Neurobiology of fear and specific phobias

Garcia, René

doi:10.1101/lm.044115.116

Cited by 239Memory and Neural MechanismsAnxiety, Depression, Psychometrics, Treatment, Cognitive ProcessesNeuroscience and Neuropharmacology Research

Neurobiology of fear and specific phobias

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Garcia, René·2017·Learning & Memory

DOI 10.1101/lm.044115.116PMC PMC5580526

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Abstract

Fear, which can be expressed innately or after conditioning, is triggered when a danger or a stimulus predicting immediate danger is perceived. Its role is to prepare the body to face this danger. However, dysfunction in fear processing can lead to psychiatric disorders in which fear outweighs the danger or possibility of harm. Although recognized as highly debilitating, pathological fear remains insufficiently treated, indicating the importance of research on fear processing. The neurobiological basis of normal and pathological fear reactions is reviewed in this article. Innate and learned fear mechanisms, particularly those involving the amygdala, are considered. These fear mechanisms are also distinguished in specific phobias, which can indeed be nonexperiential (implicating innate, learning-independent mechanisms) or experiential (implicating learning-dependent mechanisms). Poor habituation and poor extinction are presented as dysfunctional mechanisms contributing to persistence of nonexperiential and experiential phobias, respectively.

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Traumatic events can lead to specific phobias.
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Insula–amygdala functional connectivity is correlated with habituation to repeated negative images
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SPIDER OR NO SPIDER? NEURAL CORRELATES OF SUSTAINED AND PHASIC FEAR IN SPIDER PHOBIA
Klahn, A. L., Notzon, S., Redlich, R., Grotegerd, D., Dohm, K., Arolt, V., Kugel, H., Zwanzger, P., & Dannlowski, U. (2015) · Depression and Anxiety · doi:10.1002/da.22382 · Cited by 62 · see citing works
New Perspectives on β-Adrenergic Mediation of Innate and Learned Fear Responses to Predator Odor
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Controllability Modulates the Anticipatory Response in the Human Ventromedial Prefrontal Cortex
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Signaling through cGMP-Dependent Protein Kinase I in the Amygdala Is Critical for Auditory-Cued Fear Memory and Long-Term Potentiation
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TMT predator odor activated neural circuit in C57BL/6J mice indicates TMT-stress as a suitable model for uncontrollable intense stress
Janitzky, K., D’Hanis, W., Kröber, A., & Schwegler, H. (2014) · Brain Research · doi:10.1016/j.brainres.2014.12.030 · Cited by 57 · see citing works
Effects of systemic injections of Vilazodone, a selective serotonin reuptake inhibitor and serotonin 1A receptor agonist, on anxiety induced by predator stress in rats
Adamec, R. E., Bartoszyk, G. D., & Burton, P. (2004) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2004.09.009 · Cited by 55 · see citing works
Large Intercalated Neurons of Amygdala Relay Noxious Sensory Information
Bienvenu, T., Busti, D., Micklem, B. R., Mansouri, M., Magill, P. J., Ferraguti, F., & Capogna, M. (2015) · Journal of Neuroscience · doi:10.1523/jneurosci.1323-14.2015 · Cited by 53 · see citing works
CREB regulates spine density of lateral amygdala neurons: implications for memory allocation
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Out with the old and in with the new: Synaptic mechanisms of extinction in the amygdala
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Why do some individuals develop social phobia? A review with emphasis on the neurobiological influences
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The 5-HT3A receptor is essential for fear extinctionPreprint
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Fluoxetine Facilitates Fear Extinction Through Amygdala Endocannabinoids
Gunduz‐Cinar, O., Flynn, S., Brockway, E. T., Kaugars, K. E., Báldi, R., Ramikie, T. S., Çınar, R., Kunos, G., Patel, S., & Holmes, A. (2015) · Neuropsychopharmacology · doi:10.1038/npp.2015.318 · Cited by 47 · see citing works
Optimizing Treatment in Social Phobia: A Review of Treatment Resistance
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Hippocampal dendritic spines remodeling and fear memory are modulated by GABA ergic signaling within the basolateral amygdala complex
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Beyond the HPA-axis: The role of the gonadal steroid hormone receptors in modulating stress-related responses in an animal model of PTSD
Fenchel, D., Levkovitz, Y., Vainer, E., Kaplan, Z., Zohar, J., & Cohen, H. (2015) · European Neuropsychopharmacology · doi:10.1016/j.euroneuro.2015.02.004 · Cited by 42 · see citing works
Tiagabine for social anxiety disorder
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Dynamic amino acid increases in the basolateral amygdala during acquisition and expression of conditioned fear
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The effects of midazolam and D-cycloserine on the release of glutamate and GABA in the basolateral amygdala of low and high anxiety rats during extinction trial of a conditioned fear test.
Lehner, M., Wisłowska-Stanek, A., Taracha, E., Maciejak, P., Szyndler, J., Skórzewska, A., Turzyńska, D., Sobolewska, A., Hamed, A., Bidziński, A., et al. (2010) · Neurobiology of Learning and Memory · doi:10.1016/j.nlm.2010.08.014 · Cited by 33 · see citing works
Behavioral and Endocrine Consequences of Simultaneous Exposure to Two Different Stressors in Rats: Interaction or Independence?
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Graded fear generalization enhances the level of cfos‐positive neurons specifically in the basolateral amygdala
Rajbhandari, A. K., Zhu, R., Adling, C., Fanselow, M. S., & Waschek, J. A. (2016) · Journal of Neuroscience Research · doi:10.1002/jnr.23947 · Cited by 28 · see citing works
Combination of fluoxetine and extinction treatments forms a unique synaptic protein profile that correlates with long-term fear reduction in adult mice
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Fear conditioning selectively disrupts noradrenergic facilitation of GABAergic inhibition in the basolateral amygdala
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Commonalities and differences in the neural substrates of threat predictability in panic disorder and specific phobia
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Identification of Features Associated with Flying Phobia in Aircrew
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Prefrontal tetanic stimulation, following fear reconditioning, facilitates expression of previously acquired extinction.
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Self-citation
Quantitative representations of an exaggerated anxiety response in the brain of female spider phobics—a parametric f MRI study
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“Pandemic fear” and COVID-19: mental health burden and strategies
Ornell, F., Schuch, J. B., Sordi, A. O., & Kessler, F. H. P. (2020) · Brazilian Journal of Psychiatry · doi:10.1590/1516-4446-2020-0008 · Cited by 1,852 · see citing works
Understanding coronaphobia
Arora, A., Jha, A. K., Alat, P., & Das, S. S. (2020) · Asian Journal of Psychiatry · doi:10.1016/j.ajp.2020.102384 · Cited by 252 · see citing works
“Traumatic events can lead to specific phobias (Garcia, 2017).”
Background
A review of decreased sound tolerance in autism: Definitions, phenomenology, and potential mechanisms
Williams, Z. J., He, J. L., Cascio, C. J., & Woynaroski, T. G. (2021) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2020.11.030 · Cited by 175 · see citing works
Sleep quality in times of Covid-19 pandemic
Pinto, J., van Zeller, M., Amorim, P., Pimentel, A., Dantas, P. M., Eusébio, E., Neves, A., Pipa, J., Clara, E. S., Santiago, T., et al. (2020) · Sleep Medicine · doi:10.1016/j.sleep.2020.07.012 · Cited by 168 · see citing works
Perceived Job Insecurity and Depressive Symptoms among Italian Dentists: The Moderating Role of Fear of COVID-19
Gasparro, R., Scandurra, C., Maldonato, N. M., Dolce, P., Bochicchio, V., Valletta, A., Sammartino, G., Sammartino, P., Mariniello, M., di Lauro, A. E., et al. (2020) · International Journal of Environmental Research and Public Health · doi:10.3390/ijerph17155338 · Cited by 146 · see citing works
An Investigation of the Effect of COVID-19 on OCD in Youth in the Context of Emotional Reactivity, Experiential Avoidance, Depression and Anxiety
Seçer, İ., & Ulaş, S. (2021) · International Journal of Mental Health and Addiction · doi:10.1007/s11469-020-00322-z · Cited by 142 · see citing works
Microglial P2Y12 receptor regulates ventral hippocampal CA1 neuronal excitability and innate fear in mice
Peng, J., Liu, Y., Umpierre, A. D., Xie, M., Tian, D., Richardson, J. R., & Wu, L. (2019) · Molecular Brain · doi:10.1186/s13041-019-0492-x · Cited by 124 · see citing works
THE IMPORTANCE OF PSYCHODYNAMIC APPROACH DURING COVID-19 PANDEMIC
Marčinko, D., Jakovljević, M., Jakšić, N., Bjedov, S., & Drakulić, A. M. (2020) · Psychiatria Danubina · doi:10.24869/psyd.2020.15 · Cited by 119 · see citing works
Divergent medial amygdala projections regulate approach–avoidance conflict behavior
Miller, S. M., Marcotulli, D., Shen, A., & Zweifel, L. S. (2019) · Nature Neuroscience · doi:10.1038/s41593-019-0337-z · Cited by 112 · see citing works
Pandemia de medo e Covid-19: impacto na saúde mental e possíveis estratégias
Ornell, F. R., Schuch, J. B., Sordi, A. O., & Kessler, F. H. P. (2020) · Debates em Psiquiatria · doi:10.25118/2236-918x-10-2-2 · Cited by 109 · see citing works
The role of learning in threat imminence and defensive behaviors
Fanselow, M. S. (2018) · Current Opinion in Behavioral Sciences · doi:10.1016/j.cobeha.2018.03.003 · Cited by 104 · see citing works
An Emotion Care Model using Multimodal Textual Analysis on COVID-19
Gupta, V., Jain, N., Katariya, P., Kumar, A., Mohan, S., Ahmadian, A., & Феррара, М. (2021) · Chaos Solitons & Fractals · doi:10.1016/j.chaos.2021.110708 · Cited by 81 · see citing works
The Effect of the Fear of COVID-19 on Healthcare Professionals’ Psychological Adjustment Skills: Mediating Role of Experiential Avoidance and Psychological Resilience
Seçer, İ., Ulaş, S., & Karaman-Özlü, Z. (2020) · Frontiers in Psychology · doi:10.3389/fpsyg.2020.561536 · Cited by 75 · see citing works
Fear and Trembling of Cruise Ship Employees: Psychological Effects of the COVID-19 Pandemic
Radić, A., Lück, M., Ariza‐Montes, A., & Han, H. (2020) · International Journal of Environmental Research and Public Health · doi:10.3390/ijerph17186741 · Cited by 67 · see citing works
Associations Between Fear of COVID-19, Affective Symptoms and Risk Perception Among Community-Dwelling Older Adults During a COVID-19 Lockdown
Han, M., Mahendran, R., & Yu, J. (2021) · Frontiers in Psychology · doi:10.3389/fpsyg.2021.638831 · Cited by 69 · see citing works
Fear of COVID-19 and Life Satisfaction: The Role of the Health-Related Hardiness and Sense of Coherence
Dymecka, J., Gerymski, R., Machnik-Czerwik, A., Derbis, R., & Bidzan, M. (2021) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2021.712103 · Cited by 59 · see citing works
Avoidant restrictive food intake disorder: recent advances in neurobiology and treatment
da Fonseca, N. K. D. O., Curtarelli, V. D., Bertoletti, J., Azevedo, K., Cardinal, T. M., Moreira, J. D., & Antunes, L. D. C. (2024) · Journal of Eating Disorders · doi:10.1186/s40337-024-01021-z · Cited by 64 · see citing works
Aging and Mental Health
Bhattacharyya, K. K. (2021) · Springer eBooks · doi:10.1007/978-3-030-88870-1_6 · Cited by 51 · see citing works
The effect of ego-resiliency and COVID-19-related stress on mental health among the Japanese population
Kubo, T., Sugawara, D., & Masuyama, A. (2021) · Personality and Individual Differences · doi:10.1016/j.paid.2021.110702 · Cited by 48 · see citing works
Relationship of fear of COVID-19 and pregnancy-related quality of life during the COVID-19 pandemic
Naghizadeh, S., & Mirghafourvand‬‬‬‬‬‬‬‬‬‬‬‬‬‬, M. (2021) · Archives of Psychiatric Nursing · doi:10.1016/j.apnu.2021.05.006 · Cited by 45 · see citing works
Kinesiophobia and Fear Avoidance in Older Adults: A Scoping Review on the State of Research Activity
Alpalhão, V. L. B., Cordeiro, N., & Pezarat‐Correia, P. (2022) · Journal of Aging and Physical Activity · doi:10.1123/japa.2021-0409 · Cited by 44 · see citing works
Mood of India During Covid-19 - An Interactive Web Portal Based on Emotion Analysis of Twitter Data
Venigalla, A. S. M., Chimalakonda, S., & Vagavolu, D. (2020) · ACM Conference on Computer Supported Cooperative Work (CSCW) · doi:10.1145/3406865.3418567 · Cited by 45 · see citing works
An animal model of trait anxiety: Carioca high freezing rats as a model of generalized anxiety disorder
Cruz, A. P. D. M., Gomes, V. D. C., & Landeira-Fernández, J. (2024) · Personality Neuroscience · doi:10.1017/pen.2023.6 · Cited by 35 · see citing works
Adaptive virtual reality horror games based on Machine learning and player modeling
de Lima, E. S., Silva, B. M. C., & Galam, G. T. (2022) · Entertainment Computing · doi:10.1016/j.entcom.2022.100515 · Cited by 34 · see citing works
Fear of COVID ‐19, stress and depression: A meta‐analytic test of the mediating role of anxiety
Çıkrıkçı, Ö., Çıkrıkçı, N., & Griffiths, M. D. (2022) · Psychology and Psychotherapy Theory Research and Practice · doi:10.1111/papt.12406 · Cited by 34 · see citing works
Obsessive-compulsive disorder reinforcement during the COVID-19 pandemic
Ornell, F. R., Braga, D. T., Bavaresco, D. V., Francke, I. D., Scherer, J. N., DIEMEN, L. V., & Kessler, F. H. P. (2021) · Trends in Psychiatry and Psychotherapy · doi:10.47626/2237-6089-2020-0054 · Cited by 31 · see citing works
Dental fear, anxiety, and phobia; causes, diagnostic criteria and the medical and social impact
Avramova, N. (2022) · Journal of Mind and Medical Sciences · doi:10.22543/2392-7674.1348 · Cited by 29 · see citing works
New insights into fever phobia: a pilot qualitative study with caregivers and their healthcare providers
Merlo, F., Falvo, I., Zufferey, M. C., Schulz, P. J., Milani, G. P., Simonetti, G. D., Bianchetti, M. G., & Fadda, M. (2022) · European Journal of Pediatrics · doi:10.1007/s00431-022-04704-4 · Cited by 29 · see citing works
Beyond Emotions: Oscillations of the Amygdala and Their Implications for Electrical Neuromodulation
Schönfeld, L.-M., & Wojtecki, L. (2019) · Frontiers in Neuroscience · doi:10.3389/fnins.2019.00366 · Cited by 29 · see citing works
A Fear of COVID-19 and PTSD Symptoms in Pathological Personality: The Mediating Effect of Dissociation and Emotion Dysregulation
Velotti, P., Civilla, C., Rogier, G., & Zobel, S. B. (2021) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2021.590021 · Cited by 29 · see citing works
Percepção do medo de ser contaminado pelo novo coronavírus
Lindemann, I. L., Simonetti, A. B., do Amaral, C. P., Riffel, R. T., Simon, T. T., Stobbe, J. C., & Acrani, G. O. (2021) · Jornal Brasileiro de Psiquiatria · doi:10.1590/0047-2085000000306 · Cited by 28 · see citing works
Angiotensin II Regulates the Neural Expression of Subjective Fear in Humans: A Precision Pharmaco-Neuroimaging Approach
Zhang, R., Zhao, W., Qi, Z., Xu, T., Zhou, F., & Becker, B. (2022) · Biological Psychiatry Cognitive Neuroscience and Neuroimaging · doi:10.1016/j.bpsc.2022.09.008 · Cited by 21 · see citing works
Coping with COVID-19: social representations underlying blaming processes and fear
Mondragón, N. I., Sancho, N. B., Ozamiz-Etxebarria, N., & Sáez, I. A. (2021) · Psychology and Health · doi:10.1080/08870446.2021.1896717 · Cited by 24 · see citing works
The Psychological Impact of Coronavirus Pandemic Restrictions in Italy. The Mediating Role of the Fear of COVID-19 in the Relationship between Positive and Negative Affect with Positive and Negative Outcomes
Zammitti, A., Imbrogliera, C., Russo, A., Zarbo, R., & Magnano, P. (2021) · European Journal of Investigation in Health Psychology and Education · doi:10.3390/ejihpe11030050 · Cited by 23 · see citing works
Corona virus fear among health workers during the early phase of pandemic response in Nepal: A web-based cross-sectional study
Khanal, P., Devkota, N., Dahal, M., Paudel, K., Mishra, S. R., & Joshi, D. (2021) · PLOS Global Public Health · doi:10.1371/journal.pgph.0000083 · Cited by 22 · see citing works
Hallucinogenic drugs and their potential for treating fear‐related disorders: Through the lens of fear extinction
Glavonic, E., Mitić, M., & Adžić, M. (2022) · Journal of Neuroscience Research · doi:10.1002/jnr.25017 · Cited by 21 · see citing works
Suicidal ideation and its related factors among older adults: a population-based study in Southwestern Iran
Shiraly, R., Mahdaviazad, H., Zohrabi, R., & Griffiths, M. D. (2022) · BMC Geriatrics · doi:10.1186/s12877-022-03049-9 · Cited by 21 · see citing works
Fears during the Covid-19 pandemics and their influence on physical health: A cross-sectional study on the general population in Spain
Silla, J. M. P., Luque-García, A., Soriano, A., & Martínez‐Tur, V. (2022) · International Journal of Clinical and Health Psychology · doi:10.1016/j.ijchp.2022.100361 · Cited by 19 · see citing works
Distinct Circuits From the Central Lateral Amygdala to the Ventral Part of the Bed Nucleus of Stria Terminalis Regulate Different Fear Memory
Zhu, Y., Xie, S., Peng, A.-B., Yu, X., Li, C., Fu, J., Shen, C.-J., Cao, S.-X., Zhang, Y., Chen, J., et al. (2023) · Biological Psychiatry · doi:10.1016/j.biopsych.2023.08.022 · Cited by 19 · see citing works
COVID-19 pandemic fears and obsessive-compulsive symptoms in adolescents with pre-existing mental disorders: An exploratory cross-sectional study
Khan, Y. S., Jouda, M., Albobali, Y., Abouelseoud, M. O., Souid, A., AlMeraisi, M. J., & Alabdulla, M. (2021) · Clinical Child Psychology and Psychiatry · doi:10.1177/13591045211017606 · Cited by 18 · see citing works
Pandemic and mental adjustment disorders. Therapy options
Vasileva, A. V. (2020) · S S Korsakov Journal of Neurology and Psychiatry · doi:10.17116/jnevro2020120051146 · Cited by 19 · see citing works
Portuguese Version of COVID-19 Perceived Risk Scale and COVID-19 Phobia Scale: Psychometric Properties
Leite, Â. M. T., Vidal, D. G., Sousa, H. F. P. E., Dinis, M. A. P., & Magano, J. (2021) · European Journal of Investigation in Health Psychology and Education · doi:10.3390/ejihpe11030078 · Cited by 17 · see citing works
Involvement of Serotonergic and Relaxin-3 Neuropeptide Systems in the Expression of Anxiety-like Behavior
Lawther, A. J., Flavell, A., Ma, S., Kent, S., Lowry, C. A., Gundlach, A. L., & Hale, M. W. (2018) · Neuroscience · doi:10.1016/j.neuroscience.2018.08.007 · Cited by 17 · see citing works
Meta-analysis of prospective longitudinal cohort studies on the impact of childhood traumas on anxiety disorders
Liu, J., Shi, Y., Xie, S., Xing, L., Wang, L., Li, W., & Zhao, X. (2025) · Journal of Affective Disorders · doi:10.1016/j.jad.2025.01.067 · Cited by 16 · see citing works
Covid-19 Pandemi Sürecinde Diş Hekimliği Uzmanlık Öğrencilerinin Korku ve Anksiyete Düzeylerinin Değerlendirilmesi
Atay, Ü. T., Dinçer, N. N., Yarkaç, F. U., & Öncü, E. (2020) · Necmettin Erbakan Universitesi Dis Hekimligi Dergisi (NEU Dent J) Necmettin Erbakan · doi:10.51122/neudentj.2020.1 · Cited by 16 · see citing works
Oxytocin: An Old Hormone, a Novel Psychotropic Drug and its Possible Use in Treating Psychiatric Disorders
Marazziti, D., Diep, P.-T., Carter, C. S., & Carbone, M. G. (2022) · Current Medicinal Chemistry · doi:10.2174/0929867329666220727120646 · Cited by 16 · see citing works
Pandemic COVID-19 and mental disorders international experience and therapeutic approaches
Vasileva, A. V. (2020) · S S Korsakov Journal of Neurology and Psychiatry · doi:10.17116/jnevro2020120091121 · Cited by 15 · see citing works
Differences in Sense of Belonging, Pride, and Mental Health in the Daegu Metropolitan Region due to COVID-19: Comparison between the Presence and Absence of National Disaster Relief Fund
Kim, Y., Cho, J.-H., & Kim, E.-S. (2020) · International Journal of Environmental Research and Public Health · doi:10.3390/ijerph17134910 · Cited by 15 · see citing works
COVID-19 ve Psikolojik Etkileri: Klinik Psikoloji Perspektifinden Bir Derleme
Bekaroğlu, E., & Yilmaz, T. (2020) · Nesne Psikoloji Dergisi · doi:10.7816/nesne-08-18-14 · Cited by 15 · see citing works
Fear of clowns: An investigation into the aetiology of coulrophobia
Tyson, P. J., Davies, S. K., Scorey, S., & Greville, W. J. (2023) · Frontiers in Psychology · doi:10.3389/fpsyg.2023.1109466 · Cited by 13 · see citing works
Comparative Proteomic Analysis Reveals the Effect of Selenoprotein W Deficiency on Oligodendrogenesis in Fear Memory
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Development of Fears
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Authors: Garcia, R.
Venue: Learning & Memory
Publisher: Cold Spring Harbor Laboratory
Published: 2017-08-16
Volume: 24
Issue: 9
Pages: 462-471
ISSN: 1072-0502 (ISSN-L)
1549-5485
DOI: 10.1101/lm.044115.116
PMC: PMC5580526
OpenAlex: W2750397098
Cited by: 239
References: 119
Citations by year: 2026: 8 · 2025: 20 · 2024: 45 · 2023: 25 · 2022: 42 · 2021: 44 · 2020: 44 · 2019: 8 · 2018: 2
Type: posted content
Language: en
Open access: hybrid
doi.org
Licence: cc-by-nc
Locations: Learning & Memory (publishedVersion, cc-by-nc)
Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
PubMed Central (publishedVersion, cc-by-nc)
PubMed (publishedVersion)
HighWire Press Open Archive (submittedVersion)
Topics: Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
Social Sciences › Psychology › Experimental and Cognitive Psychology › Anxiety, Depression, Psychometrics, Treatment, Cognitive Processes
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords: fear, specific phobia, amygdala, innate fear, learned fear, fear conditioning, fear extinction, habituation, fear processing
MeSH terms: Animals, Brain, Fear, Humans, Instinct, Neurobiology, Phobic Disorders

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Neurobiology of fear and specific phobias

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