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A low dose of Δ9-THC improves cognitive functions and synaptogenesis in old mice through an epigenetic mechanism

ABSTRACT: THC, the active ingredient of cannabis has been reported to impair learning and memory in humans and in laboratory animals when administered acutely. Unfortunately, most studies have been performed with young individuals although the activity of the endocannabinoid system changes during the aging process. Here we report that low doses of Δ9-THC (Delta-9-Tetrahydrocannabinol) improves learning and memory in old mice, enhances synaptic density, increases the expression of anti-ageing genes and decreases expression of pro-ageing genes in old but not in young animals. Δ9-THC elicited its beneficial effect through the CB1 receptors and increased histone acetylation was crucial for the long lasting effect. Elevation of the cannabinoid signaling may thus represent an exciting new approach to improve brain functions in old individuals.

ORGANISM(S): Mus musculus

PROVIDER: GSE57823 | GEO | 2017/05/08

SECONDARY ACCESSION(S): PRJNA248276

REPOSITORIES: GEO

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Project description:The study describes miRNA expression in colon tissue following delta 9 tetrahydrocannabinol (Δ9-THC) administration to chronically SIV-infected rhesus macaques. To identify the underlying molecular mechanisms underlying its anti-inflammatory effects, we simultaneously profiled miRNA and mRNA expression in colon of chronically simian immunodeficiency virus (SIV)-infected rhesus macaques (RMs) administered either vehicle (VEH/SIV; n=9) or Δ9- tetrahydrocannabinol (THC; THC/SIV; n=8). Relative to controls, differentially expressed miRNAs were ~2 fold higher in VEH/SIV than THC/SIV RMs. Proinflammatory miR-130a, miR-222 and miR-29b, Lipopolysaccharide-responsive miR-146b-5p and SIV-induced miR-190b were significantly upregulated in VEH/SIV RMs. Compared to VEH/SIV RMs, 10 miRNAs were significantly upregulated in THC-SIV RMs, among which miR-204 was confirmed to directly target MMP8, an extracellular matrix-degrading collagenase that was significantly downregulated in THC/SIV RMs. Moreover, THC/SIV RMs failed to upregulate proinflammatory miR-21, miR-141 and miR-222 and alpha/beta defensins, suggesting attenuated intestinal inflammation. Further, THC/SIV RMs showed higher expression of tight junction proteins (occludin, claudin-3), anti-inflammatory MUC13, keratin-8 (stress protection), PROM1 (epithelial proliferation) and anti-HIV CCL5. Trichrome mason staining detected significant collagen deposition (fibrosis) in the paracortex and B cell follicular zones of axillary lymph nodes from all VEH/SIV but none of the THC/SIV RMs, thus demonstrating the ability of THC to prevent lymph node fibrosis, a serious irreversible consequence of HIV induced chronic inflammation. Furthermore, using flow cytometry, we showed that THC suppressed intestinal T cell proliferation/activation (Ki67/HLADR) and exhaustion (PD1) and increased the percentages of anti-inflammatory CD163+ macrophages. Finally, while THC did not affect CD4+ T cell levels, it significantly reduced CD8+ T cell percentages in blood at 150 and 180 days post SIV infection. These translational findings strongly support a role for differential miRNA/gene induction and T cell activation in THC-mediated suppression of intestinal inflammation in HIV/SIV and potentially other chronic inflammatory diseases of the intestine.

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A low dose of Δ9-THC improves cognitive functions and synaptogenesis in old mice through an epigenetic mechanism

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