Fear conditioning

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Pavlovian fear conditioning is a behavioral paradigm in which organisms learn to predict aversive events.[1] It is a form of learning in which an aversive stimulus (e.g. an electrical shock) is associated with a particular neutral context (e.g., a room) or neutral stimulus (e.g., a tone), resulting in the expression of fear responses to the originally neutral stimulus or context. This can be done by pairing the neutral stimulus with an aversive stimulus (e.g., a shock, loud noise, or unpleasant odor[2]). Eventually, the neutral stimulus alone can elicit the state of fear. In the vocabulary of classical conditioning, the neutral stimulus or context is the "conditional stimulus" (CS), the aversive stimulus is the "unconditional stimulus" (US), and the fear is the "conditional response" (CR).

Fear conditioning apparatus for mice equipped with a sound, a foot shock and an activity sensor with photobeams to measure freezing. Environment context can be changed. This apparatus is also used for PTSD studies.

Fear conditioning has been studied in numerous species, from snails[3] to humans.[4] In humans, conditioned fear is often measured with verbal report and galvanic skin response. In other animals, conditioned fear is often measured with freezing (a period of watchful immobility) or fear potentiated startle (the augmentation of the startle reflex by a fearful stimulus). Changes in heart rate, breathing, and muscle responses via electromyography can also be used to measure conditioned fear. A number of theorists have argued that conditioned fear coincides substantially with the mechanisms, both functional and neural, of clinical anxiety disorders.[5] Research into the acquisition, consolidation and extinction of conditioned fear promises to inform new drug based and psychotherapeutic treatments for an array of pathological conditions such as dissociation, phobias and post-traumatic stress disorder.[6]

Scientists have discovered that there is a set of brain connections that determine how fear memories are stored and recalled. While studying rats' ability to recall fear memories, researchers found a newly identified brain circuit is involved. Initially, the pre-limbic prefrontal cortex (PL) and the basolateral amygdala (BLA) were identified in memory recall. A week later, the central amygdala (CeA) and the paraventricular nucleus of the thalamus (PVT) were identified in memory recall, which are responsible for maintaining fear memories. This study shows how there are shifting circuits between short term recall and long term recall of fear memories. There is no change in behavior or response, only change in where the memory was recalled from.[7]



Fear conditioning is thought to depend upon an area of the brain called the amygdala. The amygdala is involved in acquisition, storage, and expression of conditioned fear memory.[8] Lesion studies have revealed that lesions drilled into the amygdala before fear conditioning prevent the acquisition of the conditioned response of fear, and lesions drilled in the amygdala after conditioning cause conditioned responses to be forgotten.[9] Electrophysiological recordings from the amygdala have demonstrated that cells in that region undergo long-term potentiation (LTP), a form of synaptic plasticity believed to underlie learning.[10] Pharmacological studies, synaptic studies, and human studies also implicate the amygdala as chiefly responsible for fear learning and memory.[11] Additionally, inhibition of neurons in the amygdala disrupts fear acquisition, while stimulation of those neurons can drive fear-related behaviors, such as freezing behavior in rodents.[12] This indicates that proper function of the amygdala is both necessary for fear conditioning and sufficient to drive fear behaviors. The amygdala is not exclusively the fear center, but also an area for responding to various environmental stimuli. Several studies have shown that when faced with unpredictable neutral stimuli, amygdala activity increases. Therefore, even in situations of uncertainty and not necessarily fear, the amygdala plays a role in alerting other brain regions that encourage safety and survival responses.[13]

In the mid 1950s Lawrence Weiskrantz demonstrated that monkeys with lesions of amygdala failed to avoid an aversive shock while the normal monkeys learned to avoid them. He concluded that a key function of the amygdala was to connect external stimuli with aversive consequences.[14] Following Weiskrantz’s discovery many researchers used avoidance conditioning to study neural mechanisms of fear.[15]

Joseph E. LeDoux has been instrumental in elucidating the amygdala's role in fear conditioning. He was one of the first to show that the amygdala undergoes long-term potentiation during fear conditioning, and that ablation of amygdala cells disrupts both learning and expression of fear.[16]


Some types of fear conditioning (e.g. contextual and trace) also involve the hippocampus, an area of the brain believed to receive affective impulses from the amygdala and to integrate those impulses with previously existing information to make it meaningful. Some theoretical accounts of traumatic experiences suggest that amygdala-based fear bypasses the hippocampus during intense stress and can be stored somatically or as images that can return as physical symptoms or flashbacks without cognitive meaning.[17]

Molecular mechanisms[edit]

Intra-amygdala circuit[edit]

Neurons in the basolateral amygdala are responsible for the formation of conditioned fear memory. These neurons project to neurons in the central amygdala for the expression of a conditioned fear response. Damage to these areas in the amygdala would result in disruption of the expression of conditioned fear responses. Lesions in the basolateral amygdala have shown severe deficits in the expression of conditioned fear responses. Lesions in the central amygdala have shown mild deficits in the expression of conditioned fear responses.[8]

NMDA receptors and glutamate[edit]

One of the major neurotransmitters involved in conditioned fear learning is glutamate.[18] It has been suggested that NMDA receptors (NMDARs) in the amygdala are necessary for fear memory acquisition, because disruption of NMDAR function disrupts development of fear responses in rodents.[19] In addition, the associative nature of fear conditioning is reflected in the role of NMDARs as coincident detectors, where NMDAR activation requires simultaneous depolarization by US inputs combined with concurrent CS activation.[20]


Conditioned fear may be inherited transgenerationally. In one experiment, mice were conditioned to fear an acetophenone odor and then set up to breed subsequent generations of mice. Those subsequent generations of mice also showed a behavioral sensitivity to acetophenone, which was accompanied by neuroanatomical and epigenetic changes that are believed to have been inherited from the parents' gametes.[21]

Across development[edit]

The learning involved in conditioned fear, as well as the underlying neurobiology, changes dramatically from infancy, across childhood and adolescence, into adulthood and aging. Specifically, infant animals show an inability to develop fear associations, whereas their adult counterparts develop fear memories much more readily.[22]

Prior experience with stress

A history of stressors preceding a traumatic event increases the effect of fear conditioning in rodents.[23] This phenomena, named Stress-Enhanced Fear Learning (SEFL), has been demonstrated in both young (e.g. [24]) and adult (e.g. [25]) rodents. Biological mechanisms underpinning SEFL have not yet been made clear, though it has been associated with a rise in corticosterone, the stress hormone, following the initial stressor.[26]

See also[edit]


  1. ^ Maren S (2001). "Neurobiology of Pavlovian fear conditioning". Annual Review of Neuroscience. 24: 897–931. doi:10.1146/annurev.neuro.24.1.897. hdl:2027.42/61939. PMID 11520922.
  2. ^ Wallace KJ, Rosen JB (October 2000). "Predator odor as an unconditioned fear stimulus in rats: elicitation of freezing by trimethylthiazoline, a component of fox feces". Behavioral Neuroscience. 114 (5): 912–22. doi:10.1037/0735-7044.114.5.912. PMID 11085605.
  3. ^ Walters ET, Carew TJ, Kandel ER (January 1981). "Associative Learning in Aplysia: evidence for conditioned fear in an invertebrate". Science. 211 (4481): 504–6. Bibcode:1981Sci...211..504W. doi:10.1126/science.7192881. PMID 7192881.
  4. ^ Critchley HD, Mathias CJ, Dolan RJ (February 2002). "Fear conditioning in humans: the influence of awareness and autonomic arousal on functional neuroanatomy". Neuron. 33 (4): 653–63. doi:10.1016/s0896-6273(02)00588-3. PMID 11856537.
  5. ^ Rosen JB, Schulkin J (April 1998). "From normal fear to pathological anxiety". Psychological Review. 105 (2): 325–50. doi:10.1037/0033-295X.105.2.325. PMID 9577241.
  6. ^ VanElzakker MB, Dahlgren MK, Davis FC, Dubois S, Shin LM (September 2014). "From Pavlov to PTSD: the extinction of conditioned fear in rodents, humans, and anxiety disorders". Neurobiology of Learning and Memory. 113: 3–18. doi:10.1016/j.nlm.2013.11.014. PMC 4156287. PMID 24321650.
  7. ^ Yeager A (19 January 2015). "Newly identified brain circuit hints at how fear memories are made" (PDF). Science News.
  8. ^ a b Kim JJ, Jung MW (2006). "Neural circuits and mechanisms involved in Pavlovian fear conditioning: a critical review". Neuroscience and Biobehavioral Reviews. 30 (2): 188–202. doi:10.1016/j.neubiorev.2005.06.005. PMC 4342048. PMID 16120461.
  9. ^ Maren S (1998). "Neurotoxic Basolateral Amygdala Lesions Impair Learning and Memory But Not the Performance of Conditional Fear in Rats". The Journal of Neuroscience. 19 (19): 8696–9703. doi:10.1523/JNEUROSCI. hdl:1842/36564. PMC 6783031. PMID 10493770.
  10. ^ Sah P, Westbrook RF, Lüthi A (2008-05-01). "Fear conditioning and long-term potentiation in the amygdala: what really is the connection?". Annals of the New York Academy of Sciences. 1129 (1): 88–95. Bibcode:2008NYASA1129...88S. doi:10.1196/annals.1417.020. PMID 18591471. S2CID 36506768.
  11. ^ Kim JJ, Jung MW (2006). "Neural circuits and mechanisms involved in Pavlovian fear conditioning: a critical review". Neuroscience and Biobehavioral Reviews. 30 (2): 188–202. doi:10.1016/j.neubiorev.2005.06.005. PMC 4342048. PMID 16120461.
  12. ^ Bocchio M, Nabavi S, Capogna M (May 2017). "Synaptic Plasticity, Engrams, and Network Oscillations in Amygdala Circuits for Storage and Retrieval of Emotional Memories". Neuron. 94 (4): 731–743. doi:10.1016/j.neuron.2017.03.022. PMID 28521127.
  13. ^ Grupe, D. W., & Nitschke, J. B. (2011). Anxiety disorders and the amygdala. In AccessScience. McGraw-Hill Education. doi:10.1036/1097-8542.YB110087
  14. ^ Weiskrantz L (August 1956). "Behavioral changes associated with ablation of the amygdaloid complex in monkeys". Journal of Comparative and Physiological Psychology. 49 (4): 381–91. doi:10.1037/h0088009. PMID 13345917.
  15. ^ Kandel ER, Schwartz JH, Jessel TH, Siegelbaum SA, Hudspeth AJ (2013). Principles of neural science. United States of America: McGraw Hill Medical. p. 1084. ISBN 978-0-07-139011-8.
  16. ^ LeDoux JE (2000-03-01). "Emotion circuits in the brain". Annual Review of Neuroscience. 23 (1): 155–84. doi:10.1146/annurev.neuro.23.1.155. PMID 10845062.
  17. ^ Bromberg PM (2003). "Something wicked this way comes: Trauma, dissociation, and conflict: The space where psychoanalysis, cognitive science, and neuroscience overlap". Psychoanalytic Psychology. 20 (3): 558–74. doi:10.1037/0736-9735.20.3.558.
  18. ^ Johansen JP, Cain CK, Ostroff LE, LeDoux JE (October 2011). "Molecular mechanisms of fear learning and memory". Cell. 147 (3): 509–24. doi:10.1016/j.cell.2011.10.009. PMC 3215943. PMID 22036561.
  19. ^ Johansen JP, Cain CK, Ostroff LE, LeDoux JE (October 2011). "Molecular mechanisms of fear learning and memory". Cell. 147 (3): 509–24. doi:10.1016/j.cell.2011.10.009. PMC 3215943. PMID 22036561.
  20. ^ Johansen JP, Hamanaka H, Monfils MH, Behnia R, Deisseroth K, Blair HT, LeDoux JE (July 2010). "Optical activation of lateral amygdala pyramidal cells instructs associative fear learning". Proceedings of the National Academy of Sciences of the United States of America. 107 (28): 12692–7. Bibcode:2010PNAS..10712692J. doi:10.1073/pnas.1002418107. PMC 2906568. PMID 20615999.
  21. ^ Dias BG, Ressler KJ (January 2014). "Parental olfactory experience influences behavior and neural structure in subsequent generations". Nature Neuroscience. 17 (1): 89–96. doi:10.1038/nn.3594. PMC 3923835. PMID 24292232.
  22. ^ Ganella DE, Kim JH (October 2014). "Developmental rodent models of fear and anxiety: from neurobiology to pharmacology". British Journal of Pharmacology. 171 (20): 4556–74. doi:10.1111/bph.12643. PMC 4209932. PMID 24527726.
  23. ^ Sneddon EA, Riddle CA, Schuh KM, Quinn JJ, Radke AK (January 2021). "Selective enhancement of fear learning and resistance to extinction in a mouse model of acute early life trauma". Learning & Memory. 28 (1): 12–16. doi:10.1101/lm.052373.120. PMC 7747648. PMID 33323497.
  24. ^ Poulos AM, Reger M, Mehta N, Zhuravka I, Sterlace SS, Gannam C, et al. (August 2014). "Amnesia for early life stress does not preclude the adult development of posttraumatic stress disorder symptoms in rats". Biological Psychiatry. 76 (4): 306–14. doi:10.1016/j.biopsych.2013.10.007. PMC 3984614. PMID 24231200.
  25. ^ Rau V, Fanselow MS (March 2009). "Exposure to a stressor produces a long lasting enhancement of fear learning in rats". Stress. 12 (2): 125–33. doi:10.1080/10253890802137320. PMID 18609302. S2CID 15453890.
  26. ^ Beylin AV, Shors TJ (January 2003). "Glucocorticoids are necessary for enhancing the acquisition of associative memories after acute stressful experience". Hormones and Behavior. 43 (1): 124–131. doi:10.1016/S0018-506X(02)00025-9. PMC 3363955. PMID 12614642.