Opioid Modulation of Fos Protein Expression and Olfactory Circuitry Plays a Pivotal Role in What Neonates Remember

ERIC Educational Resources Information Center

Roth, Tania L.; Moriceau, Stephanie; Sullivan, Regina M.

2006-01-01

Paradoxically, fear conditioning (odor-0.5 mA shock) yields a learned odor preference in the neonate, presumably due to a unique learning and memory circuit that does not include apparent amygdala participation. Post-training opioid antagonism with naltrexone (NTX) blocks consolidation of this odor preference and instead yields memory of a learned…

Olfactory-triggered panic attacks among Khmer refugees: a contextual approach.

PubMed

Hinton, Devon; Pich, Vuth; Chhean, Dara; Pollack, Mark

2004-06-01

One hundred Khmer refugees attending a psychiatric clinic were surveyed to determine the prevalence of olfactory-triggered panic attacks as well as certain characteristics of the episodes, including trigger (i.e. type of odor), frequency, length, somatic symptoms, and the rate of associated flashbacks and catastrophic cognitions. Forty-five of the 100 patients had experienced an olfactory-triggered panic attack in the last month. Trauma associations and catastrophic cognitions (e.g. fears of a 'wind attack', 'weakness', and 'weak heart') were common during events of olfactory panic. Several case examples are presented. A multifactorial model of the generation of olfactory panic is adduced. The therapeutic implications of this model for the treatment of olfactory panic are discussed.

Olfactory-Triggered Panic Attacks Among Khmer Refugees: A Contextual Approach

PubMed Central

Hinton, Devon; Pich, Vuth; Chhean, Dara; Pollack, Mark

2009-01-01

One hundred Khmer refugees attending a psychiatric clinic were surveyed to determine the prevalence of olfactory-triggered panic attacks as well as certain characteristics of the episodes, including trigger (i.e. type of odor), frequency, length, somatic symptoms, and the rate of associated flashbacks and catastrophic cognitions. Forty-five of the 100 patients had experienced an olfactory-triggered panic attack in the last month. Trauma associations and catastrophic cognitions (e.g. fears of a ‘wind attack,’ ‘weakness,’ and ‘weak heart’) were common during events of olfactory panic. Several case examples are presented. A multifactorial model of the generation of olfactory panic is adduced. The therapeutic implications of this model for the treatment of olfactory panic are discussed. PMID:15446720

Kinase Activity in the Olfactory Bulb Is Required for Odor Memory Consolidation

ERIC Educational Resources Information Center

Tong, Michelle T.; Kim, Tae-Young P.; Cleland, Thomas A.

2018-01-01

Long-term fear memory formation in the hippocampus and neocortex depends upon brain-derived neurotrophic factor (BDNF) signaling after acquisition. Incremental, appetitive odor discrimination learning is thought to depend substantially on the differentiation of adult-born neurons within the olfactory bulb (OB)--a process that is closely associated…

Methods to measure olfactory behavior in mice

PubMed Central

Zou, Junhui; Wang, Wenbin; Pan, Yung-Wei; Lu, Song; Xia, Zhengui

2015-01-01

Mice rely on the sense of olfaction to detect food sources, recognize social and mating partners, and avoid predators. Many behaviors of mice including learning and memory, social interaction, fear, and anxiety are closely associated with their function of olfaction, and behavior tasks designed to evaluate those brain functions may use odors as cues. Accurate assessment of olfaction is not only essential for the study of olfactory system but also critical for proper interpretation of various mouse behaviors especially learning and memory, emotionality and affect, and sociality. Here we describe a series of behavior experiments that offer multidimensional and quantitative assessments for mouse’s olfactory function, including olfactory habituation, discrimination, odor preference, odor detection sensitivity, and olfactory memory, to both social and nonsocial odors. PMID:25645244

The smell of fear: innate threat of 2,5-dihydro-2,4,5-trimethylthiazoline, a single molecule component of a predator odor

PubMed Central

Rosen, Jeffrey B.; Asok, Arun; Chakraborty, Trisha

2015-01-01

In the last several years, the importance of understanding what innate threat and fear is, in addition to learning of threat and fear, has become evident. Odors from predators are ecologically relevant stimuli used by prey animals as warnings for the presence of danger. Of importance, these odors are not necessarily noxious or painful, but they have innate threat-like properties. This review summarizes the progress made on the behavioral and neuroanatomical fundamentals of innate fear of the predator odor, 2,5-dihydro-2,4,5-trimethylthiazoline (TMT), a component of fox feces. TMT is one of several single molecule components of predator odors that have been isolated in the last several years. Isolation of these single molecules has allowed for rapid advances in delineating the behavioral constraints and selective neuroanatomical pathways of predator odor induced fear. In naïve mice and rats, TMT induces a number of fear and defensive behaviors, including robust freezing, indicating it is an innate threat stimulus. However, there are a number of behavioral constraints that we do not yet understand. Similarly, while some of the early olfactory sensory pathways for TMT-induced fear are being delineated, the pathways from olfactory systems to emotional and motor output regions are less well understood. This review will focus on what we know and what we still need to learn about the behavior and neuroanatomy of TMT-induced fear. PMID:26379483

Innate Predator Odor Aversion Driven by Parallel Olfactory Subsystems that Converge in the Ventromedial Hypothalamus

PubMed Central

Pérez-Gómez, Anabel; Bleymehl, Katherin; Stein, Benjamin; Pyrski, Martina; Birnbaumer, Lutz; Munger, Steven D.; Leinders-Zufall, Trese; Zufall, Frank; Chamero, Pablo

2015-01-01

Summary The existence of innate predator aversion evoked by predator-derived chemostimuli called kairomones offers a strong selective advantage for potential prey animals. However, it is unclear how chemically-diverse kairomones can elicit similar avoidance behaviors. Using a combination of behavioral analyses and single-cell Ca2+ imaging in wild-type and gene-targeted mice, we show that innate predator-evoked avoidance is driven by parallel, non-redundant processing of volatile and nonvolatile kairomones through the activation of multiple olfactory subsystems including the Grueneberg ganglion, the vomeronasal organ, and chemosensory neurons within the main olfactory epithelium. Perturbation of chemosensory responses in specific subsystems through disruption of genes encoding key sensory transduction proteins (Cnga3, Gnao1) or by surgical axotomy abolished avoidance behaviors and/or cellular Ca2+ responses to different predator odors. Stimulation of these different subsystems resulted in the activation of widely distributed target regions in the olfactory bulb, as assessed by c-Fos expression. However, in each case this c-Fos increase was observed within the same subnuclei of the medial amygdala and ventromedial hypothalamus, regions implicated in fear, anxiety and defensive behaviors. Thus, the mammalian olfactory system has evolved multiple, parallel mechanisms for kairomone detection that converge in the brain to facilitate a common behavioral response. Our findings provide significant insights into the genetic substrates and circuit logic of predator-driven, innate aversion and may serve as a valuable model for studying instinctive fear [1] and human emotional and panic disorders [2, 3]. PMID:25936549

Innate Predator Odor Aversion Driven by Parallel Olfactory Subsystems that Converge in the Ventromedial Hypothalamus.

PubMed

Pérez-Gómez, Anabel; Bleymehl, Katherin; Stein, Benjamin; Pyrski, Martina; Birnbaumer, Lutz; Munger, Steven D; Leinders-Zufall, Trese; Zufall, Frank; Chamero, Pablo

2015-05-18

The existence of innate predator aversion evoked by predator-derived chemostimuli called kairomones offers a strong selective advantage for potential prey animals. However, it is unclear how chemically diverse kairomones can elicit similar avoidance behaviors. Using a combination of behavioral analyses and single-cell Ca(2+) imaging in wild-type and gene-targeted mice, we show that innate predator-evoked avoidance is driven by parallel, non-redundant processing of volatile and nonvolatile kairomones through the activation of multiple olfactory subsystems including the Grueneberg ganglion, the vomeronasal organ, and chemosensory neurons within the main olfactory epithelium. Perturbation of chemosensory responses in specific subsystems through disruption of genes encoding key sensory transduction proteins (Cnga3, Gnao1) or by surgical axotomy abolished avoidance behaviors and/or cellular Ca(2+) responses to different predator odors. Stimulation of these different subsystems resulted in the activation of widely distributed target regions in the olfactory bulb, as assessed by c-Fos expression. However, in each case, this c-Fos increase was observed within the same subnuclei of the medial amygdala and ventromedial hypothalamus, regions implicated in fear, anxiety, and defensive behaviors. Thus, the mammalian olfactory system has evolved multiple, parallel mechanisms for kairomone detection that converge in the brain to facilitate a common behavioral response. Our findings provide significant insights into the genetic substrates and circuit logic of predator-driven innate aversion and may serve as a valuable model for studying instinctive fear and human emotional and panic disorders. Copyright © 2015 Elsevier Ltd. All rights reserved.

Afferent and efferent projections of the anterior cortical amygdaloid nucleus in the mouse.

PubMed

Cádiz-Moretti, Bernardita; Abellán-Álvaro, María; Pardo-Bellver, Cecília; Martínez-García, Fernando; Lanuza, Enrique

2017-09-01

The anterior cortical amygdaloid nucleus (ACo) is a chemosensory area of the cortical amygdala that receives afferent projections from both the main and accessory olfactory bulbs. The role of this structure is unknown, partially due to a lack of knowledge of its connectivity. In this work, we describe the pattern of afferent and efferent projections of the ACo by using fluorogold and biotinylated dextranamines as retrograde and anterograde tracers, respectively. The results show that the ACo is reciprocally connected with the olfactory system and basal forebrain, as well as with the chemosensory and basomedial amygdala. In addition, it receives dense projections from the midline and posterior intralaminar thalamus, and moderate projections from the posterior bed nucleus of the stria terminalis, mesocortical structures and the hippocampal formation. Remarkably, the ACo projects moderately to the central nuclei of the amygdala and anterior bed nucleus of the stria terminalis, and densely to the lateral hypothalamus. Finally, minor connections are present with some midbrain and brainstem structures. The afferent projections of the ACo indicate that this nucleus might play a role in emotional learning involving chemosensory stimuli, such as olfactory fear conditioning. The efferent projections confirm this view and, given its direct output to the medial part of the central amygdala and the hypothalamic 'aggression area', suggest that the ACo can initiate defensive and aggressive responses elicited by olfactory or, to a lesser extent, vomeronasal stimuli. © 2017 Wiley Periodicals, Inc.

An FMRI Study of Olfactory Cues to Perception of Conspecific Stress

DTIC Science & Technology

2010-04-01

modulate recognition of fear in ambiguous facial expressions. Psychol Sci 20: 177-183. 23. Pause BM, Ohrt A, Prehn A, Ferstl R (2004) Positive...emotional priming of facial affect perception in females is diminished by chemosensory anxiety signals. Chem Senses 29: 797-805. 24. Prehn A, Ohrt A

Delta-9-Tetrahydrocannabinol Potentiates Fear Memory Salience Through Functional Modulation of Mesolimbic Dopaminergic Activity States.

PubMed

Fitoussi, Aurelie; Zunder, Jordan; Tan, Huibing; Laviolette, Steven R

2018-05-18

Chronic or acute exposure to delta-9-tetrahydrocannabinol (THC), the main psychoactive compound in cannabis, has been associated with numerous neuropsychiatric side-effects, including dysregulation of emotional processing and associative memory formation. Clinical and pre-clinical evidence suggests that the effects of THC are due to the ability to modulate mesolimbic dopamine (DA) activity states in the nucleus accumbens (NAc) and ventral tegmental area (VTA). Nevertheless, the mechanisms by which THC modulates mesolimbic DA function and emotional processing are not well understood. Using an olfactory associative fear memory procedure combined with in vivo neuronal electrophysiology, we examined the effects of direct THC microinfusions targeting the shell region of the NAc (NASh) and examined how THC may modulate the processing of fear-related emotional memory and concomitant activity states of the mesolimbic DA system. We report that intra-NASh THC dose-dependently potentiates the emotional salience of normally sub-threshold fear-conditioning cues. These effects were dependent upon intra-VTA transmission through GABAergic receptor mechanisms and intra-NASh DAergic transmission. Furthermore, doses of intra-NASh THC that potentiated fear memory salience were found to modulate intra-VTA neuronal network activity by increasing the spontaneous firing and bursting frequency of DAergic neurons whilst decreasing the activity levels of a subpopulation of putative GABAergic VTA neurons. These findings demonstrate that THC can act directly in the NASh to modulate mesolimbic activity states and induce disturbances in emotional salience and memory formation through modulation of VTA DAergic transmission. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Cognitive and locomotor/exploratory behavior after chronic exercise in the olfactory bulbectomy animal model of depression.

PubMed

Van Hoomissen, Jacqueline; Kunrath, Julie; Dentlinger, Renee; Lafrenz, Andrew; Krause, Mark; Azar, Afaf

2011-09-12

Despite the evidence that exercise improves cognitive behavior in animal models, little is known about these beneficial effects in animal models of pathology. We examined the effects of activity wheel (AW) running on contextual fear conditioning (CFC) and locomotor/exploratory behavior in the olfactory bulbectomy (OBX) model of depression, which is characterized by hyperactivity and changes in cognitive function. Twenty-four hours after the conditioning session of the CFC protocol, the animals were tested for the conditioned response in a conditioned and a novel context to test for the effects of both AW and OBX on CFC, but also the context specificity of the effect. OBX reduced overall AW running behavior throughout the experiment, but increased locomotor/exploratory behavior during CFC, thus demonstrating a context-dependent effect. OBX animals, however, displayed normal CFC behavior that was context-specific, indicating that aversively conditioned memory is preserved in this model. AW running increased freezing behavior during the testing session of the CFC protocol in the control animals but only in the conditioned context, supporting the hypothesis that AW running improves cognitive function in a context-specific manner that does not generalize to an animal model of pathology. Blood corticosterone levels were increased in all animals at the conclusion of the testing sessions, but levels were higher in AW compared to sedentary groups indicating an effect of exercise on neuroendocrine function. Given the differential results of AW running on behavior and neuroendocrine function after OBX, further exploration of the beneficial effects of exercise in animal models of neuropathology is warranted. Copyright © 2011 Elsevier B.V. All rights reserved.

Reinstatement of an extinguished fear conditioned response in infant rats.

PubMed

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

2016-01-01

Although it is currently accepted that the extinction effect reflects new context-dependent learning, this is not so clear during infancy, because some studies did not find recovery of the extinguished conditioned response (CR) in rodents during this ontogenetic stage. However, recent studies have shown the return of an extinguished CR in infant rats. The present study analyzes the possibility of recovering an extinguished CR with a reinstatement procedure in a fear conditioning paradigm, on PD17 (Experiments 1-4) and on PD24 (Experiment 5), while exploring the role of the olfactory content of the context upon the reinstatement effect during the preweanling period. Preweanling rats expressed a previously extinguished CR after a single experience with an unsignaled US. Furthermore, this result was only found when subjects were trained and tested in contexts that included an explicit odor, but not in standard experimental cages. Finally, Experiment 5 demonstrated the reinstatement effect on PD24 in a standard context. These results support the notion that extinction during infancy has the same characteristics as those described for extinction that occurs in adulthood. Instead of postulating a different mechanism for extinction during infancy, we propose that it may be more accurate to view the problem in terms of the variables that may differentially modulate the extinction effect according to the stages of ontogeny. © 2015 Revillo et al.; Published by Cold Spring Harbor Laboratory Press.

Changes of pressure and humidity affect olfactory function.

PubMed

Kuehn, Michael; Welsch, Heiko; Zahnert, Thomas; Hummel, Thomas

2008-03-01

The present study aimed at investigating the question whether olfactory function changes in relation to barometric pressure and humidity. Using climate chambers, odor threshold and discrimination for butanol were tested in 75 healthy volunteers under hypobaric and hyperbaric, and different humidity conditions. Among other effects, olfactory sensitivity at threshold level, but not suprathreshold odor discrimination, was impaired in a hypobaric compared to a hyperbaric milieu, and thresholds were lower in humid, compared to relatively dry conditions. In conclusion, environmental conditions modulate the sense of smell, and may, consecutively, influence results from olfactory tests.

Ictal fear: Associations with age, gender, and other experiential phenomena.

PubMed

Chong, Derek J; Dugan, Patricia

2016-09-01

The aim of this study was to determine the relationship of fear to other auras and to gender and age using a large database. The Epilepsy Phenome/Genome Project (EPGP) is a multicenter, multicontinental cross-sectional study in which ictal symptomatology and other data were ascertained in a standardized series of questionnaires then corroborated by epilepsy specialists. Auras were classified into subgroups of symptoms, with ictal fear, panic, or anxiety as a single category. Of 536 participants with focal epilepsy, 72 were coded as having ictal fear/panic/anxiety. Reviewing raw patient responses, 12 participants were deemed not to have fear, and 24 had inadequate data, leaving 36 (7%) of 512 with definite ictal fear. In univariate analyses, fear was significantly associated with auras historically considered temporal lobe in origin, including cephalic, olfactory, and visceral complaints; déjà vu; and derealization. On both univariate and multivariate stepwise analyses, fear was associated with jamais vu and auras with cardiac symptoms, dyspnea, and chest tightening. Expressive aphasia was associated with fear on univariate analysis only, but the general category of aphasias was associated with fear only in the multivariate model. There was no age or gender relationship with fear when compared to the overall population with focal epilepsy that was studied under the EPGP. Patients with ictal fear were more likely to have a right hemisphere seizure focus. Ictal fear was strongly associated with other auras considered to originate from the limbic system. No relationship of fear with age or gender was observed. Copyright © 2016 Elsevier Inc. All rights reserved.

Stimulation of the Locus Ceruleus Modulates Signal-to-Noise Ratio in the Olfactory Bulb.

PubMed

Manella, Laura C; Petersen, Nicholas; Linster, Christiane

2017-11-29

Norepinephrine (NE) has been shown to influence sensory, and specifically olfactory processing at the behavioral and physiological levels, potentially by regulating signal-to-noise ratio (S/N). The present study is the first to look at NE modulation of olfactory bulb (OB) in regards to S/N in vivo We show, in male rats, that locus ceruleus stimulation and pharmacological infusions of NE into the OB modulate both spontaneous and odor-evoked neural responses. NE in the OB generated a non-monotonic dose-response relationship, suppressing mitral cell activity at high and low, but not intermediate, NE levels. We propose that NE enhances odor responses not through direct potentiation of the afferent signal per se, but rather by reducing the intrinsic noise of the system. This has important implications for the ways in which an animal interacts with its olfactory environment, particularly as the animal shifts from a relaxed to an alert behavioral state. SIGNIFICANCE STATEMENT Sensory perception can be modulated by behavioral states such as hunger, fear, stress, or a change in environmental context. Behavioral state often affects neural processing via the release of circulating neurochemicals such as hormones or neuromodulators. We here show that the neuromodulator norepinephrine modulates olfactory bulb spontaneous activity and odor responses so as to generate an increased signal-to-noise ratio at the output of the olfactory bulb. Our results help interpret and improve existing ideas for neural network mechanisms underlying behaviorally observed improvements in near-threshold odor detection and discrimination. Copyright © 2017 the authors 0270-6474/17/3711605-11$15.00/0.

Associative Processes in Early Olfactory Preference Acquisition

PubMed Central

Sullivan, Regina M.; Wilson, Donald A.; Leon, Michael

2007-01-01

Acquisition of behavioral conditioned responding and learned odor preferences during olfactory classical conditioning in rat pups requires forward or simultaneous pairings of the conditioned stimulus (CS) and the unconditioned stimulus (US). Other temporal relationships between the CS and US do not usually result in learning. The present study examined the influence of this CS-US relationship upon the neural olfactory bulb modifications that are acquired during early classical conditioning. Wistar rat pups were trained from Postnatal Days (PN) 1-18 with either forward (odor overlapping temporally with reinforcing stroking) or backward (stroking followed by odor) CS-US pairings. On PN 19, pups received either a behavioral odor preference test to the odor CS or an injection of 14C 2-DG and exposure to the odor CS, or olfactory bulb single unit responses were recorded in response to exposure to the odor CS. Only pups that received forward presentations of the CS and US exhibited both a preference for the CS and modified olfactory bulb neural responses to the CS. These results, then, suggest that the modified olfactory bulb neural responses acquired during classical conditioning are guided by the same temporal constraints as those which govern the acquisition of behavioral conditioned responses. PMID:17572798

Congenital anosmia and emotion recognition: A case-control study.

PubMed

Lemogne, Cédric; Smadja, Julien; Zerdazi, El-Hadi; Soudry, Yaël; Robin, Marion; Berthoz, Sylvie; Limosin, Frédéric; Consoli, Silla M; Bonfils, Pierre

2015-06-01

Patients with anosmia are not able to detect volatile chemicals signaling the presence of infectious and non-infectious environmental hazards, which typically elicit disgust and fear, respectively. Social animals may compensate a loss of olfaction by taking advantage of signals of threat that are produced by their conspecifics. Among humans and other primates, body postures and facial expressions are powerful cues conveying emotional information, including fear and disgust. The aim of the present study was to examine whether humans with agenesis of the olfactory bulb, a rare disorder characterized by congenital anosmia, would be more accurate in recognizing facial expressions of fear and disgust. A total of 90 participants with no history of mental disorder or traumatic brain injury were recruited, including 17 patients with congenital anosmia (10 men, mean age ± standard deviation: 36.5 ± 14.8 years), 34 patients with acquired anosmia (18 men, mean age ± standard deviation: 57.2 ± 11.8 years) and 39 healthy subjects (22 men, mean age ± standard deviation: 36.7 ± 13.2 years). For each patient with congenital anosmia, the agenesis of the olfactory bulb was ascertained through magnetic resonance imaging. Emotion recognition abilities were examined with a dynamic paradigm in which a morphing technique allowed displaying emotional facial expressions increasing in intensity over time. Adjusting for age, education, depression and anxiety, patients with congenital anosmia required similar levels of intensity to correctly recognize fear and disgust than healthy subjects while they displayed decreased error rates for both fear (mean difference [95% confidence interval] = -28.3% [-46.3%, -10.2%], P = 0.003) and disgust (mean difference [95% confidence interval] = -15.8% [-31.5%, -0.2%], P = 0.048). Furthermore, among patients with acquired anosmia, there was a negative correlation between duration of anosmia and the rate of errors for fearful (Spearman's ρ = -0.531, P= 0.001) or disgust (Spearman's ρ = -0.719, P < 0.001) faces recognition. No significant difference was observed for the other primary emotions. Overall, these results suggest that patients with congenital anosmia and long-lasting acquired anosmia may compensate their inability to detect environmental hazards through olfaction by an increased ability to detect fear or disgust as facially expressed by others. Copyright © 2015 Elsevier Ltd. All rights reserved.

Olfactory performance segregates effects of anhedonia and anxiety on social function in patients with schizophrenia

PubMed Central

Cieslak, Kristina; Walsh-Messinger, Julie; Stanford, Arielle; Vaez-Azizi, Leila; Antonius, Daniel; Harkavy-Friedman, Jill; Goetz, Deborah; Goetz, Raymond R.; Malaspina, Dolores

2015-01-01

Background Social dysfunction is common among individuals with schizophrenia. While often attributed to anhedonia, social dysfunction could also result from unrecognized anxiety. We examined the contributions of anhedonia and anxiety to social function using olfactory function to examine whether the domains had separate underpinnings. Methods We assessed anhedonia, anxiety and social function as well as olfactory function in well-characterized patients with schizophrenia or schizoaffective disorder and healthy controls. Results We included 56 patients and 37 controls in our study. Patients exhibited significantly higher levels of anhedonia and anxiety than controls, and the domains were highly correlated in patients. The combination of anhedonia and anxiety more strongly predicted social dysfunction than either measure alone. Smell identification was differentially related to the symptoms, with better performance predicting less anhedonia but more social fear in male patients. Limitations The use of self-report measures precludes differentiation between recollected or recounted experience. Aside from smell identification and odour threshold, additional measures of olfaction may be considered for future studies. Conclusion Anhedonia and anxiety were strongly correlated and both negatively impacted social function. The olfactory biomarker results support the conclusion that these domains are separate. Social function in patients with schizophrenia may improve with interventions for anxiety, even in the presence of marked negative symptoms. PMID:26107162

Why humans do not make good vampires. Testing the ability of humans to detect true blood.

PubMed

De Smet, Delphine; Van Speybroeck, Linda; Verplaetse, Jan

2012-01-01

Research indicating the effects of real blood or of its iconic representation on human behaviour has thus far concentrated on phobia and aggressiveness. Little is known about other responses or, more fundamentally, about the biological basis of all such responses. In this study it is examined whether or not humans are able to detect real blood. Human subjects (n = 89) were asked to distinguish different kinds of blood from red control fluids under varying visual and choice conditions. Relevant differences between subjects were tested for through written questionnaires, including standardized scales for disgust sensitivity (DS-R) and blood phobia (MBPI) and performance on two clinical olfactory tests. Analysis of variance shows that humans are excellent detectors of animal blood (in casu pig blood), whereas the ability of detecting human blood is much less developed. Surprisingly, differences in olfactory capacities and personal experience with blood have no effect on blood detection, while blood fear lowers and disgust sensitivity ameliorates this performance. This study allows further mapping of the exact role of disgust sensitivity in human behaviour, as well as a deliberate choice of materials in blood-related experiments. It is imperative for further research on the behavioural and psychological impact 'blood' resorts on humans.

Olfactory Detection Thresholds and Adaptation in Adults with Autism Spectrum Condition

ERIC Educational Resources Information Center

Tavassoli, T.; Baron-Cohen, S.

2012-01-01

Sensory issues have been widely reported in Autism Spectrum Conditions (ASC). Since olfaction is one of the least investigated senses in ASC, the current studies explore olfactory detection thresholds and adaptation to olfactory stimuli in adults with ASC. 80 participants took part, 38 (18 females, 20 males) with ASC and 42 control participants…

Cellular prion protein modulates defensive attention and innate fear-induced behaviour evoked in transgenic mice submitted to an agonistic encounter with the tropical coral snake Oxyrhopus guibei.

PubMed

Lobão-Soares, Bruno; Walz, Roger; Prediger, Rui Daniel Schröder; Freitas, Renato Leonardo; Calvo, Fabrício; Bianchin, Marino Muxfeldt; Leite, João Pereira; Landemberger, Michele Christine; Coimbra, Norberto Cysne

2008-12-12

The cellular prion protein (PrP(C)) is a neuronal anchored glycoprotein that has been associated with distinct functions in the CNS, such as cellular adhesion and differentiation, synaptic plasticity and cognition. Here we investigated the putative involvement of the PrP(C) in the innate fear-induced behavioural reactions in wild-type (WT), PrP(C) knockout (Prnp(0/0)) and the PrP(C) overexpressing Tg-20 mice evoked in a prey versus predator paradigm. The behavioural performance of these mouse strains in olfactory discrimination tasks was also investigated. When confronted with coral snakes, mice from both Prnp(0/0) and Tg-20 strains presented a significant decrease in frequency and duration of defensive attention and risk assessment, compared to WT mice. Tg-20 mice presented decreased frequency of escape responses, increased exploratory behaviour, and enhancement of interaction with the snake, suggesting a robust fearlessness caused by PrP(C) overexpression. Interestingly, there was also a discrete decrease in the attentional defensive response (decreased frequency of defensive alertness) in Prnp(0/0) mice in the presence of coral snakes. Moreover, Tg-20 mice presented an increased exploration of novel environment and odors. The present findings indicate that the PrP(C) overexpression causes hyperactivity, fearlessness, and increased preference for visual, tactile and olfactory stimuli-associated novelty, and that the PrP(c) deficiency might lead to attention deficits. These results suggest that PrP(c) exerts an important role in the modulation of innate fear and novelty-induced exploration.

Odors and incontinence: What does the nose know?

PubMed

Dalton, Pamela; Maute, Christopher

2018-06-01

The fear of producing malodors that can be detected by others is a daily cause of anxiety for millions of people with incontinence. For many, the risk-whether real or imagined-that leaked waste products will be detectable by odor is sufficiently concerning to result in limitations on many types of activities. However, worry about personal odors can sensitize our olfactory system and cause us to be more aware of odors that may otherwise not be perceptible. In addition, heightened olfactory attention can often lead to odor misattributions, such as when we erroneously identify our body as the source of an odor that may simply be present in the environment. Odors produced by our bodies (endogenous odors) do enjoy a greater access to emotional brain centers and are processed faster than general odors. Here we provide examples from both everyday life and laboratory studies to explain how and why the olfactory system is unique among our sensory systems and how this knowledge can provide insights to our concerns about smell and incontinence and inform the development of products and solutions for incontinence.

Female Fear: Influence of Estrus Cycle on Behavioral Response and Neuronal Activation

PubMed Central

Chen, Wei; Shields, Jessica; Huang, Wei; King, Jean A

2009-01-01

Our observation that male rats innate fear response differed with hormonal status, as well as the higher prevalence of fear and anxiety disorders in human females led to the current investigation of the impact of phases of the estrous cycle on innate fear responding. Female rats in different phases of the cycle were exposed to an innate fear-inducing stimulus (2,5-dihydro- 2,4,5-trimethylthiazoline, TMT odor) and monitored for changes in behavior and brain activation. Behavioral data showed freezing responses to TMT were significantly enhanced during estrus as compared to other phases of the cycle. This data was supported by significant increases in pixel intensity in cortical and sub-cortical regions in estrus compared to proestrus and diestrus. Imaging results demonstrated significant increases in brain activation in the somatosensory and insular cortices when comparing estrus to diestrus. There were significant increases in neural activity in the BNST and septum in estrus as compared to proestrus. Additionally, the hippocampus, hypothalamus, olfactory system, and cingulate cortex show significant increases in the estrus phase when compared to both diestrus and proestrus. Taken together, these results suggest that the female's hormonal status may be correlated with alterations in both neuronal and behavioral indices of fear. PMID:19428610

Appetitive but Not Aversive Olfactory Conditioning Modifies Antennal Movements in Honeybees

ERIC Educational Resources Information Center

Cholé, Hanna; Junca, Pierre; Sandoz, Jean-Christophe

2015-01-01

In honeybees, two olfactory conditioning protocols allow the study of appetitive and aversive Pavlovian associations. Appetitive conditioning of the proboscis extension response (PER) involves associating an odor, the conditioned stimulus (CS) with a sucrose solution, the unconditioned stimulus (US). Conversely, aversive conditioning of the sting…

Enhanced Chemosensory Detection of Negative Emotions in Congenital Blindness

PubMed Central

Iversen, Katrine D.; Ptito, Maurice; Møller, Per; Kupers, Ron

2015-01-01

It is generally acknowledged that congenitally blind individuals develop superior sensory abilities in order to compensate for their lack of vision. Substantial research has been done on somatosensory and auditory sensory information processing of the blind. However, relatively little information is available about compensatory plasticity in the olfactory domain. Although previous studies indicate that blind individuals have superior olfactory abilities, no studies so far have investigated their sense of smell in relation to social and affective communication. The current study compares congenitally blind and normal sighted individuals in their ability to discriminate and identify emotions from body odours. A group of 14 congenitally blind and 14 age- and sex-matched sighted control subjects participated in the study. We compared participants' abilities to detect and identify by smelling sweat from donors who had been watching excerpts from emotional movies showing amusement, fear, disgust, or sexual arousal. Our results show that congenitally blind subjects outperformed sighted controls in identifying fear from male donors. In addition, there was a strong tendency that blind individuals were also better in detecting disgust. Our findings reveal that congenitally blind individuals are better at identifying ecologically important emotions and provide new insights into the mechanisms of social and affective communication in blindness. PMID:25878902

Olfactory priming reinstates extinguished chocolate-induced conditioned place preference.

PubMed

La Mela, Immacolata; Latagliata, Emanuele Claudio; Patrono, Enrico; Puglisi-Allegra, Stefano; Ventura, Rossella

2010-02-01

A major problem in the dietary treatment of disorders associated with excessive eating, such as obesity, is the high rate of relapse into maladaptive eating habits after withdrawal from consumption of palatable, energy-dense food. As olfaction has a major role in appetite and eating behavior, in this study we used a reinstatement model based on conditioned place preference to investigate the ability of olfactory priming to reinstate extinguished chocolate-induced conditioned place preference in sated mice. We found that olfactory priming, which was ineffective in inducing conditioned place preference in the control group, reactivated place preference following the extinction procedure in the experimental group. These results extend previous reports of the reinstatement of food seeking induced by pellet priming and, for the first time, show the possibility of using olfactory priming in an animal model of relapse. In light of the major role of olfactory inputs in appetite and of cues in relapse, the present results indicate that smell is an important factor to consider in the treatment of eating disorders. 2009 Elsevier Ltd. All rights reserved.

Olfactory short-term memory encoding and maintenance - an event-related potential study.

PubMed

Lenk, Steffen; Bluschke, Annet; Beste, Christian; Iannilli, Emilia; Rößner, Veit; Hummel, Thomas; Bender, Stephan

2014-09-01

This study examined whether the memory encoding and short term maintenance of olfactory stimuli is associated with neurophysiological activation patterns which parallel those described for sensory modalities such as vision and auditory. We examined olfactory event-related potentials in an olfactory change detection task in twenty-four healthy adults and compared the measured activation to that found during passive olfactory stimulation. During the early olfactory post-processing phase, we found a sustained negativity over bilateral frontotemporal areas in the passive perception condition which was enhanced in the active memory task. There was no significant lateralization in either experimental condition. During the maintenance interval at the end of the delay period, we still found sustained activation over bilateral frontotemporal areas which was more negative in trials with correct - as compared to incorrect - behavioural responses. This was complemented by a general significantly stronger frontocentral activation. Summarizing, we were able to show that olfactory short term memory involves a parallel sequence of activation as found in other sensory modalities. In addition to olfactory-specific frontotemporal activations in the memory encoding phase, we found slow cortical potentials over frontocentral areas during the memory maintenance phase indicating the activation of a supramodal memory maintenance system. These findings could represent the neurophysiological underpinning of the 'olfactory flacon', the olfactory counter-part to the visual sketchpad and phonological loop embedded in Baddeley's working memory model. Copyright © 2014 Elsevier Inc. All rights reserved.

Kinase activity in the olfactory bulb is required for odor memory consolidation.

PubMed

Tong, Michelle T; Kim, Tae-Young P; Cleland, Thomas A

2018-05-01

Long-term fear memory formation in the hippocampus and neocortex depends upon brain-derived neurotrophic factor (BDNF) signaling after acquisition. Incremental, appetitive odor discrimination learning is thought to depend substantially on the differentiation of adult-born neurons within the olfactory bulb (OB)-a process that is closely associated with BDNF signaling. We sought to elucidate the role of neurotrophin signaling within the OB on odor memory consolidation. Male mice were trained on odor-reward associative discriminations after bilateral infusion of the kinase inhibitor K252a, or vehicle control, into the OB. K252a is a partially selective inhibitor of tyrosine kinase (Trk) receptors, including the TrkB receptor for BDNF, though it also inhibits other plasticity-related kinases such as PKC and CaMKII/IV. K252a infusion into the OB did not impair odor acquisition or short-term (2 h) memory for the learned discriminations, but significantly impaired long-term (48 h) odor memory (LTM). This LTM deficit also was associated with reduced selectivity for the conditioned odorant in a reward-seeking digging task. Infusions of K252a immediately prior to testing did not impair LTM recall. These results indicate that kinase activation in the OB is required for the consolidation of odor memory of incrementally acquired information. © 2018 Tong et al.; Published by Cold Spring Harbor Laboratory Press.

The effects of partial sleep restriction and altered sleep timing on olfactory performance.

PubMed

McNeil, J; Forest, G; Hintze, L J; Brunet, J-F; Doucet, É

2017-12-01

Olfaction can increase the drive to eat and may partially explain the consistent increases in energy intake (EI) following sleep restriction. We investigated the effects of 50% sleep restriction with altered sleep timing on olfactory performance. We also evaluated whether changes (Δ) in olfactory performance were associated with Δ24 h EI. Twelve men and six women (age: 23±4 years; BMI: 23±3 kg/m 2 ) completed three randomized cross-over conditions: habitual sleep duration, 50% sleep restriction with advanced wake-time, and 50% sleep restriction with delayed bedtime. Sleep was measured in-laboratory (polysomnography). Olfactory performance ('sniffin sticks') and 24 h EI (food menu) were evaluated the next day. A trend for a significant condition*sex interaction was noted for threshold-discrimination-identification (TDI) scores (P=0.09); TDI scores were lowest in women and highest in men, following sleep restriction with advanced wake-time. Δolfactory performance were not associated with Δ24 h EI. The impact of sleep restriction on olfactory performance may differ between sexes. Changes in olfactory performance were not associated with changes in 24 h EI. Studies investigating prolonged effects of sleep loss on the relationship between olfactory performance with EI are needed.

Functional neuronal processing of body odors differs from that of similar common odors.

PubMed

Lundström, Johan N; Boyle, Julie A; Zatorre, Robert J; Jones-Gotman, Marilyn

2008-06-01

Visual and auditory stimuli of high social and ecological importance are processed in the brain by specialized neuronal networks. To date, this has not been demonstrated for olfactory stimuli. By means of positron emission tomography, we sought to elucidate the neuronal substrates behind body odor perception to answer the question of whether the central processing of body odors differs from perceptually similar nonbody odors. Body odors were processed by a network that was distinctly separate from common odors, indicating a separation in the processing of odors based on their source. Smelling a friend's body odor activated regions previously seen for familiar stimuli, whereas smelling a stranger activated amygdala and insular regions akin to what has previously been demonstrated for fearful stimuli. The results provide evidence that social olfactory stimuli of high ecological relevance are processed by specialized neuronal networks similar to what has previously been demonstrated for auditory and visual stimuli.

Morphological and electrophysiological examination of olfactory sensory neurons during the early developmental prolarval stage of the sea lamprey Petromyzon marinus L

USGS Publications Warehouse

Zielinski, B.S.; Fredricks, Keith; McDonald, R.; Zaidi, A.U.

2005-01-01

This study examined olfactory sensory neuron morphology and physiological responsiveness in newly hatched sea lamprey, Petromyzon marinus L. These prolarvae hatch shortly after neural tube formation, and stay within nests for approximately 18 days, before moving downstream to silty areas where they burrow, feed and pass to the larval stage. To explore the possibility that the olfactory system is functioning during this prolarval stage, morphological and physiological development of olfactory sensory neurons was examined. The nasal cavity contained an olfactory epithelium with ciliated olfactory sensory neurons. Axons formed aggregates in the basal portion of the olfactory epithelium and spanned the narrow distance between the olfactory epithelium and the brain. The presence of asymmetric synapses with agranular vesicles within fibers in the brain, adjacent to the olfactory epithelium suggests that there was synaptic connectivity between olfactory sensory axons and the brain. Neural recordings from the surface of the olfactory epithelium showed responses following the application of L-arginine, taurocholic acid, petromyzonol sulfate (a lamprey migratory pheromone), and water conditioned by conspecifics. These results suggest that lampreys may respond to olfactory sensory input during the prolarval stage. ?? 2006 Springer Science + Business Media, LLC.

Olfactory epithelium: Cells, clinical disorders, and insights from an adult stem cell niche

PubMed Central

Choi, Rhea

2018-01-01

Disorders causing a loss of the sense of smell remain a therapeutic challenge. Basic research has, however, greatly expanded our knowledge of the organization and function of the olfactory system. This review describes advances in our understanding of the cellular components of the peripheral olfactory system, specifically the olfactory epithelium in the nose. The article discusses recent findings regarding the mechanisms involved in regeneration and cellular renewal from basal stem cells in the adult olfactory epithelium, considering the strategies involved in embryonic olfactory development and insights from research on other stem cell niches. In the context of clinical conditions causing anosmia, the current view of adult olfactory neurogenesis, tissue homeostasis, and failures in these processes is considered, along with current and future treatment strategies. Level of Evidence NA PMID:29492466

The Sense of Smell Impacts Metabolic Health and Obesity.

PubMed

Riera, Celine E; Tsaousidou, Eva; Halloran, Jonathan; Follett, Patricia; Hahn, Oliver; Pereira, Mafalda M A; Ruud, Linda Engström; Alber, Jens; Tharp, Kevin; Anderson, Courtney M; Brönneke, Hella; Hampel, Brigitte; Filho, Carlos Daniel de Magalhaes; Stahl, Andreas; Brüning, Jens C; Dillin, Andrew

2017-07-05

Olfactory inputs help coordinate food appreciation and selection, but their role in systemic physiology and energy balance is poorly understood. Here we demonstrate that mice upon conditional ablation of mature olfactory sensory neurons (OSNs) are resistant to diet-induced obesity accompanied by increased thermogenesis in brown and inguinal fat depots. Acute loss of smell perception after obesity onset not only abrogated further weight gain but also improved fat mass and insulin resistance. Reduced olfactory input stimulates sympathetic nerve activity, resulting in activation of β-adrenergic receptors on white and brown adipocytes to promote lipolysis. Conversely, conditional ablation of the IGF1 receptor in OSNs enhances olfactory performance in mice and leads to increased adiposity and insulin resistance. These findings unravel a new bidirectional function for the olfactory system in controlling energy homeostasis in response to sensory and hormonal signals. Copyright © 2017 Elsevier Inc. All rights reserved.

Chronically reinforced, operant olfactory conditioning increases the number of newborn GABAergic olfactory periglomerular neurons in the adult rat.

PubMed

Tapia-Rodríguez, Miguel; Esquivelzeta-Rabell, José F; Gutiérrez-Ospina, Gabriel

2012-12-01

The mammalian brain preserves the ability to replace olfactory periglomerular cells (PGC) throughout life. Even though we have detailed a great deal the mechanisms underlying stem and amplifying cells maintenance and proliferation, as well as those modulating migration and differentiation, our knowledge on PGC phenotypic plasticity is at best fragmented and controversial. Here we explored whether chronically reinforced olfactory conditioning influences the phenotype of newborn PGC. Accordingly, olfactory conditioned rats showed increased numbers of GAD 65/67 positive PGC. Because such phenotypic change was not accompanied neither by increments in the total number of PGC, or periglomerular cell nuclei labeled with bromodeoxyuridine, nor by reductions in the number of tyrosine hydroxylase (TH), calbindin (CB) or calretinin (CR) immunoreactive PGC, we speculate that increments in the number of GABAergic PGC occur at the expense of other PGC phenotypes. In any event, these results support that adult newborn PGC phenotype may be subjected to phenotypic plasticity influenced by sensory stimulation. Copyright © 2012 Elsevier B.V. All rights reserved.

Distinct amyloid precursor protein processing machineries of the olfactory system.

PubMed

Kim, Jae Yeon; Rasheed, Ameer; Yoo, Seung-Jun; Kim, So Yeun; Cho, Bongki; Son, Gowoon; Yu, Seong-Woon; Chang, Keun-A; Suh, Yoo-Hun; Moon, Cheil

2018-01-01

Processing of amyloid precursor protein (APP) occurs through sequential cleavages first by β-secretase and then by the γ-secretase complex. However, abnormal processing of APP leads to excessive production of β-amyloid (Aβ) in the central nervous system (CNS), an event which is regarded as a primary cause of Alzheimer's disease (AD). In particular, gene mutations of the γ-secretase complex-which contains presenilin 1 or 2 as the catalytic core-could trigger marked Aβ accumulation. Olfactory dysfunction usually occurs before the onset of typical AD-related symptoms (eg, memory loss or muscle retardation), suggesting that the olfactory system may be one of the most vulnerable regions to AD. To date however, little is known about why the olfactory system is affected so early by AD prior to other regions. Thus, we examined the distribution of secretases and levels of APP processing in the olfactory system under either healthy or pathological conditions. Here, we show that the olfactory system has distinct APP processing machineries. In particular, we identified higher expressions levels and activity of γ-secretase in the olfactory epithelium (OE) than other regions of the brain. Moreover, APP c-terminal fragments (CTF) are markedly detected. During AD progression, we note increased expression of presenilin2 of γ-secretases in the OE, not in the OB, and show that neurotoxic Aβ*56 accumulates more quickly in the OE. Taken together, these results suggest that the olfactory system has distinct APP processing machineries under healthy and pathological conditions. This finding may provide a crucial understanding of the unique APP-processing mechanisms in the olfactory system, and further highlights the correlation between olfactory deficits and AD symptoms. Copyright © 2017 Elsevier Inc. All rights reserved.

Blockade of CB1 receptors prevents retention of extinction but does not increase low preincubated conditioned fear in the fear incubation procedure.

PubMed

Pickens, Charles L; Theberge, Florence R

2014-02-01

We recently developed a procedure to study fear incubation, in which rats given 100 tone-shock pairings over 10 days show low fear 2 days after conditioned fear training and high fear after 30 days. Notably, fear 2 days after 10 sessions of fear conditioning is lower than fear seen 2 days after a single session of fear conditioning, suggesting that fear is suppressed. Here, we investigate the potential role of CB1 receptor activation by endocannabinoids in this fear suppression. We subjected rats to 10 days of fear conditioning and then administered systemic injections of the CB1 receptor antagonist SR141716 before a conditioned fear test was conducted 2 days later under extinction conditions. A second test was conducted without any injections on the following day (3 days after training) to examine retention of fear extinction. SR141716 injections did not increase fear expression 2 days after extended fear conditioning or affect within-session extinction; however, it impaired retention of between-session fear extinction in the day 3 test. These data suggest that CB1 receptor activation does not suppress fear soon after extended fear conditioning in the fear incubation task. The data also add to the existing literature on the role of CB1 receptors in extinction of conditioned fear.

Blockade of CB1 receptors prevents retention of extinction but does not increase low pre-incubated conditioned fear in the fear incubation procedure

PubMed Central

Pickens, Charles L.; Theberge, Florence R.

2015-01-01

We recently developed a procedure to study fear incubation in which rats given 100 tone-shock pairings over 10 days show low fear 2 days after conditioned fear training and high fear after 30 days. Notably, fear 2 days after 10 sessions of fear conditioning is lower than fear seen 2 days after a single session of fear conditioning, suggesting that fear is suppressed. Here, we investigate the potential role of CB1 receptor activation by endocannabinoids in this fear suppression. We gave rats 10 days of fear conditioning and then gave systemic injections of the CB1 receptor antagonist SR141716 before a conditioned fear test conducted 2 days later under extinction conditions. A second test was conducted without any injections on the following day (3 days post-training) to examine fear extinction retention. SR141716 injections did not increase fear expression 2 days after extended fear conditioning or affect within-session extinction, but impaired retention of between-session fear extinction in the day 3 test. These data suggest that CB1 receptor activation is not suppressing fear soon after extended fear conditioning in the fear incubation task. The data also add to an existing literature on the effects of CB1 receptors in extinction of conditioned fear. PMID:24346290

Norepinephrine and Learning-Induced Plasticity in Infant Rat Olfactory System

PubMed Central

Sullivan, Regina M.; Wilson, Donald A.; Leon, Michael

2007-01-01

Postnatal olfactory learning produces both a conditioned behavioral response and a modified olfactory bulb neural response to the learned odor. The present report describes the role of norepinephrine (NE) on both of these learned responses in neonatal rat pups. Pups received olfactory classical conditioning training from postnatal days (PN) 1-18. Training consisted of 18 trials with an intertrial interval of 24 hr. For the experimental group, a trial consisted of a pairing of unconditioned stimulus (UCS, stroking/tactile stimulation) and the conditioned stimulus (CS, odor). Control groups received either only the CS (Odor only) or only the UCS (Stroke only). Within each training condition, pups were injected with either the NE β-receptor agonist isoproterenol (1, 20, or 4 mg/kg), the NE β-receptor antagonist propranolol (10, 20, 40 mg/kg), or saline 30 min prior to training. On day 20, pups received one of the following tests: (1) behavioral conditioned responding, (2) injection with 14C-2-deoxyglucase (2-DG) and exposed to the CS odor, or (3) tested for olfactory bulb mitral/tufted cell single-unit responses to the CS odor. The results indicated that training with either: (1) Odor-Stroke-Saline, (2) Odor-Stroke-lsoproterenol-Propranolol, or (3) Odor only-lsoproterenol (2 mg/kg) was sufficient to produce a learned behavioral odor preference, enhanced uptake of 14C-2-DG in the odor-specific foci within the bulb, and a modified output signal from the bulb as measured by single-cell recordings of mitral/tufted cells. Moreover, propranolol injected prior to Odor-Stroke training blocked the acquisition of both the learned behavior and olfactory bulb responses. PMID:2585063

Neuropeptide F neurons modulate sugar reward during associative olfactory learning of Drosophila larvae.

PubMed

Rohwedder, Astrid; Selcho, Mareike; Chassot, Bérénice; Thum, Andreas S

2015-12-15

All organisms continuously have to adapt their behavior according to changes in the environment in order to survive. Experience-driven changes in behavior are usually mediated and maintained by modifications in signaling within defined brain circuits. Given the simplicity of the larval brain of Drosophila and its experimental accessibility on the genetic and behavioral level, we analyzed if Drosophila neuropeptide F (dNPF) neurons are involved in classical olfactory conditioning. dNPF is an ortholog of the mammalian neuropeptide Y, a highly conserved neuromodulator that stimulates food-seeking behavior. We provide a comprehensive anatomical analysis of the dNPF neurons on the single-cell level. We demonstrate that artificial activation of dNPF neurons inhibits appetitive olfactory learning by modulating the sugar reward signal during acquisition. No effect is detectable for the retrieval of an established appetitive olfactory memory. The modulatory effect is based on the joint action of three distinct cell types that, if tested on the single-cell level, inhibit and invert the conditioned behavior. Taken together, our work describes anatomically and functionally a new part of the sugar reinforcement signaling pathway for classical olfactory conditioning in Drosophila larvae. © 2015 Wiley Periodicals, Inc.

Levels-of-processing effects on a task of olfactory naming.

PubMed

Royet, Jean-Pierre; Koenig, Olivier; Paugam-Moisy, Helene; Puzenat, Didier; Chasse, Jean-Luc

2004-02-01

The effects of odor processing were investigated at various analytical levels, from simple sensory analysis to deep or semantic analysis, on a subsequent task of odor naming. Students (106 women, 23.6 +/- 5.5 yr. old; 65 men, 25.1 +/- 7.1 yr. old) were tested. The experimental procedure included two successive sessions, a first session to characterize a set of 30 odors with criteria that used various depths of processing and a second session to name the odors as quickly as possible. Four processing conditions rated the odors using descriptors before naming the odor. The control condition did not rate the odors before naming. The processing conditions were based on lower-level olfactory judgments (superficial processing), higher-level olfactory-gustatory-somesthetic judgments (deep processing), and higher-level nonolfactory judgments (Deep-Control processing, with subjects rating odors with auditory and visual descriptors). One experimental condition successively grouped lower- and higher-level olfactory judgments (Superficial-Deep processing). A naming index which depended on response accuracy and the subjects' response time were calculated. Odor naming was modified for 18 out of 30 odorants as a function of the level of processing required. For 94.5% of significant variations, the scores for odor naming were higher following those tasks for which it was hypothesized that the necessary olfactory processing was carried out at a deeper level. Performance in the naming task was progressively improved as follows: no rating of odors, then superficial, deep-control, deep, and superficial-deep processings. These data show that the deepest olfactory encoding was later associated with progressively higher performance in naming.

Modulation of cerebral haemodynamic response to olfactory stimuli by emotional valence detected by functional magnetic resonance imaging

PubMed Central

Caous, Cristofer André; Tobo, Patrícia Renovato; Talarico, Vânia Hercília; Gonçales, Luciana Ribeiro Lopes; Yoshimine, Elise; da Cruz Jr, Antonio Cesário; Albuquerque, Cristóvão; Amaro Jr, Edson

2015-01-01

Olfactory perception, although restricted to just a few contexts in everyday life, is key in medicine. Several dementia conditions have been associated with early loss of olfactory discrimination. Despite the fact that several brain areas have been associated with olfaction in functional magnetic resonance imaging (fMRI), the mechanisms by which emotional valence is conveyed to the brain are not fully understood. Methods In this study, we compared cerebral activations by olfactory stimuli using different emotional valence stimuli on event-related fMRI. We used three standard olfactory odorants with different valence (positive, neutral and negative). Forty-three healthy subjects (22 males) were scanned on a 3.0T MR system. Olfactory stimulation was attained through a delivery system synchronized with image acquisition and subjects´ breathing instructions. fMRI data analysis was performed by the FSL package (Oxford University) including head movement correction, GLM modeling of the neurovascular (BOLD) response and group activation maps produced at p<0.05and corrected for multiple comparison. Results Increased cerebral responses within the anterior cingulate, amygdaloid nuclei, as well as the dorsolateral prefrontal, occipital and orbitofrontal cortices were observed in positive and negative valence conditions, while response to neutral valence arousal was less intense and not observed in the amygdaloid complex. The most significant statistical response aroused from the stimuli clusters was observed in the negative condition. Conclusion The results of the present study support the hypothesis that neutral stimuli may be more sensitive to early losses in pathological conditions, particularly dementia. PMID:29213990

Detection and avoidance of a carnivore odor by prey

PubMed Central

Ferrero, David M.; Lemon, Jamie K.; Fluegge, Daniela; Pashkovski, Stan L.; Korzan, Wayne J.; Datta, Sandeep Robert; Spehr, Marc; Fendt, Markus; Liberles, Stephen D.

2011-01-01

Predator–prey relationships provide a classic paradigm for the study of innate animal behavior. Odors from carnivores elicit stereotyped fear and avoidance responses in rodents, although sensory mechanisms involved are largely unknown. Here, we identified a chemical produced by predators that activates a mouse olfactory receptor and produces an innate behavioral response. We purified this predator cue from bobcat urine and identified it to be a biogenic amine, 2-phenylethylamine. Quantitative HPLC analysis across 38 mammalian species indicates enriched 2-phenylethylamine production by numerous carnivores, with some producing >3,000-fold more than herbivores examined. Calcium imaging of neuronal responses in mouse olfactory tissue slices identified dispersed carnivore odor-selective sensory neurons that also responded to 2-phenylethylamine. Two prey species, rat and mouse, avoid a 2-phenylethylamine odor source, and loss-of-function studies involving enzymatic depletion of 2-phenylethylamine from a carnivore odor indicate it to be required for full avoidance behavior. Thus, rodent olfactory sensory neurons and chemosensory receptors have the capacity for recognizing interspecies odors. One such cue, carnivore-derived 2-phenylethylamine, is a key component of a predator odor blend that triggers hard-wired aversion circuits in the rodent brain. These data show how a single, volatile chemical detected in the environment can drive an elaborate danger-associated behavioral response in mammals. PMID:21690383

Presence of neuropathic pain may explain poor performances on olfactory testing in diabetes mellitus patients.

PubMed

Brady, Shauna; Lalli, Paul; Midha, Nisha; Chan, Ayechen; Garven, Alexandra; Chan, Cynthia; Toth, Cory

2013-07-01

Olfactory dysfunction in neurodegenerative conditions such as Parkinson's syndrome and Alzheimer's disease can hallmark disease onset. We hypothesized that patients with diabetes mellitus, a condition featuring peripheral and central neurodegeneration, would have decreased olfaction abilities. We examined participants with diabetic peripheral neuropathy, participants with diabetes without diabetic peripheral neuropathy, and control participants in blinded fashion using standardized Sniffin' Sticks. Diabetic peripheral neuropathy severity was quantified using the Utah Early Neuropathy Scale. Further subcategorization of diabetic peripheral neuropathy based on presence of neuropathic pain was performed with Douleur Neuropathique 4 Questionnaires. Participants with diabetes had decreased olfactory sensitivity, impaired olfactory discrimination abilities, and reduced odor identification skills when compared with controls. However, loss of olfaction ability was, at least partially, attributed to presence of neuropathic pain on subcategory assessment, although pain severity was not associated with dysfunction. Those participants with diabetes without diabetic peripheral neuropathy and those with diabetic peripheral neuropathy without neuropathic pain had similar olfactory function as controls in general. The presence of neuropathic pain, associated with limited attention and concentration, may explain at least a portion of the olfactory dysfunction witnessed in the diabetic patient population.

Olfactory memory formation and the influence of reward pathway during appetitive learning by honey bees.

PubMed

Wright, Geraldine A; Mustard, Julie A; Kottcamp, Sonya M; Smith, Brian H

2007-11-01

Animals possess the ability to assess food quality via taste and via changes in state that occur after ingestion. Here, we investigate the extent to which a honey bee's ability to assess food quality affected the formation of association with an odor stimulus and the retention of olfactory memories associated with reward. We used three different conditioning protocols in which the unconditioned stimulus (food) was delivered as sucrose stimulation to the proboscis (mouthparts), the antennae or to both proboscis and antennae. All means of delivery of the unconditioned stimulus produced robust associative conditioning with an odor. However, the memory of a conditioned odor decayed at a significantly greater rate for subjects experiencing antennal-only stimulation after either multiple- or single-trial conditioning. Finally, to test whether the act of feeding on a reward containing sucrose during conditioning affected olfactory memory formation, we conditioned honey bees to associate an odor with antennal stimulation with sucrose followed by feeding on a water droplet. We observed that a honey bee's ability to recall the conditioned odor was not significantly different from that of subjects conditioned with an antennal-only sucrose stimulus. Our results show that stimulation of the sensory receptors on the proboscis and/or ingestion of the sucrose reward during appetitive olfactory conditioning are necessary for long-term memory formation.

Incubation of conditioned fear in the conditioned suppression model in rats: role of food-restriction conditions, length of conditioned stimulus, and generality to conditioned freezing

PubMed Central

Pickens, Charles L.; Navarre, Brittany M.; Nair, Sunila G.

2010-01-01

We recently adapted the conditioned suppression of operant responding method to study fear incubation. We found that food-restricted rats show low fear 2 days after extended (10 d; 100 30-sec tone-shock pairings) fear training and high fear after 1–2 months. Here, we studied a potential mechanism of fear incubation: extended food-restriction stress. We also studied whether fear incubation is observed after fear training with a prolonged-duration (6-min) tone conditioned stimulus (CS), and whether conditioned freezing incubates after extended training in rats with or without a concurrent operant task. Conditioned fear was assessed 2 days and 1 month after training. In the conditioned suppression method, fear incubation was reliably observed in rats under moderate food-restriction conditions (18–20 g food/day) that allowed for weight gain, and after extended (10 d), but not limited (1 d), fear training with the 6-min CS. Incubation of conditioned freezing was observed after extended fear training in rats lever-pressing for food and, to a lesser degree, in rats not performing an operant task. Results indicate that prolonged hunger-related stress does not account for fear incubation in the conditioned suppression method, and that fear incubation occurs to a longer-duration (6-min) fear CS. Extended training also leads to robust fear incubation of conditioned freezing in rats performing an operant task and weaker fear incubation in rats not performing an operant task. PMID:20600654

Incubation of conditioned fear in the conditioned suppression model in rats: role of food-restriction conditions, length of conditioned stimulus, and generality to conditioned freezing.

PubMed

Pickens, C L; Navarre, B M; Nair, S G

2010-09-15

We recently adapted the conditioned suppression of operant responding method to study fear incubation. We found that food-restricted rats show low fear 2 days after extended (10 d; 100 30-s tone-shock pairings) fear training and high fear after 1-2 months. Here, we studied a potential mechanism of fear incubation: extended food-restriction stress. We also studied whether fear incubation is observed after fear training with a prolonged-duration (6-min) tone conditioned stimulus (CS), and whether conditioned freezing incubates after extended training in rats with or without a concurrent operant task. Conditioned fear was assessed 2 days and 1 month after training. In the conditioned suppression method, fear incubation was reliably observed in rats under moderate food-restriction conditions (18-20 g food/day) that allowed for weight gain, and after extended (10 d), but not limited (1 d), fear training with the 6-min CS. Incubation of conditioned freezing was observed after extended fear training in rats lever-pressing for food and, to a lesser degree, in rats not performing an operant task. Results indicate that prolonged hunger-related stress does not account for fear incubation in the conditioned suppression method, and that fear incubation occurs to a longer-duration (6-min) fear CS. Extended training also leads to robust fear incubation of conditioned freezing in rats performing an operant task and weaker fear incubation in rats not performing an operant task. (c) 2010 IBRO. Published by Elsevier Ltd. All rights reserved.

Nasal Respiration Entrains Human Limbic Oscillations and Modulates Cognitive Function

PubMed Central

Jiang, Heidi; Zhou, Guangyu; Arora, Nikita; Schuele, Stephan; Rosenow, Joshua; Gottfried, Jay A.

2016-01-01

The need to breathe links the mammalian olfactory system inextricably to the respiratory rhythms that draw air through the nose. In rodents and other small animals, slow oscillations of local field potential activity are driven at the rate of breathing (∼2–12 Hz) in olfactory bulb and cortex, and faster oscillatory bursts are coupled to specific phases of the respiratory cycle. These dynamic rhythms are thought to regulate cortical excitability and coordinate network interactions, helping to shape olfactory coding, memory, and behavior. However, while respiratory oscillations are a ubiquitous hallmark of olfactory system function in animals, direct evidence for such patterns is lacking in humans. In this study, we acquired intracranial EEG data from rare patients (Ps) with medically refractory epilepsy, enabling us to test the hypothesis that cortical oscillatory activity would be entrained to the human respiratory cycle, albeit at the much slower rhythm of ∼0.16–0.33 Hz. Our results reveal that natural breathing synchronizes electrical activity in human piriform (olfactory) cortex, as well as in limbic-related brain areas, including amygdala and hippocampus. Notably, oscillatory power peaked during inspiration and dissipated when breathing was diverted from nose to mouth. Parallel behavioral experiments showed that breathing phase enhances fear discrimination and memory retrieval. Our findings provide a unique framework for understanding the pivotal role of nasal breathing in coordinating neuronal oscillations to support stimulus processing and behavior. SIGNIFICANCE STATEMENT Animal studies have long shown that olfactory oscillatory activity emerges in line with the natural rhythm of breathing, even in the absence of an odor stimulus. Whether the breathing cycle induces cortical oscillations in the human brain is poorly understood. In this study, we collected intracranial EEG data from rare patients with medically intractable epilepsy, and found evidence for respiratory entrainment of local field potential activity in human piriform cortex, amygdala, and hippocampus. These effects diminished when breathing was diverted to the mouth, highlighting the importance of nasal airflow for generating respiratory oscillations. Finally, behavioral data in healthy subjects suggest that breathing phase systematically influences cognitive tasks related to amygdala and hippocampal functions. PMID:27927961

Nasal Respiration Entrains Human Limbic Oscillations and Modulates Cognitive Function.

PubMed

Zelano, Christina; Jiang, Heidi; Zhou, Guangyu; Arora, Nikita; Schuele, Stephan; Rosenow, Joshua; Gottfried, Jay A

2016-12-07

The need to breathe links the mammalian olfactory system inextricably to the respiratory rhythms that draw air through the nose. In rodents and other small animals, slow oscillations of local field potential activity are driven at the rate of breathing (∼2-12 Hz) in olfactory bulb and cortex, and faster oscillatory bursts are coupled to specific phases of the respiratory cycle. These dynamic rhythms are thought to regulate cortical excitability and coordinate network interactions, helping to shape olfactory coding, memory, and behavior. However, while respiratory oscillations are a ubiquitous hallmark of olfactory system function in animals, direct evidence for such patterns is lacking in humans. In this study, we acquired intracranial EEG data from rare patients (Ps) with medically refractory epilepsy, enabling us to test the hypothesis that cortical oscillatory activity would be entrained to the human respiratory cycle, albeit at the much slower rhythm of ∼0.16-0.33 Hz. Our results reveal that natural breathing synchronizes electrical activity in human piriform (olfactory) cortex, as well as in limbic-related brain areas, including amygdala and hippocampus. Notably, oscillatory power peaked during inspiration and dissipated when breathing was diverted from nose to mouth. Parallel behavioral experiments showed that breathing phase enhances fear discrimination and memory retrieval. Our findings provide a unique framework for understanding the pivotal role of nasal breathing in coordinating neuronal oscillations to support stimulus processing and behavior. Animal studies have long shown that olfactory oscillatory activity emerges in line with the natural rhythm of breathing, even in the absence of an odor stimulus. Whether the breathing cycle induces cortical oscillations in the human brain is poorly understood. In this study, we collected intracranial EEG data from rare patients with medically intractable epilepsy, and found evidence for respiratory entrainment of local field potential activity in human piriform cortex, amygdala, and hippocampus. These effects diminished when breathing was diverted to the mouth, highlighting the importance of nasal airflow for generating respiratory oscillations. Finally, behavioral data in healthy subjects suggest that breathing phase systematically influences cognitive tasks related to amygdala and hippocampal functions. Copyright © 2016 the authors 0270-6474/16/3612448-20$15.00/0.

Conditioned Fear Acquisition and Generalization in Generalized Anxiety Disorder.

PubMed

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

2015-09-01

Abnormal fear conditioning processes (including fear acquisition and conditioned fear-generalization) have been implicated in the pathogenesis of anxiety disorders. Previous research has shown that individuals with panic disorder present enhanced conditioned fear-generalization in comparison to healthy controls. Enhanced conditioned fear-generalization could also characterize generalized anxiety disorder (GAD), but research so far is inconclusive. An important confounding factor in previous research is comorbidity. The present study examined conditioned fear-acquisition and fear-generalization in 28 patients with GAD and 30 healthy controls using a recently developed fear acquisition and generalization paradigm assessing fear-potentiated startle and online expectancies of the unconditioned stimulus. Analyses focused on GAD patients without comorbidity but included also patients with comorbid anxiety disorders. Patients and controls did not differ as regards fear acquisition. However, contrary to our hypothesis, both groups did not differ either in most indexes of conditioned fear-generalization. Moreover, dimensional measures of GAD symptoms were not correlated with conditioned fear-generalization indexes. Comorbidity did not have a significant impact on the results. Our data suggest that conditioned fear-generalization is not enhanced in GAD. Results are discussed with special attention to the possible effects of comorbidity on fear learning abnormalities. Copyright © 2014. Published by Elsevier Ltd.

Olfactory acuity in theropods: palaeobiological and evolutionary implications.

PubMed

Zelenitsky, Darla K; Therrien, François; Kobayashi, Yoshitsugu

2009-02-22

This research presents the first quantitative evaluation of the olfactory acuity in extinct theropod dinosaurs. Olfactory ratios (i.e. the ratio of the greatest diameter of the olfactory bulb to the greatest diameter of the cerebral hemisphere) are analysed in order to infer the olfactory acuity and behavioural traits in theropods, as well as to identify phylogenetic trends in olfaction within Theropoda. A phylogenetically corrected regression of olfactory ratio to body mass reveals that, relative to predicted values, the olfactory bulbs of (i) tyrannosaurids and dromaeosaurids are significantly larger, (ii) ornithomimosaurs and oviraptorids are significantly smaller, and (iii) ceratosaurians, allosauroids, basal tyrannosauroids, troodontids and basal birds are within the 95% CI. Relative to other theropods, olfactory acuity was high in tyrannosaurids and dromaeosaurids and therefore olfaction would have played an important role in their ecology, possibly for activities in low-light conditions, locating food, or for navigation within large home ranges. Olfactory acuity was the lowest in ornithomimosaurs and oviraptorids, suggesting a reduced reliance on olfaction and perhaps an omnivorous diet in these theropods. Phylogenetic trends in olfaction among theropods reveal that olfactory acuity did not decrease in the ancestry of birds, as troodontids, dromaeosaurids and primitive birds possessed typical or high olfactory acuity. Thus, the sense of smell must have remained important in primitive birds and its presumed decrease associated with the increased importance of sight did not occur until later among more derived birds.

Olfactory acuity in theropods: palaeobiological and evolutionary implications

PubMed Central

Zelenitsky, Darla K.; Therrien, François; Kobayashi, Yoshitsugu

2008-01-01

This research presents the first quantitative evaluation of the olfactory acuity in extinct theropod dinosaurs. Olfactory ratios (i.e. the ratio of the greatest diameter of the olfactory bulb to the greatest diameter of the cerebral hemisphere) are analysed in order to infer the olfactory acuity and behavioural traits in theropods, as well as to identify phylogenetic trends in olfaction within Theropoda. A phylogenetically corrected regression of olfactory ratio to body mass reveals that, relative to predicted values, the olfactory bulbs of (i) tyrannosaurids and dromaeosaurids are significantly larger, (ii) ornithomimosaurs and oviraptorids are significantly smaller, and (iii) ceratosaurians, allosauroids, basal tyrannosauroids, troodontids and basal birds are within the 95% CI. Relative to other theropods, olfactory acuity was high in tyrannosaurids and dromaeosaurids and therefore olfaction would have played an important role in their ecology, possibly for activities in low-light conditions, locating food, or for navigation within large home ranges. Olfactory acuity was the lowest in ornithomimosaurs and oviraptorids, suggesting a reduced reliance on olfaction and perhaps an omnivorous diet in these theropods. Phylogenetic trends in olfaction among theropods reveal that olfactory acuity did not decrease in the ancestry of birds, as troodontids, dromaeosaurids and primitive birds possessed typical or high olfactory acuity. Thus, the sense of smell must have remained important in primitive birds and its presumed decrease associated with the increased importance of sight did not occur until later among more derived birds. PMID:18957367

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.

Participation of the Olfactory Bulb in Circadian Organization during Early Postnatal Life in Rabbits

PubMed Central

Navarrete, Erika; Ortega-Bernal, Juan Roberto; Trejo-Muñoz, Lucero; Díaz, Georgina; Montúfar-Chaveznava, Rodrigo; Caldelas, Ivette

2016-01-01

Experimental evidence indicates that during pre-visual stages of development in mammals, circadian regulation is still not under the control of the light-entrainable hypothalamic pacemaker, raising the possibility that the circadian rhythmicity that occurs during postnatal development is under the control of peripheral oscillators, such as the main olfactory bulb (MOB). We evaluated the outcome of olfactory bulbectomy on the temporal pattern of core body temperature and gross locomotor activity in newborn rabbits. From postnatal day 1 (P1), pups were randomly assigned to one of the following conditions: intact pups (INT), intact pups fed by enteral gavage (INT+ENT), sham operated pups (SHAM), pups with unilateral lesions of the olfactory bulb (OBx-UNI), and pups with bilateral lesions of the olfactory bulb (OBx-BI). At the beginning of the experiment, from P1-8, the animals in all groups were fed at 11:00, from P9-13 the feeding schedule was delayed 6 h (17:00), and finally, from P14-15 the animals were subjected to fasting conditions. The rabbit pups of the INT, INT+ENT, SHAM and OBx-UNI groups exhibited a clear circadian rhythmicity in body temperature and locomotor activity, with a conspicuous anticipatory rise hours prior to the nursing or feeding schedule, which persisted even during fasting conditions. In addition, phase delays in the nursing or feeding schedule induced a clear phase shift in both parameters. In contrast, the OBx-BI group exhibited atypical rhythmicity in both parameters under entrained conditions that altered the anticipatory component, as well as deficient phase control of both rhythms. The present results demonstrate that the expression of circadian rhythmicity at behavioral and physiological levels during early stages of rabbit development largely depends on the integrity of the main olfactory bulb. PMID:27305041

Peripheral anosmia attenuates female-enhanced aggression in male rats.

PubMed

Bergvall, A H; Vega Matuszczyk, J; Dahlöf, L G; Hansen, S

1991-07-01

It is well established that male rats with prior access to sexually active females show enhanced offensive aggression toward unfamiliar male intruders. The present study assessed the importance of the sense of smell for this facilitatory effect. It was found in 2 independent experiments that anosmia, induced peripherally by surgically removing the olfactory epithelium and cutting the olfactory nerves, reduced baseline levels of offensive aggression and significantly attenuated the female-enhanced aggression effect. It was also found that sexual performance of anosmic rats was context-dependent, in that it was more impaired in the homecage environment than in standard observation cages. In contrast to sham-operated males, the experimental animals showed no preference for estrous over anestrous females in a mate choice test. Anosmic males did not appear more fearful than controls, as assessed in a hyponeophagia test, but they showed less exploratory behavior (rearing and head-dipping) in the hole-board test, and less rearing activity in automated activity boxes.

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.

Cross-modal interaction between visual and olfactory learning in Apis cerana.

PubMed

Zhang, Li-Zhen; Zhang, Shao-Wu; Wang, Zi-Long; Yan, Wei-Yu; Zeng, Zhi-Jiang

2014-10-01

The power of the small honeybee brain carrying out behavioral and cognitive tasks has been shown repeatedly to be highly impressive. The present study investigates, for the first time, the cross-modal interaction between visual and olfactory learning in Apis cerana. To explore the role and molecular mechanisms of cross-modal learning in A. cerana, the honeybees were trained and tested in a modified Y-maze with seven visual and five olfactory stimulus, where a robust visual threshold for black/white grating (period of 2.8°-3.8°) and relatively olfactory threshold (concentration of 50-25%) was obtained. Meanwhile, the expression levels of five genes (AcCREB, Acdop1, Acdop2, Acdop3, Actyr1) related to learning and memory were analyzed under different training conditions by real-time RT-PCR. The experimental results indicate that A. cerana could exhibit cross-modal interactions between visual and olfactory learning by reducing the threshold level of the conditioning stimuli, and that these genes may play important roles in the learning process of honeybees.

Olfaction: New Understandings, Diagnostic Applications.

PubMed

Ruggiero, Gabrielle F; Wick, Jeannette Y

2016-11-01

Estimates indicate that 14 million Americans have olfactory dysfunction. As with other senses, such as sight and hearing, olfaction frequently declines with age. Impaired olfaction can be a warning sign of Parkinson's disease, sometimes occurring before motor symptoms develop. It's also an initial symptom of Alzheimer's dementia (AD); the amyloid plaques and tangles characterizing AD invade the olfactory bulb and hippocampus early in its course, hampering odor identification. Olfactory dysfunction is associated with some serious problems, including inability to smell warning odors (fire, gas) and impaired ability to taste food. Standardized, validated methods are available to measure several different dimensions of olfactory function, including odor identification, discrimination, and threshold levels. Researchers are currently studying the unique olfactory deficits associated with different conditions in hopes of identifying new, noninvasive tools for early diagnosis and treatment. Drugs may cause or contribute to olfactory dysfunction, but it can be difficult to pinpoint offending medications.

Enhanced olfactory sensitivity in autism spectrum conditions.

PubMed

Ashwin, Chris; Chapman, Emma; Howells, Jessica; Rhydderch, Danielle; Walker, Ian; Baron-Cohen, Simon

2014-01-01

People with autism spectrum conditions (ASC) report heightened olfaction. Previous sensory experiments in people with ASC have reported hypersensitivity across visual, tactile, and auditory domains, but not olfaction. The aims of the present study were to investigate olfactory sensitivity in ASC, and to test the association of sensitivity to autistic traits. We recruited 17 adult males diagnosed with ASC and 17 typical adult male controls and tested their olfactory sensitivity using the Alcohol Sniff Test (AST), a standardised clinical evaluation of olfactory detection. The AST involves varying the distance between subject and stimulus until an odour is barely detected. Participants with ASC also completed the Autism Spectrum Quotient (AQ) as a measure of autism traits. The ASC group detected the odour at a mean distance of 24.1 cm (SD =11.5) from the nose, compared to the control group, who detected it at a significantly shorter mean distance of 14.4 cm (SD =5.9). Detection distance was independent of age and IQ for both groups, but showed a significant positive correlation with autistic traits in the ASC group (r =0.522). This is the first experimental demonstration, as far as the authors are aware, of superior olfactory perception in ASC and showing that greater olfactory sensitivity is correlated with a higher number of autistic traits. This is consistent with results from previous findings showing hypersensitivity in other sensory domains and may help explain anecdotal and questionnaire accounts of heightened olfactory sensitivity in ASC. Results are discussed in terms of possible underlying neurophysiology.

Effect of Flumethrin on Survival and Olfactory Learning in Honeybees

PubMed Central

Tan, Ken; Yang, Shuang; Wang, Zhengwei; Menzel, Randolf

2013-01-01

Flumethrin has been widely used as an acaricide for the control of Varroa mites in commercial honeybee keeping throughout the world for many years. Here we test the mortality of the Asian honeybee Apis cerana cerana after treatment with flumethrin. We also ask (1) how bees react to the odor of flumethrin, (2) whether its odor induces an innate avoidance response, (3) whether its taste transmits an aversive reinforcing component in olfactory learning, and (4) whether its odor or taste can be associated with reward in classical conditioning. Our results show that flumethrin has a negative effect on Apis ceranàs lifespan, induces an innate avoidance response, acts as a punishing reinforcer in olfactory learning, and interferes with the association of an appetitive conditioned stimulus. Furthermore flumethrin uptake within the colony reduces olfactory learning over an extended period of time. PMID:23785490

Allosteric ligands for the pharmacologically dark receptors GPR68 and GPR65

PubMed Central

Huang, Xi-Ping; Karpiak, Joel; Kroeze, Wesley K.; Zhu, Hu; Chen, Xin; Moy, Sheryl S.; Saddoris, Kara A.; Nikolova, Viktoriya; Farrell, Martilias S.; Wang, Sheng; Mangano, Thomas J.; Deshpande, Deepak A.; Jiang, Alice; Penn, Raymond B.; Jin, Jian; Koller, Beverly H.; Kenakin, Terry; Shoichet, Brian K.; Roth, Bryan L.

2016-01-01

At least 120 non-olfactory G protein-coupled receptors in the human genome are ”orphans” for which endogenous ligands are unknown, and many have no selective ligands, hindering elucidation of their biological functions and clinical relevance. Among these is GPR68, a proton receptor that lacks small molecule modulators for probing its biology. Yeast-based screens against GPR68 identified the benzodiazepine drug lorazepam as a non-selective GPR68 positive allosteric modulator. Over 3000 GPR68 homology models were refined to recognize lorazepam in a putative allosteric site. Docking 3.1 million molecules predicted new GPR68 modulators many of which were confirmed in functional assays. One potent GPR68 modulator—ogerin– suppressed recall in fear conditioning in wild-type, but not in GPR68 knockout mice. The same approach led to the discovery of allosteric agonists and negative allosteric modulators for GPR65. Combining physical and structure-based screening may be broadly useful for ligand discovery for understudied and orphan GPCRs. PMID:26550826

Acute ethanol ingestion impairs appetitive olfactory learning and odor discrimination in the honey bee

PubMed Central

Mustard, Julie A; Wright, Geraldine A; Edgar, Elaina A; Mazade, Reece E.; Wu, Chen; Lillvis, Joshua L

2008-01-01

Invertebrates are valuable models for increasing our understanding of the effects of ethanol on the nervous system, but most studies on invertebrates and ethanol have focused on the effects of ethanol on locomotor behavior. In this work we investigate the influence of an acute dose of ethanol on appetitive olfactory learning in the honey bee (Apis mellifera), a model system for learning and memory. Adult worker honey bees were fed a range of doses (2.5, 5, 10 or 25%) of ethanol and then conditioned to associate an odor with a sucrose reward using either a simple or differential conditioning paradigm. Consumption of ethanol before conditioning significantly reduced both the rate of acquisition and the asymptotic strength of the association. Honey bees also exhibited a dose dependent reduction in arousal/attention during conditioning. Consumption of ethanol after conditioning did not affect recall 24 h later. The observed deficits in acquisition were not due to the affect of ethanol on gustatory sensitivity or motor function. However, honey bees given higher doses of ethanol had difficulty discriminating amongst different odors suggesting that ethanol consumption influences olfactory processing. Taken together, these results demonstrate that an acute dose of ethanol affects appetitive learning and olfactory perception in the honey bee. PMID:18723103

Effects of 20 mg oral Δ9-tetrahydrocannabinol on the olfactory function of healthy volunteers*

PubMed Central

Walter, Carmen; Oertel, Bruno G; Ludyga, Dagmar; Ultsch, Alfred; Hummel, Thomas; Lötsch, Jörn

2014-01-01

Aims Olfactory loss impairs the patient's quality of life. In individualized therapies, olfactory drug effects gain clinical importance. Molecular evidence suggests that among drugs with potential olfactory effects is Δ9-tetrahydrocannabinol (THC), which is approved for several indications, including neuropathic pain or analgesia in cancer patients. The present study aimed at assessing the olfactory effects of THC to be expected during analgesic treatment. Methods The effects of 20 mg oral THC on olfaction were assessed in a placebo-controlled, randomized cross-over study in healthy volunteers. Using an established olfactory test (Sniffin' Sticks), olfactory thresholds, odour discrimination and odour identification were assessed in 15 subjects at baseline and 2 h after THC administration. Results Δ9-Tetrahydrocannabinol impaired the performance of subjects (n = 15) in the olfactory test. Specifically, olfactory thresholds were increased and odour discrimination performance was reduced. This resulted in a significant drop in composite threshold, discrimination, identification (TDI) olfactory score by 5.5 points (from 37.7 ± 4.2 to 32.2 ± 5.6, 95% confidence interval for differences THC vs. placebo, −7.8 to −2.0, P = 0.003), which is known to be a subjectively perceptible impairment of olfactory function. Conclusions Considering the resurgence of THC in medical use for several pathological conditions, the present results indicate that THC-based analgesics may be accompanied by subjectively noticeable reductions in olfactory acuity. In particular, for patients relying on their sense of smell, this might be relevant information for personalized therapy strategies. PMID:24802974

Effects of 20 mg oral Δ(9) -tetrahydrocannabinol on the olfactory function of healthy volunteers.

PubMed

Walter, Carmen; Oertel, Bruno G; Ludyga, Dagmar; Ultsch, Alfred; Hummel, Thomas; Lötsch, Jörn

2014-11-01

Olfactory loss impairs the patient's quality of life. In individualized therapies, olfactory drug effects gain clinical importance. Molecular evidence suggests that among drugs with potential olfactory effects is Δ(9) -tetrahydrocannabinol (THC), which is approved for several indications, including neuropathic pain or analgesia in cancer patients. The present study aimed at assessing the olfactory effects of THC to be expected during analgesic treatment. The effects of 20 mg oral THC on olfaction were assessed in a placebo-controlled, randomized cross-over study in healthy volunteers. Using an established olfactory test (Sniffin' Sticks), olfactory thresholds, odour discrimination and odour identification were assessed in 15 subjects at baseline and 2 h after THC administration. Δ(9) -Tetrahydrocannabinol impaired the performance of subjects (n = 15) in the olfactory test. Specifically, olfactory thresholds were increased and odour discrimination performance was reduced. This resulted in a significant drop in composite threshold, discrimination, identification (TDI) olfactory score by 5.5 points (from 37.7 ± 4.2 to 32.2 ± 5.6, 95% confidence interval for differences THC vs. placebo, -7.8 to -2.0, P = 0.003), which is known to be a subjectively perceptible impairment of olfactory function. Considering the resurgence of THC in medical use for several pathological conditions, the present results indicate that THC-based analgesics may be accompanied by subjectively noticeable reductions in olfactory acuity. In particular, for patients relying on their sense of smell, this might be relevant information for personalized therapy strategies. © 2014 The British Pharmacological Society.

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

A twin study of the genetics of fear conditioning.

PubMed

Hettema, John M; Annas, Peter; Neale, Michael C; Kendler, Kenneth S; Fredrikson, Mats

2003-07-01

Fear conditioning is a traditional model for the acquisition of fears and phobias. Studies of the genetic architecture of fear conditioning may inform gene-finding strategies for anxiety disorders. The objective of this study was to determine the genetic and environmental sources of individual differences in fear conditioning by means of a twin sample. Classic fear conditioning data were experimentally obtained from 173 same-sex twin pairs (90 monozygotic and 83 dizygotic). Sequences of evolutionary fear-relevant (snakes and spiders) and fear-irrelevant (circles and triangles) pictorial stimuli served as conditioned stimuli paired with a mild electric shock serving as the unconditioned stimulus. The outcome measure was the electrodermal skin conductance response. We applied structural equation modeling methods to the 3 conditioning phases of habituation, acquisition, and extinction to determine the extent to which genetic and environmental factors underlie individual variation in associative and nonassociative learning. All components of the fear conditioning process in humans demonstrated moderate heritability, in the range of 35% to 45%. Best-fitting multivariate models suggest that 2 sets of genes may underlie the trait of fear conditioning: one that most strongly affects nonassociative processes of habituation that also is shared with acquisition and extinction, and a second that appears related to associative fear conditioning processes. In addition, these data provide tentative evidence of differences in heritability based on the fear relevance of the stimuli. Genes represent a significant source of individual variation in the habituation, acquisition, and extinction of fears, and genetic effects specific to fear conditioning are involved.

Probing the influence of unconscious fear-conditioned visual stimuli on eye movements.

PubMed

Madipakkam, Apoorva Rajiv; Rothkirch, Marcus; Wilbertz, Gregor; Sterzer, Philipp

2016-11-01

Efficient threat detection from the environment is critical for survival. Accordingly, fear-conditioned stimuli receive prioritized processing and capture overt and covert attention. However, it is unknown whether eye movements are influenced by unconscious fear-conditioned stimuli. We performed a classical fear-conditioning procedure and subsequently recorded participants' eye movements while they were exposed to fear-conditioned stimuli that were rendered invisible using interocular suppression. Chance-level performance in a forced-choice-task demonstrated unawareness of the stimuli. Differential skin conductance responses and a change in participants' fearfulness ratings of the stimuli indicated the effectiveness of conditioning. However, eye movements were not biased towards the fear-conditioned stimulus. Preliminary evidence suggests a relation between the strength of conditioning and the saccadic bias to the fear-conditioned stimulus. Our findings provide no strong evidence for a saccadic bias towards unconscious fear-conditioned stimuli but tentative evidence suggests that such an effect may depend on the strength of the conditioned response. Copyright © 2016 Elsevier Inc. All rights reserved.

Generalization of conditioned fear along a dimension of increasing fear intensity

PubMed Central

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

2009-01-01

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

Lesion of olfactory epithelium attenuates expression of morphine-induced behavioral sensitization and reinstatement of drug-primed conditioned place preference in mice.

PubMed

Niu, Haichen; Zheng, Yingwei; Huma, Tanzeel; Rizak, Joshua D; Li, Ling; Wang, Guimei; Ren, He; Xu, Liqi; Yang, Jianzhen; Ma, Yuanye; Lei, Hao

2013-01-01

Previous studies have shown that olfactory impairment by disrupting the olfactory epithelium prior to morphine administration attenuated the development addiction-related behaviors. However, it is unclear whether olfactory impairment will affect the expression of already established addiction-related behaviors. To address this issue, mice were conditioned with morphine to induce behavioral sensitization and condition placed preference (CPP). After an abstinence period, the animals were subjected to either an intranasal ZnSO(4) effusion (ZnE) or sham treatment with saline. Behavioral sensitization and CPP reinstatement were evaluated 24h later, as well as the expression of c-Fos protein, a marker of activated neural sites, in brain regions of interest. It was found that ZnE treatment attenuated morphine-induced behavioral sensitization and reinstatement of CPP. Compared to the saline-treated ones, the ZnE-treated animals showed reduced c-Fos expression in the nucleus accumbens (NAc) associated with behavioral sensitization, and in the NAc, cingulate cortex, dentate gyrus, amygdala, lateral hypothalamus and ventral tegmental area associated with CPP reinstatement. Together, these results demonstrated that acute olfactory impairment could attenuate already established addiction-related behaviors and expression of c-Fos in drug addiction related brain regions, perhaps by affecting the coordination between reward and motivational systems in the brain. Copyright © 2012 Elsevier Inc. All rights reserved.

Posterior insular cortex is necessary for conditioned inhibition of fear

PubMed Central

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

2016-01-01

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

Perceptual and Neural Olfactory Similarity in Honeybees

PubMed Central

Sandoz, Jean-Christophe

2005-01-01

The question of whether or not neural activity patterns recorded in the olfactory centres of the brain correspond to olfactory perceptual measures remains unanswered. To address this question, we studied olfaction in honeybees Apis mellifera using the olfactory conditioning of the proboscis extension response. We conditioned bees to odours and tested generalisation responses to different odours. Sixteen odours were used, which varied both in their functional group (primary and secondary alcohols, aldehydes and ketones) and in their carbon-chain length (from six to nine carbons).The results obtained by presentation of a total of 16 × 16 odour pairs show that (i) all odorants presented could be learned, although acquisition was lower for short-chain ketones; (ii) generalisation varied depending both on the functional group and the carbon-chain length of odours trained; higher generalisation was found between long-chain than between short-chain molecules and between groups such as primary and secondary alcohols; (iii) for some odour pairs, cross-generalisation between odorants was asymmetric; (iv) a putative olfactory space could be defined for the honeybee with functional group and carbon-chain length as inner dimensions; (v) perceptual distances in such a space correlate well with physiological distances determined from optophysiological recordings of antennal lobe activity. We conclude that functional group and carbon-chain length are inner dimensions of the honeybee olfactory space and that neural activity in the antennal lobe reflects the perceptual quality of odours. PMID:15736975

Default Mode Network (DMN) Deactivation during Odor-Visual Association

PubMed Central

Karunanayaka, Prasanna R.; Wilson, Donald A.; Tobia, Michael J.; Martinez, Brittany; Meadowcroft, Mark; Eslinger, Paul J.; Yang, Qing X.

2017-01-01

Default mode network (DMN) deactivation has been shown to be functionally relevant for goal-directed cognition. In this study, we investigated the DMN’s role during olfactory processing using two complementary functional magnetic resonance imaging (fMRI) paradigms with identical timing, visual-cue stimulation and response monitoring protocols. Twenty-nine healthy, non-smoking, right-handed adults (mean age = 26±4 yrs., 16 females) completed an odor-visual association fMRI paradigm that had two alternating odor+visual and visual-only trial conditions. During odor+visual trials, a visual cue was presented simultaneously with an odor, while during visual-only trial conditions the same visual cue was presented alone. Eighteen of the 29 participants (mean age = 27.0 ± 6.0 yrs.,11 females) also took part in a control no-odor fMRI paradigm that consisted of visual-only trial conditions which were identical to the visual-only trials in the odor-visual association paradigm. We used Independent Component Analysis (ICA), extended unified structural equation modeling (euSEM), and psychophysiological interaction (PPI) to investigate the interplay between the DMN and olfactory network. In the odor-visual association paradigm, DMN deactivation was evoked by both the odor+visual and visual-only trial conditions. In contrast, the visual-only trials in the no-odor paradigm did not evoke consistent DMN deactivation. In the odor-visual association paradigm, the euSEM and PPI analyses identified a directed connectivity between the DMN and olfactory network which was significantly different between odor+visual and visual-only trial conditions. The results support a strong interaction between the DMN and olfactory network and highlights DMN’s role in task-evoked brain activity and behavioral responses during olfactory processing. PMID:27785847

Olfactory-visual congruence effects stable across ages: yellow is warmer when it is pleasantly lemony.

PubMed

Guerdoux, Estelle; Trouillet, Raphaël; Brouillet, Denis

2014-07-01

This study aimed to examine the age-related differences in the olfactory-visual cross-correspondences and the extent to which they are moderated by the odors pleasantness. Sixty participants aged from 20- to 75- years (young, middle-aged and older adults) performed a priming task to explore the influence of six olfactory primes (lemon, orange, rose, thyme, mint and fish) on the categorization (cool vs. warm) of six subsequent color targets (yellow, orange, pink, malachite green, grass-green, and blue-gray). We tested mixed effects models. Response times were regressed on covariates models using both fixed effects (Groups of age, olfactory Pleasantness and multimodal Condition) and cross-random effects (Subject, Color and Odor). The random effects coding for Odor (p < .001) and Color (p = .001) were significant. There was a significant interaction effect ( p= .004) between Condition × Pleasantness, but not with Groups of age. The compatibility effect (i.e., when odors and colors were congruent, the targets processing were facilitated) was as much enhanced as the olfactory primes were pleasant. Cross-correspondences between olfaction and vision may be robust in aging. They should be considered alongside spatiotemporal but also emotional congruency.

Olfactory Functioning in First-Episode Psychosis.

PubMed

Kamath, Vidyulata; Lasutschinkow, Patricia; Ishizuka, Koko; Sawa, Akira

2018-04-06

Though olfactory deficits are well-documented in schizophrenia, fewer studies have examined olfactory performance profiles across the psychosis spectrum. The current study examined odor identification, discrimination, and detection threshold performance in first-episode psychosis (FEP) patients diagnosed with schizophrenia, schizoaffective disorder, bipolar disorder with psychotic features, major depression with psychotic features, and other psychotic conditions. FEP patients (n = 97) and healthy adults (n = 98) completed birhinal assessments of odor identification, discrimination, and detection threshold sensitivity for lyral and citralva. Participants also completed measures of anticipatory pleasure, anhedonia, and empathy. Differences in olfactory performances were assessed between FEP patients and controls and within FEP subgroups. Sex-stratified post hoc analyses were employed for a complete analysis of sex differences. Relationships between self-report measures and olfactory scores were also examined. Individuals with psychosis had poorer scores across all olfactory measures when compared to the control group. Within the psychosis cohort, patients with schizophrenia-associated psychosis had poorer odor identification, discrimination, and citralva detection threshold scores relative to controls. In schizophrenia patients, greater olfactory disturbance was associated with increased negative symptomatology, greater self-reported anhedonia, and lower self-reported anticipatory pleasure. Patients with mood-associated psychosis performed comparable to controls though men and women in this cohort showed differential olfactory profiles. These findings indicate that olfactory deficits extend beyond measures of odor identification in FEP with greater deficits observed in schizophrenia-related subgroups of psychosis. Studies examining whether greater olfactory dysfunction confers greater risk for developing schizophrenia relative to other forms of psychosis are warranted.

The Genetic Covariation between Fear Conditioning and Self-Report Fears

PubMed Central

Hettema, John M.; Annas, Peter; Neale, Michael C.; Fredrikson, Mats; Sci, Dr Med; Kendler, Kenneth S.

2008-01-01

Background Fear conditioning is a traditional model for the acquisition of phobias, while behavioral therapies utilize processes underlying extinction to treat phobic and other anxiety disorders. Furthermore, fear conditioning has been proposed as an endophenotype for genetic studies of anxiety disorders. While prior studies have demonstrated that fear conditioning and self-report fears are heritable, no studies have determined whether they share a common genetic basis. Methods We obtained fear conditioning data from 173 twin pairs from the Swedish Twin Registry who also provided self-report ratings of 16 common fears. Using multivariate structural equation modeling, we analyzed factor-derived scores for the subjective fear ratings together with the electrophysiologic skin conductance responses during habituation, acquisition, and extinction to determine the extent of their genetic covariation. Results Phenotypic correlations between experimental and self-report fear measures were modest and, and counter-intuitively, negative; that is, subjects who reported themselves as more fearful had smaller electrophysiologic responses. Best-fit models estimated a significant (negative) genetic correlation between them, although genetic factors underlying fear conditioning accounted for only 9% of individual differences in self-report fears. Conclusions Experimentally-derived fear conditioning measures share only a small portion of the genetic factors underlying individual differences in subjective fears, cautioning against relying too heavily on the former as an endophenotype for genetic studies of phobic disorders. PMID:17698042

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

PubMed

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

2015-11-01

Fear conditioning studies in adults have found that posttraumatic stress disorder (PTSD) is associated with heightened fear responses and impaired discrimination. The objective of the current study was to examine the association between PTSD symptoms and fear conditioned responses in children from a highly traumatized urban population. Children between 8 and 13 years old participated in a fear conditioning study in addition to providing information about their trauma history and PTSD symptoms. Results showed that females showed less discrimination between danger and safety signals during conditioning compared to age-matched males. In boys, intrusive symptoms were predictive of fear responses, even after controlling for trauma exposure. However, in girls, conditioned fear to the danger cue was predictive of self-blame and fear of repeated trauma. This study suggests there are early sex differences in the patterns of fear conditioning and that these sex differences may translate to differential risk for trauma-related psychopathology. © 2015 Wiley Periodicals, Inc.

Comprehensive behavioral phenotyping of a new Semaphorin 3 F mutant mouse.

PubMed

Matsuda, Ikuo; Shoji, Hirotaka; Yamasaki, Nobuyuki; Miyakawa, Tsuyoshi; Aiba, Atsu

2016-02-09

Semaphorin 3 F (Sema3F) is a secreted type of the Semaphorin family of axon guidance molecules. Sema3F and its receptor neuropilin-2 (Npn-2) are expressed in a mutually exclusive manner in the embryonic mouse brain regions including olfactory bulb, hippocampus, and cerebral cortex. Sema3F is thought to have physiological functions in the formation of neuronal circuitry and its refinement. However, functional roles of Sema3F in the brain remain to be clarified. Here, we examined behavioral effects of Sema3F deficiency through a comprehensive behavioral test battery in Sema3F knockout (KO) male mice to understand the possible functions of Sema3F in the brain. Male Sema3F KO and wild-type (WT) control mice were subjected to a battery of behavioral tests, including neurological screen, rotarod, hot plate, prepulse inhibition, light/dark transition, open field, elevated plus maze, social interaction, Porsolt forced swim, tail suspension, Barnes maze, and fear conditioning tests. In the open field test, Sema3F KO mice traveled shorter distance and spent less time in the center of the field than WT controls during the early testing period. In the light/dark transition test, Sema3F KO mice also exhibited decreased distance traveled, fewer number of transitions, and longer latency to enter the light chamber compared with WT mice. In addition, Sema3F KO mice traveled shorter distance than WT mice in the elevated plus maze test, although there were no differences between genotypes in open arm entries and time spent in open arms. Similarly, Sema3F KO mice showed decreased distance traveled in the social interaction test. Sema3F KO mice displayed reduced immobility in the Porsolt forced swim test whereas there was no difference in immobility between genotypes in the tail suspension test. In the fear conditioning test, Sema3F KO mice exhibited increased freezing behavior when exposed to a conditioning context and an altered context in absence of a conditioned stimulus. In the tests for assessing motor function, pain sensitivity, startle response to an acoustic stimulus, sensorimotor gating, or spatial reference memory, there were no significant behavioral differences between Sema3F KO and WT mice. These results suggest that Sema3F deficiency induces decreased locomotor activity and possibly abnormal anxiety-related behaviors and also enhances contextual memory and generalized fear in mice. Thus, our findings suggest that Sema3F plays important roles in the development of neuronal circuitry underlying the regulation of some aspects of anxiety and fear responses.

The Medial Amygdala-Medullary PrRP-Synthesizing Neuron Pathway Mediates Neuroendocrine Responses to Contextual Conditioned Fear in Male Rodents

PubMed Central

Yoshida, Masahide; Takayanagi, Yuki

2014-01-01

Fear responses play evolutionarily beneficial roles, although excessive fear memory can induce inappropriate fear expression observed in posttraumatic stress disorder, panic disorder, and phobia. To understand the neural machineries that underlie these disorders, it is important to clarify the neural pathways of fear responses. Contextual conditioned fear induces freezing behavior and neuroendocrine responses. Considerable evidence indicates that the central amygdala plays an essential role in expression of freezing behavior after contextual conditioned fear. On the other hand, mechanisms of neuroendocrine responses remain to be clarified. The medial amygdala (MeA), which is activated after contextual conditioned fear, was lesioned bilaterally by infusion of N-methyl-d-aspartate after training of fear conditioning. Plasma oxytocin, ACTH, and prolactin concentrations were significantly increased after contextual conditioned fear in sham-lesioned rats. In MeA-lesioned rats, these neuroendocrine responses but not freezing behavior were significantly impaired compared with those in sham-lesioned rats. In contrast, the magnitudes of neuroendocrine responses after exposure to novel environmental stimuli were not significantly different in MeA-lesioned rats and sham-lesioned rats. Contextual conditioned fear activated prolactin-releasing peptide (PrRP)-synthesizing neurons in the medulla oblongata. In MeA-lesioned rats, the percentage of PrRP-synthesizing neurons activated after contextual conditioned fear was significantly decreased. Furthermore, neuroendocrine responses after contextual conditioned fear disappeared in PrRP-deficient mice. Our findings suggest that the MeA-medullary PrRP-synthesizing neuron pathway plays an important role in neuroendocrine responses to contextual conditioned fear. PMID:24877622

The medial amygdala-medullary PrRP-synthesizing neuron pathway mediates neuroendocrine responses to contextual conditioned fear in male rodents.

PubMed

Yoshida, Masahide; Takayanagi, Yuki; Onaka, Tatsushi

2014-08-01

Fear responses play evolutionarily beneficial roles, although excessive fear memory can induce inappropriate fear expression observed in posttraumatic stress disorder, panic disorder, and phobia. To understand the neural machineries that underlie these disorders, it is important to clarify the neural pathways of fear responses. Contextual conditioned fear induces freezing behavior and neuroendocrine responses. Considerable evidence indicates that the central amygdala plays an essential role in expression of freezing behavior after contextual conditioned fear. On the other hand, mechanisms of neuroendocrine responses remain to be clarified. The medial amygdala (MeA), which is activated after contextual conditioned fear, was lesioned bilaterally by infusion of N-methyl-d-aspartate after training of fear conditioning. Plasma oxytocin, ACTH, and prolactin concentrations were significantly increased after contextual conditioned fear in sham-lesioned rats. In MeA-lesioned rats, these neuroendocrine responses but not freezing behavior were significantly impaired compared with those in sham-lesioned rats. In contrast, the magnitudes of neuroendocrine responses after exposure to novel environmental stimuli were not significantly different in MeA-lesioned rats and sham-lesioned rats. Contextual conditioned fear activated prolactin-releasing peptide (PrRP)-synthesizing neurons in the medulla oblongata. In MeA-lesioned rats, the percentage of PrRP-synthesizing neurons activated after contextual conditioned fear was significantly decreased. Furthermore, neuroendocrine responses after contextual conditioned fear disappeared in PrRP-deficient mice. Our findings suggest that the MeA-medullary PrRP-synthesizing neuron pathway plays an important role in neuroendocrine responses to contextual conditioned fear.

The number of functional olfactory receptor genes and the relative size of olfactory brain structures are poor predictors of olfactory discrimination performance with enantiomers.

PubMed

Laska, Matthias; Genzel, Daria; Wieser, Alexandra

2005-02-01

The ability of four squirrel monkeys and three pigtail macaques to distinguish between nine enantiomeric odor pairs sharing an isopropenyl group at the chiral center was investigated in terms of a conditioning paradigm. All animals from both species were able to discriminate between the optical isomers of limonene, carvone, dihydrocarvone, dihydrocarveole and dihydrocarvyl acetate, whereas they failed to distinguish between the (+)- and (-)-forms of perillaaldehyde and limonene oxide. The pigtail macaques, but not the squirrel monkeys, also discriminated between the antipodes of perillaalcohol and isopulegol. A comparison of the across-task patterns of discrimination performance shows a high degree of similarity among the two primate species and also between these nonhuman primates and human subjects tested in an earlier study on the same tasks. These findings suggest that between-species comparisons of the relative size of olfactory brain structures or of the number of functional olfactory receptor genes are poor predictors of olfactory discrimination performance with enantiomers.

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

DTIC Science & Technology

2009-09-01

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

The styryl dye FM1-43 suppresses odorant responses in a subset of olfactory neurons by blocking cyclic nucleotide-gated (CNG) channels.

PubMed

Breunig, Esther; Kludt, Eugen; Czesnik, Dirk; Schild, Detlev

2011-08-12

Many olfactory receptor neurons use a cAMP-dependent transduction mechanism to transduce odorants into depolarizations. This signaling cascade is characterized by a sequence of two currents: a cation current through cyclic nucleotide-gated channels followed by a chloride current through calcium-activated chloride channels. To date, it is not possible to interfere with these generator channels under physiological conditions with potent and specific blockers. In this study we identified the styryl dye FM1-43 as a potent blocker of native olfactory cyclic nucleotide-gated channels. Furthermore, we characterized this substance to stain olfactory receptor neurons that are endowed with cAMP-dependent transduction. This allows optical differentiation and pharmacological interference with olfactory receptor neurons at the level of the signal transduction.

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.

Extinction during reconsolidation eliminates recovery of fear conditioned to fear-irrelevant and fear-relevant stimuli.

PubMed

Thompson, Alina; Lipp, Ottmar V

2017-05-01

Extant literature suggests that extinction training delivered during the memory reconsolidation period is superior to traditional extinction training in the reduction of fear recovery, as it targets the original fear memory trace. At present it is debated whether different types of fear memories are differentially sensitive to behavioral manipulations of reconsolidation. Here, we examined post-reconsolidation recovery of fear as a function of conditioned stimulus (CS) fear-relevance, using the unconditioned stimulus (US) to reactivate and destabilize conditioned fear memories. Participants (N = 56; 25 male; M = 24.39 years, SD = 7.71) in the US-reactivation and control group underwent differential fear conditioning to fear-relevant (spiders/snakes) and fear-irrelevant (geometric shapes) CSs on Day 1. On Day 2, participants received either reminded (US-reactivation) or non-reminded extinction training. Tests of fear recovery, conducted 24 h later, revealed recovery of differential electrodermal responding to both classes of CSs in the control group, but not in the US-reactivation group. These findings indicate that the US reactivation-extinction procedure eliminated recovery of extinguished responding not only to fear-irrelevant, but also to fear-relevant CSs. Contrasting previous reports, our findings show that post-reconsolidation recovery of conditioned responding is not a function of CS fear-relevance and that persistent reduction of fear, conditioned to fear-relevant CSs, can be achieved through behavioral manipulations of reconsolidation. Copyright © 2017 Elsevier Ltd. All rights reserved.

Posterior insular cortex is necessary for conditioned inhibition of fear.

PubMed

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

2016-10-01

Veridical detection of safety versus danger is critical to survival. Learned signals for safety inhibit fear, and so when presented, reduce fear responses produced by danger signals. This phenomenon is termed conditioned inhibition of fear. Here, we report that CS+/CS- fear discrimination conditioning over 5 days in rats leads the CS- to become a conditioned inhibitor of fear, as measured by the classic tests of conditioned inhibition: summation and retardation of subsequent fear acquisition. We then show that NMDA-receptor antagonist AP5 injected to posterior insular cortex (IC) before training completely prevented the acquisition of a conditioned fear inhibitor, while intra-AP5 to anterior and medial IC had no effect. To determine if the IC contributes to the recall of learned fear inhibition, injections of the GABAA agonist muscimol were made to posterior IC before a summation test. This resulted in fear inhibition per se, which obscured inference to the effect of IC inactivation with recall of the safety cue. Control experiments sought to determine if the role of the IC in conditioned inhibition learning could be reduced to simpler fear discrimination function, but fear discrimination and recall were unaffected by AP5 or muscimol, respectively, in the posterior IC. These data implicate a role of posterior IC in the learning of conditioned fear inhibitors. Copyright © 2016 Elsevier Inc. All rights reserved.

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.

Excitatory strength of expressive faces: effects of happy and fear expressions and context on the extinction of a conditioned fear response.

PubMed

Lanzetta, J T; Orr, S P

1986-01-01

In a recent study, Orr and Lanzetta (1984) showed that the excitatory properties of fear facial expressions previously described (Lanzetta & Orr, 1981; Orr & Lanzetta, 1980) do not depend on associative mechanisms; even in the absence of reinforcement, fear faces intensify the emotional reaction to a previously conditioned stimulus and disrupt extinction of an acquired fear response. In conjunction with the findings on acquisition, the failure to obtain extinction suggests that fear faces have some of the functional properties of "prepared" (fear-relevant) stimuli. In the present study we compared the magnitude of conditioned fear responses to happy and fear faces when a potent danger signal, the shock electrodes, are attached or unattached. If fear faces are functionally analogous to prepared stimuli, then, even in the absence of veridical support for an expectation of shock, they should retain excitatory strength, whereas happy faces should not. The results are consistent with this view of fear expressions. In the absence of reinforcement, and with shock electrodes removed, conditioned fear responses and basal levels of arousal were of greater magnitude for the fear-face condition than for the happy-face condition.

Effects of Caffeine on Olfactory Learning in Crickets.

PubMed

Sugimachi, Seigo; Matsumoto, Yukihisa; Mizunami, Makoto; Okada, Jiro

2016-10-01

Caffeine is a plant-derived alkaloid that is generally known as a central nervous system (CNS) stimulant. In order to examine the effects of caffeine on higher CNS functions in insects, we used an appetitive olfactory learning paradigm for the cricket Gryllus bimaculatus. Crickets can form significant long-term memories (LTMs) after repetitive training sessions, during which they associate a conditioned stimulus (CS: odor) with an unconditioned stimulus (US: reward). Administration of hemolymphal injections of caffeine established LTM after only single-trial conditioning over a wide range of caffeine dosages (1.6 µµg/kg to 39 mg/kg). We investigated the physiological mechanisms underlying this enhancement of olfactory learning performance pharmacologically, focusing on three major physiological roles of caffeine: 1) inhibition of phosphodiesterase (PDE), 2) agonism of ryanodine receptors, and 3) antagonism of adenosine receptors. Application of drugs relevant to these actions resulted in significant effects on LTM formation. These results suggest that externally applied caffeine enhances LTM formation in insect olfactory learning via multiple cellular mechanisms.

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

PubMed Central

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

2015-01-01

Previous research suggests that morphology and arborization of dendritic spines change as a result of fear conditioning in cortical and subcortical brain regions. This study uniquely aims to delineate these structural changes in the basolateral amygdala (BLA) after both fear conditioning and fear extinction. C57BL/6 mice acquired robust conditioned fear responses (70–80% cued freezing behavior) after six pairings with a tone cue associated with footshock in comparison to unshocked controls. During fear acquisition, freezing behavior was significantly affected by both shock exposure and trial number. For fear extinction, mice were exposed to the conditioned stimulus tone in the absence of shock administration and behavioral responses significantly varied by shock treatment. In the retention tests over 3 weeks, the percentage time spent freezing varied with the factor of extinction training. In all treatment groups, alterations in dendritic plasticity were analyzed using Golgi–Cox staining of dendrites in the BLA. Spine density differed between the fear conditioned group and both the fear extinction and control groups on third order dendrites. Spine density was significantly increased in the fear conditioned group compared to the fear extinction group and controls. Similarly in Sholl analyses, fear conditioning significantly increased BLA spine numbers and dendritic intersections while subsequent extinction training reversed these effects. In summary, fear extinction produced enduring behavioral plasticity that is associated with a reversal of alterations in BLA dendritic plasticity produced by fear conditioning. These neuroplasticity findings can inform our understanding of structural mechanisms underlying stress-related pathology can inform treatment research into these disorders. PMID:23570859

Thalamocortical interactions underlying visual fear conditioning in humans.

PubMed

Lithari, Chrysa; Moratti, Stephan; Weisz, Nathan

2015-11-01

Despite a strong focus on the role of the amygdala in fear conditioning, recent works point to a more distributed network supporting fear conditioning. We aimed to elucidate interactions between subcortical and cortical regions in fear conditioning in humans. To do this, we used two fearful faces as conditioned stimuli (CS) and an electrical stimulation at the left hand, paired with one of the CS, as unconditioned stimulus (US). The luminance of the CS was rhythmically modulated leading to "entrainment" of brain oscillations at a predefined modulation frequency. Steady-state responses (SSR) were recorded by MEG. In addition to occipital regions, spectral analysis of SSR revealed increased power during fear conditioning particularly for thalamus and cerebellum contralateral to the upcoming US. Using thalamus and amygdala as seed-regions, directed functional connectivity was calculated to capture the modulation of interactions that underlie fear conditioning. Importantly, this analysis showed that the thalamus drives the fusiform area during fear conditioning, while amygdala captures the more general effect of fearful faces perception. This study confirms ideas from the animal literature, and demonstrates for the first time the central role of the thalamus in fear conditioning in humans. © 2015 Wiley Periodicals, Inc.

Aversive olfactory associative memory loses odor specificity over time

PubMed Central

König, Christian; Antwi-Adjei, Emmanuel; Ganesan, Mathangi; Kilonzo, Kasyoka; Viswanathan, Vignesh; Durairaja, Archana; Voigt, Anne

2017-01-01

ABSTRACT Avoiding associatively learned predictors of danger is crucial for survival. Aversive memories can, however, become counter-adaptive when they are overly generalized to harmless cues and contexts. In a fruit fly odor–electric shock associative memory paradigm, we found that learned avoidance lost its specificity for the trained odor and became general to novel odors within a day of training. We discuss the possible neural circuit mechanisms of this effect and highlight the parallelism to over-generalization of learned fear behavior after an incubation period in rodents and humans, with due relevance for post-traumatic stress disorder. PMID:28468811

Opioid receptors regulate blocking and overexpectation of fear learning in conditioned suppression.

PubMed

Arico, Carolyn; McNally, Gavan P

2014-04-01

Endogenous opioids play an important role in prediction error during fear learning. However, the evidence for this role has been obtained almost exclusively using the species-specific defense response of freezing as the measure of learned fear. It is unknown whether opioid receptors regulate predictive fear learning when other measures of learned fear are used. Here, we used conditioned suppression as the measure of learned fear to assess the role of opioid receptors in fear learning. Experiment 1a studied associative blocking of fear learning. Rats in an experimental group received conditioned stimulus A (CSA) + training in Stage I and conditioned stimulus A and B (CSAB) + training in Stage II, whereas rats in a control group received only CSAB + training in Stage II. The prior fear conditioning of CSA blocked fear learning to conditioned stimulus B (CSB) in the experimental group. In Experiment 1b, naloxone (4 mg/kg) administered before Stage II prevented this blocking, thereby enabling normal fear learning to CSB. Experiment 2a studied overexpectation of fear. Rats received CSA + training and CSB + training in Stage I, and then rats in the experimental group received CSAB + training in Stage II whereas control rats did not. The Stage II compound training of CSAB reduced fear to CSA and CSB on test. In Experiment 2b, naloxone (4 mg/kg) administered before Stage II prevented this overexpectation. These results show that opioid receptors regulate Pavlovian fear learning, augmenting learning in response to positive prediction error and impairing learning in response to negative prediction error, when fear is assessed via conditioned suppression. These effects are identical to those observed when freezing is used as the measure of learned fear. These findings show that the role for opioid receptors in regulating fear learning extends across multiple measures of learned fear.

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

PubMed

Sengupta, Auntora; McNally, Gavan P

2014-01-01

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

Fear learning circuitry is biased toward generalization of fear associations in posttraumatic stress disorder

PubMed Central

Morey, R A; Dunsmoor, J E; Haswell, C C; Brown, V M; Vora, A; Weiner, J; Stjepanovic, D; Wagner, H R; Brancu, Mira; Marx, Christine E; Naylor, Jennifer C; Van Voorhees, Elizabeth; Taber, Katherine H; Beckham, Jean C; Calhoun, Patrick S; Fairbank, John A; Szabo, Steven T; LaBar, K S

2015-01-01

Fear conditioning is an established model for investigating posttraumatic stress disorder (PTSD). However, symptom triggers may vaguely resemble the initial traumatic event, differing on a variety of sensory and affective dimensions. We extended the fear-conditioning model to assess generalization of conditioned fear on fear processing neurocircuitry in PTSD. Military veterans (n=67) consisting of PTSD (n=32) and trauma-exposed comparison (n=35) groups underwent functional magnetic resonance imaging during fear conditioning to a low fear-expressing face while a neutral face was explicitly unreinforced. Stimuli that varied along a neutral-to-fearful continuum were presented before conditioning to assess baseline responses, and after conditioning to assess experience-dependent changes in neural activity. Compared with trauma-exposed controls, PTSD patients exhibited greater post-study memory distortion of the fear-conditioned stimulus toward the stimulus expressing the highest fear intensity. PTSD patients exhibited biased neural activation toward high-intensity stimuli in fusiform gyrus (P<0.02), insula (P<0.001), primary visual cortex (P<0.05), locus coeruleus (P<0.04), thalamus (P<0.01), and at the trend level in inferior frontal gyrus (P=0.07). All regions except fusiform were moderated by childhood trauma. Amygdala–calcarine (P=0.01) and amygdala–thalamus (P=0.06) functional connectivity selectively increased in PTSD patients for high-intensity stimuli after conditioning. In contrast, amygdala–ventromedial prefrontal cortex (P=0.04) connectivity selectively increased in trauma-exposed controls compared with PTSD patients for low-intensity stimuli after conditioning, representing safety learning. In summary, fear generalization in PTSD is biased toward stimuli with higher emotional intensity than the original conditioned-fear stimulus. Functional brain differences provide a putative neurobiological model for fear generalization whereby PTSD symptoms are triggered by threat cues that merely resemble the index trauma. PMID:26670285

Brain activation associated to olfactory conditioned same-sex partner preference in male rats.

PubMed

Coria-Avila, Genaro A; Cibrian-Llanderal, Tamara; Díaz-Estrada, Victor X; García, Luis I; Toledo-Cárdenas, Rebeca; Pfaus, James G; Manzo, Jorge

2018-03-01

Sexual preferences can be strongly modified by Pavlovian learning. For instance, olfactory conditioned same-sex partner preference can occur when a sexually naïve male cohabits with an scented male during repeated periods under the effects of enhanced D2-type activity. Preference is observed days later via social and sexual behaviors. Herein we explored brain activity related to learned same-sex preference (Fos-Immunoreactivity, IR) following exposure to a conditioned odor paired with same-sex preference. During conditioning trials males received either saline or the D2-type receptor agonist quinpirole (QNP) and cohabitated during 24 h with a stimulus male that bore almond scent on the back as conditioned stimulus. This was repeated every 4 days, for a total of three trials. In a drug-free final test we assessed socio/sexual partner preference between the scented male and a receptive female. The results indicated that QNP-conditioned males developed a same-sex preference observed via contact, time spent, olfactory investigations, and non-contact erections. By contrast, saline-conditioned and intact (non-exposed to conditioning) males expressed an unconditioned preference for the female. Four days later the males were exposed to almond scent and their brains were processed for Fos-IR. Results indicated that the QNP-conditioned group expressed more Fos-IR in the nucleus accumbens (AcbSh), medial preoptic area (MPA), piriform cortex (Pir) and ventromedial nucleus of the hypothalamus (VMH) as compared to saline-conditioned. Intact males expressed the lowest Fos-IR in AcbSh and VMH, but the highest in MPA and Pir. We discuss the role of these areas in the learning process of same-sex partner preferences and olfactory discrimination. Copyright © 2018 Elsevier Inc. All rights reserved.

Association of poor childhood fear conditioning and adult crime.

PubMed

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

2010-01-01

Amygdala dysfunction is theorized to give rise to poor fear conditioning, which in turn predisposes to crime, but it is not known whether poor conditioning precedes criminal offending. This study prospectively assessed whether poor fear conditioning early in life predisposes to adult crime in a large cohort. Electrodermal fear conditioning was assessed in a cohort of 1,795 children at age 3, and registration for criminal offending was ascertained at age 23. In a case-control design, 137 cohort members with a criminal record were matched on gender, ethnicity, and social adversity with 274 noncriminal comparison members. Statistical analyses compared childhood fear conditioning for the two groups. Criminal offenders showed significantly reduced electrodermal fear conditioning at age 3 compared to matched comparison subjects. Poor fear conditioning at age 3 predisposes to crime at age 23. Poor fear conditioning early in life implicates amygdala and ventral prefrontal cortex dysfunction and a lack of fear of socializing punishments in children who grow up to become criminals. These findings are consistent with a neurodevelopmental contribution to crime causation.

Encoding of Discriminative Fear Memory by Input-Specific LTP in the Amygdala.

PubMed

Kim, Woong Bin; Cho, Jun-Hyeong

2017-08-30

In auditory fear conditioning, experimental subjects learn to associate an auditory conditioned stimulus (CS) with an aversive unconditioned stimulus. With sufficient training, animals fear conditioned to an auditory CS show fear response to the CS, but not to irrelevant auditory stimuli. Although long-term potentiation (LTP) in the lateral amygdala (LA) plays an essential role in auditory fear conditioning, it is unknown whether LTP is induced selectively in the neural pathways conveying specific CS information to the LA in discriminative fear learning. Here, we show that postsynaptically expressed LTP is induced selectively in the CS-specific auditory pathways to the LA in a mouse model of auditory discriminative fear conditioning. Moreover, optogenetically induced depotentiation of the CS-specific auditory pathways to the LA suppressed conditioned fear responses to the CS. Our results suggest that input-specific LTP in the LA contributes to fear memory specificity, enabling adaptive fear responses only to the relevant sensory cue. VIDEO ABSTRACT. Copyright © 2017 Elsevier Inc. All rights reserved.

Odors as effective retrieval cues for stressful episodes.

PubMed

Wiemers, Uta S; Sauvage, Magdalena M; Wolf, Oliver T

2014-07-01

Olfactory information seems to play a special role in memory due to the fast and direct processing of olfactory information in limbic areas like the amygdala and the hippocampus. This has led to the assumption that odors can serve as effective retrieval cues for autobiographic memories, especially emotional memories. The current study sought to investigate whether an olfactory cue can serve as an effective retrieval cue for memories of a stressful episode. A total of 95 participants were exposed to a psychosocial stressor or a well matching but not stressful control condition. During both conditions were visual objects present, either bound to the situation (central objects) or not (peripheral objects). Additionally, an ambient odor was present during both conditions. The next day, participants engaged in an unexpected object recognition task either under the influence of the same odor as was present during encoding (congruent odor) or another odor (non-congruent odor). Results show that stressed participants show a better memory for all objects and especially for central visual objects if recognition took place under influence of the congruent odor. An olfactory cue thus indeed seems to be an effective retrieval cue for stressful memories. Copyright © 2013 Elsevier Inc. All rights reserved.

Hippocampal Processing of Ambiguity Enhances Fear Memory

PubMed Central

Amadi, Ugwechi; Lim, Seh Hong; Liu, Elizabeth; Baratta, Michael V.; Goosens, Ki Ann

2016-01-01

Despite the ubiquitous use of Pavlovian fear conditioning as a model for fear learning, the highly predictable conditions used in the laboratory do not resemble real-world conditions, where dangerous situations can lead to unpleasant outcomes in unpredictable ways. Here we varied the timing of aversive events following predictive cues in rodents and discovered that temporal ambiguity of aversive events greatly enhances fear. During fear conditioning with unpredictably timed aversive events, pharmacological inactivation of the dorsal hippocampus or optogenetic silencing of CA1 cells during aversive negative prediction errors prevented this enhancement of fear without impacting fear learning for predictable events. Dorsal hippocampal inactivation also prevented ambiguity-related enhancement of fear during auditory fear conditioning under a partial reinforcement schedule. These results reveal that information about the timing and occurrence of aversive events is rapidly acquired and that unexpectedly timed or omitted aversive events generate hippocampal signals to enhance fear learning. PMID:28182526

Hippocampal Processing of Ambiguity Enhances Fear Memory.

PubMed

Amadi, Ugwechi; Lim, Seh Hong; Liu, Elizabeth; Baratta, Michael V; Goosens, Ki A

2017-02-01

Despite the ubiquitous use of Pavlovian fear conditioning as a model for fear learning, the highly predictable conditions used in the laboratory do not resemble real-world conditions, in which dangerous situations can lead to unpleasant outcomes in unpredictable ways. In the current experiments, we varied the timing of aversive events after predictive cues in rodents and discovered that temporal ambiguity of aversive events greatly enhances fear. During fear conditioning with unpredictably timed aversive events, pharmacological inactivation of the dorsal hippocampus or optogenetic silencing of cornu ammonis 1 cells during aversive negative prediction errors prevented this enhancement of fear without affecting fear learning for predictable events. Dorsal hippocampal inactivation also prevented ambiguity-related enhancement of fear during auditory fear conditioning under a partial-reinforcement schedule. These results reveal that information about the timing and occurrence of aversive events is rapidly acquired and that unexpectedly timed or omitted aversive events generate hippocampal signals to enhance fear learning.

Instructed fear learning, extinction, and recall: additive effects of cognitive information on emotional learning of fear.

PubMed

Javanbakht, Arash; Duval, Elizabeth R; Cisneros, Maria E; Taylor, Stephan F; Kessler, Daniel; Liberzon, Israel

2017-08-01

The effects of instruction on learning of fear and safety are rarely studied. We aimed to examine the effects of cognitive information and experience on fear learning. Fourty healthy participants, randomly assigned to three groups, went through fear conditioning, extinction learning, and extinction recall with two conditioned stimuli (CS+). Information was presented about the presence or absence of conditioned stimulus-unconditioned stimulus (CS-US) contingency at different stages of the experiment. Information about the CS-US contingency prior to fear conditioning enhanced fear response and reduced extinction recall. Information about the absence of CS-US contingency promoted extinction learning and recall, while omission of this information prior to recall resulted in fear renewal. These findings indicate that contingency information can facilitate fear expression during fear learning, and can facilitate extinction learning and recall. Information seems to function as an element of the larger context in which conditioning occurs.

The behavioral context of visual displays in common marmosets (Callithrix jacchus).

PubMed

de Boer, Raïssa A; Overduin-de Vries, Anne M; Louwerse, Annet L; Sterck, Elisabeth H M

2013-11-01

Communication is important in social species, and may occur with the use of visual, olfactory or auditory signals. However, visual communication may be hampered in species that are arboreal have elaborate facial coloring and live in small groups. The common marmoset fits these criteria and may have limited visual communication. Nonetheless, some (contradictive) propositions concerning visual displays in the common marmoset have been made, yet quantitative data are lacking. The aim of this study was to assign a behavioral context to different visual displays using pre-post-event-analyses. Focal observations were conducted on 16 captive adult and sub-adult marmosets in three different family groups. Based on behavioral elements with an unambiguous meaning, four different behavioral contexts were distinguished: aggression, fear, affiliation, and play behavior. Visual displays concerned behavior that included facial expressions, body postures, and pilo-erection of the fur. Visual displays related to aggression, fear, and play/affiliation were consistent with the literature. We propose that the visual display "pilo-erection tip of tail" is related to fear. Individuals receiving these fear signals showed a higher rate of affiliative behavior. This study indicates that several visual displays may provide cues or signals of particular social contexts. Since the three displays of fear elicited an affiliative response, they may communicate a request of anxiety reduction or signal an external referent. Concluding, common marmosets, despite being arboreal and living in small groups, use several visual displays to communicate with conspecifics and their facial coloration may not hamper, but actually promote the visibility of visual displays. © 2013 Wiley Periodicals, Inc.

Neurobiology of secure infant attachment and attachment despite adversity: a mouse model.

PubMed

Roth, T L; Raineki, C; Salstein, L; Perry, R; Sullivan-Wilson, T A; Sloan, A; Lalji, B; Hammock, E; Wilson, D A; Levitt, P; Okutani, F; Kaba, H; Sullivan, R M

2013-10-01

Attachment to an abusive caregiver has wide phylogenetic representation, suggesting that animal models are useful in understanding the neural basis underlying this phenomenon and subsequent behavioral outcomes. We previously developed a rat model, in which we use classical conditioning to parallel learning processes evoked during secure attachment (odor-stroke, with stroke mimicking tactile stimulation from the caregiver) or attachment despite adversity (odor-shock, with shock mimicking maltreatment). Here we extend this model to mice. We conditioned infant mice (postnatal day (PN) 7-9 or 13-14) with presentations of peppermint odor and either stroking or shock. We used (14) C 2-deoxyglucose (2-DG) to assess olfactory bulb and amygdala metabolic changes following learning. PN7-9 mice learned to prefer an odor following either odor-stroke or shock conditioning, whereas odor-shock conditioning at PN13-14 resulted in aversion/fear learning. 2-DG data indicated enhanced bulbar activity in PN7-9 preference learning, whereas significant amygdala activity was present following aversion learning at PN13-14. Overall, the mouse results parallel behavioral and neural results in the rat model of attachment, and provide the foundation for the use of transgenic and knockout models to assess the impact of both genetic (biological vulnerabilities) and environmental factors (abusive) on attachment-related behaviors and behavioral development. © 2013 John Wiley & Sons Ltd and International Behavioural and Neural Genetics Society.

Enhanced startle responsivity 24 hours after acute stress exposure.

PubMed

Herten, Nadja; Otto, Tobias; Adolph, Dirk; Pause, Bettina M; Kumsta, Robert; Wolf, Oliver T

2016-10-01

Cortisol release in a stressful situation can be beneficial for memory encoding and memory consolidation. Stimuli, such as odors, related to the stressful episode may successfully cue memory contents of the stress experience. The current investigation aimed at testing the potency of stress to influence startle responsivity 24 hr later and to implicitly reactivate emotional memory traces triggered by an odor involved. Participants were assigned to either a stress (Trier Social Stress Test [TSST]) or control (friendly TSST [f-TSST]) condition featuring an ambient odor. On the next day, participants underwent an auditory startle paradigm while their eyeblink reflex was recorded by an electrooculogram. Three different olfactory stimuli were delivered, one being the target odor presented the day before. Additionally, negative, positive, and pictures of the committee members were included for comparing general startle responsivity and fear-potentiated startle. Participants of the stress group demonstrated an enhanced startle response across all stimuli compared to participants of the control group. There were no specific effects with regard to the target odor. The typical fear-potentiated startle response occurred. Stressed participants tended to rate the target odor more aversive than control participants. Odor recognition memory did not differ between the groups, suggesting an implicit effect on odor valence. Our results show that acute stress exposure enhances startle responsivity 24 hr later. This effect might be caused by a shift of amygdala function causing heightened sensitivity, but lower levels of specificity. (PsycINFO Database Record (c) 2016 APA, all rights reserved).

Neural circuits and mechanisms involved in Pavlovian fear conditioning: A critical review

PubMed Central

Kim, Jeansok J.; Jung, Min Whan

2015-01-01

Pavlovian or classical fear conditioning is recognized as a model system to investigate the neurobiological mechanisms of learning and memory in the mammalian brain and to understand the root of fear-related disorders in humans. In recent decades, important progress has been made in delineating the essential neural circuitry and cellular–molecular mechanisms of fear conditioning. Converging lines of evidence indicate that the amygdala is necessarily involved in the acquisition, storage and expression of conditioned fear memory, and long-term potentiation (LTP) in the lateral nucleus of the amygdala is often proposed as the underlying synaptic mechanism of associative fear memory. Recent studies further implicate the prefrontal cortex–amygdala interaction in the extinction (or inhibition) of conditioned fear. Despite these advances, there are unresolved issues and findings that challenge the validity and sufficiency of the current amygdalar LTP hypothesis of fear conditioning. The purpose of this review is to critically evaluate the strengths and weaknesses of evidence indicating that fear conditioning depend crucially upon the amygdalar circuit and plasticity. PMID:16120461

Side-Specificity of Olfactory Learning in the Honeybee: Generalization between Odors and Sides

PubMed Central

Sandoz, Jean-Christophe; Menzel, Randolf

2001-01-01

Honeybees (Apis mellifera) can be trained to associate an odor stimulus with a sucrose reward. The neural structures involved in the detection and integration of olfactory stimuli are represented bilaterally in the brain. Little is known about the respective roles of the two sides of the brain in olfactory learning. Does each side learn independently of the other, or do they communicate, and if so, to what extent and at what level of neural integration? We addressed these questions using the proboscis extension response (PER) conditioning paradigm applied in a preparation that allows the separation of the two input sides during olfactory stimulations. Bees conditioned to two odorants A and B, one being learned on each side (A+/B+ training), showed in extinction tests rather unspecific responses: They responded to both odorants on both sides. This could be attributable to either a transfer of the learned information between sides, or to a generalization between odorants on each side. By subjecting bees to conditioning on one side only (A+/0 training), we found that the learned information is indeed transferred between sides. However, when bees were trained explicitly to give opposite values to the two odorants on the two sides (A+B−/B+A− training), they showed clear side-specific response patterns to these odorants. These results are used in the elaboration of a functional model of laterality of olfactory learning and memory processing in the honeybee brain. PMID:11584076

Extended fear conditioning reveals a role for both N-methyl-D-aspartic acid and non-N-methyl-D-aspartic acid receptors in the amygdala in the acquisition of conditioned fear.

PubMed

Pistell, P J; Falls, W A

2008-09-09

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

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.

NPY controls fear conditioning and fear extinction by combined action on Y₁ and Y₂ receptors.

PubMed

Verma, D; Tasan, R O; Herzog, H; Sperk, G

2012-06-01

Neuropeptide Y (NPY) and its receptors have been implicated in the control of emotional-affective processing, but the mechanism is unclear. While it is increasingly evident that stimulation of Y₁ and inhibition of Y₂ receptors produce prominent anxiolytic and antidepressant effects, the contribution of the individual NPY receptor subtypes in the acquisition and extinction of learned fear are unknown. Here we performed Pavlovian fear conditioning and extinction in NPY knockout (KO) and in NPY receptor KO mice. NPY KO mice display a dramatically accelerated acquisition of conditioned fear. Deletion of Y₁ receptors revealed only a moderately accelerated acquisition of conditioned fear, while lack of Y₂ receptors was without any effect on fear learning. However, the strong phenotype seen in NPY KO mice was reproduced in mice lacking both Y₁ and Y₂ receptors. In addition, NPY KO mice showed excessive recall of conditioned fear and impaired fear extinction. This behaviour was replicated only after deletion of both Y₁ and Y₂ receptors. In Y₁ receptor single KO mice, fear extinction was delayed and was unchanged in Y₂ receptor KO mice. Deletion of NPY and particularly Y₂ receptors resulted in a generalization of conditioned fear. Our data demonstrate that NPY delays the acquisition, reduces the expression of conditioned fear while promoting fear extinction. Although these effects appear to be primarily mediated by Y₁ receptors, the pronounced phenotype of Y₁Y₂ receptor double KO mice suggests a synergistic role of Y₂ receptors in fear acquisition and in fear extinction. © 2012 The Authors. British Journal of Pharmacology © 2012 The British Pharmacological Society.

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

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

PubMed

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

2014-01-01

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

Distinct molecular underpinnings of Drosophila olfactory trace conditioning

PubMed Central

Shuai, Yichun; Hu, Ying; Qin, Hongtao; Campbell, Robert A. A.; Zhong, Yi

2011-01-01

Trace conditioning is valued as a simple experimental model to assess how the brain associates events that are discrete in time. Here, we adapted an olfactory trace conditioning procedure in Drosophila melanogaster by training fruit flies to avoid an odor that is followed by foot shock many seconds later. The molecular underpinnings of the learning are distinct from the well-characterized simultaneous conditioning, where odor and punishment temporally overlap. First, Rutabaga adenylyl cyclase (Rut-AC), a putative molecular coincidence detector vital for simultaneous conditioning, is dispensable in trace conditioning. Second, dominant-negative Rac expression, thought to sustain early labile memory, significantly enhances learning of trace conditioning, but leaves simultaneous conditioning unaffected. We further show that targeting Rac inhibition to the mushroom body (MB) but not the antennal lobe (AL) suffices to achieve the enhancement effect. Moreover, the absence of trace conditioning learning in D1 dopamine receptor mutants is rescued by restoration of expression specifically in the adult MB. These results suggest the MB as a crucial neuroanatomical locus for trace conditioning, which may harbor a Rac activity-sensitive olfactory “sensory buffer” that later converges with the punishment signal carried by dopamine signaling. The distinct molecular signature of trace conditioning revealed here shall contribute to the understanding of how the brain overcomes a temporal gap in potentially related events. PMID:22123966

Response-Specific Sex Difference in the Retention of Fear Extinction

ERIC Educational Resources Information Center

Voulo, Meagan E.; Parsons, Ryan G.

2017-01-01

Fear conditioning studies in rodents allow us to assess vulnerability factors which might underlie fear-based psychopathology such as post-traumatic stress disorder (PTSD). Despite PTSD being more prevalent in females than males, very few fear conditioning studies in rodents have tested females. Our study assessed fear conditioning and extinction…

Behavioral mechanisms of context fear generalization in mice

PubMed Central

Huckleberry, Kylie A.; Ferguson, Laura B.

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 generalization of contextual fear. We assessed the relative contribution of different contextual features to context fear generalization and characterized how two common conditioning protocols—foreground (uncued) and background (cued) contextual fear conditioning—affected context fear generalization. In one experiment, mice were fear conditioned in context A, and then tested for contextual fear both in A and in an alternate context created by changing a subset of A's elements. The results suggest that floor configuration and odor are more salient features than chamber shape. A second experiment compared context fear generalization in background and foreground context conditioning. Although foreground conditioning produced more context fear than background conditioning, the two procedures produced equal amounts of generalized fear. Finally, results indicated that the order of context tests (original first versus alternate first) significantly modulates context fear generalization, perhaps because the original and alternate contexts are differentially sensitive to extinction. Overall, results demonstrate that context fear generalization is sensitive to procedural variations and likely reflects the operation of multiple interacting psychological and neural mechanisms. PMID:27918275

Ventromedial prefrontal cortex activity and rapid eye movement sleep are associated with subsequent fear expression in human subjects.

PubMed

Spoormaker, V I; Gvozdanovic, G A; Sämann, P G; Czisch, M

2014-05-01

In humans, activity patterns in the ventromedial prefrontal cortex (vmPFC) have been found to be predictive of subsequent fear memory consolidation. Pioneering work in rodents has further shown that vmPFC-amygdala theta synchronization is correlated with fear memory consolidation. We aimed to evaluate whether vmPFC activity during fear conditioning is (1) correlated with fear expression the subsequent day and whether (2) this relationship is mediated by rapid eye movement (REM) sleep. We analyzed data from 17 young healthy subjects undergoing a fear conditioning task, followed by a fear extinction task 24 h later, both recorded with simultaneous skin conductance response (SCR) and functional magnetic resonance imaging measurements, with a polysomnographically recorded night sleep in between. Our results showed a correlation between vmPFC activity during fear conditioning and subsequent REM sleep amount, as well as between REM sleep amount and SCR to the conditioned stimulus 24 h later. Moreover, we observed a significant correlation between vmPFC activity during fear conditioning and SCR responses during extinction, which was no longer significant after controlling for REM sleep amount. vmPFC activity during fear conditioning was further correlated with sleep latency. Interestingly, hippocampus activity during fear conditioning was correlated with stage 2 and stage 4 sleep amount. Our results provide preliminary evidence that the relationship between REM sleep and fear conditioning and extinction observed in rodents can be modeled in healthy human subjects, highlighting an interrelated set of potentially relevant trait markers.

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

PubMed

Gazendam, Femke J; Kindt, Merel

2012-01-01

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

Aromatherapy for travel-induced excitement in dogs.

PubMed

Wells, Deborah L

2006-09-15

To evaluate the efficacy of the ambient odor of lavender as a treatment for travel-induced excitement in dogs. Clinical trial. Animals-32 dogs with a history of travel-induced excitement in owners' cars. Each dog was studied during travel in the owner's car to a familiar walking site during 2 conditions of olfactory stimulation. The first condition was a control condition, during which dogs were exposed to no odor other than that arising naturally from the environment. The second condition was an experimental condition during which dogs were exposed to the ambient odor of lavender. Dogs' behavior was recorded during the car journey for 3 consecutive days under the control condition and for 3 consecutive days under the experimental condition. The percentage of time spent moving, standing, sitting, resting, and vocalizing in each condition of olfactory stimulation was quantified for each dog. Dogs spent significantly more time resting and sitting and less time moving and vocalizing during the experimental condition. There was no significant relationship between dogs' behavior and sex, castration status, day, or the order of exposure to each olfactory condition. Traditional treatments for travel-induced excitement in dogs may be time-consuming, expensive, or associated with adverse effects. Aromatherapy in the form of diffused lavender odor may offer a practical alternative treatment for travel-induced excitement in this species.

Opposite effects of fear conditioning and extinction on dendritic spine remodelling.

PubMed

Lai, Cora Sau Wan; Franke, Thomas F; Gan, Wen-Biao

2012-02-19

It is generally believed that fear extinction is a form of new learning that inhibits rather than erases previously acquired fear memories. Although this view has gained much support from behavioural and electrophysiological studies, the hypothesis that extinction causes the partial erasure of fear memories remains viable. Using transcranial two-photon microscopy, we investigated how neural circuits are modified by fear learning and extinction by examining the formation and elimination of postsynaptic dendritic spines of layer-V pyramidal neurons in the mouse frontal association cortex. Here we show that fear conditioning by pairing an auditory cue with a footshock increases the rate of spine elimination. By contrast, fear extinction by repeated presentation of the same auditory cue without a footshock increases the rate of spine formation. The degrees of spine remodelling induced by fear conditioning and extinction strongly correlate with the expression and extinction of conditioned fear responses, respectively. Notably, spine elimination and formation induced by fear conditioning and extinction occur on the same dendritic branches in a cue- and location-specific manner: cue-specific extinction causes formation of dendritic spines within a distance of two micrometres from spines that were eliminated after fear conditioning. Furthermore, reconditioning preferentially induces elimination of dendritic spines that were formed after extinction. Thus, within vastly complex neuronal networks, fear conditioning, extinction and reconditioning lead to opposing changes at the level of individual synapses. These findings also suggest that fear memory traces are partially erased after extinction.

Flavor-Intensity Perception: Effects of Stimulus Context

PubMed Central

Marks, Lawrence E.; Shepard, Timothy G.; Burger, Kelly; Chakwin, Emily M.

2011-01-01

Stimulus context affects judgments of intensity of both gustatory and olfactory flavors, and the contextual effects are modality-specific. Does context also exert separate effects on the gustatory and olfactory components of flavor mixtures? To answer this question, in each of 4 experiments, subjects rated the perceived intensity of 16 mixtures constructed by combining 4 concentrations of the gustatory flavorant sucrose with 4 concentrations of the retronasal olfactory flavorant citral. In 1 contextual condition of each experiment, concentrations of sucrose were relatively high and those of citral low; in the other condition, the relative concentrations of sucrose and citral reversed. There were 2 main results: First, consistent with earlier findings, in 5 of the 8 conditions, the ratings were consistent with linear addition of perceived sucrose and citral; departures from additivity appeared, however, in 3 conditions where the relative concentrations of citral were high. Second, changes in context produced contrast (adaptation-like changes) in perceived intensity: The contribution to perceived intensity of a given concentration of a flavorant was smaller when the contextual concentrations of that flavorant were high rather than low. A notable exception was the absence of contextual effects on the perceived intensity of near-threshold citral. These findings suggest that the contextual effects may arise separately in the gustatory and olfactory channels, prior to the integration of perceived flavor intensity. PMID:21930139

Hormonal Regulation of Extinction: Implications for Gender Differences in the Mechanisms of PTSD

DTIC Science & Technology

2010-03-01

Unlimited 13. SUPPLEMENTARY NOTES 14. ABSTRACT This project investigates the role of gonadal hormones in the regulation of Pavlovian fear conditioning ...and its extinction. Pavlovian fear conditioning and its extinction serve as an animal model for the development of pathological fear in humans that...gonadal hormones in the regulation of Pavlovian fear conditioning and its extinction. Pavlovian fear conditioning and its extinction serve as an animal

Rapid Remission of Conditioned Fear Expression with Extinction Training Paired with Vagus Nerve Stimulation

PubMed Central

Peña, David F.; Engineer, Navzer D.; McIntyre, Christa K.

2012-01-01

Background Fearful experiences can produce long-lasting and debilitating memories. Extinction of conditioned fear requires consolidation of new memories that compete with fearful associations. In human subjects, as well as rats, posttraining stimulation of the vagus nerve enhances memory consolidation. Subjects with posttraumatic stress disorder (PTSD) show impaired extinction of conditioned fear. The objective of this study was to determine whether vagus nerve stimulation (VNS) can enhance the consolidation of extinction of conditioned fear. Methods Male Sprague-Dawley rats were trained on an auditory fear conditioning task followed by 1–10 days of extinction training. Treatment with vagus nerve or sham stimulation was administered concurrently with exposure to the fear conditioned stimulus. Another group was given VNS and extinction training but the VNS was not paired with exposure to conditioned cues. Retention of fear conditioning was tested 24 hours after each treatment. Results VNS paired with exposure to conditioned cues enhanced the extinction of conditioned fear. After a single extinction trial, rats given VNS stimulation demonstrated a significantly lower level of freezing, compared to that of sham controls. When extinction trials were extended to 10 days, paired VNS accelerated extinction of the conditioned response. Conclusions Extinction paired with VNS is more rapid than extinction paired with sham stimulation. As it is currently approved by the Federal Food and Drug Administration for depression and seizure prevention, VNS is a readily-available and promising adjunct to exposure therapy for the treatment of severe anxiety disorders. PMID:23245749

Respiratory and olfactory turbinal size in canid and arctoid carnivorans.

PubMed

Green, Patrick A; Van Valkenburgh, Blaire; Pang, Benison; Bird, Deborah; Rowe, Timothy; Curtis, Abigail

2012-12-01

Within the nasal cavity of mammals is a complex scaffold of paper-thin bones that function in respiration and olfaction. Known as turbinals, the bones greatly enlarge the surface area available for conditioning inspired air, reducing water loss, and improving olfaction. Given their functional significance, the relative development of turbinal bones might be expected to differ among species with distinct olfactory, thermoregulatory and/or water conservation requirements. Here we explore the surface area of olfactory and respiratory turbinals relative to latitude and diet in terrestrial Caniformia, a group that includes the canid and arctoid carnivorans (mustelids, ursids, procyonids, mephitids, ailurids). Using high-resolution computed tomography x-ray scans, we estimated respiratory and olfactory turbinal surface area and nasal chamber volume from three-dimensional virtual models of skulls. Across the Caniformia, respiratory surface area scaled isometrically with estimates of body size and there was no significant association with climate, as estimated by latitude. Nevertheless, one-on-one comparisons of sister taxa suggest that arctic species may have expanded respiratory turbinals. Olfactory surface area scaled isometrically among arctoids, but showed positive allometry in canids, reflecting the fact that larger canids, all of which are carnivorous, had relatively greater olfactory surface areas. In addition, among the arctoids, large carnivorous species such as the polar bear (Ursus maritimus) and wolverine (Gulo gulo) also displayed enlarged olfactory turbinals. More omnivorous caniform species that feed on substantial quantities of non-vertebrate foods had less expansive olfactory turbinals. Because large carnivorous species hunt widely dispersed prey, an expanded olfactory turbinal surface area may improve a carnivore's ability to detect prey over great distances using olfactory cues. © 2012 The Authors. Journal of Anatomy © 2012 Anatomical Society.

Respiratory and olfactory turbinal size in canid and arctoid carnivorans

PubMed Central

Green, Patrick A; Valkenburgh, Blaire; Pang, Benison; Bird, Deborah; Rowe, Timothy; Curtis, Abigail

2012-01-01

Within the nasal cavity of mammals is a complex scaffold of paper-thin bones that function in respiration and olfaction. Known as turbinals, the bones greatly enlarge the surface area available for conditioning inspired air, reducing water loss, and improving olfaction. Given their functional significance, the relative development of turbinal bones might be expected to differ among species with distinct olfactory, thermoregulatory and/or water conservation requirements. Here we explore the surface area of olfactory and respiratory turbinals relative to latitude and diet in terrestrial Caniformia, a group that includes the canid and arctoid carnivorans (mustelids, ursids, procyonids, mephitids, ailurids). Using high-resolution computed tomography x-ray scans, we estimated respiratory and olfactory turbinal surface area and nasal chamber volume from three-dimensional virtual models of skulls. Across the Caniformia, respiratory surface area scaled isometrically with estimates of body size and there was no significant association with climate, as estimated by latitude. Nevertheless, one-on-one comparisons of sister taxa suggest that arctic species may have expanded respiratory turbinals. Olfactory surface area scaled isometrically among arctoids, but showed positive allometry in canids, reflecting the fact that larger canids, all of which are carnivorous, had relatively greater olfactory surface areas. In addition, among the arctoids, large carnivorous species such as the polar bear (Ursus maritimus) and wolverine (Gulo gulo) also displayed enlarged olfactory turbinals. More omnivorous caniform species that feed on substantial quantities of non-vertebrate foods had less expansive olfactory turbinals. Because large carnivorous species hunt widely dispersed prey, an expanded olfactory turbinal surface area may improve a carnivore's ability to detect prey over great distances using olfactory cues. PMID:23035637

Olfactory Blocking and Odorant Similarity in the Honeybee

ERIC Educational Resources Information Center

Gerber, Bertram; Giurfa, Martin; Guerrieri, Fernando; Lachnit, Harald

2005-01-01

Blocking occurs when previous training with a stimulus A reduces (blocks) subsequent learning about a stimulus B, when A and B are trained in compound. The question of whether blocking exists in olfactory conditioning of proboscis extension reflex (PER) in honeybees is under debate. The last published accounts on blocking in honeybees state that…

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

IGF1-Dependent Synaptic Plasticity of Mitral Cells in Olfactory Memory during Social Learning.

PubMed

Liu, Zhihui; Chen, Zijun; Shang, Congping; Yan, Fei; Shi, Yingchao; Zhang, Jiajing; Qu, Baole; Han, Hailin; Wang, Yanying; Li, Dapeng; Südhof, Thomas C; Cao, Peng

2017-07-05

During social transmission of food preference (STFP), mice form long-term memory of food odors presented by a social partner. How does the brain associate a social context with odor signals to promote memory encoding? Here we show that odor exposure during STFP, but not unconditioned odor exposure, induces glomerulus-specific long-term potentiation (LTP) of synaptic strength selectively at the GABAergic component of dendrodendritic synapses of granule and mitral cells in the olfactory bulb. Conditional deletion of synaptotagmin-10, the Ca 2+ sensor for IGF1 secretion from mitral cells, or deletion of IGF1 receptor in the olfactory bulb prevented the socially relevant GABAergic LTP and impaired memory formation after STFP. Conversely, the addition of IGF1 to acute olfactory bulb slices elicited the GABAergic LTP in mitral cells by enhancing postsynaptic GABA receptor responses. Thus, our data reveal a synaptic substrate for a socially conditioned long-term memory that operates at the level of the initial processing of sensory information. Copyright © 2017 Elsevier Inc. All rights reserved.

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.

Olfactory Nerve—A Novel Invasion Route of Neisseria meningitidis to Reach the Meninges

PubMed Central

Sjölinder, Hong; Jonsson, Ann-Beth

2010-01-01

Neisseria meningitidis is a human-specific pathogen with capacity to cause septic shock and meningitis. It has been hypothesized that invasion of the central nervous system (CNS) is a complication of a bacteremic condition. In this study, we aimed to characterize the invasion route of N. meningitidis to the CNS. Using an intranasally challenged mouse disease model, we found that twenty percent of the mice developed lethal meningitis even though no bacteria could be detected in blood. Upon bacterial infection, epithelial lesions and redistribution of intracellular junction protein N-cadherin were observed at the nasal epithelial mucosa, especially at the olfactory epithelium, which is functionally and anatomically connected to the CNS. Bacteria were detected in the submucosa of the olfactory epithelium, along olfactory nerves in the cribriform plate, at the olfactory bulb and subsequently at the meninges and subarachnoid space. Furthermore, our data suggest that a threshold level of bacteremia is required for the development of meningococcal sepsis. Taken together, N. meningitidis is able to pass directly from nasopharynx to meninges through the olfactory nerve system. This study enhances our understanding how N. meningitidis invades the meninges. The nasal olfactory nerve system may be a novel target for disease prevention that can improve outcome and survival. PMID:21124975

Olfactory nerve--a novel invasion route of Neisseria meningitidis to reach the meninges.

PubMed

Sjölinder, Hong; Jonsson, Ann-Beth

2010-11-18

Neisseria meningitidis is a human-specific pathogen with capacity to cause septic shock and meningitis. It has been hypothesized that invasion of the central nervous system (CNS) is a complication of a bacteremic condition. In this study, we aimed to characterize the invasion route of N. meningitidis to the CNS. Using an intranasally challenged mouse disease model, we found that twenty percent of the mice developed lethal meningitis even though no bacteria could be detected in blood. Upon bacterial infection, epithelial lesions and redistribution of intracellular junction protein N-cadherin were observed at the nasal epithelial mucosa, especially at the olfactory epithelium, which is functionally and anatomically connected to the CNS. Bacteria were detected in the submucosa of the olfactory epithelium, along olfactory nerves in the cribriform plate, at the olfactory bulb and subsequently at the meninges and subarachnoid space. Furthermore, our data suggest that a threshold level of bacteremia is required for the development of meningococcal sepsis. Taken together, N. meningitidis is able to pass directly from nasopharynx to meninges through the olfactory nerve system. This study enhances our understanding how N. meningitidis invades the meninges. The nasal olfactory nerve system may be a novel target for disease prevention that can improve outcome and survival.

A coupled-oscillator model of olfactory bulb gamma oscillations

PubMed Central

2017-01-01

The olfactory bulb transforms not only the information content of the primary sensory representation, but also its underlying coding metric. High-variance, slow-timescale primary odor representations are transformed by bulbar circuitry into secondary representations based on principal neuron spike patterns that are tightly regulated in time. This emergent fast timescale for signaling is reflected in gamma-band local field potentials, presumably serving to efficiently integrate olfactory sensory information into the temporally regulated information networks of the central nervous system. To understand this transformation and its integration with interareal coordination mechanisms requires that we understand its fundamental dynamical principles. Using a biophysically explicit, multiscale model of olfactory bulb circuitry, we here demonstrate that an inhibition-coupled intrinsic oscillator framework, pyramidal resonance interneuron network gamma (PRING), best captures the diversity of physiological properties exhibited by the olfactory bulb. Most importantly, these properties include global zero-phase synchronization in the gamma band, the phase-restriction of informative spikes in principal neurons with respect to this common clock, and the robustness of this synchronous oscillatory regime to multiple challenging conditions observed in the biological system. These conditions include substantial heterogeneities in afferent activation levels and excitatory synaptic weights, high levels of uncorrelated background activity among principal neurons, and spike frequencies in both principal neurons and interneurons that are irregular in time and much lower than the gamma frequency. This coupled cellular oscillator architecture permits stable and replicable ensemble responses to diverse sensory stimuli under various external conditions as well as to changes in network parameters arising from learning-dependent synaptic plasticity. PMID:29140973

Coactivation of Gustatory and Olfactory Signals in Flavor Perception

PubMed Central

Veldhuizen, Maria G.; Shepard, Timothy G.; Wang, Miao-Fen

2010-01-01

It is easier to detect mixtures of gustatory and olfactory flavorants than to detect either component alone. But does the detection of mixtures exceed the level predicted by probability summation, assuming independent detection of each component? To answer this question, we measured simple response times (RTs) to detect brief pulses of one of 3 flavorants (sucrose [gustatory], citral [olfactory], sucrose–citral mixture) or water, presented into the mouth by a computer-operated, automated flow system. Subjects were instructed to press a button as soon as they detected any of the 3 nonwater stimuli. Responses to the mixtures were faster (RTs smaller) than predicted by a model of probability summation of independently detected signals, suggesting positive coactivation (integration) of gustation and retronasal olfaction in flavor perception. Evidence for integration appeared mainly in the fastest 60% of the responses, indicating that integration arises relatively early in flavor processing. Results were similar when the 3 possible flavorants, and water, were interleaved within the same session (experimental condition), and when each flavorant was interleaved with water only (control conditions). This outcome suggests that subjects did not attend selectively to one flavor component or the other in the experimental condition and further supports the conclusion that (late) decisional or attentional strategies do not exert a large influence on the gustatory–olfactory flavor integration. PMID:20032112

Time frequency analysis of olfactory induced EEG-power change.

PubMed

Schriever, Valentin Alexander; Han, Pengfei; Weise, Stefanie; Hösel, Franziska; Pellegrino, Robert; Hummel, Thomas

2017-01-01

The objective of the present study was to investigate the usefulness of time-frequency analysis (TFA) of olfactory-induced EEG change with a low-cost, portable olfactometer in the clinical investigation of smell function. A total of 78 volunteers participated. The study was composed of three parts where olfactory stimuli were presented using a custom-built olfactometer. Part I was designed to optimize the stimulus as well as the recording conditions. In part II EEG-power changes after olfactory/trigeminal stimulation were compared between healthy participants and patients with olfactory impairment. In Part III the test-retest reliability of the method was evaluated in healthy subjects. Part I indicated that the most effective paradigm for stimulus presentation was cued stimulus, with an interstimulus interval of 18-20s at a stimulus duration of 1000ms with each stimulus quality presented 60 times in blocks of 20 stimuli each. In Part II we found that central processing of olfactory stimuli analyzed by TFA differed significantly between healthy controls and patients even when controlling for age. It was possible to reliably distinguish patients with olfactory impairment from healthy individuals at a high degree of accuracy (healthy controls vs anosmic patients: sensitivity 75%; specificity 89%). In addition we could show a good test-retest reliability of TFA of chemosensory induced EEG-power changes in Part III. Central processing of olfactory stimuli analyzed by TFA reliably distinguishes patients with olfactory impairment from healthy individuals at a high degree of accuracy. Importantly this can be achieved with a simple olfactometer.

Behavioral and Neurophysiological Study of Olfactory Perception and Learning in Honeybees

PubMed Central

Sandoz, Jean Christophe

2011-01-01

The honeybee Apis mellifera has been a central insect model in the study of olfactory perception and learning for more than a century, starting with pioneer work by Karl von Frisch. Research on olfaction in honeybees has greatly benefited from the advent of a range of behavioral and neurophysiological paradigms in the Lab. Here I review major findings about how the honeybee brain detects, processes, and learns odors, based on behavioral, neuroanatomical, and neurophysiological approaches. I first address the behavioral study of olfactory learning, from experiments on free-flying workers visiting artificial flowers to laboratory-based conditioning protocols on restrained individuals. I explain how the study of olfactory learning has allowed understanding the discrimination and generalization ability of the honeybee olfactory system, its capacity to grant special properties to olfactory mixtures as well as to retain individual component information. Next, based on the impressive amount of anatomical and immunochemical studies of the bee brain, I detail our knowledge of olfactory pathways. I then show how functional recordings of odor-evoked activity in the brain allow following the transformation of the olfactory message from the periphery until higher-order central structures. Data from extra- and intracellular electrophysiological approaches as well as from the most recent optical imaging developments are described. Lastly, I discuss results addressing how odor representation changes as a result of experience. This impressive ensemble of behavioral, neuroanatomical, and neurophysiological data available in the bee make it an attractive model for future research aiming to understand olfactory perception and learning in an integrative fashion. PMID:22163215

Determinants of human olfactory performance: a cross-cultural study.

PubMed

Sorokowska, Agnieszka; Sorokowski, Piotr; Frackowiak, Tomasz

2015-02-15

Olfaction allows us to detect subtle changes in our environment, but sensitivity of the sense of smell varies among individuals. Although a significant number of research papers discuss the relationship between olfactory abilities and environmental factors, most studies have been conducted on Western populations or in developed Asian societies. The potential environmental and cultural determinants of olfactory acuity warrant further exploration. In the current study, we compared previously published data on olfaction in an industrialized, modern society (i.e., Europeans) and an indigenous society living in unpolluted, natural environmental conditions (i.e., Tsimane'), with novel data on the olfactory acuity of inhabitants of the Cook Islands. Like the European population (and contrary to the Tsimane'), the Cook Islands people form a modern society, and like the Tsimane' population (and contrary to the Europeans), they live in an unpolluted region. Thus, these comparisons enabled us to independently assess the importance of both air pollution and changes in lifestyle for olfactory abilities in modern societies. Our results indicate that people from the Cook Islands had significantly higher olfactory acuity (i.e., lower thresholds of odor detection) than did Europeans and Tsimane' people. Interestingly, the olfactory sensitivity of Europeans was significantly lower than the olfactory sensitivity of the remaining two groups. Our data suggest that air pollution is an important factor in the deterioration of the sense of smell. However, it is also possible that factors such as agricultural and/or cooking practices, alcohol consumption, and access to medical service may also influence olfactory acuity. Copyright © 2014 Elsevier B.V. All rights reserved.

Potentiation of GluN2C/D NMDA receptor subtypes in the amygdala facilitates the retention of fear and extinction learning in mice.

PubMed

Ogden, Kevin K; Khatri, Alpa; Traynelis, Stephen F; Heldt, Scott A

2014-02-01

NMDA receptors are glutamate receptor ion channels that contribute to synaptic plasticity and are important for many forms of learning and memory. In the amygdala, NMDA receptors are critical for the acquisition, retention, and extinction of classically conditioned fear responses. Although the GluN2B subunit has been implicated in both the acquisition and extinction of conditioned fear, GluN2C-knockout mice show reduced conditioned fear responses. Moreover, D-cycloserine (DCS), which facilitates fear extinction, selectively enhances the activity of GluN2C-containing NMDA receptors. To further define the contribution of GluN2C receptors to fear learning, we infused the GluN2C/GluN2D-selective potentiator CIQ bilaterally into the basolateral amygdala (3, 10, or 30 μg/side) following either fear conditioning or fear extinction training. CIQ both increased the expression of conditioned fear 24 h later and enhanced the extinction of the previously conditioned fear response. These results support a critical role for GluN2C receptors in the amygdala in the consolidation of learned fear responses and suggest that increased activity of GluN2C receptors may underlie the therapeutic actions of DCS.

Bacopa monnieri ameliorates memory deficits in olfactory bulbectomized mice: possible involvement of glutamatergic and cholinergic systems.

PubMed

Le, Xoan Thi; Pham, Hang Thi Nguyet; Do, Phuong Thi; Fujiwara, Hironori; Tanaka, Ken; Li, Feng; Van Nguyen, Tai; Nguyen, Khoi Minh; Matsumoto, Kinzo

2013-10-01

This study investigated the effects of alcoholic extract of Bacopa monnieri (L.) Wettst. (BM) on cognitive deficits using olfactory bulbectomized (OBX) mice and the underlying molecular mechanisms of its action. OBX mice were treated daily with BM (50 mg/kg, p.o.) or a reference drug, tacrine (2.5 mg/kg, i.p.), 1 week before and continuously 3 days after OBX. Cognitive performance of the animals was analyzed by the novel object recognition test, modified Y maze test, and fear conditioning test. Brain tissues of OBX animals were used for neurochemical and immunohistochemical studies. OBX impaired non-spatial short-term memory, spatial working memory, and long-term fair memory. BM administration ameliorated these memory disturbances. The effect of BM on short-term memory deficits was abolished by a muscarinic receptor antagonist, scopolamine. OBX downregulated phosphorylation of synaptic plasticity-related signaling proteins: NR1 subunit of N-methyl-D-aspartate receptor, glutamate receptor 1 (GluR1), and calmodulin-dependent kinase II but not cyclic AMP-responsive element binding protein (CREB), and reduced brain-derived neurotrophic factor (BDNF) mRNA in the hippocampus. OBX also reduced choline acetyltransferase in the hippocampus and cholinergic neurons in the medial septum, and enlarged the size of lateral ventricle. BM administration reversed these OBX-induced neurochemical and histological alterations, except the decrease of GluR1 phosphorylation, and enhanced CREB phosphorylation. Moreover, BM treatment inhibited ex vivo activity of acetylcholinesterase in the brain. These results indicate that BM treatment ameliorates OBX-induced cognition dysfunction via a mechanism involving enhancement of synaptic plasticity-related signaling and BDNF transcription and protection of cholinergic systems from OBX-induced neuronal damage.

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

PubMed

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

2016-05-01

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

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.

MOLECULAR MECHANISMS OF FEAR LEARNING AND MEMORY

PubMed Central

Johansen, Joshua P.; Cain, Christopher K.; Ostroff, Linnaea E.; LeDoux, Joseph E.

2011-01-01

Pavlovian fear conditioning is a useful behavioral paradigm for exploring the molecular mechanisms of learning and memory because a well-defined response to a specific environmental stimulus is produced through associative learning processes. Synaptic plasticity in the lateral nucleus of the amygdala (LA) underlies this form of associative learning. Here we summarize the molecular mechanisms that contribute to this synaptic plasticity in the context of auditory fear conditioning, the form of fear conditioning best understood at the molecular level. We discuss the neurotransmitter systems and signaling cascades that contribute to three phases of auditory fear conditioning: acquisition, consolidation, and reconsolidation. These studies suggest that multiple intracellular signaling pathways, including those triggered by activation of Hebbian processes and neuromodulatory receptors, interact to produce neural plasticity in the LA and behavioral fear conditioning. Together, this research illustrates the power of fear conditioning as a model system for characterizing the mechanisms of learning and memory in mammals, and potentially for understanding fear related disorders, such as PTSD and phobias. PMID:22036561

Genetic disruptions of Drosophila Pavlovian learning leave extinction learning intact.

PubMed

Qin, H; Dubnau, J

2010-03-01

Individuals who experience traumatic events may develop persistent posttraumatic stress disorder. Patients with this disorder are commonly treated with exposure therapy, which has had limited long-term success. In experimental neurobiology, fear extinction is a model for exposure therapy. In this behavioral paradigm, animals are repeatedly exposed in a safe environment to the fearful stimulus, which leads to greatly reduced fear. Studying animal models of extinction already has lead to better therapeutic strategies and development of new candidate drugs. Lack of a powerful genetic model of extinction, however, has limited progress in identifying underlying molecular and genetic factors. In this study, we established a robust behavioral paradigm to study the short-term effect (acquisition) of extinction in Drosophila melanogaster. We focused on the extinction of olfactory aversive 1-day memory with a task that has been the main workhorse for genetics of memory in flies. Using this paradigm, we show that extinction can inhibit each of two genetically distinct forms of consolidated memory. We then used a series of single-gene mutants with known impact on associative learning to examine the effects on extinction. We find that extinction is intact in each of these mutants, suggesting that extinction learning relies on different molecular mechanisms than does Pavlovian learning.

The Topological Properties of Stimuli Influence Fear Generalization and Extinction in Humans

PubMed Central

Xu, Liang; Su, Hongyu; Xie, Xiaoyuan; Yan, Pei; Li, Junjiao; Zheng, Xifu

2018-01-01

Fear generalization is an etiologically significant indicator of anxiety disorders, and understanding how to inhibit it is important in their treatment. Prior studies have found that reducing fear generalization using a generalization stimulus (GS) is ineffective in removing a conditioned fear that incorporates local features, and that topological properties appear to play a comparatively more significant role in the processes of perception and categorization. Our study utilized a conditioned-fear generalization design to examine whether the topological properties of stimuli influence the generalization and return of fear. Fear was indexed using online expectancy ratings and skin conductance responses (SCRs). The study’s 52 participants were divided into three groups: Group 1, conditioned danger cue (CS+) extinction; Group 2, extinction of one GS; Group 3, extinction of three GSs. We found that the three groups acquired conditioned fear at the same level. In the generalization and extinction phase, fear was transferred to the GS with the same topological properties as CS+, and gradual decreases in both shock expectancy and SCRs over non-reinforced extinction trials were observed. In the test phase, participants’ online expectancy ratings indicated that fear did not return in Group 1, but did return in Groups 2 and 3. All three groups demonstrated successful GS fear extinction, but only Group 1 did not show a return of fear for CS+. Regarding SCRs results, none of the groups demonstrated a return of fear, suggesting that utilization of topological properties successfully reduced the return of conditioned fear. Our results indicate that, in clinical settings, using GS with topological equivalence to CS+ might offer a potential method with which to extinct conditioned fear. PMID:29643824

Oxytocin receptor neurotransmission in the dorsolateral bed nucleus of the stria terminalis facilitates the acquisition of cued fear in the fear-potentiated startle paradigm in rats.

PubMed

Moaddab, Mahsa; Dabrowska, Joanna

2017-07-15

Oxytocin (OT) is a hypothalamic neuropeptide that modulates fear and anxiety-like behaviors. Dorsolateral bed nucleus of the stria terminalis (BNST dl ) plays a critical role in the regulation of fear and anxiety, and expresses high levels of OT receptor (OTR). However, the role of OTR neurotransmission within the BNST dl in mediating these behaviors is unknown. Here, we used adult male Sprague-Dawley rats to investigate the role of OTR neurotransmission in the BNST dl in the modulation of the acoustic startle response, as well as in the acquisition and consolidation of conditioned fear using fear potentiated startle (FPS) paradigm. Bilateral intra-BNST dl administration of OT (100 ng) did not affect the acquisition of conditioned fear response. However, intra-BNST dl administration of specific OTR antagonist (OTA), (d(CH 2 ) 5 1 , Tyr(Me) 2 , Thr 4 , Orn 8 , des-Gly-NH 2 9 )-vasotocin, (200 ng), prior to the fear conditioning session, impaired the acquisition of cued fear, without affecting a non-cued fear component of FPS. Neither OTA, nor OT affected baseline startle or shock reactivity during fear conditioning. Therefore, the observed impairment of cued fear after OTA infusion resulted from the specific effect on the formation of cued fear. In contrast to the acquisition, neither OTA nor OT affected the consolidation of FPS, when administered after the completion of fear conditioning session. Taken together, these results reveal the important role of OTR neurotransmission in the BNST dl in the formation of conditioned fear to a discrete cue. This study also highlights the role of the BNST dl in learning to discriminate between threatening and safe stimuli. Copyright © 2017 Elsevier Ltd. All rights reserved.

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.

Olfaction and Environment: Tsimane’ of Bolivian Rainforest Have Lower Threshold of Odor Detection Than Industrialized German People

PubMed Central

Sorokowska, Agnieszka; Sorokowski, Piotr; Hummel, Thomas; Huanca, Tomas

2013-01-01

Olfactory sensitivity varies between individuals. However, data regarding cross-cultural and inter-group differences are scarce. We compared the thresholds of odor detection of the traditional society of Tsimane’ (native Amazonians of the Bolivian rainforest; n = 151) and people living in Dresden (Germany; n = 286) using “Sniffin’ Sticks” threshold subtest. Tsimane’ detected n-butanol at significantly lower concentrations than the German subjects. The distribution of thresholds of the Tsimane’ was very specific, with 25% of Tsimane’ obtaining better results in the olfactory test than any member of the German group. These data suggest that differences in olfactory sensitivity seem to be especially salient between industrialized and non-industrialized populations inhabiting different environmental conditions. We hypothesize that the possible sources of such differences are: (i) the impact of pollution which impairs the olfactory abilities of people from industrialized countries; (ii) better training of olfaction because of the higher importance of smell in traditional populations; (iii) environmental pressures shaping olfactory abilities in these populations. PMID:23922693

Olfaction and environment: Tsimane' of Bolivian rainforest have lower threshold of odor detection than industrialized German people.

PubMed

Sorokowska, Agnieszka; Sorokowski, Piotr; Hummel, Thomas; Huanca, Tomas

2013-01-01

Olfactory sensitivity varies between individuals. However, data regarding cross-cultural and inter-group differences are scarce. We compared the thresholds of odor detection of the traditional society of Tsimane' (native Amazonians of the Bolivian rainforest; n = 151) and people living in Dresden (Germany; n = 286) using "Sniffin' Sticks" threshold subtest. Tsimane' detected n-butanol at significantly lower concentrations than the German subjects. The distribution of thresholds of the Tsimane' was very specific, with 25% of Tsimane' obtaining better results in the olfactory test than any member of the German group. These data suggest that differences in olfactory sensitivity seem to be especially salient between industrialized and non-industrialized populations inhabiting different environmental conditions. We hypothesize that the possible sources of such differences are: (i) the impact of pollution which impairs the olfactory abilities of people from industrialized countries; (ii) better training of olfaction because of the higher importance of smell in traditional populations; (iii) environmental pressures shaping olfactory abilities in these populations.

Olfactory bulb size, odor discrimination and magnetic insensitivity in hummingbirds.

PubMed

Ioalé, P; Papi, F

1989-05-01

Relative olfactory bulb size with respect to telencephalic hemispheres (olfactory ratio) was measured in five species of hummingbirds. Trochiliformes were found to be next to last among 25 avian orders with respect to olfactory bulb development. One hummingbird species, the White-vented Violetear (Colibri serrirostris), was trained in a successive go/no-go discrimination task, and learned to feed or not to feed from a container dependent on the olfactory stimuli associated with it. Test birds learned to discriminate amyl acetate vs. turpentine essence, jasmine essence vs. lavender essence, eucalyptus essence vs. no odor, beta-ionone vs. no odor, carvone vs. eucalyptol. In contrast, 1-phenylethanol vs. beta-ionone discrimination, two odorants which appear similar to humans, was unsuccessful. Using a similar procedure, attempts were made to condition a White-vented Violetear and a Versicolored Emerald (Amazilia versicolor) to magnetic stimuli. The birds were unable to discriminate between a normal field and an oscillating field (square wave, 1 Hz, amplitude +/- 0.40 G).

Learning Modifies Odor Mixture Processing to Improve Detection of Relevant Components

PubMed Central

Chen, Jen-Yung; Marachlian, Emiliano; Assisi, Collins; Huerta, Ramon; Smith, Brian H.

2015-01-01

Honey bees have a rich repertoire of olfactory learning behaviors, and they therefore are an excellent model to study plasticity in olfactory circuits. Recent behavioral, physiological, and molecular evidence suggested that the antennal lobe, the first relay of the olfactory system in insects and analog to the olfactory bulb in vertebrates, is involved in associative and nonassociative olfactory learning. Here we use calcium imaging to reveal how responses across antennal lobe projection neurons change after association of an input odor with appetitive reinforcement. After appetitive conditioning to 1-hexanol, the representation of an odor mixture containing 1-hexanol becomes more similar to this odor and less similar to the background odor acetophenone. We then apply computational modeling to investigate how changes in synaptic connectivity can account for the observed plasticity. Our study suggests that experience-dependent modulation of inhibitory interactions in the antennal lobe aids perception of salient odor components mixed with behaviorally irrelevant background odors. PMID:25568113

[Changes in olfaction during ageing and in certain neurodegenerative diseases: up-to-date].

PubMed

Bianchi, A-J; Guépet-Sordet, H; Manckoundia, P

2015-01-01

Olfaction is a complex sensory system, and increasing interest is being shown in the link between olfaction and cognition, notably in the elderly. In this literature review, we revisit the specific neurophysiological features of the olfactory system and odorants that lead to a durable olfactory memory and an emotional memory, for which the implicit component produces subconscious olfactory conditioning. Olfaction is known to affect cognitive abilities and mood. We also consider the impairment of olfactory function due to ageing and to neurodegenerative diseases, in particular Alzheimer's disease and Parkinson's disease, through anatomopathological changes in the peripheral and central olfactory structures. The high frequency of these olfactory disorders as well as their early occurrence in Alzheimer disease and Parkinson disease are in favour of their clinical detection in subjects suffering from these two neurodegenerative diseases. Finally, we analyse the impact of olfactory stimulation on cognitive performance and attention. Current observational data from studies in elderly patients with Alzheimer-type dementia are limited to multiple sensory stimulation methods, such as the Snoezelen method, and aromatherapy. These therapies have shown benefits for dementia-related mood and behaviour disorders in the short term, with few side effects. Since olfactory chemosensory stimulation may be beneficial, it may be proposed in patients with dementia, especially Alzheimer-type dementia, as a complementary or even alternative therapy to existing medical strategies. Copyright © 2014 Société nationale française de médecine interne (SNFMI). Published by Elsevier SAS. All rights reserved.

Negative Social Evaluative Fears Produce Social Anxiety, Food Intake, and Body Dissatisfaction: Evidence of Similar Mechanisms through Different Pathways

PubMed Central

Levinson, Cheri A.; Rodebaugh, Thomas L.

2014-01-01

Social anxiety and eating disorders are highly comorbid, suggesting there are shared vulnerabilities that underlie the development of these disorders. Two proposed vulnerabilities are fear of negative evaluation and social appearance anxiety (i.e., fear of negative evaluation regarding one's appearance). In the current experimental study (N=160 women) we measured these fears: (a) through a manipulation comparing fear conditions, (b) with trait fears, and (c) state fears. Results indicated that participants in the fear of negative evaluation condition increased food consumption, whereas participants in the social appearance anxiety condition and high in trait social appearance anxiety experienced the highest amounts of body dissatisfaction. Participants in the fear of evaluation and social appearance anxiety conditions experienced elevated social anxiety. These results support the idea that negative evaluation fears are shared vulnerabilities for eating and social anxiety disorders, but that the way these variables exert their effects may lead to disorder specific behaviors. PMID:26504674

The orexin component of fasting triggers memory processes underlying conditioned food selection in the rat.

PubMed

Ferry, Barbara; Duchamp-Viret, Patricia

2014-03-14

To test the selectivity of the orexin A (OXA) system in olfactory sensitivity, the present study compared the effects of fasting and of central infusion of OXA on the memory processes underlying odor-malaise association during the conditioned odor aversion (COA) paradigm. Animals implanted with a cannula in the left ventricle received ICV infusion of OXA or artificial cerebrospinal fluid (ACSF) 1 h before COA acquisition. An additional group of intact rats were food-deprived for 24 h before acquisition. Results showed that the increased olfactory sensitivity induced by fasting and by OXA infusion was accompanied by enhanced COA performance. The present results suggest that fasting-induced central OXA release influenced COA learning by increasing not only olfactory sensitivity, but also the memory processes underlying the odor-malaise association.

The orexin component of fasting triggers memory processes underlying conditioned food selection in the rat

PubMed Central

Ferry, Barbara; Duchamp-Viret, Patricia

2014-01-01

To test the selectivity of the orexin A (OXA) system in olfactory sensitivity, the present study compared the effects of fasting and of central infusion of OXA on the memory processes underlying odor–malaise association during the conditioned odor aversion (COA) paradigm. Animals implanted with a cannula in the left ventricle received ICV infusion of OXA or artificial cerebrospinal fluid (ACSF) 1 h before COA acquisition. An additional group of intact rats were food-deprived for 24 h before acquisition. Results showed that the increased olfactory sensitivity induced by fasting and by OXA infusion was accompanied by enhanced COA performance. The present results suggest that fasting-induced central OXA release influenced COA learning by increasing not only olfactory sensitivity, but also the memory processes underlying the odor–malaise association. PMID:24634353

Plasticity of Fear and Safety Neurons of the Amygdala in Response to Fear Extinction

PubMed Central

Sangha, Susan

2015-01-01

Fear inhibition learning induces plasticity and remodeling of circuits within the amygdala. Most studies examine these changes in nondiscriminative fear conditioning paradigms. Using a discriminative fear, safety, and reward conditioning task, Sangha et al. (2013) have previously reported several neural microcircuits within the basal amygdala (BA) which discriminate among these cues, including a subpopulation of neurons responding selectively to a safety cue and not a fear cue. Here, the hypothesis that these “safety” neurons isolated during discriminative conditioning are biased to become fear cue responsive as a result of extinction, when fear behavior diminishes, was tested. Although 41% of “safety” neurons became fear cue responsive as a result of extinction, the data revealed that there was no bias for these neurons to become preferentially responsive during fear extinction compared to the other identified subgroups. In addition to the plasticity seen in the “safety” neurons, 44% of neurons unresponsive to either the fear cue or safety cue during discriminative conditioning became fear cue responsive during extinction. Together these emergent responses to the fear cue as a result of extinction support the hypothesis that new learning underlies extinction. In contrast, 47% of neurons responsive to the fear cue during discriminative conditioning became unresponsive to the fear cue during extinction. These findings are consistent with a suppression of neural responding mediated by inhibitory learning, or, potentially, by direct unlearning. Together, the data support extinction as an active process involving both gains and losses of responses to the fear cue and suggests the final output of the integrated BA circuit in influencing fear behavior is a balance of excitation and inhibition, and perhaps reversal of learning-induced changes. PMID:26733838

Hormonal Regulation of Extinction: Implication for Mechanisms of Gender Difference in PTSD

DTIC Science & Technology

2009-09-01

role of gonadal hormones in the regulation of Pavlovian fear conditioning and its extinction. Pavlovian fear conditioning and its extinction serve...learning in Pavlovian fear conditioning involves training with the presentation of an innocuous stimulus (the conditioned stimulus – CS) that is associated...GD, Schlinger BA, Fanselow MS (1998) Testicular hormones do not regulate sexually dimorphic Pavlovian fear conditioning or perforant- path long-term

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

ERIC Educational Resources Information Center

Chang, Chun-hui; Maren, Stephen

2009-01-01

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

Dopamine D1-like receptor signalling in the hippocampus and amygdala modulates the acquisition of contextual fear conditioning.

PubMed

Heath, Florence C; Jurkus, Regimantas; Bast, Tobias; Pezze, Marie A; Lee, Jonathan L C; Voigt, J Peter; Stevenson, Carl W

2015-07-01

Dopamine D1-like receptor signalling is involved in contextual fear conditioning, but the brain regions involved and its role in other contextual fear memory processes remain unclear. The objective of this study was to investigate (1) the effects of SCH 23390, a dopamine D1/D5 receptor antagonist, on contextual fear memory encoding, retrieval and reconsolidation, and (2) if the effects of SCH 23390 on conditioning involve the dorsal hippocampus (DH) and/or basolateral amygdala (BLA). Rats were used to examine the effects of systemically administering SCH 23390 on the acquisition, consolidation, retrieval and reconsolidation of contextual fear memory, and on locomotor activity and shock sensitivity. We also determined the effects of MK-801, an NMDA receptor antagonist, on contextual fear memory reconsolidation. The effects of infusing SCH 23390 locally into DH or BLA on contextual fear conditioning and locomotor activity were also examined. Systemic administration of SCH 23390 impaired contextual fear conditioning but had no effects on fear memory consolidation, retrieval or reconsolidation. MK-801 was found to impair reconsolidation, suggesting that the behavioural parameters used allowed for the pharmacological disruption of memory reconsolidation. The effects of SCH 23390 on conditioning were unlikely the result of any lasting drug effects on locomotor activity at memory test or any acute drug effects on shock sensitivity during conditioning. SCH 23390 infused into either DH or BLA impaired contextual fear conditioning and decreased locomotor activity. These findings suggest that dopamine D1-like receptor signalling in DH and BLA contributes to the acquisition of contextual fear memory.

Drought and increased CO2 alter floral visual and olfactory traits with context-dependent effects on pollinator visitation

Treesearch

William R. Glenny; Justin B. Runyon; Laura A. Burkle

2018-01-01

Climate change can alter species interactions essential for maintaining biodiversity and ecosystem function, such as pollination. Understanding the interactive effects of multiple abiotic conditions on floral traits and pollinator visitation are important to anticipate the implications of climate change on pollinator services. Floral visual and olfactory traits were...

Steroid Hormone (20-Hydroxyecdysone) Modulates the Acquisition of Aversive Olfactory Memories in Pollen Forager Honeybees

ERIC Educational Resources Information Center

Geddes, Lisa H.; McQuillan, H. James; Aiken, Alastair; Vergoz, Vanina; Mercer, Alison R.

2013-01-01

Here, we examine effects of the steroid hormone, 20-hydroxyecdysone (20-E), on associative olfactory learning in the honeybee, "Apis mellifera." 20-E impaired the bees' ability to associate odors with punishment during aversive conditioning, but did not interfere with their ability to associate odors with a food reward (appetitive…

Post-Extinction Conditional Stimulus Valence Predicts Reinstatement Fear: Relevance for Long Term Outcomes of Exposure Therapy

PubMed Central

Zbozinek, Tomislav D.; Hermans, Dirk; Prenoveau, Jason M.; Liao, Betty; Craske, Michelle G.

2014-01-01

Exposure therapy for anxiety disorders is translated from fear conditioning and extinction. While exposure therapy is effective in treating anxiety, fear sometimes returns after exposure. One pathway for return of fear is reinstatement: unsignaled unconditional stimuli following completion of extinction. The present study investigated the extent to which valence of the conditional stimulus (CS+) after extinction predicts return of CS+ fear after reinstatement. Participants (N = 84) engaged in a differential fear conditioning paradigm and were randomized to reinstatement or non-reinstatement. We hypothesized that more negative post-extinction CS+ valence would predict higher CS+ fear after reinstatement relative to non-reinstatement and relative to extinction retest. Results supported the hypotheses and suggest that strategies designed to decrease negative valence of the CS+ may reduce the return of fear via reinstatement following exposure therapy. PMID:24957680

Muscarinic ACh Receptors Contribute to Aversive Olfactory Learning in Drosophila.

PubMed

Silva, Bryon; Molina-Fernández, Claudia; Ugalde, María Beatriz; Tognarelli, Eduardo I; Angel, Cristian; Campusano, Jorge M

2015-01-01

The most studied form of associative learning in Drosophila consists in pairing an odorant, the conditioned stimulus (CS), with an unconditioned stimulus (US). The timely arrival of the CS and US information to a specific Drosophila brain association region, the mushroom bodies (MB), can induce new olfactory memories. Thus, the MB is considered a coincidence detector. It has been shown that olfactory information is conveyed to the MB through cholinergic inputs that activate acetylcholine (ACh) receptors, while the US is encoded by biogenic amine (BA) systems. In recent years, we have advanced our understanding on the specific neural BA pathways and receptors involved in olfactory learning and memory. However, little information exists on the contribution of cholinergic receptors to this process. Here we evaluate for the first time the proposition that, as in mammals, muscarinic ACh receptors (mAChRs) contribute to memory formation in Drosophila. Our results show that pharmacological and genetic blockade of mAChRs in MB disrupts olfactory aversive memory in larvae. This effect is not explained by an alteration in the ability of animals to respond to odorants or to execute motor programs. These results show that mAChRs in MB contribute to generating olfactory memories in Drosophila.

Low Endogenous Fibroblast Growth Factor 2 Levels Are Associated With Heightened Conditioned Fear Expression in Rats and Humans.

PubMed

Graham, Bronwyn M; Zagic, Dino; Richardson, Rick

2017-10-15

Hippocampal concentrations of the neurotrophic factor fibroblast growth factor 2 (FGF2) are negatively associated with the expression of fear following conditioning in rats. Heightened conditioned fear expression may be a prospective risk factor for the development of human anxiety and trauma disorders. However, the relationship between conditioned fear expression and FGF2 is yet to be established in humans. Using a cross-species approach, we first investigated the relationship between serum concentrations of FGF2 and individual differences in conditioned fear expression in rats (n = 19). We then subjected 88 human participants, who were recruited from university and community advertisements, to a differential fear conditioning procedure and assessed the relationship between salivary concentrations of FGF2 and fear expression to a conditioned stimulus (CS) (a stimulus paired with a shock) and a CS that was never paired with shock. Rats with low serum levels of FGF2 exhibited significantly more freezing than rats with high serum levels of FGF2. Similarly, relative to those with high salivary FGF2, human participants with low salivary FGF2 exhibited significantly heightened skin conductance responses to the CS without shock during fear conditioning and to both the CS with shock and CS without shock during fear recall. These studies establish that peripheral markers of FGF2 concentrations are negatively associated with fear expression in both rats and humans. To the extent that conditioned fear expression predicts anxiety and trauma disorder vulnerability, FGF2 may be a clinically useful biomarker in the prediction and eventual prevention of these disorders. Copyright © 2017 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

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

PubMed

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

2007-05-01

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

[Is olfactory function impaired in moderate height?].

PubMed

Kühn, M; Welsch, H; Zahnert, T; Hummel, Thomas

2009-09-01

The human sense of smell seems to be influenced by the surrounding barometric pressure. These factors appear to be especially important during flights, for example, in order to recognize the smell of fire etc. Thus, questions are whether pilots or passengers exhibit an impaired smell sensitivity when tested at moderate heights, or, whether changes in humidity would affect the sense of smell. Using climate chambers, odor discrimination and butanol odor thresholds were tested in 77 healthy normosmic volunteers (5 female, 72 male; aged 25+/-8 years from 18 up to 53 years) under hypobaric (2 700+/-20 m, 20 degrees C+/-1 K, rh=50+/-5%) and hyperbaric, (10+/-0.5 m (2 bar)) and different humidity conditions (30 vs. 80%, 20 degrees C+/-1 K, normobaric). During all conditions cognitive performance was tested. Among other effects, olfactory sensitivity was impaired at threshold, but not suprathreshold level, in a hypobaric compared to a hyperbaric milieu, and thresholds were lower in humid, compared to relatively dry conditions. In conclusion, environmental conditions modulate the sense of smell, and may, consecutively, influence results from olfactory tests. During flight hypobaric conditions, mild hypoxia and dry air may cause impaired sensitivity of smell. Georg Thieme Verlag KG Stuttgart * New York.

The effect of hyperbaric conditions on olfactory functions.

PubMed

Ay, Hakan; Salihoglu, Murat; Altundag, Aytug; Tekeli, Hakan; Memis, Ali; Cayonu, Melih

2014-01-01

The aim of this study was to investigate the effect of increased atmospheric pressure (AP) on olfactory function. The present study included 40 healthy volunteers with no history of chronic rhinosinusitis and nasal polyposis. The experimental procedure consisted of two episodes: (a) baseline episode, with normal AP; 1 absolute atmosphere (atm abs) in a test room at sea level; (b) experimental episode, increased level of AP; 2.4 atm abs in the hyperbaric chamber. Sino-nasal outcome test-20, Trail Making Test A and olfactory testing were performed in each episodes. The study group consisted of 23 men (57.5%) and 17 women (42.5%); the mean age of the study population was 38.7 +/- 9 years (range 23-58 years). The current investigation produced two major findings: (1) the mean of odor threshold scores was significantly increased in the hyperbaric condition when compared to the normobaric condition; (2) rather, there was no significant change in odor discrimination and identification scores in the hyperbaric condition. Based on two measurements taken at two different barometric pressures and the same temperature and relative humidity, this study suggests that odor threshold scores increase under hyperbaric conditions.

Generalization of Conditioned Fear along a Dimension of Increasing Fear Intensity

ERIC Educational Resources Information Center

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

2009-01-01

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

Assessing Fear Following Retrieval + Extinction Through Suppression of Baseline Reward Seeking vs. Freezing

PubMed Central

Shumake, Jason; Monfils, Marie H.

2015-01-01

Freezing has become the predominant measure used in rodent studies of conditioned fear, but conditioned suppression of reward-seeking behavior may provide a measure that is more relevant to human anxiety disorders; that is, a measure of how fear interferes with the enjoyment of pleasurable activities. Previous work has found that an isolated presentation of a fear conditioned stimulus (CS) prior to extinction training (retrieval + extinction) results in a more robust and longer-lasting reduction in fear. The objective of this study was to assess whether the retrieval + extinction effect is evident using conditioned suppression of reward seeking, operationalized as a reduction in baseline licking (without prior water deprivation) for a 10% sucrose solution. We found that, compared to freezing, conditioned suppression of reward seeking was much more sensitive to fear conditioning and far less responsive to extinction training. As in previous work, we found that retrieval + extinction reduced post-extinction fear reinstatement when measured as freezing, but it did not reduce fear reinstatement when measured as conditioned suppression. This suggests that there is still residual fear following retrieval + extinction, or that this procedure only modifies memory traces in neural circuits relevant to the expression of freezing, but not to the suppression of reward seeking. PMID:26778985

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

PubMed Central

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

2016-01-01

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

Stressor controllability modulates fear extinction in humans

PubMed Central

Hartley, Catherine A.; Gorun, Alyson; Reddan, Marianne C.; Ramirez, Franchesca; Phelps, Elizabeth A.

2014-01-01

Traumatic events are proposed to play a role in the development of anxiety disorders, however not all individuals exposed to extreme stress experience a pathological increase in fear. Recent studies in animal models suggest that the degree to which one is able to control an aversive experience is a critical factor determining its behavioral consequences. In this study, we examined whether stressor controllability modulates subsequent conditioned fear expression in humans. Participants were randomly assigned to an escapable stressor condition, a yoked inescapable stressor condition, or a control condition involving no stress exposure. One week later, all participants underwent fear conditioning, fear extinction, and a test of extinction retrieval the following day. Participants exposed to inescapable stress showed impaired fear extinction learning and increased fear expression the following day. In contrast, escapable stress improved fear extinction and prevented the spontaneous recovery of fear. Consistent with the bidirectional controllability effects previously reported in animal models, these results suggest that one's degree of control over aversive experiences may be an important factor influencing the development of psychological resilience or vulnerability in humans. PMID:24333646

Early survival factor deprivation in the olfactory epithelium enhances activity-driven survival

PubMed Central

François, Adrien; Laziz, Iman; Rimbaud, Stéphanie; Grebert, Denise; Durieux, Didier; Pajot-Augy, Edith; Meunier, Nicolas

2013-01-01

The neuronal olfactory epithelium undergoes permanent renewal because of environmental aggression. This renewal is partly regulated by factors modulating the level of neuronal apoptosis. Among them, we had previously characterized endothelin as neuroprotective. In this study, we explored the effect of cell survival factor deprivation in the olfactory epithelium by intranasal delivery of endothelin receptors antagonists to rat pups. This treatment induced an overall increase of apoptosis in the olfactory epithelium. The responses to odorants recorded by electroolfactogram were decreased in treated animal, a result consistent with a loss of olfactory sensory neurons (OSNs). However, the treated animal performed better in an olfactory orientation test based on maternal odor compared to non-treated littermates. This improved performance could be due to activity-dependent neuronal survival of OSNs in the context of increased apoptosis level. In order to demonstrate it, we odorized pups with octanal, a known ligand for the rI7 olfactory receptor (Olr226). We quantified the number of OSN expressing rI7 by RT-qPCR and whole mount in situ hybridization. While this number was reduced by the survival factor removal treatment, this reduction was abolished by the presence of its ligand. This improved survival was optimal for low concentration of odorant and was specific for rI7-expressing OSNs. Meanwhile, the number of rI7-expressing OSNs was not affected by the odorization in non-treated littermates; showing that the activity-dependant survival of OSNs did not affect the OSN population during the 10 days of odorization in control conditions. Overall, our study shows that when apoptosis is promoted in the olfactory mucosa, the activity-dependent neuronal plasticity allows faster tuning of the olfactory sensory neuron population toward detection of environmental odorants. PMID:24399931

Lack of TRPM5-Expressing Microvillous Cells in Mouse Main Olfactory Epithelium Leads to Impaired Odor-Evoked Responses and Olfactory-Guided Behavior in a Challenging Chemical Environment

PubMed Central

Lemons, Kayla; Aoudé, Imad; Ogura, Tatsuya; Mbonu, Kenechukwu; Matsumoto, Ichiro; Arakawa, Hiroyuki

2017-01-01

The mammalian main olfactory epithelium (MOE) modifies its activities in response to changes in the chemical environment. This process is essential for maintaining the functions of the olfactory system and the upper airway. However, mechanisms involved in this functional maintenance, especially those occurring via paracrine regulatory pathways within the multicellular MOE, are poorly understood. Previously, a population of non-neuronal, transient receptor potential M5-expressing microvillous cells (TRPM5-MCs) was identified in the MOE, and the initial characterization of these cells showed that they are cholinergic and responsive to various xenobiotics including odorants at high concentrations. Here, we investigated the role of TRPM5-MCs in maintaining olfactory function using transcription factor Skn-1a knockout (Skn-1a-/-) mice, which lack TRPM5-MCs in the MOE. Under our standard housing conditions, Skn-1a-/- mice do not differ significantly from control mice in odor-evoked electro-olfactogram (EOG) responses and olfactory-guided behaviors, including finding buried food and preference reactions to socially and sexually relevant odors. However, after a 2-wk exposure to high-concentration odor chemicals and chitin powder, Skn-1a-/- mice exhibited a significant reduction in their odor and pheromone-evoked EOG responses. Consequently, their olfactory-guided behaviors were impaired compared with vehicle-exposed Skn-1a-/- mice. Conversely, the chemical exposure did not induce significant changes in the EOG responses and olfactory behaviors of control mice. Therefore, our physiological and behavioral results indicate that TRPM5-MCs play a protective role in maintaining the olfactory function of the MOE. PMID:28612045

Molecular mechanisms of fear learning and memory.

PubMed

Johansen, Joshua P; Cain, Christopher K; Ostroff, Linnaea E; LeDoux, Joseph E

2011-10-28

Pavlovian fear conditioning is a particularly useful behavioral paradigm for exploring the molecular mechanisms of learning and memory because a well-defined response to a specific environmental stimulus is produced through associative learning processes. Synaptic plasticity in the lateral nucleus of the amygdala (LA) underlies this form of associative learning. Here, we summarize the molecular mechanisms that contribute to this synaptic plasticity in the context of auditory fear conditioning, the form of fear conditioning best understood at the molecular level. We discuss the neurotransmitter systems and signaling cascades that contribute to three phases of auditory fear conditioning: acquisition, consolidation, and reconsolidation. These studies suggest that multiple intracellular signaling pathways, including those triggered by activation of Hebbian processes and neuromodulatory receptors, interact to produce neural plasticity in the LA and behavioral fear conditioning. Collectively, this body of research illustrates the power of fear conditioning as a model system for characterizing the mechanisms of learning and memory in mammals and potentially for understanding fear-related disorders, such as PTSD and phobias. Copyright © 2011 Elsevier Inc. All rights reserved.

Distinct state anxiety after predictable and unpredictable fear training in mice.

PubMed

Seidenbecher, Thomas; Remmes, Jasmin; Daldrup, Thiemo; Lesting, Jörg; Pape, Hans-Christian

2016-05-01

Sustained fear paradigms in rodents have been developed to monitor states of anxious apprehension and to model situations in patients suffering from long-lasting anxiety disorders. A recent report describes a fear conditioning paradigm, allowing distinction between phasic and sustained states of conditioned fear in non-restrained mice. However, so far no prospective studies have yet been conducted to elucidate whether induction of phasic or sustained fear can affect states of anxiety. Here, we used CS (conditioned stimulus) and US (unconditioned stimulus) pairing with predictable and unpredictable timing to induce phasic and sustained fear in mice. State anxiety during various fear response components was assessed using the elevated plus-maze test. Training with unpredictable CS-US timing resulted in CS-evoked sustained components of fear (freezing), while predictable CS-US timing resulted in rapid decline. Data suggested the influence of training procedure on state anxiety which is dependent on progression of conditioned fear during fear memory retrieval. Animals trained with unpredictable CS-US timing showed an unchanged high anxiety state throughout behavioral observation. In contrast, mice trained with predictable CS-US timing showed anxiolytic-like behavior 3 min after CS onset, which was accompanied by a fast decline of the fear conditioned response (freezing). Further systematic studies are needed to validate the phasic/sustained fear model in rodents as translational model for anxiety disorders in humans. Copyright © 2016 Elsevier B.V. All rights reserved.

Persistence of Amygdala-Hippocampal Connectivity and Multi-Voxel Correlation Structures During Awake Rest After Fear Learning Predicts Long-Term Expression of Fear.

PubMed

Hermans, Erno J; Kanen, Jonathan W; Tambini, Arielle; Fernández, Guillén; Davachi, Lila; Phelps, Elizabeth A

2017-05-01

After encoding, memories undergo a process of consolidation that determines long-term retention. For conditioned fear, animal models postulate that consolidation involves reactivations of neuronal assemblies supporting fear learning during postlearning "offline" periods. However, no human studies to date have investigated such processes, particularly in relation to long-term expression of fear. We tested 24 participants using functional MRI on 2 consecutive days in a fear conditioning paradigm involving 1 habituation block, 2 acquisition blocks, and 2 extinction blocks on day 1, and 2 re-extinction blocks on day 2. Conditioning blocks were preceded and followed by 4.5-min rest blocks. Strength of spontaneous recovery of fear on day 2 served as a measure of long-term expression of fear. Amygdala connectivity primarily with hippocampus increased progressively during postacquisition and postextinction rest on day 1. Intraregional multi-voxel correlation structures within amygdala and hippocampus sampled during a block of differential fear conditioning furthermore persisted after fear learning. Critically, both these main findings were stronger in participants who exhibited spontaneous recovery 24 h later. Our findings indicate that neural circuits activated during fear conditioning exhibit persistent postlearning activity that may be functionally relevant in promoting consolidation of the fear memory. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Bilateral Alternating Auditory Stimulations Facilitate Fear Extinction and Retrieval.

PubMed

Boukezzi, Sarah; Silva, Catarina; Nazarian, Bruno; Rousseau, Pierre-François; Guedj, Eric; Valenzuela-Moguillansky, Camila; Khalfa, Stéphanie

2017-01-01

Disruption of fear conditioning, its extinction and its retrieval are at the core of posttraumatic stress disorder (PTSD). Such deficits, especially fear extinction delay, disappear after alternating bilateral stimulations (BLS) during eye movement desensitization and reprocessing (EMDR) therapy. An animal model of fear recovery, based on auditory cued fear conditioning and extinction learning, recently showed that BLS facilitate fear extinction and fear extinction retrieval. Our goal was to determine if these previous results found in animals can be reproduced in humans. Twenty-two healthy participants took part in a classical fear conditioning, extinction, and extinction recall paradigm. Behavioral responses (fear expectations) as well as psychophysiological measures (skin conductance responses, SCRs) were recorded. The results showed a significant fear expectation decrease during fear extinction with BLS. Additionally, SCR for fear extinction retrieval were significantly lower with BLS. Our results demonstrate the importance of BLS to reduce negative emotions, and provide a successful model to further explore the neural mechanisms underlying the sole BLS effect in the EMDR.

Bilateral Alternating Auditory Stimulations Facilitate Fear Extinction and Retrieval

PubMed Central

Boukezzi, Sarah; Silva, Catarina; Nazarian, Bruno; Rousseau, Pierre-François; Guedj, Eric; Valenzuela-Moguillansky, Camila; Khalfa, Stéphanie

2017-01-01

Disruption of fear conditioning, its extinction and its retrieval are at the core of posttraumatic stress disorder (PTSD). Such deficits, especially fear extinction delay, disappear after alternating bilateral stimulations (BLS) during eye movement desensitization and reprocessing (EMDR) therapy. An animal model of fear recovery, based on auditory cued fear conditioning and extinction learning, recently showed that BLS facilitate fear extinction and fear extinction retrieval. Our goal was to determine if these previous results found in animals can be reproduced in humans. Twenty-two healthy participants took part in a classical fear conditioning, extinction, and extinction recall paradigm. Behavioral responses (fear expectations) as well as psychophysiological measures (skin conductance responses, SCRs) were recorded. The results showed a significant fear expectation decrease during fear extinction with BLS. Additionally, SCR for fear extinction retrieval were significantly lower with BLS. Our results demonstrate the importance of BLS to reduce negative emotions, and provide a successful model to further explore the neural mechanisms underlying the sole BLS effect in the EMDR. PMID:28659851

Mechanisms of Pavlovian fear conditioning: has the engram been located?

PubMed

Paré, Denis

2002-09-01

Uncertainty persists as to whether the amygdala is a crucial site of plasticity for classically conditioned fear or merely a sensory relay to structures generating fear responses. A recent Nature study suggests that associative synaptic changes take place in neurons of the amygdala during fear conditioning, and that these changes require dopamine-mediated modulation. Nevertheless, these findings do not prove that the amygdala is a sufficient site of plasticity for fear memory.

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

PubMed

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

2014-08-01

Strain comparison studies have been critical to the identification of novel genetic and molecular mechanisms in learning and memory. However, even within a single learning paradigm, the behavioral data for the same strain can vary greatly, making it difficult to form meaningful conclusions at both the behavioral and cellular level. In fear conditioning, there is a high level of variability across reports, especially regarding responses to the conditioned stimulus (CS). Here, we compare C57BL/6 and DBA/2 mice using delay fear conditioning, trace fear conditioning, and a nonassociative condition. Our data highlight both the significant strain differences apparent in these fear conditioning paradigms and the significant differences in conditioning type within each strain. We then compare our data to an extensive literature review of delay and trace fear conditioning in these two strains. Finally, we apply a number of commonly used baseline normalization approaches to compare how they alter the reported differences. Our findings highlight three major sources of variability in the fear conditioning literature: CS duration, number of CS presentations, and data normalization to baseline measures. © 2014 Tipps et al.; Published by Cold Spring Harbor Laboratory Press.

Influence of cued-fear conditioning and its impairment on NREM sleep.

PubMed

Kumar, Tankesh; Jha, Sushil K

2017-10-01

Many studies suggest that fear conditioning influences sleep. It is, however, not known if the changes in sleep architecture after fear conditioning are essentially associated with the consolidation of fearful memory or with fear itself. Here, we have observed that within sleep, NREM sleep consistently remained augmented after the consolidation of cued fear-conditioned memory. But a similar change did not occur after impairing memory consolidation by blocking new protein synthesis and glutamate transmission between glial-neuronal loop in the lateral amygdala (LA). Anisomycin (a protein synthesis inhibitor) and DL-α-amino-adipic acid (DL- α -AA) (a glial glutamine synthetase enzyme inhibitor) were microinjected into the LA soon after cued fear-conditioning to induce memory impairment. On the post-conditioning day, animals in both the groups exhibited significantly less freezing. In memory-consolidated groups (vehicle groups), NREM sleep significantly increased during 2nd to 5th hours after training compared to their baseline days. However, in memory impaired groups (anisomycin and DL- α -AA microinjected groups), similar changes were not observed. Our results thus suggest that changes in sleep architecture after cued fear-conditioning are indeed a consolidation dependent event. Copyright © 2017 Elsevier Inc. All rights reserved.

Pain pathways involved in fear conditioning measured with fear-potentiated startle: lesion studies.

PubMed

Shi, C; Davis, M

1999-01-01

It is well established that the basolateral amygdala is critically involved in the association between an unconditioned stimulus (US), such as a foot shock, and a conditioned stimulus (CS), such as a light, during classic fear conditioning. However, little is known about how the US (pain) inputs are relayed to the basolateral amygdala. The present studies were designed to define potential US pathways to the amygdala using lesion methods. Electrolytic lesions before or after training were placed in caudal granular/dysgranular insular cortex (IC) alone or in conjunction with the posterior intralaminar nuclei of the thalamus (PoT/PIL), and the effects on fear conditioning were examined. Pretraining lesions of both IC and PoT/PIL, but not lesions of IC alone, blocked the acquisition of fear-potentiated startle. However, post-training combined lesions of IC and PoT/PIL did not prevent expression of conditioned fear. Given that previous studies have shown that lesions of PoT/PIL alone had no effect on acquisition of conditioned fear, these results suggest that two parallel cortical (insula-amygdala) and subcortical (PoT/PIL-amygdala) pathways are involved in relaying shock information to the basolateral amygdala during fear conditioning.

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.

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

PubMed

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

2013-02-01

Previous studies have shown that individuals with anxiety disorders exhibit deficits in fear inhibition and excessive generalization of fear, but little data exist on individuals at risk from these disorders. The present study examined the role of trait anxiety in the acquisition and generalization of fear in 126 healthy participants selected on the basis of their trait-anxiety scores. Measures of conditioning included fear-potentiated startle, skin conductance response and online risk ratings for the unconditioned stimulus. Contrary to our hypotheses, trait anxiety did not have any effect either on the acquisition or the generalization of fear. Our results suggest that these fear conditioning processes are not impaired in individuals at risk from anxiety. Copyright © 2012 Elsevier B.V. All rights reserved.

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

A peripheral immune response to remembering trauma contributes to the maintenance of fear memory in mice.

PubMed

Young, Matthew B; Howell, Leonard L; Hopkins, Lauren; Moshfegh, Cassandra; Yu, Zhe; Clubb, Lauren; Seidenberg, Jessica; Park, Jeanie; Swiercz, Adam P; Marvar, Paul J

2018-05-17

Alterations in peripheral immune markers are observed in individuals with post-traumatic stress disorder (PTSD). PTSD is characterized in part by impaired extinction of fear memory for a traumatic experience. We hypothesized that fear memory extinction is regulated by immune signaling stimulated when fear memory is retrieved. The relationship between fear memory and the peripheral immune response was tested using auditory Pavlovian fear conditioning in mice. Memory for the association was quantified by the amount of conditioned freezing exhibited in response to the conditioned stimulus (CS), extinction and time-dependent changes in circulating inflammatory cytokines. Brief extinction training with 12 CS rapidly and acutely increased circulating levels of the cytokine interleukin-6 (IL-6), downstream IL-6 signaling, other IL-6 related pro-inflammatory cytokines. Transgenic manipulations or neutralizing antibodies that inhibit IL-6 activity did not affect conditioned freezing during the acquisition of fear conditioning or extinction but significantly reduced conditioned freezing 24 h after extinction training with 12 CS. Conversely, conditioned freezing after extinction training was unchanged by IL-6 inhibition when 40 CS were used during the extinction training session. In addition to effectively diminishing conditioned freezing, extinction training with 40 CS also diminished the subsequent IL-6 response to the CS. These data demonstrate that IL-6 released following fear memory retrieval contributes to the maintenance of that fear memory and that this effect is extinction dependent. These findings extend the current understanding for the role of the immune system in PTSD and suggest that IL-6 and other IL-6 related pro-inflammatory cytokines may contribute to the persistence of fear memory in PTSD where fear memory extinction is impaired. Copyright © 2018 Elsevier Ltd. All rights reserved.

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.

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…

Exposure to a fearful context during periods of memory plasticity impairs extinction via hyperactivation of frontal-amygdalar circuits

PubMed Central

Stafford, James M.; Maughan, DeeAnna K.; Ilioi, Elena C.; Lattal, K. Matthew

2013-01-01

An issue of increasing theoretical and translational importance is to understand the conditions under which learned fear can be suppressed, or even eliminated. Basic research has pointed to extinction, in which an organism is exposed to a fearful stimulus (such as a context) in the absence of an expected aversive outcome (such as a shock). This extinction process results in the suppression of fear responses, but is generally thought to leave the original fearful memory intact. Here, we investigate the effects of extinction during periods of memory lability on behavioral responses and on expression of the immediate–early gene c-Fos within fear conditioning and extinction circuits. Our results show that long-term extinction is impaired when it occurs during time periods during which the memory should be most vulnerable to disruption (soon after conditioning or retrieval). These behavioral effects are correlated with hyperactivation of medial prefrontal cortex and amygdala subregions associated with fear expression rather than fear extinction. These findings demonstrate that behavioral experiences during periods of heightened fear prevent extinction and prolong the conditioned fear response. PMID:23422280

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

ERIC Educational Resources Information Center

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

2004-01-01

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

Reciprocal Patterns of c-Fos Expression in the Medial Prefrontal Cortex and Amygdala after Extinction and Renewal of Conditioned Fear

ERIC Educational Resources Information Center

Knapska, Ewelina; Maren, Stephen

2009-01-01

After extinction of conditioned fear, memory for the conditioning and extinction experiences becomes context dependent. Fear is suppressed in the extinction context, but renews in other contexts. This study characterizes the neural circuitry underlying the context-dependent retrieval of extinguished fear memories using c-Fos immunohistochemistry.…

Relationships between pathologic subjective halitosis, olfactory reference syndrome, and social anxiety in young Japanese women.

PubMed

Tsuruta, Miho; Takahashi, Toru; Tokunaga, Miki; Iwasaki, Masanori; Kataoka, Shota; Kakuta, Satoko; Soh, Inho; Awano, Shuji; Hirata, Hiromi; Kagawa, Masaharu; Ansai, Toshihiro

2017-03-14

Pathologic subjective halitosis is known as a halitosis complaint without objective confirmation of halitosis by others or by halitometer measurements; it has been reported to be associated with social anxiety disorder. Olfactory reference syndrome is a preoccupation with the false belief that one emits a foul and offensive body odor. Generally, patients with olfactory reference syndrome are concerned with multiple body parts. However, the mouth is known to be the most common source of body odor for those with olfactory reference syndrome, which could imply that the two conditions share similar features. Therefore, we investigated potential causal relationships among pathologic subjective halitosis, olfactory reference syndrome, social anxiety, and preoccupations with body part odors. A total of 1360 female students (mean age 19.6 ± 1.1 years) answered a self-administered questionnaire regarding pathologic subjective halitosis, olfactory reference syndrome, social anxiety, and preoccupation with odors of body parts such as mouth, body, armpits, and feet. The scale for pathologic subjective halitosis followed that developed by Tsunoda et al.; participants were divided into three groups based on their scores (i.e., levels of pathologic subjective halitosis). A Bayesian network was used to analyze causal relationships between pathologic subjective halitosis, olfactory reference syndrome, social anxiety, and preoccupations with body part odors. We found statistically significant differences in the results for olfactory reference syndrome and social anxiety among the various levels of pathologic subjective halitosis (P < 0.001). Residual analyses indicated that students with severe levels of pathologic subjective halitosis showed greater preoccupations with mouth and body odors (P < 0.05). Bayesian network analysis showed that social anxiety directly influenced pathologic subjective halitosis and olfactory reference syndrome. Preoccupations with mouth and body odors also influenced pathologic subjective halitosis. Social anxiety may be a causal factor of pathologic subjective halitosis and olfactory reference syndrome.

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.

Drosophila Learn Opposing Components of a Compound Food Stimulus

PubMed Central

Das, Gaurav; Klappenbach, Martín; Vrontou, Eleftheria; Perisse, Emmanuel; Clark, Christopher M.; Burke, Christopher J.; Waddell, Scott

2014-01-01

Summary Dopaminergic neurons provide value signals in mammals and insects [1–3]. During Drosophila olfactory learning, distinct subsets of dopaminergic neurons appear to assign either positive or negative value to odor representations in mushroom body neurons [4–9]. However, it is not known how flies evaluate substances that have mixed valence. Here we show that flies form short-lived aversive olfactory memories when trained with odors and sugars that are contaminated with the common insect repellent DEET. This DEET-aversive learning required the MB-MP1 dopaminergic neurons that are also required for shock learning [7]. Moreover, differential conditioning with DEET versus shock suggests that formation of these distinct aversive olfactory memories relies on a common negatively reinforcing dopaminergic mechanism. Surprisingly, as time passed after training, the behavior of DEET-sugar-trained flies reversed from conditioned odor avoidance into odor approach. In addition, flies that were compromised for reward learning exhibited a more robust and longer-lived aversive-DEET memory. These data demonstrate that flies independently process the DEET and sugar components to form parallel aversive and appetitive olfactory memories, with distinct kinetics, that compete to guide learned behavior. PMID:25042590

Improving intranasal delivery of neurological nanomedicine to the olfactory region using magnetophoretic guidance of microsphere carriers

PubMed Central

Xi, Jinxiang; Zhang, Ze; Si, Xiuhua A

2015-01-01

Background Although direct nose-to-brain drug delivery has multiple advantages, its application is limited by the extremely low delivery efficiency (<1%) to the olfactory region where drugs can enter the brain. It is crucial to developing new methods that can deliver drug particles more effectively to the olfactory region. Materials and methods We introduced a delivery method that used magnetophoresis to improve olfactory delivery efficiency. The performance of the proposed method was assessed numerically in an image-based human nose model. Influences of the magnet layout, magnet strength, drug-release position, and particle diameter on the olfactory dosage were examined. Results and discussion Results showed that particle diameter was a critical factor in controlling the motion of nasally inhaled ferromagnetic drug particles. The optimal particle size was found to be approximately 15 μm for effective magnetophoretic guidance while avoiding loss of particles to the walls in the anterior nose. Olfactory delivery efficiency was shown to be sensitive to the position and strength of magnets and the release position of drug particles. The results of this study showed that clinically significant olfactory doses (up to 45%) were feasible using the optimal combination of magnet layout, selective drug release, and microsphere-carrier diameter. A 64-fold-higher delivery of dosage was predicted in the magnetized nose compared to the control case, which did not have a magnetic field. However, the sensitivity of olfactory dosage to operating conditions and the unstable nature of magnetophoresis make controlled guidance of nasally inhaled aerosols still highly challenging. PMID:25709443

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

PubMed

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

2012-03-01

Interoceptive fear conditioning is at the core of contemporary behavioral accounts of panic disorder. Yet, to date only one study has attempted to evaluate interoceptive fear conditioning in humans (see Acheson, Forsyth, Prenoveau, & Bouton, 2007). That study used brief (physiologically inert) and longer-duration (panicogenic) inhalations of 20% CO(2)-enriched air as an interoceptive conditioned (CS) and unconditioned (US) stimulus and evaluated fear learning in three conditions: CS only, CS-US paired, and CS-US unpaired. Results showed fear conditioning in the paired condition, and fearful responding and resistance to extinction in an unpaired condition. The authors speculated that such effects may be due to difficulty discriminating between the CS and the US. The aims of the present study are to (a) replicate and expand this line of work using an improved methodology, and (b) clarify the role of CS-US discrimination difficulties in either potentiating or depotentiating fear learning. Healthy participants (N=104) were randomly assigned to one of four conditions: (a) CS only, (b) contingent CS-US pairings, (c) unpaired CS and US presentations, or (d) an unpaired "discrimination" contingency, which included an exteroceptive discrimination cue concurrently with CS onset. Electrodermal and self-report ratings served as indices of conditioned responding. Consistent with expectation, the paired contingency and unpaired contingencies yielded elevated fearful responding to the CS alone. Moreover, adding a discrimination cue to the unpaired contingency effectively attenuated fearful responding. Overall, findings are consistent with modern learning theory accounts of panic and highlight the role of interoceptive conditioning and unpredictability in the etiology of panic disorder. Copyright © 2011. Published by Elsevier Ltd.

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

PubMed

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

2016-07-01

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

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

PubMed Central

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

2016-01-01

Alterations in learning processes and the neural circuitry that supports fear conditioning and extinction represent mechanisms through which trauma exposure might influence risk for psychopathology. Few studies examine how trauma or neural structure relates to fear conditioning in children. Children (n=94) aged 6–18 years, 40.4% (n=38) with exposure to maltreatment (physical abuse, sexual abuse, or domestic violence), completed a fear conditioning paradigm utilizing blue and yellow bells as conditioned stimuli (CS+/CS−) and an aversive alarm noise as the unconditioned stimulus. Skin conductance responses (SCR) and self-reported fear were acquired. Magnetic resonance imaging data were acquired from 60 children. Children without maltreatment exposure exhibited strong differential conditioning to the CS+ vs CS−, based on SCR and self-reported fear. In contrast, maltreated children exhibited blunted SCR to the CS+ and failed to exhibit differential SCR to the CS+ vs CS− during early conditioning. Amygdala and hippocampal volume were reduced among children with maltreatment exposure and were negatively associated with SCR to the CS+ during early conditioning in the total sample, although these associations were negative only among non-maltreated children and were positive among maltreated children. The association of maltreatment with externalizing psychopathology was mediated by this perturbed pattern of fear conditioning. Child maltreatment is associated with failure to discriminate between threat and safety cues during fear conditioning in children. Poor threat–safety discrimination might reflect either enhanced fear generalization or a deficit in associative learning, which may in turn represent a central mechanism underlying the development of maltreatment-related externalizing psychopathology in children. PMID:26677946

Adult Hippocampal Neurogenesis Modulates Fear Learning through Associative and Nonassociative Mechanisms

PubMed Central

Seo, Dong-oh; Carillo, Mary Ann; Chih-Hsiung Lim, Sean; Tanaka, Kenji F.

2015-01-01

Adult hippocampal neurogenesis is believed to support hippocampus-dependent learning and emotional regulation. These putative functions of adult neurogenesis have typically been studied in isolation, and little is known about how they interact to produce adaptive behavior. We used trace fear conditioning as a model system to elucidate mechanisms through which adult hippocampal neurogenesis modulates processing of aversive experience. To achieve a specific ablation of neurogenesis, we generated transgenic mice that express herpes simplex virus thymidine kinase specifically in neural progenitors and immature neurons. Intracerebroventricular injection of the prodrug ganciclovir caused a robust suppression of neurogenesis without suppressing gliogenesis. Neurogenesis ablation via this method or targeted x-irradiation caused an increase in context conditioning in trace but not delay fear conditioning. Data suggest that this phenotype represents opposing effects of neurogenesis ablation on associative and nonassociative components of fear learning. Arrest of neurogenesis sensitizes mice to nonassociative effects of fear conditioning, as evidenced by increased anxiety-like behavior in the open field after (but not in the absence of) fear conditioning. In addition, arrest of neurogenesis impairs associative trace conditioning, but this impairment can be masked by nonassociative fear. The results suggest that adult neurogenesis modulates emotional learning via two distinct but opposing mechanisms: it supports associative trace conditioning while also buffering against the generalized fear and anxiety caused by fear conditioning. SIGNIFICANCE STATEMENT The role of adult hippocampal neurogenesis in fear learning is controversial, with some studies suggesting neurogenesis is needed for aspects of fear learning and others suggesting it is dispensable. We generated transgenic mice in which neural progenitors can be selectively and inducibly ablated. Our data suggest that adult neurogenesis supports fear learning through two distinct mechanisms: it supports the ability to learn associations between traumatic events (unconditioned stimuli) and predictors (conditioned stimuli) while also buffering against nonassociative, anxiogenic effects of a traumatic experience. As a result, arrest of neurogenesis can enhance or impair learned fear depending on intensity of the traumatic experience and the extent to which it recruits associative versus nonassociative learning. PMID:26269640

Experience-dependent modification of a central amygdala fear circuit

PubMed Central

Li, Haohong; Penzo, Mario A.; Taniguchi, Hiroki; Kopec, Charles D.; Huang, Z. Josh; Li, Bo

2013-01-01

The amygdala is essential for fear learning and expression. The central amygdala (CeA), once viewed as a passive relay between the amygdala complex and downstream fear effectors, has emerged as an active participant in fear conditioning. However, how CeA contributes to the learning and expression of fear is unclear. Here we show in mice that fear conditioning induces robust plasticity of excitatory synapses onto inhibitory neurons in the lateral subdivision of CeA (CeL). This experience-dependent plasticity is cell-specific, bidirectional, and expressed presynaptically by inputs from the lateral amygdala. In particular, preventing synaptic potentiation onto somatostatin-positive neurons impairs fear memory formation. Furthermore, activation of these neurons is necessary for fear memory recall and sufficient to drive fear responses. Our findings support a model in which the fear conditioning-induced synaptic modifications in CeL favor the activation of somatostatin-positive neurons, which inhibit CeL output thereby disinhibiting the medial subdivision of CeA and releasing fear expression. PMID:23354330

Modeling startle eyeblink electromyogram to assess fear learning.

PubMed

Khemka, Saurabh; Tzovara, Athina; Gerster, Samuel; Quednow, Boris B; Bach, Dominik R

2017-02-01

Pavlovian fear conditioning is widely used as a laboratory model of associative learning in human and nonhuman species. In this model, an organism is trained to predict an aversive unconditioned stimulus from initially neutral events (conditioned stimuli, CS). In humans, fear memory is typically measured via conditioned autonomic responses or fear-potentiated startle. For the latter, various analysis approaches have been developed, but a systematic comparison of competing methodologies is lacking. Here, we investigate the suitability of a model-based approach to startle eyeblink analysis for assessment of fear memory, and compare this to extant analysis strategies. First, we build a psychophysiological model (PsPM) on a generic startle response. Then, we optimize and validate this PsPM on three independent fear-conditioning data sets. We demonstrate that our model can robustly distinguish aversive (CS+) from nonaversive stimuli (CS-, i.e., has high predictive validity). Importantly, our model-based approach captures fear-potentiated startle during fear retention as well as fear acquisition. Our results establish a PsPM-based approach to assessment of fear-potentiated startle, and qualify previous peak-scoring methods. Our proposed model represents a generic startle response and can potentially be used beyond fear conditioning, for example, to quantify affective startle modulation or prepulse inhibition of the acoustic startle response. © 2016 The Authors. Psychophysiology published by Wiley Periodicals, Inc. on behalf of Society for Psychophysiological Research.

Selective Control of Fear Expression by Optogenetic Manipulation of Infralimbic Cortex after Extinction

PubMed Central

Kim, Hyung-Su; Cho, Hye-Yeon; Augustine, George J; Han, Jin-Hee

2016-01-01

Evidence from rodent and human studies has identified the ventromedial prefrontal cortex, specifically the infralimbic cortex (IL), as a critical brain structure in the extinction of conditioned fear. However, how IL activity controls fear expression at the time of extinction memory retrieval is unclear and controversial. To address this issue, we used optogenetics to precisely manipulate the activity of genetically targeted cells and to examine the real-time contribution of IL activity to expression of auditory-conditioned fear extinction in mice. We found that inactivation of IL, but not prelimbic cortex, impaired extinction retrieval. Conversely, photostimulation of IL excitatory neurons robustly enhanced the inhibition of fear expression after extinction, but not before extinction. Moreover, this effect was specific to the conditioned stimulus (CS): IL activity had no effect on expression of fear in response to the conditioned context after auditory fear extinction. Thus, in contrast to the expectation from a generally held view, artificial activation of IL produced no significant effect on expression of non-extinguished conditioned fear. Therefore, our data provide compelling evidence that IL activity is critical for expression of fear extinction and establish a causal role for IL activity in controlling fear expression in a CS-specific manner after extinction. PMID:26354044

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

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

PubMed Central

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

2002-01-01

Ascending 5-HT projections from the median raphe nucleus (MRN), probably to the hippocampus, are implicated in the acquisition of contextual fear (background stimuli), as assessed by freezing behavior. Foreground cues like light, used as a conditioned stimulus (CS) in classical fear conditioning, also cause freezing through thalamic transmission to the amygdala. As the MRN projects to the hippocampus and amygdala, the role of this raphe nucleus in fear conditioning to explicit cues remains to be explained. Here we analyzed the behavior of rats with MRN electrolytic lesions in a contextual conditioning situation and in a fear-potentiated startle procedure. The animals received MRN electrolytic lesions either before or on the day after two consecutive training sessions in which they were submitted to 10 conditioning trials, each in an experimental chamber (same context) where they. received foot-shocks (0.6 mA, 1 sec) paired to a 4-sec light CS. Seven to ten days later, the animals were submitted to testing sessions for assessing conditioned fear when they were placed for five shocks, and the duration of contextual freezing was recorded. The animals were then submitted to a fear-potentiated startle in response to a 4-sec light-CS, followed by white noise (100 dB, 50 ms). Control rats (sham) tested in the same context showed more freezing than did rats with pre- or post-training MRN lesions. Startle was clearly potentiated in the presence of light CS in the sham-lesioned animals. Whereas pretraining lesions reduced both freezing and fear-potentiated startle, the post-training lesions reduced only freezing to context, without changing the fear-potentiated startle. In a second experiment, neurotoxic lesions of the MRN with local injections of N-methyl-D-aspartate or the activation of 5-HT1A somatodendritic auto-receptors of the MRN by microinjections of the 5-HT1A receptor agonist 8-hydroxy- 2-(di-n-propylamino)tetralin (8-OH-DPAT) before the training sessions also reduced the amount of freezing and the fear-potentiated startle. Freezing is a prominent response of contextual fear conditioning, but does not seem to be crucial for the enhancement of the startle reflex by explicit aversive cues. As fear-potentiated startle may be produced in posttraining lesioned rats that are unable to freeze to fear contextual stimuli, dissociable systems seem to be recruited in each condition. Thus, contextual fear and fear-potentiated startle are conveyed by distinct 5-HT-mediated circuits of the MRN. PMID:12959153

Temporal factors in the extinction of fear in inbred mouse strains differing in extinction efficacy.

PubMed

MacPherson, Kathryn; Whittle, Nigel; Camp, Marguerite; Gunduz-Cinar, Ozge; Singewald, Nicolas; Holmes, Andrew

2013-07-05

Various neuropsychiatric conditions, including posttraumatic stress disorder (PTSD), are characterized by deficient fear extinction, but individuals differ greatly in risk for these. While there is growing evidence that fear extinction is influenced by certain procedural variables, it is unclear how these influences might vary across individuals and subpopulations. To model individual differences in fear extinction, prior studies identified a strain of inbred mouse, 129S1/SvImJ (S1), which exhibits a profound deficit in fear extinction, as compared to other inbred strains, such as C57BL/6J (B6). Here, we assessed the effects of procedural variables on the impaired extinction phenotype of the S1 strain and, by comparison, the extinction-intact B6 strain. The variables studied were 1) the interval between conditioning and extinction, 2) the interval between cues during extinction training, 3) single-cue exposure before extinction training, and 4) extinction of a second-order conditioned cue. Conducting extinction training soon after ('immediately') conditioning attenuated fear retrieval in S1 mice and impaired extinction in B6 mice. Spacing cue presentations with long inter-trial intervals during extinction training augmented fear in S1 and B6 mice. The effect of spacing was lost with one-trial fear conditioning in B6, but not S1 mice. A single exposure to a conditioned cue before extinction training did not alter extinction retrieval, either in B6 or S1 mice. Both the S1 and B6 strains exhibited robust second-order fear conditioning, in which a cue associated with footshock was sufficient to serve as a conditioned exciter to condition a fear association to a second cue. B6 mice extinguished the fear response to the second-order conditioned cue, but S1 mice failed to do so. These data provide further evidence that fear extinction is strongly influenced by multiple procedural variables and is so in a highly strain-dependent manner. This suggests that the efficacy of extinction-based behavioral interventions, such as exposure therapy, for trauma-related anxiety disorders will be determined by the procedural parameters employed and the degree to which the patient can extinguish.

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…

Systemic or Intra-Amygdala Injection of a Benzodiazepine (Midazolam) Impairs Extinction but Spares Re-Extinction of Conditioned Fear Responses

ERIC Educational Resources Information Center

Hart, Genevra; Harris, Justin A.; Westbrook, R. Frederick

2009-01-01

Rats were subjected to one or two cycles of fear conditioning and extinction, injected with a benzodiazepine, midazolam, before the first or second extinction, and tested for long-term inhibition of fear responses (freezing). In Experiment 1, inhibition of context-conditioned fear was spared when midazolam was injected before the second…

Sound tuning of amygdala plasticity in auditory fear conditioning

PubMed Central

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

2016-01-01

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

Fear Conditioning Increases NREM Sleep

PubMed Central

Hellman, Kevin; Abel, Ted

2010-01-01

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

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

Origins of common fears in South African children.

PubMed

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

2008-12-01

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

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

PubMed

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

2009-07-01

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

Muscarinic ACh Receptors Contribute to Aversive Olfactory Learning in Drosophila

PubMed Central

Silva, Bryon; Molina-Fernández, Claudia; Ugalde, María Beatriz; Tognarelli, Eduardo I.; Angel, Cristian; Campusano, Jorge M.

2015-01-01

The most studied form of associative learning in Drosophila consists in pairing an odorant, the conditioned stimulus (CS), with an unconditioned stimulus (US). The timely arrival of the CS and US information to a specific Drosophila brain association region, the mushroom bodies (MB), can induce new olfactory memories. Thus, the MB is considered a coincidence detector. It has been shown that olfactory information is conveyed to the MB through cholinergic inputs that activate acetylcholine (ACh) receptors, while the US is encoded by biogenic amine (BA) systems. In recent years, we have advanced our understanding on the specific neural BA pathways and receptors involved in olfactory learning and memory. However, little information exists on the contribution of cholinergic receptors to this process. Here we evaluate for the first time the proposition that, as in mammals, muscarinic ACh receptors (mAChRs) contribute to memory formation in Drosophila. Our results show that pharmacological and genetic blockade of mAChRs in MB disrupts olfactory aversive memory in larvae. This effect is not explained by an alteration in the ability of animals to respond to odorants or to execute motor programs. These results show that mAChRs in MB contribute to generating olfactory memories in Drosophila. PMID:26380118

Sad man's nose: Emotion induction and olfactory perception.

PubMed

Flohr, Elena L R; Erwin, Elena; Croy, Ilona; Hummel, Thomas

2017-03-01

Emotional and olfactory processing is frequently shown to be closely linked both anatomically and functionally. Depression, a disease closely related to the emotional state of sadness, has been shown to be associated with a decrease in olfactory sensitivity. The present study focuses on the state of sadness in n = 31 healthy subjects in order to investigate the specific contribution of this affective state in the modulation of olfactory processing. A sad or indifferent affective state was induced using 2 movies that were presented on 2 separate days. Afterward, chemosensory-evoked potentials were recorded after stimulation with an unpleasant (hydrogen sulfide: "rotten eggs") or a pleasant (phenyl ethyl alcohol: "rose") odorant. Latencies of N1 and P2 peaks were longer after induction of the sad affective state. Additionally, amplitudes were lower in a sad affective state when being stimulated with the unpleasant odorant. Processing of olfactory input has thus been reduced under conditions of the sad affective state. We argue that the affective state per se could at least partially account for the reduced olfactory sensitivity in depressed patients. To our knowledge, the present study is the first to show influence of affective state on chemosensory event-related potentials. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

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.

Reciprocal synapses between mushroom body and dopamine neurons form a positive feedback loop required for learning.

PubMed

Cervantes-Sandoval, Isaac; Phan, Anna; Chakraborty, Molee; Davis, Ronald L

2017-05-10

Current thought envisions dopamine neurons conveying the reinforcing effect of the unconditioned stimulus during associative learning to the axons of Drosophila mushroom body Kenyon cells for normal olfactory learning. Here, we show using functional GFP reconstitution experiments that Kenyon cells and dopamine neurons from axoaxonic reciprocal synapses. The dopamine neurons receive cholinergic input via nicotinic acetylcholine receptors from the Kenyon cells; knocking down these receptors impairs olfactory learning revealing the importance of these receptors at the synapse. Blocking the synaptic output of Kenyon cells during olfactory conditioning reduces presynaptic calcium transients in dopamine neurons, a finding consistent with reciprocal communication. Moreover, silencing Kenyon cells decreases the normal chronic activity of the dopamine neurons. Our results reveal a new and critical role for positive feedback onto dopamine neurons through reciprocal connections with Kenyon cells for normal olfactory learning.

Olfactory source localization in the open field using one or both nostrils.

PubMed

Welge-Lussen, A; Looser, G L; Westermann, B; Hummel, T

2014-03-01

This study aims to examine humans ́ abilities to localize odorants within the open field. Young participants were tested on a localization task using a relatively selective olfactory stimulus (2-phenylethyl-alcohol, PEA) and cineol, an odorant with a strong trigeminal component. Participants were blindfolded and had to localize an odorant source at 2 m distance (far-field condition) and a 0.4 m distance (near-field condition) with either two nostrils open or only one open nostril. For the odorant with trigeminal properties, the number of correct trials did not differ when one or both nostrils were used, while more PEA localization trials were correctly completed with both rather than one nostril. In the near-field condition, correct localization was possible in 72-80% of the trials, irrespective of the odorant and the number of nostrils used. Localization accuracy, measured as spatial deviation from the olfactory source, was significantly higher in the near-field compared to the far-field condition, but independent of the odorant being localized. Odorant localization within the open field is difficult, but possible. In contrast to the general view, humans seem to be able to exploit the two-nostril advantage with increasing task difficulty.

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

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

PubMed Central

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

2015-01-01

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

The relative effectiveness of extinction and counter-conditioning in diminishing children's fear.

PubMed

Newall, Carol; Watson, Tiffany; Grant, Kerry-Ann; Richardson, Rick

2017-08-01

Two behavioural strategies for reducing learned fear are extinction and counter-conditioning, and in this study we compared the relative effectiveness of the two procedures at diminishing fear in children. Seventy-three children aged 7-12 years old (M = 9.30, SD = 1.62) were exposed to pictures of two novel animals on a computer screen during the fear acquisition phase. One of these animals was paired with a picture of a scared human face (CS+) while the other was not (CS-). The children were then randomly assigned to one of three conditions: counter-conditioning (animal paired with a happy face), extinction (animal without scared face), or control (no fear reduction procedure). Changes in fear beliefs and behavioural avoidance of the animal were measured. Counter-conditioning was more effective at reducing fear to the CS + than extinction. The findings are discussed in terms of implications for behavioural treatments of childhood anxiety disorders. Crown Copyright © 2017. Published by Elsevier Ltd. All rights reserved.

Contextual fear conditioning depresses infralimbic excitability.

PubMed

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

2016-04-01

Patients with posttraumatic stress disorder (PTSD) show hypo-active ventromedial prefrontal cortices (vmPFC) that correlate with their impaired ability to discriminate between safe and dangerous contexts and cues. Previously, we found that auditory fear conditioning depresses the excitability of neurons populating the homologous structure in rodents, the infralimbic cortex (IL). However, it is undetermined if IL depression was mediated by the cued or contextual information. The objective of this study was to examine whether contextual information was sufficient to depress IL neuronal excitability. After exposing rats to context-alone, pseudoconditioning, or contextual fear conditioning, we used whole-cell current-clamp recordings to examine the excitability of IL neurons in prefrontal brain slices. We found that contextual fear conditioning reduced IL neuronal firing in response to depolarizing current steps. In addition, neurons from contextual fear conditioned animals showed increased slow afterhyperpolarization potentials (sAHPs). Moreover, the observed changes in IL excitability correlated with contextual fear expression, suggesting that IL depression may contribute to the encoding of contextual fear. Copyright © 2016 Elsevier Inc. All rights reserved.

Predator Cat Odors Activate Sexual Arousal Pathways in Brains of Toxoplasma gondii Infected Rats

PubMed Central

House, Patrick K.; Vyas, Ajai; Sapolsky, Robert

2011-01-01

Cat odors induce rapid, innate and stereotyped defensive behaviors in rats at first exposure, a presumed response to the evolutionary pressures of predation. Bizarrely, rats infected with the brain parasite Toxoplasma gondii approach the cat odors they typically avoid. Since the protozoan Toxoplasma requires the cat to sexually reproduce, this change in host behavior is thought to be a remarkable example of a parasite manipulating a mammalian host for its own benefit. Toxoplasma does not influence host response to non-feline predator odor nor does it alter behavior on olfactory, social, fear or anxiety tests, arguing for specific manipulation in the processing of cat odor. We report that Toxoplasma infection alters neural activity in limbic brain areas necessary for innate defensive behavior in response to cat odor. Moreover, Toxoplasma increases activity in nearby limbic regions of sexual attraction when the rat is exposed to cat urine, compelling evidence that Toxoplasma overwhelms the innate fear response by causing, in its stead, a type of sexual attraction to the normally aversive cat odor. PMID:21858053

Predator cat odors activate sexual arousal pathways in brains of Toxoplasma gondii infected rats.

PubMed

House, Patrick K; Vyas, Ajai; Sapolsky, Robert

2011-01-01

Cat odors induce rapid, innate and stereotyped defensive behaviors in rats at first exposure, a presumed response to the evolutionary pressures of predation. Bizarrely, rats infected with the brain parasite Toxoplasma gondii approach the cat odors they typically avoid. Since the protozoan Toxoplasma requires the cat to sexually reproduce, this change in host behavior is thought to be a remarkable example of a parasite manipulating a mammalian host for its own benefit. Toxoplasma does not influence host response to non-feline predator odor nor does it alter behavior on olfactory, social, fear or anxiety tests, arguing for specific manipulation in the processing of cat odor. We report that Toxoplasma infection alters neural activity in limbic brain areas necessary for innate defensive behavior in response to cat odor. Moreover, Toxoplasma increases activity in nearby limbic regions of sexual attraction when the rat is exposed to cat urine, compelling evidence that Toxoplasma overwhelms the innate fear response by causing, in its stead, a type of sexual attraction to the normally aversive cat odor.

Systemic propranolol acts centrally to reduce conditioned fear in rats without impairing extinction.

PubMed

Rodriguez-Romaguera, Jose; Sotres-Bayon, Francisco; Mueller, Devin; Quirk, Gregory J

2009-05-15

Previous work has implicated noradrenergic beta-receptors in the consolidation and reconsolidation of conditioned fear. Less is known, however, about their role in fear expression and extinction. The beta-receptor blocker propranolol has been used clinically to reduce anxiety. With an auditory fear conditioning task in rats, we assessed the effects of systemic propranolol on the expression and extinction of two measures of conditioned fear: freezing and suppression of bar-pressing. One day after receiving auditory fear conditioning, rats were injected with saline, propranolol, or peripheral beta-receptor blocker sotalol (both 10 mg/kg, IP). Twenty minutes after injection, rats were given either 6 or 12 extinction trials and were tested for extinction retention the following day. The effect of propranolol on the firing rate of neurons in prelimbic (PL) prefrontal cortex was also assessed. Propranolol reduced freezing by more than 50%, an effect that was evident from the first extinction trial. Suppression was also significantly reduced. Despite this, propranolol had no effect on the acquisition or retention of extinction. Unlike propranolol, sotalol did not affect fear expression, although both drugs significantly reduced heart rate. This suggests that propranolol acts centrally to reduce fear. Consistent with this, propranolol reduced the firing rate of PL neurons. Propranolol reduced the expression of conditioned fear, without interfering with extinction learning. Reduced fear with intact extinction suggests a possible use for propranolol in reducing anxiety during extinction-based exposure therapies, without interfering with long-term clinical response.

Contextual fear conditioning in zebrafish.

PubMed

Kenney, Justin W; Scott, Ian C; Josselyn, Sheena A; Frankland, Paul W

2017-10-01

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 of a contextual fear conditioning paradigm using an electric shock as the aversive stimulus. We find that contextual fear conditioning is modulated by shock intensity, prevented by an established amnestic agent (MK-801), lasts at least 14 d, and exhibits extinction. Furthermore, fish of various background strains (AB, Tu, and TL) are able to acquire fear conditioning, but differ in fear extinction rates. Taken together, we find that contextual fear conditioning in zebrafish shares many similarities with the widely used contextual fear conditioning paradigm in rodents. Combined with the amenability of genetic manipulation in zebrafish, we anticipate that our paradigm will prove to be a useful complementary system in which to examine the molecular basis of vertebrate learning and memory. © 2017 Kenney et al.; Published by Cold Spring Harbor Laboratory Press.

A Neutral Odor May Become a Sexual Incentive through Classical Conditioning in Male Rats

ERIC Educational Resources Information Center

Kvitvik, Inger-Line; Berg, Kristine Marit; Agmo, Anders

2010-01-01

A neutral olfactory stimulus was employed as CS in a series of experiments with a sexually receptive female as UCS and the execution of an intromission as the UCR. Each experimental session lasted until the male ejaculated. The time the experimental subject spent in a zone adjacent to the source of the olfactory stimulus during the 10 s of CS…

Right Occipital Cortex Activation Correlates with Superior Odor Processing Performance in the Early Blind

PubMed Central

Grandin, Cécile B.; Dricot, Laurence; Plaza, Paula; Lerens, Elodie; Rombaux, Philippe; De Volder, Anne G.

2013-01-01

Using functional magnetic resonance imaging (fMRI) in ten early blind humans, we found robust occipital activation during two odor-processing tasks (discrimination or categorization of fruit and flower odors), as well as during control auditory-verbal conditions (discrimination or categorization of fruit and flower names). We also found evidence for reorganization and specialization of the ventral part of the occipital cortex, with dissociation according to stimulus modality: the right fusiform gyrus was most activated during olfactory conditions while part of the left ventral lateral occipital complex showed a preference for auditory-verbal processing. Only little occipital activation was found in sighted subjects, but the same right-olfactory/left-auditory-verbal hemispheric lateralization was found overall in their brain. This difference between the groups was mirrored by superior performance of the blind in various odor-processing tasks. Moreover, the level of right fusiform gyrus activation during the olfactory conditions was highly correlated with individual scores in a variety of odor recognition tests, indicating that the additional occipital activation may play a functional role in odor processing. PMID:23967263

Extinction after fear memory reactivation fails to eliminate renewal in rats.

PubMed

Goode, Travis D; Holloway-Erickson, Crystal M; Maren, Stephen

2017-07-01

Retrieving fear memories just prior to extinction has been reported to effectively erase fear memories and prevent fear relapse. The current study examined whether the type of retrieval procedure influences the ability of extinction to impair fear renewal, a form of relapse in which responding to a conditional stimulus (CS) returns outside of the extinction context. Rats first underwent Pavlovian fear conditioning with an auditory CS and footshock unconditional stimulus (US); freezing behavior served as the index of conditioned fear. Twenty-four hours later, the rats underwent a retrieval-extinction procedure. Specifically, 1h prior to extinction (45 CS-alone trials; 44 for rats receiving a CS reminder), fear memory was retrieved by either a single exposure to the CS alone, the US alone, a CS paired with the US, or exposure to the conditioning context itself. Over the next few days, conditional freezing to the extinguished CS was tested in the extinction and conditioning context in that order (i.e., an ABBA design). In the extinction context, rats that received a CS+US trial before extinction exhibited higher levels of conditional freezing than animals in all other groups, which did not differ from one another. In the renewal context, all groups showed renewal, and none of the reactivation procedures reduced renewal relative to a control group that did not receive a reactivation procedure prior to extinction. These data suggest retrieval-extinction procedures may have limited efficacy in preventing fear renewal. Copyright © 2017 Elsevier Inc. All rights reserved.

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

Disrupting reconsolidation of fear memory in humans by a noradrenergic β-blocker.

PubMed

Kindt, Merel; Soeter, Marieke; Sevenster, Dieuwke

2014-12-18

The basic design used in our human fear-conditioning studies on disrupting reconsolidation includes testing over different phases across three consecutive days. On day 1 - the fear acquisition phase, healthy participants are exposed to a series of picture presentations. One picture stimulus (CS1+) is repeatedly paired with an aversive electric stimulus (US), resulting in the acquisition of a fear association, whereas another picture stimulus (CS2-) is never followed by an US. On day 2 - the memory reactivation phase, the participants are re-exposed to the conditioned stimulus without the US (CS1-), which typically triggers a conditioned fear response. After the memory reactivation we administer an oral dose of 40 mg of propranolol HCl, a β-adrenergic receptor antagonist that indirectly targets the protein synthesis required for reconsolidation by inhibiting the noradrenaline-stimulated CREB phosphorylation. On day 3 - the test phase, the participants are again exposed to the unreinforced conditioned stimuli (CS1- and CS2-) in order to measure the fear-reducing effect of the manipulation. This retention test is followed by an extinction procedure and the presentation of situational triggers to test for the return of fear. Potentiation of the eye blink startle reflex is measured as an index for conditioned fear responding. Declarative knowledge of the fear association is measured through online US expectancy ratings during each CS presentation. In contrast to extinction learning, disrupting reconsolidation targets the original fear memory thereby preventing the return of fear. Although the clinical applications are still in their infancy, disrupting reconsolidation of fear memory seems to be a promising new technique with the prospect to persistently dampen the expression of fear memory in patients suffering from anxiety disorders and other psychiatric disorders.

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.

An appetitive conditioned stimulus enhances fear acquisition and impairs fear extinction

PubMed Central

Leung, Hiu T.; Holmes, Nathan M.

2016-01-01

Four experiments used between- and within-subject designs to examine appetitive–aversive interactions in rats. Experiments 1 and 2 examined the effect of an excitatory appetitive conditioned stimulus (CS) on acquisition and extinction of conditioned fear. In Experiment 1, a CS shocked in a compound with an appetitive excitor (i.e., a stimulus previously paired with sucrose) underwent greater fear conditioning than a CS shocked in a compound with a neutral stimulus. Conversely, in Experiment 2, a CS extinguished in a compound with an appetitive excitor underwent less extinction than a CS extinguished in a compound with a neutral stimulus. Experiments 3 and 4 compared the amount of fear conditioning to an appetitive excitor and a familiar but neutral target CS when the compound of these stimuli was paired with shock. In each experiment, more fear accrued to the appetitive excitor than to the neutral CS. These results show that an appetitive excitor influences acquisition and extinction of conditioned fear to a neutral CS and itself undergoes a greater associative change than the neutral CS across compound conditioning. They are discussed with respect to the role of motivational information in regulating an associative change in appetitive–aversive interactions. PMID:26884229

Fear conditioning and extinction across development: Evidence from human studies and animal models☆

PubMed Central

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

2015-01-01

The ability to differentiate danger and safety through associative processes emerges early in life. Understanding the mechanisms underlying associative learning of threat and safety can clarify the processes that shape development of normative fears and pathological anxiety. Considerable research has used fear conditioning and extinction paradigms to delineate underlying mechanisms in animals and human adults; however, little is known about these mechanisms in children and adolescents. The current paper summarizes the empirical data on the development of fear conditioning and extinction. It reviews methodological considerations and future directions for research on fear conditioning and extinction in pediatric populations. PMID:24746848

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.

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.

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

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.

Predicting fear of heights, snakes, and public speaking from multimodal classical conditioning events.

PubMed

Wu, Ning Ying; Conger, Anthony J; Dygdon, Judith A

2006-04-01

Two hundred fifty one men and women participated in a study of the prediction of fear of heights, snakes, and public speaking by providing retrospective accounts of multimodal classical conditioning events involving those stimuli. The fears selected for study represent those believed by some to be innate (i.e., heights), prepared (i.e., snakes), and purely experientially learned (i.e., public speaking). This study evaluated the extent to which classical conditioning experiences in direct, observational, and verbal modes contributed to the prediction of the current level of fear severity. Subjects were asked to describe their current level of fear and to estimate their experience with fear response-augmenting events (first- and higher-order aversive pairings) and fear response-moderating events (first- and higher-order appetitive pairings, and pre- and post-conditioning neutral presentations) in direct, observational, and verbal modes. For each stimulus, fear was predictable from direct response-augmenting events and prediction was enhanced by the inclusion of response-moderating events. Furthermore, for each fear, maximum prediction was attained by the addition of variables tapping experiences in the observational and/or verbal modes. Conclusions are offered regarding the importance of including response-augmenting and response-moderating events in all three modes in both research and clinical applications of classical conditioning.

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…

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

ERIC Educational Resources Information Center

Bradfield, Laura A.; McNally, Gavan P.

2010-01-01

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

Neurotoxic lesions of the dorsal and ventral hippocampus impair acquisition and expression of trace-conditioned fear-potentiated startle in rats.

PubMed

Trivedi, Mehul A; Coover, Gary D

2006-04-03

Pavlovian delay conditioning, in which a conditioned stimulus (CS) and unconditioned stimulus (US) co-terminate, is thought to reflect non-declarative memory. In contrast, trace conditioning, in which the CS and US are temporally separate, is thought to reflect declarative memory. Hippocampal lesions impair acquisition and expression of trace conditioning measured by the conditioned freezing and eyeblink responses, while having little effect on the acquisition of delay conditioning. Recent evidence suggests that lesions of the ventral hippocampus (VH) impair conditioned fear under conditions in which dorsal hippocampal (DH) lesions have little effect. In the present study, we examined the time-course of fear expression after delay and trace conditioning using the fear-potentiated startle (FPS) reflex, and the effects of pre- and post-training lesions to the VH and DH on trace-conditioned FPS. We found that both delay- and trace-conditioned rats displayed significant FPS near the end of the CS relative to the unpaired control group. In contrast, trace-conditioned rats displayed significant FPS throughout the duration of the trace interval, whereas FPS decayed rapidly to baseline after CS offset in delay-conditioned rats. In experiment 2, both DH and VH lesions were found to significantly reduce the overall magnitude of FPS compared to the control group, however, no differences were found between the DH and VH groups. These findings support a role for both the DH and VH in trace fear conditioning, and suggest that the greater effect of VH lesions on conditioned fear might be specific to certain measures of fear.

Young and old Pavlovian fear memories can be modified with extinction training during reconsolidation in humans

PubMed Central

Steinfurth, Elisa C.K.; Kanen, Jonathan W.; Raio, Candace M.; Clem, Roger L.; Huganir, Richard L.; Phelps, Elizabeth A.

2014-01-01

Extinction training during reconsolidation has been shown to persistently diminish conditioned fear responses across species. We investigated in humans if older fear memories can benefit similarly. Using a Pavlovian fear conditioning paradigm we compared standard extinction and extinction after memory reactivation 1 d or 7 d following acquisition. Participants who underwent extinction during reconsolidation showed no evidence of fear recovery, whereas fear responses returned in participants who underwent standard extinction. We observed this effect in young and old fear memories. Extending the beneficial use of reconsolidation to older fear memories in humans is promising for therapeutic applications. PMID:24934333

Parallel Olfactory Processing in the Honey Bee Brain: Odor Learning and Generalization under Selective Lesion of a Projection Neuron Tract

PubMed Central

Carcaud, Julie; Giurfa, Martin; Sandoz, Jean Christophe

2016-01-01

The function of parallel neural processing is a fundamental problem in Neuroscience, as it is found across sensory modalities and evolutionary lineages, from insects to humans. Recently, parallel processing has attracted increased attention in the olfactory domain, with the demonstration in both insects and mammals that different populations of second-order neurons encode and/or process odorant information differently. Among insects, Hymenoptera present a striking olfactory system with a clear neural dichotomy from the periphery to higher-order centers, based on two main tracts of second-order (projection) neurons: the medial and lateral antennal lobe tracts (m-ALT and l-ALT). To unravel the functional role of these two pathways, we combined specific lesions of the m-ALT tract with behavioral experiments, using the classical conditioning of the proboscis extension response (PER conditioning). Lesioned and intact bees had to learn to associate an odorant (1-nonanol) with sucrose. Then the bees were subjected to a generalization procedure with a range of odorants differing in terms of their carbon chain length or functional group. We show that m-ALT lesion strongly affects acquisition of an odor-sucrose association. However, lesioned bees that still learned the association showed a normal gradient of decreasing generalization responses to increasingly dissimilar odorants. Generalization responses could be predicted to some extent by in vivo calcium imaging recordings of l-ALT neurons. The m-ALT pathway therefore seems necessary for normal classical olfactory conditioning performance. PMID:26834589

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

PubMed

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

2017-06-01

The so-called 'replicability crisis' has sparked methodological discussions in many areas of science in general, and in psychology in particular. This has led to recent endeavours to promote the transparency, rigour, and ultimately, replicability of research. Originating from this zeitgeist, the challenge to discuss critical issues on terminology, design, methods, and analysis considerations in fear conditioning research is taken up by this work, which involved representatives from fourteen of the major human fear conditioning laboratories in Europe. This compendium is intended to provide a basis for the development of a common procedural and terminology framework for the field of human fear conditioning. Whenever possible, we give general recommendations. When this is not feasible, we provide evidence-based guidance for methodological decisions on study design, outcome measures, and analyses. Importantly, this work is also intended to raise awareness and initiate discussions on crucial questions with respect to data collection, processing, statistical analyses, the impact of subtle procedural changes, and data reporting specifically tailored to the research on fear conditioning. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

Differential effects of unilateral olfactory deprivation on noradrenergic and cholinergic systems in the main olfactory bulb of the rat.

PubMed

Gómez, C; Briñón, J G; Colado, M I; Orio, L; Vidal, M; Barbado, M V; Alonso, J R

2006-09-15

The lack of environmental olfactory stimulation produced by sensory deprivation causes significant changes in the deprived olfactory bulb. Olfactory transmission in the main olfactory bulb (MOB) is strongly modulated by centrifugal systems. The present report examines the effects of unilateral deprivation on the noradrenergic and cholinergic centrifugal systems innervating the MOB. The morphology, distribution, and density of positive axons were studied in the MOBs of control and deprived rats, using dopamine-beta-hydroxylase (DBH)-immunohistochemistry and acetylcholinesterase (AChE) histochemistry in serial sections. Catecholamine content was compared among the different groups of MOBs (control, contralateral, and ipsilateral to the deprivation) using high-performance liquid chromatography analysis. Sensory deprivation revealed that the noradrenergic system developed adaptive plastic changes after olfactory deprivation, including important modifications in its fiber density and distribution, while no differences in cholinergic innervation were observed under the same conditions. The noradrenergic system underwent an important alteration in the glomerular layer, in which some glomeruli showed a dense noradrenergic innervation that was not detected in control animals. The DBH-positive glomeruli with the highest noradrenergic fiber density were compared with AChE-stained sections and it was observed that the strongly noradrenergic-innervated glomeruli were always atypical glomeruli (characterized by their strong degree of cholinergic innervation). In addition to the morphological findings, our biochemical data revealed that olfactory deprivation caused a decrease in the content of dopamine and its metabolite 3,4-dihydroxyphenylacetic acid in the ipsilateral MOB in comparison to the contralateral and control MOBs, together with an increase in noradrenaline levels in both the ipsilateral and contralateral MOBs. Our results show that regulation of the noradrenergic centrifugal system in the MOB depends on environmental olfactory stimulation and that it is highly reactive to sensory deprivation. By contrast, the cholinergic system is fairly stable and does not exhibit clear changes after the loss of sensory inputs.

Temporal factors in the extinction of fear in inbred mouse strains differing in extinction efficacy

PubMed Central

2013-01-01

Background Various neuropsychiatric conditions, including posttraumatic stress disorder (PTSD), are characterized by deficient fear extinction, but individuals differ greatly in risk for these. While there is growing evidence that fear extinction is influenced by certain procedural variables, it is unclear how these influences might vary across individuals and subpopulations. To model individual differences in fear extinction, prior studies identified a strain of inbred mouse, 129S1/SvImJ (S1), which exhibits a profound deficit in fear extinction, as compared to other inbred strains, such as C57BL/6J (B6). Methods Here, we assessed the effects of procedural variables on the impaired extinction phenotype of the S1 strain and, by comparison, the extinction-intact B6 strain. The variables studied were 1) the interval between conditioning and extinction, 2) the interval between cues during extinction training, 3) single-cue exposure before extinction training, and 4) extinction of a second-order conditioned cue. Results Conducting extinction training soon after (‘immediately’) conditioning attenuated fear retrieval in S1 mice and impaired extinction in B6 mice. Spacing cue presentations with long inter-trial intervals during extinction training augmented fear in S1 and B6 mice. The effect of spacing was lost with one-trial fear conditioning in B6, but not S1 mice. A single exposure to a conditioned cue before extinction training did not alter extinction retrieval, either in B6 or S1 mice. Both the S1 and B6 strains exhibited robust second-order fear conditioning, in which a cue associated with footshock was sufficient to serve as a conditioned exciter to condition a fear association to a second cue. B6 mice extinguished the fear response to the second-order conditioned cue, but S1 mice failed to do so. Conclusions These data provide further evidence that fear extinction is strongly influenced by multiple procedural variables and is so in a highly strain-dependent manner. This suggests that the efficacy of extinction-based behavioral interventions, such as exposure therapy, for trauma-related anxiety disorders will be determined by the procedural parameters employed and the degree to which the patient can extinguish. PMID:23830244

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

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.

The effect of verbal context on olfactory neural responses.

PubMed

Bensafi, Moustafa; Croy, Ilona; Phillips, Nicola; Rouby, Catherine; Sezille, Caroline; Gerber, Johannes; Small, Dana M; Hummel, Thomas

2014-03-01

Odor names refer usually to "source" object categories. For example, the smell of rose is often described with its source category (flower). However, linguistic studies suggest that odors can also be named with labels referring to categories of "practices". This is the case when rose odor is described with a verbal label referring to its use in fragrance practices ("body lotion," cosmetic for example). It remains unknown whether naming an odor by its practice category influences olfactory neural responses differently than that observed when named with its source category. The aim of this study was to investigate this question. To this end, functional MRI was used in a within-subjects design comparing brain responses to four different odors (peach, chocolate, linden blossom, and rose) under two conditions whereby smells were described either (1) with their source category label (food and flower) or (2) with a practice category label (body lotion). Both types of labels induced activations in secondary olfactory areas (orbitofrontal cortex), whereas only the source label condition induced activation in the cingulate cortex and the insula. In summary, our findings offer a new look at olfactory perception by indicating differential brain responses depending on whether odors are named according to their source or practice category. Copyright © 2012 Wiley Periodicals, Inc.

A role of nucleus accumbens dopamine receptors in the nucleus accumbens core, but not shell, in fear prediction error.

PubMed

Li, Susan S Y; McNally, Gavan P

2015-08-01

Two experiments used an associative blocking design to study the role of dopamine receptors in the nucleus accumbens shell (AcbSh) and core (AcbC) in fear prediction error. Rats in the experimental groups were trained to a visual fear-conditioned stimulus (conditional stimulus [CS]) A in Stage I, whereas rats in the control groups were not. In Stage II, all rats received compound fear conditioning of the visual CSA and an auditory CSB. Rats were later tested for their fear responses to CSB. All rats received microinjections of saline or the D1-D2 receptor antagonist cis-(z)-flupenthixol prior to Stage II. These microinjections targeted either the AcbSh (Experiment 1) or the AcbC (Experiment 2). In each experiment, Stage I fear conditioning of CSA blocked fear learning to CSB. Microinjection of cis-(z)-flupenthixol (10 or 20 μg) into the AcbSh (Experiment 1) had no effect on fear learning or associative blocking. In contrast, microinjection of cis-(z)-flupenthixol (10 or 20 μg) into the AcbC (Experiment 2) attenuated blocking and so enabled fear learning to CSB. These results identify the AcbC as the critical locus for dopamine receptor contributions to fear prediction error and the associative blocking of fear learning. (c) 2015 APA, all rights reserved).

Visualization of Plasticity in Fear-Evoked Calcium Signals in Midbrain Dopamine Neurons

ERIC Educational Resources Information Center

Gore, Bryan B.; Soden, Marta E.; Zweifel, Larry S.

2014-01-01

Dopamine is broadly implicated in fear-related processes, yet we know very little about signaling dynamics in these neurons during active fear conditioning. We describe the direct imaging of calcium signals of dopamine neurons during Pavlovian fear conditioning using fiber-optic confocal microscopy coupled with the genetically encoded calcium…

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.

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

PubMed

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

2014-07-01

The ability to differentiate danger and safety through associative processes emerges early in life. Understanding the mechanisms underlying associative learning of threat and safety can clarify the processes that shape development of normative fears and pathological anxiety. Considerable research has used fear conditioning and extinction paradigms to delineate underlying mechanisms in animals and human adults; however, little is known about these mechanisms in children and adolescents. The current paper summarizes the empirical data on the development of fear conditioning and extinction. It reviews methodological considerations and future directions for research on fear conditioning and extinction in pediatric populations. Copyright © 2014 Elsevier B.V. All rights reserved.

AMYGDALA MICROCIRCUITS CONTROLLING LEARNED FEAR

PubMed Central

Duvarci, Sevil; Pare, Denis

2014-01-01

We review recent work on the role of intrinsic amygdala networks in the regulation of classically conditioned defensive behaviors, commonly known as conditioned fear. These new developments highlight how conditioned fear depends on far more complex networks than initially envisioned. Indeed, multiple parallel inhibitory and excitatory circuits are differentially recruited during the expression versus extinction of conditioned fear. Moreover, shifts between expression and extinction circuits involve coordinated interactions with different regions of the medial prefrontal cortex. However, key areas of uncertainty remain, particularly with respect to the connectivity of the different cell types. Filling these gaps in our knowledge is important because much evidence indicates that human anxiety disorders results from an abnormal regulation of the networks supporting fear learning. PMID:24908482

Eye closure in darkness animates olfactory and gustatory cortical areas.

PubMed

Wiesmann, M; Kopietz, R; Albrecht, J; Linn, J; Reime, U; Kara, E; Pollatos, O; Sakar, V; Anzinger, A; Fesl, G; Brückmann, H; Kobal, G; Stephan, T

2006-08-01

In two previous fMRI studies, it was reported that eyes-open and eyes-closed conditions in darkness had differential effects on brain activity, and typical patterns of cortical activity were identified. Without external stimulation, ocular motor and attentional systems were activated when the eyes were open. On the contrary, the visual, somatosensory, vestibular, and auditory systems were activated when the eyes were closed. In this study, we investigated whether cortical areas related to the olfactory and gustatory system are also animated by eye closure without any other external stimulation. In a first fMRI experiment (n = 22), we identified cortical areas including the piriform cortex activated by olfactory stimulation. In a second experiment (n = 12) subjects lying in darkness in the MRI scanner alternately opened and closed their eyes. In accordance to previous studies, we found activation clusters bilaterally in visual, somatosensory, vestibular and auditory cortical areas for the contrast eyes-closed vs. eyes-open. In addition, we were able to show that cortical areas related to the olfactory and gustatory system were also animated by eye closure. These results support the hypothesis that there are two different states of mental activity: with the eyes closed, an "interoceptive" state characterized by imagination and multisensory activity and with the eyes open, an "exteroceptive" state characterized by attention and ocular motor activity. Our study also suggests that the chosen baseline condition may have a considerable impact on activation patterns and on the interpretation of brain activation studies. This needs to be considered for studies of the olfactory and gustatory system.

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

PubMed

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

2015-02-01

Autonomic fear conditioning deficits have been linked to child aggression and adult criminal behavior. However, it is unknown if fear conditioning deficits are specific to certain subtypes of aggression, and longitudinal research is rare. In the current study, reactive and proactive aggression were assessed in a sample of males and females when aged 10, 12, 15, and 18 years old. Skin conductance fear conditioning data were collected when they were 18 years old. Individuals who were persistently high on proactive aggression measures had significantly poorer conditioned responses at 18 years old when compared to others. This association was not found for reactive aggression. Consistent with prior literature, findings suggest that persistent antisocial individuals have unique neurobiological characteristics and that poor autonomic fear conditioning is associated with the presence of increased instrumental aggressive behavior. © 2014 Society for Psychophysiological Research.

Intracellular signalling and plasma hormone profiles associated with the expression of unconditioned and conditioned fear and anxiety in female rats.

PubMed

Simone, Jonathan J; McCormick, Cheryl M

2017-02-01

There is considerable overlap in the neural regions and intracellular signalling pathways implicated in anxiety and fear, although less is known in females. Here, we investigated whether unconditioned and conditioned fear are associated with distinct patterns of expression of extracellular signal-regulated kinase-1 and -2 (ERK1/2), protein kinase B (Akt), and calcineurin (CaN) (proteins that are key regulators of the expression of and/or memory processes of fear and anxiety) in the dorsal and ventral hippocampus, medial prefrontal cortex, and amygdala (important regions in neural fear circuitry) of adult female rats, and used a multivariate approach to find patterns of signalling that might discriminate between the different states of fear. To isolate fear to the conditioned cue from generalized fear to the test context, rats were conditioned to an auditory tone (i.e. tone paired with footshock) and twenty-four hours later exposed to a novel context in the presence or absence of the conditioned cue. A third group that was exposed to the conditioning context without undergoing fear conditioning was included to control for unconditioned responses to the testing procedures, which are anxiogenic. A discriminate function analysis and MANOVA determined that hippocampal signalling best discriminated the three groups from each other. The addition of values for plasma concentrations of corticosterone and progesterone (as indices of activation of the hypothalamic-pituitary-adrenal stress axis) to statistical analyses increased the separation of the three groups. There was high degree of association among the three signalling molecules in the four brain regions within each group. There was an absence of the associations between the medial prefrontal cortex and the amygdala in the cued fear recall group that were strong for the non-conditioned group. These results demonstrated unique neuronal and hormonal signalling profiles associated with unconditioned, generalized, and conditioned fear expression in females and highlight the importance of including appropriate comparisons to best discriminate between these different emotional states. Copyright © 2016 Elsevier Inc. All rights reserved.

What Can Ethobehavioral Studies Tell Us About The Brain’s Fear System?

PubMed Central

Pellman, Blake A.; Kim, Jeansok J.

2016-01-01

Foraging-associated predation risk is a natural problem all prey must face. Fear evolved due to its protective functions, guiding and shaping behaviors that help animals adapt to various ecological challenges. Despite the breadth of risky situations in nature that demand diversity in fear behaviors, contemporary neurobiological models of fear stem largely from Pavlovian fear conditioning studies that focus on how a particular cue becomes capable of eliciting learned fear responses, thus oversimplifying the brain’s fear system. Here we review fear from functional, mechanistic, and phylogenetic perspectives where environmental threats cause animals to alter their foraging strategies in terms of spatial and temporal navigation, and discuss whether the inferences we draw from fear conditioning studies operate in the natural world. PMID:27130660

Toward an account of clinical anxiety predicated on basic, neurally mapped mechanisms of Pavlovian fear-learning: the case for conditioned overgeneralization.

PubMed

Lissek, Shmuel

2012-04-01

The past two decades have brought dramatic progress in the neuroscience of anxiety due, in no small part, to animal findings specifying the neurobiology of Pavlovian fear-conditioning. Fortuitously, this neurally mapped process of fear learning is widely expressed in humans, and has been centrally implicated in the etiology of clinical anxiety. Fear-conditioning experiments in anxiety patients thus represent a unique opportunity to bring recent advances in animal neuroscience to bear on working, brain-based models of clinical anxiety. The current presentation details the neural basis and clinical relevance of fear conditioning, and highlights generalization of conditioned fear to stimuli resembling the conditioned danger cue as one of the more robust conditioning markers of clinical anxiety. Studies testing such generalization across a variety of anxiety disorders (panic, generalized anxiety disorder, and social anxiety disorder) with systematic methods developed in animals will next be presented. Finally, neural accounts of overgeneralization deriving from animal and human data will be described with emphasis given to implications for the neurobiology and treatment of clinical anxiety. © 2012 Wiley Periodicals, Inc.

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.

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.

Genetic Correlation between Alcohol Preference and Conditioned Fear: Exploring a Functional Relationship

PubMed Central

Chester, Julia A.; Weera, Marcus M.

2016-01-01

Post-traumatic stress disorder (PTSD) and alcohol-use disorders have a high rate of co-occurrence, possibly because they are regulated by common genes. In support of this idea, mice selectively bred for high (HAP) alcohol preference show greater fear potentiated startle (FPS), a model for fear-related disorders such as PTSD, compared to mice selectively bred for low (LAP) alcohol preference. This positive genetic correlation between alcohol preference and FPS behavior suggests that the two traits may be functionally related. This study examined the effects of fear conditioning on alcohol consumption and the effects of alcohol consumption on the expression of FPS in male and female HAP2 and LAP2 mice. In experiment 1, alcohol consumption (g/kg) under continuous-access conditions was monitored daily for 4 weeks following a single fear-conditioning or control treatment (foot shock and no shock). FPS was assessed three times (once at the end of the 4-week alcohol access period, once at 24 h after removal of alcohol, and once at 6–8 days after removal of alcohol), followed by two more weeks of alcohol access. Results showed no change in alcohol consumption, but alcohol-consuming, fear-conditioned, HAP2 males showed increased FPS at 24 h during the alcohol abstinence period compared to control groups. In experiment 2, alcohol consumption under limited-access conditions was monitored daily for 4 weeks. Fear-conditioning or control treatments occurred four times during the first 12 days and FPS testing occurred four times during the second 12 days of the 4-week alcohol consumption period. Results showed that fear conditioning increased alcohol intake in both HAP2 and LAP2 mice immediately following the first conditioning session. Fear-conditioned HAP2 but not LAP2 mice showed greater alcohol intake compared to control groups on drinking days that occurred between fear conditioning and FPS test sessions. FPS did not change as a function of alcohol consumption in either line. These results in mice help shed light on how a genetic propensity toward high alcohol consumption may be related to the risk for developing PTSD and co-morbid alcohol-use disorders in humans. PMID:27908524

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.

Out with the old and in with the new: Synaptic mechanisms of extinction in the amygdala

PubMed Central

Maren, Stephen

2014-01-01

Considerable research indicates that long-term synaptic plasticity in the amygdala underlies the acquisition of emotional memories, including those learned during Pavlovian fear conditioning. Much less is known about the synaptic mechanisms involved in other forms of associative learning, including extinction, that update fear memories. Extinction learning might reverse conditioning-related changes (e.g., depotentiation) or induce plasticity at inhibitory synapses (e.g., long-term potentiation) to suppress conditioned fear responses. Either mechanism must account for fear recovery phenomena after extinction, as well as savings of extinction after fear recovery. PMID:25312830

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…

Brain processing of biologically relevant odors in the awake rat, as revealed by manganese-enhanced MRI.

PubMed

Lehallier, Benoist; Rampin, Olivier; Saint-Albin, Audrey; Jérôme, Nathalie; Ouali, Christian; Maurin, Yves; Bonny, Jean-Marie

2012-01-01

So far, an overall view of olfactory structures activated by natural biologically relevant odors in the awake rat is not available. Manganese-enhanced MRI (MEMRI) is appropriate for this purpose. While MEMRI has been used for anatomical labeling of olfactory pathways, functional imaging analyses have not yet been performed beyond the olfactory bulb. Here, we have used MEMRI for functional imaging of rat central olfactory structures and for comparing activation maps obtained with odors conveying different biological messages. Odors of male fox feces and of chocolate flavored cereals were used to stimulate conscious rats previously treated by intranasal instillation of manganese (Mn). MEMRI activation maps showed Mn enhancement all along the primary olfactory cortex. Mn enhancement elicited by male fox feces odor and to a lesser extent that elicited by chocolate odor, differed from that elicited by deodorized air. This result was partly confirmed by c-Fos immunohistochemistry in the piriform cortex. By providing an overall image of brain structures activated in awake rats by odorous stimulation, and by showing that Mn enhancement is differently sensitive to different stimulating odors, the present results demonstrate the interest of MEMRI for functional studies of olfaction in the primary olfactory cortex of laboratory small animals, under conditions close to natural perception. Finally, the factors that may cause the variability of the MEMRI signal in response to different odor are discussed.

Working Memory Systems in the Rat.

PubMed

Bratch, Alexander; Kann, Spencer; Cain, Joshua A; Wu, Jie-En; Rivera-Reyes, Nilda; Dalecki, Stefan; Arman, Diana; Dunn, Austin; Cooper, Shiloh; Corbin, Hannah E; Doyle, Amanda R; Pizzo, Matthew J; Smith, Alexandra E; Crystal, Jonathon D

2016-02-08

A fundamental feature of memory in humans is the ability to simultaneously work with multiple types of information using independent memory systems. Working memory is conceptualized as two independent memory systems under executive control [1, 2]. Although there is a long history of using the term "working memory" to describe short-term memory in animals, it is not known whether multiple, independent memory systems exist in nonhumans. Here, we used two established short-term memory approaches to test the hypothesis that spatial and olfactory memory operate as independent working memory resources in the rat. In the olfactory memory task, rats chose a novel odor from a gradually incrementing set of old odors [3]. In the spatial memory task, rats searched for a depleting food source at multiple locations [4]. We presented rats with information to hold in memory in one domain (e.g., olfactory) while adding a memory load in the other domain (e.g., spatial). Control conditions equated the retention interval delay without adding a second memory load. In a further experiment, we used proactive interference [5-7] in the spatial domain to compromise spatial memory and evaluated the impact of adding an olfactory memory load. Olfactory and spatial memory are resistant to interference from the addition of a memory load in the other domain. Our data suggest that olfactory and spatial memory draw on independent working memory systems in the rat. Copyright © 2016 Elsevier Ltd. All rights reserved.

Odours reduce the magnitude of object substitution masking for matching visual targets in females.

PubMed

Robinson, Amanda K; Laning, Julia; Reinhard, Judith; Mattingley, Jason B

2016-08-01

Recent evidence suggests that olfactory stimuli can influence early stages of visual processing, but there has been little focus on whether such olfactory-visual interactions convey an advantage in visual object identification. Moreover, despite evidence that some aspects of olfactory perception are superior in females than males, no study to date has examined whether olfactory influences on vision are gender-dependent. We asked whether inhalation of familiar odorants can modulate participants' ability to identify briefly flashed images of matching visual objects under conditions of object substitution masking (OSM). Across two experiments, we had male and female participants (N = 36 in each group) identify masked visual images of odour-related objects (e.g., orange, rose, mint) amongst nonodour-related distracters (e.g., box, watch). In each trial, participants inhaled a single odour that either matched or mismatched the masked, odour-related target. Target detection performance was analysed using a signal detection (d') approach. In females, but not males, matching odours significantly reduced OSM relative to mismatching odours, suggesting that familiar odours can enhance the salience of briefly presented visual objects. We conclude that olfactory cues exert a subtle influence on visual processes by transiently enhancing the salience of matching object representations. The results add to a growing body of literature that points towards consistent gender differences in olfactory perception.

Effects of bright light exposure on human fear conditioning, extinction, and associated prefrontal activation.

PubMed

Yoshiike, Takuya; Honma, Motoyasu; Yamada, Naoto; Kim, Yoshiharu; Kuriyama, Kenichi

2018-06-18

Bright light (BL) not only regulates human emotion and circadian physiology but can also directly modulate emotional memories. Impaired fear extinction and enhanced fear acquisition and consolidation are hallmarks of fear-circuitry disorders; thus, we tested whether BL facilitates fear extinction and inhibits fear acquisition. We randomly exposed 29 healthy humans to high- (9000 lx) or low-intensity light (<500 lx) for 15 min, near the nadir of the phase response to light, in a single-blind manner. Simultaneously with the light exposure, subjects performed fear extinction training and second fear acquisition, where a visual conditioned stimulus (CS), previously paired with an electric shock unconditioned stimulus (US), was presented without the US, while another CS was newly paired with the US. Conditioned responses (CRs) and changes in prefrontal cortex (PFC) activity were determined during encoding and delayed recall sessions. BL-exposed subjects exhibited lower extinction-related PFC activity and marginally higher acquisition-related PFC activity during light exposure than subjects exposed to control light. Twenty-four hours later, BL reduced CRs to both the extinguished and non-extinguished CSs with marginally lower extinction-related PFC activation, suggesting that BL enhanced fear extinction, while suppressing fear acquisition. Further, BL sustained tolerance to fear re-conditioning. Our results demonstrate that a single and brief BL exposure, synchronized with fear extinction and acquisition, instantaneously influences prefrontal hemodynamic responses and alleviates fear expression after 24 h. Although the specificity of BL effects deems further investigation, our findings indicate the clinical relevance of adjunctive BL intervention in exposure-based cognitive-behavioral therapy for fear-circuitry disorders. Copyright © 2018 Elsevier Inc. All rights reserved.

Sex differences in catechol contents in the olfactory bulb of control and unilaterally deprived rats.

PubMed

Gómez, C; Briñón, J G; Valero, J; Recio, J S; Murias, A R; Curto, G G; Orio, L; Colado, M I; Alonso, J R

2007-03-01

The dopaminergic system plays important roles in the modulation of olfactory transmission. The present study examines the distribution of dopaminergic cells and the content of dopamine (DA) and its metabolites in control and deprived olfactory bulbs (OB), focusing on the differences between sexes. The content of DA and of its metabolites, dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), were measured by HPLC. The morphology and distribution of dopaminergic neurons were studied using tyrosine hydroxylase (TH) immunohistochemistry. Cells were typified with TH-parvalbumin, TH-cholecystokinin or TH-neurocalcin double-immunofluorescence assays. Biochemical analyses revealed sex differences in the content of DA and of its metabolites. In normal conditions, the OBs of male rats had higher concentrations of DA, DOPAC and HVA than the OBs of females. The immunohistochemical data pointed to sex differences in the number of TH-immunopositive cells (higher in male than in female rats). Colocalization analyses revealed that dopaminergic cells constitute a different cell subpopulation from those labelled after parvalbumin, cholecystokinin or neurocalcin immunostaining. Unilateral olfactory deprivation caused dramatic alterations in the dopaminergic system. The DA content and the density of dopaminergic cells decreased, the contents of DA and DOPAC as well as TH immunoreactivity were similar in deprived males and females and, finally, the metabolite/neurotransmitter ratio increased. Our results show that the dopaminergic modulation of olfactory transmission seems to differ between males and females and that it is regulated by peripheral olfactory activity. A possible role of the dopaminergic system in the sexually different olfactory sensitivity, discrimination and memory is discussed.

Plasticity in the olfactory bulb of the maternal mouse is prevented by gestational stress

PubMed Central

Belnoue, Laure; Malvaut, Sarah; Ladevèze, Elodie; Abrous, Djoher Nora; Koehl, Muriel

2016-01-01

Maternal stress is associated with an altered mother-infant relationship that endangers offspring development, leading to emotional/behavioral problems. However, little research has investigated the stress-induced alterations of the maternal brain that could underlie such a disruption of mother-infant bonding. Olfactory cues play an extensive role in the coordination of mother-infant interactions, suggesting that motherhood may be associated to enhanced olfactory performances, and that this effect may be abolished by maternal stress. To test this hypothesis, we analyzed the impact of motherhood under normal conditions or after gestational stress on olfactory functions in C57BL/6 J mice. We report that gestational stress alters maternal behavior and prevents both mothers’ ability to discriminate pup odors and motherhood-induced enhancement in odor memory. We investigated adult bulbar neurogenesis as a potential mechanism of the enhanced olfactory function in mothers and found that motherhood was associated with an increased complexity of the dendritic tree of newborn neurons. This motherhood-evoked remodeling was totally prevented by gestational stress. Altogether, our results may thus provide insight into the neural changes that could contribute to altered maternal behavior in stressed mothers. PMID:27886228

Bioelectronic nose and its application to smell visualization.

PubMed

Ko, Hwi Jin; Park, Tai Hyun

2016-01-01

There have been many trials to visualize smell using various techniques in order to objectively express the smell because information obtained from the sense of smell in human is very subjective. So far, well-trained experts such as a perfumer, complex and large-scale equipment such as GC-MS, and an electronic nose have played major roles in objectively detecting and recognizing odors. Recently, an optoelectronic nose was developed to achieve this purpose, but some limitations regarding the sensitivity and the number of smells that can be visualized still persist. Since the elucidation of the olfactory mechanism, numerous researches have been accomplished for the development of a sensing device by mimicking human olfactory system. Engineered olfactory cells were constructed to mimic the human olfactory system, and the use of engineered olfactory cells for smell visualization has been attempted with the use of various methods such as calcium imaging, CRE reporter assay, BRET, and membrane potential assay; however, it is not easy to consistently control the condition of cells and it is impossible to detect low odorant concentration. Recently, the bioelectronic nose was developed, and much improved along with the improvement of nano-biotechnology. The bioelectronic nose consists of the following two parts: primary transducer and secondary transducer. Biological materials as a primary transducer improved the selectivity of the sensor, and nanomaterials as a secondary transducer increased the sensitivity. Especially, the bioelectronic noses using various nanomaterials combined with human olfactory receptors or nanovesicles derived from engineered olfactory cells have a potential which can detect almost all of the smells recognized by human because an engineered olfactory cell might be able to express any human olfactory receptor as well as can mimic human olfactory system. Therefore, bioelectronic nose will be a potent tool for smell visualization, but only if two technologies are completed. First, a multi-channel array-sensing system has to be applied for the integration of all of the olfactory receptors into a single chip for mimicking the performance of human nose. Second, the processing technique of the multi-channel system signals should be simultaneously established with the conversion of the signals to visual images. With the use of this latest sensing technology, the realization of a proper smell-visualization technology is expected in the near future.

Dynamic expression of FKBP5 in the medial prefrontal cortex regulates resiliency to conditioned fear

PubMed Central

Criado-Marrero, Marangelie; Morales Silva, Roberto J.; Velazquez, Bethzaly; Hernández, Anixa; Colon, María; Cruz, Emmanuel; Soler-Cedeño, Omar; Porter, James T.

2017-01-01

The factors influencing resiliency to the development of post-traumatic stress disorder (PTSD) remain to be elucidated. Clinical studies associate PTSD with polymorphisms of the FK506 binding protein 5 (FKBP5). However, it is unclear whether changes in FKBP5 expression alone could produce resiliency or susceptibility to PTSD-like symptoms. In this study, we used rats as an animal model to examine whether FKBP5 in the infralimbic (IL) or prelimbic (PL) medial prefrontal cortex regulates fear conditioning or extinction. First, we examined FKBP5 expression in IL and PL during fear conditioning or extinction. In contrast to the stable expression of FKBP5 seen in PL, FKBP5 expression in IL increased after fear conditioning and remained elevated even after extinction suggesting that IL FKBP5 levels may modulate fear conditioning or extinction. Consistent with this possibility, reducing basal FKBP5 expression via local infusion of FKBP5–shRNA into IL reduced fear conditioning. Furthermore, reducing IL FKBP5, after consolidation of the fear memory, enhanced extinction memory indicating that IL FKBP5 opposed formation of the extinction memory. Our findings demonstrate that lowering FKBP5 expression in IL is sufficient to both reduce fear acquisition and enhance extinction, and suggest that lower expression of FKBP5 in the ventral medial prefrontal cortex could contribute to resiliency to PTSD. PMID:28298552

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.

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

ERIC Educational Resources Information Center

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

2006-01-01

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

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

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…

Young and Old Pavlovian Fear Memories Can Be Modified with Extinction Training during Reconsolidation in Humans

ERIC Educational Resources Information Center

Steinfurth, Elisa C. K.; Kanen, Jonathan W.; Raio, Candace M.; Clem, Roger L.; Huganir, Richard L.; Phelps, Elizabeth A.

2014-01-01

Extinction training during reconsolidation has been shown to persistently diminish conditioned fear responses across species. We investigated in humans if older fear memories can benefit similarly. Using a Pavlovian fear conditioning paradigm we compared standard extinction and extinction after memory reactivation 1 d or 7 d following acquisition.…

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.

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

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.

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

PubMed

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

2013-01-01

The effects of sex and stress hormones on classical fear conditioning have been subject of recent experimental studies. A correlation approach between basal cortisol concentrations and neuronal activation in fear-related structures seems to be a promising alternative approach in order to foster our understanding of how cortisol influences emotional learning. In this functional magnetic resonance imaging study, participants with varying sex hormone status (20 men, 15 women taking oral contraceptives, 15 women tested in the luteal phase) underwent an instructed fear conditioning protocol with geometrical figures as conditioned stimuli and an electrical stimulation as unconditioned stimulus. Salivary cortisol concentrations were measured and afterwards correlated with fear conditioned brain responses. Results revealed a positive correlation between basal cortisol levels and differential activation in the amygdala in men and OC women only. These results suggest that elevated endogenous cortisol levels are associated with enhanced fear anticipation depending on current sex hormone availability. Copyright © 2012 Elsevier B.V. All rights reserved.

Emotion-attention interactions in fear conditioning: Moderation by executive load, neuroticism, and awareness.

PubMed

Hur, Juyoen; Iordan, Alexandru D; Berenbaum, Howard; Dolcos, Florin

2016-12-01

Despite increasing evidence suggesting interactive effects of emotion and attention on perceptual processing, it still remains unclear how their interplay influences affective learning, such as fear conditioning. In the present study, a conditioning procedure using threat-related conditioned stimuli (CSs) was implemented while executive load and attentional focus were manipulated. The modulation effects of neuroticism and contingency awareness were also examined. Results showed that fear conditioning depended on the available executive resources even with threat-related CSs. In addition, although individuals with high neuroticism showed an enhanced conditioning effect overall, this facilitation effect still depended on the availability of executive resources. Finally, the impact of attentional focus was most evident among individuals with high neuroticism who were aware of the contingency. Overall, the present study demonstrates interactive effects of emotion and attention in fear conditioning, while illuminating mechanisms of individual differences and clarifying the controversial role of contingency awareness in fear conditioning. Copyright © 2015 Elsevier B.V. All rights reserved.

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

Temporal-difference prediction errors and Pavlovian fear conditioning: role of NMDA and opioid receptors.

PubMed

Cole, Sindy; McNally, Gavan P

2007-10-01

Three experiments studied temporal-difference (TD) prediction errors during Pavlovian fear conditioning. In Stage I, rats received conditioned stimulus A (CSA) paired with shock. In Stage II, they received pairings of CSA and CSB with shock that blocked learning to CSB. In Stage III, a serial overlapping compound, CSB --> CSA, was followed by shock. The change in intratrial durations supported fear learning to CSB but reduced fear of CSA, revealing the operation of TD prediction errors. N-methyl- D-aspartate (NMDA) receptor antagonism prior to Stage III prevented learning, whereas opioid receptor antagonism selectively affected predictive learning. These findings support a role for TD prediction errors in fear conditioning. They suggest that NMDA receptors contribute to fear learning by acting on the product of predictive error, whereas opioid receptors contribute to predictive error. (PsycINFO Database Record (c) 2007 APA, all rights reserved).

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

PubMed Central

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

2015-01-01

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

Effects of chemogenetic excitation or inhibition of the ventrolateral periaqueductal gray on the acquisition and extinction of Pavlovian fear conditioning.

PubMed

Arico, Carolyn; Bagley, Elena E; Carrive, Pascal; Assareh, Neda; McNally, Gavan P

2017-10-01

The midbrain periaqueductal gray (PAG) has been implicated in the generation and transmission of a prediction error signal that instructs amygdala-based fear and extinction learning. However, the PAG also plays a key role in the expression of conditioned fear responses. The evidence for a role of the PAG in fear learning and extinction learning has been obtained almost exclusively using PAG-dependent fear responses. It is less clear whether the PAG regulates fear learning when other measures of learned fear are used. Here we combined a chemogenetic approach, permitting excitation or inhibition of neurons in the ventrolateral PAG (VLPAG), with conditioned suppression as the measure of learned fear to assess the role of VLPAG in the acquisition and extinction of fear learning. We show that chemogenetic excitation of VLPAG (with some encroachment on lateral PAG [LPAG]) impairs acquisition of fear and, conversely, chemogenetic inhibition impairs extinction of fear. These effects on fear and extinction learning were specific to the combination of DREADD expression and injection of CNO because they were observed relative to both eYFP controls injected with CNO as well as DREADD expressing controls injected with vehicle. Taken together, these results show that activity of L/VLPAG neurons regulates both the acquisition and extinction of Pavlovian fear learning. Copyright © 2017 Elsevier Inc. All rights reserved.

Human fear extinction and return of fear using reconsolidation update mechanisms: The contribution of on-line expectancy ratings

PubMed Central

Warren, Victor Taylor; Anderson, Kemp M.; Kwon, Cliffe; Bosshardt, Lauren; Jovanovic, Tanja; Bradley, Bekh; Norrholm, Seth Davin

2015-01-01

Disruption of the reconsolidation of conditioned fear memories has been suggested as a non-pharmacological means of preventing the return of learned fear in human populations. A reconsolidation update paradigm was developed in which a reconsolidation window is opened by a single isolated retrieval trial of a previously reinforced CS+ which is then followed by Extinction Training within that window. However, follow-up studies in humans using multi-methods fear conditioning indices (e.g., fear-potentiated startle, skin conductance, US-expectancy) have failed to replicate the retrieval + extinction effects. In the present study, we further investigated the retrieval + extinction reconsolidation update paradigm by directly comparing the acquisition, extinction, and return of fear-potentiated startle in the absence or presence of US-expectancy measures (using a trial-by-trial response keypad) with and without retrieval of a previously acquired CS-US association. Participants were fear conditioned to two visual cue CS+'s, one of which was presented as a single, isolated retrieval trial before Extinction Training and one that was extinguished as usual. The results show that the inclusion of US-expectancy measures strengthens the CS–US association to provide enhanced fear conditioning and maintenance of fear memories over the experimental sessions. In addition, in the groups that used on-line US-expectancy measures, the retrieval + extinction procedure reduced reinstatement of fear-potentiated startle to both previously reinforced CS+'s, as compared to the extinction as usual group. PMID:24183839

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

ERIC Educational Resources Information Center

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

2006-01-01

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

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

PubMed

Pavlova, I V; Rysakova, M P

2015-01-01

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

Growth and histamine formation of Morganella morganii in determining the safety and quality of inoculated and uninoculated bluefish (Pomatomus saltatrix).

PubMed

Lorca, T A; Gingerich, T M; Pierson, M D; Flick, G J; Hackney, C R; Sumner, S S

2001-12-01

The objective of this study was to determine the effect of normal microflora and Morganella morganii on histamine formation and olfactory acceptability in raw bluefish under controlled storage conditions. Fillets inoculated with and without M. morganii were stored at 5, 10, and 15 degrees C for 7 days. Microbial isolates from surface swabs were identified and screened for histidine decarboxylase activity. Olfactory acceptance was performed by an informal sensory panel. Histamine levels were quantified using high-performance liquid chromatography and fluorescence detection. While olfactory acceptance decreased, histamine concentration and bacterial counts increased. Storage temperature had a significant effect on histamine levels, bacterial counts, and olfactory acceptance of the bluefish. Inoculation with M. morganii had a positive significant effect on histamine formation for bluefish held at 10 and 15 degrees C (P < 0.0001). The results of the study will serve in supporting U.S. Food and Drug Administration (FDA) regulations regarding guidance and hazard levels of histamine in fresh bluefish.

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.

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

Fear Conditioning Selectively Disrupts Noradrenergic Facilitation of GABAergic Inhibition in the Basolateral Amygdala

PubMed Central

Skelly, M. J.; Ariwodola, O. J.; Weiner, J. L.

2016-01-01

Inappropriate fear memory formation is symptomatic of many psychopathologies, and delineating the neurobiology of non-pathological fear learning may provide critical insight into treating these disorders. Fear memory formation is associated with decreased inhibitory signaling in the basolateral amygdala (BLA), and disrupted noradrenergic signaling may contribute to this decrease. BLA noradrenergic neurotransmission has been implicated in fear memory formation, and distinct adrenoreceptor (AR) subtypes modulate excitatory and inhibitory neurotransmission in this region. For example, α1-ARs promote GABA release from local inhibitory interneurons, while β3-ARs potentiate neurotransmission at lateral paracapsular (LPC) GABAergic synapses. Conversely, β1/2-ARs amplify excitatory signaling at glutamatergic synapses in the BLA. As increased BLA excitability promotes fear memory formation, we hypothesized that fear learning shifts the balanced regional effects of noradrenergic signaling toward excitation. To test this hypothesis, we used the fear-potentiated startle paradigm in combination with whole cell patch clamp electrophysiology to examine the effects of AR activation on BLA synaptic transmission following fear conditioning in male Long-Evans rats. We first demonstrated that inhibitory neurotransmission is decreased at both local and LPC synapses following fear conditioning. We next measured noradrenergic facilitation of BLA inhibitory signaling at local and LPC synapses using α1- and β3-AR agonists (1μM A61603 and 10μM BRL37344), and found that the ability of these agents to facilitate inhibitory neurotransmission is disrupted following fear conditioning. Conversely, we found that fear learning does not disrupt noradrenergic modulation of glutamatergic signaling via a β1/2-AR agonist (1μM isoproterenol). Taken together, these studies suggest that fear learning increases BLA excitability by selectively disrupting the inhibitory effects of noradrenaline. PMID:27720769

Fear conditioning selectively disrupts noradrenergic facilitation of GABAergic inhibition in the basolateral amygdala.

PubMed

Skelly, M J; Ariwodola, O J; Weiner, J L

2017-02-01

Inappropriate fear memory formation is symptomatic of many psychopathologies, and delineating the neurobiology of non-pathological fear learning may provide critical insight into treating these disorders. Fear memory formation is associated with decreased inhibitory signaling in the basolateral amygdala (BLA), and disrupted noradrenergic signaling may contribute to this decrease. BLA noradrenergic neurotransmission has been implicated in fear memory formation, and distinct adrenoreceptor (AR) subtypes modulate excitatory and inhibitory neurotransmission in this region. For example, α1-ARs promote GABA release from local inhibitory interneurons, while β3-ARs potentiate neurotransmission at lateral paracapsular (LPC) GABAergic synapses. Conversely, β1/2-ARs amplify excitatory signaling at glutamatergic synapses in the BLA. As increased BLA excitability promotes fear memory formation, we hypothesized that fear learning shifts the balanced regional effects of noradrenergic signaling toward excitation. To test this hypothesis, we used the fear-potentiated startle paradigm in combination with whole cell patch clamp electrophysiology to examine the effects of AR activation on BLA synaptic transmission following fear conditioning in male Long-Evans rats. We first demonstrated that inhibitory neurotransmission is decreased at both local and LPC synapses following fear conditioning. We next measured noradrenergic facilitation of BLA inhibitory signaling at local and LPC synapses using α1-and β3-AR agonists (1 μM A61603 and 10 μM BRL37344), and found that the ability of these agents to facilitate inhibitory neurotransmission is disrupted following fear conditioning. Conversely, we found that fear learning does not disrupt noradrenergic modulation of glutamatergic signaling via a β1/2-AR agonist (1 μM isoproterenol). Taken together, these studies suggest that fear learning increases BLA excitability by selectively disrupting the inhibitory effects of noradrenaline. Copyright © 2016 Elsevier Ltd. All rights reserved.

Fear inhibition in high trait anxiety.

PubMed

Kindt, Merel; Soeter, Marieke

2014-01-01

Trait anxiety is recognized as an individual risk factor for the development of anxiety disorders but the neurobiological mechanisms remain unknown. Here we test whether trait anxiety is associated with impaired fear inhibition utilizing the AX+/BX- conditional discrimination procedure that allows for the independent evaluation of startle fear potentiation and inhibition of fear. Sixty undergraduate students participated in the study--High Trait Anxious: n = 28 and Low Trait Anxious: n = 32. We replicated earlier findings that a transfer of conditioned inhibition for startle responses requires contingency awareness. However, contrary to the fear inhibition hypothesis, our data suggest that high trait anxious individuals show a normal fear inhibition of conditioned startle responding. Only at the cognitive level the high trait anxious individuals showed evidence for impaired inhibitory learning of the threat cue. Together with other findings where impaired fear inhibition was only observed in those PTSD patients who were either high on hyperarousal symptoms or with current anxiety symptoms, we question whether impaired fear inhibition is a biomarker for the development of anxiety disorders.

Minocycline attenuates interferon-α-induced impairments in rat fear extinction.

PubMed

Bi, Qiang; Shi, Lijuan; Yang, Pingting; Wang, Jianing; Qin, Ling

2016-06-30

Extinction of conditioned fear is an important brain function for animals to adapt to a new environment. Accumulating evidence suggests that innate immune cytokines are involved in the pathology of psychotic disorders. However, the involvement of cytokines in fear dysregulation remains less investigated. In the present study, we investigated how interferon (IFN)-α disrupts the extinction of conditioned fear and propose an approach to rescue IFN-α-induced neurologic impairment. We used a rat model of auditory fear conditioning to study the effect of IFN-α on the fear memory process. IFN-α was infused directly into the amygdala of rats and examined the rats' behavioral response (freezing) to fear-conditioned stimuli. Immunohistochemical staining was used to examine the glia activity status of glia in the amygdala. The levels of the proinflammatory cytokines interleukin (IL)-1β and tumor necrosis factor (TNF)-α in the amygdala were measured by enzyme-linked immunosorbent assay. We also administrated minocycline, a microglial activation inhibitor, before the IFN-α infusion to testify the possibility to reverse the IFN-α-induced effects. Infusing the amygdala with IFN-α impaired the extinction of conditioned fear in rats and activated microglia and astrocytes in the amygdala. Administering minocycline prevented IFN-α from impairing fear extinction. The immunohistochemical and biochemical results show that minocycline inhibited IFN-α-induced microglial activation and reduced IL-1β and TNF-α production. Our findings suggest that IFN-α disrupts the extinction of auditory fear by activating glia in the amygdala and provides direction for clinical studies of novel treatments to modulate the innate immune system in patients with psychotic disorders.

Homeobox gene distal-less is required for neuronal differentiation and neurite outgrowth in the Drosophila olfactory system

PubMed Central

Plavicki, Jessica; Mader, Sara; Pueschel, Eric; Peebles, Patrick; Boekhoff-Falk, Grace

2012-01-01

Vertebrate Dlx genes have been implicated in the differentiation of multiple neuronal subtypes, including cortical GABAergic interneurons, and mutations in Dlx genes have been linked to clinical conditions such as epilepsy and autism. Here we show that the single Drosophila Dlx homolog, distal-less, is required both to specify chemosensory neurons and to regulate the morphologies of their axons and dendrites. We establish that distal-less is necessary for development of the mushroom body, a brain region that processes olfactory information. These are important examples of distal-less function in an invertebrate nervous system and demonstrate that the Drosophila larval olfactory system is a powerful model in which to understand distal-less functions during neurogenesis. PMID:22307614

Hypnotherapeutic olfactory conditioning (HOC): case studies of needle phobia, panic disorder, and combat-induced PTSD.

PubMed

Abramowitz, Eitan G; Lichtenberg, Pesach

2009-04-01

The authors developed a technique, which they call hypnotherapeutic olfactory conditioning (HOC), for exploiting the ability of scents to arouse potent emotional reactions. During hypnosis, the patient learns to associate pleasant scents with a sense of security and self-control. The patient can subsequently use this newfound association to overcome phobias and prevent panic attacks. This may be especially effective for posttraumatic stress disorder (PTSD) with episodes of anxiety, flashbacks, and dissociation triggered by smells. The authors present 3 cases, patients with needle phobia, panic disorder, and combat-induced PTSD who were successfully treated with the HOC technique.

Glutamate receptors in the medial geniculate nucleus are necessary for expression and extinction of conditioned fear in rats.

PubMed

Orsini, Caitlin A; Maren, Stephen

2009-11-01

Auditory fear conditioning requires anatomical projections from the medial geniculate nucleus (MGN) of the thalamus to the amygdala. Several lines of work indicate that the MGN is a critical sensory relay for auditory information during conditioning, but is not itself involved in the encoding of long-term fear memories. In the present experiments, we examined whether the MGN plays a similar role in the extinction of conditioned fear. Twenty-four hours after Pavlovian fear conditioning, rats received bilateral intra-thalamic infusions of either with NBQX (an AMPA receptor antagonist; Experiment 1) or MK-801 (an NMDA receptor antagonist; Experiment 1), anisomycin (a protein synthesis inhibitor; Experiment 2) or U0126 (a MEK inhibitor; Experiment 3) immediately prior to an extinction session in a novel context. The next day rats received a tone test in a drug-free state to assess their extinction memory; freezing served as an index of fear. Glutamate receptor antagonism prevented both the expression and extinction of conditioned fear. In contrast, neither anisomycin nor U0126 affected extinction. These results suggest that the MGN is a critical sensory relay for auditory information during extinction training, but is not itself a site of plasticity underlying the formation of the extinction memory.

Pharmacogenetic reactivation of the original engram evokes an extinguished fear memory.

PubMed

Yoshii, Takahiro; Hosokawa, Hiroshi; Matsuo, Naoki

2017-02-01

Fear memory extinction has several characteristic behavioral features, such as spontaneous recovery, renewal, and reinstatement, suggesting that extinction training does not erase the original association between the conditioned stimulus (CS) and the unconditioned stimulus (US). However, it is unclear whether reactivation of the original physical record of memory (i.e., memory trace) is sufficient to produce conditioned fear response after extinction. Here, we performed pharmacogenetic neuronal activation using transgenic mice expressing hM3Dq DREADD (designer receptor exclusively activated by designer drug) under the control of the activity-dependent c-fos gene promoter. Neuronal ensembles activated during fear-conditioned learning were tagged with hM3Dq and subsequently reactivated after extinction training. The mice exhibited significant freezing, even when the fear memory was no longer triggered by external CS, indicating that the artificial reactivation of a specific neuronal ensemble was sufficient to evoke the extinguished fear response. This freezing was not observed in non-fear-conditioned mice expressing hM3dq in the same brain areas. These results directly demonstrated that at least part of the original fear memory trace remains after extinction, and such residual plasticity might reflect the persistent memory. Copyright © 2016 Elsevier Ltd. All rights reserved.

Intra-amygdala microinfusion of IL-6 impairs the auditory fear conditioning of rats via JAK/STAT activation.

PubMed

Hao, Yongxin; Jing, He; Bi, Qiang; Zhang, Jiaozhen; Qin, Ling; Yang, Pingting

2014-12-15

Though accumulating literature implicates that cytokines are involved in the pathophysiology of mental disorders, the role of interleukin-6 (IL-6) in learning and memory functions remains unresolved. The present study was undertaken to investigate the effect of IL-6 on amygdala-dependent fear learning. Adult Wistar rats were used along with the auditory fear conditioning test and pharmacological techniques. The data showed that infusions of IL-6, aimed at the amygdala, dose-dependently impaired the acquisition and extinction of conditioned fear. In addition, the results in the Western blot analysis confirmed that JAK/STAT was temporally activated-phosphorylated by the IL-6 treatment. Moreover, the rats were treated with JSI-124, a JAK/STAT3 inhibitor, prior to the IL-6 treatment showed a significant decrease in the IL-6 induced impairments of fear conditioning. Taken together, our results demonstrate that the learning behavior of rats in the auditory fear conditioning could be modulated by IL-6 via the amygdala. Furthermore, the JAK/STAT3 activation in the amygdala seemed to play a role in the IL-6 mediated behavioral alterations of rats in auditory fear learning. Copyright © 2014 Elsevier B.V. All rights reserved.

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

PubMed Central

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

2014-01-01

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

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

PubMed

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

2014-09-01

Nearly 100 years ago, Ivan Pavlov demonstrated that dogs could learn to use a neutral cue to predict a biologically relevant event: after repeated predictive pairings, Pavlov's dogs were conditioned to anticipate food at the sound of a bell, which caused them to salivate. Like sustenance, danger is biologically relevant, and neutral cues can take on great salience when they predict a threat to survival. In anxiety disorders such as posttraumatic stress disorder (PTSD), this type of conditioned fear fails to extinguish, and reminders of traumatic events can cause pathological conditioned fear responses for decades after danger has passed. In this review, we use fear conditioning and extinction studies to draw a direct line from Pavlov to PTSD and other anxiety disorders. We explain how rodent studies have informed neuroimaging studies of healthy humans and humans with PTSD. We describe several genes that have been linked to both PTSD and fear conditioning and extinction and explain how abnormalities in fear conditioning or extinction may reflect a general biomarker of anxiety disorders. Finally, we explore drug and neuromodulation treatments that may enhance therapeutic extinction in anxiety disorders. Copyright © 2013 Elsevier Inc. All rights reserved.

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

Dexamethasone facilitates fear extinction and safety discrimination in PTSD: A placebo-controlled, double-blind study.

PubMed

Michopoulos, Vasiliki; Norrholm, Seth D; Stevens, Jennifer S; Glover, Ebony M; Rothbaum, Barbara O; Gillespie, Charles F; Schwartz, Ann C; Ressler, Kerry J; Jovanovic, Tanja

2017-09-01

Psychophysiological hallmarks of posttraumatic stress disorder (PTSD) include exaggerated fear responses, impaired inhibition and extinction of conditioned fear, and decreased discrimination between safety and fear cues. This increased fear load associated with PTSD can be a barrier to effective therapy thus indicating the need for new treatments to reduce fear expression in people with PTSD. One potential biological target for reducing fear expression in PTSD is the hypothalamic-pituitary-adrenal (HPA) axis, which is dysregulated in PTSD. Recent translational rodent studies and cross-sectional clinical studies have shown that dexamethasone administration and the resulting suppression of cortisol in individuals with PTSD leads to a decrease in the fear responses characteristic of PTSD. These data, taken together, suggest that dexamethasone may serve as a novel pharmacologic intervention for heightened fear responses in PTSD. We conducted a double-blind, placebo-controlled trial to test our hypothesis that dexamethasone administration and the concomitant suppression of HPA axis hyperactivity would attenuate fear expression and enhance fear extinction in individuals with PTSD. Study participants (n=62) were recruited from Grady Memorial Hospital in Atlanta, GA. Participants were randomized to receive dexamethasone or placebo prior to fear conditioning and extinction, in a counterbalanced design (treatments separated by a week). Both PTSD- (n=37) and PTSD+ (n=25) participants showed significant startle increases in the presence of the danger signal during placebo and dexamethasone treatments (all p<0.05). However, only PTSD- control participants showed decreases in fear-potentiated startle across extinction blocks during both conditions (p's≤0.001), with PTSD+ participants showing deficits in fear extinction and safety discrimination in the placebo condition. Notably, extinction and discrimination deficits in PTSD+ subjects were markedly reversed with dexamethasone (p<0.001). These data suggest that dexamethasone may serve as a pharmacological agent with which to facilitate fear extinction and discrimination in individuals with PTSD. Copyright © 2017 Elsevier Ltd. All rights reserved.

Habitat-dependent olfactory discrimination in three-spined sticklebacks (Gasterosteus aculeatus).

PubMed

Hiermes, Meike; Mehlis, Marion; Rick, Ingolf P; Bakker, Theo C M

2015-07-01

The ability to recognize conspecifics is indispensible for differential treatment of particular individuals in social contexts like grouping behavior. The advantages of grouping are multifarious, and there exist numerous additional benefits of joining aggregations of conspecifics. Recognition is based on different signals and transmitted via multiple channels, among others the olfactory channel. The sensory system or the combination of sensory modalities used in recognition processes is highly dependent on the availability and effectiveness of modalities, which are a function of the environmental conditions. Using F1-generations of six three-spined stickleback (Gasterosteus aculeatus) populations from two habitat types (tea-stained and clear-water lakes) from the Outer Hebrides, Scotland, we investigated whether individuals are able to recognize members of their own population solely based on olfactory cues and whether the habitat type an individual originated from had an influence on its recognition abilities. When given the choice (own vs. foreign population) sticklebacks from tea-stained lakes significantly preferred the odor of their own population, whereas fish from clear-water habitats did not show any preference. Moreover, fish from the two habitat types differed significantly in their recognition abilities, indicating that olfactory communication is better developed when visual signaling is disturbed. Thus, the observed odor preferences appear to be the consequence of different selective constraints and adaptations as a result of the differences in environmental conditions that have acted on the parental generations. These adaptations are likely genetically based as the differences are present in the F1-generation that had been reared under identical laboratory conditions.

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

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

Disruption of human fear reconsolidation using imaginal and in vivo extinction.

PubMed

Agren, Thomas; Björkstrand, Johannes; Fredrikson, Mats

2017-02-15

Memories are not set forever, but can be altered following reactivation, which renders memories malleable, before they are again stabilized through reconsolidation. Fear memories can be attenuated by using extinction during the malleable period. The present study adopts a novel form of extinction, using verbal instructions, in order to examine whether fear memory reconsolidation can be affected by an imaginal exposure. The extinction using verbal instructions, called imaginal extinction, consists of a recorded voice encouraging participants to imagine the scene in which fear was acquired, and to envision the stimuli before their inner eye. The voice signals stimuli appearance, and identical to standard (in vivo) extinction, participants discover that the conditioned stimulus no longer is followed by unconditioned stimulus (UCS). In this way, imaginal extinction translates clinically used imaginal exposure into the standard experimental fear conditioning paradigm. Fear was acquired by pairing pictorial stimuli with an electric shock UCS. Then, both standard and imaginal extinction were given following fear memory reactivation, either after 10min, within the reconsolidation interval, or after 6h, outside of the reconsolidation interval. In vivo and imaginal extinction produced comparable reductions in conditioned responses during extinction and importantly, both disrupted reconsolidation of conditioned fear and abolished stimulus discrimination between reinforced and non-reinforced cues. Thus, disrupted reconsolidation of fear conditioning can be achieved without in vivo stimulus presentation, through purely cognitive means, suggesting possible therapeutic applications. Copyright © 2016 Elsevier B.V. All rights reserved.

Appetitive but not aversive olfactory conditioning modifies antennal movements in honeybees

PubMed Central

Cholé, Hanna; Junca, Pierre

2015-01-01

In honeybees, two olfactory conditioning protocols allow the study of appetitive and aversive Pavlovian associations. Appetitive conditioning of the proboscis extension response (PER) involves associating an odor, the conditioned stimulus (CS) with a sucrose solution, the unconditioned stimulus (US). Conversely, aversive conditioning of the sting extension response (SER) involves associating the odor CS with an electric or thermal shock US. Each protocol is based on the measure of a different behavioral response (proboscis versus sting) and both only provide binary responses (extension or not of the proboscis or sting). These limitations render the measure of the acquired valence of an odor CS difficult without testing the animals in a freely moving situation. Here, we studied the effects of both olfactory conditioning protocols on the movements of the antennae, which are crucial sensory organs for bees. As bees’ antennae are highly mobile, we asked whether their movements in response to an odorant change following appetitive or aversive conditioning and if so, do odor-evoked antennal movements contain information about the acquired valence of the CS? We implemented a tracking system for harnessed bees’ antennal movements based on a motion capture principle at a high frequency rate. We observed that differential appetitive conditioning had a strong effect on antennal movements. Bees responded to the reinforced odorant with a marked forward motion of the antennae and a strong velocity increase. Conversely, differential aversive conditioning had no associative effect on antennal movements. Rather than revealing the acquired valence of an odorant, antennal movements may represent a novel conditioned response taking place during appetitive conditioning and may provide a possible advantage to bees when foraging in natural situations. PMID:26572651

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

PubMed Central

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

2013-01-01

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

An Appetitive Conditioned Stimulus Enhances Fear Acquisition and Impairs Fear Extinction

ERIC Educational Resources Information Center

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

2016-01-01

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

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

ERIC Educational Resources Information Center

Gould, Thomas J.; Lewis, Michael C.

2005-01-01

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

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

ERIC Educational Resources Information Center

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

2010-01-01

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

Coming to terms with fear

PubMed Central

LeDoux, Joseph E.

2014-01-01

The brain mechanisms of fear have been studied extensively using Pavlovian fear conditioning, a procedure that allows exploration of how the brain learns about and later detects and responds to threats. However, mechanisms that detect and respond to threats are not the same as those that give rise to conscious fear. This is an important distinction because symptoms based on conscious and nonconscious processes may be vulnerable to different predisposing factors and may also be treatable with different approaches in people who suffer from uncontrolled fear or anxiety. A conception of so-called fear conditioning in terms of circuits that operate nonconsciously, but that indirectly contribute to conscious fear, is proposed as way forward. PMID:24501122

Low-Cost Avoidance Behaviors are Resistant to Fear Extinction in Humans

PubMed Central

Vervliet, Bram; Indekeu, Ellen

2015-01-01

Elevated levels of fear and avoidance are core symptoms across the anxiety disorders. It has long been known that fear serves to motivate avoidance. Consequently, fear extinction has been the primary focus in pre-clinical anxiety research for decades, under the implicit assumption that removing the motivator of avoidance (fear) would automatically mitigate the avoidance behaviors as well. Although this assumption has intuitive appeal, it has received little scientific scrutiny. The scarce evidence from animal studies is mixed, while the assumption remains untested in humans. The current study applied an avoidance conditioning protocol in humans to investigate the effects of fear extinction on the persistence of low-cost avoidance. Online danger-safety ratings and skin conductance responses documented the dynamics of conditioned fear across avoidance and extinction phases. Anxiety- and avoidance-related questionnaires explored individual differences in rates of avoidance. Participants first learned to click a button during a predictive danger signal, in order to cancel an upcoming aversive electrical shock (avoidance conditioning). Next, fear extinction was induced by presenting the signal in the absence of shocks while button-clicks were prevented (by removing the button in Experiment 1, or by instructing not to click the button in Experiment 2). Most importantly, post-extinction availability of the button caused a significant return of avoidant button-clicks. In addition, trait-anxiety levels correlated positively with rates of avoidance during a predictive safety signal, and with the rate of pre- to post-extinction decrease during this signal. Fear measures gradually decreased during avoidance conditioning, as participants learned that button-clicks effectively canceled the shock. Preventing button-clicks elicited a sharp increase in fear, which subsequently extinguished. Fear remained low during avoidance testing, but danger-safety ratings increased again when button-clicks were subsequently prevented. Together, these results show that low-cost avoidance behaviors can persist following fear extinction and induce increased threat appraisal. On the other hand, fear extinction did reduce augmented rates of unnecessary avoidance during safety in trait-anxious individuals, and instruction-based response prevention was more effective than removal of response cues. More research is needed to characterize the conditions under which fear extinction might mitigate avoidance. PMID:26733837

Differential associative training enhances olfactory acuity in Drosophila melanogaster.

PubMed

Barth, Jonas; Dipt, Shubham; Pech, Ulrike; Hermann, Moritz; Riemensperger, Thomas; Fiala, André

2014-01-29

Training can improve the ability to discriminate between similar, confusable stimuli, including odors. One possibility of enhancing behaviorally expressed discrimination (i.e., sensory acuity) relies on differential associative learning, during which animals are forced to detect the differences between similar stimuli. Drosophila represents a key model organism for analyzing neuronal mechanisms underlying both odor processing and olfactory learning. However, the ability of flies to enhance fine discrimination between similar odors through differential associative learning has not been analyzed in detail. We performed associative conditioning experiments using chemically similar odorants that we show to evoke overlapping neuronal activity in the fly's antennal lobes and highly correlated activity in mushroom body lobes. We compared the animals' performance in discriminating between these odors after subjecting them to one of two types of training: either absolute conditioning, in which only one odor is reinforced, or differential conditioning, in which one odor is reinforced and a second odor is explicitly not reinforced. First, we show that differential conditioning decreases behavioral generalization of similar odorants in a choice situation. Second, we demonstrate that this learned enhancement in olfactory acuity relies on both conditioned excitation and conditioned inhibition. Third, inhibitory local interneurons in the antennal lobes are shown to be required for behavioral fine discrimination between the two similar odors. Fourth, differential, but not absolute, training causes decorrelation of odor representations in the mushroom body. In conclusion, differential training with similar odors ultimately induces a behaviorally expressed contrast enhancement between the two similar stimuli that facilitates fine discrimination.

Learned together, extinguished apart: reducing fear to complex stimuli

PubMed Central

Jones, Carolyn E.; Ringuet, Stephanie; Monfils, Marie-H.

2013-01-01

Pairing a previously neutral conditioned stimulus (CS; e.g., a tone) to an aversive unconditioned stimulus (US; e.g., a footshock) leads to associative learning such that the tone alone comes to elicit a conditioned response (e.g., freezing). We have previously shown that an extinction session that occurs within the reconsolidation window attenuates fear responding and prevents the return of fear in pure tone Pavlovian fear conditioning. Here we sought to examine whether this effect also applies to a more complex fear memory. First, we show that after fear conditioning to the simultaneous presentation of a tone and a light (T+L) coterminating with a shock, the compound memory that ensues is more resistant to fear extinction than simple tone-shock pairings. Next, we demonstrate that the compound memory can be disrupted by interrupting the reconsolidation of the two individual components using a sequential retrieval+extinction paradigm, provided the stronger compound component is retrieved first. These findings provide insight into how compound memories are encoded, and could have important implications for PTSD treatment. PMID:24241750

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

PubMed

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

2017-05-30

Stressors can be actively or passively coped with, and adequate adaption of the coping response to environmental conditions can reduce their potential deleterious effects. One major factor influencing stress coping behaviour is serotonin transporter (5-HTT) availability. Abolishment of 5-HTT is known to impair fear extinction but facilitates acquisition of signalled active avoidance (AA), a behavioural task in which an animal learns to avoid an aversive stimulus that is predicted by a cue. Flexibility in adapting coping behaviour to the nature of the stressor shapes resilience to stress-related disorders. Therefore, we investigated the relation between 5-HTT expression and ability to adapt a learned coping response to changing environmental conditions. To this end, we first established and consolidated a cue-conditioned passive fear response in 5-HTT -/- and wildtype rats. Next, we used the conditioned stimulus (CS) to signal oncoming shocks during signalled AA training in 5-HTT -/- and wildtype rats to study their capability to acquire an active coping response to the CS following fear conditioning. Finally, we investigated the behavioural response to the CS in a novel environment and measured freezing, exploration and self-grooming, behaviours reflective of stress coping strategy. We found that fear conditioned and sham conditioned 5-HTT -/- animals acquired the signalled AA response faster than wildtypes, while prior conditioning briefly delayed AA learning similarly in both genotypes. Subsequent exposure to the CS in the novel context reduced freezing and increased locomotion in 5-HTT -/- compared to wildtype rats. This indicates that improved AA performance in 5-HTT -/- rats resulted in a weaker residual passive fear response to the CS in a novel context. Fear conditioning prior to AA training did not affect freezing upon re-encountering the CS, although it did reduce locomotion in 5-HTT -/- rats. We conclude that independent of 5-HTT signalling, prior fear conditioning does not greatly impair the acquisition of subsequent active coping behaviour when the situation allows for it. Abolishment of 5-HTT results in a more active coping style in case of novelty-induced fear and upon CS encounter in a novel context after AA learning. Copyright © 2017 Elsevier B.V. All rights reserved.

Vanadium Exposure Induces Olfactory Dysfunction in an Animal Model of Metal Neurotoxicity

PubMed Central

Ngwa, Hilary Afeseh; Kanthasamy, Arthi; Jin, Huajun; Anantharam, Vellareddy; Kanthasamy, Anumantha G.

2014-01-01

Epidemiological evidence indicates chronic environmental exposure to transition metals may play a role in chronic neurodegenerative conditions such as Parkinson’s disease (PD). Chronic inhalation exposure to welding fumes containing metal mixtures may be associated with development of PD. A significant amount of vanadium is present in welding fumes, as vanadium pentoxide (V2O5), and incorporation of vanadium in the production of high strength steel has become more common. Despite the increased vanadium use in recent years, the neurotoxicological effects of this metal are not well characterized. Recently, we demonstrated that V2O5 induces dopaminergic neurotoxicity via protein kinase C delta (PKCδ)-dependent oxidative signaling mechanisms in dopaminergic neuronal cells. Since anosmia (inability to perceive odors) and non-motor deficits are considered to be early symptoms of neurological diseases, in the present study, we examined the effect of V2O5 on the olfactory bulb in animal models. To mimic the inhalation exposure, we intranasally administered C57 black mice a low-dose of 182 µg of V2O5 three times a week for one month, and behavioral, neurochemical and biochemical studies were performed. Our results revealed a significant decrease in olfactory bulb weights, tyrosine hydroxylase (TH) levels, levels of dopamine (DA) and its metabolite, 3, 4-dihydroxyphenylacetic acid (DOPAC) and increases in astroglia of the glomerular layer of the olfactory bulb in the treatment groups relative to vehicle controls. Neurochemical changes were accompanied by impaired olfaction and locomotion. These findings suggest that nasal exposure to V2O5 adversely affects olfactory bulbs, resulting in neurobehavioral and neurochemical impairments. These results expand our understanding of vanadium neurotoxicity in environmentally-linked neurological conditions. PMID:24362016

Evidence of conscious and subconscious olfactory information processing during word encoding: a magnetoencephalographic (MEG) study.

PubMed

Walla, Peter; Hufnagl, Bernd; Lehrner, Johann; Mayer, Dagmar; Lindinger, Gerald; Deecke, Lüder; Lang, Wilfried

2002-11-01

The present study was meant to distinguish between unconscious and conscious olfactory information processing and to investigate the influence of olfaction on word information processing. Magnetic field changes were recorded in healthy young participants during deep encoding of visually presented words whereby some of the words were randomly associated with an odor. All recorded data were then split into two groups. One group consisted of participants who did not consciously perceive the odor during the whole experiment whereas the other group did report continuous conscious odor perception. The magnetic field changes related to the condition 'words without odor' were subtracted from the magnetic field changes related to the condition 'words with odor' for both groups. First, an odor-induced effect occurred between about 200 and 500 ms after stimulus onset which was similar in both groups. It is interpreted to reflect an activity reduction during word encoding related to the additional olfactory stimulation. Second, a later effect occurred between about 600 and 900 ms after stimulus onset which differed between the two groups. This effect was due to higher brain activity related to the additional olfactory stimulation. It was more pronounced in the group consisting of participants who consciously perceived the odor during the whole experiment as compared to the other group. These results are interpreted as evidence that the later effect is related to conscious odor perception whereas the earlier effect reflects unconscious olfactory information processing. Furthermore, our study provides evidence that only the conscious perception of an odor which is simultaneously presented to the visual presentation of a word reduces its chance to be subsequently recognized.

Tbr2 Deficiency in Mitral and Tufted Cells Disrupts Excitatory–Inhibitory Balance of Neural Circuitry in the Mouse Olfactory Bulb

PubMed Central

Mizuguchi, Rumiko; Naritsuka, Hiromi; Mori, Kensaku; Mao, Chai-An; Klein, William H.; Yoshihara, Yoshihiro

2013-01-01

The olfactory bulb (OB) is the first relay station in the brain where odor information from the olfactory epithelium is integrated, processed through its intrinsic neural circuitry, and conveyed to higher olfactory centers. Compared with profound mechanistic insights into olfactory axon wiring from the nose to the OB, little is known about the molecular mechanisms underlying the formation of functional neural circuitry among various types of neurons inside the OB. T-box transcription factor Tbr2 is expressed in various types of glutamatergic excitatory neurons in the brain including the OB projection neurons, mitral and tufted cells. Here we generated conditional knockout mice in which the Tbr2 gene is inactivated specifically in mitral and tufted cells from late embryonic stages. Tbr2 deficiency caused cell-autonomous changes in molecular expression including a compensatory increase of another T-box member, Tbr1, and a concomitant shift of vesicular glutamate transporter (VGluT) subtypes from VGluT1 to VGluT2. Tbr2-deficient mitral and tufted cells also exhibited anatomical abnormalities in their dendritic morphology and projection patterns. Additionally, several non-cell-autonomous phenotypes were observed in parvalbumin-, calbindin-, and 5T4-positive GABAergic interneurons. Furthermore, the number of dendrodendritic reciprocal synapses between mitral/tufted cells and GABAergic interneurons was significantly reduced. Upon stimulation with odorants, larger numbers of mitral and tufted cells were activated in Tbr2 conditional knockout mice. These results suggest that Tbr2 is required for not only the proper differentiation of mitral and tufted cells, but also for the establishment of functional neuronal circuitry in the OB and maintenance of excitatory–inhibitory balance crucial for odor information processing. PMID:22745484

Tbr2 deficiency in mitral and tufted cells disrupts excitatory-inhibitory balance of neural circuitry in the mouse olfactory bulb.

PubMed

Mizuguchi, Rumiko; Naritsuka, Hiromi; Mori, Kensaku; Mao, Chai-An; Klein, William H; Yoshihara, Yoshihiro

2012-06-27

The olfactory bulb (OB) is the first relay station in the brain where odor information from the olfactory epithelium is integrated, processed through its intrinsic neural circuitry, and conveyed to higher olfactory centers. Compared with profound mechanistic insights into olfactory axon wiring from the nose to the OB, little is known about the molecular mechanisms underlying the formation of functional neural circuitry among various types of neurons inside the OB. T-box transcription factor Tbr2 is expressed in various types of glutamatergic excitatory neurons in the brain including the OB projection neurons, mitral and tufted cells. Here we generated conditional knockout mice in which the Tbr2 gene is inactivated specifically in mitral and tufted cells from late embryonic stages. Tbr2 deficiency caused cell-autonomous changes in molecular expression including a compensatory increase of another T-box member, Tbr1, and a concomitant shift of vesicular glutamate transporter (VGluT) subtypes from VGluT1 to VGluT2. Tbr2-deficient mitral and tufted cells also exhibited anatomical abnormalities in their dendritic morphology and projection patterns. Additionally, several non-cell-autonomous phenotypes were observed in parvalbumin-, calbindin-, and 5T4-positive GABAergic interneurons. Furthermore, the number of dendrodendritic reciprocal synapses between mitral/tufted cells and GABAergic interneurons was significantly reduced. Upon stimulation with odorants, larger numbers of mitral and tufted cells were activated in Tbr2 conditional knockout mice. These results suggest that Tbr2 is required for not only the proper differentiation of mitral and tufted cells, but also for the establishment of functional neuronal circuitry in the OB and maintenance of excitatory-inhibitory balance crucial for odor information processing.

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

PubMed

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

2012-01-18

Posttraumatic stress disorder (PTSD) is characterized by stress-induced symptoms including exaggerated fear memories, hypervigilance and hyperarousal. However, we are unaware of an animal model that investigates these hallmarks of PTSD especially in relation to fear extinction and habituation. Therefore, to develop a valid animal model of PTSD, we exposed rats to different intensities of footshock stress to determine their effects on either auditory predator odor fear extinction or habituation of fear sensitization. In Experiment 1, rats were exposed to acute footshock stress (no shock control, 0.4 mA, or 0.8 mA) immediately prior to auditory fear conditioning training involving the pairing of auditory clicks with a cloth containing cat odor. When presented to the conditioned auditory clicks in the next 5 days of extinction testing conducted in a runway apparatus with a hide box, rats in the two shock groups engaged in higher levels of freezing and head out vigilance-like behavior from the hide box than the no shock control group. This increase in fear behavior during extinction testing was likely due to auditory activation of the conditioned fear state because Experiment 2 demonstrated that conditioned fear behavior was not broadly increased in the absence of the conditioned auditory stimulus. Experiment 3 was then conducted to determine whether acute exposure to stress induces a habituation resistant sensitized fear state. We found that rats exposed to 0.8 mA footshock stress and subsequently tested for 5 days in the runway hide box apparatus with presentations of nonassociative auditory clicks exhibited high initial levels of freezing, followed by head out behavior and culminating in the occurrence of locomotor hyperactivity. In addition, Experiment 4 indicated that without delivery of nonassociative auditory clicks, 0.8 mA footshock stressed rats did not exhibit robust increases in sensitized freezing and locomotor hyperactivity, albeit head out vigilance-like behavior continued to be observed. In summary, our animal model provides novel information on the effects of different intensities of footshock stress, auditory-predator odor fear conditioning, and their interactions on facilitating either extinction-resistant or habituation-resistant fear-related behavior. These results lay the foundation for exciting new investigations of the hallmarks of PTSD that include the stress-induced formation and persistence of traumatic memories and sensitized fear. Copyright © 2011 Elsevier Inc. All rights reserved.

The effect of fear and anger on selective attention.

PubMed

Finucane, Anne M

2011-08-01

This experiment examined the effects of two discrete negative emotions, fear and anger, on selective attention. A within-subjects design was used, and all participants (N = 98) experienced the control, anger, and fear conditions. During each condition, participants viewed a film clip eliciting the target emotion and subsequently completed a flanker task and emotion report. Selective attention costs were assessed by comparing reaction times (RTs) on congruent (baseline) trials with RTs on incongruent trials. There was a significant interaction between emotion condition (control, anger, fear) and flanker type (congruent, incongruent). Contrasts further revealed a significant interaction between emotion and flanker type when comparing RTs in the control and fear conditions, and a marginally significant interaction when comparing RTs in the control and anger conditions. This indicates that selective attention costs were significantly lower in the fear compared to the control condition and were marginally lower in the anger compared with the control condition. Further analysis of participants reporting heightened anger in the anger condition revealed significantly lower selective attention costs during anger compared to a control state. These findings support the general prediction that high arousal negative emotional states inhibit processing of nontarget information and enhance selective attention. This study is the first to show an enhancing effect of anger on selective attention. It also offers convergent evidence to studies that have previously shown an influence of fear on attentional focus using the global-local paradigm. 2011 APA, all rights reserved

Enhanced Extinction of Aversive Memories by High-Frequency Stimulation of the Rat Infralimbic Cortex

PubMed Central

Maroun, Mouna; Kavushansky, Alexandra; Holmes, Andrew; Wellman, Cara; Motanis, Helen

2012-01-01

Electrical stimulation of the rodent medial prefrontal cortex (mPFC), including the infralimbic cortex (IL), immediately prior to or during fear extinction training facilitates extinction memory. Here we examined the effects of high-frequency stimulation (HFS) of the rat IL either prior to conditioning or following retrieval of the conditioned memory, on extinction of Pavlovian fear and conditioned taste aversion (CTA). IL-HFS applied immediately after fear memory retrieval, but not three hours after retrieval or prior to conditioning, subsequently reduced freezing during fear extinction. Similarly, IL-HFS given immediately, but not three hours after, retrieval of a CTA memory reduced aversion during extinction. These data indicate that HFS of the IL may be an effective method for reducing both learned fear and learned aversion. PMID:22586453

Effects of vagus nerve stimulation on extinction of conditioned fear and post-traumatic stress disorder symptoms in rats.

PubMed

Noble, L J; Gonzalez, I J; Meruva, V B; Callahan, K A; Belfort, B D; Ramanathan, K R; Meyers, E; Kilgard, M P; Rennaker, R L; McIntyre, C K

2017-08-22

Exposure-based therapies help patients with post-traumatic stress disorder (PTSD) to extinguish conditioned fear of trauma reminders. However, controlled laboratory studies indicate that PTSD patients do not extinguish conditioned fear as well as healthy controls, and exposure therapy has high failure and dropout rates. The present study examined whether vagus nerve stimulation (VNS) augments extinction of conditioned fear and attenuates PTSD-like symptoms in an animal model of PTSD. To model PTSD, rats were subjected to a single prolonged stress (SPS) protocol, which consisted of restraint, forced swim, loss of consciousness, and 1 week of social isolation. Like PTSD patients, rats subjected to SPS show impaired extinction of conditioned fear. The SPS procedure was followed, 1 week later, by auditory fear conditioning (AFC) and extinction. VNS or sham stimulation was administered during half of the extinction days, and was paired with presentations of the conditioned stimulus. One week after completion of extinction training, rats were given a battery of behavioral tests to assess anxiety, arousal and avoidance. Results indicated that rats given SPS 1 week prior to AFC (PTSD model) failed to extinguish the freezing response after eleven consecutive days of extinction. Administration of VNS reversed the extinction impairment and attenuated reinstatement of the conditioned fear response. Delivery of VNS during extinction also eliminated the PTSD-like symptoms, such as anxiety, hyperarousal and social avoidance for more than 1 week after VNS treatment. These results provide evidence that extinction paired with VNS treatment can lead to remission of fear and improvements in PTSD-like symptoms. Taken together, these findings suggest that VNS may be an effective adjunct to exposure therapy for the treatment of PTSD.

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.

A NMDA Receptor Antagonist, MK-801 Impairs Consolidating Extinction of Auditory Conditioned Fear Responses in a Pavlovian Model

PubMed Central

Wang, Zheng-Hong; Rao, Zhi-Ren; Wu, Sheng-Xi; Li, Yun-Qing; Wang, Wen

2009-01-01

Background In auditory fear conditioning, repeated presentation of the tone in the absence of shock leads to extinction of the acquired fear responses. The glutamate N-methyl-D-aspartate receptor (NMDAR) is thought to be involved in the extinction of the conditioned fear responses, but its detailed role in initiating and consolidating or maintaining the fear extinction memory is unclear. Here we investigated this issue by using a NMDAR antagonist, MK-801. Methods/Main Findings The effects of immediate (beginning at 10 min after the conditioning) and delayed (beginning at 24 h after conditioning) extinctions were first compared with the finding that delayed extinction caused a better and long-lasting (still significant on the 20th day after extinction) depression on the conditioned fear responses. In a second experiment, MK-801 was intraperitoneally (i.p.) injected at 40 min before, 4 h or 12 h after the delayed extinction, corresponding to critical time points for initiating, consolidating or maintaining the fear extinction memory. i.p. injection of MK-801 at either 40 min before or 4 h after delayed extinction resulted in an impairment of initiating and consolidating fear extinction memory, which caused a long lasting increased freezing score that was still significant on the 7th day after extinction, compared with extinction group. However, MK-801 administered at 12 h after the delayed extinction, when robust consolidation has been occurred and stabilized, did not affect the established extinction memory. Furthermore, the changed freezing behaviors was not due to an alteration in general anxiety levels, since MK-801 treatment had no effect on the percentage of open-arm time or open-arm entries in an Elevated Plus Maze (EPM) task. Conclusions/Significance Our data suggested that the activation of NMDARs plays important role in initiation and consolidation but not maintenance of fear extinction memory. Together with the fact that NMDA receptor is very important for memory, our data added experimental evidence to the concept that the extinction of conditioned fear responses is a procedure of initiating and consolidating new memory other than simply “erasing” the fear memory. PMID:19855841

A NMDA receptor antagonist, MK-801 impairs consolidating extinction of auditory conditioned fear responses in a Pavlovian model.

PubMed

Liu, Jun-Li; Li, Min; Dang, Xiao-Rong; Wang, Zheng-Hong; Rao, Zhi-Ren; Wu, Sheng-Xi; Li, Yun-Qing; Wang, Wen

2009-10-26

In auditory fear conditioning, repeated presentation of the tone in the absence of shock leads to extinction of the acquired fear responses. The glutamate N-methyl-D-aspartate receptor (NMDAR) is thought to be involved in the extinction of the conditioned fear responses, but its detailed role in initiating and consolidating or maintaining the fear extinction memory is unclear. Here we investigated this issue by using a NMDAR antagonist, MK-801. The effects of immediate (beginning at 10 min after the conditioning) and delayed (beginning at 24 h after conditioning) extinctions were first compared with the finding that delayed extinction caused a better and long-lasting (still significant on the 20(th) day after extinction) depression on the conditioned fear responses. In a second experiment, MK-801 was intraperitoneally (i.p.) injected at 40 min before, 4 h or 12 h after the delayed extinction, corresponding to critical time points for initiating, consolidating or maintaining the fear extinction memory. i.p. injection of MK-801 at either 40 min before or 4 h after delayed extinction resulted in an impairment of initiating and consolidating fear extinction memory, which caused a long lasting increased freezing score that was still significant on the 7th day after extinction, compared with extinction group. However, MK-801 administered at 12 h after the delayed extinction, when robust consolidation has been occurred and stabilized, did not affect the established extinction memory. Furthermore, the changed freezing behaviors was not due to an alteration in general anxiety levels, since MK-801 treatment had no effect on the percentage of open-arm time or open-arm entries in an Elevated Plus Maze (EPM) task. Our data suggested that the activation of NMDARs plays important role in initiation and consolidation but not maintenance of fear extinction memory. Together with the fact that NMDA receptor is very important for memory, our data added experimental evidence to the concept that the extinction of conditioned fear responses is a procedure of initiating and consolidating new memory other than simply "erasing" the fear memory.

Trait Anxiety and Perceptual Load as Determinants of Emotion Processing in a Fear Conditioning Paradigm

PubMed Central

Fox, Elaine; Yates, Alan; Ashwin, Chris

2012-01-01

The impact of trait anxiety and perceptual load on selective attention was examined in a fear conditioning paradigm. A fear-conditioned angry face (CS+), an unconditioned angry face (CS−), or an unconditioned face with a neutral or happy expression were used in distractor interference and attentional probe tasks. In Experiments 1 and 2, participants classified centrally presented letters under two conditions of perceptual load. When perceptual load was high, distractors had no effect on selective attention, even with aversive conditioning. However, when perceptual load was low, strong response interference effects for CS+ face distractors were found for low trait-anxious participants. Across both experiments, this enhanced distractor interference reversed to strong facilitation effects for those reporting high trait anxiety. Thus, high trait-anxious participants were faster, rather than slower, when ignoring CS+ distractors. Using an attentional probe task in Experiment 3, it was found that fear conditioning resulted in strong attentional avoidance in a high trait-anxious group, which contrasted with enhanced vigilance in a low trait-anxious group. These results demonstrate that the impact of fear conditioning on attention is modulated by individual variation in trait anxiety when perceptual load is low. Fear conditioning elicits an avoidance of threat-relevant stimuli in high trait-anxious participants. PMID:21875186

Olfactory Interference during Inhibitory Backward Pairing in Honey Bees

PubMed Central

Dacher, Matthieu; Smith, Brian H.

2008-01-01

Background Restrained worker honey bees are a valuable model for studying the behavioral and neural bases of olfactory plasticity. The proboscis extension response (PER; the proboscis is the mouthpart of honey bees) is released in response to sucrose stimulation. If sucrose stimulation is preceded one or a few times by an odor (forward pairing), the bee will form a memory for this association, and subsequent presentations of the odor alone are sufficient to elicit the PER. However, backward pairing between the two stimuli (sucrose, then odor) has not been studied to any great extent in bees, although the vertebrate literature indicates that it elicits a form of inhibitory plasticity. Methodology/Principal Findings If hungry bees are fed with sucrose, they will release a long lasting PER; however, this PER can be interrupted if an odor is presented 15 seconds (but not 7 or 30 seconds) after the sucrose (backward pairing). We refer to this previously unreported process as olfactory interference. Bees receiving this 15 second backward pairing show reduced performance after a subsequent single forward pairing (excitatory conditioning) trial. Analysis of the results supported a relationship between olfactory interference and a form of backward pairing-induced inhibitory learning/memory. Injecting the drug cimetidine into the deutocerebrum impaired olfactory interference. Conclusions/Significance Olfactory interference depends on the associative link between odor and PER, rather than between odor and sucrose. Furthermore, pairing an odor with sucrose can lead either to association of this odor to PER or to the inhibition of PER by this odor. Olfactory interference may provide insight into processes that gate how excitatory and inhibitory memories for odor-PER associations are formed. PMID:18946512

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.

Prominent facilitation at beta and gamma frequency range revealed with physiological calcium concentration in adult mouse piriform cortex in vitro

PubMed Central

Gleizes, Marie; Perrier, Simon P.; Fonta, Caroline

2017-01-01

Neuronal activity is characterized by a diversity of oscillatory phenomena that are associated with multiple behavioral and cognitive processes, yet the functional consequences of these oscillations are not fully understood. Our aim was to determine whether and how these different oscillatory activities affect short-term synaptic plasticity (STP), using the olfactory system as a model. In response to odorant stimuli, the olfactory bulb displays a slow breathing rhythm as well as beta and gamma oscillations. Since the firing of olfactory bulb projecting neurons is phase-locked with beta and gamma oscillations, structures downstream from the olfactory bulb should be driven preferentially at these frequencies. We examined STP exhibited by olfactory bulb inputs in slices of adult mouse piriform cortex maintained in vitro in an in vivo-like ACSF (calcium concentration: 1.1 mM). We replaced the presynaptic neuronal firing rate by repeated electrical stimulation (frequency between 3.125 and 100 Hz) applied to the lateral olfactory tract. Our results revealed a considerable enhancement of postsynaptic response amplitude for stimulation frequencies in the beta and gamma range. A phenomenological model of STP fitted to the data suggests that the experimental results can be explained by the interplay between three mechanisms: a short-term facilitation mechanism (time constant ≈160 msec), and two short-term depression mechanisms (recovery time constants <20 msec and ≈140 msec). Increasing calcium concentration (2.2 mM) resulted in an increase in the time constant of facilitation and in a strengthening of the slowest depression mechanism. As a result, response enhancement was reduced and its peak shifted toward the low beta and alpha ranges while depression became predominant in the gamma band. Using environmental conditions corresponding to those that prevail in vivo, our study shows that STP in the lateral olfactory tract to layer Ia synapse allows amplification of olfactory bulb inputs at beta and gamma frequencies. PMID:28820903

Sexual odor preference and dopamine release in the nucleus accumbens by estrous olfactory cues in sexually naïve and experienced male rats.

PubMed

Fujiwara, Masaya; Chiba, Atsuhiko

2018-03-01

Sexual behavior is a natural reward that activates mesolimbic dopaminergic system. Microdialysis studies have shown that extracellular level of dopamine (DA) in the nucleus accumbens (NAcc) significantly increases during copulation in male rats. The NAcc DA level is also known to be increased during the presentation of a sexually receptive female before mating. This rise in DA was probably associated with sexual motivation elicited by incentive stimuli from the receptive female. These microdialysis studies, however, did not thoroughly investigated if olfactory stimuli from estrous females could significantly increase the extracellular DA in the NAcc of male rats. The present study was designed to examine systematically the relationship between the expression of preference for the olfactory stimuli from estrous females and the effects of these stimuli on the extracellular DA levels in the NAcc measured by in vivo microdialysis in male Long-Evans (LE) rats. We used two types of olfactory stimuli, either airborne odors (volatile stimuli) or soiled bedding (volatile plus nonvolatile stimuli). The sexually experienced male rats, which experienced six ejaculations, significantly preferred both of these olfactory stimuli from estrous females as opposed to males. Exposure to these female olfactory stimuli gradually increased extracellular DA in the NAcc, which reached significantly higher level above baseline during the period following the removal of the stimuli although not during the 15-min stimulus presentation period. The sexually naïve male rats, on the other hand, showed neither preference for olfactory stimuli from estrous females nor increase in the NAcc DA after exposure to these stimuli. These data suggest that in male LE rats olfactory stimuli from estrous females in and of themselves can be conditional cues that induce both incentive motivation and a significant increase in the NAcc DA probably as a result of being associated with sexual reward through copulatory experience. Copyright © 2017. Published by Elsevier Inc.

Mechanisms of Regulation of Olfactory Transduction and Adaptation in the Olfactory Cilium

PubMed Central

Antunes, Gabriela; Sebastião, Ana Maria; Simoes de Souza, Fabio Marques

2014-01-01

Olfactory adaptation is a fundamental process for the functioning of the olfactory system, but the underlying mechanisms regulating its occurrence in intact olfactory sensory neurons (OSNs) are not fully understood. In this work, we have combined stochastic computational modeling and a systematic pharmacological study of different signaling pathways to investigate their impact during short-term adaptation (STA). We used odorant stimulation and electroolfactogram (EOG) recordings of the olfactory epithelium treated with pharmacological blockers to study the molecular mechanisms regulating the occurrence of adaptation in OSNs. EOG responses to paired-pulses of odorants showed that inhibition of phosphodiesterases (PDEs) and phosphatases enhanced the levels of STA in the olfactory epithelium, and this effect was mimicked by blocking vesicle exocytosis and reduced by blocking cyclic adenosine monophosphate (cAMP)-dependent protein kinase (PKA) and vesicle endocytosis. These results suggest that G-coupled receptors (GPCRs) cycling is involved with the occurrence of STA. To gain insights on the dynamical aspects of this process, we developed a stochastic computational model. The model consists of the olfactory transduction currents mediated by the cyclic nucleotide gated (CNG) channels and calcium ion (Ca2+)-activated chloride (CAC) channels, and the dynamics of their respective ligands, cAMP and Ca2+, and it simulates the EOG results obtained under different experimental conditions through changes in the amplitude and duration of cAMP and Ca2+ response, two second messengers implicated with STA occurrence. The model reproduced the experimental data for each pharmacological treatment and provided a mechanistic explanation for the action of GPCR cycling in the levels of second messengers modulating the levels of STA. All together, these experimental and theoretical results indicate the existence of a mechanism of regulation of STA by signaling pathways that control GPCR cycling and tune the levels of second messengers in OSNs, and not only by CNG channel desensitization as previously thought. PMID:25144232

Phobias and Preparedness - Republished Article.

PubMed

Seligman, Martin E P

2016-09-01

Some inadequacies of the classical conditioning analysis of phobias are discussed: phobias are highly resistant to extinction, whereas laboratory fear conditioning, unlike avoidance conditioning, extinguishes rapidly; phobias comprise a nonarbitrary and limited set of objects, whereas fear conditioning is thought to occur to an unlimited range of conditioned stimuli. Furthermore, phobias, unlike laboratory fear conditioning, are often acquired in one trial and seem quite resistant to change by "cognitive" means. An analysis of phobias using a more contemporary model of fear conditioning is proposed. In this view, phobias are seen as instances of highly "prepared" learning (Seligman, 1970). Such prepared learning is selective, highly resistant to extinction, probably noncognitive and can be acquired in one trial. A reconstruction of the notion of symbolism is suggested. Copyright © 2016 Elsevier Ltd. All rights reserved.

Odorant Metabolism Analysis by an Automated Ex Vivo Headspace Gas-Chromatography Method.

PubMed

Faure, Philippe; Legendre, Arièle; Hanser, Hassan-Ismail; Andriot, Isabelle; Artur, Yves; Guichard, Elisabeth; Coureaud, Gérard; Heydel, Jean-Marie

2016-01-01

In the olfactory epithelium (OE), odorant metabolizing enzymes have the dual function of volatile component detoxification and active clearance of odorants from the perireceptor environment to respectively maintain the integrity of the tissues and the sensitivity of the detection. Although emphasized by recent studies, this enzymatic mechanism is poorly documented in mammals. Thus, olfactory metabolism has been characterized mainly in vitro and for a limited number of odorants. The automated ex vivo headspace gas-chromatography method that was developed here was validated to account for odorant olfactory metabolism. This method easily permits the measurement of the fate of an odorant in the OE environment, taking into account the odorant gaseous state and the cellular structure of the tissue, under experimental conditions close to physiological conditions and with a high reproducibility. We confirmed here our previous results showing that a high olfactory metabolizing activity of the mammary pheromone may be necessary to maintain a high level of sensitivity toward this molecule, which is critical for newborn rabbit survival. More generally, the method that is presented here may permit the screening of odorants metabolism alone or in mixture or studying the impact of aging, pathology, polymorphism or inhibitors on odorant metabolism. © The Author 2015. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Modification of Fear Memory by Pharmacological and Behavioural Interventions during Reconsolidation.

PubMed

Thome, Janine; Koppe, Georgia; Hauschild, Sophie; Liebke, Lisa; Schmahl, Christian; Lis, Stefanie; Bohus, Martin

2016-01-01

Dysfunctional fear responses play a central role in many mental disorders. New insights in learning and memory suggest that pharmacological and behavioural interventions during the reconsolidation of reactivated fear memories may increase the efficacy of therapeutic interventions. It has been proposed that interventions applied during reconsolidation may modify the original fear memory, and thus prevent the spontaneous recovery and reinstatement of the fear response. We investigated whether pharmacological (propranolol) and behavioural (reappraisal, multisensory stimulation) interventions reduce fear memory, and prevent reinstatement of fear in comparison to a placebo control group. Eighty healthy female subjects underwent a differential fear conditioning procedure with three stimuli (CS). Two of these (CS+) were paired with an electric shock on day 1. On day 2, 20 subjects were pseudo-randomly assigned to either the propranolol or placebo condition, or underwent one of the two behavioural interventions after one of the two CS+ was reactivated. On day 3, all subjects underwent an extinction phase, followed by a reinstatement test. Dependent variables were US expectancy ratings, fear-potentiated startle, and skin conductance response. Differential fear responses to the reactivated and non-reactivated CS+ were observed only in the propranolol condition. Here, the non-reactivated CS+ evoked stronger fear-potentiated startle-responses compared to the placebo group. None of the interventions prevented the return of the extinguished fear response after re-exposure to the unconditioned stimulus. Our data are in line with an increasing body of research stating that the occurrence of reconsolidation may be constrained by boundary conditions such as subtle differences in experimental manipulations and instructions. In conclusion, our findings do not support a beneficial effect in using reconsolidation processes to enhance effects of psychotherapeutic interventions. This implies that more research is required before therapeutic interventions may benefit from a combination with reconsolidation processes.

SPIDER OR NO SPIDER? NEURAL CORRELATES OF SUSTAINED AND PHASIC FEAR IN SPIDER PHOBIA.

PubMed

Münsterkötter, Anna Luisa; Notzon, Swantje; Redlich, Ronny; Grotegerd, Dominik; Dohm, Katharina; Arolt, Volker; Kugel, Harald; Zwanzger, Peter; Dannlowski, Udo

2015-09-01

Processes of phasic fear responses to threatening stimuli are thought to be distinct from sustained, anticipatory anxiety toward an unpredicted, potential threat. There is evidence for dissociable neural correlates of phasic fear and sustained anxiety. Whereas increased amygdala activity has been associated with phasic fear, sustained anxiety has been linked with activation of the bed nucleus of stria terminalis (BNST), anterior cingulate cortex (ACC), and the insula. So far, only a few studies have focused on the dissociation of neural processes related to both phasic and sustained fear in specific phobia. We suggested that first, conditions of phasic and sustained fear would involve different neural networks and, second, that overall neural activity would be enhanced in a sample of phobic compared to nonphobic participants. Pictures of spiders and neutral stimuli under conditions of either predicted (phasic) or unpredicted (sustained) fear were presented to 28 subjects with spider phobia and 28 nonphobic control subjects during functional magnetic resonance imaging (fMRI) scanning. Phobic patients revealed significantly higher amygdala activation than controls under conditions of phasic fear. Sustained fear processing was significantly related to activation in the insula and ACC, and phobic patients showed a stronger activation than controls of the BNST and the right ACC under conditions of sustained fear. Functional connectivity analysis revealed enhanced connectivity of the BNST and the amygdala in phobic subjects. Our findings support the idea of distinct neural correlates of phasic and sustained fear processes. Increased neural activity and functional connectivity in these networks might be crucial for the development and maintenance of anxiety disorders. © 2015 Wiley Periodicals, Inc.

The effect of intranasal oxytocin treatment on conditioned fear extinction and recall in a healthy human sample.

PubMed

Acheson, Dean; Feifel, David; de Wilde, Sofieke; McKinney, Rebecca; Lohr, James; Risbrough, Victoria

2013-09-01

To improve outcomes for patients undergoing extinction-based therapies (e.g., exposure therapy) for anxiety disorders such as post-traumatic stress disorder (PTSD), there has been interest in identifying pharmaceutical compounds that might facilitate fear extinction learning and recall. Oxytocin (OT) is a mammalian neuropeptide that modulates activation of fear extinction-based neural circuits and fear responses. Little is known, however, about the effects of OT treatment on conditioned fear responding and extinction in humans. The purpose of the present study was to assess the effects of OT in a fear-potentiated startle task of fear conditioning and extinction. A double-blind, placebo-controlled study of 44 healthy human participants was conducted. Participants underwent a conditioned fear acquisition procedure, after which they were randomized to treatment group and delivered OT (24 IU) or placebo via intranasal (IN) spray. Forty-five minutes after treatment, participants underwent extinction training. Twenty-four hours later, subjects were tested for extinction recall. Relative to placebo, the OT group showed increased fear-potentiated startle responding during the earliest stage of extinction training relative to placebo; however, all treatment groups showed the same level of reduced responding by the end of extinction training. Twenty-four hours later, the OT group showed significantly higher recall of extinction relative to placebo. The current study provides preliminary evidence that OT may facilitate fear extinction recall in humans. These results support further study of OT as a potential adjunctive treatment for extinction-based therapies in fear-related disorders.

Defensive aggregation (huddling) in Rattus norvegicus toward predator odor: individual differences, social buffering effects and neural correlates.

PubMed

Bowen, Michael T; Kevin, Richard C; May, Matthew; Staples, Lauren G; Hunt, Glenn E; McGregor, Iain S

2013-01-01

Aggregation is a defensive strategy employed by many prey species in response to predatory threat. Our group has characterized defensive aggregation (huddling) in Rattus norvegicus in response to a ball of cat fur. In this situation some rats huddle less, and approach the threatening cue more than others (active vs. passive responders). The present study explored whether active responding is a stable phenotype associated with behaviors outside direct predatory encounters. The neural substrates of active and passive responding under predatory threat were explored using c-Fos immunohistochemistry. Finally, we examined whether the presence of conspecifics during predatory threat biases behavior towards active responding. Active and passive responding styles were found to be stable in individual rats across consecutive group exposures to cat fur, and were predicted by anxiety-like behavior in an open-field emergence test. Active responders displayed less conditioned fear in an environment associated with predatory threat, and had higher post-exposure intake of a weak sucrose solution (a test of "anhedonia"). Active responding was associated with: greater cat fur-induced activation of the accessory olfactory bulb, reflecting greater olfactory stimulation in rats actively approaching the fur; lowered activation of somatosensory cortex, reflecting reduced huddling with conspecifics; and reduced activation in the lateral septum. Social exposure to cat fur promoted active responding relative to individual exposure, and lowered c-Fos expression in the dorsomedial periaqueductal grey, medial caudate putamen and lateral habenula. We conclude that individual differences in anti-predator behavior appear stable traits with active responders having a more resilient phenotype. Social exposure to predatory threat has an acute buffering effect, subtly changing the neural and behavioral response towards threat and encouraging active responding. An association between active responding and lower c-Fos expression in the lateral septum is consistent with previous studies that highlight this region as an important neurobiological substrate of defensive aggregation.

Defensive Aggregation (Huddling) in Rattus Norvegicus toward Predator Odor: Individual Differences, Social Buffering Effects and Neural Correlates

PubMed Central

Bowen, Michael T.; Kevin, Richard C.; May, Matthew; Staples, Lauren G.; Hunt, Glenn E.; McGregor, Iain S.

2013-01-01

Aggregation is a defensive strategy employed by many prey species in response to predatory threat. Our group has characterized defensive aggregation (huddling) in Rattus norvegicus in response to a ball of cat fur. In this situation some rats huddle less, and approach the threatening cue more than others (active vs. passive responders). The present study explored whether active responding is a stable phenotype associated with behaviors outside direct predatory encounters. The neural substrates of active and passive responding under predatory threat were explored using c-Fos immunohistochemistry. Finally, we examined whether the presence of conspecifics during predatory threat biases behavior towards active responding. Active and passive responding styles were found to be stable in individual rats across consecutive group exposures to cat fur, and were predicted by anxiety-like behavior in an open-field emergence test. Active responders displayed less conditioned fear in an environment associated with predatory threat, and had higher post-exposure intake of a weak sucrose solution (a test of “anhedonia”). Active responding was associated with: greater cat fur-induced activation of the accessory olfactory bulb, reflecting greater olfactory stimulation in rats actively approaching the fur; lowered activation of somatosensory cortex, reflecting reduced huddling with conspecifics; and reduced activation in the lateral septum. Social exposure to cat fur promoted active responding relative to individual exposure, and lowered c-Fos expression in the dorsomedial periaqueductal grey, medial caudate putamen and lateral habenula. We conclude that individual differences in anti-predator behavior appear stable traits with active responders having a more resilient phenotype. Social exposure to predatory threat has an acute buffering effect, subtly changing the neural and behavioral response towards threat and encouraging active responding. An association between active responding and lower c-Fos expression in the lateral septum is consistent with previous studies that highlight this region as an important neurobiological substrate of defensive aggregation. PMID:23922655

Inhibition of amygdaloid dopamine D2 receptors impairs emotional learning measured with fear-potentiated startle.

PubMed

Greba, Q; Gifkins, A; Kokkinidis, L

2001-04-27

Considerable advances have been made in understanding the neurocircuitry underlying the acquisition and expression of Pavlovian conditioned fear responses. Within the complex cellular and molecular processes mediating fearfulness, amygdaloid dopamine (DA), originating from cells in the ventral tegmental area (VTA) of the midbrain, is thought to contribute to fear-motivated responding. Considering that blockade of DA D(2) receptors is a common mechanism of action for antipsychotic agents, we hypothesized that inhibition of D(2) receptors in the amygdala may be involved in the antiparanoid effects of these drugs. To assess the role of amygdaloid DA D(2) receptors in aversive emotionality, the D(2) receptor antagonist raclopride was infused into the amygdala prior to Pavlovian fear conditioning. Potentiated startle was used as a behavioral indicator of fear and anxiety. Classical fear conditioning and acoustic startle testing were conducted in a single session allowing for the concomitant assessment of shock reactivity with startle enhancement. Depending on dose, the results found conditioned fear acquisition and retention to be impaired following administration of raclopride into the amygdala. Additionally, the learning deficit was dissociated from shock detection and from fear expression assessed with the shock sensitization of acoustic startle. These findings further refine the known neural mechanisms of amygdala-based emotional learning and memory and were interpreted to suggest that, along with D(1) receptors, D(2) receptors in the amygdala may mediate the formation and the retention of newly-acquired fear associations.

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.

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.

Enduring abolishment of remote but not recent expression of conditioned fear by the blockade of calcium-permeable AMPA receptors before extinction training.

PubMed

Zelena, Dóra; Mikics, Éva; Balázsfi, Diána; Varga, János; Klausz, Barbara; Urbán, Eszter; Sipos, Eszter; Biró, László; Miskolczi, Christina; Kovács, Krisztina; Ferenczi, Szilamér; Haller, József

2016-06-01

Calcium-permeable (GluA2 subunit-free) AMPA receptors (CP-AMPAR) play prominent roles in fear extinction; however, no blockers of these receptors were studied in tests relevant to extinction learning so far. The CP-AMPAR antagonist IEM-1460 was administered once before extinction trainings, which were started either 1 or 28 days after fear conditioning (FC). We used a mild extinction protocol that durably decreased but did not abolish conditioned fear. The messenger RNA (mRNA) expression of GluA1 and GluA2 subunits were investigated at both time points in the ventromedial prefrontal cortex (vmPFC) and amygdala. IEM-1460 transiently facilitated extinction 1 day after conditioning, but learned fear spontaneously recovered 4 weeks later. When the extinction protocol was applied 28 days after training, IEM-1460 enhanced extinction memory, moreover abolished conditioned fear for at least a month. The expression of GluA1 and GluA2 mRNAs was increased at both time points in the vmPFC. In the basolateral and central amygdala, the GluA1/GluA2 mRNA ratio increased, suggesting a shift towards the preponderance of GluA1 over GluA2 expression. AMPAR blockade lastingly enhanced the extinction of remote but not recent fear memories. Time-dependent changes in AMPA receptor subunit mRNA expression may explain the differential effects of CP-AMPAR blockade on recent and remote conditioned fear, further supporting the notion that the mechanisms maintaining learned fear change over time. Our findings suggest clinical implications for CP-AMPAR blockers, particularly for acquired anxieties (e.g., post-traumatic stress disorder) which have a slow onset and are durable.

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

The neuroregenerative capacity of olfactory stem cells is not limitless: implications for aging.

PubMed

Child, Kevin M; Herrick, Daniel B; Schwob, James E; Holbrook, Eric H; Jang, Woochan

2018-06-22

The olfactory epithelium (OE) of vertebrates is a highly regenerative neuroepithelium, maintained under normal condition by a population of stem and progenitor cells - globose basal cells (GBCs) that also contribute to epithelial reconstitution after injury. However, aging of the OE often leads to neurogenic exhaustion - the disappearance of both GBCs and olfactory sensory neurons (OSNs). Aneuronal tissue may remain as olfactory, with an uninterrupted sheet of apically arrayed microvillar-capped sustentacular cell, or may undergo respiratory metaplasia. We have generated a transgenic mouse model for neurogenic exhaustion using OMP-driven Tet-off regulation of the A subunit of Diphtheria toxin such that the death of mature OSNs is accelerated. As early as 2 months of age the epithelium of transgenic mice, regardless of sex, recapitulates what is seen in the aged OE of humans and rodents. Areas of the epithelium completely lack neurons and GBCs, while the horizontal basal cells, a reserve stem cell population, show no evidence of activation. Surprisingly, other areas that were olfactory undergo respiratory metaplasia. The impact of accelerated neuronal death and reduced innervation on the olfactory bulb (OB) is also examined. Constant neuronal turnover leaves glomeruli shrunken and impacts the dopaminergic interneurons in the periglomerular layer. Moreover, the acceleration of OSN death can be reversed in those areas where some GBCs persist. However, the projection onto the OB recovers incompletely and the reinnervated glomeruli are markedly altered. Thus, the capacity for OE regeneration is tempered when GBCs disappear. SIGNIFICANCE STATEMENT A large percentage of humans lose or suffer a significant decline in olfactory function as they age. Consequently, quality of life suffers, and safety and nutritional status are put at risk. With age, the OE apparently becomes incapable of fully maintaining the neuronal population of the epithelium despite its well-known capacity for recovering from most forms of injury when younger which may contribute to age-related olfactory loss. Efforts to identify the mechanism by which olfactory neurogenesis becomes exhausted with age require a powerful model for accelerating age-related tissue pathology. The current OMP-tTA ; TetO-DTA transgenic mouse model, in which olfactory neurons die when they reach maturity and accelerated death can be aborted to assess the capacity for structural recovery, satisfies that need. Copyright © 2018 the authors.

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…

Monetary effects on fear conditioning.

PubMed

Qu, Chen; Zhang, Aiyi; Chen, Qishan

2013-04-01

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

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

PubMed

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

2015-08-01

Memory formation is thought to occur via enhanced synaptic connectivity between populations of neurons in the brain. However, it has been difficult to localize and identify the neurons that are directly involved in the formation of any specific memory. We have previously used fos-tau-lacZ (FTL) transgenic mice to identify discrete populations of neurons in amygdala and hypothalamus, which were specifically activated by fear conditioning to a context. Here we have examined neuronal activation due to fear conditioning to a more specific auditory cue. Discrete populations of learning-specific neurons were identified in only a small number of locations in the brain, including those previously found to be activated in amygdala and hypothalamus by context fear conditioning. These populations, each containing only a relatively small number of neurons, may be directly involved in fear learning and memory. © 2015 Butler et al.; Published by Cold Spring Harbor Laboratory Press.

Passive avoidance is linked to impaired fear extinction in humans

PubMed Central

Cornwell, Brian R.; Overstreet, Cassie; Krimsky, Marissa; Grillon, Christian

2013-01-01

Conventional wisdom dictates we must face our fears to conquer them. This idea is embodied in exposure-based treatments for anxiety disorders, where the intent of exposure is to reverse a history of avoidant behavior that is thought to fuel a patient’s irrational fears. We tested in humans the relationship between fear and avoidance by combining Pavlovian differential fear conditioning with a novel task for quantifying spontaneous passive avoidant behavior. During self-guided navigation in virtual reality following de novo fear conditioning, we observed participants keeping their distance from the feared object. At the individual level, passive avoidant behavior was highly associated with maladaptive fear expression (fear-potentiated startle) during late extinction training, indicating that extinction learning was impaired following a brief episode of avoidance. Avoidant behavior, however, was not related to initial acquired fear, raising doubt about a straightforward link between physiological fear and behavioral avoidance. We conclude that a deeper understanding of what motivates avoidance may offer a target for early intervention, before fears transition from the rational to the irrational. PMID:23427168

Successful acquisition of an olfactory discrimination test by Asian elephants, Elephas maximus.

PubMed

Arvidsson, Josefin; Amundin, Mats; Laska, Matthias

2012-02-01

The present study demonstrates that Asian elephants, Elephas maximus, can successfully be trained to cooperate in an olfactory discrimination test based on a food-rewarded two-alternative instrumental conditioning procedure. The animals learned the basic principle of the test within only 60 trials and readily mastered intramodal stimulus transfer tasks. Further, they were capable of distinguishing between structurally related odor stimuli and remembered the reward value of previously learned odor stimuli after 2, 4, 8, and 16 weeks of recess without any signs of forgetting. The precision and consistency of the elephants' performance in tests of odor discrimination ability and long-term odor memory demonstrate the suitability of this method for assessing olfactory function in this proboscid species. An across-species comparison of several measures of olfactory learning capabilities such as speed of initial task acquisition and ability to master intramodal stimulus transfer tasks shows that Asian elephants are at least as good in their performance as mice, rats, and dogs, and clearly superior to nonhuman primates and fur seals. The results support the notion that Asian elephants may use olfactory cues for social communication and food selection and that the sense of smell may play an important role in the control of their behavior. Copyright © 2011 Elsevier Inc. All rights reserved.

Nasal neuron PET imaging quantifies neuron generation and degeneration

PubMed Central

Van de Bittner, Genevieve C.; Riley, Misha M.; Cao, Luxiang; Herrick, Scott P.; Ricq, Emily L.; O’Neill, Michael J.; Ahmed, Zeshan; Murray, Tracey K.; Smith, Jaclyn E.; Wang, Changning; Schroeder, Frederick A.; Albers, Mark W.; Hooker, Jacob M.

2017-01-01

Olfactory dysfunction is broadly associated with neurodevelopmental and neurodegenerative diseases and predicts increased mortality rates in healthy individuals. Conventional measurements of olfactory health assess odor processing pathways within the brain and provide a limited understanding of primary odor detection. Quantification of the olfactory sensory neurons (OSNs), which detect odors within the nasal cavity, would provide insight into the etiology of olfactory dysfunction associated with disease and mortality. Notably, OSNs are continually replenished by adult neurogenesis in mammals, including humans, so OSN measurements are primed to provide specialized insights into neurological disease. Here, we have evaluated a PET radiotracer, [11C]GV1-57, that specifically binds mature OSNs and quantifies the mature OSN population in vivo. [11C]GV1-57 monitored native OSN population dynamics in rodents, detecting OSN generation during postnatal development and aging-associated neurodegeneration. [11C]GV1-57 additionally measured rates of neuron regeneration after acute injury and early-stage OSN deficits in a rodent tauopathy model of neurodegenerative disease. Preliminary assessment in nonhuman primates suggested maintained uptake and saturable binding of [18F]GV1-57 in primate nasal epithelium, supporting its translational potential. Future applications for GV1-57 include monitoring additional diseases or conditions associated with olfactory dysregulation, including cognitive decline, as well as monitoring effects of neuroregenerative or neuroprotective therapeutics. PMID:28112682

The scent of wolves: pyrazine analogs induce avoidance and vigilance behaviors in prey

PubMed Central

Osada, Kazumi; Miyazono, Sadaharu; Kashiwayanagi, Makoto

2015-01-01

The common gray wolf (Canis lupus) is an apex predator located at the top of the food chain in the Northern Hemisphere. It preys on rodents, rabbits, ungulates, and many other kinds of mammal. However, the behavioral evidence for, and the chemical basis of, the fear-inducing impact of wolf urine on prey are unclear. Recently, the pyrazine analogs 2, 6-dimethylpyrazine, 2, 3, 5-trimethylpyrazine and 3-ethyl-2, 5-dimethyl pyrazine were identified as kairomones in the urine of wolves. When mice were confronted with a mixture of purified pyrazine analogs, vigilance behaviors, including freezing and excitation of neurons at the accessory olfactory bulb, were markedly increased. Additionally, the odor of the pyrazine cocktail effectively suppressed the approach of deer to a feeding area, and for those close to the feeding area elicited fear-related behaviors such as the “tail-flag,” “flight,” and “jump” actions. In this review, we discuss the transfer of chemical information from wolf to prey through the novel kairomones identified in wolf urine and also compare the characteristics of wolf kairomones with other predator-produced kairomones that affect rodents. PMID:26500485

Disordered eating and food restrictions in children with PANDAS/PANS.

PubMed

Toufexis, Megan D; Hommer, Rebecca; Gerardi, Diana M; Grant, Paul; Rothschild, Leah; D'Souza, Precilla; Williams, Kyle; Leckman, James; Swedo, Susan E; Murphy, Tanya K

2015-02-01

Sudden onset clinically significant eating restrictions are a defining feature of the clinical presentation of some of the cases of pediatric acute-onset neuropsychiatric syndrome (PANS). Restrictions in food intake are typically fueled by contamination fears; fears of choking, vomiting, or swallowing; and/or sensory issues, such as texture, taste, or olfactory concerns. However, body image distortions may also be present. We investigate the clinical presentation of PANS disordered eating and compare it with that of other eating disorders. We describe 29 patients who met diagnostic criteria for PANS. Most also exhibited evidence that the symptoms might be sequelae of infections with Group A streptococcal bacteria (the pediatric autoimmune neuropsychiatric disorder associated with streptococcal infections [PANDAS] subgroup of PANS). The clinical presentations are remarkable for a male predominance (2:1 M:F), young age of the affected children (mean=9 years; range 5-12 years), acuity of symptom onset, and comorbid neuropsychiatric symptoms. The food refusal associated with PANS is compared with symptoms listed for the new Diagnostic and Statistical Manual of Mental Disorders, 5th ed. (DSM-V) diagnosis of avoidant/restrictive food intake disorder (ARFID). Treatment implications are discussed, as well as directions for further research.

A face versus non-face context influences amygdala responses to masked fearful eye whites.

PubMed

Kim, M Justin; Solomon, Kimberly M; Neta, Maital; Davis, F Caroline; Oler, Jonathan A; Mazzulla, Emily C; Whalen, Paul J

2016-12-01

The structure of the mask stimulus is crucial in backward masking studies and we recently demonstrated such an effect when masking faces. Specifically, we showed that activity of the amygdala is increased to fearful facial expressions masked with neutral faces and decreased to fearful expressions masked with a pattern mask-but critically both masked conditions discriminated fearful expressions from happy expressions. Given this finding, we sought to test whether masked fearful eye whites would produce a similar profile of amygdala response in a face vs non-face context. During functional magnetic resonance imaging scanning sessions, 30 participants viewed fearful or happy eye whites masked with either neutral faces or pattern images. Results indicated amygdala activity was increased to fearful vs happy eye whites in the face mask condition, but decreased to fearful vs happy eye whites in the pattern mask condition-effectively replicating and expanding our previous report. Our data support the idea that the amygdala is responsive to fearful eye whites, but that the nature of this activity observed in a backward masking design depends on the mask stimulus. © The Author (2016). Published by Oxford University Press.

Developing Memory Reconsolidation Blockers as Novel PTSD Treatments

DTIC Science & Technology

2012-06-01

freezing in a Pavlovian cue- conditioned fear task in rats. In Stage II, we will evaluate the ability of candidate drugs to reverse fear conditioning ...disorder (PTSD). The underlying theory is that candidate drugs , when given following the reactivation of a conditioned fear response in animals, or a...traumatic memory in humans, will reduce the strength of the conditioned response or traumatic memory. We plan to test such drugs , either alone or in

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.

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

PubMed Central

Pape, Hans-Christian; Pare, Denis

2009-01-01

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

Immediate extinction promotes the return of fear.

PubMed

Merz, Christian J; Hamacher-Dang, Tanja C; Wolf, Oliver T

2016-05-01

Accumulating evidence indicates that immediate extinction is less effective than delayed extinction in attenuating the return of fear. This line of fear conditioning research impacts the proposed onset of psychological interventions after threatening situations. In the present study, forty healthy men were investigated in a differential fear conditioning paradigm with fear acquisition in context A, extinction in context B, followed by retrieval testing in both contexts 24h later to test fear renewal. Differently coloured lights served as conditioned stimuli (CS): two CS (CS+) were paired with an electrical stimulation that served as unconditioned stimulus, the third CS was never paired (CS-). Extinction took place immediately after fear acquisition or 24h later. One CS+ was extinguished whereas the second CS+ remained unextinguished to control for different time intervals between fear acquisition and retrieval testing. Immediate extinction led to larger skin conductance responses during fear retrieval to both the extinguished and unextinguished CS relative to the CS-, indicating a stronger return of fear compared to delayed extinction. Taken together, immediate extinction is less potent than delayed extinction and is associated with a stronger renewal effect. Thus, the time-point of psychological interventions relative to the offset of threatening situations needs to be carefully considered to prevent relapses. Copyright © 2016 Elsevier Inc. All rights reserved.

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.

Development of fear acquisition and extinction in children: effects of age and anxiety.

PubMed

Jovanovic, Tanja; Nylocks, Karin Maria; Gamwell, Kaitlyn L; Smith, Ami; Davis, Telsie A; Norrholm, Seth Davin; Bradley, Bekh

2014-09-01

Development of anxiety disorders is associated with neurobiological changes in areas that are a critical part of the fear neurocircuitry. Fear conditioning paradigms can offer insight into the mechanisms underlying the neurobiological ontogeny of anxiety. A small number of studies have focused on the effects of age and anxiety separately in school age children. The present study aimed to investigate these effects in 8-13 year old children with higher and lower trait anxiety. We examined differential fear conditioning and extinction using skin conductance responses and fear-potentiated startle in 60 children recruited from a low-income urban population. The results indicated that children under 10 years of age show poor discrimination of conditioned stimuli, and that anxiety increases fear responses during fear acquisition. After controlling for age and trauma exposure, fear-potentiated startle to the safety cue predicted child anxiety levels suggesting that impaired safety signal learning may be a risk factor for anxiety disorders in adulthood. Identifying risk phenotypes in children may provide opportunities for early intervention and prevention of illness. Copyright © 2013 Elsevier Inc. All rights reserved.

Development of Fear Acquisition and Extinction in Children: Effects of Age and Anxiety

PubMed Central

Jovanovic, Tanja; Nylocks, Karin Maria; Gamwell, Kaitlyn L.; Smith, Ami; Davis, Telsie A.; Norrholm, Seth Davin; Bradley, Bekh

2013-01-01

Development of anxiety disorders is associated with neurobiological changes in areas that are a critical part of the fear neurocircuitry. Fear conditioning paradigms can offer insight into the mechanisms underlying the neurobiological ontogeny of anxiety. A small number of studies have focused on the effects of age and anxiety separately in school age children. The present study aimed to investigate these effects in 8-13 year old children with higher and lower trait anxiety. We examined differential fear conditioning and extinction using skin conductance responses and fear-potentiated startle in 60 children recruited from a low-income urban population. The results indicated that children under 10 years of age show poor discrimination of conditioned stimuli, and that anxiety increases fear responses during fear acquisition. After controlling for age and trauma exposure, fear-potentiated startle to the safety cue predicted child anxiety levels suggesting that impaired safety signal learning may be a risk factor for anxiety disorders in adulthood. Identifying risk phenotypes in children may provide opportunities for early intervention and prevention of illness. PMID:24183838

Preventing the return of fear using reconsolidation updating and methylene blue is differentially dependent on extinction learning

PubMed Central

Auchter, Allison M.; Shumake, Jason; Gonzalez-Lima, Francisco; Monfils, Marie H.

2017-01-01

Many factors account for how well individuals extinguish conditioned fears, such as genetic variability, learning capacity and conditions under which extinction training is administered. We predicted that memory-based interventions would be more effective to reduce the reinstatement of fear in subjects genetically predisposed to display more extinction learning. We tested this hypothesis in rats genetically selected for differences in fear extinction using two strategies: (1) attenuation of fear memory using post-retrieval extinction training, and (2) pharmacological enhancement of the extinction memory after extinction training by low-dose USP methylene blue (MB). Subjects selectively bred for divergent extinction phenotypes were fear conditioned to a tone stimulus and administered either standard extinction training or retrieval + extinction. Following extinction, subjects received injections of saline or MB. Both reconsolidation updating and MB administration showed beneficial effects in preventing fear reinstatement, but differed in the groups they targeted. Reconsolidation updating showed an overall effect in reducing fear reinstatement, whereas pharmacological memory enhancement using MB was an effective strategy, but only for individuals who were responsive to extinction. PMID:28397861

Dissociating response systems: erasing fear from memory.

PubMed

Soeter, Marieke; Kindt, Merel

2010-07-01

In addition to the extensive evidence in animals, we previously showed that disrupting reconsolidation by noradrenergic blockade produced amnesia for the original fear response in humans. Interestingly, the declarative memory for the fear association remained intact. These results asked for a solid replication. Moreover, given the constructive nature of memories, the intact recollection of the fear association could eventually 'rebuild' the fear memory, resulting in the spontaneous recovery of the fear response. Yet, perseverance of the amnesic effects would have substantial clinical implications, as even the most effective treatments for psychiatric disorders display high percentages of relapse. Using a differential fear conditioning procedure in humans, we replicated our previous findings by showing that administering propranolol (40mg) prior to memory reactivation eliminated the startle fear response 24h later. But most importantly, this effect persisted at one month follow-up. Notably, the propranolol manipulation not only left the declarative memory for the acquired contingency untouched, but also skin conductance discrimination. In addition, a close association between declarative knowledge and skin conductance responses was found. These findings are in line with the supposed double dissociation of fear conditioning and declarative knowledge relative to the amygdala and hippocampus in humans. They support the view that skin conductance conditioning primarily reflects contingency learning, whereas the startle response is a rather specific measure of fear. Furthermore, the results indicate the absence of a causal link between the actual knowledge of a fear association and its fear response, even though they often operate in parallel. Interventions targeting the amygdalar fear memory may be essential in specifically and persistently dampening the emotional impact of fear. From a clinical and ethical perspective, disrupting reconsolidation points to promising interventions persistently erasing fear responses from trauma memory without affecting the actual recollection.

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

PubMed Central

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

2013-01-01

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

Medial prefrontal cortex activity during the extinction of conditioned fear: an investigation using functional near-infrared spectroscopy.

PubMed

Guhn, Anne; Dresler, Thomas; Hahn, Tim; Mühlberger, Andreas; Ströhle, Andreas; Deckert, Jürgen; Herrmann, Martin J

2012-06-01

The majority of fear conditioning studies in humans have focused on fear acquisition rather than fear extinction. For this reason only a few functional imaging studies on fear extinction are available. A large number of animal studies indicate the medial prefrontal cortex (mPFC) as neuronal substrate of extinction. We therefore determined mPFC contribution during extinction learning after a discriminative fear conditioning in 34 healthy human subjects by using functional near-infrared spectroscopy. During the extinction training, a previously conditioned neutral face (conditioned stimulus, CS+) no longer predicted an aversive scream (unconditioned stimulus, UCS). Considering differential valence and arousal ratings as well as skin conductance responses during the acquisition phase, we found a CS+ related increase in oxygenated haemoglobin concentration changes within the mPFC over the time course of extinction. Late CS+ trials further revealed higher activation than CS- trials in a cluster of probe set channels covering the mPFC. These results are in line with previous findings on extinction and further emphasize the mPFC as significant for associative learning processes. During extinction, the diminished fear association between a former CS+ and a UCS is inversely correlated with mPFC activity--a process presumably dysfunctional in anxiety disorders. Copyright © 2012 S. Karger AG, Basel.

Impaired extinction of fear and maintained amygdala-hippocampal theta synchrony in a mouse model of temporal lobe epilepsy.

PubMed

Lesting, Jörg; Geiger, Matthias; Narayanan, Rajeevan T; Pape, Hans-Christian; Seidenbecher, Thomas

2011-02-01

The relationship between epilepsy and fear has received much attention. However, seizure-modulated fear and physiologic or structural correlates have not been examined systematically, and the underlying basics of network levels remain unclear to date. Therefore, this project was set up to characterize the neurophysiologic basis of seizure-related fear and the contribution of the amygdala-hippocampus system. The experimental strategy was composed of the following steps: (1) use of the mouse pilocarpine model of temporal lobe epilepsy (TLE); (2) behavioral analyses of anxiety states in the elevated plus maze test, light-dark avoidance test, and Pavlovian fear conditioning; and (3) probing neurophysiologic activity patterns in amygdala-hippocampal circuits in freely behaving mice. Our results displayed no significant differences in basic anxiety levels comparing mice that developed spontaneous recurrent seizures (SRS) and controls. Furthermore, conditioned fear memory retrieval was not influenced in SRS mice. However, during fear memory extinction, SRS mice showed an extended freezing behavior and a maintained amygdala-hippocampal theta frequency synchronization compared to controls. These results indicate specific alterations in conditioned fear behavior and related neurophysiologic activities in the amygdala-hippocampal network contributing to impaired fear memory extinction in mice with TLE. Clinically, the nonextinguished fear memories may well contribute to the experience of fear in patients with TLE. Wiley Periodicals, Inc. © 2010 International League Against Epilepsy.

Zinc transporter 3 is involved in learned fear and extinction, but not in innate fear.

PubMed

Martel, Guillaume; Hevi, Charles; Friebely, Olivia; Baybutt, Trevor; Shumyatsky, Gleb P

2010-11-01

Synaptically released Zn²+ is a potential modulator of neurotransmission and synaptic plasticity in fear-conditioning pathways. Zinc transporter 3 (ZnT3) knock-out (KO) mice are well suited to test the role of zinc in learned fear, because ZnT3 is colocalized with synaptic zinc, responsible for its transport to synaptic vesicles, highly enriched in the amygdala-associated neural circuitry, and ZnT3 KO mice lack Zn²+ in synaptic vesicles. However, earlier work reported no deficiency in fear memory in ZnT3 KO mice, which is surprising based on the effects of Zn²+ on amygdala synaptic plasticity. We therefore reexamined ZnT3 KO mice in various tasks for learned and innate fear. The mutants were deficient in a weak fear-conditioning protocol using single tone-shock pairing but showed normal memory when a stronger, five-pairing protocol was used. ZnT3 KO mice were deficient in memory when a tone was presented as complex auditory information in a discontinuous fashion. Moreover, ZnT3 KO mice showed abnormality in trace fear conditioning and in fear extinction. By contrast, ZnT3 KO mice had normal anxiety. Thus, ZnT3 is involved in associative fear memory and extinction, but not in innate fear, consistent with the role of synaptic zinc in amygdala synaptic plasticity.

Human Fear Conditioning and Extinction in Neuroimaging: A Systematic Review

PubMed Central

Sehlmeyer, Christina; Schöning, Sonja; Zwitserlood, Pienie; Pfleiderer, Bettina; Kircher, Tilo; Arolt, Volker; Konrad, Carsten

2009-01-01

Fear conditioning and extinction are basic forms of associative learning that have gained considerable clinical relevance in enhancing our understanding of anxiety disorders and facilitating their treatment. Modern neuroimaging techniques have significantly aided the identification of anatomical structures and networks involved in fear conditioning. On closer inspection, there is considerable variation in methodology and results between studies. This systematic review provides an overview of the current neuroimaging literature on fear conditioning and extinction on healthy subjects, taking into account methodological issues such as the conditioning paradigm. A Pubmed search, as of December 2008, was performed and supplemented by manual searches of bibliographies of key articles. Two independent reviewers made the final study selection and data extraction. A total of 46 studies on cued fear conditioning and/or extinction on healthy volunteers using positron emission tomography or functional magnetic resonance imaging were reviewed. The influence of specific experimental factors, such as contingency and timing parameters, assessment of conditioned responses, and characteristics of conditioned and unconditioned stimuli, on cerebral activation patterns was examined. Results were summarized descriptively. A network consisting of fear-related brain areas, such as amygdala, insula, and anterior cingulate cortex, is activated independently of design parameters. However, some neuroimaging studies do not report these findings in the presence of methodological heterogeneities. Furthermore, other brain areas are differentially activated, depending on specific design parameters. These include stronger hippocampal activation in trace conditioning and tactile stimulation. Furthermore, tactile unconditioned stimuli enhance activation of pain related, motor, and somatosensory areas. Differences concerning experimental factors may partly explain the variance between neuroimaging investigations on human fear conditioning and extinction and should, therefore, be taken into serious consideration in the planning and the interpretation of research projects. PMID:19517024

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.

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.

Compound Stimulus Extinction Reduces Spontaneous Recovery in Humans

ERIC Educational Resources Information Center

Coelho, Cesar A. O.; Dunsmoor, Joseph E.; Phelps, Elizabeth A.

2015-01-01

Fear-related behaviors are prone to relapse following extinction. We tested in humans a compound extinction design ("deepened extinction") shown in animal studies to reduce post-extinction fear recovery. Adult subjects underwent fear conditioning to a visual and an auditory conditioned stimulus (CSA and CSB, respectively) separately…

Attraction under Aversive Conditions: Misattributions or Fear-Reduction?

ERIC Educational Resources Information Center

Miller, Rowland S.

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

The central amygdala circuits in fear regulation

NASA Astrophysics Data System (ADS)

Li, Bo

The amygdala is essential for fear learning and expression. The central amygdala (CeA), once viewed as a passive relay between the amygdala complex and downstream fear effectors, has emerged as an active participant in fear conditioning. However, how the CeA contributes to the learning and expression of fear remains unclear. Our recent studies in mice indicate that fear conditioning induces robust plasticity of excitatory synapses onto inhibitory neurons in the lateral subdivision of CeA (CeL). In particular, this plasticity is cell-type specific and is required for the formation of fear memory. In addition, sensory cues that predict threat can cause activation of the somatostatin-positive CeL neurons, which is sufficient to drive freezing behavior. Here I will report our recent findings regarding the circuit and cellular mechanisms underlying CeL function in fear processing.

The birth, death and resurrection of avoidance: a reconceptualization of a troubled paradigm.

PubMed

LeDoux, J E; Moscarello, J; Sears, R; Campese, V

2017-01-01

Research on avoidance conditioning began in the late 1930s as a way to use laboratory experiments to better understand uncontrollable fear and anxiety. Avoidance was initially conceived of as a two-factor learning process in which fear is first acquired through Pavlovian aversive conditioning (so-called fear conditioning), and then behaviors that reduce the fear aroused by the Pavlovian conditioned stimulus are reinforced through instrumental conditioning. Over the years, criticisms of both the avoidance paradigm and the two-factor fear theory arose. By the mid-1980s, avoidance had fallen out of favor as an experimental model relevant to fear and anxiety. However, recent progress in understanding the neural basis of Pavlovian conditioning has stimulated a new wave of research on avoidance. This new work has fostered new insights into contributions of not only Pavlovian and instrumental learning but also habit learning, to avoidance, and has suggested that the reinforcing event underlying the instrumental phase should be conceived in terms of cellular and molecular events in specific circuits rather than in terms of vague notions of fear reduction. In our approach, defensive reactions (freezing), actions (avoidance) and habits (habitual avoidance) are viewed as being controlled by unique circuits that operate nonconsciously in the control of behavior, and that are distinct from the circuits that give rise to conscious feelings of fear and anxiety. These refinements, we suggest, overcome older criticisms, justifying the value of the new wave of research on avoidance, and offering a fresh perspective on the clinical implications of this work.

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

PubMed

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

2015-11-01

The basolateral and lateral amygdala nuclei complex (BLC) is implicated in a number of emotional responses including conditioned fear and social anxiety. Based on previous studies demonstrating that enhanced serotonin release in the BLC leads to increased anxiety and fear responses, we hypothesized that pharmacologically depleting serotonin in the BLC using 5,7-dihydroxytryptamine (5,7-DHT) injections would lead to diminished anxiety and disrupted fear conditioning. To test this hypothesis, 5,7-DHT(a serotonin-depleting agent) was bilaterally injected into the BLC. Desipramine (a norepinephrine reuptake inhibitor) was systemically administered to prevent non-selective effects on norepinephrine. After 5days, 5-7-DHT-treated rats showed increases in the duration of social interaction (SI) time, suggestive of reduced anxiety-like behavior. We then used a cue-induced fear conditioning protocol with shock as the unconditioned stimulus and tone as the conditioned stimulus for rats pretreated with bilateral 5,7-DHT, or vehicle, injections into the BLC. Compared to vehicle-treated rats, 5,7-DHT rats had reduced acquisition of fear during conditioning (measured by freezing time during tone), also had reduced fear retrieval/recall on subsequent testing days. Ex vivo analyses revealed that 5,7-DHT reduced local 5-HT concentrations in the BLC by ~40% without altering local norepinephrine or dopamine concentrations. These data provide additional support for 5-HT playing a critical role in modulating anxiety-like behavior and fear-associated memories through its actions within the BLC. Copyright © 2015 Elsevier Inc. All rights reserved.

The birth, death and resurrection of avoidance: a reconceptualization of a troubled paradigm

PubMed Central

LeDoux, J E; Moscarello, J; Sears, R; Campese, V

2017-01-01

Research on avoidance conditioning began in the late 1930s as a way to use laboratory experiments to better understand uncontrollable fear and anxiety. Avoidance was initially conceived of as a two-factor learning process in which fear is first acquired through Pavlovian aversive conditioning (so-called fear conditioning), and then behaviors that reduce the fear aroused by the Pavlovian conditioned stimulus are reinforced through instrumental conditioning. Over the years, criticisms of both the avoidance paradigm and the two-factor fear theory arose. By the mid-1980s, avoidance had fallen out of favor as an experimental model relevant to fear and anxiety. However, recent progress in understanding the neural basis of Pavlovian conditioning has stimulated a new wave of research on avoidance. This new work has fostered new insights into contributions of not only Pavlovian and instrumental learning but also habit learning, to avoidance, and has suggested that the reinforcing event underlying the instrumental phase should be conceived in terms of cellular and molecular events in specific circuits rather than in terms of vague notions of fear reduction. In our approach, defensive reactions (freezing), actions (avoidance) and habits (habitual avoidance) are viewed as being controlled by unique circuits that operate nonconsciously in the control of behavior, and that are distinct from the circuits that give rise to conscious feelings of fear and anxiety. These refinements, we suggest, overcome older criticisms, justifying the value of the new wave of research on avoidance, and offering a fresh perspective on the clinical implications of this work. PMID:27752080

An automatic recording system for the study of escape from fear in rats.

PubMed

Li, Ming; He, Wei

2013-11-01

Escape from fear (EFF) is an active response to a conditioned stimulus (CS) previously paired with an unconditioned fearful stimulus (US), which typically leads to the termination of the CS. In this paradigm, animals acquire two distinct associations: S-S [CS-US] and R-O [response-outcome] through Pavlovian and instrumental conditioning, respectively. The present study describes a computer controlled automatic recording system that captures the development of EFF and allows the determination of the respective roles of S-S and R-O associations in this process. We validated this system by showing that only rats subjected to a simultaneous CS-US conditioning (i.e., CS and US occur together at the beginning of each trial) acquired EFF, not those subjected to an unpaired CS-US conditioning. Paired rats had a progressively increased number of EFF and significantly shorter escape latencies than unpaired rats across the 5-trial blocks on the test day. However, during the conditioning phase, the unpaired rats emitted more 22kHz ultrasonic vocalizations, a validated measure of conditioned reactive fear responses. Our results demonstrate that the acquisition of EFF is contingent upon pairing of the CS with the US, not simply the consequence of a high level of generalized fear. Because this commercially available system is capable of examining both conditioned active and reactive fear responses in a single setup, it could be used to determine the relative roles of S-S and R-O associations in EFF, the neurobiology of conditioned active fear response and neuropharmacology of psychotherapeutic drugs. Copyright © 2013 Elsevier B.V. All rights reserved.

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.

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

PubMed

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

2014-05-01

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

Psychophysiology of Delayed Extinction and Reconsolidation in Humans

DTIC Science & Technology

2013-02-01

to modify or block it. The aim of this project is to create an experimental assay in the form of an optimal Pavlovian differential fear- conditioning ...group. Data from the pharmacological group demonstrate that participants show differential conditioning learning on Day 1, supporting the validity of...our modified fear- conditioning paradigm. Results suggest that propranolol administration at the time of memory reactivation does not decrease the fear

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,…

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.

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.

33 CFR 165.530 - Safety Zone: Cape Fear and Northeast Cape Fear Rivers, NC.

Code of Federal Regulations, 2010 CFR

2010-07-01

... Northeast Cape Fear Rivers, NC. 165.530 Section 165.530 Navigation and Navigable Waters COAST GUARD... § 165.530 Safety Zone: Cape Fear and Northeast Cape Fear Rivers, NC. (a) Location. The following area is a moving safety zone during the specified conditions: The waters of the Cape Fear and Northeast Cape...

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

PubMed

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

2013-08-01

Drugs that modulate serotonin (5-HT) synaptic concentrations impact neurogenesis and hippocampal (HPC)-dependent learning. The primary objective is to determine the extent to which psilocybin (PSOP) modulates neurogenesis and thereby affects acquisition and extinction of HPC-dependent trace fear conditioning. PSOP, the 5-HT2A agonist 25I-NBMeO and the 5-HT2A/C antagonist ketanserin were administered via an acute intraperitoneal injection to mice. Trace fear conditioning was measured as the amount of time spent immobile in the presence of the conditioned stimulus (CS, auditory tone), trace (silent interval) and post-trace interval over 10 trials. Extinction was determined by the number of trials required to resume mobility during CS, trace and post-trace when the shock was not delivered. Neurogenesis was determined by unbiased counts of cells in the dentate gyrus of the HPC birth-dated with BrdU co-expressing a neuronal marker. Mice treated with a range of doses of PSOP acquired a robust conditioned fear response. Mice injected with low doses of PSOP extinguished cued fear conditioning significantly more rapidly than high-dose PSOP or saline-treated mice. Injection of PSOP, 25I-NBMeO or ketanserin resulted in significant dose-dependent decreases in number of newborn neurons in hippocampus. At the low doses of PSOP that enhanced extinction, neurogenesis was not decreased, but rather tended toward an increase. Extinction of "fear conditioning" may be mediated by actions of the drugs at sites other than hippocampus such as the amygdala, which is known to mediate the perception of fear. Another caveat is that PSOP is not purely selective for 5-HT2A receptors. PSOP facilitates extinction of the classically conditioned fear response, and this, and similar agents, should be explored as potential treatments for post-traumatic stress disorder and related conditions.

Fear conditioning induced by interpersonal conflicts in healthy individuals.

PubMed

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

2015-01-01

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

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.

Fear acquisition and liking of out-group and in-group members: Learning bias or attention?

PubMed

Koenig, Stephan; Nauroth, Peter; Lucke, Sara; Lachnit, Harald; Gollwitzer, Mario; Uengoer, Metin

2017-10-01

The present study explores the notion of an out-group fear learning bias that is characterized by facilitated fear acquisition toward harm-doing out-group members. Participants were conditioned with two in-group and two out-group faces as conditioned stimuli. During acquisition, one in-group and one out-group face was paired with an aversive shock whereas the other in-group and out-group face was presented without shock. Psychophysiological measures of fear conditioning (skin conductance and pupil size) and explicit and implicit liking exhibited increased differential responding to out-group faces compared to in-group faces. However, the results did not clearly indicate that harm-doing out-group members were more readily associated with fear than harm-doing in-group members. In contrast, the out-group face not paired with shock decreased conditioned fear and disliking at least to the same extent that the shock-associated out-group face increased these measures. Based on these results, we suggest an account of the out-group fear learning bias that relates to an attentional bias to process in-group information. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

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

PubMed

Fox, Elaine; Yates, Alan; Ashwin, Chris

2012-04-01

The impact of trait anxiety and perceptual load on selective attention was examined in a fear conditioning paradigm. A fear-conditioned angry face (CS+), an unconditioned angry face (CS-), or an unconditioned face with a neutral or happy expression were used in distractor interference and attentional probe tasks. In Experiments 1 and 2, participants classified centrally presented letters under two conditions of perceptual load. When perceptual load was high, distractors had no effect on selective attention, even with aversive conditioning. However, when perceptual load was low, strong response interference effects for CS+ face distractors were found for low trait-anxious participants. Across both experiments, this enhanced distractor interference reversed to strong facilitation effects for those reporting high trait anxiety. Thus, high trait-anxious participants were faster, rather than slower, when ignoring CS+ distractors. Using an attentional probe task in Experiment 3, it was found that fear conditioning resulted in strong attentional avoidance in a high trait-anxious group, which contrasted with enhanced vigilance in a low trait-anxious group. These results demonstrate that the impact of fear conditioning on attention is modulated by individual variation in trait anxiety when perceptual load is low. Fear conditioning elicits an avoidance of threat-relevant stimuli in high trait-anxious participants. (PsycINFO Database Record (c) 2012 APA, all rights reserved).

Medial Prefrontal Cortex Activation Facilitates Re-Extinction of Fear in Rats

ERIC Educational Resources Information Center

Chang, Chun-hui; Maren, Stephen

2011-01-01

It has been suggested that reduced infralimbic (IL) cortical activity contributes to impairments of fear extinction. We therefore explored whether pharmacological activation of the IL would facilitate extinction under conditions it normally fails (i.e., immediate extinction). Rats received auditory fear conditioning 1 h before extinction training.…

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…

Reconsolidation and extinction are dissociable and mutually exclusive processes: behavioral and molecular evidence.

PubMed

Merlo, Emiliano; Milton, Amy L; Goozée, Zara Y; Theobald, David E; Everitt, Barry J

2014-02-12

Memory persistence is critically influenced by retrieval. In rats, a single presentation of a conditioned fear stimulus induces memory reconsolidation and fear memory persistence, while repeated fear cue presentations result in loss of fear through extinction. These two opposite behavioral outcomes are operationally linked by the number of cue presentations at memory retrieval. However, the behavioral properties and mechanistic determinants of the transition have not yet been explored; in particular, whether reconsolidation and extinction processes coexist or are mutually exclusive, depending on the exposure to non-reinforced retrieval events. We characterized both behaviorally and molecularly the transition from reconsolidation to extinction of conditioned fear and showed that an increase in calcineurin (CaN) in the basolateral amygdala (BLA) supports the shift from fear maintenance to fear inhibition. Gradually increasing the extent of retrieval induces a gradual decrease in freezing responses to the conditioned stimulus and a gradual increase in amygdala CaN level. This newly synthesized CaN is required for the extinction, but not the reconsolidation, of conditioned fear. During the transition from reconsolidation to extinction, we have revealed an insensitive state of the fear memory where NMDA-type glutamate receptor agonist and antagonist drugs are unable either to modulate CaN levels in the BLA or alter the reconsolidation or extinction processes. Together, our data indicate both that reconsolidation and extinction are mutually exclusive processes and also reveal the presence of a transitional, or "limbo," state of the original memory between these two alternative outcomes of fear memory retrieval, when neither process is engaged.

Individual Differences in the Flexibility of Peripersonal Space.

PubMed

Hunley, Samuel B; Marker, Arwen M; Lourenco, Stella F

2017-01-01

The current study investigated individual differences in the flexibility of peripersonal space (i.e., representational space near the body), specifically in relation to trait claustrophobic fear (i.e., fear of suffocating or being physically restricted). Participants completed a line bisection task with either a laser pointer (Laser condition), allowing for a baseline measure of the size of one's peripersonal space, or a stick (Stick condition), which produces expansion of one's peripersonal space. Our results revealed that individuals high in claustrophobic fear had larger peripersonal spaces than those lower in claustrophobic fear, replicating previous research. We also found that, whereas individuals low in claustrophobic fear demonstrated the expected expansion of peripersonal space in the Stick condition, individuals high in claustrophobic fear showed less expansion, suggesting decreased flexibility. We discuss these findings in relation to the defensive function of peripersonal space and reduced attentional flexibility associated with trait anxieties.

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

PubMed Central

Miskovic, Vladimir; Keil, Andreas

2012-01-01

The capacity to associate neutral stimuli with affective value is an important survival strategy that can be accomplished by cell assemblies obeying Hebbian learning principles. In the neuroscience laboratory, classical fear conditioning has been extensively used as a model to study learning related changes in neural structure and function. Here, we review the effects of classical fear conditioning on electromagnetic brain activity in humans, focusing on how sensory systems adapt to changing fear-related contingencies. By considering spatio-temporal patterns of mass neuronal activity we illustrate a range of cortical changes related to a retuning of neuronal sensitivity to amplify signals consistent with fear-associated stimuli at the cost of other sensory information. Putative mechanisms that may underlie fear-associated plasticity at the level of the sensory cortices are briefly considered and several avenues for future work are outlined. PMID:22891639

Failure to extinguish fear and genetic variability in the human cannabinoid receptor 1.

PubMed

Heitland, I; Klumpers, F; Oosting, R S; Evers, D J J; Leon Kenemans, J; Baas, J M P

2012-09-25

Failure to extinguish fear can lead to persevering anxiety and has been postulated as an important mechanism in the pathogenesis of human anxiety disorders. In animals, it is well documented that the endogenous cannabinoid system has a pivotal role in the successful extinction of fear, most importantly through the cannabinoid receptor 1. However, no human studies have reported a translation of this preclinical evidence yet. Healthy medication-free human subjects (N=150) underwent a fear conditioning and extinction procedure in a virtual reality environment. Fear potentiation of the eyeblink startle reflex was measured to assess fear-conditioned responding, and subjective fear ratings were collected. Participants were genotyped for two polymorphisms located within the promoter region (rs2180619) and the coding region (rs1049353) of cannabinoid receptor 1. As predicted from the preclinical literature, acquisition and expression of conditioned fear did not differ between genotypes. Crucially, whereas both homozygote (G/G, N=23) and heterozygote (A/G, N=68) G-allele carriers of rs2180619 displayed robust extinction of fear, extinction of fear-potentiated startle was absent in A/A homozygotes (N=51). Additionally, this resistance to extinguish fear left A/A carriers of rs2180619 with significantly higher levels of fear-potentiated startle at the end of the extinction training. No effects of rs1049353 genotype were observed regarding fear acquisition and extinction. These results suggest for the first time involvement of the human endocannabinoid system in fear extinction. Implications are that genetic variability in this system may underlie individual differences in anxiety, rendering cannabinoid receptor 1 a potential target for novel pharmacological treatments of anxiety disorders.

Conditioned Fear Inhibits c-fos mRNA Expression in the Central Extended Amygdala

PubMed Central

Day, Heidi E.W.; Kryskow, Elisa M.; Nyhuis, Tara J.; Herlihy, Lauren; Campeau, Serge

2008-01-01

We have shown previously that unconditioned stressors inhibit neurons of the lateral/capsular division of the central nucleus of the amygdala (CEAl/c) and oval division of the bed nucleus of the stria terminalis (BSTov), which form part of the central extended amygdala. The current study investigated whether conditioned fear inhibits c-fos mRNA expression in these regions. Male rats were trained either to associate a visual stimulus (light) with footshock or were exposed to the light alone. After training, animals were replaced in the apparatus, and 2 hours later injected remotely, via a catheter, with amphetamine (2 mg/kg i.p.), to induce c-fos mRNA and allow inhibition of expression to be measured. The rats were then presented with 15 visual stimuli over a 30 minute period. As expected, fear conditioned animals that were not injected with amphetamine, had extremely low levels of c-fos mRNA in the central extended amygdala. In contrast, animals that were trained with the light alone (no fear conditioning) and were injected with amphetamine had high levels of c-fos mRNA in the CEAl/c and BSTov. Animals that underwent fear-conditioning, and were re-exposed to the conditioned stimulus after amphetamine injection had significantly reduced levels of c-fos mRNA in both the BSTov and CEAl/c, compared to the non-conditioned animals. These data suggest that conditioned fear can inhibit neurons of the central extended amygdala. Because these neurons are GABAergic, and project to the medial CEA (an amygdaloid output region), this may be a novel mechanism whereby conditioned fear potentiates amygdaloid output. PMID:18634767

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

PubMed

Lonsdorf, Tina B; Golkar, Armita; Lindström, Kara M; Haaker, Jan; Öhman, Arne; Schalling, Martin; Ingvar, Martin

2015-05-01

Brain-derived neurotrophic factor (BDNF), the most abundant neutrophin in the mammalian central nervous system, is critically involved in synaptic plasticity. In both rodents and humans, BDNF has been implicated in hippocampus- and amygdala-dependent learning and memory and has more recently been linked to fear extinction processes. Fifty-nine healthy participants, genotyped for the functional BDNFval66met polymorphism, underwent a fear conditioning and 24h-delayed extinction protocol while skin conductance and blood oxygenation level dependent (BOLD) responses (functional magnetic resonance imaging) were acquired. We present the first report of neural activation pattern during fear acquisition 'and' extinction for the BDNFval66met polymorphism using a differential conditioned stimulus (CS)+ > CS- comparison. During conditioning, we observed heightened allele dose-dependent responses in the amygdala and reduced responses in the subgenual anterior cingulate cortex in BDNFval66met met-carriers. During early extinction, 24h later, we again observed heightened responses in several regions ascribed to the fear network in met-carriers as opposed to val-carriers (insula, amygdala, hippocampus), which likely reflects fear memory recall. No differences were observed during late extinction, which likely reflects learned extinction. Our data thus support previous associations of the BDNFval66met polymorphism with neural activation in the fear and extinction network, but speak against a specific association with fear extinction processes. © The Author (2014). Published by Oxford University Press. For Permissions, please email: journals.permissions@oup.com.

Infection with an acanthocephalan manipulates an amphipod's reaction to a fish predator's odours.

PubMed

Baldauf, Sebastian A; Thünken, Timo; Frommen, Joachim G; Bakker, Theo C M; Heupel, Oliver; Kullmann, Harald

2007-01-01

Many parasites with complex life cycles increase the chances of reaching a final host by adapting strategies to manipulate their intermediate host's appearance, condition or behaviour. The acanthocephalan parasite Pomphorhynchus laevis uses freshwater amphipods as intermediate hosts before reaching sexual maturity in predatory fish. We performed a series of choice experiments with infected and uninfected Gammarus pulex in order to distinguish between the effects of visual and olfactory predator cues on parasite-induced changes in host behaviour. When both visual and olfactory cues, as well as only olfactory cues were offered, infected and uninfected G. pulex showed significantly different preferences for the predator or the non-predator side. Uninfected individuals significantly avoided predator odours while infected individuals significantly preferred the side with predator odours. When only visual contact with a predator was allowed, infected and uninfected gammarids behaved similarly and had no significant preference. Thus, we believe we show for the first time that P. laevis increases its chance to reach a final host by olfactory-triggered manipulation of the anti-predator behaviour of its intermediate host.

Inactivation of ventral hippocampus interfered with cued-fear acquisition but did not influence later recall or discrimination.

PubMed

Chen, Veronica M; Foilb, Allison R; Christianson, John P

2016-01-01

The ventral hippocampus (VH) is involved in the both the acquisition and recall of conditioned fear. Here, we tested the role of VH in acquisition and recall of a conditioned fear discrimination. Intra-VH vehicle or muscimol injections were made 1h prior to a CS+/CS- conditioning or prior to later recall. Vehicle treated rats exhibited discrimination with significantly greater freezing to the CS+ than to the CS- whereas muscimol treated rats did not freeze. Injections made before recall had no effect as both treatment groups displayed equal freezing in response to the CS+, and discrimination. While these results are consistent with several reports, the failure to influence fear discrimination upon recall appears to contrast with the hypothesized role of VH in recall of extinguished conditioned fear cues. Copyright © 2015 Elsevier B.V. All rights reserved.

The role of nucleus accumbens shell in learning about neutral versus excitatory stimuli during Pavlovian fear conditioning.

PubMed

Bradfield, Laura A; McNally, Gavan P

2010-07-01

We studied the role of nucleus accumbens shell (AcbSh) in Pavlovian fear conditioning. Rats were trained to fear conditioned stimulus A (CSA) in Stage I, which was then presented in compound with a neutral stimulus and paired with shock in Stage II. AcbSh lesions had no effect on fear-learning to CSA in Stage I, but selectively prevented learning about the neutral conditioned stimulus (CS) in Stage II. These results add to a growing body of evidence indicating an important role for the ventral striatum in fear-learning. They suggest that the ventral striatum and AcbSh, in particular, directs learning toward or away from a CS as a consequence of how well that CS predicts the shock unconditioned stimulus (US). AcbSh is required to reduce the processing of established predictors, thereby permitting neutral or less predictive stimuli to be learned about.

Prefrontal neuronal circuits of contextual fear conditioning.

PubMed

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

2015-01-01

Over the past years, numerous studies have provided a clear understanding of the neuronal circuits and mechanisms involved in the formation, expression and extinction phases of conditioned cued fear memories. Yet, despite a strong clinical interest, a detailed understanding of these memory phases for contextual fear memories is still missing. Besides the well-known role of the hippocampus in encoding contextual fear behavior, growing evidence indicates that specific regions of the medial prefrontal cortex differentially regulate contextual fear acquisition and storage in both animals and humans that ultimately leads to expression of contextual fear memories. In this review, we provide a detailed description of the recent literature on the role of distinct prefrontal subregions in contextual fear behavior and provide a working model of the neuronal circuits involved in the acquisition, expression and generalization of contextual fear memories. © 2014 John Wiley & Sons Ltd and International Behavioural and Neural Genetics Society.

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.

Isoflurane causes anterograde but not retrograde amnesia for pavlovian fear conditioning.

PubMed

Dutton, Robert C; Maurer, Anya J; Sonner, James M; Fanselow, Michael S; Laster, Michael J; Eger, Edmond I

2002-05-01

Production of retrograde amnesia by anesthetics would indicate that these drugs can disrupt mechanisms that stabilize memory. Such disruption would allow suppression of memory of previous untoward events. The authors examined whether isoflurane provides retrograde amnesia for classic (Pavlovian) fear conditioning. Rats were trained to fear tone by applying three (three-trial) or one (one-trial) tone-shock pairs while breathing various constant concentrations of isoflurane. Immediately after training, isoflurane administration was either discontinued, maintained unchanged, or rapidly increased to 1.0 minimum alveolar concentration for 1 h longer. Groups of rats were similarly trained to fear context while breathing isoflurane by applying shocks (without tones) in a distinctive environment. The next day, memory for the conditioned stimuli was determined by presenting the tone or context (without shock) and measuring the proportion of time each rat froze (appeared immobile). For each conditioning procedure, the effects of the three posttraining isoflurane treatments were compared. Rapid increases in posttraining isoflurane administration did not suppress conditioned fear for any of the training procedures. In contrast, isoflurane administration during conditioning dose-dependently suppressed conditioning (P < 0.05). Training to tone was more resistant to the effects of isoflurane than training to context (P < 0.05), and the three-trial learning procedure was more was more resistant than the one-trial procedure (P < 0.05). Isoflurane provided intense dose-dependent anterograde but not retrograde amnesia for classic fear conditioning. Isoflurane appears to disrupt memory processes that occur at or within a few minutes of the conditioning procedure.

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.

Fear recognition impairment in early-stage Alzheimer's disease: when focusing on the eyes region improves performance.

PubMed

Hot, Pascal; Klein-Koerkamp, Yanica; Borg, Céline; Richard-Mornas, Aurélie; Zsoldos, Isabella; Paignon Adeline, Adeline; Thomas Antérion, Catherine; Baciu, Monica

2013-06-01

A decline in the ability to identify fearful expression has been frequently reported in patients with Alzheimer's disease (AD). In patients with severe destruction of the bilateral amygdala, similar difficulties have been reduced by using an explicit visual exploration strategy focusing on gaze. The current study assessed the possibility of applying a similar strategy in AD patients to improve fear recognition. It also assessed the possibility of improving fear recognition when a visual exploration strategy induced AD patients to process the eyes region. Seventeen patients with mild AD and 34 healthy subjects (17 young adults and 17 older adults) performed a classical task of emotional identification of faces expressing happiness, anger, and fear in two conditions: The face appeared progressively from the eyes region to the periphery (eyes region condition) or it appeared as a whole (global condition). Specific impairment in identifying a fearful expression was shown in AD patients compared with older adult controls during the global condition. Fear expression recognition was significantly improved in AD patients during the eyes region condition, in which they performed similarly to older adult controls. Our results suggest that using a different strategy of face exploration, starting first with processing of the eyes region, may compensate for a fear recognition deficit in AD patients. Findings suggest that a part of this deficit could be related to visuo-perceptual impairments. Additionally, these findings suggest that the decline of fearful face recognition reported in both normal aging and in AD may result from impairment of non-amygdalar processing in both groups and impairment of amygdalar-dependent processing in AD. Copyright © 2013 Elsevier Inc. 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.

Psychophysiology of Delayed Extinction and Reconsideration in Humans

DTIC Science & Technology

2012-02-01

modify or block it. The aim of this project is to create an experimental assay in the form of an optimal Pavlovian differential fear conditioning ...The aim of this project is to create an experimental assay in the form of an optimal Pavlovian differential fear conditioning paradigm. Animal...open label study examining the relative efficacies of pharmacological and non- drug interventions within a fear conditioning paradigm. At the time of

Preservation of Essential Odor-Guided Behaviors and Odor-Based Reversal Learning after Targeting Adult Brain Serotonin Synthesis.

PubMed

Carlson, Kaitlin S; Whitney, Meredith S; Gadziola, Marie A; Deneris, Evan S; Wesson, Daniel W

2016-01-01

The neurotransmitter serotonin (5-HT) is considered a powerful modulator of sensory system organization and function in a wide range of animals. The olfactory system is innervated by midbrain 5-HT neurons into both its primary and secondary odor-processing stages. Facilitated by this circuitry, 5-HT and its receptors modulate olfactory system function, including odor information input to the olfactory bulb. It is unknown, however, whether the olfactory system requires 5-HT for even its most basic behavioral functions. To address this question, we established a conditional genetic approach to specifically target adult brain tryptophan hydroxylase 2 ( Tph2 ), encoding the rate-limiting enzyme in brain 5-HT synthesis, and nearly eliminate 5-HT from the mouse forebrain. Using this novel model, we investigated the behavior of 5-HT-depleted mice during performance in an olfactory go/no-go task. Surprisingly, the near elimination of 5-HT from the forebrain, including the olfactory bulbs, had no detectable effect on the ability of mice to perform the odor-based task. Tph2 -targeted mice not only were able to learn the task, but also had levels of odor acuity similar to those of control mice when performing coarse odor discrimination. Both groups of mice spent similar amounts of time sampling odors during decision-making. Furthermore, odor reversal learning was identical between 5-HT-depleted and control mice. These results suggest that 5-HT neurotransmission is not necessary for the most essential aspects of olfaction, including odor learning, discrimination, and certain forms of cognitive flexibility.

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.

Cortisol modifies extinction learning of recently acquired fear in men

PubMed Central

Hermann, Andrea; Stark, Rudolf; Wolf, Oliver Tobias

2014-01-01

Exposure therapy builds on the mechanism of fear extinction leading to decreased fear responses. How the stress hormone cortisol affects brain regions involved in fear extinction in humans is unknown. For this reason, we tested 32 men randomly assigned to receive either 30 mg hydrocortisone or placebo 45 min before fear extinction. In fear acquisition, a picture of a geometrical figure was either partially paired (conditioned stimulus; CS+) or not paired (CS−) with an electrical stimulation (unconditioned stimulus; UCS). In fear extinction, each CS was presented again, but no UCS occurred. Cortisol increased conditioned skin conductance responses in early and late extinction. In early extinction, higher activation towards the CS− than to the CS+ was found in the amygdala, hippocampus and posterior parahippocampal gyrus. This pattern might be associated with the establishment of a new memory trace. In late extinction, the placebo compared with the cortisol group displayed enhanced CS+/CS− differentiation in the amygdala, medial frontal cortex and nucleus accumbens. A change from early deactivation to late activation of the extinction circuit as seen in the placebo group seems to be needed to enhance extinction and to reduce fear. Cortisol appears to interfere with this process thereby impairing extinction of recently acquired conditioned fear. PMID:23945999

Brain oxytocin in social fear conditioning and its extinction: involvement of the lateral septum.

PubMed

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

2014-12-01

Central oxytocin (OXT) has anxiolytic and pro-social properties both in humans and rodents, and has been proposed as a therapeutic option for anxiety and social dysfunctions. Here, we utilized a mouse model of social fear conditioning (SFC) to study the effects of OXT on social fear, and to determine whether SFC causes alterations in central OXT receptor (OXTR) binding and local OXT release. Central infusion of OXT, but not arginine vasopressin, prior to social fear extinction training completely abolished social fear expression in an OXTR-mediated fashion without affecting general anxiety or locomotion. SFC caused increased OXTR binding in the dorso-lateral septum (DLS), central amygdala, dentate gyrus, and cornu ammunis 1, which normalized after social fear extinction, suggesting that these areas form part of a brain network involved in the development and neural support of social fear. Microdialysis revealed that the increase in OXT release observed in unconditioned mice within the DLS during social fear extinction training was attenuated in conditioned mice. Consequently, increasing the availability of local OXT by infusion of OXT into the DLS reversed social fear. Thus, alterations in the brain OXT system, including altered OXTR binding and OXT release within the DLS, play an important role in SFC and social fear extinction. Thus, we suggest that the OXT system is adversely affected in disorders associated with social fear, such as social anxiety disorder and reinstalling an appropriate balance of the OXT system may alleviate some of the symptoms.

Dorsal periaqueductal gray-amygdala pathway conveys both innate and learned fear responses in rats

PubMed Central

Kim, Eun Joo; Horovitz, Omer; Pellman, Blake A.; Tan, Lancy Mimi; Li, Qiuling; Richter-Levin, Gal; Kim, Jeansok J.

2013-01-01

The periaqueductal gray (PAG) and amygdala are known to be important for defensive responses, and many contemporary fear-conditioning models present the PAG as downstream of the amygdala, directing the appropriate behavior (i.e., freezing or fleeing). However, empirical studies of this circuitry are inconsistent and warrant further examination. Hence, the present study investigated the functional relationship between the PAG and amygdala in two different settings, fear conditioning and naturalistic foraging, in rats. In fear conditioning, electrical stimulation of the dorsal PAG (dPAG) produced unconditional responses (URs) composed of brief activity bursts followed by freezing and 22-kHz ultrasonic vocalization. In contrast, stimulation of ventral PAG and the basolateral amygdalar complex (BLA) evoked freezing and/or ultrasonic vocalization. Whereas dPAG stimulation served as an effective unconditional stimulus for fear conditioning to tone and context conditional stimuli, neither ventral PAG nor BLA stimulation supported fear conditioning. The conditioning effect of dPAG, however, was abolished by inactivation of the BLA. In a foraging task, dPAG and BLA stimulation evoked only fleeing toward the nest. Amygdalar lesion/inactivation blocked the UR of dPAG stimulation, but dPAG lesions did not block the UR of BLA stimulation. Furthermore, in vivo recordings demonstrated that electrical priming of the dPAG can modulate plasticity of subiculum–BLA synapses, providing additional evidence that the amygdala is downstream of the dPAG. These results suggest that the dPAG conveys unconditional stimulus information to the BLA, which directs both innate and learned fear responses, and that brain stimulation-evoked behaviors are modulated by context. PMID:23959880

Effect of dietary fat source and exercise on odorant-detecting ability of canine athletes.

PubMed

Altom, Eric K; Davenport, Gary M; Myers, Lawrence J; Cummins, Keith A

2003-10-01

Eighteen male English Pointers (2-4 years of age, 23.94+/-0.54 kg body weight) were allotted to three diet and two physical conditioning groups to evaluate the effect of level and source of dietary fat on the olfactory acuity of canine athletes subjected to treadmill exercise. Diet groups (6 dogs/diet) consisted of commercially prepared diets (minimum of 26% crude protein) containing 12% fat as beef tallow (A), 16% fat provided by equivalent amounts of beef tallow and corn oil (B), or 16% fat provided by equivalent amounts of beef tallow and coconut oil (C). This dietary formulation resulted in approximately 60% of the total fatty acid being saturated for diets A and C, while approximately 72% of the total fatty acids were unsaturated in diet B. One-half of the dogs within each dietary group were subjected to treadmill exercise 3 times per week for 30 min (8.05 km/h, 0% grade) for 12 weeks. All dogs were subjected to a submaximal exercise stress test (8.05 km/h, 10% slope for 60 min) every four weeks beginning at week 0. Olfactory acuity was measured utilizing behavioral olfactometry before and after each physical stress test. Non-conditioned (NON) dogs displayed a greater decrease (P<0.05) in olfactory acuity following exercise, while physically conditioned (EXE) dogs did not show a change from pre-test values. A diet by treatment interaction (P<0.10) was detected over the course of the study. NON dogs fed coconut oil had decreased odorant-detecting capabilities when week 4 values were compared with week 12 values. Feeding a diet that is predominately high in saturated fat may affect the odorant-detecting capabilities of working dogs. Additionally, these data indicate that utilization of a moderate physical conditioning program can assist canine athletes in maintaining olfactory acuity during periods of intense exercise.

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.

Sex Differences in Context Fear Generalization and Recruitment of Hippocampus and Amygdala during Retrieval

PubMed Central

Keiser, Ashley A; Turnbull, Lacie M; Darian, Mara A; Feldman, Dana E; Song, Iris; Tronson, Natalie C

2017-01-01

Anxiety disorders are commonly associated with increased generalization of fear from a stress- or trauma-associated environment to a neutral context or environment. Differences in context-associated memory in males and females may contribute to increased susceptibility to anxiety disorders in women. Here we examined sex differences in context fear generalization and its neural correlates. We observed stronger context fear conditioning and more generalization of fear to a similar context in females than males. In addition, context preexposure increased fear conditioning in males and decreased generalization in females. Accordingly, males showed stronger cFos activity in dorsal hippocampus during memory retrieval and context generalization, whereas females showed preferential recruitment of basal amygdala. Together, these findings are consistent with previous research showing that hippocampal activity correlates with reduced context fear generalization. Differential competition between hippocampus and amygdala-dependent processes may thus contribute to sex differences in retrieval of context fear and greater generalization of fear-associated memory. PMID:27577601

Prefrontal NMDA receptors expressed in excitatory neurons control fear discrimination and fear extinction.

PubMed

Vieira, Philip A; Corches, Alex; Lovelace, Jonathan W; Westbrook, Kevin B; Mendoza, Michael; Korzus, Edward

2015-03-01

N-methyl-D-aspartate receptors (NMDARs) are critically involved in various learning mechanisms including modulation of fear memory, brain development and brain disorders. While NMDARs mediate opposite effects on medial prefrontal cortex (mPFC) interneurons and excitatory neurons, NMDAR antagonists trigger profound cortical activation. The objectives of the present study were to determine the involvement of NMDARs expressed specifically in excitatory neurons in mPFC-dependent adaptive behaviors, specifically fear discrimination and fear extinction. To achieve this, we tested mice with locally deleted Grin1 gene encoding the obligatory NR1 subunit of the NMDAR from prefrontal CamKIIα positive neurons for their ability to distinguish frequency modulated (FM) tones in fear discrimination test. We demonstrated that NMDAR-dependent signaling in the mPFC is critical for effective fear discrimination following initial generalization of conditioned fear. While mice with deficient NMDARs in prefrontal excitatory neurons maintain normal responses to a dangerous fear-conditioned stimulus, they exhibit abnormal generalization decrement. These studies provide evidence that NMDAR-dependent neural signaling in the mPFC is a component of a neural mechanism for disambiguating the meaning of fear signals and supports discriminative fear learning by retaining proper gating information, viz. both dangerous and harmless cues. We also found that selective deletion of NMDARs from excitatory neurons in the mPFC leads to a deficit in fear extinction of auditory conditioned stimuli. These studies suggest that prefrontal NMDARs expressed in excitatory neurons are involved in adaptive behavior. Copyright © 2015 Elsevier Inc. All rights reserved.

Inhibition of Vicariously Learned Fear in Children Using Positive Modeling and Prior Exposure

PubMed Central

2015-01-01

One of the challenges to conditioning models of fear acquisition is to explain how different individuals can experience similar learning events and only some of them subsequently develop fear. Understanding factors moderating the impact of learning events on fear acquisition is key to understanding the etiology and prevention of fear in childhood. This study investigates these moderators in the context of vicarious (observational) learning. Two experiments tested predictions that the acquisition or inhibition of fear via vicarious learning is driven by associative learning mechanisms similar to direct conditioning. In Experiment 1, 3 groups of children aged 7 to 9 years received 1 of 3 inhibitive information interventions—psychoeducation, factual information, or no information (control)—prior to taking part in a vicarious fear learning procedure. In Experiment 2, 3 groups of children aged 7 to 10 years received 1 of 3 observational learning interventions—positive modeling (immunization), observational familiarity (latent inhibition), or no prevention (control)—before vicarious fear learning. Results indicated that observationally delivered manipulations inhibited vicarious fear learning, while preventions presented via written information did not. These findings confirm that vicarious learning shares some of the characteristics of direct conditioning and can explain why not all individuals will develop fear following a vicarious learning event. They also suggest that the modality of inhibitive learning is important and should match the fear learning pathway for increased chances of inhibition. Finally, the results demonstrate that positive modeling is likely to be a particularly effective method for preventing fear-related observational learning in children. PMID:26653136

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.

Chronic stress enhanced fear memories are associated with increased amygdala zif268 mRNA expression and are resistant to reconsolidation

PubMed Central

Hoffman, Ann N.; Parga, Alejandro; Paode, Pooja; Watterson, Lucas R.; Nikulina, Ella M.; Hammer, Ronald P.; Conrad, Cheryl D.

2015-01-01

The chronically stressed brain may present a vulnerability to develop maladaptive fear-related behaviors in response to a traumatic event. In rodents, chronic stress leads to amygdala hyperresponsivity and dendritic hypertrophy and produces a post traumatic stress disorder (PTSD)-like phenotype that includes exaggerated fear learning following Pavlovian fear conditioning and resistance to extinction. It is unknown whether chronic stress-induced enhanced fear memories are vulnerable to disruption via reconsolidation blockade, as a novel therapeutic approach for attenuating exaggerated fear memories. We used a chronic stress procedure in a rat model (wire mesh restraint for 6h/d/21d) to create a vulnerable brain that leads to a PTSD-like phenotype. We then examined freezing behavior during acquisition, reactivation and after post-reactivation rapamycin administration (i.p., 40 mg/kg) in a Pavlovian fear conditioning paradigm to determine its effects on reconsolidation as well as the subsequent functional activation of limbic structures using zif268 mRNA. Chronic stress increased amygdala zif268 mRNA during fear memory retrieval at reactivation. Moreover, these enhanced fear memories were unaffected by post reactivation rapamycin to disrupt long-term fear memory. Also, post-reactivation long term memory processing was also associated with increased amygdala (LA and BA), and decreased hippocampal CA1 zif268 mRNA expression. These results suggest potential challenges for reconsolidation blockade as an effective approach in treating exaggerated fear memories, as in PTSD. Our findings also support chronic stress manipulations combined with fear conditioning as a useful preclinical approach to study a PTSD-like phenotype. PMID:25732249

Inhibition of vicariously learned fear in children using positive modeling and prior exposure.

PubMed

Askew, Chris; Reynolds, Gemma; Fielding-Smith, Sarah; Field, Andy P

2016-02-01

One of the challenges to conditioning models of fear acquisition is to explain how different individuals can experience similar learning events and only some of them subsequently develop fear. Understanding factors moderating the impact of learning events on fear acquisition is key to understanding the etiology and prevention of fear in childhood. This study investigates these moderators in the context of vicarious (observational) learning. Two experiments tested predictions that the acquisition or inhibition of fear via vicarious learning is driven by associative learning mechanisms similar to direct conditioning. In Experiment 1, 3 groups of children aged 7 to 9 years received 1 of 3 inhibitive information interventions-psychoeducation, factual information, or no information (control)-prior to taking part in a vicarious fear learning procedure. In Experiment 2, 3 groups of children aged 7 to 10 years received 1 of 3 observational learning interventions-positive modeling (immunization), observational familiarity (latent inhibition), or no prevention (control)-before vicarious fear learning. Results indicated that observationally delivered manipulations inhibited vicarious fear learning, while preventions presented via written information did not. These findings confirm that vicarious learning shares some of the characteristics of direct conditioning and can explain why not all individuals will develop fear following a vicarious learning event. They also suggest that the modality of inhibitive learning is important and should match the fear learning pathway for increased chances of inhibition. Finally, the results demonstrate that positive modeling is likely to be a particularly effective method for preventing fear-related observational learning in children. (c) 2016 APA, all rights reserved).

Generalization of Fear Inhibition by Disrupting Hippocampal Protein Synthesis-Dependent Reconsolidation Process

PubMed Central

Yang, Chih-Hao; Huang, Chiung-Chun; Hsu, Kuei-Sen

2011-01-01

Repetitive replay of fear memories may precipitate the occurrence of post-traumatic stress disorder and other anxiety disorders. Hence, the suppression of fear memory retrieval may help prevent and treat these disorders. The formation of fear memories is often linked to multiple environmental cues and these interconnected cues may act as reminders for the recall of traumatic experiences. However, as a convenience, a simple paradigm of one cue pairing with the aversive stimulus is usually used in studies of fear conditioning in animals. Here, we built a more complex fear conditioning model by presenting several environmental stimuli during fear conditioning and characterize the effectiveness of extinction training and the disruption of reconsolidation process on the expression of learned fear responses. We demonstrate that extinction training with a single-paired cue resulted in cue-specific attenuation of fear responses but responses to other cures were unchanged. The cue-specific nature of the extinction persisted despite training sessions combined with -cycloserine treatment reveals a significant weakness in extinction-based treatment. In contrast, the inhibition of the dorsal hippocampus (DH) but not the basolateral amygdala (BLA)-dependent memory reconsolidation process using either protein synthesis inhibitors or genetic disruption of cAMP-response-element-binding protein-mediated transcription comprehensively disrupted the learned connections between fear responses and all paired environmental cues. These findings emphasize the distinct role of the DH and the BLA in the reconsolidation process of fear memories and further indicate that the disruption of memory reconsolidation process in the DH may result in generalization of fear inhibition. PMID:21593730

Generalization of fear inhibition by disrupting hippocampal protein synthesis-dependent reconsolidation process.

PubMed

Yang, Chih-Hao; Huang, Chiung-Chun; Hsu, Kuei-Sen

2011-09-01

Repetitive replay of fear memories may precipitate the occurrence of post-traumatic stress disorder and other anxiety disorders. Hence, the suppression of fear memory retrieval may help prevent and treat these disorders. The formation of fear memories is often linked to multiple environmental cues and these interconnected cues may act as reminders for the recall of traumatic experiences. However, as a convenience, a simple paradigm of one cue pairing with the aversive stimulus is usually used in studies of fear conditioning in animals. Here, we built a more complex fear conditioning model by presenting several environmental stimuli during fear conditioning and characterize the effectiveness of extinction training and the disruption of reconsolidation process on the expression of learned fear responses. We demonstrate that extinction training with a single-paired cue resulted in cue-specific attenuation of fear responses but responses to other cures were unchanged. The cue-specific nature of the extinction persisted despite training sessions combined with D-cycloserine treatment reveals a significant weakness in extinction-based treatment. In contrast, the inhibition of the dorsal hippocampus (DH) but not the basolateral amygdala (BLA)-dependent memory reconsolidation process using either protein synthesis inhibitors or genetic disruption of cAMP-response-element-binding protein-mediated transcription comprehensively disrupted the learned connections between fear responses and all paired environmental cues. These findings emphasize the distinct role of the DH and the BLA in the reconsolidation process of fear memories and further indicate that the disruption of memory reconsolidation process in the DH may result in generalization of fear inhibition.

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

Reduced expression of conditioned fear in the R6/2 mouse model of Huntington’s disease is related to abnormal activity in prelimbic cortex

PubMed Central

Walker, Adam G.; Ummel, Jason R.; Rebec, George V.

2011-01-01

Prefrontal cortex (PFC) dysfunction is common in patients with Huntington’s disease (HD), a dominantly inherited neurological disorder, and has been linked to cognitive disruption. We previously reported alterations in neuronal firing patterns recorded from PFC of the R6/2 mouse model of HD. To determine if PFC dysfunction results in behavioral impairments, we evaluated performance of wild-type (WT) and R6/2 mice in a fear conditioning and extinction behavioral task. Fear conditioning and extinction retrieval were similar in both genotypes, but R6/2s exhibited less fear during extinction by freezing less than WTs. A fear reinstatement test after extinction retrieval indicated that faster extinction was not due to poor memory for conditioning. During initial extinction and extinction retrieval training, neuronal activity was recorded from prelimbic (PL) cortex, a subregion of PFC known to be important for fear expression. In WTs, a large number of neurons were activated by the conditioned stimulus during initial extinction and this activation was significantly impaired in R6/2s. Notably, there was no genotype difference in PFC activity during extinction retrieval. Thus, altered extinction is likely a result of reduced fear expression due to impairments in PL activation. Collectively, our results suggest that PFC dysfunction may play a key role in R6/2 cognitive impairments. PMID:21515374

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.

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

PubMed

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

2012-09-19

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

Strain dependent effects of conditioned fear in adult C57Bl/6 and Balb/C mice following postnatal exposure to chlorpyrifos: relation to expression of brain acetylcholinesterase mRNA

PubMed Central

Oriel, Sarit; Kofman, Ora

2015-01-01

Following reports of emotional psychopathology in children and adults exposed to organophosphates, the effects of postnatal chlorpyrifos (CPF) on fear-conditioning and depression-like behaviors were tested in adult mice. Concomitant changes in expression of mRNA for synaptic and soluble splice variants of acetylcholinesterase (AChE) were examined in mouse pups and adults of the Balb/C and C57Bl/6 (B6) strains, which differ in their behavioral and hormonal stress response. Mice were injected subcutaneously with 1 mg/kg CPF on postnatal days 4–10 and tested as adults for conditioned fear, sucrose preference, and forced swim. Acetylcholinesterase activity was assessed in the brains of pups on the first and last day of treatment. Expression of soluble and synaptic AChE mRNA was assessed in brains of treated pups and fear-conditioned adults using real-time PCR. Adult Balb/C mice exposed postnatally to CPF showed exacerbated fear-conditioning and impaired active avoidance. Adult B6 mice exposed postnatally to CPF showed a more specific fear response to tones and less freezing in the inter-tone intervals, in contrast to the vehicle-pretreated mice. Chlorpyrifos also attenuated sweet preference and enhanced climbing in the forced swim test. Chlorpyrifos-treated mice had increased expression of both synaptic and readthrough AChE transcripts in the hippocampus of Balb/C mice and decreased expression in the amygdala following fear-conditioning. In conclusion, postnatal CPF had long-term effects on fear and depression, as well as on expression of AChE mRNA. These changes may be related to alteration in the interaction between hippocampus and amygdala in regulating negative emotions. PMID:25972795

Extinction of cued fear memory involves a distinct form of depotentiation at cortical input synapses onto the lateral amygdala.

PubMed

Hong, Ingie; Song, Beomjong; Lee, Sukwon; Kim, Jihye; Kim, Jeongyeon; Choi, Sukwoo

2009-12-03

The amygdala is known to be a critical storage site of conditioned fear memory. Among the two major pathways to the lateral amygdala (LA), the cortical pathway is known to display a presynaptic long-term potentiation which is occluded with fear conditioning. Here we show that fear extinction results in a net depression of conditioning-induced potentiation at cortical input synapses onto the LA (C-LA synapses). Fear conditioning induced a significant potentiation of excitatory postsynaptic currents at C-LA synapses compared with naïve and unpaired controls, whereas extinction apparently reversed this potentiation. Paired-pulse low-frequency stimulation (pp-LFS) induced synaptic depression in the C-LA pathway of fear-conditioned rats, but not in naïve or unpaired controls, indicating that the pp-LFS-induced depression is specific to associative learning-induced changes (pp-LFS-induced depotentiation(ex vivo)). Importantly, extinction occluded pp-LFS-induced depotentiation(ex vivo), suggesting that extinction shares some mechanisms with the depotentiation. pp-LFS-induced depotentiation(ex vivo) required NMDA receptor (NMDAR) activity, consistent with a previous finding that blockade of amygdala NMDARs impaired fear extinction. In addition, pp-LFS-induced depotentiation(ex vivo) required activity of group II metabotropic glutamate receptors (mGluRs), known to be present at presynaptic terminals, but not AMPAR internalization, consistent with a presynaptic mechanism for pp-LFS-induced depotentiation(ex vivo). This result is in contrast with another form of ex vivo depotentiation in the thalamic pathway that requires both group I mGluR activity and AMPAR internalization. We thus suggest that extinction of conditioned fear involves a distinct form of depotentiation at C-LA synapses, which depends upon both NMDARs and group II mGluRs.

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 Role of the Medial Prefrontal Cortex in Trace Fear Extinction

ERIC Educational Resources Information Center

Kwapis, Janine L.; Jarome, Timothy J.; Helmstetter, Fred J.

2015-01-01

The extinction of delay fear conditioning relies on a neural circuit that has received much attention and is relatively well defined. Whether this established circuit also supports the extinction of more complex associations, however, is unclear. Trace fear conditioning is a better model of complex relational learning, yet the circuit that…

Fear memory for cue and context: opposite and time-dependent effects of a physiological dose of corticosterone in male BALB/c and C57BL/6J mice.

PubMed

Diamantopoulou, Anastasia; Oitzl, Melly S; Grauer, Ettie

2012-07-23

Highly emotional, stress reactive BALB/c mice secrete more corticosterone in response to fear conditioning than the low stress reactive C57BL/6J mice. Fear memory to cue and context differs between the strains. We injected corticosterone at physiological concentrations (250 μg/kg i.p.) 30 min before fear conditioning. Fear memory was tested 48 and 72 h later. Although corticosterone had little effect on acquisition, it differentially affected fear memories in strain dependent manner: while BALB/c mice decreased freezing during cue and context episodes, C57BL/6J mice showed an overall increase in freezing. BALB/c mice showed extinction over days while no such extinction was seen in C57BL/6J mice. Evaluation of these data in the perspective of previous studies using the same fear conditioning paradigm with corticosterone injections 5 min before or immediately after acquisition, revealed the impact of corticosterone during conditioning on the strength of fear memories. In C57BL/6J mice the overall increase in fear memories was higher if corticosterone was injected 30 min pre acquisition than if injected 5 min pre. In contrast, BALB/c mice showed reduced fear memories when injected 30 min pre compared to that seen 5 min pre acquisition. Both strains showed decreased fear memories compared to vehicle if corticosterone was administered immediately after acquisition. We conclude that the timing of physiologically relevant, stress levels increase in corticosterone is essential for the processing of aversive events and the formation of fear memories. However, the quality of the effect depends on the genetic background. These findings contribute to the understanding of the etiology of stress-related disorders. Copyright © 2012 Elsevier B.V. All rights reserved.

Modification of Fear Memory by Pharmacological and Behavioural Interventions during Reconsolidation

PubMed Central

Thome, Janine; Koppe, Georgia; Hauschild, Sophie; Liebke, Lisa; Schmahl, Christian; Lis, Stefanie; Bohus, Martin

2016-01-01

Background Dysfunctional fear responses play a central role in many mental disorders. New insights in learning and memory suggest that pharmacological and behavioural interventions during the reconsolidation of reactivated fear memories may increase the efficacy of therapeutic interventions. It has been proposed that interventions applied during reconsolidation may modify the original fear memory, and thus prevent the spontaneous recovery and reinstatement of the fear response. Methods We investigated whether pharmacological (propranolol) and behavioural (reappraisal, multisensory stimulation) interventions reduce fear memory, and prevent reinstatement of fear in comparison to a placebo control group. Eighty healthy female subjects underwent a differential fear conditioning procedure with three stimuli (CS). Two of these (CS+) were paired with an electric shock on day 1. On day 2, 20 subjects were pseudo-randomly assigned to either the propranolol or placebo condition, or underwent one of the two behavioural interventions after one of the two CS+ was reactivated. On day 3, all subjects underwent an extinction phase, followed by a reinstatement test. Dependent variables were US expectancy ratings, fear-potentiated startle, and skin conductance response. Results Differential fear responses to the reactivated and non-reactivated CS+ were observed only in the propranolol condition. Here, the non-reactivated CS+ evoked stronger fear-potentiated startle-responses compared to the placebo group. None of the interventions prevented the return of the extinguished fear response after re-exposure to the unconditioned stimulus. Conclusions Our data are in line with an increasing body of research stating that the occurrence of reconsolidation may be constrained by boundary conditions such as subtle differences in experimental manipulations and instructions. In conclusion, our findings do not support a beneficial effect in using reconsolidation processes to enhance effects of psychotherapeutic interventions. This implies that more research is required before therapeutic interventions may benefit from a combination with reconsolidation processes. PMID:27537364

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

PubMed

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

2016-01-01

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

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

PubMed Central

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

2016-01-01

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

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 in an Abdominal Pain Model: Neural Responses during Associative Learning and Extinction in Healthy Subjects

PubMed Central

Kattoor, Joswin; Gizewski, Elke R.; Kotsis, Vassilios; Benson, Sven; Gramsch, Carolin; Theysohn, Nina; Maderwald, Stefan; Forsting, Michael; Schedlowski, Manfred; Elsenbruch, Sigrid

2013-01-01

Fear conditioning is relevant for elucidating the pathophysiology of anxiety, but may also be useful in the context of chronic pain syndromes which often overlap with anxiety. Thus far, no fear conditioning studies have employed aversive visceral stimuli from the lower gastrointestinal tract. Therefore, we implemented a fear conditioning paradigm to analyze the conditioned response to rectal pain stimuli using fMRI during associative learning, extinction and reinstatement. In N = 21 healthy humans, visual conditioned stimuli (CS+) were paired with painful rectal distensions as unconditioned stimuli (US), while different visual stimuli (CS−) were presented without US. During extinction, all CSs were presented without US, whereas during reinstatement, a single, unpaired US was presented. In region-of-interest analyses, conditioned anticipatory neural activation was assessed along with perceived CS-US contingency and CS unpleasantness. Fear conditioning resulted in significant contingency awareness and valence change, i.e., learned unpleasantness of a previously neutral stimulus. This was paralleled by anticipatory activation of the anterior cingulate cortex, the somatosensory cortex and precuneus (all during early acquisition) and the amygdala (late acquisition) in response to the CS+. During extinction, anticipatory activation of the dorsolateral prefrontal cortex to the CS− was observed. In the reinstatement phase, a tendency for parahippocampal activation was found. Fear conditioning with rectal pain stimuli is feasible and leads to learned unpleasantness of previously neutral stimuli. Within the brain, conditioned anticipatory activations are seen in core areas of the central fear network including the amygdala and the anterior cingulate cortex. During extinction, conditioned responses quickly disappear, and learning of new predictive cue properties is paralleled by prefrontal activation. A tendency for parahippocampal activation during reinstatement could indicate a reactivation of the old memory trace. Together, these findings contribute to our understanding of aversive visceral learning and memory processes relevant to the pathophysiology of chronic abdominal pain. PMID:23468832

A role for the interoceptive insular cortex in the consolidation of learned fear.

PubMed

Casanova, José Patricio; Madrid, Carlos; Contreras, Marco; Rodríguez, María; Vasquez, Mónica; Torrealba, Fernando

2016-01-01

A growing body of evidence suggests that learned fear may be related to the function of the interoceptive insular cortex. Using an auditory fear conditioning paradigm in rats, we show that the inactivation of the posterior insular cortex (pIC), the target of the interoceptive thalamus, prior to training produced a marked reduction in fear expression tested 24h later. Accordingly, post-training anisomycin infused immediately, but not 6h after, also reduced fear expression tested the following day, supporting a role for the pIC in consolidation of fear memory. The long-term (ca. a week) and reversible inactivation of the pIC with the sodium channel blocker neosaxitoxin, immediately after fear memory reactivation induced a progressive decrease in the behavioral expression of conditioned fear. In turn, we observed that fear memory reactivation is accompanied by an enhanced expression of Fos and Zif268, early genes involved in neural activity and plasticity. Taken together these data indicate that the pIC is involved in the regulation of fear memories. Copyright © 2015 Elsevier B.V. All rights reserved.

Interference with olfactory memory by visual and verbal tasks.

PubMed

Annett, J M; Cook, N M; Leslie, J C

1995-06-01

It has been claimed that olfactory memory is distinct from memory in other modalities. This study investigated the effectiveness of visual and verbal tasks in interfering with olfactory memory and included methodological changes from other recent studies. Subjects were allocated to one of four experimental conditions involving interference tasks [no interference task; visual task; verbal task; visual-plus-verbal task] and presented 15 target odours. Either recognition of the odours or free recall of the odour names was tested on one occasion, either within 15 minutes of presentation or one week later. Recognition and recall performance both showed effects of interference of visual and verbal tasks but there was no effect for time of testing. While the results may be accommodated within a dual coding framework, further work is indicated to resolve theoretical issues relating to task complexity.

Zincergic innervation from the anterior olfactory nucleus to the olfactory bulb displays plastic responses after mitral cell loss.

PubMed

Airado, Carmen; Gómez, Carmela; Recio, Javier S; Baltanás, Fernando C; Weruaga, Eduardo; Alonso, José R

2008-12-01

Zinc ions are selectively accumulated in certain neurons (zinc-enriched neurons). The mouse olfactory bulb is richly innervated by zinc-enriched terminals. Here, the plasticity of the zincergic system was studied in the olfactory bulb of the Purkinje Cell Degeneration mutant mouse, an animal with specific postnatal neurodegeneration of the main projection neurons of the olfactory bulb. The analysis focused particularly on the anterior olfactory nucleus since most centrifugal afferents coming to the olfactory bulb arise from this structure. Zinc-enriched terminals in the olfactory bulb and zinc-enriched somata in the anterior olfactory nucleus were visualized after selenite injections. Immunohistochemistry against the vesicular zinc transporter was also carried out to confirm the distribution pattern of zinc-enriched terminals in the olfactory bulb. The mutant mice showed a clear reorganization of zincergic centrifugal projections from the anterior olfactory nucleus to the olfactory bulb. First, all zincergic contralateral neurons projecting to the olfactory bulb were absent in the mutant mice. Second, a significant increase in the number of stained somata was detected in the ipsilateral anterior olfactory nucleus. Since no noticeable changes were observed in the zinc-enriched terminals in the olfactory bulb, it is conceivable that mitral cell loss could induce a reorganization of zinc-enriched projections coming from the anterior olfactory nucleus, probably directed at balancing the global zincergic centrifugal modulation. These results show that zincergic anterior olfactory nucleus cells projecting to the olfactory bulb undergo plastic changes to adapt to the loss of mitral cells in the olfactory bulb of Purkinje Cell Degeneration mutant mice.

Fear Conditioning Induced by Interpersonal Conflicts in Healthy Individuals

PubMed Central

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

2015-01-01

Psychophysiological markers have been focused to investigate the psychopathology of psychiatric disorders and personality subtypes. In order to understand neurobiological mechanisms underlying these conditions, fear-conditioning model has been widely used. However, simple aversive stimuli are too simplistic to understand mechanisms because most patients with psychiatric disorders are affected by social stressors. The objective of this study was to test the feasibility of a newly-designed conditioning experiment using a stimulus to cause interpersonal conflicts and examine associations between personality traits and response to that stimulus. Twenty-nine healthy individuals underwent the fear conditioning and extinction experiments in response to three types of stimuli: a simple aversive sound, disgusting pictures, and pictures of an actors’ face with unpleasant verbal messages that were designed to cause interpersonal conflicts. Conditioned response was quantified by the skin conductance response (SCR). Correlations between the SCR changes, and personality traits measured by the Zanarini Rating Scale for Borderline Personality Disorder (ZAN-BPD) and Revised NEO Personality Inventory were explored. The interpersonal conflict stimulus resulted in successful conditioning, which was subsequently extinguished, in a similar manner as the other two stimuli. Moreover, a greater degree of conditioned response to the interpersonal conflict stimulus correlated with a higher ZAN-BPD total score. Fear conditioning and extinction can be successfully achieved, using interpersonal conflicts as a stimulus. Given that conditioned fear caused by the interpersonal conflicts is likely associated with borderline personality traits, this paradigm could contribute to further understanding of underlying mechanisms of interpersonal fear implicated in borderline personality disorder. PMID:25978817

Stress exposure prior to fear acquisition interacts with estradiol status to alter recall of fear extinction in humans.

PubMed

Antov, Martin I; Stockhorst, Ursula

2014-11-01

Classical fear acquisition and extinction are important models for the etiology and treatment of anxiety disorders such as posttraumatic stress disorder (PTSD). Women are at a higher risk for PTSD than men. Levels of circulating 17-β estradiol (E2) in women have been linked to deficits in fear extinction and extinction recall. In PTSD, fear learning coincides with acute traumatic stress. However, little is known about the possible interaction between stress exposure and hormone status on fear acquisition and extinction learning. In a 2-day, 2×3 between-subjects design with healthy participants, we examined the effects of stress (psychosocial stressor vs. control, placed 45 min prior to conditioning) and natural E2-status on differential fear conditioning, covering fear acquisition, immediate extinction (Day 1), and 24h-delayed extinction recall (Day 2). To operationalize E2-status, we compared women in the early follicular phase (EF) of their menstrual cycle (low E2, low progesterone plasma levels), women in the midcycle phase (MC, high E2, low progesterone), and men. Conditioning was indicated by differential skin conductance responses. We found an interaction between stress exposure and natural E2-status in women only: In MC-women, extinction recall on Day 2 (24h after initial extinction training) was better when fear acquisition had been preceded by stress. In EF-women, the inverse was true. We show that extinction recall of conditioned fear acquired after stress depends on estrogen status in women. Therefore, extinction-based exposure therapy in free-cycling female anxiety patients should take cycle status into account. Copyright © 2014 Elsevier Ltd. All rights reserved.

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.

Acute Exercise Enhances the Consolidation of Fear Extinction Memory and Reduces Conditioned Fear Relapse in a Sex-Dependent Manner

ERIC Educational Resources Information Center

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

2017-01-01

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…

Contingency learning in human fear conditioning involves the ventral striatum.

PubMed

Klucken, Tim; Tabbert, Katharina; Schweckendiek, Jan; Merz, Christian Josef; Kagerer, Sabine; Vaitl, Dieter; Stark, Rudolf

2009-11-01

The ability to detect and learn contingencies between fearful stimuli and their predictive cues is an important capacity to cope with the environment. Contingency awareness refers to the ability to verbalize the relationships between conditioned and unconditioned stimuli. Although there is a heated debate about the influence of contingency awareness on conditioned fear responses, neural correlates behind the formation process of contingency awareness have gained only little attention in human fear conditioning. Recent animal studies indicate that the ventral striatum (VS) could be involved in this process, but in human studies the VS is mostly associated with positive emotions. To examine this question, we reanalyzed four recently published classical fear conditioning studies (n = 117) with respect to the VS at three distinct levels of contingency awareness: subjects, who did not learn the contingencies (unaware), subjects, who learned the contingencies during the experiment (learned aware) and subjects, who were informed about the contingencies in advance (instructed aware). The results showed significantly increased activations in the left and right VS in learned aware compared to unaware subjects. Interestingly, this activation pattern was only found in learned but not in instructed aware subjects. We assume that the VS is not involved when contingency awareness does not develop during conditioning or when contingency awareness is unambiguously induced already prior to conditioning. VS involvement seems to be important for the transition from a contingency unaware to a contingency aware state. Implications for fear conditioning models as well as for the contingency awareness debate are discussed.

Altered top-down and bottom-up processing of fear conditioning in panic disorder with agoraphobia.

PubMed

Lueken, U; Straube, B; Reinhardt, I; Maslowski, N I; Wittchen, H-U; Ströhle, A; Wittmann, A; Pfleiderer, B; Konrad, C; Ewert, A; Uhlmann, C; Arolt, V; Jansen, A; Kircher, T

2014-01-01

Although several neurophysiological models have been proposed for panic disorder with agoraphobia (PD/AG), there is limited evidence from functional magnetic resonance imaging (fMRI) studies on key neural networks in PD/AG. Fear conditioning has been proposed to represent a central pathway for the development and maintenance of this disorder; however, its neural substrates remain elusive. The present study aimed to investigate the neural correlates of fear conditioning in PD/AG patients. The blood oxygen level-dependent (BOLD) response was measured using fMRI during a fear conditioning task. Indicators of differential conditioning, simple conditioning and safety signal processing were investigated in 60 PD/AG patients and 60 matched healthy controls. Differential conditioning was associated with enhanced activation of the bilateral dorsal inferior frontal gyrus (IFG) whereas simple conditioning and safety signal processing were related to increased midbrain activation in PD/AG patients versus controls. Anxiety sensitivity was associated positively with the magnitude of midbrain activation. The results suggest changes in top-down and bottom-up processes during fear conditioning in PD/AG that can be interpreted within a neural framework of defensive reactions mediating threat through distal (forebrain) versus proximal (midbrain) brain structures. Evidence is accumulating that this network plays a key role in the aetiopathogenesis of panic disorder.

Adult Olfactory Bulb Interneuron Phenotypes Identified by Targeting Embryonic and Postnatal Neural Progenitors

PubMed Central

Figueres-Oñate, Maria; López-Mascaraque, Laura

2016-01-01

Neurons are generated during embryonic development and in adulthood, although adult neurogenesis is restricted to two main brain regions, the hippocampus and olfactory bulb. The subventricular zone (SVZ) of the lateral ventricles generates neural stem/progenitor cells that continually provide the olfactory bulb (OB) with new granule or periglomerular neurons, cells that arrive from the SVZ via the rostral migratory stream. The continued neurogenesis and the adequate integration of these newly generated interneurons is essential to maintain homeostasis in the olfactory bulb, where the differentiation of these cells into specific neural cell types is strongly influenced by temporal cues. Therefore, identifying the critical features that control the generation of adult OB interneurons at either pre- or post-natal stages is important to understand the dynamic contribution of neural stem cells. Here, we used in utero and neonatal SVZ electroporation along with a transposase-mediated stable integration plasmid, in order to track interneurons and glial lineages in the OB. These plasmids are valuable tools to study the development of OB interneurons from embryonic and post-natal SVZ progenitors. Accordingly, we examined the location and identity of the adult progeny of embryonic and post-natally transfected progenitors by examining neurochemical markers in the adult OB. These data reveal the different cell types in the olfactory bulb that are generated in function of age and different electroporation conditions. PMID:27242400

The Role of Astrocytes in the Generation, Migration, and Integration of New Neurons in the Adult Olfactory Bulb

PubMed Central

Gengatharan, Archana; Bammann, Rodrigo R.; Saghatelyan, Armen

2016-01-01

In mammals, new neurons in the adult olfactory bulb originate from a pool of neural stem cells in the subventricular zone of the lateral ventricles. Adult-born cells play an important role in odor information processing by adjusting the neuronal network to changing environmental conditions. Olfactory bulb neurogenesis is supported by several non-neuronal cells. In this review, we focus on the role of astroglial cells in the generation, migration, integration, and survival of new neurons in the adult forebrain. In the subventricular zone, neural stem cells with astrocytic properties display regional and temporal specificity when generating different neuronal subtypes. Non-neurogenic astrocytes contribute to the establishment and maintenance of the neurogenic niche. Neuroblast chains migrate through the rostral migratory stream ensheathed by astrocytic processes. Astrocytes play an important regulatory role in neuroblast migration and also assist in the development of a vasculature scaffold in the migratory stream that is essential for neuroblast migration in the postnatal brain. In the olfactory bulb, astrocytes help to modulate the network through a complex release of cytokines, regulate blood flow, and provide metabolic support, which may promote the integration and survival of new neurons. Astrocytes thus play a pivotal role in various processes of adult olfactory bulb neurogenesis, and it is likely that many other functions of these glial cells will emerge in the near future. PMID:27092050

Refining the dual olfactory hypothesis: pheromone reward and odour experience.

PubMed

Martínez-García, Fernando; Martínez-Ricós, Joana; Agustín-Pavón, Carmen; Martínez-Hernández, Jose; Novejarque, Amparo; Lanuza, Enrique

2009-06-25

In rodents, sexual advertisement and gender recognition are mostly (if not exclusively) mediated by chemosignals. Specifically, there is ample evidence indicating that female mice are 'innately' attracted by male sexual pheromones that have critical non-volatile components and are detected by the vomeronasal organ. These pheromones can only get access to the vomeronasal organ by active pumping mechanisms that require close contact with the source of the stimulus (e.g. urine marks) during chemoinvestigation. We have hypothesised that male sexual pheromones are rewarding to female mice. Indeed, male-soiled bedding can be used as a reinforcer to induce conditioned place preference, provided contact with the bedding is allowed. The neural mechanisms of pheromone reward seem, however, different from those employed by other natural reinforcers, such as the sweetness or postingestive effects of sucrose. In contrast to vomeronasal-detected male sexual pheromones, male-derived olfactory stimuli (volatiles) are not intrinsically attractive to female mice. However, after repeated exposure to male-soiled bedding, intact female mice develop an acquired preference for male odours. On the contrary, in females whose accessory olfactory bulbs have been lesioned, exposure to male-soiled bedding induces aversion to male odorants. These considerations, together with data on the different properties of olfactory and vomeronasal receptors, lead us to make a proposal for the complementary roles that the olfactory and vomeronasal systems play in intersexual attraction and in other forms of intra- or inter-species communication.

Impact of olfactory and auditory priming on the attraction to foods with high energy density.

PubMed

Chambaron, S; Chisin, Q; Chabanet, C; Issanchou, S; Brand, G

2015-12-01

\\]\\Recent research suggests that non-attentively perceived stimuli may significantly influence consumers' food choices. The main objective of the present study was to determine whether an olfactory prime (a sweet-fatty odour) and a semantic auditory prime (a nutritional prevention message), both presented incidentally, either alone or in combination can influence subsequent food choices. The experiment included 147 participants who were assigned to four different conditions: a control condition, a scented condition, an auditory condition or an auditory-scented condition. All participants remained in the waiting room during15 min while they performed a 'lure' task. For the scented condition, the participants were unobtrusively exposed to a 'pain au chocolat' odour. Those in the auditory condition were exposed to an audiotape including radio podcasts and a nutritional message. A third group of participants was exposed to both olfactory and auditory stimuli simultaneously. In the control condition, no stimulation was given. Following this waiting period, all participants moved into a non-odorised test room where they were asked to choose, from dishes served buffet-style, the starter, main course and dessert that they would actually eat for lunch. The results showed that the participants primed with the odour of 'pain au chocolat' tended to choose more desserts with high energy density (i.e., a waffle) than the participants in the control condition (p = 0.06). Unexpectedly, the participants primed with the nutritional auditory message chose to consume more desserts with high energy density than the participants in the control condition (p = 0.03). In the last condition (odour and nutritional message), they chose to consume more desserts with high energy density than the participants in the control condition (p = 0.01), and the data reveal an additive effect of the two primes. Copyright © 2015 Elsevier Ltd. All rights reserved.

One-year-old fear memories rapidly activate human fusiform gyrus

PubMed Central

Pizzagalli, Diego A.

2016-01-01

Fast threat detection is crucial for survival. In line with such evolutionary pressure, threat-signaling fear-conditioned faces have been found to rapidly (<80 ms) activate visual brain regions including the fusiform gyrus on the conditioning day. Whether remotely fear conditioned stimuli (CS) evoke similar early processing enhancements is unknown. Here, 16 participants who underwent a differential face fear-conditioning and extinction procedure on day 1 were presented the initial CS 24 h after conditioning (Recent Recall Test) as well as 9-17 months later (Remote Recall Test) while EEG was recorded. Using a data-driven segmentation procedure of CS evoked event-related potentials, five distinct microstates were identified for both the recent and the remote memory test. To probe intracranial activity, EEG activity within each microstate was localized using low resolution electromagnetic tomography analysis (LORETA). In both the recent (41–55 and 150–191 ms) and remote (45–90 ms) recall tests, fear conditioned faces potentiated rapid activation in proximity of fusiform gyrus, even in participants unaware of the contingencies. These findings suggest that rapid processing enhancements of conditioned faces persist over time. PMID:26416784

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.

Cornering the fear engram: long-term synaptic changes in the lateral nucleus of the amygdala after fear conditioning.

PubMed

Kwon, Jeong-Tae; Choi, June-Seek

2009-08-05

Use-dependent synaptic modifications in the lateral nucleus of the amygdala (LA) have been suggested to be the cellular analog of memory trace after pavlovian fear conditioning. However, whether neurophysiological changes in the LA are produced as a direct consequence of associative learning awaits additional proof. Using microstimulation of the medial geniculate nucleus of the thalamus as the conditioned stimulus (CS), we demonstrated that contingent pairings of the brain-stimulation CS and a footshock unconditioned stimulus lead to enhanced synaptic efficacy in the thalamic input to the LA, supporting the hypothesis that localized synaptic alterations underlie fear memory formation.

Relapse of extinguished fear after exposure to a dangerous context is mitigated by testing in a safe context

PubMed Central

Goode, Travis D.; Kim, Janice J.

2015-01-01

Aversive events can trigger relapse of extinguished fear memories, presenting a major challenge to the long-term efficacy of therapeutic interventions. Here, we examined factors regulating the relapse of extinguished fear after exposure of rats to a dangerous context. Rats received unsignaled shock in a distinct context (“dangerous” context) 24 h prior to auditory fear conditioning in another context. Fear to the auditory conditioned stimulus (CS) was subsequently extinguished either in the conditioning context (“ambiguous” context) or in a third novel context (“safe” context). Exposure to the dangerous context 30 min before a CS retention test caused relapse to the CS in the ambiguous and safe test contexts relative to nonextinguished controls. When rats were tested 24 h later (with or without short-term testing), rats tested in the ambiguous context continued to exhibit relapse, whereas rats tested in the safe context did not. Additionally, exposure of rats to the conditioning context—in place of the unsignaled shock context—did not result in relapse of fear to the CS in the safe testing context. Our work highlights the vulnerabilities of extinction recall to interference, and demonstrates the importance of context associations in the relapse of fear after extinction. PMID:25691517

Postural control is associated with cognition and fear of falling in patients with multiple sclerosis.

PubMed

Perrochon, A; Holtzer, R; Laidet, M; Armand, S; Assal, F; Lalive, P H; Allali, G

2017-04-01

Multiple sclerosis (MS) is a chronic inflammatory and neurodegenerative disease affecting various neurological domains, such as postural control, cognition, fear of falling, depression-anxiety, and fatigue. This study examined the associations of cognitive functions, fear of falling, depression-anxiety, and fatigue with postural control in patients with MS. Postural control (sway velocity) of 63 patients with MS (age 39.0 ± 8.9 years; %female 57%; Expanded Disability Status Scale score median (interquartile range) 2.0 (1.5)) was recorded on two platforms at stable and unstable conditions. Cognition, fear of falling, depression-anxiety, and fatigue were evaluated by a comprehensive neuropsychological assessment. The associations between these domains and postural control have been measured by multivariable linear regression (adjusted for age, gender, disability, and education). In stable condition, only working memory was associated with postural control (p < 0.05). In unstable condition, working memory, executive functions, attention/processing speed, and fear of falling were associated with postural control (p < 0.05). Specific cognitive domains and fear of falling were associated with postural control in MS patients, particularly in unstable condition. These findings highlight the association of cognitive functions and fear of falling with postural control in MS.

Relapse of extinguished fear after exposure to a dangerous context is mitigated by testing in a safe context.

PubMed

Goode, Travis D; Kim, Janice J; Maren, Stephen

2015-03-01

Aversive events can trigger relapse of extinguished fear memories, presenting a major challenge to the long-term efficacy of therapeutic interventions. Here, we examined factors regulating the relapse of extinguished fear after exposure of rats to a dangerous context. Rats received unsignaled shock in a distinct context ("dangerous" context) 24 h prior to auditory fear conditioning in another context. Fear to the auditory conditioned stimulus (CS) was subsequently extinguished either in the conditioning context ("ambiguous" context) or in a third novel context ("safe" context). Exposure to the dangerous context 30 min before a CS retention test caused relapse to the CS in the ambiguous and safe test contexts relative to nonextinguished controls. When rats were tested 24 h later (with or without short-term testing), rats tested in the ambiguous context continued to exhibit relapse, whereas rats tested in the safe context did not. Additionally, exposure of rats to the conditioning context--in place of the unsignaled shock context--did not result in relapse of fear to the CS in the safe testing context. Our work highlights the vulnerabilities of extinction recall to interference, and demonstrates the importance of context associations in the relapse of fear after extinction. © 2015 Goode et al.; Published by Cold Spring Harbor Laboratory Press.

Leptin: a potential anxiolytic by facilitation of fear extinction.

PubMed

Wang, Wei; Liu, Song-Lin; Li, Kuan; Chen, Yu; Jiang, Bo; Li, Yan-Kun; Xiao, Jun-Li; Yang, Si; Chen, Tao; Chen, Jian-Guo; Li, Jia-Geng; Wang, Fang

2015-05-01

Anxiety disorders are characterized by a deficient extinction of fear memory. Evidence is growing that leptin influences numerous neuronal functions. The aims of this study were to investigate the effects and the mechanism of leptin on fear extinction. Leptin (1 mg/kg, i.p) was applied to evaluate the anxiolytic effect in rat behavioral tests. Field potentials recording were used to investigate the changes in synaptic transmission in the thalamic-lateral amygadala (LA) pathway of rat. We found that leptin produced strong anxiolytic effects under basal condition and after acute stress. Systemic administration and intra-LA infusions of leptin facilitated extinction of conditioned fear responses. The antagonist of NMDA receptor, MK-801, blocked the effect of leptin on fear extinction completely. Furthermore, these effects of leptin on fear extinction were accompanied by a reversal of conditioning-induced synaptic potentiation in the LA. Leptin facilitated NMDA receptor-mediated synaptic transmission, and reversed amygdala long-term potentiation (LTP) in a dose-dependent manner in vitro, and this LTP depotentiation effect was mediated by NMDA receptor and MAPK signaling pathway. These results identify a key role of leptin in dampening fear conditioning-induced synaptic potentiation in the LA through NMDA receptor and indicate a new strategy for treating anxiety disorders. © 2015 John Wiley & Sons Ltd.

Conditioned fear in low- and high-anxious rats is differentially regulated by cortical subcortical and midbrain 5-HT(1A) receptors.

PubMed

Ferreira, R; Nobre, M J

2014-05-30

Interactions between the prelimbic cortex and the basolateral amygdala underlie fear memory processing, mostly through acquiring and consolidating the learning of a conditioned fear. More recently, studies highlighted the role of the dorsal periaqueductal gray (DPAG) in the modulation of learning fear responses. In addition, extensive data in the literature have signaled the importance of serotonin (5-HT) on fear and anxiety. In the present study, the role of 5-HT neurotransmission of the prelimbic cortex, basolateral amygdala or the DPAG on the unconditioned and conditioned fear responses in rats previously selected as low- (LA) or high-anxious (HA) were assessed through local infusions of 5-HT itself (10nmol/0.2μl) or the selective 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT - 0.3μg/0.2μl). Behavioral analysis was conducted using the fear-potentiated startle (FPS) procedure. Dependent variables recorded were the latency and amplitude of the unconditioned startle response and FPS. Our findings suggest that, on the prelimbic cortex, 5-HT modulates the expression of conditioned fear response in HA rats and this modulation is dependent on 5-HT1A receptors. This is not true, however, for the basolateral amygdala or the DPAG. In these regions LA but not HA rats were susceptible to the anxiolytic-like effect of 5-HT1A receptor activation. It is thought that the expression of conditioned fear in HA subjects may be dependent on other 5-HT receptors, as the 5-HT1B subtype, and/or changes in other systems such as the GABA and glutamate neurotransmitters. These results increase our understanding of the rostrocaudal influence of 5-HT on the unconditioned and conditioned fear responses in LA and HA subjects and, to some extent, are in disagreement with the theoretical current that emphasizes the role of 5-HT on anxiety, mainly at the subcortical and midbrain levels. Copyright © 2014 IBRO. Published by Elsevier Ltd. All rights reserved.

Positive thinking elevates tolerance: Experimental effects of happiness on adolescents' attitudes toward asylum seekers.

PubMed

Tenenbaum, Harriet R; Capelos, Tereza; Lorimer, Jessica; Stocks, Thomas

2018-04-01

Inducing emotional reactions toward social groups can influence individuals' political tolerance. This study examines the influence of incidental fear and happiness on adolescents' tolerant attitudes and feelings toward young Muslim asylum seekers. In our experiment, 219 16- to 21-year-olds completed measures of prejudicial attitudes. After being induced to feel happiness, fear, or no emotion (control), participants reported their tolerant attitudes and feelings toward asylum-seeking young people. Participants assigned to the happiness condition demonstrated more tolerant attitudes toward asylum-seeking young people than did those assigned to the fear or control conditions. Participants in the control condition did not differ from participants in the fear condition. The participants in the happiness condition also had more positive feelings toward asylum-seeking young people than did participants in the control condition. The findings suggest that one way to increase positive attitudes toward asylum-seeking young people is to improve general emotional state.

One-trial overshadowing: Evidence for fast specific fear learning in humans.

PubMed

Haesen, Kim; Beckers, Tom; Baeyens, Frank; Vervliet, Bram

2017-03-01

Adaptive defensive actions necessitate a fear learning system that is both fast and specific. Fast learning serves to minimize the number of threat confrontations, while specific learning ensures that the acquired fears are tied to threat-relevant cues only. In Pavlovian fear conditioning, fear acquisition is typically studied via repetitive pairings of a single cue with an aversive experience, which is not optimal for the examination of fast specific fear learning. In this study, we adopted the one-trial overshadowing procedure from basic learning research, in which a combination of two visual cues is presented once and paired with an aversive electrical stimulation. Using on-line shock expectancy ratings, skin conductance reactivity and startle reflex modulation as indices of fear learning, we found evidence of strong fear after a single conditioning trial (fast learning) as well as attenuated fear responding when only half of the trained stimulus combination was presented (specific learning). Moreover, specificity of fear responding tended to correlate with levels of state and trait anxiety. These results suggest that one-trial overshadowing can be used as a model to study fast specific fear learning in humans and individual differences therein. Copyright © 2016 Elsevier Ltd. All rights reserved.

Trace Fear Conditioning Differentially Modulates Intrinsic Excitability of Medial Prefrontal Cortex-Basolateral Complex of Amygdala Projection Neurons in Infralimbic and Prelimbic Cortices.

PubMed

Song, Chenghui; Ehlers, Vanessa L; Moyer, James R

2015-09-30

Neuronal activity in medial prefrontal cortex (mPFC) is critical for the formation of trace fear memory, yet the cellular mechanisms underlying these memories remain unclear. One possibility involves the modulation of intrinsic excitability within mPFC neurons that project to the basolateral complex of amygdala (BLA). The current study used a combination of retrograde labeling and in vitro whole-cell patch-clamp recordings to examine the effect of trace fear conditioning on the intrinsic excitability of layer 5 mPFC-BLA projection neurons in adult rats. Trace fear conditioning significantly enhanced the intrinsic excitability of regular spiking infralimbic (IL) projection neurons, as evidenced by an increase in the number of action potentials after current injection. These changes were also associated with a reduction in spike threshold and an increase in h current. In contrast, trace fear conditioning reduced the excitability of regular spiking prelimbic (PL) projection neurons, through a learning-related decrease of input resistance. Interestingly, the amount of conditioned freezing was (1) positively correlated with excitability of IL-BLA projection neurons after conditioning and (2) negatively correlated with excitability of PL-BLA projection neurons after extinction. Trace fear conditioning also significantly enhanced the excitability of burst spiking PL-BLA projection neurons. In both regions, conditioning-induced plasticity was learning specific (observed in conditioned but not in pseudoconditioned rats), flexible (reversed by extinction), and transient (lasted <10 d). Together, these data suggest that intrinsic plasticity within mPFC-BLA projection neurons occurs in a subregion- and cell-type-specific manner during acquisition, consolidation, and extinction of trace fear conditioning. Significance statement: Frontal lobe-related function is vital for a variety of important behaviors, some of which decline during aging. This study involves a novel combination of electrophysiological recordings from fluorescently labeled mPFC-to-amygdala projection neurons in rats with acquisition and extinction of trace fear conditioning to determine how specific neurons change during behavior. This is the first study to demonstrate that trace fear conditioning significantly alters the intrinsic excitability of mPFC-to-amygdala projection neurons in a subregion- and cell-type-specific manner, which is also transient and reversed by extinction. These data are of broad interest to the neuroscientific community, and the results will inspire additional studies investigating the cellular mechanisms underlying circuit-specific changes within the brain as a result of associative learning and memory. Copyright © 2015 the authors 0270-6474/15/3513511-14$15.00/0.

Optogenetic stimulation of a hippocampal engram activates fear memory recall.

PubMed

Liu, Xu; Ramirez, Steve; Pang, Petti T; Puryear, Corey B; Govindarajan, Arvind; Deisseroth, Karl; Tonegawa, Susumu

2012-03-22

A specific memory is thought to be encoded by a sparse population of neurons. These neurons can be tagged during learning for subsequent identification and manipulation. Moreover, their ablation or inactivation results in reduced memory expression, suggesting their necessity in mnemonic processes. However, the question of sufficiency remains: it is unclear whether it is possible to elicit the behavioural output of a specific memory by directly activating a population of neurons that was active during learning. Here we show in mice that optogenetic reactivation of hippocampal neurons activated during fear conditioning is sufficient to induce freezing behaviour. We labelled a population of hippocampal dentate gyrus neurons activated during fear learning with channelrhodopsin-2 (ChR2) and later optically reactivated these neurons in a different context. The mice showed increased freezing only upon light stimulation, indicating light-induced fear memory recall. This freezing was not detected in non-fear-conditioned mice expressing ChR2 in a similar proportion of cells, nor in fear-conditioned mice with cells labelled by enhanced yellow fluorescent protein instead of ChR2. Finally, activation of cells labelled in a context not associated with fear did not evoke freezing in mice that were previously fear conditioned in a different context, suggesting that light-induced fear memory recall is context specific. Together, our findings indicate that activating a sparse but specific ensemble of hippocampal neurons that contribute to a memory engram is sufficient for the recall of that memory. Moreover, our experimental approach offers a general method of mapping cellular populations bearing memory engrams.

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

Uncertainty-Dependent Extinction of Fear Memory in an Amygdala-mPFC Neural Circuit Model

PubMed Central

Li, Yuzhe; Nakae, Ken; Ishii, Shin; Naoki, Honda

2016-01-01

Uncertainty of fear conditioning is crucial for the acquisition and extinction of fear memory. Fear memory acquired through partial pairings of a conditioned stimulus (CS) and an unconditioned stimulus (US) is more resistant to extinction than that acquired through full pairings; this effect is known as the partial reinforcement extinction effect (PREE). Although the PREE has been explained by psychological theories, the neural mechanisms underlying the PREE remain largely unclear. Here, we developed a neural circuit model based on three distinct types of neurons (fear, persistent and extinction neurons) in the amygdala and medial prefrontal cortex (mPFC). In the model, the fear, persistent and extinction neurons encode predictions of net severity, of unconditioned stimulus (US) intensity, and of net safety, respectively. Our simulation successfully reproduces the PREE. We revealed that unpredictability of the US during extinction was represented by the combined responses of the three types of neurons, which are critical for the PREE. In addition, we extended the model to include amygdala subregions and the mPFC to address a recent finding that the ventral mPFC (vmPFC) is required for consolidating extinction memory but not for memory retrieval. Furthermore, model simulations led us to propose a novel procedure to enhance extinction learning through re-conditioning with a stronger US; strengthened fear memory up-regulates the extinction neuron, which, in turn, further inhibits the fear neuron during re-extinction. Thus, our models increased the understanding of the functional roles of the amygdala and vmPFC in the processing of uncertainty in fear conditioning and extinction. PMID:27617747

Generalization of Fear to Respiratory Sensations.

PubMed

Schroijen, Mathias; Pappens, Meike; Schruers, Koen; Van den Bergh, Omer; Vervliet, Bram; Van Diest, Ilse

2015-09-01

Interoceptive fear conditioning (IFC), fear generalization and a lack of safety learning have all been hypothesized to play a role in the pathogenesis of panic disorder, but have never been examined in a single paradigm. The present study aims to investigate whether healthy participants (N=43) can learn both fear and safety to an interoceptive sensation, and whether such learning generalizes to other, similar sensations. Two intensities of inspiratory breathing impairment (induced by two pressure threshold loads of 6 and 25 cm H2O) served as interoceptive conditional stimuli (CSs) in a differential conditioning paradigm. An inspiratory occlusion was used as the unconditioned stimulus (US). Generalization was tested 24h after conditioning, using four generalization stimuli with intensities in-between CS+ and CS- (GSs: 8-10.5-14-18.5 cm H2O). Measures included US-expectancy, startle blink EMG responses, electrodermal activity and respiration. Perceptual discrimination of interoceptive CSs and GSs was explored with a discrimination task prior to acquisition and after generalization. Results indicate that differential fear learning was established for US-expectancy ratings. The group with a low intensity CS+ and a high intensity CS- showed the typical pattern of differential fear responding and a similarity-based generalization gradient. In contrast, the high intensity CS+ and low intensity CS- group showed impaired differential learning and complete generalization of fear. Our findings suggest that interoceptive fear learning and generalization are modulated by stimulus intensity and that the occurrence of discriminatory learning is closely related to fear generalization. Copyright © 2015. Published by Elsevier Ltd.

Uncertainty-Dependent Extinction of Fear Memory in an Amygdala-mPFC Neural Circuit Model.

PubMed

Li, Yuzhe; Nakae, Ken; Ishii, Shin; Naoki, Honda

2016-09-01

Uncertainty of fear conditioning is crucial for the acquisition and extinction of fear memory. Fear memory acquired through partial pairings of a conditioned stimulus (CS) and an unconditioned stimulus (US) is more resistant to extinction than that acquired through full pairings; this effect is known as the partial reinforcement extinction effect (PREE). Although the PREE has been explained by psychological theories, the neural mechanisms underlying the PREE remain largely unclear. Here, we developed a neural circuit model based on three distinct types of neurons (fear, persistent and extinction neurons) in the amygdala and medial prefrontal cortex (mPFC). In the model, the fear, persistent and extinction neurons encode predictions of net severity, of unconditioned stimulus (US) intensity, and of net safety, respectively. Our simulation successfully reproduces the PREE. We revealed that unpredictability of the US during extinction was represented by the combined responses of the three types of neurons, which are critical for the PREE. In addition, we extended the model to include amygdala subregions and the mPFC to address a recent finding that the ventral mPFC (vmPFC) is required for consolidating extinction memory but not for memory retrieval. Furthermore, model simulations led us to propose a novel procedure to enhance extinction learning through re-conditioning with a stronger US; strengthened fear memory up-regulates the extinction neuron, which, in turn, further inhibits the fear neuron during re-extinction. Thus, our models increased the understanding of the functional roles of the amygdala and vmPFC in the processing of uncertainty in fear conditioning and extinction.

Optogenetic stimulation of a hippocampal engram activates fear memory recall

PubMed Central

Liu, Xu; Ramirez, Steve; Pang, Petti T.; Puryear, Corey B.; Govindarajan, Arvind; Deisseroth, Karl; Tonegawa, Susumu

2012-01-01

A specific memory is thought to be encoded by a sparse population of neurons1,2. These neurons can be tagged during learning for subsequent identification3 and manipulation4,5,6. Moreover, their ablation or inactivation results in reduced memory expression, suggesting their necessity in mnemonic processes. However, a critical question of sufficiency remains: can one elicit the behavioral output of a specific memory by directly activating a population of neurons that was active during learning? Here we show that optogenetic reactivation of hippocampal neurons activated during fear conditioning is sufficient to induce freezing behavior. We labeled a population of hippocampal dentate gyrus neurons activated during fear learning with channelrhodopsin-2 (ChR2)7,8 and later optically reactivated these neurons in a different context. The mice showed increased freezing only upon light stimulation, indicating light-induced fear memory recall. This freezing was not detected in non-fear conditioned mice expressing ChR2 in a similar proportion of cells, nor in fear conditioned mice with cells labeled by EYFP instead of ChR2. Finally, activation of cells labeled in a context not associated with fear did not evoke freezing in mice that were previously fear conditioned in a different context, suggesting that light-induced fear memory recall is context-specific. Together, our findings indicate that activating a sparse but specific ensemble of hippocampal neurons that contribute to a memory engram is sufficient for the recall of that memory. Moreover, our experimental approach offers a general method of mapping cellular populations bearing memory engrams. PMID:22441246

Exposure to Novelty Weakens Conditioned Fear in Long-Evans Rats

ERIC Educational Resources Information Center

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

2013-01-01

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

Prefrontal Cortex Lesions and Sex Differences in Fear Extinction and Perseveration

ERIC Educational Resources Information Center

Baran, Sarah E.; Armstrong, Charles E.; Niren, Danielle C.; Conrad, Cheryl D.

2010-01-01

Electrolytic lesions of the medial prefrontal cortex (PFCX) were examined using fear conditioning to assess the recall of fear extinction and performance in the Y-maze, open field, and object location/recognition in male and female Sprague-Dawley rats. Rats were conditioned to seven tone/footshocks, followed by extinction after 1-h and 24-h…

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

ERIC Educational Resources Information Center

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

2005-01-01

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

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…

Olfactory Perceptual Learning Requires Action of Noradrenaline in the Olfactory Bulb: Comparison with Olfactory Associative Learning

ERIC Educational Resources Information Center

Vinera, Jennifer; Kermen, Florence; Sacquet, Joëlle; Didier, Anne; Mandairon, Nathalie; Richard, Marion

2015-01-01

Noradrenaline contributes to olfactory-guided behaviors but its role in olfactory learning during adulthood is poorly documented. We investigated its implication in olfactory associative and perceptual learning using local infusion of mixed a1-ß adrenergic receptor antagonist (labetalol) in the adult mouse olfactory bulb. We reported that…

Aging results in reduced epidermal growth factor receptor signaling, diminished olfactory neurogenesis, and deficits in fine olfactory discrimination.

PubMed

Enwere, Emeka; Shingo, Tetsuro; Gregg, Christopher; Fujikawa, Hirokazu; Ohta, Shigeki; Weiss, Samuel

2004-09-22

Previous studies demonstrating olfactory interneuron involvement in olfactory discrimination and decreased proliferation in the forebrain subventricular zone with age led us to ask whether olfactory neurogenesis and, consequently, olfactory discrimination were impaired in aged mice. Pulse labeling showed that aged mice (24 months of age) had fewer new interneurons in the olfactory bulb than did young adult (2 months of age) mice. However, the aged mice had more olfactory interneurons in total than their younger counterparts. Aged mice exhibited no differences from young adult mice in their ability to discriminate between two discrete odors but were significantly poorer at performing discriminations between similar odors (fine olfactory discrimination). Leukemia inhibitory factor receptor heterozygote mice, which have less neurogenesis and fewer olfactory interneurons than their wild-type counterparts, performed more poorly at fine olfactory discrimination than the wild types, suggesting that olfactory neurogenesis, rather than the total number of interneurons, was responsible for fine olfactory discrimination. Immunohistochemistry and Western blot analyses revealed a selective reduction in expression levels of epidermal growth factor (EGF) receptor (EGFR) signaling elements in the aged forebrain subventricular zone. Waved-1 mutant mice, which express reduced quantities of transforming growth factor-alpha, the predominant EGFR ligand in adulthood, phenocopy aged mice in olfactory neurogenesis and performance on fine olfactory discrimination tasks. These results suggest that the impairment in fine olfactory discrimination with age may result from a reduction in EGF-dependent olfactory neurogenesis.

Distribution of olfactory epithelium in the primate nasal cavity: are microsmia and macrosmia valid morphological concepts?

PubMed

Smith, Timothy D; Bhatnagar, Kunwar P; Tuladhar, Praphul; Burrows, Annie M

2004-11-01

The terms "microsmatic" and "macrosmatic" are used to compare species with greater versus lesser olfactory capabilities, such as carnivores compared to certain primates. These categories have been morphologically defined based on the size of olfactory bulb and surface area of olfactory epithelium in the nasal fossa. The present study examines assumptions regarding the morphological relationship of bony elements to the olfactory mucosa, the utility of olfactory epithelial surface area as a comparative measurement, and the utility of the microsmatic concept. We examined the distribution of olfactory neuroepithelium (OE) across the anteroposterior length of the nasal fossa (from the first completely enclosed cross-section of the nasal fossa to the choanae) in the microsmatic marmoset (Callithrix jacchus) compared to four species of nocturnal strepsirrhines (Otolemur crassicaudatus, O. garnetti, Microcebus murinus, and Cheirogaleus medius). Adults of all species were examined and infant C. jacchus, O. crassicaudatus, M. murinus, and C. medius were also examined. All specimens were serially sectioned in the coronal plane and prepared for light microscopic study. Distribution of OE across all the turbinals, nasal septal surfaces, and accessory spaces of the nasal chamber was recorded for each specimen. The right nasal fossae of one adult C. jacchus and one neonatal M. murinus were also three-dimensionally reconstructed using Scion Image software to reveal OE distribution. Findings showed OE to be distributed relatively more anteriorly in adult C. jacchus compared to strepsirrhines. It was also distributed more anteriorly along the nasal septal walls and recesses in neonates than adults. Our findings also showed that OE surface area was not a reliable proxy for receptor neuron numbers due to differing OE thickness among species. Such results indicate that nasal cavity morphology must be carefully reconsidered regarding traditional functional roles (olfaction versus air conditioning) assigned to various nasal cavity structures. At present, the microsmatic concept itself lacks a basis in nasal chamber morphology, since OE may have varying patterns of distribution among different primates. (c) 2004 Wiley-Liss, Inc.

Influence of olfactory and visual cover on nest site selection and nest success for grassland-nesting birds.

PubMed

Fogarty, Dillon T; Elmore, R Dwayne; Fuhlendorf, Samuel D; Loss, Scott R

2017-08-01

Habitat selection by animals is influenced by and mitigates the effects of predation and environmental extremes. For birds, nest site selection is crucial to offspring production because nests are exposed to extreme weather and predation pressure. Predators that forage using olfaction often dominate nest predator communities; therefore, factors that influence olfactory detection (e.g., airflow and weather variables, including turbulence and moisture) should influence nest site selection and survival. However, few studies have assessed the importance of olfactory cover for habitat selection and survival. We assessed whether ground-nesting birds select nest sites based on visual and/or olfactory cover. Additionally, we assessed the importance of visual cover and airflow and weather variables associated with olfactory cover in influencing nest survival. In managed grasslands in Oklahoma, USA, we monitored nests of Northern Bobwhite ( Colinus virginianus ), Eastern Meadowlark ( Sturnella magna ), and Grasshopper Sparrow ( Ammodramus savannarum ) during 2015 and 2016. To assess nest site selection, we compared cover variables between nests and random points. To assess factors influencing nest survival, we used visual cover and olfactory-related measurements (i.e., airflow and weather variables) to model daily nest survival. For nest site selection, nest sites had greater overhead visual cover than random points, but no other significant differences were found. Weather variables hypothesized to influence olfactory detection, specifically precipitation and relative humidity, were the best predictors of and were positively related to daily nest survival. Selection for overhead cover likely contributed to mitigation of thermal extremes and possibly reduced detectability of nests. For daily nest survival, we hypothesize that major nest predators focused on prey other than the monitored species' nests during high moisture conditions, thus increasing nest survival on these days. Our study highlights how mechanistic approaches to studying cover informs which dimensions are perceived and selected by animals and which dimensions confer fitness-related benefits.

Forming Competing Fear Learning and Extinction Memories in Adolescence Makes Fear Difficult to Inhibit

ERIC Educational Resources Information Center

Baker, Kathryn D.; Richardson, Rick

2015-01-01

Fear inhibition is markedly impaired in adolescent rodents and humans. The present experiments investigated whether this impairment is critically determined by the animal's age at the time of fear learning or their age at fear extinction. Male rats (n = 170) were tested for extinction retention after conditioning and extinction at different ages.…

Extinction training during the reconsolidation window prevents recovery of fear.

PubMed

Schiller, Daniela; Raio, Candace M; Phelps, Elizabeth A

2012-08-24

Fear is maladaptive when it persists long after circumstances have become safe. It is therefore crucial to develop an approach that persistently prevents the return of fear. Pavlovian fear-conditioning paradigms are commonly employed to create a controlled, novel fear association in the laboratory. After pairing an innocuous stimulus (conditioned stimulus, CS) with an aversive outcome (unconditioned stimulus, US) we can elicit a fear response (conditioned response, or CR) by presenting just the stimulus alone. Once fear is acquired, it can be diminished using extinction training, whereby the conditioned stimulus is repeatedly presented without the aversive outcome until fear is no longer expressed. This inhibitory learning creates a new, safe representation for the CS, which competes for expression with the original fear memory. Although extinction is effective at inhibiting fear, it is not permanent. Fear can spontaneously recover with the passage of time. Exposure to stress or returning to the context of initial learning can also cause fear to resurface. Our protocol addresses the transient nature of extinction by targeting the reconsolidation window to modify emotional memory in a more permanent manner. Ample evidence suggests that reactivating a consolidated memory returns it to a labile state, during which the memory is again susceptible to interference. This window of opportunity appears to open shortly after reactivation and close approximately 6 hrs later, although this may vary depending on the strength and age of the memory. By allowing new information to incorporate into the original memory trace, this memory may be updated as it reconsolidates. Studies involving non-human animals have successfully blocked the expression of fear memory by introducing pharmacological manipulations within the reconsolidation window, however, most agents used are either toxic to humans or show equivocal effects when used in human studies. Our protocol addresses these challenges by offering an effective, yet non-invasive, behavioral manipulation that is safe for humans. By prompting fear memory retrieval prior to extinction, we essentially trigger the reconsolidation process, allowing new safety information (i.e., extinction) to be incorporated while the fear memory is still susceptible to interference. A recent study employing this behavioral manipulation in rats has successfully blocked fear memory using these temporal parameters. Additional studies in humans have demonstrated that introducing new information after the retrieval of previously consolidated motor, episodic, or declarative memories leads to interference with the original memory trace. We outline below a novel protocol used to block fear recovery in humans.

Fear conditioning and stimulus generalization in patients with social anxiety disorder.

PubMed

Ahrens, Lea M; Pauli, Paul; Reif, Andreas; Mühlberger, Andreas; Langs, Gernot; Aalderink, Tim; Wieser, Matthias J

2016-12-01

Although overgeneralization seems to be a hallmark of several anxiety disorders, this until now has not been investigated in social anxiety disorder (SAD). Therefore, we examined fear generalization in 26 SAD patients and 29 healthy controls (HC) using two faces as conditioned stimuli (CS+, CS-), and a loud scream and a fearful face as unconditioned stimulus (US). Generalization was tested by presenting both CS and four morphs of the two faces (generalization stimuli [GSs]), while ratings, heart rate (HR) and skin conductance responses (SCR) were recorded. Results revealed that SAD patients rated all stimuli as less pleasant and more arousing compared to HC. Moreover, ratings and SCR indicated that both groups generalized their acquired fear from the CS+ to GSs. Remarkably, only SAD patients showed generalization in HR responses (fear bradycardia). Overall, SAD seems not to be characterized by strong overgeneralization but discrepancies in fear responses to both conditioned and generalized threat stimuli. Copyright © 2016 Elsevier Ltd. All rights reserved.

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

PubMed Central

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

2012-01-01

A differential fear conditioning paradigm was used with 107 healthy undergraduate participants to evaluate the effect of conditioned stimulus (CS) temporal properties on fear acquisition and extinction. Two minute duration CSs were used for Day 1 fear acquisition. Participants were randomized to receive either 1, 2, or 4 minute CS durations during Day 2 extinction. Extinction re-test was examined on Day 3 using the original acquisition CS duration (2 minutes). Findings indicated that participants who were aware of the CS+/unconditioned stimulus (US) contingency (n=52) develop a temporal expectation about when the unconditioned stimulus will be delivered. Although the shorter duration CS resulted in greater fear reduction during extinction, cessation of fear responding at re-test was the same for CS extinction durations ranging from half the CS acquisition duration to twice the CS acquisition duration. Thus, extinction performance did not predict extinction at re-test, which could have important implications for optimizing exposure therapy for anxiety disorders. PMID:22349998