Endocannabinoid signalling modulates susceptibility to traumatic stress exposure

Rebecca J Bluett, Rita Báldi, Andre Haymer, Andrew D Gaulden, Nolan D Hartley, Walker P Parrish, Jordan Baechle, David J Marcus, Ramzi Mardam-Bey, Brian C Shonesy, Md Jashim Uddin, Lawrence J Marnett, Ken Mackie, Roger J Colbran, Danny G Winder, Sachin Patel, Rebecca J Bluett, Rita Báldi, Andre Haymer, Andrew D Gaulden, Nolan D Hartley, Walker P Parrish, Jordan Baechle, David J Marcus, Ramzi Mardam-Bey, Brian C Shonesy, Md Jashim Uddin, Lawrence J Marnett, Ken Mackie, Roger J Colbran, Danny G Winder, Sachin Patel

Abstract

Stress is a ubiquitous risk factor for the exacerbation and development of affective disorders including major depression and posttraumatic stress disorder. Understanding the neurobiological mechanisms conferring resilience to the adverse consequences of stress could have broad implications for the treatment and prevention of mood and anxiety disorders. We utilize laboratory mice and their innate inter-individual differences in stress-susceptibility to demonstrate a critical role for the endogenous cannabinoid 2-arachidonoylglycerol (2-AG) in stress-resilience. Specifically, systemic 2-AG augmentation is associated with a stress-resilient phenotype and enhances resilience in previously susceptible mice, while systemic 2-AG depletion or CB1 receptor blockade increases susceptibility in previously resilient mice. Moreover, stress-resilience is associated with increased phasic 2-AG-mediated synaptic suppression at ventral hippocampal-amygdala glutamatergic synapses and amygdala-specific 2-AG depletion impairs successful adaptation to repeated stress. These data indicate amygdala 2-AG signalling mechanisms promote resilience to adverse effects of acute traumatic stress and facilitate adaptation to repeated stress exposure.

Conflict of interest statement

S.P. and L.M. have an active collaborative research contract with Lundbeck Pharmaceuticals, however, the work presented in the paper was supported solely by the NIH, the Brain & Behavior Research Foundation, and Vanderbilt University.

Figures

Figure 1. Modulation of stress-induced anxiety-like behaviour…
Figure 1. Modulation of stress-induced anxiety-like behaviour by 2-AG signalling.
(a–c) Effects of JZL-184 (8 mg kg−1; blue) on 2-arachidonoylglycerol (2-AG), arachidonic acid (AA), and anandamide (AEA) in the prefrontal cortex (PFC), amygdala (AMY), nucleus accumbens (NAc), and ventral hippocampus (vHIP). Data combined from two independent experiments. (d,e) Effects of JZL-184 treatment on feeding latency (top) and consumption (bottom) in the novelty-induced hypophagia test (NIH) without stress, after 1 or 5 days of foot-shock stress, and after 5 days of stress in combination with the CB1R inverse agonist Rimonabant (RIM; 1 mg kg−1). (f–i) Cumulative feeding latency distributions of vehicle and JZL-184-treated mice without stress, after 1 or 5 days of foot-shock stress, and after 5 days of stress in combination with Rimonabant. (j,k) Effects of Rimonabant (orange) on feeding latency and consumption in NIH without stress, and after 1 and 5 days of foot-shock stress. (i) Effects of JZL-184 treatment in the light-dark box test after 1 day of foot-shock stress. F and P values for two-way ANOVA shown above (a–e,j–l). P values shown for pairwise comparisons derived from Holm-Sidak multiple comparisons test after ANOVA or unpaired two-tailed t-test (l). Data are presented as mean±s.e.m.
Figure 2. Elevating 2-AG shifts the distribution…
Figure 2. Elevating 2-AG shifts the distribution of stress-susceptibility toward resilience.
(a) Schematic of behavioural paradigm. (b) Histogram of stress-induced change in latency (stress latency minus baseline latency) to consume in the NIH novel-cage test. (c) Gaussian curves fitting the resilient (black) and susceptible (red) subpopulations. Dashed line indicates 120-second post-stress latency increase susceptibility cutoff. (d) Stress-induced change in latency in the whole population and split into susceptible and resilient subgroups. (e) Histogram of pre-stress novel cage latencies categorized by resilience. (f) Individuals' pre-stress novel-cage latencies. (g) Correlation of resilient subpopulation's baseline and post-stress changes in latency. (h) Elevated plus maze (EPM) and (i) open-field test (OFT) measured 24 h after foot-shock stress, one week after susceptibility characterization. (j) Histogram of 24 h post-stress changes in latency with JZL-184 treatment 2 h before testing. (k) Gaussian distributions for resilient and susceptible subpopulations with JZL-184 treatment. (l) Stress-induced change in latency in the whole population and split into susceptible and resilient subgroups with JZL-184 treatment. (m) Proportion of susceptible and resilient mice after either vehicle (VEH) or JZL-184 treatment. (n) Correlation between pre-stress latencies and stress-induced changes in latency with JZL-184. Data in a–g was aggregated from 3 cohorts of 40 mice that were used for subsequent experiments (see Methods for details). F and P values for one-way ANOVA shown above (d,f,l). P values shown for pairwise comparisons derived from Sidak multiple comparisons test after ANOVA (d,f,l) or unpaired one-tailed t-test (h,i) shown in each panel. R2 and P value for linear regression reported in g,n. P value from chi-squared test reported with susceptibility ratios (m). Data are presented as mean±s.e.m.
Figure 3. Stress susceptibility is a stable…
Figure 3. Stress susceptibility is a stable trait.
(a–c) Home cage training (blue lines) and novel cage (NC-V) latencies and (d–f) consumption across one baseline and two novel-cage foot-shock stress tests (NC-FS1-V and NC-FS2-V) with vehicle treatment. (g) Direct comparison of the latency change from baseline between the two post-stress NIH novel cage tests. (h) Correlation between the first stress-test latency and the change in latency between the 2nd and 1st stress novel-cage tests for susceptible individuals. Blue arrows indicate foot-shock stress exposure. F and P values for one-way (a–f) or two-way (g) ANOVA shown above individual panels. P values shown for pairwise comparisons from Holm-Sidak multiple comparisons test after ANOVA. R2 and P value for linear regression shown in h. Data are presented as mean±s.e.m.
Figure 4. 2-AG augmentation promotes resilience to…
Figure 4. 2-AG augmentation promotes resilience to acute stress-induced anxiety-like behaviour.
(a) Home cage training (blue lines) and novel cage (NC) latencies and (b) consumption before (NC-V) and after (NC-FS-V) foot-shock stress with vehicle (V), JZL-184, and JZL-184+Rimonabant (RIM) treatment. (c) Resilient subgroup latencies separated from a. (d) Resilient individuals' baseline and post-stress latencies and consumption. (e) Susceptible subgroup latencies separated from a. (f) Susceptible individuals' baseline and post-stress latencies and consumption. (g) Direct comparison of changes in latency from baseline between the 2nd stress test with JZL-184 (NC-FS2-JZL) and the first stress test with vehicle (NC-FS1-V). (h) Correlation between stress-test latency and change in latency between JZL-184 and vehicle treatment for susceptible individuals. (i) Stress-susceptibility ratios for the same cohort of mice across three weeks after vehicle, JZL-184, or JZL-184+Rimonabant treatment. (j) Home cage testing latency (left) and consumption as % of previous day's home cage/no stress consumption (right) 24 h after stress exposure with resilient (black circles) and susceptible (red circles) individuals treated with vehicle (VEH) or JZL-184 (blue) one week after susceptibility categorization. (k) Whole population correlations between post-stress novel cage test feeding latency and consumption with vehicle and JZL-184 treatment. Blue arrows indicate foot-shock stress exposure. F and P values for one-way (a–c,e) or two-way (g) ANOVA shown above individual panels. P values for pairwise comparisons derived from Holm-Sidak multiple comparisons test after ANOVA, unpaired two-tailed t-test (j), or paired two-tailed t-test (d,f) shown in panels. R2 and P value for linear regression shown in h,k. P values from chi-squared tests reported in i. Data are presented as mean±s.e.m.
Figure 5. 2-AG depletion increases susceptibility to…
Figure 5. 2-AG depletion increases susceptibility to acute stress-induced anxiety-like behaviour.
(a–c) Effects of DO34 (50 mg kg−1; purple) on 2-arachidonoylglycerol (2-AG), arachidonic acid (AA), and anandamide (AEA) in the prefrontal cortex (PFC), amygdala (AMY), nucleus accumbens (NAc), and ventral hippocampus (vHIP). (d) Home cage training (blue lines) and novel cage (NC) latencies and (e) consumption before (NC-V) and after (NC-FS-V) foot-shock stress with vehicle (V) or DO34 treatment. (f) Resilient and (g) susceptible subgroup latencies separated from d. (h) Effects of DO34 on feeding latency relative to vehicle treatment in resilient (black) and susceptible (red) mice. (i) Stress-susceptibility ratios for the same cohort of mice across two weeks after vehicle or DO34 treatment. (j) Resilient population correlations between novel cage test feeding latency and consumption with vehicle and DO34 treatment. (k) Elevated plus maze 24 h after stress exposure with resilient individuals treated with vehicle (VEH) or DO34 (purple) one week after susceptibility categorization. Blue arrows indicate foot-shock stress exposure. F and P values for one-way (d–g) or two-way (a–c) ANOVA shown above individual panels. P values for pairwise comparisons derived from Holm-Sidak multiple comparisons test after ANOVA, unpaired two-tailed t-test (k), or paired two-tailed t-test (h) shown in panels. R2 and P value for linear regression shown in j. P value from chi-squared test reported in i. Data are presented as mean±s.e.m.
Figure 6. Conditional DAGLα knockout mice and…
Figure 6. Conditional DAGLα knockout mice and BLA-specific DAGLα deletion.
(a) Diagram of targeting construct and strategy for the generation of DAGLαf/f mouse. Mice harboring dagla gene-trap cassette were crossed to pgk-Flpo mice to generate conditional knockouts with loxP sites flanking exon 9. (b) PCR products for genotyping of germline (DAGLα−/−) and conditional (DAGLαf/f) knockouts. Primer binding sites shown in a. (c) Representative coronal brain slices from DAGLαf/f mouse after BLA-AAV-GFP (left) and BLA-AAV-GFP-CRE (right) injection, and 20X magnification of BLA-DAGLα immunoreactivity of BLA-GFP control and BLA-GFP-CRE injected mice (square insets). White circles represent typical brain punch dissections for mass spectrometry. Inset scale bars are 500 μm. (d) Amygdala 2-AG levels after AAV-GFP and AAV-GFP-CRE BLA-injection from punch biopsies as indicated by white circles in c. (e) PFC 2-AG levels after BLA-AAV-GFP and BLA-AAV-GFP-CRE injection. (f) Effect of AAV-GFP vs. AAV-GFP-CRE BLA-injection on behaviour in open-field, (g) light-dark box, and (h) elevated plus-maze. (i) Effect of AAV-GFP vs. AAV-GFP-CRE BLA-injection on baseline novelty-induced hypophagia (NIH) testing. P values shown for unpaired one-tailed t-test above each d–i. F and P values for two-way ANOVA shown in i. Data are presented as mean±s.e.m.
Figure 7. BLA-2-AG signalling is required for…
Figure 7. BLA-2-AG signalling is required for resilience to repeated traumatic stress.
(a) Effect of AAV-GFP vs. AAV-GFP-CRE BLA-injection on home cage NIH training (blue lines) and novel cage latency (top) and consumption (bottom) with no stress (NC), 24 h after 1 day of stress (NC-1FS), and 24 h after a 5th day of stress (NC-5FS). (b) AAV-GFP latency (top) and consumption (bottom) from a split into resilient (black) and susceptible (red) groups. (c) AAV-GFP-CRE latency (top) and consumption (bottom) from a split into resilient (black) and susceptible (red) groups. (d) 5-day stress susceptibility ratios for BLA AAV-GFP and AAV-GFP-CRE injected groups. (e) Paired individual baseline and post-stress latencies in AAV-GFP and AAV-GFP-CRE BLA-injected groups. (f) Direct comparison of stress-induced changes in latency in resilient and susceptible AAV-GFP vs. AAV-GFP-CRE BLA-injected mice. Data combined from 2 independent cohorts. Blue arrows in a–c indicate stress exposure, which occurred once per day for 5 consecutive days. F and P values for two-way ANOVA shown above individual (a–c,f). P values for pairwise comparisons derived from Holm-Sidak multiple comparisons test after ANOVA, paired two-tailed t-test (e), and chi-squared test reported (d) in each panel. Data are presented as mean±s.e.m.
Figure 8. Stress-induced increases in sEPSC frequency…
Figure 8. Stress-induced increases in sEPSC frequency in the BLA are eliminated by JZL-184 incubation.
(a) Effect of JZL-184 incubation on the inter-event interval (IEI; left), frequency (left inset) and amplitude (right) of spontaneous excitatory postsynaptic currents (sEPSCs) onto BLA pyramidal cells in control non-stressed mice, and (b) 24 h after foot-shock stress exposure. (c) Direct comparison of stress effect and JZL-184 effect from a and b. (d) Direct comparison of resilient (left; black) and susceptible (right; red) BLA sEPSC frequency (top) and amplitude (bottom) with vehicle (VEH) and either JZL-184 (blue hash) or Rimonabant (RIM; orange hash) incubation. (e) Direct comparison of the dynamic range of eCB signalling (defined as the difference in sEPSC frequency (top) and amplitude (bottom) between JZL-184 and Rimonabant conditions shown in d with representative traces in f. Number of cells is shown for each group. Number of (cells; animals) are reported in a and b. Number of cells reported in d. F and P values for one-way (d) or two-way (c,e) ANOVA shown above individual panels. P value for pairwise comparisons derived from Holm-Sidak multiple comparison test after ANOVA (c–e) or unpaired t-test (a,b) shown in individual panels. Data are presented as mean±s.e.m.
Figure 9. Stress-resilience is associated with greater…
Figure 9. Stress-resilience is associated with greater 2-AG modulation of vHIP-BLA glutamatergic synapses.
(a) Schematic of the experimental procedure for optogenetic recordings. (b–g) Optogenetic recordings at vHIP-BLA synapses. (h–m) Optogenetic recordings at PFC-BLA synapses. (b,h) Optically evoked input-output curves and paired pulse ratio. (c,i) Depolarization-induced suppression of excitation (oDSE) in susceptible and resilient population. (d,j) Direct comparison of the effect of JZL-184 on the magnitude of oDSE in resilient versus susceptible groups. (e,k) Paired comparison of % maximal oDSE in the same cell pre- and post-JZL-184 incubation for resilient and susceptible groups. (f,l) 1 μM JZL-184-induced depression of optically evoked EPSCs. (g,m) Representative images of the vHIP and PFC injection sites, and the corresponding BLA recording sites. Number of (cells, animals) are presented within each panel. F and P values for two-way ANOVA shown above individual (b–d,f,h–j,l). P values shown for pairwise comparisons derived from Holm-Sidak multiple comparisons test after ANOVA or paired two-tailed t-test (e,k). Data are presented as mean±s.e.m. Scale bars are 500 μm for vHIP and PFC images, 50 μm for BLA.

References

    1. McEwen B. S. Brain on stress: how the social environment gets under the skin. Proc. Natl Acad. Sci. USA 109, 17180–17185 (2012).
    1. Sharma S., Powers A., Bradley B. & Ressler K. Gene x environment determinants of stress- and anxiety-related disorders. Annu. Rev. Psychol. 67, 239–261 (2015).
    1. Faravelli C. Life events preceding the onset of panic disorder. J. Affect. Disord. 9, 103–105 (1985).
    1. Kendler K. S., Karkowski L. M. & Prescott C. A. Causal relationship between stressful life events and the onset of major depression. Am. J. Psychiatry 156, 837–841 (1999).
    1. Kessler R. C. et al.. Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication. Arch. Gen. Psychiatry 62, 593–602 (2005).
    1. Goeders N. E. The impact of stress on addiction. Eur. Neuropsychopharmacol. 13, 435–441 (2003).
    1. McEwen B. S. Protection and damage from acute and chronic stress: allostasis and allostatic overload and relevance to the pathophysiology of psychiatric disorders. Ann. N. Y. Acad. Sci. 1032, 1–7 (2004).
    1. McEwen B. S., Gray J. & Nasca C. Recognizing resilience: learning from the effects of stress on the brain. Neurobiol. Stress 1, 1–11 (2015).
    1. Russo S. J., Murrough J. W., Han M. H., Charney D. S. & Nestler E. J. Neurobiology of resilience. Nat. Neurosci. 15, 1475–1484 (2012).
    1. Swartz J. R., Knodt A. R., Radtke S. R. & Hariri A. R. A neural biomarker of psychological vulnerability to future life stress. Neuron 85, 505–511 (2015).
    1. Norrholm S. D. & Ressler K. J. Genetics of anxiety and trauma-related disorders. Neuroscience 164, 272–287 (2009).
    1. Pfau M. L. & Russo S. J. Peripheral and central mechanisms of stress resilience. Neurobiol. Stress 1, 66–79 (2015).
    1. Krishnan V. et al.. Molecular adaptations underlying susceptibility and resistance to social defeat in brain reward regions. Cell 131, 391–404 (2007).
    1. Mechoulam R. & Parker L. A. The endocannabinoid system and the brain. Annu. Rev. Psychol. 64, 21–47 (2013).
    1. Kano M. Control of synaptic function by endocannabinoid-mediated retrograde signaling. Proc. Jpn Acad. Ser. B Phys. Biol. Sci. 90, 235–250 (2014).
    1. Shonesy B. C. et al.. Genetic disruption of 2-arachidonoylglycerol synthesis reveals a key role for endocannabinoid signaling in anxiety modulation. Cell Rep. 9, 1644–1653 (2014).
    1. Yoshino H. et al.. Postsynaptic diacylglycerol lipase mediates retrograde endocannabinoid suppression of inhibition in mouse prefrontal cortex. J. Physiol. 589, 4857–4884 (2011).
    1. Blankman J. L. & Cravatt B. F. Chemical probes of endocannabinoid metabolism. Pharmacol. Rev. 65, 849–871 (2013).
    1. Castillo P. E., Younts T. J., Chavez A. E. & Hashimotodani Y. Endocannabinoid signaling and synaptic function. Neuron 76, 70–81 (2012).
    1. Morena M., Patel S., Bains J. S. & Hill M. N. Neurobiological interactions between stress and the endocannabinoid system. Neuropsychopharmacology 41, 80–102 (2016).
    1. Ruehle S., Rey A. A., Remmers F. & Lutz B. The endocannabinoid system in anxiety, fear memory and habituation. J. Psychopharmacol. 26, 23–39 (2012).
    1. Lutz B. Endocannabinoid signals in the control of emotion. Curr. Opin. Pharmacol. 9, 46–52 (2009).
    1. Bluett R. J. et al.. Central anandamide deficiency predicts stress-induced anxiety: behavioral reversal through endocannabinoid augmentation. Transl. Psychiatry 4, e408 (2014).
    1. Hill M. N. & Patel S. Translational evidence for the involvement of the endocannabinoid system in stress-related psychiatric illnesses. Biol. Mood Anxiety Disord. 3, 19 (2013).
    1. Busquets-Garcia A. et al.. Differential role of anandamide and 2-arachidonoylglycerol in memory and anxiety-like responses. Biol. Psychiatry 70, 479–486 (2011).
    1. Sciolino N. R., Zhou W. & Hohmann A. G. Enhancement of endocannabinoid signaling with JZL184, an inhibitor of the 2-arachidonoylglycerol hydrolyzing enzyme monoacylglycerol lipase, produces anxiolytic effects under conditions of high environmental aversiveness in rats. Pharmacol. Res. 64, 226–234 (2011).
    1. Sumislawski J. J., Ramikie T. S. & Patel S. Reversible gating of endocannabinoid plasticity in the amygdala by chronic stress: a potential role for monoacylglycerol lipase inhibition in the prevention of stress-induced behavioral adaptation. Neuropsychopharmacology 36, 2750–2761 (2011).
    1. Zhong P. et al.. Monoacylglycerol lipase inhibition blocks chronic stress-induced depressive-like behaviors via activation of mTOR signaling. Neuropsychopharmacology 39, 1763–1776 (2014).
    1. Lim J. et al.. Endocannabinoid modulation of predator stress-induced long-term anxiety in rats. Neuropsychopharmacology 41, 1329–1339 (2016).
    1. Patel S., Shonesy B. C., Bluett R. J., Winder D. G. & Colbran R. J. The anxiolytic actions of 2-arachidonoylglycerol: converging evidence from two recent genetic endocannabinoid deficiency models. Biol. Psychiatry 79, e78–e79 (2015).
    1. Patel S. & Hillard C. J. Adaptations in endocannabinoid signaling in response to repeated homotypic stress: a novel mechanism for stress habituation. Eur. J. Neurosci. 27, 2821–2829 (2008).
    1. Patel S., Roelke C. T., Rademacher D. J. & Hillard C. J. Inhibition of restraint stress-induced neural and behavioural activation by endogenous cannabinoid signalling. Eur. J. Neurosci. 21, 1057–1069 (2005).
    1. Gamble-George J. C. et al.. Dissociable effects of CB1 receptor blockade on anxiety-like and consummatory behaviors in the novelty-induced hypophagia test in mice. Psychopharmacology 228, 401–409 (2013).
    1. Silvestri C. & Di Marzo V. The endocannabinoid system in energy homeostasis and the etiopathology of metabolic disorders. Cell Metab. 17, 475–490 (2013).
    1. Dulawa S. C. & Hen R. Recent advances in animal models of chronic antidepressant effects: the novelty-induced hypophagia test. Neurosci. Biobehav. Rev. 29, 771–783 (2005).
    1. Morena M. et al.. Emotional arousal state influences the ability of amygdalar endocannabinoid signaling to modulate anxiety. Neuropharmacology 111, 59–69 (2016).
    1. Ogasawara D. et al.. Rapid and profound rewiring of brain lipid signaling networks by acute diacylglycerol lipase inhibition. Proc. Natl Acad. Sci. USA 113, 26–33 (2016).
    1. Shonesy B. C. et al.. CaMKII regulates diacylglycerol lipase-alpha and striatal endocannabinoid signaling. Nat. Neurosci. 16, 456–463 (2013).
    1. Jung K. M. et al.. Uncoupling of the endocannabinoid signalling complex in a mouse model of fragile X syndrome. Nat. Commun. 3, 1080 (2012).
    1. Dotsey E. Y. et al.. Peroxide-dependent MGL sulfenylation regulates 2-AG-mediated endocannabinoid signaling in brain neurons. Chem. Biol. 22, 619–628 (2015).
    1. Kevorkian S. et al.. Associations among trauma, posttraumatic stress disorder, cannabis use, and cannabis use disorder in a nationally representative epidemiologic sample. Psychol. Addict. Behav. 29, 633–638 (2015).
    1. Bonn-Miller M. O., Boden M. T., Bucossi M. M. & Babson K. A. Self-reported cannabis use characteristics, patterns and helpfulness among medical cannabis users. Am. J. Drug Alcohol Abuse 40, 23–30 (2014).
    1. Ganon-Elazar E. & Akirav I. Cannabinoids and traumatic stress modulation of contextual fear extinction and GR expression in the amygdala-hippocampal-prefrontal circuit. Psychoneuroendocrinology 38, 1675–1687 (2013).
    1. Ganon-Elazar E. & Akirav I. Cannabinoids prevent the development of behavioral and endocrine alterations in a rat model of intense stress. Neuropsychopharmacology 37, 456–466 (2012).
    1. Fanselow M. S. & Dong H. W. Are the dorsal and ventral hippocampus functionally distinct structures? Neuron 65, 7–19 (2010).
    1. Herry C. et al.. Switching on and off fear by distinct neuronal circuits. Nature 454, 600–606 (2008).
    1. Kim Y. et al.. Whole-brain mapping of neuronal activity in the learned helplessness model of depression. Front. Neural Circuits 10, 3 (2016).
    1. Li B. et al.. Synaptic potentiation onto habenula neurons in the learned helplessness model of depression. Nature 470, 535–539 (2011).
    1. Wang M., Perova Z., Arenkiel B. R. & Li B. Synaptic modifications in the medial prefrontal cortex in susceptibility and resilience to stress. J. Neurosci. 34, 7485–7492 (2014).
    1. Patel S., Kingsley P. J., Mackie K., Marnett L. J. & Winder D. G. Repeated homotypic stress elevates 2-arachidonoylglycerol levels and enhances short-term endocannabinoid signaling at inhibitory synapses in basolateral amygdala. Neuropsychopharmacology 34, 2699–2709 (2009).
    1. Hill M. N. et al.. Suppression of amygdalar endocannabinoid signaling by stress contributes to activation of the hypothalamic-pituitary-adrenal axis. Neuropsychopharmacology 34, 2733–2745 (2009).
    1. Rademacher D. J. et al.. Effects of acute and repeated restraint stress on endocannabinoid content in the amygdala, ventral striatum, and medial prefrontal cortex in mice. Neuropharmacology 54, 108–116 (2008).
    1. Hill M. N. et al.. Reductions in circulating endocannabinoid levels in individuals with post-traumatic stress disorder following exposure to the World Trade Center attacks. Psychoneuroendocrinology 38, 2952–2961 (2013).
    1. Jenniches I. et al.. Anxiety, stress, and fear response in mice with reduced endocannabinoid levels. Biol. Psychiatry 79, 858–868 (2015).
    1. Hill M. N., Miller G. E., Carrier E. J., Gorzalka B. B. & Hillard C. J. Circulating endocannabinoids and N-acyl ethanolamines are differentially regulated in major depression and following exposure to social stress. Psychoneuroendocrinology 34, 1257–1262 (2009).
    1. Lafourcade M. et al.. Molecular components and functions of the endocannabinoid system in mouse prefrontal cortex. PLoS ONE 2, e709 (2007).
    1. Azad S. C. et al.. Activation of the cannabinoid receptor type 1 decreases glutamatergic and GABAergic synaptic transmission in the lateral amygdala of the mouse. Learn. Memory 10, 116–128 (2003).
    1. Price J. L. & Drevets W. C. Neurocircuitry of mood disorders. Neuropsychopharmacology 35, 192–216 (2010).
    1. Etkin A. & Wager T. D. Functional neuroimaging of anxiety: a meta-analysis of emotional processing in PTSD, social anxiety disorder, and specific phobia. Am. J. Psychiatry 164, 1476–1488 (2007).
    1. Kim M. J. et al.. The structural and functional connectivity of the amygdala: from normal emotion to pathological anxiety. Behav. Brain Res. 223, 403–410 (2011).
    1. Martin E. I., Ressler K. J., Binder E. & Nemeroff C. B. The neurobiology of anxiety disorders: brain imaging, genetics, and psychoneuroendocrinology. Psychiatr. Clin. North Am. 32, 549–575 (2009).
    1. Masneuf S. et al.. Glutamatergic mechanisms associated with stress-induced amygdala excitability and anxiety-related behavior. Neuropharmacology 85, 190–197 (2014).
    1. Mozhui K. et al.. Strain differences in stress responsivity are associated with divergent amygdala gene expression and glutamate-mediated neuronal excitability. J. Neurosci. 30, 5357–5367 (2010).
    1. Rey A. A., Purrio M., Viveros M. P. & Lutz B. Biphasic effects of cannabinoids in anxiety responses: CB1 and GABA(B) receptors in the balance of GABAergic and glutamatergic neurotransmission. Neuropsychopharmacology 37, 2624–2634 (2012).
    1. Ruehle S. et al.. Cannabinoid CB1 receptor in dorsal telencephalic glutamatergic neurons: distinctive sufficiency for hippocampus-dependent and amygdala-dependent synaptic and behavioral functions. J. Neurosci. 33, 10264–10277 (2013).
    1. Jacob W. et al.. Endocannabinoids render exploratory behaviour largely independent of the test aversiveness: role of glutamatergic transmission. Genes Brain Behav. 8, 685–698 (2009).
    1. Felix-Ortiz A. C. et al.. BLA to vHPC inputs modulate anxiety-related behaviors. Neuron 79, 658–664 (2013).
    1. Hill M. N. et al.. The therapeutic potential of the endocannabinoid system for the development of a novel class of antidepressants. Trends Pharmacol. Sci. 30, 484–493 (2009).
    1. Keimpema E. et al.. Differential subcellular recruitment of monoacylglycerol lipase generates spatial specificity of 2-arachidonoyl glycerol signaling during axonal pathfinding. J. Neurosci. 30, 13992–14007 (2010).
    1. Katona I. et al.. Molecular composition of the endocannabinoid system at glutamatergic synapses. J. Neurosci. 26, 5628–5637 (2006).
    1. Ting J. T., Daigle T. L., Chen Q. & Feng G. Acute brain slice methods for adult and aging animals: application of targeted patch clamp analysis and optogenetics. Methods Mol. Biol. 1183, 221–242 (2014).
    1. Ramikie T. S. et al.. Multiple mechanistically distinct modes of endocannabinoid mobilization at central amygdala glutamatergic synapses. Neuron 81, 1111–1125 (2014).

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