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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]

Contents

NeurobiologyEdit

AmygdalaEdit

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] 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.[9] 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.[10] 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. [11]

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.[12]

HippocampusEdit

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.[13]

Molecular mechanismsEdit

Intra-amygdala circuitEdit

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.[14]

NMDA receptors and glutamateEdit

One of the major neurotransmitters involved in conditioned fear learning is glutamate. 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.[15]

EpigeneticsEdit

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.[16]

Across developmentEdit

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.[17]

See alsoEdit

ReferencesEdit

  1. ^ Maren, Stephen (2001). "Neurobiology of Pavlovian fear conditioning" (PDF). Annual Review of Neuroscience. 24: 897–931. doi:10.1146/annurev.neuro.24.1.897. PMID 11520922.
  2. ^ Wallace, Karin J.; Rosen, Jeffrey B. "Predator odor as an unconditioned fear stimulus in rats: Elicitation of freezing by trimethylthiazoline, a component of fox feces". Behavioral Neuroscience. 114 (5): 912–922. doi:10.1037/0735-7044.114.5.912.
  3. ^ Walters, E. T.; Carew, T. J.; Kandel, E. R. (1981-01-30). "Associative Learning in Aplysia: evidence for conditioned fear in an invertebrate". Science. 211 (4481): 504–506. doi:10.1126/science.7192881. ISSN 0036-8075. PMID 7192881.
  4. ^ Critchley, Hugo D; Mathias, Christopher J; Dolan, Raymond J. "Fear Conditioning in Humans". Neuron. 33 (4): 653–663. doi:10.1016/s0896-6273(02)00588-3.
  5. ^ Rosen, Jeffrey B.; Schulkin, Jay (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, M. B., Dahlgren, M. K., Davis, F. C., Dubois, S. & Shin, L. M. (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 | PMID 24321650
  7. ^ Ashley Yeager. (2015, January 19). Newly identified brain circuit hints at how fear memories are made. Science News. Retrieved February 17, 2019, from AccessScience: https://www-accessscience-com.ezproxy3.lhl.uab.edu/content/newly-identified-brain-circuit-hints-at-how-fear-memories-are-made/SN0122151
  8. ^ Kim, J. J., & Jung, M. W. (2006). Neural circuits and mechanisms involved in pavlovian fear conditioning: A critical review. Neuroscience and Biobehavioral Reviews, 30(2), 188-202. doi:http://dx.doi.org.ezproxy3.lhl.uab.edu/10.1016/j.neubiorev.2005.06.005
  9. ^ Sah, P.; Westbrook, R. F.; Lüthi, A. (2008-05-01). "Fear Conditioning and Long-term Potentiation in the Amygdala". Annals of the New York Academy of Sciences. 1129 (1): 88–95. doi:10.1196/annals.1417.020. ISSN 1749-6632.
  10. ^ Bocchio, Marco; Nabavi, Sadegh; Capogna, Marco (2017-05-17). "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. ISSN 0896-6273.
  11. ^ Grupe, D. W., & Nitschke, J. B. (2011). Anxiety disorders and the amygdala. In AccessScience. McGraw-Hill Education. https://doi-org.ezproxy3.lhl.uab.edu/10.1036/1097-8542.YB110087
  12. ^ LeDoux, Joseph E. (2000-03-01). "Emotion Circuits in the Brain". Annual Review of Neuroscience. 23 (1): 155–184. doi:10.1146/annurev.neuro.23.1.155. ISSN 0147-006X.
  13. ^ Bromberg, Philip M. (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.
  14. ^ Kim, J. J., & Jung, M. W. (2006). Neural circuits and mechanisms involved in pavlovian fear conditioning: A critical review. Neuroscience and Biobehavioral Reviews, 30(2), 188-202. doi:http://dx.doi.org.ezproxy3.lhl.uab.edu/10.1016/j.neubiorev.2005.06.005
  15. ^ Johansen, Joshua P.; Cain, Christopher K.; Ostroff, Linnaea E.; LeDoux, Joseph E. (2011-10-28). "Molecular Mechanisms of Fear Learning and Memory". Cell. 147 (3): 509–524. doi:10.1016/j.cell.2011.10.009. ISSN 0092-8674. PMC 3215943.
  16. ^ Dias, Brian G; Ressler, Kerry J (January 2014). "Parental olfactory experience influences behavior and neural structure in subsequent generations". Nature Neuroscience. 17 (1): 89–96. doi:10.1038/nn.3594. ISSN 1546-1726. PMC 3923835.
  17. ^ Ganella, Despina E; Kim, Jee Hyun (2014-10-01). "Developmental rodent models of fear and anxiety: from neurobiology to pharmacology". British Journal of Pharmacology. 171 (20): 4556–4574. doi:10.1111/bph.12643. ISSN 1476-5381. PMC 4209932.