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Role of endocannabinoids in the hippocampus and amygdala in emotional memory and plasticity

Neuropsychopharmacology (2018) | Download Citation

Abstract

Posttraumatic stress disorder (PTSD) is characterized by the reexperiencing of a traumatic event and is associated with slower extinction of fear responses. Impaired extinction of fearful associations to trauma-related cues may interfere with treatment response, and extinction deficits may be premorbid risk factors for the development of PTSD. We examined the effects of exposure to a severe footshock followed by situational reminders (SRs) on extinction, plasticity, and endocannabinoid (eCB) content and activity in the hippocampal CA1 area and basolateral amygdala (BLA). We also examined whether enhancing eCB signaling before extinction, using the fatty acid amide hydrolase (FAAH) inhibitor URB597, could prevent the shock/SRs-induced effects on fear response and plasticity. URB597 administered systemically (0.3 mg/kg) or locally into the CA1 or BLA (0.1 µg/side) prior to extinction decreased fear retrieval and this effect persisted throughout extinction training and did not recuperate during spontaneous recovery. A low dose of the CB1 receptor antagonist AM251 (0.3 mg/kg i.p. or 0.01 µg/0.5 µl intra-CA1 or intra-BLA) blocked these effects suggesting that the effects of URB597 were CB1 receptor-dependent. Exposure to shock and reminders induced behavioral metaplasticity with opposite effects on long-term potentiation (LTP) in the hippocampus (impairment) and the BLA (enhancement). URB597 was found to prevent the opposite shock/SR-induced metaplasticity in hippocampal and BLA-LTP. Exposure to shock and reminders might cause variation in endogenous cannabinoid levels that could affect fear-circuit function. Indeed, exposure to shock and SRs affected eCB content: increased 2-arachidonoyl-glycerol (2-AG) and N-arachidonylethanolamine (AEA) levels in the CA1, decreased serum and BLA AEA levels while shock exposure increased FAAH activity in the CA1 and BLA. FAAH inhibition before extinction abolished fear and modulated LTP in the hippocampus and amygdala, brain regions pertinent to emotional memory. The findings suggest that targeting the eCB system before extinction may be beneficial in fear memory attenuation and these effects may involve metaplasticity in the CA1 and BLA.

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References

  1. 1.

    Guthrie RM, Bryant RA. Extinction learning before trauma and subsequent posttraumatic stress. Psychosom Med. 2006;68:307–11.

  2. 2.

    Ganon-Elazar E, Akirav I. Cannabinoids prevent the development of behavioral and endocrine alterations in a rat model of intense stress. Neuropsychopharmacology. 2012;37:456–66.

  3. 3.

    Hillard CJ. Stress regulates endocannabinoid-CB1 receptor signaling. Semin Immunol. 2014;26:380–8.

  4. 4.

    Lutz B, Marsicano G, Maldonado R, Hillard CJ. The endocannabinoid system in guarding against fear, anxiety and stress. Nat Rev Neurosci. 2015;16:705–18.

  5. 5.

    Moreira FA, Wotjak CT. Cannabinoids and anxiety. Behav Neurobiol Anxiety Treat. 2010;2:429–50.

  6. 6.

    Shoshan N, Segev A, Abush H, Mizrachi Zer‐Aviv T, Akirav I. Cannabinoids prevent the differential long‐term effects of exposure to severe stress on hippocampal‐ and amygdala‐dependent memory and plasticity. Hippocampus. 2017;27:1093–109.

  7. 7.

    Korem N, Akirav I. Cannabinoids prevent the effects of a footshock followed by situational reminders on emotional processing. Neuropsychopharmacology. 2014;39:2709–22.

  8. 8.

    Haller J, Goldberg SR, Pelczer KG, Aliczki M, Panlilio LV. The effects of anandamide signaling enhanced by the FAAH inhibitor URB597 on coping styles in rats. Psychopharmacol (Berl). 2013;230:353–62.

  9. 9.

    Adamczyk P, Golda A, McCreary AC, Filip M, Przegaliriski E. Activation of endocannabinoid transmission induces antidepressant-like effects in rats. Acta Physiol Pol. 2008;59:217.

  10. 10.

    Kathuria S, Gaetani S, Fegley D, Valiño F, Duranti A, Tontini A et al. Modulation of anxiety through blockade of anandamide hydrolysis. Nat Med. 2003;9:76–81.

  11. 11.

    Aliczki M, Barna I, Till I, Baranyi M, Sperlagh B, Goldberg SR et al. The effects anandamide signaling in the prelimbic cortex and basolateral amygdala on coping with environmental stimuli in rats. Psychopharmacology. 2016;233:1889–99.

  12. 12.

    Burstein O, Shoshan N, Doron R, Akirav I. Cannabinoids prevent depressive-like symptoms and alterations in BDNF expression in a rat model of PTSD. Prog Neuropsychopharmacol Biol Psychiatry. 2018;84:129–39.

  13. 13.

    Aisenberg N, Serova L, Sabban EL, Akirav I. The effects of enhancing endocannabinoid signaling and blocking corticotrophin releasing factor receptor in the amygdala and hippocampus on the consolidation of a stressful event. Eur Neuropsychopharmacol. 2017;27:913–27.

  14. 14.

    Morena M, Leitl KD, Vecchiarelli HA, Gray JM, Campolongo P, Hill MN. Emotional arousal state influences the ability of amygdalar endocannabinoid signaling to modulate anxiety. Neuropharmacology. 2016;111:59–69.

  15. 15.

    Neumeister A. The endocannabinoid system provides an avenue for evidence-based treatment development for PTSD. Depress Anxiety. 2013;30:93–6.

  16. 16.

    Nader K, Schafe GE, Le Doux JE. Fear memories require protein synthesis in the amygdala for reconsolidation after retrieval. Nature. 2000;406:722.

  17. 17.

    Abraham WC, Bear MF. Metaplasticity: the plasticity of synaptic plasticity. Trends Neurosci. 1996;19:126–30.

  18. 18.

    Schmidt MV, Abraham WC, Maroun M, Stork O, Richter-Levin G. Stress-induced metaplasticity: from synapses to behavior. Neuroscience. 2013;250:112–20.

  19. 19.

    Abraham WC, Tate WP. Metaplasticity: a new vista across the field of synaptic plasticity. Prog Neurobiol. 1997;52:303–23.

  20. 20.

    Kim JJ, Yoon KS. Stress: metaplastic effects in the hippocampus. Trends Neurosci. 1998;21:505–9.

  21. 21.

    Mizrachi Zer‐Aviv T, Akirav I. Sex differences in hippocampal response to endocannabinoids after exposure to severe stress. Hippocampus. 2016;26:947–57.

  22. 22.

    Arenos JD, Musty RE, Bucci DJ. Blockade of cannabinoid CB1 receptors alters contextual learning and memory. Eur J Pharmacol. 2006;539:177–83.

  23. 23.

    Rodríguez-Cueto C, Hernández-Gálvez M, Hillard CJ, Maciel P, García-García L, Valdeolivas S, et al. Dysregulation of the endocannabinoid signaling system in the cerebellum and brainstem in a transgenic mouse model of spinocerebellar ataxia type-3. Neuroscience. 2016;339:191–209.

  24. 24.

    Spagnolo PA, Ramchandani VA, Schwandt ML, Kwako LE, George DT, Mayo LM, et al. FAAH gene variation moderates stress response and symptom severity in patients with posttraumatic stress disorder and comorbid alcohol dependence. Alcohol Clin Exp Res. 2016;40:2426–34.

  25. 25.

    Dean C, Hillard CJ, Seagard JL, Hopp FA, Hogan QH. Components of the cannabinoid system in the dorsal periaqueductal gray are related to resting heart rate. Am J Physiol Regul Integr Comp Physiol. 2016;311:R254–62.

  26. 26.

    Chhatwal JP, Davis M, Maguschak KA, Ressler KJ. Enhancing cannabinoid neurotransmission augments the extinction of conditioned fear. Neuropsychopharmacology. 2005;30:516–24.

  27. 27.

    Gunduz-Cinar O, Hill MN, McEwen BS, Holmes A. Amygdala FAAH and anandamide: mediating protection and recovery from stress. Trends Pharmacol Sci. 2013;34:637–44.

  28. 28.

    Morena M, Berardi A, Colucci P, Palmery M, Trezza V, Hill MN et al. Enhancing endocannabinoid neurotransmission augments the efficacy of extinction training and ameliorates traumatic stress-induced behavioral alterations in rats. Neuropsychopharmacology. 2018;43:1284–96.

  29. 29.

    Korem N, Lange R, Hillard CJ, Akirav I. Role of beta-catenin and endocannabinoids in the nucleus accumbens in extinction in rats exposed to shock and reminders. Neuroscience. 2017;357:285–94.

  30. 30.

    Levin N, Kritman M, Maroun M, Akirav I. Differential roles of the infralimbic and prelimbic areas of the prefrontal cortex in reconsolidation of a traumatic memory. Eur Neuropsychopharmacol. 2017;27:900–12.

  31. 31.

    Zubedat S, Akirav I. The involvement of cannabinoids and mTOR in the reconsolidation of an emotional memory in the hippocampal–amygdala–insular circuit. Eur Neuropsychopharmacol. 2017;27:336–49.

  32. 32.

    Elzinga BM, Bremner JD. Are the neural substrates of memory the final common pathway in posttraumatic stress disorder (PTSD)? J Affect Disord. 2002;70:1–17.

  33. 33.

    Garcia R, Paquereau J, Vouimba RM, Jaffard R. Footshock stress but not contextual fear conditioning induces long‐term enhancement of auditory‐evoked potentials in the basolateral amygdala of the freely behaving rat. Eur J Neurosci. 1998;10:457–63.

  34. 34.

    Shin LM, Liberzon I. The neurocircuitry of fear, stress, and anxiety disorders. Neuropsychopharmacology. 2010;35:169–91.

  35. 35.

    Hillard CJ, Beatka M, Sarvaideo J. Endocannabinoid signaling and the hypothalamic–pituitary–adrenal axis. Compr Physiol. 2016;7:1–15.

  36. 36.

    Patel S,Roelke CT,Rademacher DJ,Cullinan WE,Hillard CJ, Endocannabinoid signaling negatively modulates stress-induced activation of the hypothalamic–pituitary–adrenal axis. Endocrinology. 2004;145:5431–8.

  37. 37.

    Akirav I. Cannabinoids and glucocorticoids modulate emotional memory after stress. Neurosci Biobehav Rev. 2013;37:2554–63.

  38. 38.

    Ganon-Elazar E, Akirav I. Cannabinoid receptor activation in the basolateral amygdala blocks the effects of stress on the conditioning and extinction of inhibitory avoidance. J Neurosci. 2009;29:11078–88.

  39. 39.

    Hill MN,McLaughlin RJ,Morrish AC,Viau V,Floresco SB,Hillard CJ, et al. Suppression of amygdalar endocannabinoid signaling by stress contributes to activation of the hypothalamic–pituitary–adrenal axis. Neuropsychopharmacology. 2009;34:2733–45.

  40. 40.

    Kim JJ, Diamond DM. The stressed hippocampus, synaptic plasticity and lost memories. Nat Rev Neurosci. 2002;3:453–62.

  41. 41.

    Watanabe Y, Saito H, Abe K. Effects of glycine and structurally related amino acids on generation of long-term potentiation in rat hippocampal slices. Eur J Pharmacol. 1992;223:179–84.

  42. 42.

    Wang M, Hill MN, Zhang L, Gorzalka BB, Hillard CJ, Alger BE. Acute restraint stress enhances hippocampal endocannabinoid function via glucocorticoid receptor activation. J Psychopharmacol (Oxf). 2011;26:56–70.

  43. 43.

    Maren S, Fanselow MS. Synaptic plasticity in the basolateral amygdala induced by hippocampal formation stimulation in vivo. J Neurosci. 1995;15:7548–64.

  44. 44.

    Popoli M, Yan Z, McEwen BS, Sanacora G. The stressed synapse: the impact of stress and glucocorticoids on glutamate transmission. Nat Rev Neurosci. 2012;13:22–37.

  45. 45.

    Rey AA, Purrio M, Viveros M-P, Lutz B. Biphasic effects of cannabinoids in anxiety responses: CB1 and GABAB receptors in the balance of GABAergic and glutamatergic neurotransmission. Neuropsychopharmacology. 2012;37:2624–34.

  46. 46.

    Natividad LA, Buczynski MW, Herman MA, Kirson D, Oleata CS, Irimia C, et al. Constitutive increases in amygdalar corticotropin-releasing factor and fatty acid amide hydrolase drive an anxious phenotype. Biol Psychiatry. 2017;82:500–10.

  47. 47.

    Ramikie TS, Nyilas R, Bluett RJ, Gamble-George JC, Hartley ND, Mackie K, et al. Multiple mechanistically distinct modes of endocannabinoid mobilization at central amygdala glutamatergic synapses. Neuron. 2014;81:1111–25.

  48. 48.

    Campolongo P, Roozendaal B, Trezza V, Hauer D, Schelling G, McGaugh JL et al. Endocannabinoids in the rat basolateral amygdala enhance memory consolidation and enable glucocorticoid modulation of memory. Proc Natl Acad Sci USA. 2009;106:4888–93.

  49. 49.

    Abush H, Akirav I. Cannabinoids ameliorate impairments induced by chronic stress to synaptic plasticity and short-term memory. Neuropsychopharmacology. 2013;38:1521–34.

  50. 50.

    Rademacher DJ, Meier SE, Shi L, Vanessa Ho W-S, Jarrahian A, Hillard CJ. Effects of acute and repeated restraint stress on endocannabinoid content in the amygdala, ventral striatum, and medial prefrontal cortex in mice. Neuropharmacology. 2008;54:108–16.

  51. 51.

    Hill MN,Bierer LM,Makotkine I,Golier JA,Galea S,McEwen BS, et al. Reductions in circulating endocannabinoid levels in individuals with posttraumatic stress disorder following exposure to the World Trade Center attacks. Psychoneuroendocrinology. 2013;38:2952–61.

  52. 52.

    Schaefer C, Enning F, Mueller JK, Bumb JM, Rohleder C, Odorfer TM, et al. Fatty acid ethanolamide levels are altered in borderline personality and complex posttraumatic stress disorders. Eur Arch Psychiatry Clin Neurosci. 2014;264:459–63.

  53. 53.

    Lim J, Igarashi M, Jung K-M, Butini S, Campiani G, Piomelli D. Endocannabinoid modulation of predator stress-induced long-term anxiety in rats. Neuropsychopharmacology. 2016;41:1329–39.

  54. 54.

    Hill MN,McLaughlin RJ,Bingham B,Shrestha L,Lee TT,Gray JM, et al. Endogenous cannabinoid signaling is essential for stress adaptation. Proc Natl Acad Sci. 2010;107:9406–11.

  55. 55.

    Gray JM, Vecchiarelli HA, Morena M, Lee TT, Hermanson DJ, Kim AB, et al. Corticotropin-releasing hormone drives anandamide hydrolysis in the amygdala to promote anxiety. J Neurosci. 2015;35:3879–92.

  56. 56.

    Hill MN,Karatsoreos IN,Hillard CJ,McEwen BS, Rapid elevations in limbic endocannabinoid content by glucocorticoid hormones in vivo. Psychoneuroendocrinology. 2010;35:1333–8.

  57. 57.

    Bluett RJ,Gamble-George JC,Hermanson DJ,Hartley ND,Marnett LJ,Patel S, Central anandamide deficiency predicts stress-induced anxiety: behavioral reversal through endocannabinoid augmentation. Transl Psychiatry. 2014;4:e408

  58. 58.

    Hill MN,Miller GE,Carrier EJ,Gorzalka BB,Hillard CJ, Circulating endocannabinoids and N-acyl ethanolamines are differentially regulated in major depression and following exposure to social stress. Psychoneuroendocrinology. 2009;34:1257–62.

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Funding

This research was supported by The Binational Science Foundation (BSF) [Grant no. 2011/256 to I.A. and C.J.H. (URL: www.bsf.org.il/)] and by the Research and Education Component of the Advancing a Healthier Wisconsin Endowment at the Medical College of Wisconsin.

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Author notes

  1. These authors contributed equally: Tomer Mizrachi Zer-Aviv, Nachshon Korem, Amir Segev.

Affiliations

  1. Department of Psychology, University of Haifa, Haifa, 3498838, Israel

    • Amir Segev
    • , Nachshon Korem
    • , Tomer Mizrachi Zer-Aviv
    • , Hila Abush
    •  & Irit Akirav
  2. Department of Pharmacology and Toxicology, Neuroscience Research Center, Medical College of Wisconsin, Milwaukee, 53226, USA

    • Rachel Lange
    • , Garrett Sauber
    •  & Cecilia J. Hillard

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The authors declare no competing interests.

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Correspondence to Amir Segev.

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https://doi.org/10.1038/s41386-018-0135-4