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Fear Conditioning

Fear Conditioning: Modulation by Diseases and Disorders

By October 7, 2019December 4th, 2019No Comments

Fear conditioning, like many models of learning and memory, is highly susceptible to modulation by a variety of pathological diseases and disorders. While fear conditioning itself may not have immediately evident translational value to understanding these disorders, it is a behavior that implicates function in a variety of important brain regions impacted by these conditions and is therefore highly relevant to understanding compromised brain function. Moreover, identifying specific deficits in memory function is a crucial component of dissecting the nuances of neurological disorders and works to inform both our understanding and treatment of such conditions. Finally, since fear conditioning findings are readily generalizable between rodents and humans, both of whom exhibit similar time-courses and learning profiles, these findings have significant implications for the therapeutic approaches used in addressing such behavioral disorders such as post-traumatic stress disorder (PTSD), addiction, and both naturally occurring and disease-associated aging.[1]

Post-Traumatic Stress Disorder

Fear conditioning, and impairments within, have long been associated with models of stress and anxiety. Perhaps the most salient of these is PTSD, where impaired fear conditioning extinction underlies the persistent and difficult to reverse association between fear-inducing conditions and otherwise innocuous stimuli.[2] PTSD is most strongly correlated with deficits in the function of the prefrontal cortex, the amygdala, and the hippocampus, all three of which are crucial for the formation and subsequent extinction of fear-associated memories.[3] At its core, PTSD is indeed an example of impaired extinction from fear conditioning wherein repeated exposure to the conditioned stimulus (for example, a loud noise) fails to become dissociated from the unconditioned stimulus (for example, a gunshot previously paired with a similar loud noise). The treatments for PTSD are varied, but one of the most common is exposure therapy,[4] which is essentially the human equivalent of a prolonged extinction protocol.

To induce PTSD in mice, the animals are often exposed to chronic, unpredictable stress (CUS). Following CUS, the animals become more susceptible to acquired fear conditioning and more resilient to extinction, much like human PTSD patients.[5] Thus, the goal amongst researchers investigating PTSD treatments has long been to find ways to enhance extinction following CUS and subsequent fear conditioning. One such success down this path is the use of the selective serotonin reuptake inhibitor, paroxetine.[6] Using a PTSD model that exhibited enhanced acquisition and impaired extinction of a fear response in mice, researchers found that animals given paroxetine were less likely to experience reactivation of the extinguished memory when the conditioned stimulus was re-paired with the footshock after an effective extinction protocol. This is of particular importance since PTSD patients are highly susceptible to the reactivation of fear-associated memories even after long periods without symptomatic responses. Thus, paroxetine treatment presents a potentially valuable avenue for ameliorating PTSD symptoms in chronic sufferers and has already seen positive results in human trials.[7]

Alzheimer’s Disease

Due to the known impacts of Alzheimer’s disease (AD) on memory function, it is no surprise that fear conditioning is a behavior that is significantly impacted in models of the disease. While AD is most commonly associated with impairments in semantic and episodic memory, several studies have observed impaired fear conditioning, an emotional and instinctive form of memory, in AD models. In fact, the presence and quantity of amyloid-beta oligomers, the hallmark of AD development, is strongly correlated with impaired acquisition of contextual fear memory.[8] Other AD models, such as the 3xTg-AD mouse model, show similar deficits in contextual fear conditioning.[9]

In humans, the acquisition of a fear response has been observed as significantly impaired in patients with AD. One study which examined this effect used a simple conditioning paradigm, pairing the presentation of a green rectangle (the conditioned stimulus or CS+) with an abrupt, jarring loud noise (the unconditioned stimulus, US).[10] As a control, the patients were also shown a red rectangle, termed the CS-. While normal, age-matched (elderly) people showed a robust association between the CS+ and the US, while showing no response to the CS-, AD patients never learned to associate the CS+ with the US at all and did not differentiate between the CS+ and the CS-. Since fear conditioning is a largely instinctual behavior (or, nondeclarative memory) relying on brain regions such as the amygdala, rather than a cognitive and perceptual behavior (such as declarative memory), this finding is important in identifying impairments in basic mechanistic functions of the brain in AD patients.

Addiction

Drugs of abuse, often associated with stress, are also known to modulate fear conditioning. In particular, the extinction of a conditioned response is impaired in a variety of abuse and addiction models and in humans with substance abuse disorders.

In one prime translational example, researchers investigated the effects of chronic cannabis use in human subjects in order to validate numerous pervious findings showing that giving both mice and rats cannabinoid agonists, which mimic the effects of cannabis, impairs fear extinction. Comparing 20 age, sex, and demographically matched chronic cannabis users with non-cannabis users, the authors showed that those who abused the drug exhibited two main differences from those who did not.[11] First, after establishing a paired fear response in the subjects, researchers began an extinction protocol which was found to be significantly less effective in the cannabis users when tested on the same day as the initial conditioning. Then, when the subjects were tested the following day to examine the magnitude of the remnant fear response, the cannabis users continued to exhibit a heightened response. Importantly, the authors cannot determine whether this effect may be reversed through abstinence from cannabis, however, the finding is nonetheless significant for therapeutic approach determination in cannabis abuse patients.

Contrary to the above study, investigations into the impact of alcohol on fear extinction have focused primarily on the withdrawal and long-term consequences.[1] In part, this is because alcohol itself interferes with memory function and therefore disrupts the acquisition of fear conditioning in the first place. Additionally, understanding how alcohol withdrawal impacts memory is a crucial step towards treating relapse amongst addicts, thus pointing researchers towards such long-term models. One study which harnessed this information in order to investigate a possible therapeutic approach to treating alcoholics used contextual fear conditioning initiated three days after a two-week alcohol binge in adult rats.[12] The alcohol-withdrawn rats exhibited enhanced acquisition of contextual fear conditioning, as well as impaired extinction (consistent with a stronger memory formed during the acquisition). Then, when the animals were treated with the D-cycloserine (an accepted treatment for anxiety amongst other disorders), extinction was normalized in the alcoholic rats. The fact, moreover, that this treatment had no effect in the non-alcoholic rats, points towards an important mechanistic underpinning of alcohol-withdrawal-enhanced fear memory and illuminates a valuable pharmacological approach to treating addicts.

Conclusions

Fear conditioning has served as a basic model for memory function in an extremely wide range of conditions and disorders. Understanding how diseases modulate memory and emotional instincts is a crucial step in the development of intelligent, targeted therapies for their treatment. As such, investigating impaired fear conditioning in models of PTSD, Alzheimer’s disease and addiction, as discussed here, is the basis on which we work towards a complete understanding of these conditions and how we may best treat them. Impaired fear conditioning has also been exhibited a variety of disorders not detailed above, from nicotine addiction[13] to Fragile X mental retardation[14] and schizophrenia.[15] As researchers continue to investigate this relationship, important advances will similarly continue to be made in the collective conceptualization and therapeutic treatment of these disorders.

References

  1. Singewald, N., & Holmes, A. (2019). Rodent models of impaired fear extinction. Psychopharmacology, 236(1), 21–32.
  2. Deslauriers, J., Toth, M., Der-Avakian, A., & Risbrough, V. B. (2018). Current status of animal models of PTSD: Behavioral and biological phenotypes, and future challenges in improving translation. Biological Psychiatry, 83(10), 895–907.
  3. Mahan, A. L., & Ressler, K. J. (2012). Fear Conditioning, Synaptic Plasticity, and the Amygdala: Implications for Posttraumatic Stress Disorder. Trends in Neurosciences, 35(1), 24–35.
  4. Paredes, D., & Morilak, D. A. (2019). A Rodent Model of Exposure Therapy: The Use of Fear Extinction as a Therapeutic Intervention for PTSD. Frontiers in Behavioral Neuroscience, 13.
  5. Bondi, C. O., Rodriguez, G., Gould, G. G., Frazer, A., & Morilak, D. A. (2008). Chronic unpredictable stress induces a cognitive deficit and anxiety-like behavior in rats that is prevented by chronic antidepressant drug treatment. Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology, 33(2), 320–331.
  6. Bentefour, Y., Rakibi, Y., Bennis, M., Ba-M’hamed, S., & Garcia, R. (2016). Paroxetine treatment, following behavioral suppression of PTSD-like symptoms in mice, prevents relapse by activating the infralimbic cortex. European Neuropsychopharmacology: The Journal of the European College of Neuropsychopharmacology, 26(2), 195–207.
  7. Schneier, F. R., Neria, Y., Pavlicova, M., Hembree, E., Suh, E. J., Amsel, L., & Marshall, R. D. (2012). Combined prolonged exposure therapy and paroxetine for PTSD related to the World Trade Center attack: A randomized controlled trial. The American Journal of Psychiatry, 169(1), 80–88.
  8. Kittelberger, K. A., Piazza, F., Tesco, G., & Reijmers, L. G. (2012). Natural Amyloid-Beta Oligomers Acutely Impair the Formation of a Contextual Fear Memory in Mice. PLoS ONE, 7(1).
  9. Stover, K. R., Campbell, M. A., Van Winssen, C. M., & Brown, R. E. (2015). Early detection of cognitive deficits in the 3xTg-AD mouse model of Alzheimer’s disease. Behavioural Brain Research, 289, 29–38.
  10. Hamann, S., Monarch, E. S., & Goldstein, F. C. (2002). Impaired fear conditioning in Alzheimer’s disease. Neuropsychologia, 40(8), 1187–1195.
  11. Papini, S., Ruglass, L. M., Lopez-Castro, T., Powers, M. B., Smits, J. A. J., & Hien, D. A. (2017). Chronic cannabis use is associated with impaired fear extinction in humans. Journal of Abnormal Psychology, 126(1), 117–124.
  12. Bertotto, M. E., Bustos, S. G., Molina, V. A., & Martijena, I. D. (2006). Influence of ethanol withdrawal on fear memory: Effect of D-cycloserine. Neuroscience, 142(4), 979–990.
  13. Haaker, J., Lonsdorf, T. B., Schümann, D., Bunzeck, N., Peters, J., Sommer, T., & Kalisch, R. (2017). Where There is Smoke There is Fear—Impaired Contextual Inhibition of Conditioned Fear in Smokers. Neuropsychopharmacology, 42(8), 1640–1646.
  14. Olmos-Serrano, J. L., & Corbin, J. G. (2011). Amygdala regulation of fear and emotionality in fragile X syndrome. Developmental Neuroscience, 33(5), 365–378.
  15. Gill, K. M., Miller, S. A., & Grace, A. A. (2018). Impaired contextual fear-conditioning in MAM rodent model of schizophrenia. Schizophrenia Research, 195, 343–352.
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