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Upregulation of Anandamide Hydrolysis in the Basolateral Complex of Amygdala Reduces Fear Memory Expression and Indices of Stress and Anxiety.
J Neurosci. 2019 02 13; 39(7):1275-1292.JN

Abstract

Increased anandamide (AEA) signaling through inhibition of its catabolic enzyme fatty acid amide hydrolase (FAAH) in the basolateral complex of amygdala (BLA) is thought to buffer against the effects of stress and reduces behavioral signs of anxiety and fear. However, examining the role of AEA signaling in stress, anxiety, and fear through pharmacological depletion has been challenging due to the redundant complexity of its biosynthesis and the lack of a pharmacological synthesis inhibitor. We developed a herpes simplex viral vector to rapidly yet transiently overexpress FAAH specifically within the BLA to assess the impact of suppressing AEA signaling on stress, fear, and anxiety in male rats. Surprisingly, FAAH overexpression in BLA dampened stress-induced corticosterone release, reduced anxiety-like behaviors, and decreased conditioned fear expression. Interestingly, depleting AEA signaling in the BLA did not prevent fear conditioning itself or fear reinstatement. These effects were specific to the overexpression of FAAH because they were reversed by intra-BLA administration of an FAAH inhibitor. Moreover, the fear-suppressive effects of FAAH overexpression were also mitigated by intra-BLA administration of a low dose of a GABAA receptor antagonist, but not an NMDA/AMPA/kainate receptor antagonist, suggesting that they were mediated by an increase in GABAergic neurotransmission. Our data suggest that a permissive AEA tone within the BLA might gate GABA release and that loss of this tone through elevated AEA hydrolysis increases inhibition in the BLA, which in turn reduces stress, anxiety, and fear. These data provide new insights on the mechanisms by which amygdalar endocannabinoid signaling regulates emotional behavior.SIGNIFICANCE STATEMENT Amygdala endocannabinoid signaling is involved in the regulation of stress, anxiety, and fear. Our data indicate that viral-mediated augmentation of anandamide hydrolysis within the basolateral amygdala reduces behavioral indices of stress, anxiety, and conditioned fear expression. These same effects have been previously documented with inhibition of anandamide hydrolysis in the same brain region. Our results indicate that the ability of anandamide signaling to regulate emotional behavior is nonlinear and may involve actions at distinct neuronal populations, which could be influenced by the basal level of anandamide. Modulation of anandamide signaling is a current clinical therapeutic target for stress-related psychiatric illnesses, so these data underscore the importance of fully understanding the mechanisms by which anandamide signaling regulates amygdala-dependent changes in emotionality.

Authors+Show Affiliations

Hotchkiss Brain Institute, mnhill@ucalgary.ca mmorena@ucalgary.ca. Mathison Centre for Mental Health Research. Departments of Cell Biology and Anatomy and Psychiatry.Hotchkiss Brain Institute. Mathison Centre for Mental Health Research. Neuroscicence Program, Cumming School of Medicine, University of Calgary, T2N 4N1 Calgary, Alberta, Canada, and.Hotchkiss Brain Institute. Mathison Centre for Mental Health Research.Hospital for Sick Children and Departments of Psychology and Physiology, University of Toronto, M5G 1X8 Toronto, Ontario, Canada.Hotchkiss Brain Institute. Mathison Centre for Mental Health Research. Neuroscicence Program, Cumming School of Medicine, University of Calgary, T2N 4N1 Calgary, Alberta, Canada, and.Hospital for Sick Children and Departments of Psychology and Physiology, University of Toronto, M5G 1X8 Toronto, Ontario, Canada.Hotchkiss Brain Institute, mnhill@ucalgary.ca mmorena@ucalgary.ca. Mathison Centre for Mental Health Research. Departments of Cell Biology and Anatomy and Psychiatry.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

30573646

Citation

Morena, Maria, et al. "Upregulation of Anandamide Hydrolysis in the Basolateral Complex of Amygdala Reduces Fear Memory Expression and Indices of Stress and Anxiety." The Journal of Neuroscience : the Official Journal of the Society for Neuroscience, vol. 39, no. 7, 2019, pp. 1275-1292.
Morena M, Aukema RJ, Leitl KD, et al. Upregulation of Anandamide Hydrolysis in the Basolateral Complex of Amygdala Reduces Fear Memory Expression and Indices of Stress and Anxiety. J Neurosci. 2019;39(7):1275-1292.
Morena, M., Aukema, R. J., Leitl, K. D., Rashid, A. J., Vecchiarelli, H. A., Josselyn, S. A., & Hill, M. N. (2019). Upregulation of Anandamide Hydrolysis in the Basolateral Complex of Amygdala Reduces Fear Memory Expression and Indices of Stress and Anxiety. The Journal of Neuroscience : the Official Journal of the Society for Neuroscience, 39(7), 1275-1292. https://doi.org/10.1523/JNEUROSCI.2251-18.2018
Morena M, et al. Upregulation of Anandamide Hydrolysis in the Basolateral Complex of Amygdala Reduces Fear Memory Expression and Indices of Stress and Anxiety. J Neurosci. 2019 02 13;39(7):1275-1292. PubMed PMID: 30573646.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Upregulation of Anandamide Hydrolysis in the Basolateral Complex of Amygdala Reduces Fear Memory Expression and Indices of Stress and Anxiety. AU - Morena,Maria, AU - Aukema,Robert J, AU - Leitl,Kira D, AU - Rashid,Asim J, AU - Vecchiarelli,Haley A, AU - Josselyn,Sheena A, AU - Hill,Matthew N, Y1 - 2018/12/20/ PY - 2018/08/31/received PY - 2018/12/09/revised PY - 2018/12/14/accepted PY - 2018/12/24/pubmed PY - 2018/12/24/medline PY - 2018/12/22/entrez KW - anandamide KW - anxiety KW - basolateral amygdala KW - endocannabinoid KW - fear conditioning KW - fear memory SP - 1275 EP - 1292 JF - The Journal of neuroscience : the official journal of the Society for Neuroscience JO - J. Neurosci. VL - 39 IS - 7 N2 - Increased anandamide (AEA) signaling through inhibition of its catabolic enzyme fatty acid amide hydrolase (FAAH) in the basolateral complex of amygdala (BLA) is thought to buffer against the effects of stress and reduces behavioral signs of anxiety and fear. However, examining the role of AEA signaling in stress, anxiety, and fear through pharmacological depletion has been challenging due to the redundant complexity of its biosynthesis and the lack of a pharmacological synthesis inhibitor. We developed a herpes simplex viral vector to rapidly yet transiently overexpress FAAH specifically within the BLA to assess the impact of suppressing AEA signaling on stress, fear, and anxiety in male rats. Surprisingly, FAAH overexpression in BLA dampened stress-induced corticosterone release, reduced anxiety-like behaviors, and decreased conditioned fear expression. Interestingly, depleting AEA signaling in the BLA did not prevent fear conditioning itself or fear reinstatement. These effects were specific to the overexpression of FAAH because they were reversed by intra-BLA administration of an FAAH inhibitor. Moreover, the fear-suppressive effects of FAAH overexpression were also mitigated by intra-BLA administration of a low dose of a GABAA receptor antagonist, but not an NMDA/AMPA/kainate receptor antagonist, suggesting that they were mediated by an increase in GABAergic neurotransmission. Our data suggest that a permissive AEA tone within the BLA might gate GABA release and that loss of this tone through elevated AEA hydrolysis increases inhibition in the BLA, which in turn reduces stress, anxiety, and fear. These data provide new insights on the mechanisms by which amygdalar endocannabinoid signaling regulates emotional behavior.SIGNIFICANCE STATEMENT Amygdala endocannabinoid signaling is involved in the regulation of stress, anxiety, and fear. Our data indicate that viral-mediated augmentation of anandamide hydrolysis within the basolateral amygdala reduces behavioral indices of stress, anxiety, and conditioned fear expression. These same effects have been previously documented with inhibition of anandamide hydrolysis in the same brain region. Our results indicate that the ability of anandamide signaling to regulate emotional behavior is nonlinear and may involve actions at distinct neuronal populations, which could be influenced by the basal level of anandamide. Modulation of anandamide signaling is a current clinical therapeutic target for stress-related psychiatric illnesses, so these data underscore the importance of fully understanding the mechanisms by which anandamide signaling regulates amygdala-dependent changes in emotionality. SN - 1529-2401 UR - https://www.unboundmedicine.com/medline/citation/30573646/Upregulation_of_Anandamide_Hydrolysis_in_the_Basolateral_Complex_of_Amygdala_Reduces_Fear_Memory_Expression_and_Indices_of_Stress_and_Anxiety_ L2 - http://www.jneurosci.org/cgi/pmidlookup?view=long&pmid=30573646 DB - PRIME DP - Unbound Medicine ER -