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Endocannabinoid signalling modulates susceptibility to traumatic stress exposure.

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.

SUBMITTER: Bluett RJ

PROVIDER: S-EPMC5379055 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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Endocannabinoid signalling modulates susceptibility to traumatic stress exposure.

Bluett Rebecca J RJ Báldi Rita R Haymer Andre A Gaulden Andrew D AD Hartley Nolan D ND Parrish Walker P WP Baechle Jordan J Marcus David J DJ Mardam-Bey Ramzi R Shonesy Brian C BC Uddin Md Jashim MJ Marnett Lawrence J LJ Mackie Ken K Colbran Roger J RJ Winder Danny G DG Patel Sachin S

Nature communications 20170328

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 endogen ...[more]

PMID: 28348378

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Project description:Traumatic brain injury is an important risk factor for development of Alzheimer's disease and dementia. Unfortunately, no effective therapies are currently available for prevention and treatment of the traumatic brain injury-induced Alzheimer's disease-like neurodegenerative disease. This is largely due to our limited understanding of the mechanisms underlying traumatic brain injury-induced neuropathology. Previous studies showed that pharmacological inhibition of monoacylglycerol lipase, a key enzyme degrading the endocannabinoid 2-arachidonoylglycerol, attenuates traumatic brain injury-induced neuropathology. However, the mechanism responsible for the neuroprotective effects produced by inhibition of monoacylglycerol lipase in traumatic brain injury remains unclear. Here we first show that genetic deletion of monoacylglycerol lipase reduces neuropathology and averts synaptic and cognitive declines in mice exposed to repeated mild closed head injury. Surprisingly, these neuroprotective effects result primarily from inhibition of 2-arachidonoylglycerol metabolism in astrocytes, rather than in neurons. Single-cell RNA-sequencing data reveal that astrocytic monoacylglycerol lipase knockout mice display greater resilience to traumatic brain injury-induced changes in expression of genes associated with inflammation or maintenance of brain homeostasis in astrocytes and microglia. The monoacylglycerol lipase inactivation-produced neuroprotection is abrogated by deletion of the cannabinoid receptor-1 or by adeno-associated virus vector-mediated silencing of astrocytic peroxisome proliferator-activated receptor-γ. This is further supported by the fact that overexpression of peroxisome proliferator-activated receptor-γ in astrocytes prevents traumatic brain injury-induced neuropathology and impairments in spatial learning and memory. Our results reveal a previously undefined cell type-specific role of 2-arachidonoylglycerol metabolism and signalling pathways in traumatic brain injury-induced neuropathology, suggesting that enhanced 2-arachidonoylglycerol signalling in astrocytes is responsible for the monoacylglycerol lipase inactivation-produced alleviation of neuropathology and deficits in synaptic and cognitive functions in traumatic brain injury.

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Endocannabinoid signalling modulates susceptibility to traumatic stress exposure.

Publications

Endocannabinoid signalling modulates susceptibility to traumatic stress exposure.

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