administration given after fear conditioning may selectively suppress fear renewal by reducing anxiety-like behavior and not by altering the consolidation, retrieval, or extinction of fear memory. Copyright © 2014 Elsevier Inc. All rights reserved.

On the Road to Translation for PTSD Treatment: Theoretical and Practical Considerations of the Use of Human Models of Conditioned Fear for Drug Development.

PubMed

Risbrough, Victoria B; Glenn, Daniel E; Baker, Dewleen G

The use of quantitative, laboratory-based measures of threat in humans for proof-of-concept studies and target development for novel drug discovery has grown tremendously in the last 2 decades. In particular, in the field of posttraumatic stress disorder (PTSD), human models of fear conditioning have been critical in shaping our theoretical understanding of fear processes and importantly, validating findings from animal models of the neural substrates and signaling pathways required for these complex processes. Here, we will review the use of laboratory-based measures of fear processes in humans including cued and contextual conditioning, generalization, extinction, reconsolidation, and reinstatement to develop novel drug treatments for PTSD. We will primarily focus on recent advances in using behavioral and physiological measures of fear, discussing their sensitivity as biobehavioral markers of PTSD symptoms, their response to known and novel PTSD treatments, and in the case of d-cycloserine, how well these findings have translated to outcomes in clinical trials. We will highlight some gaps in the literature and needs for future research, discuss benefits and limitations of these outcome measures in designing proof-of-concept trials, and offer practical guidelines on design and interpretation when using these fear models for drug discovery.

Activation of D1/5 Dopamine Receptors: A Common Mechanism for Enhancing Extinction of Fear and Reward-Seeking Behaviors.

PubMed

Abraham, Antony D; Neve, Kim A; Lattal, K Matthew

2016-07-01

Dopamine is critical for many processes that drive learning and memory, including motivation, prediction error, incentive salience, memory consolidation, and response output. Theories of dopamine's function in these processes have, for the most part, been developed from behavioral approaches that examine learning mechanisms in appetitive tasks. A parallel and growing literature indicates that dopamine signaling is involved in consolidation of memories into stable representations in aversive tasks such as fear conditioning. Relatively little is known about how dopamine may modulate memories that form during extinction, when organisms learn that the relation between previously associated events is severed. We investigated whether fear and reward extinction share common mechanisms that could be enhanced with dopamine D1/5 receptor activation. Pharmacological activation of dopamine D1/5 receptors (with SKF 81297) enhanced extinction of both cued and contextual fear. These effects also occurred in the extinction of cocaine-induced conditioned place preference, suggesting that the observed effects on extinction were not specific to a particular type of procedure (aversive or appetitive). A cAMP/PKA biased D1 agonist (SKF 83959) did not affect fear extinction, whereas a broadly efficacious D1 agonist (SKF 83822) promoted fear extinction. Together, these findings show that dopamine D1/5 receptor activation is a target for the enhancement of fear or reward extinction.

Lesions of the entorhinal cortex or fornix disrupt the context-dependence of fear extinction in rats.

PubMed

Ji, Jinzhao; Maren, Stephen

2008-12-12

Recent studies have shown that the hippocampus is critical for the context-dependent expression of extinguished fear memories. Here we used Pavlovian fear conditioning in rats to explore whether the entorhinal cortex and fornix, which are the major cortical and subcortical interfaces of the hippocampus, are also involved in the context-dependence of extinction. After pairing an auditory conditional stimulus (CS) with an aversive footshock (unconditional stimulus or US) in one context, rats received an extinction session in which the CS was presented without the US in another context. Conditional fear to the CS was then tested in either the extinction context or a third familiar context; freezing behavior served as the index of fear. Sham-operated rats exhibited little conditional freezing to the CS in the extinction context, but showed a robust renewal of fear when tested outside of the extinction context. In contrast, rats with neurotoxic lesions in the entorhinal cortex or electrolytic lesions in the fornix did not exhibit a renewal of fear when tested outside the extinction context. Impairments in freezing behavior to the auditory CS were not able to account for the observed results, insofar as rats with either entorhinal cortex or fornix lesions exhibited normal freezing behavior during the conditioning session. Thus, contextual memory retrieval requires not only the hippocampus proper, but also its cortical and subcortical interfaces.

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

PubMed

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

2017-05-01

The basolateral amygdala (BLA) is a key structure for the emotional processing and storage of memories associated with emotional events, especially fear. On the other hand, endocannabinoids and CB1 receptors play a key role in learning and memory partly through long-term synaptic depression of GABAergic synapses in the BLA. The aim of this study was to explore the effects of GABA-A receptor agonist and antagonist in the fear-related memory acquisition deficits induced by ACPA (a selective CB1 cannabinoid receptor agonist). This study used context and tone fear conditioning paradigms to assess fear-related memory in male NMRI mice. Our results showed that the pre-training intraperitoneal administration of ACPA (0.5mg/kg) or (0.1 and 0.5mg/kg) decreased the percentage of freezing time in the contextual and tone fear conditioning, respectively. This indicated an impaired context- or tone-dependent fear memory acquisition. Moreover, the pre-training intra-BLA microinjection of GABA-A receptor agonist, muscimol, at 0.05 and 0.5μg/mouse impaired context-dependent fear memory, while the same doses of GABA-A antagonist, bicuculline, impaired tone-dependent fear memory. However, a subthreshold dose of muscimol or bicuculline increased the effect of ACPA at 0.1 and 0.5 or 0.05mg/kg on context- or tone-dependent fear memory, respectively. In addition, bicuculline at the lower dose increased the ACPA response on locomotor activity compared to its respective group. Such findings highlighted an interaction between BLA GABAergic and cannabinoidergic systems during the acquisition phase of conditioned fear memories. Copyright © 2017 Elsevier Inc. All rights reserved.

Adenosine A2A Receptors in the Amygdala Control Synaptic Plasticity and Contextual Fear Memory.

PubMed

Simões, Ana Patrícia; Machado, Nuno J; Gonçalves, Nélio; Kaster, Manuella P; Simões, Ana T; Nunes, Ana; Pereira de Almeida, Luís; Goosens, Ki Ann; Rial, Daniel; Cunha, Rodrigo A

2016-11-01

The consumption of caffeine modulates working and reference memory through the antagonism of adenosine A 2A receptors (A 2A Rs) controlling synaptic plasticity processes in hippocampal excitatory synapses. Fear memory essentially involves plastic changes in amygdala circuits. However, it is unknown if A 2A Rs in the amygdala regulate synaptic plasticity and fear memory. We report that A 2A Rs in the amygdala are enriched in synapses and located to glutamatergic synapses, where they selectively control synaptic plasticity rather than synaptic transmission at a major afferent pathway to the amygdala. Notably, the downregulation of A 2A Rs selectively in the basolateral complex of the amygdala, using a lentivirus with a silencing shRNA (small hairpin RNA targeting A 2A R (shA 2A R)), impaired fear acquisition as well as Pavlovian fear retrieval. This is probably associated with the upregulation and gain of function of A 2A Rs in the amygdala after fear acquisition. The importance of A 2A Rs to control fear memory was further confirmed by the ability of SCH58261 (0.1 mg/kg; A 2A R antagonist), caffeine (5 mg/kg), but not DPCPX (0.5 mg/kg; A 1 R antagonist), treatment for 7 days before fear conditioning onwards, to attenuate the retrieval of context fear after 24-48 h and after 7-8 days. These results demonstrate that amygdala A 2A Rs control fear memory and the underlying process of synaptic plasticity in this brain region. This provides a neurophysiological basis for the association between A 2A R polymorphisms and phobia or panic attacks in humans and prompts a therapeutic interest in A 2A Rs to manage fear-related pathologies.

Mild deficits in mice lacking pituitary adenylate cyclase-activating polypeptide receptor type 1 (PAC1) performing on memory tasks.

PubMed

Sauvage, M; Brabet, P; Holsboer, F; Bockaert, J; Steckler, T

2000-12-08

Pituitary adenylate cyclase-activating polypeptide (PACAP) and its receptor subtype 1 (PAC1) have been suggested to play a role in the modulation of learning and memory. However, behavioral evidence for altered mnemonic function due to altered PAC1 activity is missing. Therefore, the role of PAC1 in learning and memory was studied in mouse mutants lacking this receptor (PAC1 knock-out mice), tested in water maze two-choice spatial discrimination, one-trial contextual and cued fear conditioning, and multiple-session contextual discrimination. Water maze spatial discrimination was unaffected in PAC1 mutants, while a mild deficit was observed in multiple session contextual discrimination in PAC1 knock-out mice. Furthermore, PAC1 knock-out mice were able to learn the association between context and shock in one-trial contextual conditioning, but showed faster return to baseline than wild-type mice. Thus, the effects of PAC1 knock-out on modulating performance in these tasks were subtle and suggest that PAC1 only plays a limited role in learning and memory.

Properties of Contextual Memory Formed in the Absence of αCaMKII Autophosphorylation

PubMed Central

2011-01-01

The alpha-isoform of calcium/calmodulin-dependent kinase II (αCaMKII) is a major synaptic kinase that undergoes autophosphorylation after NMDA receptor activation, switching the kinase into a calcium-independent activity state. This αCaMKII autophosphorylation is essential for NMDA receptor-dependent long-term potentiation (LTP), induced by a single tetanus, in hippocampal area CA1 and in neocortex. Furthermore, the αCaMKII autophosphorylation is essential for contextual long-term memory (LTM) formation after a single training trial but not after a massed training session. Here, we show that in the absence of αCaMKII autophosphorylation contextual fear conditioning is hippocampus dependent and that multi-tetanus-dependent late-LTP cannot be induced in hippocampal area CA1. Furthermore, we show that in the absence of αCaMKII autophosphorylation contextual LTM persists for 30 days, the latest time point tested. Additionally, contextual, but not cued, LTM formation in the absence of αCaMKII autophosphorylation appears to be impaired in 18 month-old mice. Taken together, our findings suggest that αCaMKII autophosphorylation-independent plasticity in the hippocampus is sufficient for contextual LTM formation and that αCaMKII autophosphorylation may be important for delaying age-related impairments in hippocampal memory formation. Furthermore, they propose that NMDA receptor-dependent LTP in hippocampal area CA1 is essential for contextual LTM formation after a single trial but not after massed training. Finally, our results challenge the proposal that NMDA receptor-dependent LTP in neocortex is required for remote contextual LTM. PMID:21276220

Fluoxetine treatment reverses the intergenerational impact of maternal separation on fear and anxiety behaviors.

PubMed

Xiong, Gui-Jing; Yang, Yuan; Cao, Jun; Mao, Rong-Rong; Xu, Lin

2015-05-01

Early life stress increases risks of fear and anxiety related disorders in adulthood, which may be alleviated by fluoxetine treatment. However, the intergenerational impacts of maternal separation (MS) on fear and anxiety behaviors from father to their offspring are little known. And the potential effects of fluoxetine treatment on the intergenerational transmission have not been well tested. Here, we investigated whether fluoxetine can reverse the intergenerational effects of MS on fear and anxiety behaviors. The first generation (F1) male rats were exposed to MS 3 h daily from postnatal day 2-14 and then treated with fluoxetine for four weeks during adulthood before fear conditioning. We found that maternal separation significantly impaired contextual fear extinction in F1 adult male rats but not in their second generation (F2). Although no obvious effects of MS on anxiety were observed in F1 male rats, the F2 offspring displayed a phenotype of low anxiety-like behaviors despite they were reared in normal condition. Fluoxetine treatment in F1 males not only reversed the impairment of fear extinction in F1 males but also the low anxiety-like behaviors in their F2 offspring. These findings highlight the intergenerational impacts of early life stress on fear and anxiety behaviors, and provide a new sight of the intergenerational effect of fluoxetine therapy for early life stress related mental problems. Copyright © 2015 Elsevier Ltd. All rights reserved.

Brain structural connectivity and context-dependent extinction memory.

PubMed

Hermann, Andrea; Stark, Rudolf; Blecker, Carlo R; Milad, Mohammed R; Merz, Christian J

2017-08-01

Extinction of conditioned fear represents an important mechanism in the treatment of anxiety disorders. Return of fear after successful extinction or exposure therapy in patients with anxiety disorders might be linked to poor temporal or contextual generalization of extinction due to individual differences in brain structural connectivity. The goal of this magnetic resonance imaging study was therefore to investigate the association of context-dependent extinction recall with brain structural connectivity. Diffusion-tensor imaging was used to determine the fractional anisotropy as a measure of white matter structural integrity of fiber tracts connecting central brain regions of the fear and extinction circuit (uncinate fasciculus, cingulum). Forty-five healthy men participated in a two-day fear conditioning experiment with fear acquisition in context A and extinction learning in context B on the first day. Extinction recall in the extinction context as well as renewal in the acquisition context and a novel context C took place one day later. Renewal of conditioned fear (skin conductance responses) in the acquisition context was associated with higher structural integrity of the hippocampal part of the cingulum. Enhanced structural integrity of the cingulum might be related to stronger hippocampal modulation of the dorsal anterior cingulate cortex, a region important for modulating conditioned fear output by excitatory projections to the amygdala. This finding underpins the crucial role of individual differences in the structural integrity of relevant fiber tracts for context-dependent extinction recall and return of fear after exposure therapy in anxiety disorders. © 2017 Wiley Periodicals, Inc.

Metyrapone Reveals That Previous Chronic Stress Differentially Impairs Hippocampal-dependent Memory

PubMed Central

CONRAD, CHERYL D.; MAULDIN-JOURDAIN, MELISSA L.; HOBBS, REBECCA J.

2007-01-01

Chronic stress facilitates fear conditioning in rats with hippocampal neuronal atrophy and in rats in which the atrophy is prevented with tianeptine, a serotonin re-uptake enhancer. The purpose of this study was to determine whether the lack of dissociation between fear conditioning performance and hippocampal integrity was masked by the presence of endogenous corticosteroids during training. As in previous studies, rats were stressed by daily restraint (6 h/day for 21 days), trained in the conditioning chamber (day 23), and then assessed for conditioned fear (day 25) at a time when hippocampal dendritic atrophy persists. On the training day, half of the control and stressed rats were injected with metyrapone to reduce corticosterone release. Two hours later, two paired or unpaired presentations of tone and footshock were delivered. Although metyrapone reduced conditioned fear in all rats, only stressed rats showed dissociated fear conditioning (i.e. tone conditioning was reduced while contextual conditioning was eliminated). Chronically stressed rats, regardless of metyrapone treatment displayed more rearing in the open field when tested immediately after the completion of fear conditioning. These data support the hypothesis that increased emotionality and enhanced fear conditioning exhibited by chronically stressed rats may be due to endogenous corticosterone secretion at the time of fear conditioned training. Moreover, these data suggest that chronic stress impairs hippocampal-dependent processes more robustly than hippocampal-independent processes after metyrapone to reduce corticosterone secretion during aversive training. PMID:18301732

Modulation of hippocampal NCAM polysialylation and spatial memory consolidation by fear conditioning.

PubMed

Sandi, Carmen; Merino, José J; Cordero, M Isabel; Kruyt, Nyika D; Murphy, Keith J; Regan, Ciaran M

2003-09-15

Cell adhesion molecule function is involved in hippocampal synaptic plasticity and associated with memory consolidation. At the infragranular zone of the dentate gyrus, neurons expressing the polysialylated form of the neural cell adhesion molecule (NCAM PSA) transiently increase their frequency 12 hours after training in different tasks. Using immunohistochemical procedures, we investigated NCAM polysialylation following training in a contextual fear conditioning paradigm that employed increasing shock intensities to separately model stressful and traumatic experiences in adult male Wistar rats. Fear conditioning with a stressful.4-mA stimulus resulted in an increased frequency of dentate polysialylated neurons, the magnitude of which was indistinguishable from that observed following water maze training. By contrast, training with a traumatic 1-mA stimulus resulted in a significant decrease in the frequency of polysialylated neurons at the 12 hours posttraining time. Whereas sequential training in the water maze paradigm followed by fear conditioning resulted in potentiated consolidation of spatial information when conditioning involved a.4-mA stimulus, amnesia for spatial learning occurred when conditioning was performed with a 1-mA stimulus. These results suggest traumatic fear conditioning suppresses NCAM-PSA-mediated plasticity and the concomitant inability to store the trace of recently acquired information.

Fear memory consolidation in sleep requires protein kinase A.

PubMed

Cho, Jiyeon; Sypniewski, Krzysztof A; Arai, Shoko; Yamada, Kazuo; Ogawa, Sonoko; Pavlides, Constantine

2018-05-01

It is well established that protein kinase A (PKA) is involved in hippocampal dependent memory consolidation. Sleep is also known to play an important role in this process. However, whether sleep-dependent memory consolidation involves PKA activation has not been clearly determined. Using behavioral observation, animals were categorized into sleep and awake groups. We show that intrahippocampal injections of the PKA inhibitor Rp-cAMPs in post-contextual fear conditioning sleep produced a suppression of long-term fear memory, while injections of Rp-cAMPs during an awake state, at a similar time point, had no effect. In contrast, injections of the PKA activator Sp-cAMPs in awake state, rescued sleep deprivation-induced memory impairments. These results suggest that following learning, PKA activation specifically in sleep is required for the consolidation of long-term memory. © 2018 Cho et al.; Published by Cold Spring Harbor Laboratory Press.

Xenon Impairs Reconsolidation of Fear Memories in a Rat Model of Post-Traumatic Stress Disorder (PTSD)

PubMed Central

Meloni, Edward G.; Gillis, Timothy E.; Manoukian, Jasmine; Kaufman, Marc J.

2014-01-01

Xenon (Xe) is a noble gas that has been developed for use in people as an inhalational anesthestic and a diagnostic imaging agent. Xe inhibits glutamatergic N-methyl-D-aspartate (NMDA) receptors involved in learning and memory and can affect synaptic plasticity in the amygdala and hippocampus, two brain areas known to play a role in fear conditioning models of post-traumatic stress disorder (PTSD). Because glutamate receptors also have been shown to play a role in fear memory reconsolidation – a state in which recalled memories become susceptible to modification – we examined whether Xe administered after fear memory reactivation could affect subsequent expression of fear-like behavior (freezing) in rats. Male Sprague-Dawley rats were trained for contextual and cued fear conditioning and the effects of inhaled Xe (25%, 1 hr) on fear memory reconsolidation were tested using conditioned freezing measured days or weeks after reactivation/Xe administration. Xe administration immediately after fear memory reactivation significantly reduced conditioned freezing when tested 48 h, 96 h or 18 d after reactivation/Xe administration. Xe did not affect freezing when treatment was delayed until 2 h after reactivation or when administered in the absence of fear memory reactivation. These data suggest that Xe substantially and persistently inhibits memory reconsolidation in a reactivation and time-dependent manner, that it could be used as a new research tool to characterize reconsolidation and other memory processes, and that it could be developed to treat people with PTSD and other disorders related to emotional memory. PMID:25162644

Differential Needs of Zinc in the CA3 Area of Dorsal Hippocampus for the Consolidation of Contextual Fear and Spatial Memories

ERIC Educational Resources Information Center

Ceccom, Johnatan; Bouhsira, Emilie; Halley, Helene; Daumas, Stephanie; Lassalle, Jean Michel

2013-01-01

One peculiarity of the hippocampal CA3 mossy fiber terminals is the co-release of zinc and glutamate upon synaptic transmission. How these two players act on hippocampal-dependent memories is still unclear. To decipher their respective involvement in memory consolidation, a pharmacological approach was chosen. Using two hippocampal-dependent…

Gender dependent contribution of muscarinic receptors in memory retrieval under sub-chronic stress.

PubMed

Rashid, Habiba; Ahmed, Touqeer

2018-05-15

Stress induces retrograde amnesia in humans and rodents. Muscarinic antagonism under normal physiological conditions causes gender dependent impairment in episodic memory retrieval. We aimed to explore the gender dependent role of muscarinic receptors in memory retrieval under sub-chronic stress condition. Male and female mice were trained for Morris water maze test and contextual fear conditioning, followed by 3 h restraint stress per day for five days. Stress was either given alone or in combination with a daily subcutaneous injection of scopolamine (1 mg/kg) or donepezil (1 mg/kg). Control mice were given saline without any stress. Sub-chronic stress (induced for five days) impaired spatial memory retrieval in males (P < 0.005) but not in females (P > 0.05). Stress induced spatial memory recall deficit in male mice was independent of muscarinic receptor activity (P > 0.05). However, stress induced contextual fear memory recall impairment was reversed by donepezil treatment in male (P < 0.005) and female (P < 0.0001) mice. These findings suggest that differential role of muscarinic activity in retrieving different types of memories under stress depends on gender of subjects. Copyright © 2018 Elsevier B.V. All rights reserved.

Dopamine D1-like receptor in lateral habenula nucleus affects contextual fear memory and long-term potentiation in hippocampal CA1 in rats.

PubMed

Chan, Jiangping; Guan, Xin; Ni, Yiling; Luo, Lilu; Yang, Liqiang; Zhang, Pengyue; Zhang, Jichuan; Chen, Yanmei

2017-03-15

The Lateral Habenula (LHb) plays an important role in emotion and cognition. Recent experiments suggest that LHb has functional interaction with the hippocampus and plays an important role in spatial learning. LHb is reciprocally connected with midbrain monoaminergic brain areas such as the ventral tegmental area (VTA). However, the role of dopamine type 1 receptor (D1R) in LHb in learning and memory is not clear yet. In the present study, D1R agonist or antagonist were administered bilaterally into the LHb in rats. We found that both D1R agonist and antagonist impaired the acquisition of contextual fear memory in rats. D1R agonist or antagonist also impaired long term potentiation (LTP) in hippocampal CA3-CA1 synapses in freely moving rats and attenuated learning induced phosphorylation of α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor (AMPAR) subunit 1 (GluA1) at Ser831 and Ser845 in hippocampus. Taken together, our results suggested that dysfunction of D1R in LHb affected the function of hippocampus. Copyright © 2016 Elsevier B.V. All rights reserved.

Low-dose sevoflurane promotes hippocampal neurogenesis and facilitates the development of dentate gyrus-dependent learning in neonatal rats.

PubMed

Chen, Chong; Shen, Feng-Yan; Zhao, Xuan; Zhou, Tao; Xu, Dao-Jie; Wang, Zhi-Ru; Wang, Ying-Wei

2015-01-01

Huge body of evidences demonstrated that volatile anesthetics affect the hippocampal neurogenesis and neurocognitive functions, and most of them showed impairment at anesthetic dose. Here, we investigated the effect of low dose (1.8%) sevoflurane on hippocampal neurogenesis and dentate gyrus-dependent learning. Neonatal rats at postnatal day 4 to 6 (P4-6) were treated with 1.8% sevoflurane for 6 hours. Neurogenesis was quantified by bromodeoxyuridine labeling and electrophysiology recording. Four and seven weeks after treatment, the Morris water maze and contextual-fear discrimination learning tests were performed to determine the influence on spatial learning and pattern separation. A 6-hour treatment with 1.8% sevoflurane promoted hippocampal neurogenesis and increased the survival of newborn cells and the proportion of immature granular cells in the dentate gyrus of neonatal rats. Sevoflurane-treated rats performed better during the training days of the Morris water maze test and in contextual-fear discrimination learning test. These results suggest that a subanesthetic dose of sevoflurane promotes hippocampal neurogenesis in neonatal rats and facilitates their performance in dentate gyrus-dependent learning tasks. © The Author(s) 2015.

Memory Retrieval Re-Activates Erk1/2 Signaling in the Same Set of CA1 Neurons Recruited During Conditioning.

PubMed

Zamorano, Cristina; Fernández-Albert, Jordi; Storm, Daniel R; Carné, Xavier; Sindreu, Carlos

2018-02-01

The hippocampus enables a range of behaviors through its intrinsic circuits and concerted actions with other brain regions. One such important function is the retrieval of episodic memories. How hippocampal cells support retrieval of contextual fear memory remains largely unclear. Here we monitored phospho-activation of extracellular-regulated kinase (Erk1/2) across neuronal populations of the hippocampus to find that CA1 pyramidal neurons, but not cells in CA3 or dentate gyrus, specifically respond to retrieval of an aversive context. In contrast, retrieval of a neutral context that fails to elicit a threat response did not activate Erk1/2. Moreover, retrieval preferentially re-activated Erk1/2 in the same set of CA1 neurons previously activated during conditioning in a context-specific manner. By confining drug inhibition within dorsal CA1, we established the crucial role for Erk1/2 activity in retrieval of long-term memory, as well as in amygdala activation associated with fear expression. These data provide functional evidence that Erk1/2 signaling in CA1 encodes a specific neural representation of contextual memory with emotional value. Copyright © 2017 IBRO. Published by Elsevier Ltd. All rights reserved.

Elemental or contextual? It depends: individual difference in the hippocampal dependence of associative learning for a simple sensory stimulus

PubMed Central

Lee, Kyung J.; Park, Seong-Beom; Lee, Inah

2014-01-01

Learning theories categorize learning systems into elemental and contextual systems, the former being processed by non-hippocampal regions and the latter being processed in the hippocampus. A set of complex stimuli such as a visual background is often considered a contextual stimulus and simple sensory stimuli such as pure tone and light are considered elemental stimuli. However, this elemental-contextual categorization scheme has only been tested in limited behavioral paradigms and it is largely unknown whether it can be generalized across different learning situations. By requiring rats to respond differently to a common object in association with various types of sensory cues including contextual and elemental stimuli, we tested whether different types of elemental and contextual sensory stimuli depended on the hippocampus to different degrees. In most rats, a surrounding visual background and a tactile stimulus served as contextual (hippocampal dependent) and elemental (non-hippocampal dependent) stimuli, respectively. However, simple tone and light stimuli frequently used as elemental cues in traditional experiments required the hippocampus to varying degrees among rats. Specifically, one group of rats showed a normal contextual bias when both contextual and elemental cues were present. These rats effectively switched to using elemental cues when the hippocampus was inactivated. The other group showed a strong contextual bias (and hippocampal dependence) because these rats were not able to use elemental cues when the hippocampus was unavailable. It is possible that the latter group of rats might have interpreted the elemental cues (light and tone) as background stimuli and depended more on the hippocampus in associating the cues with choice responses. Although exact mechanisms underlying these individual variances are unclear, our findings recommend a caution for adopting a simple sensory stimulus as a non-hippocampal sensory cue only based on the literature. PMID:24982624

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

PubMed

Burghardt, N S; Bauer, E P

2013-09-05

Selective serotonin reuptake inhibitors (SSRIs) are widely used for the treatment of a spectrum of anxiety disorders, yet paradoxically they may increase symptoms of anxiety when treatment is first initiated. Despite extensive research over the past 30 years focused on SSRI treatment, the precise mechanisms by which SSRIs exert these opposing acute and chronic effects on anxiety remain unknown. By testing the behavioral effects of SSRI treatment on Pavlovian fear conditioning, a well characterized model of emotional learning, we have the opportunity to identify how SSRIs affect the functioning of specific brain regions, including the amygdala, bed nucleus of the stria terminalis (BNST) and hippocampus. In this review, we first define different stages of learning involved in cued and context fear conditioning and describe the neural circuits underlying these processes. We examine the results of numerous rodent studies investigating how acute SSRI treatment modulates fear learning and relate these effects to the known functions of serotonin in specific brain regions. With these findings, we propose a model by which acute SSRI administration, by altering neural activity in the extended amygdala and hippocampus, enhances both acquisition and expression of cued fear conditioning, but impairs the expression of contextual fear conditioning. Finally, we review the literature examining the effects of chronic SSRI treatment on fear conditioning in rodents and describe how downregulation of N-methyl-d-aspartate (NMDA) receptors in the amygdala and hippocampus may mediate the impairments in fear learning and memory that are reported. While long-term SSRI treatment effectively reduces symptoms of anxiety, their disruptive effects on fear learning should be kept in mind when combining chronic SSRI treatment and learning-based therapies, such as cognitive behavioral therapy. Copyright © 2013 IBRO. Published by Elsevier Ltd. All rights reserved.

Emotion and sex of facial stimuli modulate conditional automaticity in behavioral and neuronal interference in healthy men.

PubMed

Kohn, Nils; Fernández, Guillén

2017-12-06

Our surrounding provides a host of sensory input, which we cannot fully process without streamlining and automatic processing. Levels of automaticity differ for different cognitive and affective processes. Situational and contextual interactions between cognitive and affective processes in turn influence the level of automaticity. Automaticity can be measured by interference in Stroop tasks. We applied an emotional version of the Stroop task to investigate how stress as a contextual factor influences the affective valence-dependent level of automaticity. 120 young, healthy men were investigated for behavioral and brain interference following a stress induction or control procedure in a counter-balanced cross-over-design. Although Stroop interference was always observed, sex and emotion of the face strongly modulated interference, which was larger for fearful and male faces. These effects suggest higher automaticity when processing happy and also female faces. Supporting behavioral patterns, brain data show lower interference related brain activity in executive control related regions in response to happy and female faces. In the absence of behavioral stress effects, congruent compared to incongruent trials (reverse interference) showed little to no deactivation under stress in response to happy female and fearful male trials. These congruency effects are potentially based on altered context- stress-related facial processing that interact with sex-emotion stereotypes. Results indicate that sex and facial emotion modulate Stroop interference in brain and behavior. These effects can be explained by altered response difficulty as a consequence of the contextual and stereotype related modulation of automaticity. Copyright © 2017 Elsevier Ltd. All rights reserved.

Interaction between scene-based and array-based contextual cueing.

PubMed

Rosenbaum, Gail M; Jiang, Yuhong V

2013-07-01

Contextual cueing refers to the cueing of spatial attention by repeated spatial context. Previous studies have demonstrated distinctive properties of contextual cueing by background scenes and by an array of search items. Whereas scene-based contextual cueing reflects explicit learning of the scene-target association, array-based contextual cueing is supported primarily by implicit learning. In this study, we investigated the interaction between scene-based and array-based contextual cueing. Participants searched for a target that was predicted by both the background scene and the locations of distractor items. We tested three possible patterns of interaction: (1) The scene and the array could be learned independently, in which case cueing should be expressed even when only one cue was preserved; (2) the scene and array could be learned jointly, in which case cueing should occur only when both cues were preserved; (3) overshadowing might occur, in which case learning of the stronger cue should preclude learning of the weaker cue. In several experiments, we manipulated the nature of the contextual cues present during training and testing. We also tested explicit awareness of scenes, scene-target associations, and arrays. The results supported the overshadowing account: Specifically, scene-based contextual cueing precluded array-based contextual cueing when both were predictive of the location of a search target. We suggest that explicit, endogenous cues dominate over implicit cues in guiding spatial attention.

Integration of contextual cues into memory depends on "prefrontal" N-methyl-D-aspartate receptors.

PubMed

Starosta, Sarah; Bartetzko, Isabelle; Stüttgen, Maik C; Güntürkün, Onur

2017-10-01

Every learning event is embedded in a context, but not always does the context become an integral part of the memory; however, for extinction learning it usually does, resulting in context-specific conditioned responding. The neuronal mechanisms underlying contextual control have been mainly investigated for Pavlovian fear extinction with a focus on hippocampal structures. However, the initial acquisition of novel responses can be subject to contextual control as well, although the neuronal mechanisms are mostly unknown. Here, we tested the hypothesis that contextual control of acquisition depends on glutamatergic transmission underlying executive functions in forebrain areas, e.g. by shifting attention to critical cues. Thus, we antagonized N-methyl-D-aspartate (NMDA) receptors with 2-amino-5-phosphonovaleric acid (AP5) in the pigeon nidopallium caudolaterale, the functional analogue of mammalian prefrontal cortex, during the concomitant acquisition and extinction of conditioned responding to two different stimuli. This paradigm has previously been shown to lead to contextual control over extinguished as well as non-extinguished responding. NMDA receptor blockade resulted in an impairment of extinction learning, but left the acquisition of responses to a novel stimulus unaffected. Critically, when responses were tested in a different context in the retrieval phase, we observed that NMDA receptor blockade led to the abolishment of contextual control over acquisition performance. This result is predicted by a model describing response inclination as the product of associative strength and contextual gain. In this model, learning under AP5 leads to a change in the contextual gain on the learned association, possibly via the modulation of attentional mechanisms. Copyright © 2017 Elsevier Inc. All rights reserved.

Long-term contextual memory in infant rats as evidenced by an ethanol conditioned tolerance procedure.

PubMed

Castelló, Stefanía; Molina, Juan Carlos; Arias, Carlos

2017-08-14

Conditioned tolerance can be conceptualized as a particular case of Pavlovian conditioning in which contextual cues play the role of the conditioned stimulus. Although the evidence is contradictory, it is frequently assumed that long-term contextual conditioning in pre-weanling rats is weak or even absent. This hypothesis comes from and is sustained mainly by behavioral studies that explored different contextual effects in 16-18day-old rats using a fear-conditioning paradigm, but their conclusions are stated in terms of an immature (hippocampal-dependent) declarative memory system. The main goal of the present manuscript was based on a recent antecedent from our laboratory, to analyze whether context-dependent tolerance induced by ethanol during the pre-weanling period persists over time. Results showed that the context was able to modulate ethanol-induced tolerance in 2- and 3-week-old rats. Interestingly, contextual conditioned tolerance was stronger (in terms of persistence) during the third than during the second postnatal week. When subjects were tested 8days after training, when the context presumably lost its influence over tolerance, the opposite effect emerged (sensitization). These results are important for the ethanol literature, adding new evidence of long-term retention of ethanol effects acquired during infancy, whilst also showing striking ontogenetic differences in the sensitivity to ethanol between the 2nd and 3rd postnatal weeks. Importantly, contextual information modulates the expression of these ethanol effects even eight days after training, a result that is particularly relevant to the discussion of the ontogeny of contextual memory. Copyright © 2017 Elsevier B.V. All rights reserved.

Neural Correlates of Inhibition and Contextual Cue Processing Related to Treatment Response in PTSD

PubMed Central

van Rooij, Sanne JH; Geuze, Elbert; Kennis, Mitzy; Rademaker, Arthur R; Vink, Matthijs

2015-01-01

Thirty to fifty percent of posttraumatic stress disorder (PTSD) patients do not respond to treatment. Understanding the neural mechanisms underlying treatment response could contribute to improve response rates. PTSD is often associated with decreased inhibition of fear responses in a safe environment. Importantly, the mechanism of effective treatment (psychotherapy) relies on inhibition and so-called contextual cue processing. Therefore, we investigate inhibition and contextual cue processing in the context of treatment. Forty-one male war veterans with PTSD and 22 healthy male war veterans (combat controls) were scanned twice with a 6- to 8-month interval, in which PTSD patients received treatment (psychotherapy). We distinguished treatment responders from nonresponders on the base of percentage symptom decrease. Inhibition and contextual cue processing were assessed with the stop-signal anticipation task. Behavioral and functional MRI measures were compared between PTSD patients and combat controls, and between responders and nonresponders using repeated measures analyses. PTSD patients showed behavioral and neural deficits in inhibition and contextual cue processing at both time points compared with combat controls. These deficits were unaffected by treatment; therefore, they likely represent vulnerability factors or scar aspects of PTSD. Second, responders showed increased pretreatment activation of the left inferior parietal lobe (IPL) during contextual cue processing compared with nonresponders. Moreover, left IPL activation predicted percentage symptom improvement. The IPL has an important role in contextual cue processing, and may therefore facilitate the effect of psychotherapy. Hence, increased left IPL activation may represent a potential predictive biomarker for PTSD treatment response. PMID:25154707

Maternal depression and anxiety associated with dental fear in children: a cohort of adolescent mothers in Southern Brazil.

PubMed

Costa, Vanessa Polina Pereira; Correa, Marcos Britto; Goettems, Marília Leão; Pinheiro, Ricardo Tavares; Demarco, Flávio Fernando

2017-11-06

Exposure to maternal symptoms of depression/anxiety has long-term negative consequences for child development, regardless of the contextual risk. The objective of this study was to investigate the relationship of the symptomatology of persistent maternal depression and anxiety with child dental fear. This study was nested in a cohort of adolescent mothers in southern Brazil. Symptomatology of maternal depression and anxiety was assessed during pregnancy and postpartum, when the mothers' children were 24-36 months old, using Beck Depression Inventory and Beck Anxiety Inventory. The mothers answered a questionnaire to assess dental fear in their children, and to obtain socioeconomic and demographic data. Both mothers and their children were submitted to clinical oral examination (n= 540 dyads) to obtain oral health data. Multivariate hierarchical Poisson regression analysis was used to determine associations (p < 0.05). At data collection, the prevalence of maternal depressive symptoms was 39.1%, and anxiety was observed in 27.8% of the mothers, whereas 21.6% of the children presented dental fear. In the adjusted analysis, children's dental fear was positively associated with mothers' presenting depressive symptomatology and caries experience. The depression symptomatology trajectory was not associated with dental fear, whereas mothers with persistent symptoms of anxiety reported higher prevalence of dental fear toward their offspring. The findings of symptomatology of maternal depression observed at data collection and persistence of anxiety may negatively impact the child's perception of dental fear. Mothers are the main caregivers and primary models responsible for transmitting health-related behaviors; consequently, mental disorders affecting mothers may negatively impact their children.

The L-type voltage-gated calcium channel CaV1.2 mediates fear extinction and modulates synaptic tone in the lateral amygdala.

PubMed

Temme, Stephanie J; Murphy, Geoffrey G

2017-11-01

L-type voltage-gated calcium channels (LVGCCs) have been implicated in both the formation and the reduction of fear through Pavlovian fear conditioning and extinction. Despite the implication of LVGCCs in fear learning and extinction, studies of the individual LVGCC subtypes, Ca V 1.2 and Ca V 1.3, using transgenic mice have failed to find a role of either subtype in fear extinction. This discontinuity between the pharmacological studies of LVGCCs and the studies investigating individual subtype contributions could be due to the limited neuronal deletion pattern of the Ca V 1.2 conditional knockout mice previously studied to excitatory neurons in the forebrain. To investigate the effects of deletion of Ca V 1.2 in all neuronal populations, we generated Ca V 1.2 conditional knockout mice using the synapsin1 promoter to drive Cre recombinase expression. Pan-neuronal deletion of Ca V 1.2 did not alter basal anxiety or fear learning. However, pan-neuronal deletion of Ca V 1.2 resulted in a significant deficit in extinction of contextual fear, implicating LVGCCs, specifically Ca V 1.2, in extinction learning. Further exploration on the effects of deletion of Ca V 1.2 on inhibitory and excitatory input onto the principle neurons of the lateral amygdala revealed a significant shift in inhibitory/excitatory balance. Together these data illustrate an important role of Ca V 1.2 in fear extinction and the synaptic regulation of activity within the amygdala. © 2017 Temme and Murphy; Published by Cold Spring Harbor Laboratory Press.

Novelty and fear conditioning induced gene expression in high and low states of anxiety.

PubMed

Donley, Melanie P; Rosen, Jeffrey B

2017-09-01

Emotional states influence how stimuli are interpreted. High anxiety states in humans lead to more negative, threatening interpretations of novel information, typically accompanied by activation of the amygdala. We developed a handling protocol that induces long-lasting high and low anxiety-like states in rats to explore the role of state anxiety on brain activation during exposure to a novel environment and fear conditioning. In situ hybridization of the inducible transcription factor Egr-1 found increased gene expression in the lateral nucleus of the amygdala (LA) following exposure to a novel environment and contextual fear conditioning in high anxiety-like rats. In contrast, low state anxiety-like rats did not generate Egr-1 increases in LA when placed in a novel chamber. Egr-1 expression was also examined in the dorsal hippocampus and prefrontal cortex. In CA1 of the hippocampus and medial prefrontal cortex (mPFC), Egr-1 expression increased in response to novel context exposure and fear conditioning, independent of state anxiety level. Furthermore, in mPFC, Egr-1 in low anxiety-like rats was increased more with fear conditioning than novel exposure. The current series of experiments show that brain areas involved in fear and anxiety-like states do not respond uniformly to novelty during high and low states of anxiety. © 2017 Donley and Rosen; Published by Cold Spring Harbor Laboratory Press.

A Mutant Mouse with a Highly Specific Contextual Fear-Conditioning Deficit Found in an N-Ethyl-N-Nitrosourea (ENU) Mutagenesis Screen

ERIC Educational Resources Information Center

Pletcher, Mathew T.; Wiltshire, Tim; Tarantino, Lisa M.; Mayford, Mark; Reijmers, Leon G.; Coats, Jennifer K.

2006-01-01

Targeted mutagenesis in mice has shown that genes from a wide variety of gene families are involved in memory formation. The efficient identification of genes involved in learning and memory could be achieved by random mutagenesis combined with high-throughput phenotyping. Here, we provide the first report of a mutagenesis screen that has…

Impaired Auditory and Contextual Fear Conditioning in Soman-Exposed Rats

DTIC Science & Technology

2011-01-01

include the piriform cortex, amygdala, thalamus and hippocampus (Carpentier et al., 1990; Petras , 1994; Shih et al., 2003). Often the resulting... Martin M, Shah R, Bertchume A, Colvin J, Dong H. Cholinesterase inhibitors ameliorate behavioral deficits induced by MK-801 in mice. Neuropsy...Csernansky CA, Martin MV, Bertchume A, Vallera D, Csernansky JG. Acetylcholinesterase inhibitors ameliorate behavioral deficits in the Tg2576 mouse

Immediate-Early Gene Transcriptional Activation in Hippocampus Ca1 and Ca3 Does Not Accurately Reflect Rapid, Pattern Completion-Based Retrieval of Context Memory

ERIC Educational Resources Information Center

Pevzner, Aleksandr; Guzowski, John F.

2015-01-01

No studies to date have examined whether immediate-early gene (IEG) activation is driven by context memory recall. To address this question, we utilized the context preexposure facilitation effect (CPFE) paradigm. In CPFE, animals acquire contextual fear conditioning through hippocampus-dependent rapid retrieval of a previously formed contextual…

Anisomycin Injection in Area CA3 of the Hippocampus Impairs Both Short-Term and Long-Term Memories of Contextual Fear

ERIC Educational Resources Information Center

Remaud, Jessica; Ceccom, Johnatan; Carponcy, Julien; Dugué, Laura; Menchon, Gregory; Pech, Stéphane; Halley, Helene; Francés, Bernard; Dahan, Lionel

2014-01-01

Protein synthesis is involved in the consolidation of short-term memory into long-term memory. Previous electrophysiological data concerning LTP in CA3 suggest that protein synthesis in that region might also be necessary for short-term memory. We tested this hypothesis by locally injecting the protein synthesis inhibitor anisomycin in hippocampal…

Yokukansan, a traditional Japanese herbal medicine, enhances the anxiolytic effect of fluvoxamine and reduces cortical 5-HT2A receptor expression in mice.

PubMed

Ohno, Rintaro; Miyagishi, Hiroko; Tsuji, Minoru; Saito, Atsumi; Miyagawa, Kazuya; Kurokawa, Kazuhiro; Takeda, Hiroshi

2018-04-24

Yokukansan is a traditional Japanese herbal medicine that has been approved in Japan as a remedy for neurosis, insomnia, and irritability in children. It has also been reported to improve behavioral and psychological symptoms in patients with various forms of dementia. To evaluate the usefulness of co-treatment with an antidepressant and an herbal medicine in the psychiatric field, the current study examined the effect of yokukansan on the anxiolytic-like effect of fluvoxamine in mice. The anxiolytic-like effect in mice was estimated by the contextual fear conditioning paradigm. Contextual fear conditioning consisted of two sessions, i.e., day 1 for the conditioning session and day 2 for the test session. The expression levels of 5-HT 1A and 5-HT 2A receptor in the mouse brain regions were quantified by western blot analysis. A single administration of fluvoxamine (5-20 mg/kg, i.p.) before the test session dose-dependently and significantly suppressed freezing behavior in mice. In the combination study, a sub-effective dose of fluvoxamine (5 mg/kg, i.p.) significantly suppressed freezing behavior in mice that had been repeatedly pretreated with yokukansan (0.3 and 1 g/kg, p.o.) once a day for 6 days after the conditioning session. Western blot analysis revealed that the expression level of 5-HT 2A receptor was specifically decreased in the prefrontal cortex of mice that had been administered yokukansan and fluvoxamine. Furthermore, microinjection of the 5-HT 2A receptor antagonist ketanserin (5 nmol/mouse) into the prefrontal cortex significantly suppressed freezing behavior. The present findings indicate that repeated treatment with yokukansan synergistically enhances the anxiolytic-like effect of fluvoxamine in the contextual fear conditioning paradigm in mice in conjunction with a decrease in 5-HT 2A receptor-mediated signaling in the prefrontal cortex. Therefore, combination therapy with fluvoxamine and yokukansan may be beneficial for the treatment of anxiety disorders. Copyright © 2018 Elsevier B.V. All rights reserved.

HDAC I inhibition in the dorsal and ventral hippocampus differentially modulates predator-odor fear learning and generalization.

PubMed

Yuan, Robin K; Hebert, Jenna C; Thomas, Arthur S; Wann, Ellen G; Muzzio, Isabel A

2015-01-01

Although predator odors are ethologically relevant stimuli for rodents, the molecular pathways and contribution of some brain regions involved in predator odor conditioning remain elusive. Inhibition of histone deacetylases (HDACs) in the dorsal hippocampus has been shown to enhance shock-induced contextual fear learning, but it is unknown if HDACs have differential effects along the dorso-ventral hippocampal axis during predator odor fear learning. We injected MS-275, a class I HDAC inhibitor, bilaterally in the dorsal or ventral hippocampus of mice and found that it had no effects on innate anxiety in either region. We then assessed the effects of MS-275 at different stages of fear learning along the longitudinal hippocampal axis. Animals were injected with MS-275 or vehicle after context pre-exposure (pre-conditioning injections), when a representation of the context is first formed, or after exposure to coyote urine (post-conditioning injections), when the context becomes associated with predator odor. When MS-275 was administered after context pre-exposure, dorsally injected animals showed enhanced fear in the training context but were able to discriminate it from a neutral environment. Conversely, ventrally injected animals did not display enhanced learning in the training context but generalized the fear response to a neutral context. However, when MS-275 was administered after conditioning, there were no differences between the MS-275 and vehicle control groups in either the dorsal or ventral hippocampus. Surprisingly, all groups displayed generalization to a neutral context, suggesting that predator odor exposure followed by a mild stressor such as restraint leads to fear generalization. These results may elucidate distinct functions of the dorsal and ventral hippocampus in predator odor-induced fear conditioning as well as some of the molecular mechanisms underlying fear generalization.

Estradiol replacement enhances fear memory formation, impairs extinction and reduces COMT expression levels in the hippocampus of ovariectomized female mice.

PubMed

McDermott, Carmel M; Liu, Dan; Ade, Catherine; Schrader, Laura A

2015-02-01

Females experience depression, posttraumatic stress disorder (PTSD), and anxiety disorders at approximately twice the rate of males, but the mechanisms underlying this difference remain undefined. The effect of sex hormones on neural substrates presents a possible mechanism. We investigated the effect of ovariectomy at two ages, before puberty and in adulthood, and 17β-estradiol (E2) replacement administered chronically in drinking water on anxiety level, fear memory formation, and extinction. Based on previous studies, we hypothesized that estradiol replacement would impair fear memory formation and enhance extinction rate. Females, age 4 weeks and 10 weeks, were divided randomly into 4 groups; sham surgery, OVX, OVX+low E2 (200nM), and OVX+high E2 (1000nM). Chronic treatment with high levels of E2 significantly increased anxiety levels measured in the elevated plus maze. In both age groups, high levels of E2 significantly increased contextual fear memory but had no effect on cued fear memory. In addition, high E2 decreased the rate of extinction in both ages. Finally, catechol-O-methyltransferase (COMT) is important for regulation of catecholamine levels, which play a role in fear memory formation and extinction. COMT expression in the hippocampus was significantly reduced by high E2 replacement, implying increased catecholamine levels in the hippocampus of high E2 mice. These results suggest that estradiol enhanced fear memory formation, and inhibited fear memory extinction, possibly stabilizing the fear memory in female mice. This study has implications for a neurobiological mechanism for PTSD and anxiety disorders. Copyright © 2014 Elsevier Inc. All rights reserved.

Dentate Gyrus Contributes to Retrieval as well as Encoding: Evidence from Context Fear Conditioning, Recall, and Extinction.

PubMed

Bernier, Brian E; Lacagnina, Anthony F; Ayoub, Adam; Shue, Francis; Zemelman, Boris V; Krasne, Franklin B; Drew, Michael R

2017-06-28

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 long-standing question about the role of DG in memory and provide insight into how disorders affecting DG, including aging, stress, and depression, influence cognitive processes. Copyright © 2017 the authors 0270-6474/17/376359-13$15.00/0.

The Kuleshov Effect: the influence of contextual framing on emotional attributions

PubMed Central

Mobbs, Dean; Weiskopf, Nikolaus; Lau, Hakwan C.; Featherstone, Eric; Dolan, Ray J.; Frith, Chris D.

2006-01-01

Filmmakers have long recognized the importance of editing techniques to guide the audiences' perceptions and enhance the impact of a scene. We demonstrate behaviorally that pairing identical faces with either neutral or emotionally salient contextual movies, an editing technique referred to as the ‘Kuleshov Effect’, results in both altered attributions of facial expression and mental-state. Using functional neuroimaging (fMRI), we show that faces paired with emotional movies enhance BOLD responses in the bilateral temporal pole, anterior cingulate cortices, amygdala and bilateral superior temporal sulcus relative to identical faces juxtaposed with neutral movies. An interaction was observed in the right amygdala when subtle happy and fear faces were juxtaposed with positive and negative movies, respectively. An interaction between happy faces and negative context was also observed in bilateral amygdala suggesting that the amygdala may act to prime or tag affective value to faces. A parametric modulation of BOLD signal by attribution ratings indicated a dissociation between ventrolateral and the ventromedial prefrontal cortex for negative and positive contextually evoked attributions, respectively. These prefrontal regions may act to guide appropriate choices across altering contexts. Together, these findings offer a neurobiological basis for contextual framing effects on social attributions. PMID:17339967

The Kuleshov Effect: the influence of contextual framing on emotional attributions.

PubMed

Mobbs, Dean; Weiskopf, Nikolaus; Lau, Hakwan C; Featherstone, Eric; Dolan, Ray J; Frith, Chris D

2006-09-01

Filmmakers have long recognized the importance of editing techniques to guide the audiences' perceptions and enhance the impact of a scene. We demonstrate behaviorally that pairing identical faces with either neutral or emotionally salient contextual movies, an editing technique referred to as the 'Kuleshov Effect', results in both altered attributions of facial expression and mental-state. Using functional neuroimaging (fMRI), we show that faces paired with emotional movies enhance BOLD responses in the bilateral temporal pole, anterior cingulate cortices, amygdala and bilateral superior temporal sulcus relative to identical faces juxtaposed with neutral movies. An interaction was observed in the right amygdala when subtle happy and fear faces were juxtaposed with positive and negative movies, respectively. An interaction between happy faces and negative context was also observed in bilateral amygdala suggesting that the amygdala may act to prime or tag affective value to faces. A parametric modulation of BOLD signal by attribution ratings indicated a dissociation between ventrolateral and the ventromedial prefrontal cortex for negative and positive contextually evoked attributions, respectively. These prefrontal regions may act to guide appropriate choices across altering contexts. Together, these findings offer a neurobiological basis for contextual framing effects on social attributions.

Mice with a fra-1 knock-in into the c-fos locus show impaired spatial but regular contextual learning and normal LTP.

PubMed

Gass, Peter; Fleischmann, Alexander; Hvalby, Oivind; Jensen, Vidar; Zacher, Christiane; Strekalova, Tatyana; Kvello, Ane; Wagner, Erwin F; Sprengel, Rolf

2004-11-04

The immediate early gene c-fos is part of the AP-1 transcription factor complex, which is involved in molecular mechanisms underlying learning and memory. Mice that lack c-Fos in the brain show impairments in spatial reference and contextual learning, and also exhibit a reduced long-term potentiation of synaptic transmission (LTP) at CA3-to-CA1 synapses. In the present study, we investigated mice in which c-fos was deleted and replaced by fra-1 (c-fos(fra-1) mice) to determine whether other members of the c-fos gene family can substitute for the functions of the c-fos gene. In c-fos(fra-1) mice, both CA3-to-CA1 LTP and contextual learning in a Pavlovian fear conditioning task were similar to wild-type littermates, indicating that Fra-1 expression restored the impairments caused by brain-specific c-Fos depletion. However, c-Fos-mediated learning deficits in a reference memory task of the Morris watermaze were also present in c-fos(fra-1) mice. These findings suggest that different c-Fos target genes are involved in LTP, contextual learning, and spatial reference memory formation.

Intraperitoneal sertraline and fluvoxamine increase contextual fear conditioning but are without effect on overshadowing between cues

PubMed Central

Cassaday, H.J.; Thur, K.E.

2015-01-01

Treatment with selective serotonin reuptake inhibitors (SSRIs) can reduce contextual conditioning. Since contexts comprise a variety of potentially competing cues, impaired overshadowing may provide an account of such effects. The present study therefore compared the effects of two SSRIs on overshadowing and contextual conditioning, testing suppression of an ongoing behavioral response (licking) by cues previously paired with foot shock. Conditioning to a 5 s light stimulus was reduced when it was presented in compound with a 5 s noise, thus overshadowing was demonstrated. In two experiments, this overshadowing was unaffected by treatment with either sertraline or fluvoxamine. However, unconditioned suppression to the noise (tested in a control group previously conditioned to the light alone) was reduced after sertraline (10 mg/kg, i.p.). The successful demonstration of overshadowing required the use of a second conditioning session or an additional conditioning trial within the same conditioning session. Neither weak nor strong overshadowing (of the light by the tone) was affected by any drug treatment. Moreover, counter to prediction, conditioning to contextual cues was increased rather than impaired by treatment with sertraline (10 mg/kg, i.p.) and fluvoxamine (30 mg/kg, i.p.). PMID:25532461

Intraperitoneal sertraline and fluvoxamine increase contextual fear conditioning but are without effect on overshadowing between cues.

PubMed

Cassaday, H J; Thur, K E

2015-02-01

Treatment with selective serotonin reuptake inhibitors (SSRIs) can reduce contextual conditioning. Since contexts comprise a variety of potentially competing cues, impaired overshadowing may provide an account of such effects. The present study therefore compared the effects of two SSRIs on overshadowing and contextual conditioning, testing suppression of an ongoing behavioral response (licking) by cues previously paired with foot shock. Conditioning to a 5 s light stimulus was reduced when it was presented in compound with a 5 s noise, thus overshadowing was demonstrated. In two experiments, this overshadowing was unaffected by treatment with either sertraline or fluvoxamine. However, unconditioned suppression to the noise (tested in a control group previously conditioned to the light alone) was reduced after sertraline (10 mg/kg, i.p.). The successful demonstration of overshadowing required the use of a second conditioning session or an additional conditioning trial within the same conditioning session. Neither weak nor strong overshadowing (of the light by the tone) was affected by any drug treatment. Moreover, counter to prediction, conditioning to contextual cues was increased rather than impaired by treatment with sertraline (10 mg/kg, i.p.) and fluvoxamine (30 mg/kg, i.p.). Copyright © 2015. Published by Elsevier Inc.

Different role of the ventral medial prefrontal cortex on modulation of innate and associative learned fear.

PubMed

Lisboa, S F; Stecchini, M F; Corrêa, F M A; Guimarães, F S; Resstel, L B M

2010-12-15

Reversible inactivation of the ventral portion of medial prefrontal cortex (vMPFC) of the rat brain has been shown to induce anxiolytic-like effects in animal models based on associative learning. The role of this brain region in situations involving innate fear, however, is still poorly understood, with several contradictory results in the literature. The objective of the present work was to verify in male Wistar rats the effects of vMPFC administration of cobalt chloride (CoCl(2)), a selective inhibitor of synaptic activity, in rats submitted to two models based on innate fear, the elevated plus-maze (EPM) and light-dark box (LDB), comparing the results with those obtained in two models involving associative learning, the contextual fear conditioning (CFC) and Vogel conflict (VCT) tests. The results showed that, whereas CoCl(2) induced anxiolytic-like effects in the CFC and VCT tests, it enhanced anxiety in rats submitted to the EPM and LDB. Together these results indicate that the vMPFC plays an important but complex role in the modulation of defensive-related behaviors, which seems to depend on the nature of the anxiety/fear inducing stimuli. Copyright © 2010 IBRO. Published by Elsevier Ltd. All rights reserved.

Effects of fear of abuse and possible STI acquisition on the sexual behavior of young African American women.

PubMed

Raiford, Jerris L; Diclemente, Ralph J; Wingood, Gina M

2009-06-01

We examined the interactive effects of fear of abuse and knowledge of sexually transmitted infections (STIs) on sexual risk behaviors in a sample of young African American women. We recruited 715 young African American women aged 15 to 21 years from a variety of health clinics and assessed them for fear of abuse because of negotiating condom use, knowledge of STIs, and several sexual risk behaviors. Overall, 75% of young African American women reported inconsistent condom use in the past 60 days. Surprisingly, under relatively higher levels of fear, young women with high STI knowledge were more likely than were those with low STI knowledge to exhibit inconsistent condom use in the past 60 days (89% vs 80%; chi(2) = 4.32; P < or = .04) and during the last sexual intercourse with a main sexual partner (76% vs 70%; chi(2) = 8.06; P < or = .01). Most HIV prevention interventions focus on increasing knowledge about the transmission of STIs. However, other contextual factors such as fear of abuse because of negotiating condom use may heighten the risk of HIV infection. Our findings highlight the need for combining dating violence prevention activities with STI and HIV prevention programs targeting young African American women.

From Foreground to Background: How Task-Neutral Context Influences Contextual Cueing of Visual Search.

PubMed

Zang, Xuelian; Geyer, Thomas; Assumpção, Leonardo; Müller, Hermann J; Shi, Zhuanghua

2016-01-01

Selective attention determines the effectiveness of implicit contextual learning (e.g., Jiang and Leung, 2005). Visual foreground-background segmentation, on the other hand, is a key process in the guidance of attention (Wolfe, 2003). In the present study, we examined the impact of foreground-background segmentation on contextual cueing of visual search in three experiments. A visual search display, consisting of distractor 'L's and a target 'T', was overlaid on a task-neutral cuboid on the same depth plane (Experiment 1), on stereoscopically separated depth planes (Experiment 2), or spread over the entire display on the same depth plane (Experiment 3). Half of the search displays contained repeated target-distractor arrangements, whereas the other half was always newly generated. The task-neutral cuboid was constant during an initial training session, but was either rotated by 90° or entirely removed in the subsequent test sessions. We found that the gains resulting from repeated presentation of display arrangements during training (i.e., contextual-cueing effects) were diminished when the cuboid was changed or removed in Experiment 1, but remained intact in Experiments 2 and 3 when the cuboid was placed in a different depth plane, or when the items were randomly spread over the whole display but not on the edges of the cuboid. These findings suggest that foreground-background segmentation occurs prior to contextual learning, and only objects/arrangements that are grouped as foreground are learned over the course of repeated visual search.

From Foreground to Background: How Task-Neutral Context Influences Contextual Cueing of Visual Search

PubMed Central

Zang, Xuelian; Geyer, Thomas; Assumpção, Leonardo; Müller, Hermann J.; Shi, Zhuanghua

2016-01-01

Selective attention determines the effectiveness of implicit contextual learning (e.g., Jiang and Leung, 2005). Visual foreground-background segmentation, on the other hand, is a key process in the guidance of attention (Wolfe, 2003). In the present study, we examined the impact of foreground-background segmentation on contextual cueing of visual search in three experiments. A visual search display, consisting of distractor ‘L’s and a target ‘T’, was overlaid on a task-neutral cuboid on the same depth plane (Experiment 1), on stereoscopically separated depth planes (Experiment 2), or spread over the entire display on the same depth plane (Experiment 3). Half of the search displays contained repeated target-distractor arrangements, whereas the other half was always newly generated. The task-neutral cuboid was constant during an initial training session, but was either rotated by 90° or entirely removed in the subsequent test sessions. We found that the gains resulting from repeated presentation of display arrangements during training (i.e., contextual-cueing effects) were diminished when the cuboid was changed or removed in Experiment 1, but remained intact in Experiments 2 and 3 when the cuboid was placed in a different depth plane, or when the items were randomly spread over the whole display but not on the edges of the cuboid. These findings suggest that foreground-background segmentation occurs prior to contextual learning, and only objects/arrangements that are grouped as foreground are learned over the course of repeated visual search. PMID:27375530

The Contextual Effect of School Satisfaction on Health-Risk Behaviors in Japanese High School Students

ERIC Educational Resources Information Center

Takakura, Minoru; Wake, Norie; Kobayashi, Minoru

2010-01-01

Background: The importance of school contextual effects on health and well-being among young people is currently recognized. This study examines the contextual effects of school satisfaction as well as the effects of individual-level school satisfaction on health-risk behaviors in Japanese high school students. Methods: Self-administered…

Contextual view including south (rear) of building 925, exercise in ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

Contextual view including south (rear) of building 925, exercise in foreground, and modern buildings in background. Facing northwest. - Travis Air Force Base, Building No. 925, W Street, Fairfield, Solano County, CA

Temporal and peripheral extraction of contextual cues from scenes during visual search.

PubMed

Koehler, Kathryn; Eckstein, Miguel P

2017-02-01

Scene context is known to facilitate object recognition and guide visual search, but little work has focused on isolating image-based cues and evaluating their contributions to eye movement guidance and search performance. Here, we explore three types of contextual cues (a co-occurring object, the configuration of other objects, and the superordinate category of background elements) and assess their joint contributions to search performance in the framework of cue-combination and the temporal unfolding of their extraction. We also assess whether observers' ability to extract each contextual cue in the visual periphery is a bottleneck that determines the utilization and contribution of each cue to search guidance and decision accuracy. We find that during the first four fixations of a visual search task observers first utilize the configuration of objects for coarse eye movement guidance and later use co-occurring object information for finer guidance. In the absence of contextual cues, observers were suboptimally biased to report the target object as being absent. The presence of the co-occurring object was the only contextual cue that had a significant effect in reducing decision bias. The early influence of object-based cues on eye movements is corroborated by a clear demonstration of observers' ability to extract object cues up to 16° into the visual periphery. The joint contributions of the cues to decision search accuracy approximates that expected from the combination of statistically independent cues and optimal cue combination. Finally, the lack of utilization and contribution of the background-based contextual cue to search guidance cannot be explained by the availability of the contextual cue in the visual periphery; instead it is related to background cues providing the least inherent information about the precise location of the target in the scene.

Effects of Pharmacologic and Genetic Inhibition of Alk on Cognitive Impairments in NF1 Mutant Mice

DTIC Science & Technology

2016-08-01

impairments. 15. SUBJECT TERMS cognitive performance, pharmacological inhibition, spatial memory , hippocampus 16. SECURITY CLASSIFICATION OF: 17...mouse model; hippocampus ; pharmacological inhibition; spatial memory 2 ACCOMPLISHMENTS: ▪ Major goals of the project Specific Aim (months 1-24...speeds seen in the water maze (Fig. 2). Contextual fear learning and memory Next the mice were tested for acquisition and extinction of hippocampus

A Systematic Review of Individual and Contextual Factors Affecting ART Initiation, Adherence, and Retention for HIV-Infected Pregnant and Postpartum Women

PubMed Central

Hodgson, Ian; Plummer, Mary L.; Konopka, Sarah N.; Colvin, Christopher J.; Jonas, Edna; Albertini, Jennifer; Amzel, Anouk; Fogg, Karen P.

2014-01-01

Background Despite progress reducing maternal mortality, HIV-related maternal deaths remain high, accounting, for example, for up to 24 percent of all pregnancy-related deaths in sub-Saharan Africa. Antiretroviral therapy (ART) is effective in improving outcomes among HIV-infected pregnant and postpartum women, yet rates of initiation, adherence, and retention remain low. This systematic literature review synthesized evidence about individual and contextual factors affecting ART use among HIV-infected pregnant and postpartum women. Methods Searches were conducted for studies addressing the population (HIV-infected pregnant and postpartum women), intervention (ART), and outcomes of interest (initiation, adherence, and retention). Quantitative and qualitative studies published in English since January 2008 were included. Individual and contextual enablers and barriers to ART use were extracted and organized thematically within a framework of individual, interpersonal, community, and structural categories. Results Thirty-four studies were included in the review. Individual-level factors included both those within and outside a woman’s awareness and control (e.g., commitment to child’s health or age). Individual-level barriers included poor understanding of HIV, ART, and prevention of mother-to-child transmission, and difficulty managing practical demands of ART. At an interpersonal level, disclosure to a spouse and spousal involvement in treatment were associated with improved initiation, adherence, and retention. Fear of negative consequences was a barrier to disclosure. At a community level, stigma was a major barrier. Key structural barriers and enablers were related to health system use and engagement, including access to services and health worker attitudes. Conclusions To be successful, programs seeking to expand access to and continued use of ART by integrating maternal health and HIV services must identify and address the relevant barriers and enablers in their own context that are described in this review. Further research on this population, including those who drop out of or never access health services, is needed to inform effective implementation. PMID:25372479

Modulation of Gene Expression in Contextual Fear Conditioning in the Rat

PubMed Central

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

2013-01-01

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

SNAP-25 in hippocampal CA3 region is required for long-term memory formation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hou Qiuling; Gao Xiang; Lu Qi

SNAP-25 is a synaptosomal protein of 25 kDa, a key component of synaptic vesicle-docking/fusion machinery, and plays a critical role in exocytosis and neurotransmitter release. We previously reported that SNAP-25 in the hippocampal CA1 region is involved in consolidation of contextual fear memory and water-maze spatial memory (Hou et al. European J Neuroscience, 20: 1593-1603, 2004). SNAP-25 is expressed not only in the CA1 region, but also in the CA3 region, and the SNAP-25 mRNA level in the CA3 region is higher than in the CA1 region. Here, we provide evidence that SNAP-25 in the CA3 region is also involvedmore » in learning/memory. Intra-CA3 infusion of SNAP-25 antisense oligonucleotide impaired both long-term contextual fear memory and water-maze spatial memory, with short-term memory intact. Furthermore, the SNAP-25 antisense oligonucleotide suppressed the long-term potentiation (LTP) of field excitatory post-synaptic potential (fEPSP) in the mossy-fiber pathway (DG-CA3 pathway), with no effect on paired-pulse facilitation of the fEPSP. These results are consistent with the notion that SNAP-25 in the hippocampal CA3 region is required for long-term memory formation.« less

Shared mechanism for emotion processing in adolescents with and without autism

PubMed Central

Ioannou, Christina; Zein, Marwa El; Wyart, Valentin; Scheid, Isabelle; Amsellem, Frédérique; Delorme, Richard; Chevallier, Coralie; Grèzes, Julie

2017-01-01

Although, the quest to understand emotional processing in individuals with Autism Spectrum Disorders (ASD) has led to an impressive number of studies, the picture that emerges from this research remains inconsistent. Some studies find that Typically Developing (TD) individuals outperform those with ASD in emotion recognition tasks, others find no such difference. In this paper, we move beyond focusing on potential group differences in behaviour to answer what we believe is a more pressing question: do individuals with ASD use the same mechanisms to process emotional cues? To this end, we rely on model-based analyses of participants’ accuracy during an emotion categorisation task in which displays of anger and fear are paired with direct vs. averted gaze. Behavioural data of 20 ASD and 20 TD adolescents revealed that the ASD group displayed lower overall performance. Yet, gaze direction had a similar impact on emotion categorisation in both groups, i.e. improved accuracy for salient combinations (anger-direct, fear-averted). Critically, computational modelling of participants’ behaviour reveals that the same mechanism, i.e. increased perceptual sensitivity, underlies the contextual impact of gaze in both groups. We discuss the specific experimental conditions that may favour emotion processing and the automatic integration of contextual information in ASD. PMID:28218248

Falls and fear of falling among community-dwelling seniors: the dynamic tension between exercising precaution and striving for independence.

PubMed

Ward-Griffin, Catherine; Hobson, Sandra; Melles, Pauline; Kloseck, Marita; Vandervoort, Anthony; Crilly, Richard

2004-01-01

The purpose of this phenomenological study was to explore the everyday experience of community-dwelling elders, with particular attention to seniors' perceptions of safety, fear of falling, independence, and quality of life. We also aimed to identify contextual factors that influence the health of elders who had fallen and/or had a fear of falling. Data from in-depth interviews with a purposeful sample (n = 9) of elders were analysed using interpretative analysis procedures. Both individual and team analysis was undertaken until interpretations of the experiences of the participants were inductively developed and crystallized into a holistic interpretation of the participants' shared experience. The holistic experience was comprised of two opposing, dynamic life forces: exercising precaution and striving for independence. Within each life force, participants used five major strategies that simultaneously constrained and expanded their life space. Health-promoting practice and policy implications, as well as areas for further research, are discussed.

HIV Diagnosis, Linkage to Care, and Retention among Men Who Have Sex with Men and Transgender Women in Guatemala City

PubMed Central

Barrington, Clare; Knudston, Kelly; Bailey, Olga Alicia Paz; Aguilar, Jose Manuel; Loya-Montiel, Marilu Itzel; Morales-Miranda, Sonia

2017-01-01

Men who have sex with men (MSM) and transgender women are disproportionately affected by HIV in Guatemala, yet little is known about their experiences with diagnosis, linkage to care, and retention. We conducted qualitative interviews with 26 MSM and transgender women living with HIV in Guatemala City. HIV diagnosis experiences changed over time with increasing asymptomatic testing at non-governmental organizations. Fear of the physical and social impacts of HIV delayed testing, acceptance of diagnosis, and linkage to HIV care. These fears were driven by layered stigma and discrimination due to non-normative gender expressions and/or sexual orientation. Retention-specific determinants included HIV clinic dynamics and limited employment opportunities. There is an urgent need to improve support systems for early testing and linkage to care and to expand employment opportunities. Stigma and discrimination must be addressed at the family, clinic and contextual levels to reduce fear of diagnosis and improve access to care. PMID:27818436

AgRP Neural Circuits Mediate Adaptive Behaviors in the Starved State

PubMed Central

Padilla, Stephanie L.; Qiu, Jian; Soden, Marta E.; Sanz, Elisenda; Nestor, Casey C; Barker, Forrest D.; Quintana, Albert; Zweifel, Larry S.; Rønnekleiv, Oline K.; Kelly, Martin J.; Palmiter, Richard D.

2016-01-01

In the face of starvation animals will engage in high-risk behaviors that would normally be considered maladaptive. Starving rodents for example will forage in areas that are more susceptible to predators and will also modulate aggressive behavior within a territory of limited or depleted nutrients. The neural basis of these adaptive behaviors likely involves circuits that link innate feeding, aggression, and fear. Hypothalamic AgRP neurons are critically important for driving feeding and project axons to brain regions implicated in aggression and fear. Using circuit-mapping techniques, we define a disynaptic network originating from a subset of AgRP neurons that project to the medial nucleus of the amygdala and then to the principle bed nucleus of the stria terminalis, which plays a role in suppressing territorial aggression and reducing contextual fear. We propose that AgRP neurons serve as a master switch capable of coordinating behavioral decisions relative to internal state and environmental cues. PMID:27019015

Contextual view of ILWU Hall, facing northwest with commercial port ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

Contextual view of ILWU Hall, facing northwest with commercial port buildings visible in the background - International Longshoremen's & Warehousemen's Union Hall, Naval Civil Engineering Laboratory, Port Hueneme Road, Port Hueneme, Ventura County, CA

Contextual view of ILWU Hall, facing southsouthwest, with ocean bank ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

Contextual view of ILWU Hall, facing south-southwest, with ocean bank visible in the background - International Longshoremen's & Warehousemen's Union Hall, Naval Civil Engineering Laboratory, Port Hueneme Road, Port Hueneme, Ventura County, CA

Different types of exercise induce differential effects on neuronal adaptations and memory performance.

PubMed

Lin, Tzu-Wei; Chen, Shean-Jen; Huang, Tung-Yi; Chang, Chia-Yuan; Chuang, Jih-Ing; Wu, Fong-Sen; Kuo, Yu-Min; Jen, Chauying J

2012-01-01

Different exercise paradigms show differential effects on various forms of memory. We hypothesize that the differential effects of exercises on memory performance are caused by different neuroplasticity changes in relevant brain regions in response to different exercise trainings. We examined the effects of treadmill running (TR) and wheel running (WR) on the Pavlovian fear conditioning task that assesses learning and memory performance associated with the amygdala (cued conditioning) and both the amygdala and hippocampus (contextual conditioning). The skeletal muscle citrate synthase activity, an indicator of aerobic capacity, was elevated in rats received 4 w of TR, but not WR. While both TR and WR elevated the contextual conditional response, only TR facilitated the cued conditional response. Using a single-neuron labeling technique, we found that while both TR and MR enlarged the dendritic field and increased the spine density in hippocampal CA3 neurons, only TR showed these effects in basolateral amygdalar neurons. Moreover, both types of exercise upregulated synaptic proteins (i.e., TrkB and SNAP-25) in the hippocampus; however only TR showed similar effects in the amygdala. Injection of K252a, a TrkB kinase inhibitor, in the dorsal hippocampus or basolateral amygdala abolished the exercise-facilitated contextual or cued fear learning and memory performance, respectively, regardless of the types of exercise. In summary, our results supported that different types of exercise affect the performance of learning and memory via BDNF-TrkB signaling and neuroplasticity in specific brain regions. The brain region-specific neuronal adaptations are possibly induced by various levels of intensity/stress elicited by different types of exercise. Copyright © 2011 Elsevier Inc. All rights reserved.

Chronic valproic acid administration impairs contextual memory and dysregulates hippocampal GSK-3β in rats.

PubMed

Sintoni, Silvia; Kurtys, Ewelina; Scandaglia, Marilyn; Contestabile, Antonio; Monti, Barbara

2013-05-01

Valproic acid (VPA), a long-standing anti-epileptic and anti-manic drug, exerts multiple actions in the nervous system through various molecular mechanisms. Neuroprotective properties have been attributed to VPA in different models of neurodegeneration, but contrasting results on its improvement of learning and memory have been reported in non-pathologic conditions. In the present study, we have tested on a hippocampal-dependent learning test, the contextual fear conditioning, the effect of chronic VPA administration through alimentary supplementation that allows relatively steady concentrations to be reached by a drug otherwise very rapidly eliminated in rodents. Contextual fear memory was significantly impaired in rats chronically treated with VPA for 4 weeks. To understand the cellular and molecular correlates of this amnesic effect with particular regard to hippocampus, we addressed three putatively memory-related targets of VPA action in this brain area, obtaining the following main results: i) chronic VPA promoted an increase of post-translational modifications of histone H3 (acetylation and phosphorylation) known to favor gene transcription; ii) adult neurogenesis in the dentate gyrus, which has been controversially reported to be affected by VPA, was unchanged; and iii) GSK-3β, a kinase playing a key role in hippocampal plasticity, as well as in learning and memory, was dysregulated by VPA treatment. These results point at GSK-3β dysregulation in the hippocampus as an important parameter in the amnesic effect of VPA. The VPA amnesic effect in the animal model here reported is also supported by some observations in patients and, therefore, it should be taken into account and monitored in VPA-based therapies. Copyright © 2013 Elsevier Inc. All rights reserved.

Increases in extracellular zinc in the amygdala in acquisition and recall of fear experience and their roles in response to fear.

PubMed

Takeda, A; Tamano, H; Imano, S; Oku, N

2010-07-14

The amygdala is enriched with histochemically reactive zinc, which is dynamically coupled with neuronal activity and co-released with glutamate. The dynamics of the zinc in the amygdala was analyzed in rats, which were subjected to inescapable stress, to understand the role of the zinc in emotional behavior. In the communication box, two rats were subjected to foot shock stress and anxiety stress experiencing emotional responses of foot-shocked rat under amygdalar perfusion. Extracellular zinc was increased by foot shock stress, while decreased by anxiety stress, suggesting that the differential changes in extracellular zinc are associated with emotional behavior. In rats conditioned with foot shock, furthermore, extracellular zinc was increased again in the recall of fear (foot shock) in the same box without foot shock. When this recall was performed under perfusion with CaEDTA, a membrane-impermeable zinc chelator, to examine the role of the increase in extracellular zinc, the time of freezing behavior was more increased, suggesting that zinc released in the lateral amygdala during the recall of fear participates in freezing behavior. To examine the role of the increase in extracellular zinc during fear conditioning, fear conditioning was also performed under perfusion with CaEDTA. The time of freezing behavior was more increased in the contextual recall, suggesting that zinc released in the lateral nucleus during fear conditioning also participates in freezing behavior in the recall. In brain slice experiment, CaEDTA enhanced presynaptic activity (exocytosis) in the lateral nucleus after activation of the entorhinal cortex. The present paper demonstrates that zinc released in the lateral amygdala may participate in emotional behavior in response to fear. Copyright 2010 IBRO. Published by Elsevier Ltd. All rights reserved.

Olfactory systems and neural circuits that modulate predator odor fear

PubMed Central

Takahashi, Lorey K.

2014-01-01

When prey animals detect the odor of a predator a constellation of fear-related autonomic, endocrine, and behavioral responses rapidly occur to facilitate survival. How olfactory sensory systems process predator odor and channel that information to specific brain circuits is a fundamental issue that is not clearly understood. However, research in the last 15 years has begun to identify some of the essential features of the sensory detection systems and brain structures that underlie predator odor fear. For instance, the main (MOS) and accessory olfactory systems (AOS) detect predator odors and different types of predator odors are sensed by specific receptors located in either the MOS or AOS. However, complex predator chemosignals may be processed by both the MOS and AOS, which complicate our understanding of the specific neural circuits connected directly and indirectly from the MOS and AOS to activate the physiological and behavioral components of unconditioned and conditioned fear. Studies indicate that brain structures including the dorsal periaqueductal gray (DPAG), paraventricular nucleus (PVN) of the hypothalamus, and the medial amygdala (MeA) appear to be broadly involved in predator odor induced autonomic activity and hypothalamic-pituitary-adrenal (HPA) stress hormone secretion. The MeA also plays a key role in predator odor unconditioned fear behavior and retrieval of contextual fear memory associated with prior predator odor experiences. Other neural structures including the bed nucleus of the stria terminalis and the ventral hippocampus (VHC) appear prominently involved in predator odor fear behavior. The basolateral amygdala (BLA), medial hypothalamic nuclei, and medial prefrontal cortex (mPFC) are also activated by some but not all predator odors. Future research that characterizes how distinct predator odors are uniquely processed in olfactory systems and neural circuits will provide significant insights into the differences of how diverse predator odors activate fear. PMID:24653685

Olfactory systems and neural circuits that modulate predator odor fear.

PubMed

Takahashi, Lorey K

2014-01-01

When prey animals detect the odor of a predator a constellation of fear-related autonomic, endocrine, and behavioral responses rapidly occur to facilitate survival. How olfactory sensory systems process predator odor and channel that information to specific brain circuits is a fundamental issue that is not clearly understood. However, research in the last 15 years has begun to identify some of the essential features of the sensory detection systems and brain structures that underlie predator odor fear. For instance, the main (MOS) and accessory olfactory systems (AOS) detect predator odors and different types of predator odors are sensed by specific receptors located in either the MOS or AOS. However, complex predator chemosignals may be processed by both the MOS and AOS, which complicate our understanding of the specific neural circuits connected directly and indirectly from the MOS and AOS to activate the physiological and behavioral components of unconditioned and conditioned fear. Studies indicate that brain structures including the dorsal periaqueductal gray (DPAG), paraventricular nucleus (PVN) of the hypothalamus, and the medial amygdala (MeA) appear to be broadly involved in predator odor induced autonomic activity and hypothalamic-pituitary-adrenal (HPA) stress hormone secretion. The MeA also plays a key role in predator odor unconditioned fear behavior and retrieval of contextual fear memory associated with prior predator odor experiences. Other neural structures including the bed nucleus of the stria terminalis and the ventral hippocampus (VHC) appear prominently involved in predator odor fear behavior. The basolateral amygdala (BLA), medial hypothalamic nuclei, and medial prefrontal cortex (mPFC) are also activated by some but not all predator odors. Future research that characterizes how distinct predator odors are uniquely processed in olfactory systems and neural circuits will provide significant insights into the differences of how diverse predator odors activate fear.

Modulation of fear memory by dietary polyunsaturated fatty acids via cannabinoid receptors.

PubMed

Yamada, Daisuke; Takeo, Jiro; Koppensteiner, Peter; Wada, Keiji; Sekiguchi, Masayuki

2014-07-01

Although the underlying mechanism remains unknown, several studies have suggested benefits of n-3 long-chain polyunsaturated fatty acid (PUFA) for patients with anxiety disorders. Elevated fear is thought to contribute to the pathogenesis of particular anxiety disorders. The aim of the present study was to evaluate whether the dietary n-3 to n-6 PUFA (3:6) ratio influences fear memory. For this purpose, the effects of various dietary 3:6 ratios on fear memory were examined in mice using contextual fear conditioning, and the effects of these diets on central synaptic transmission were examined to elucidate the mechanism of action of PUFA. We found that fear memory correlated negatively with dietary, serum, and brain 3:6 ratios in mice. The low fear memory in mice fed a high 3:6 ratio diet was increased by the cannabinoid CB1 receptor antagonist rimonabant, reaching a level seen in mice fed a low 3:6 ratio diet. The agonist sensitivity of CB1 receptor was enhanced in the basolateral nucleus of the amygdala (BLA) of mice fed a high 3:6 ratio diet, compared with that of mice fed a low 3:6 ratio diet. Similar enhancement was induced by pharmacological expulsion of cholesterol in the neuronal membrane of brain slices from mice fed a low 3:6 ratio diet. CB1 receptor-mediated short-term synaptic plasticity was facilitated in pyramidal neurons of the BLA in mice fed a high 3:6 ratio diet. These results suggest that the ratio of n-3 to n-6 PUFA is a factor regulating fear memory via cannabinoid CB1 receptors.

Adolescent social defeat alters N-methyl-D-aspartic acid receptor expression and impairs fear learning in adulthood.

PubMed

Novick, Andrew M; Mears, Mackenzie; Forster, Gina L; Lei, Yanlin; Tejani-Butt, Shanaz M; Watt, Michael J

2016-05-01

Repeated social defeat of adolescent male rats results in adult mesocortical dopamine hypofunction, impaired working memory, and increased contextual anxiety-like behavior. Given the role of glutamate in dopamine regulation, cognition, and fear and anxiety, we investigated potential changes to N-methyl-D-aspartic acid (NMDA) receptors following adolescent social defeat. As both NMDA receptors and mesocortical dopamine are implicated in the expression and extinction of conditioned fear, a separate cohort of rats was challenged with a classical fear conditioning paradigm to investigate whether fear learning is altered by adolescent defeat. Quantitative autoradiography was used to measure 3H-MK-801 binding to NMDA receptors in regions of the medial prefrontal cortex, caudate putamen, nucleus accumbens, amygdala and hippocampus. Assessment of fear learning was achieved using an auditory fear conditioning paradigm, with freezing toward the auditory tone used as a measure of conditioned fear. Compared to controls, adolescent social defeat decreased adult NMDA receptor expression in the infralimbic region of the prefrontal cortex and central amygdala, while increasing expression in the CA3 region of the hippocampus. Previously defeated rats also displayed decreased conditioned freezing during the recall and first extinction periods, which may be related to the observed decreases and increases in NMDA receptors within the central amygdala and CA3, respectively. The alteration in NMDA receptors seen following adolescent social defeat suggests that dysfunction of glutamatergic systems, combined with mesocortical dopamine deficits, likely plays a role in the some of the long-term behavioral consequences of social stressors in adolescence seen in both preclinical and clinical studies. Copyright © 2016 Elsevier B.V. All rights reserved.

Memory destabilization is critical for the success of the reactivation-extinction procedure.

PubMed

Piñeyro, Marcelo E; Ferrer Monti, Roque I; Alfei, Joaquín M; Bueno, Adrián M; Urcelay, Gonzalo P

2013-12-18

It has been suggested that, unlike pure extinction which typically results in the return of the fear response under a variety of circumstances, memory reactivation followed by extinction can attenuate the reemergence of conditioned fear. The reactivation-extinction procedure has attracted the attention of basic and clinical researchers due to its potential clinical value for the treatment of psychiatric conditions, such as anxiety and drug abuse disorders. However, mixed results have been achieved so far in replicating and understanding this paradigm. It has been proposed that memory destabilization could be critical in this sense. Using contextual fear conditioning in rats and midazolam as an amnesic agent, we first determined what reactivation conditions are necessary to destabilize the mnemonic trace. After establishing the conditions for memory destabilization, a series of experiments was conducted to determine if destabilization is critical for the success of the reactivation-extinction procedure. Data confirmed the importance of memory destabilization prior to extinction inside the reconsolidation window to attenuate spontaneous recovery and retard reacquisition of conditioned fear. The present report offers a candidate explanation of the discrepancy in results obtained with the reactivation-extinction procedure by different laboratories.

Memory destabilization is critical for the success of the reactivation–extinction procedure

PubMed Central

Piñeyro, Marcelo E.; Ferrer Monti, Roque I.; Alfei, Joaquín M.; Bueno, Adrián M.; Urcelay, Gonzalo P.

2014-01-01

It has been suggested that, unlike pure extinction which typically results in the return of the fear response under a variety of circumstances, memory reactivation followed by extinction can attenuate the reemergence of conditioned fear. The reactivation–extinction procedure has attracted the attention of basic and clinical researchers due to its potential clinical value for the treatment of psychiatric conditions, such as anxiety and drug abuse disorders. However, mixed results have been achieved so far in replicating and understanding this paradigm. It has been proposed that memory destabilization could be critical in this sense. Using contextual fear conditioning in rats and midazolam as an amnesic agent, we first determined what reactivation conditions are necessary to destabilize the mnemonic trace. After establishing the conditions for memory destabilization, a series of experiments was conducted to determine if destabilization is critical for the success of the reactivation–extinction procedure. Data confirmed the importance of memory destabilization prior to extinction inside the reconsolidation window to attenuate spontaneous recovery and retard reacquisition of conditioned fear. The present report offers a candidate explanation of the discrepancy in results obtained with the reactivation–extinction procedure by different laboratories. PMID:24353292

Rats with ventral hippocampal damage are impaired at various forms of learning including conditioned inhibition, spatial navigation, and discriminative fear conditioning to similar contexts.

PubMed

McDonald, Robert J; Balog, R J; Lee, Justin Q; Stuart, Emily E; Carrels, Brianna B; Hong, Nancy S

2018-10-01

The ventral hippocampus (vHPC) has been implicated in learning and memory functions that seem to differ from its dorsal counterpart. The goal of this series of experiments was to provide further insight into the functional contributions of the vHPC. Our previous work implicated the vHPC in spatial learning, inhibitory learning, and fear conditioning to context. However, the specific role of vHPC on these different forms of learning are not clear. Accordingly, we assessed the effects of neurotoxic lesions of the ventral hippocampus on retention of a conditioned inhibitory association, early versus late spatial navigation in the water task, and discriminative fear conditioning to context under high ambiguity conditions. The results showed that the vHPC was necessary for the expression of conditioned inhibition, early spatial learning, and discriminative fear conditioning to context when the paired and unpaired contexts have high cue overlap. We argue that this pattern of effects, combined with previous work, suggests a key role for vHPC in the utilization of broad contextual representations for inhibition and discriminative memory in high ambiguity conditions. Copyright © 2018 Elsevier B.V. All rights reserved.

Cholinergic regulation of fear learning and extinction.

PubMed

Wilson, Marlene A; Fadel, Jim R

2017-03-01

Cholinergic activation regulates cognitive function, particularly long-term memory consolidation. This Review presents an overview of the anatomical, neurochemical, and pharmacological evidence supporting the cholinergic regulation of Pavlovian contextual and cue-conditioned fear learning and extinction. Basal forebrain cholinergic neurons provide inputs to neocortical regions and subcortical limbic structures such as the hippocampus and amygdala. Pharmacological manipulations of muscarinic and nicotinic receptors support the role of cholinergic processes in the amygdala, hippocampus, and prefrontal cortex in modulating the learning and extinction of contexts or cues associated with threat. Additional evidence from lesion studies and analysis of in vivo acetylcholine release with microdialysis similarly support a critical role of cholinergic neurotransmission in corticoamygdalar or corticohippocampal circuits during acquisition of fear extinction. Although a few studies have suggested a complex role of cholinergic neurotransmission in the cellular plasticity essential for extinction learning, more work is required to elucidate the exact cholinergic mechanisms and physiological role of muscarinic and nicotinic receptors in these fear circuits. Such studies are important for elucidating the role of cholinergic neurotransmission in disorders such as posttraumatic stress disorder that involve deficits in extinction learning as well as for developing novel therapeutic approaches for such disorders. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

A robust animal model of state anxiety: fear-potentiated behaviour in the elevated plus-maze.

PubMed

Korte, S Mechiel; De Boer, Sietse F

2003-02-28

Fear (i.e., decreased percentage time spent on open-arm exploration) in the elevated plus-maze can be potentiated by prior inescapable stressor exposure, but not by escapable stress. The use of fear-potentiated plus-maze behaviour has several advantages as compared to more traditional animal models of anxiety. (a) In contrast to the traditional (spontaneous) elevated plus-maze, which measures innate fear of open spaces, fear-potentiated plus-maze behaviour reflects an enhanced anxiety state (allostatic state). This "state anxiety" can be defined as an unpleasant emotional arousal in face of threatening demands or dangers. A cognitive appraisal of threat is a prerequisite for the experience of this type of emotion. (b) Depending on the stressor used (e.g., fear of shock, predator odour, swim stress, restraint, social defeat, predator stress (cat)), this enhanced anxiety state can last from 90 min to 3 weeks. Stress effects are more severe when rats are isolated in comparison to group housing. (c) Drugs can be administered in the absence of the original stressor and after stressor exposure. As a consequence, retrieval mechanisms are not affected by drug treatment. (d) Fear-potentiated plus-maze behaviour is sensitive to proven/putative anxiolytics and anxiogenics which act via mechanisms related to the benzodiazepine-gamma-aminobutyric acid receptor, but it is also sensitive to corticotropin-releasing receptor antagonists and glucocorticoid receptor antagonists and serotonin receptor agonists/antagonists complex (high predictive validity). (e) Fear-potentiated plus-maze behaviour is very robust, and experiments can easily be replicated in other labs. (f) Fear-potentiated plus-maze behaviour can be measured both in males and females. (g) Neural mechanisms involved in contextual fear conditioning, fear potentiation and state anxiety can be studied.Thus, fear-potentiated plus-maze behaviour may be a valuable measure in the understanding of neural mechanisms involved in the development of anxiety disorders and in the search for novel anxiolytics. Finally, the involvement of corticotropin-releasing factor and corticosteroid-corticotropin-releasing factor interactions in the production of fear-potentiated plus-maze behaviour are discussed.

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

DTIC Science & Technology

2011-05-01

uring fear extinction in PTSD : an fMRI Study . CNS Neurosci Ther, print copy in press (originally published online 16 April 2010, at http://www3...alleviate one or more physiopathologies of PTSD . The effect of oxytocin on background anxiety in our fear- potentiated startle studies in rats is also...benefits for patients with PTSD . fear; anxiety; PTSD ; startle; social isolation 60 jrosen@udel.edu Table of Contents

Multilevel analysis of facial expressions of emotion and script: self-report (arousal and valence) and psychophysiological correlates.

PubMed

Balconi, Michela; Vanutelli, Maria Elide; Finocchiaro, Roberta

2014-09-26

The paper explored emotion comprehension in children with regard to facial expression of emotion. The effect of valence and arousal evaluation, of context and of psychophysiological measures was monitored. Indeed subjective evaluation of valence (positive vs. negative) and arousal (high vs. low), and contextual (facial expression vs. facial expression and script) variables were supposed to modulate the psychophysiological responses. Self-report measures (in terms of correct recognition, arousal and valence attribution) and psychophysiological correlates (facial electromyography, EMG, skin conductance response, SCR, and heart rate, HR) were observed when children (N = 26; mean age = 8.75 y; range 6-11 y) looked at six facial expressions of emotions (happiness, anger, fear, sadness, surprise, and disgust) and six emotional scripts (contextualized facial expressions). The competencies about the recognition, the evaluation on valence and arousal was tested in concomitance with psychophysiological variations. Specifically, we tested for the congruence of these multiple measures. Log-linear analysis and repeated measure ANOVAs showed different representations across the subjects, as a function of emotion. Specifically, children' recognition and attribution were well developed for some emotions (such as anger, fear, surprise and happiness), whereas some other emotions (mainly disgust and sadness) were less clearly represented. SCR, HR and EMG measures were modulated by the evaluation based on valence and arousal, with increased psychophysiological values mainly in response to anger, fear and happiness. As shown by multiple regression analysis, a significant consonance was found between self-report measures and psychophysiological behavior, mainly for emotions rated as more arousing and negative in valence. The multilevel measures were discussed at light of dimensional attribution model.

The strength of aversive and appetitive associations and maladaptive behaviors.

PubMed

Itzhak, Yossef; Perez-Lanza, Daniel; Liddie, Shervin

2014-08-01

Certain maladaptive behaviors are thought to be acquired through classical Pavlovian conditioning. Exaggerated fear response, which can develop through Pavlovian conditioning, is associated with acquired anxiety disorders such as post-traumatic stress disorders (PTSDs). Inflated reward-seeking behavior, which develops through Pavlovian conditioning, underlies some types of addictive behavior (e.g., addiction to drugs, food, and gambling). These maladaptive behaviors are dependent on associative learning and the development of long-term memory (LTM). In animal models, an aversive reinforcer (fear conditioning) encodes an aversive contextual and cued LTM. On the other hand, an appetitive reinforcer results in conditioned place preference (CPP) that encodes an appetitive contextual LTM. The literature on weak and strong associative learning pertaining to the development of aversive and appetitive LTM is relatively scarce; thus, this review is particularly focused on the strength of associative learning. The strength of associative learning is dependent on the valence of the reinforcer and the salience of the conditioned stimulus that ultimately sways the strength of the memory trace. Our studies suggest that labile (weak) aversive and appetitive LTM may share similar signaling pathways, whereas stable (strong) aversive and appetitive LTM is mediated through different pathways. In addition, we provide some evidence suggesting that extinction of aversive fear memory and appetitive drug memory is likely to be mediated through different signaling molecules. We put forward the importance of studies aimed to investigate the molecular mechanisms underlying the development of weak and strong memories (aversive and appetitive), which would ultimately help in the development of targeted pharmacotherapies for the management of maladaptive behaviors that arise from classical Pavlovian conditioning. © 2014 International Union of Biochemistry and Molecular Biology.

Ventral CA3 Activation Mediates Prophylactic Ketamine Efficacy Against Stress-Induced Depressive-like Behavior.

PubMed

Mastrodonato, Alessia; Martinez, Randy; Pavlova, Ina P; LaGamma, Christina T; Brachman, Rebecca A; Robison, Alfred J; Denny, Christine A

2018-02-23

We previously reported that a single injection of ketamine prior to stress protects against the onset of depressive-like behavior and attenuates learned fear. However, the molecular pathways and brain circuits underlying ketamine-induced stress resilience are still largely unknown. Here, we tested whether prophylactic ketamine administration altered neural activity in the prefrontal cortex and/or hippocampus. Mice were injected with saline or ketamine (30 mg/kg) 1 week before social defeat. Following behavioral tests assessing depressive-like behavior, mice were sacrificed and brains were processed to quantify ΔFosB expression. In a second set of experiments, mice were stereotaxically injected with viral vectors into ventral CA3 (vCA3) in order to silence or overexpress ΔFosB prior to prophylactic ketamine administration. In a third set of experiments, ArcCreER T2 mice, a line that allows for the indelible labeling of neural ensembles activated by a single experience, were used to quantify memory traces representing a contextual fear conditioning experience following prophylactic ketamine administration. Prophylactic ketamine administration increased ΔFosB expression in the ventral dentate gyrus and vCA3 of social defeat mice but not of control mice. Transcriptional silencing of ΔFosB activity in vCA3 inhibited prophylactic ketamine efficacy, while overexpression of ΔFosB mimicked and occluded ketamine's prophylactic effects. In ArcCreER T2 mice, ketamine administration altered memory traces representing the contextual fear conditioning experience in vCA3 but not in the ventral dentate gyrus. Our data indicate that prophylactic ketamine may be protective against a stressor by altering neural activity, specifically the neural ensembles representing an individual stressor in vCA3. Copyright © 2018 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Augmentation of the noradrenergic system in alpha-2 adrenergic receptor deficient mice: anatomical changes associated with enhanced fear memory.

PubMed

Davies, M Frances; Tsui, Janet Y; Flannery, Judy A; Li, Xiangqi; DeLorey, Timothy M; Hoffman, Brian B

2003-10-03

We have investigated sensitivity to the conditioned fear procedure of mice is influenced by the genetic deletion of alpha2A adrenoceptors (ARs). We observed a heightened freezing response in the discrete cue memory test in alpha2A AR knockout (alpha2A AR KO) mice and in D79N mice, a transgenic mouse strain with functionally impaired alpha2A ARs. No significant differences in contextual memory were observed between control and alpha2A AR KO or D79N mice suggesting a minimal role for the noradrenergic system in contextual memory. We speculated that the increased freezing response of the alpha2A AR KO and D79N mice in the discrete cue setting was due to increased release of norepinephrine evoked by the unconditioned footshock stimulus. In alpha2A AR KO mice we measured a doubling in the number of noradrenergic neurons in the locus coeruleus (LC) and a large increase in the cell volume of tyrosine hydroxylase positive neurons, likely due to selective preservation of large, multipolar neurons in the subcoeruleus. Hyperplasia of the noradrenergic neurons in the nucleus tractus solitarius, A5 and A7, was also observed. Alpha2A AR KO mice exhibit greater c-Fos expression in the LC compared to wild type mice suggesting that the LC neurons in the alpha2A AR KO mice were spontaneously more active. This study suggests that alpha2A ARs are involved in the development of the central noradrenergic system and raises the possibility that alterations in alpha2A AR expression may contribute to variations in fear and stress responses.

Differential modulation of changes in hippocampal-septal synaptic excitability by the amygdala as a function of either elemental or contextual fear conditioning in mice.

PubMed

Desmedt, A; Garcia, R; Jaffard, R

1998-01-01

Recent data obtained using a classic fear conditioning paradigm showed a dissociation between the retention of associations relative to contextual information (dependent on the hippocampal formation) and the retention of elemental associations (dependent on the amygdala). Furthermore, it was reported that conditioned emotional responses (CERs) could be dissociated from the recollection of the learning experience (declarative memory) in humans and from modifications of the hippocampal-septal excitability in animals. Our aim was to determine whether these two systems ("behavioral expression" system and "factual memory" system) interact by examining the consequences of amygdalar lesions (1) on the modifications of hippocampal-septal excitability and (2) on the behavioral expression of fear (freezing) resulting from an aversive conditioning during reexposure to conditional stimuli (CSs). During conditioning, to modulate the predictive nature of the context and of a discrete stimulus (tone) on the unconditional stimulus (US) occurrence, the phasic discrete CS was paired with the US or randomly distributed with regard to the US. After the lesion, the CER was dramatically reduced during reexposure to the CSs, whatever the type of acquisition. However, the changes in hippocampal-septal excitability persisted but were altered. For controls, a decrease in septal excitability was observed during reexposure to the conditioning context only for the "unpaired group" (predictive context case). Conversely, among lesioned subjects this decrease was observed in the "paired group" (predictive discrete CS case), whereas this decrease was significantly reduced in the unpaired group with respect to the matched control group. The amplitude and the direction of these modifications suggest a differential modulation of hippocampal-septal excitability by the amygdala to amplify the contribution of the more predictive association signaling the occurrence of the aversive event.

Role of cholinergic receptors in memory retrieval depends on gender and age of memory.

PubMed

Rashid, Habiba; Mahboob, Aamra; Ahmed, Touqeer

2017-07-28

The phenomenon of utilizing information acquired in the past to make decision and performance in present depends on memory retrieval, which is affected in retrograde amnesia. Role of cholinergic receptors in memory retrieval is not much explored. In this study we evaluated the gender specific role of cholinergic receptors, i.e. muscarinic and nicotinic receptors, in memory retrieval in young Balb/c mice. Acute (only one injection, 30min before test) and sub-chronic (five days) muscarinic blockade (using scopolamine=1mg/kg) before test impaired retrieval of contextual fear memory in male (31.45±5.39% and 33.36±3.78% respectively) and female mice (22.88±5.73%; P<0.05), except sub-chronically treated female group (33.31±4.90%; P>0.05). Only sub-chronic nicotinic receptor antagonism (using methyllycaconitine MLA=87.5μg/kg and dihydro β erythroidine DHβE=1mg/kg) in female showed significantly higher freezing response than control during contextual fear memory retrieval (60.85±7.71% and 40.91±7.53% respectively; P<0.001). Acute and sub-chronic muscarinic antagonism (but not nicotinic antagonism) impaired spatial memory retrieval in male (P<0.05) but not in female mice (P>0.05). There was no effect of acute and sub-chronic cholinergic receptor antagonism on discriminating novel object from the familiar one in male and female mice, however, nicotinic receptor blockade affected the working memory of all male and female mice on test day compared to the training sessions. Our results suggested that cholinergic receptors involvement in retrieving spatial and fear memories depends on the age of the memory and gender. Copyright © 2017 Elsevier B.V. All rights reserved.

Corticosterone administration after a single-trial contextual fear conditioning does not influence the strength and specificity of recent and remote memory in rats.

PubMed

Bueno, Ana Paula A; de Paiva, Joselisa Péres Queiroz; Corrêa, Moisés Dos Santos; Tiba, Paula Ayako; Fornari, Raquel Vecchio

2017-03-15

It is well established that corticosterone (CORT) enhances memory consolidation of emotionally arousing experiences. Despite emotional memories being usually referred to as well remembered for long periods, there are no studies that have investigated the effects of CORT in modulating the duration and specificity of memory. In the present study, we trained Wistar rats in a single-trial contextual fear conditioning protocol and injected CORT (0.3, 1.0 or 3.0mg/kg), immediately after training, to investigate its effects on memory consolidation. Rats were tested 2 and 29days after the training session or only 29days after training to assess recent or remote memory. Our results show that animals tested for recent memory discriminated the training context from a novel one, while those tested only for remote memory generalized the fear response to both contexts. Animals tested for remote memory after being tested for recent memory were able to discriminate both contexts. These results support the literature regarding memory specificity and duration. However, CORT treatment, even at the dose of 1.0mg/kg that effectively enhanced the plasmatic hormone levels, did not affect the strength or the specificity of memory in either recent or remote memory tests. We hypothesize that the lack of effect of CORT treatment could be due to the low arousing training experience of the single-trial protocol which, despite being sufficient to induce significant recent and remote memory consolidation, may not be sufficient to allow the memory-enhancing effect of CORT. Copyright © 2017 Elsevier Inc. All rights reserved.

Increased levels of conditioned fear and avoidance behavior coincide with changes in phosphorylation of the protein kinase B (AKT) within the amygdala in a mouse model of extremes in trait anxiety.

PubMed

Yen, Yi-Chun; Mauch, Christoph P; Dahlhoff, Maik; Micale, Vincenzo; Bunck, Mirjam; Sartori, Simone B; Singewald, Nicolas; Landgraf, Rainer; Wotjak, Carsten T

2012-07-01

Patients diagnosed for anxiety disorders often display faster acquisition and slower extinction of learned fear. To gain further insights into the mechanisms underlying these phenomenona, we studied conditioned fear in mice originating form a bi-directional selective breeding approach, which is based on elevated plus-maze behavior and results in CD1-derived high (HAB), normal (NAB), and low (LAB) anxiety-related behavior mice. HAB mice displayed pronounced cued-conditioned fear compared to NAB/CD1 and LAB mice that coincided with increased phosphorylation of the protein kinase B (AKT) in the basolateral amygdala 45 min after conditioning. No similar changes were observed after non-associative immediate shock presentations. Fear extinction of recent but not older fear memories was preserved. However, HAB mice were more prone to relapse of conditioned fear with the passage of time. HAB mice also displayed higher levels of contextual fear compared to NAB and LAB mice and exaggerated avoidance following step-down avoidance training. Interestingly, HAB mice showed lower and LAB mice higher levels of acoustic startle responses compared to NAB controls. The increase in arousal observed in LAB mice coincided with the general absence of conditioned freezing. Taken together, our results suggest that the genetic predisposition to high anxiety-related behavior may increase the risk of forming traumatic memories, phobic-like fear and avoidance behavior following aversive encounters, with a clear bias towards passive coping styles. In contrast, genetic predisposition to low anxiety-related and high risk-taking behavior seems to be associated with an increase in active coping styles. Our data imply changes in AKT phosphorylation as a therapeutic target for the prevention of exaggerated fear memories. Copyright © 2012 Elsevier Inc. All rights reserved.

Contextual view of ILWU Hall, facing east, with the city ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

Contextual view of ILWU Hall, facing east, with the city of Port Hueneme visible in the background - International Longshoremen's & Warehousemen's Union Hall, Naval Civil Engineering Laboratory, Port Hueneme Road, Port Hueneme, Ventura County, CA

RadMAP: The Radiological Multi-sensor Analysis Platform

NASA Astrophysics Data System (ADS)

Bandstra, Mark S.; Aucott, Timothy J.; Brubaker, Erik; Chivers, Daniel H.; Cooper, Reynold J.; Curtis, Joseph C.; Davis, John R.; Joshi, Tenzing H.; Kua, John; Meyer, Ross; Negut, Victor; Quinlan, Michael; Quiter, Brian J.; Srinivasan, Shreyas; Zakhor, Avideh; Zhang, Richard; Vetter, Kai

2016-12-01

The variability of gamma-ray and neutron background during the operation of a mobile detector system greatly limits the ability of the system to detect weak radiological and nuclear threats. The natural radiation background measured by a mobile detector system is the result of many factors, including the radioactivity of nearby materials, the geometric configuration of those materials and the system, the presence of absorbing materials, and atmospheric conditions. Background variations tend to be highly non-Poissonian, making it difficult to set robust detection thresholds using knowledge of the mean background rate alone. The Radiological Multi-sensor Analysis Platform (RadMAP) system is designed to allow the systematic study of natural radiological background variations and to serve as a development platform for emerging concepts in mobile radiation detection and imaging. To do this, RadMAP has been used to acquire extensive, systematic background measurements and correlated contextual data that can be used to test algorithms and detector modalities at low false alarm rates. By combining gamma-ray and neutron detector systems with data from contextual sensors, the system enables the fusion of data from multiple sensors into novel data products. The data are curated in a common format that allows for rapid querying across all sensors, creating detailed multi-sensor datasets that are used to study correlations between radiological and contextual data, and develop and test novel techniques in mobile detection and imaging. In this paper we will describe the instruments that comprise the RadMAP system, the effort to curate and provide access to multi-sensor data, and some initial results on the fusion of contextual and radiological data.

Examining the career development of Mexican American middle school students: A test of social cognitive career theory

NASA Astrophysics Data System (ADS)

Navarro, Rachel Leah

This study tested portions of Lent, Brown, and Hackett's (1994) Social Cognitive Career Theory (SCCT) in the domain of mathematics and science with a sample of Mexican American middle school students. Results supported a modified path model. This study's findings supported several SCCT propositions regarding the positive relationships among background contextual affordances, learning experiences, self-efficacy, outcome expectations, interests, and goals. However, findings suggested that the influence of person inputs (i.e., gender and generational status) and some background contextual affordances (i.e., acculturation level) on learning experiences may be not be direct; instead, an indirect effect via a relationship with other background contextual affordances (i.e., perceived social support and social class) was found. Furthermore, results supported direct effects of gender on self-efficacy and learning experiences on goal intentions---two relationships not posited in SCCT. Implications for future research and counseling with Mexican American adolescents are discussed.

The influence of animal fear on attentional capture by fear-relevant animal stimuli in children.

PubMed

Waters, Allison M; Lipp, Ottmar V

2008-01-01

The present study demonstrated that pictures of fear-relevant animals, snakes and spiders, presented among backgrounds of other animal stimuli captured attention and interfered in the detection of a neutral target to the same extent in a large sample of unselected children (N=81). Moreover, detection of a neutral target animal was slowed more in the presence of a feared fear-relevant distracter, e.g., a snake for snake fearful children, than in the presence of a not feared fear-relevant distracter, e.g., a spider for snake fearful children. These results indicate attentional capture by phylogenetically fear-relevant animal stimuli in children and the selective enhancement of this effect by fear of these animals. These findings are consistent with current models of preferential processing of phylogenetically prepared threat stimuli and with cognitive models of anxiety that propose an enhancing effect of fear in the processing of fear-related stimuli.

Factors contributing to delayed diagnosis of cancer among Aboriginal people in Australia: a qualitative study

PubMed Central

Shahid, Shaouli; Teng, Tiew-Hwa Katherine; Bessarab, Dawn; Aoun, Samar; Baxi, Siddhartha; Thompson, Sandra C

2016-01-01

Background/objectives Delayed presentation of symptomatic cancer is associated with poorer survival. Aboriginal patients with cancer have higher rates of distant metastases at diagnosis compared with non-Aboriginal Australians. This paper examined factors contributing to delayed diagnosis of cancer among Aboriginal Australians from patient and service providers' perspectives. Methods In-depth, open-ended interviews were conducted in two stages (2006–2007 and 2011). Inductive thematic analysis was assisted by use of NVivo looking around delays in presentation, diagnosis and referral for cancer. Participants Aboriginal patients with cancer/family members (n=30) and health service providers (n=62) were recruited from metropolitan Perth and six rural/remote regions of Western Australia. Results Three broad themes of factors were identified: (1) Contextual factors such as intergenerational impact of colonisation and racism and socioeconomic deprivation have negatively impacted on Aboriginal Australians' trust of the healthcare professionals; (2) health service-related factors included low accessibility to health services, long waiting periods, inadequate numbers of Aboriginal professionals and high staff turnover; (3) patient appraisal of symptoms and decision-making, fear of cancer and denial of symptoms were key reasons patients procrastinated in seeking help. Elements of shame, embarrassment, shyness of seeing the doctor, psychological ‘fear of the whole health system’, attachment to the land and ‘fear of leaving home’ for cancer treatment in metropolitan cities were other deterrents for Aboriginal people. Manifestation of masculinity and the belief that ‘health is women's domain’ emerged as a reason why Aboriginal men were reluctant to receive health checks. Conclusions Solutions to improved Aboriginal cancer outcomes include focusing on the primary care sector encouraging general practitioners to be proactive to suspicion of symptoms with appropriate investigations to facilitate earlier diagnosis and the need to improve Aboriginal health literacy regarding cancer. Access to health services remains a critical problem affecting timely diagnosis. PMID:27259526

Local perceptions of cholera and anticipated vaccine acceptance in Katanga province, Democratic Republic of Congo

PubMed Central

2013-01-01

Background In regions where access to clean water and the provision of a sanitary infrastructure has not been sustainable, cholera continues to pose an important public health burden. Although oral cholera vaccines (OCV) are effective means to complement classical cholera control efforts, still relatively little is known about their acceptability in targeted communities. Clarification of vaccine acceptability prior to the introduction of a new vaccine provides important information for future policy and planning. Methods In a cross-sectional study in Katanga province, Democratic Republic of Congo (DRC), local perceptions of cholera and anticipated acceptance of an OCV were investigated. A random sample of 360 unaffected adults from a rural town and a remote fishing island was interviewed in 2010. In-depth interviews with a purposive sample of key informants and focus-group discussions provided contextual information. Socio-cultural determinants of anticipated OCV acceptance were assessed with logistic regression. Results Most respondents perceived contaminated water (63%) and food (61%) as main causes of cholera. Vaccines (28%), health education (18%) and the provision of clean water (15%) were considered the most effective measures of cholera control. Anticipated vaccine acceptance reached 97% if an OCV would be provided for free. Cholera-specific knowledge of hygiene and self-help in form of praying for healing were positively associated with anticipated OCV acceptance if costs of USD 5 were assumed. Conversely, respondents who feared negative social implications of cholera were less likely to anticipate acceptance of OCVs. These fears were especially prominent among respondents who generated their income through fishing. With an increase of assumed costs to USD 10.5, fear of financial constraints was negatively associated with anticipated vaccine acceptance as well. Conclusions Results suggest a high motivation to use an OCV as long as it seems affordable. The needs of socially marginalized groups such as fishermen may have to be explicitly addressed when preparing for a mass vaccination campaign. PMID:23339647

Enhancing the Ethical Conduct of HIV Research with Migrant Sex Workers: Human Rights, Policy, and Social Contextual Influences

PubMed Central

Brouwer, Kimberly C.; Jimenez, Teresita Rocha; Miranda, Sonia Morales; Mindt, Monica Rivera

2016-01-01

Background Migrant sex workers are often highly marginalized and disproportionately experience health and social inequities, including high prevalence of HIV, sexually transmitted infections, and human rights violations. In recent years, research involving migrant sex workers has increased, yet many knowledge gaps remain regarding how best to protect research participant rights and welfare. Our objective was to identify key challenges and opportunities related to the responsible conduct of HIV research with migrant sex workers. Methods Focus groups and interviews conducted with 33 female sex workers ≥18 years old at the Guatemala-Mexico border from June 2013–February 2014 were analyzed. Participants were recruited through community outreach by a local HIV prevention organization to sex work establishments such as bars, hotels, street corners, and truck stops. Results Key themes influencing research engagement for migrant sex workers included researcher mistrust and fear related to research participation, rooted in the social isolation frequently faced by recent migrants; intersecting concerns related to immigration status, fear of criminalization, and compliance with sex work regulations; and perceived benefits and risks of HIV/STI testing for migrants (e.g., immigration implications, stigma) represent potential barriers and opportunities for the responsible conduct of research involving migrant sex workers. Conclusions Results highlight the intersection between the human rights vulnerabilities of migrant sex workers and barriers to research participation, including social isolation of migrants and policy/legal barriers related to immigration and sex work. Findings illustrate the need for researchers to develop population-tailored procedures to address fears related to immigration and criminalization, and to reinforce positive and non-stigmatizing relationships with migrant sex workers. Community-led efforts to reduce stigma and foster community organization and supports for migrant sex workers are recommended, as are broader policy shifts that move away from punitive legal approaches towards approaches that safeguard and prioritize the human rights of migrant sex workers. PMID:27159157

What Predicts Fear of School Violence among U.S. Adolescents?

ERIC Educational Resources Information Center

Akiba, Motoko

2010-01-01

Background/Context: Ensuring a safe learning environment for every student at school is a major responsibility of educators, school administrators, and policy makers in our society. Students' fear associated with school violence affects their school attendance, learning motivation, and academic achievement. Although predictors of adults' fear of…

Retrosplenial cortex is required for the retrieval of remote memory for auditory cues.

PubMed

Todd, Travis P; Mehlman, Max L; Keene, Christopher S; DeAngeli, Nicole E; Bucci, David J

2016-06-01

The restrosplenial cortex (RSC) has a well-established role in contextual and spatial learning and memory, consistent with its known connectivity with visuo-spatial association areas. In contrast, RSC appears to have little involvement with delay fear conditioning to an auditory cue. However, all previous studies have examined the contribution of the RSC to recently acquired auditory fear memories. Since neocortical regions have been implicated in the permanent storage of remote memories, we examined the contribution of the RSC to remotely acquired auditory fear memories. In Experiment 1, retrieval of a remotely acquired auditory fear memory was impaired when permanent lesions (either electrolytic or neurotoxic) were made several weeks after initial conditioning. In Experiment 2, using a chemogenetic approach, we observed impairments in the retrieval of remote memory for an auditory cue when the RSC was temporarily inactivated during testing. In Experiment 3, after injection of a retrograde tracer into the RSC, we observed labeled cells in primary and secondary auditory cortices, as well as the claustrum, indicating that the RSC receives direct projections from auditory regions. Overall our results indicate the RSC has a critical role in the retrieval of remotely acquired auditory fear memories, and we suggest this is related to the quality of the memory, with less precise memories being RSC dependent. © 2016 Todd et al.; Published by Cold Spring Harbor Laboratory Press.

Identification of Parvalbumin Interneurons as Cellular Substrate of Fear Memory Persistence.

PubMed

Çaliskan, Gürsel; Müller, Iris; Semtner, Marcus; Winkelmann, Aline; Raza, Ahsan S; Hollnagel, Jan O; Rösler, Anton; Heinemann, Uwe; Stork, Oliver; Meier, Jochen C

2016-05-01

Parvalbumin-positive (PV) basket cells provide perisomatic inhibition in the cortex and hippocampus and control generation of memory-related network activity patterns, such as sharp wave ripples (SPW-R). Deterioration of this class of fast-spiking interneurons has been observed in neuropsychiatric disorders and evidence from animal models suggests their involvement in the acquisition and extinction of fear memories. Here, we used mice with neuron type-targeted expression of the presynaptic gain-of-function glycine receptor RNA variant GlyR α3L(185L)to genetically enhance the network activity of PV interneurons. These mice showed reduced extinction of contextual fear memory but normal auditory cued fear memory. They furthermore displayed increase of SPW-R activity in area CA3 and CA1 and facilitated propagation of this particular network activity pattern, as determined in ventral hippocampal slice preparations. Individual freezing levels during extinction and SPW-R propagation were correlated across genotypes. The same was true for parvalbumin immunoreactivity in the ventral hippocampus, which was generally augmented in the GlyR mutant mice and correlated with individual freezing levels. Together, these results identify PV interneurons as critical cellular substrate of fear memory persistence and associated SPW-R activity in the hippocampus. Our findings may be relevant for the identification and characterization of physiological correlates for posttraumatic stress and anxiety disorders. © The Author 2016. Published by Oxford University Press.

Abnormal Fear Memory as a Model for Posttraumatic Stress Disorder.

PubMed

Desmedt, Aline; Marighetto, Aline; Piazza, Pier-Vincenzo

2015-09-01

For over a century, clinicians have consistently described the paradoxical co-existence in posttraumatic stress disorder (PTSD) of sensory intrusive hypermnesia and declarative amnesia for the same traumatic event. Although this amnesia is considered as a critical etiological factor of the development and/or persistence of PTSD, most current animal models in basic neuroscience have focused exclusively on the hypermnesia, i.e., the persistence of a strong fear memory, neglecting the qualitative alteration of fear memory. The latest is characterized by an underrepresentation of the trauma in the context-based declarative memory system in favor of its overrepresentation in a cue-based sensory/emotional memory system. Combining psychological and neurobiological data as well as theoretical hypotheses, this review supports the idea that contextual amnesia is at the core of PTSD and its persistence and that altered hippocampal-amygdalar interaction may contribute to such pathologic memory. In a first attempt to unveil the neurobiological alterations underlying PTSD-related hypermnesia/amnesia, we describe a recent animal model mimicking in mice some critical aspects of such abnormal fear memory. Finally, this line of argument emphasizes the pressing need for a systematic comparison between normal/adaptive versus abnormal/maladaptive fear memory to identify biomarkers of PTSD while distinguishing them from general stress-related, potentially adaptive, neurobiological alterations. Copyright © 2015 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Identification of Parvalbumin Interneurons as Cellular Substrate of Fear Memory Persistence

PubMed Central

Çalışkan, Gürsel; Müller, Iris; Semtner, Marcus; Winkelmann, Aline; Raza, Ahsan S.; Hollnagel, Jan O.; Rösler, Anton; Heinemann, Uwe; Stork, Oliver; Meier, Jochen C.

2016-01-01

Parvalbumin-positive (PV) basket cells provide perisomatic inhibition in the cortex and hippocampus and control generation of memory-related network activity patterns, such as sharp wave ripples (SPW-R). Deterioration of this class of fast-spiking interneurons has been observed in neuropsychiatric disorders and evidence from animal models suggests their involvement in the acquisition and extinction of fear memories. Here, we used mice with neuron type-targeted expression of the presynaptic gain-of-function glycine receptor RNA variant GlyR α3L185L to genetically enhance the network activity of PV interneurons. These mice showed reduced extinction of contextual fear memory but normal auditory cued fear memory. They furthermore displayed increase of SPW-R activity in area CA3 and CA1 and facilitated propagation of this particular network activity pattern, as determined in ventral hippocampal slice preparations. Individual freezing levels during extinction and SPW-R propagation were correlated across genotypes. The same was true for parvalbumin immunoreactivity in the ventral hippocampus, which was generally augmented in the GlyR mutant mice and correlated with individual freezing levels. Together, these results identify PV interneurons as critical cellular substrate of fear memory persistence and associated SPW-R activity in the hippocampus. Our findings may be relevant for the identification and characterization of physiological correlates for posttraumatic stress and anxiety disorders. PMID:26908632

Engrams and Circuits Crucial for Systems Consolidation of a Memory

PubMed Central

Kitamura, Takashi; Ogawa, Sachie K.; Roy, Dheeraj S.; Okuyama, Teruhiro; Morrissey, Mark D.; Smith, Lillian M.; Redondo, Roger L.; Tonegawa, Susumu

2017-01-01

Episodic memories initially require rapid synaptic plasticity within the hippocampus for their formation and are gradually consolidated in neocortical networks for permanent storage. However, the engrams and circuits that support neocortical memory consolidation remain unknown. We found that neocortical prefrontal memory engram cells, critical for remote contextual fear memory, were rapidly generated during initial learning via inputs from both hippocampal-entorhinal cortex and basolateral amygdala. After their generation, the prefrontal engram cells, with support from hippocampal memory engram cells, became functionally mature with time. Whereas hippocampal engram cells gradually became silent with time, engram cells in the basolateral amygdala, which were necessary for fear memory, are maintained. Our data provide new insights into the functional reorganization of engrams and circuits underlying systems consolidation of memory. PMID:28386011

Effects of Global Cerebral Ischemia in the Pregnant Rat

PubMed Central

Spencer, Sarah J.; Galic, Michael A.; Tsutsui, Mio; Pittman, Quentin J.; Mouihate, Abdeslam

2012-01-01

Background and Purpose Stroke during pregnancy is an emerging concern. Although females undergo many physiological, endocrine, and neurological alterations during pregnancy, the consequences of such changes on outcome after stroke are unclear. It is predicted that increases in steroid hormones observed during pregnancy may confer protective effects against the neurological and pathological sequelae of stroke. Methods We therefore investigated behavioral and histological consequences of a global cerebral ischemia (2-vessel occlusion; 2VO), and how these outcomes correlated with pregnancy-related changes in hormones in Sprague-Dawley rats. Results After the 2VO, pregnant rats exhibited poorer memory in a contextual fear conditioning test of learning and memory than sham-treated controls, whereas nonpregnant rats did not. They also showed enhanced CA1 hippocampal neuronal injury. This susceptibility to damage is despite significant pregnancy-associated hypothermia and is probably not associated with alterations in 17β-estradiol or corticosterone levels. Conclusion These findings are the first to show enhanced neuronal damage in pregnant animals after global cerebral ischemia. They also suggest that the mechanism may be independent of changes in estrogen, corticosterone, and body temperature. PMID:18239170

Mind bomb-1 is an essential modulator of long-term memory and synaptic plasticity via the Notch signaling pathway

PubMed Central

2012-01-01

Background Notch signaling is well recognized as a key regulator of the neuronal fate during embryonic development, but its function in the adult brain is still largely unknown. Mind bomb-1 (Mib1) is an essential positive regulator in the Notch pathway, acting non-autonomously in the signal-sending cells. Therefore, genetic ablation of Mib1 in mature neuron would give valuable insight to understand the cell-to-cell interaction between neurons via Notch signaling for their proper function. Results Here we show that the inactivation of Mib1 in mature neurons in forebrain results in impaired hippocampal dependent spatial memory and contextual fear memory. Consistently, hippocampal slices from Mib1-deficient mice show impaired late-phase, but not early-phase, long-term potentiation and long-term depression without change in basal synaptic transmission at SC-CA1 synapses. Conclusions These data suggest that Mib1-mediated Notch signaling is essential for long-lasting synaptic plasticity and memory formation in the rodent hippocampus. PMID:23111145

Negotiating gender roles: gender differences in assertive negotiating are mediated by women's fear of backlash and attenuated when negotiating on behalf of others.

PubMed

Amanatullah, Emily T; Morris, Michael W

2010-02-01

The authors propose that gender differences in negotiations reflect women's contextually contingent impression management strategies. They argue that the same behavior, bargaining assertively, is construed as congruent with female gender roles in some contexts yet incongruent in other contexts. Further, women take this contextual variation into account, adjusting their bargaining behavior to manage social impressions. A particularly important contextual variable is advocacy-whether bargaining on one's own behalf versus on another's behalf. In self-advocacy contexts, women anticipate that assertiveness will evoke incongruity evaluations, negative attributions, and subsequent "backlash"; hence, women hedge their assertiveness, using fewer competing tactics and obtaining lower outcomes. However, in other-advocacy contexts, women achieve better outcomes as they do not expect incongruity evaluations or engage in hedging. In a controlled laboratory experiment, the authors found that gender interacts with advocacy context in this way to determine negotiation style and outcomes. Additionally, process measures of anticipated attributions and backlash statistically mediated this interaction effect. Copyright 2009 APA, all rights reserved