Endocannabinoid signaling in hypothalamic circuits regulates arousal from general anesthesia in mice

Zhong, Haixing; Li, Tong; Gu, Ning; Gao, Fang; Lu, Ya-Cheng; Xie, Rou‐Gang; Liu, Jingjing; Li, Xin; Bergeron, Richard; Pomeranz, Lisa E.; Feng, Wenfang; Luo, Chunxia; Ren, Yan; Wu, Sihan; Xie, Zhongcong; Xu, Lin; Li, Jinlian; Dong, Hailong; Xiong, Lize; Zhang, X

doi:10.1172/jci91038

Cited by 45 publications

(35 citation statements)

References 55 publications

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“…Floxed and wild-type Oprm1 alleles in the offspring were detected by PCR using the following primers: Oprm1-A1 LoxP-F: 5′-GGTTAGAGTTAGGAGAATCAGGAGTTCAAG-3′; Oprm1-A2 LoxP-R: 5′-GTGAGAGTTGATGTTTGTAA TTGAGTGCC-3′, product 214 bp (wild type) and 268 bp (floxed); Oprm1-Frt-F 5′-TAGTGTTAGGAAGATGTGCC ATAG-3′ and Oprm1-Frt-R 5′-GATCAGAGTAACTGTC TTGGCTAC-3′, product 198 bp (wild type) and 328 bp (floxed). The Oprm1-floxed mice were then crossed to CMV-Cre mice [22] (from the Model Animal Research Center of Nanjing University, China) or mice expressing Cre in a cell-type-specific manner (including GFAP-CreERT2 mice [23], vGlut1-iCreERT2 mice and Gad2-iCreERT2 mice [24] from Beijing Biocytogen, China) as described previously in order to target Oprm1 in all tissues, astroglial cells (µR Astro ), glutamatergic neurons (µR Glut ) or GABAergic neurons (µR GABA ), respectively. The Oprm1 loxP/loxP ::Gad2-iCreERT2, Oprm1 loxP/loxP :: vGlut1-iCreERT2, or Oprm1 loxP/loxP ::GFAP-CreERT2 mice and their control littermates (Oprm1-flox+/+::CreERT2-/-) were treated with tamoxifen (Sigma; dissolved in corn oil; 2 mg/day, i.p.)…”

Section: Animalsmentioning

confidence: 99%

Hippocampal µ-opioid receptors on GABAergic neurons mediate stress-induced impairment of memory retrieval

Shi

Fan²,

Qiao³

et al. 2019

Mol Psychiatry

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Stressful life events induce abnormalities in emotional and cognitive behaviour. The endogenous opioid system plays an essential role in stress adaptation and coping strategies. In particular, the µ-opioid receptor (μR), one of the major opioid receptors, strongly influences memory processing in that alterations in μR signalling are associated with various neuropsychiatric disorders. However, it remains unclear whether μR signalling contributes to memory impairments induced by acute stress. Here, we utilized pharmacological methods and cell-type-selective/non-cell-type-selective μR depletion approaches combined with behavioural tests, biochemical analyses, and in vitro electrophysiological recordings to investigate the role of hippocampal μR signalling in memory-retrieval impairment induced by acute elevated platform (EP) stress in mice. Biochemical and molecular analyses revealed that hippocampal μRs were significantly activated during acute stress. Blockage of hippocampal μRs, non-selective deletion of μRs or selective deletion of μRs on GABAergic neurons (μR GABA) reversed EP-stress-induced impairment of memory retrieval, with no effect on the elevation of serum corticosterone after stress. Electrophysiological results demonstrated that stress depressed hippocampal GABAergic synaptic transmission to CA1 pyramidal neurons, thereby leading to excitation/inhibition (E/I) imbalance in a μR GABA-dependent manner. Pharmaceutically enhancing hippocampal GABA A receptor-mediated inhibitory currents in stressed mice restored their memory retrieval, whereas inhibiting those currents in the unstressed mice mimicked the stress-induced impairment of memory retrieval. Our findings reveal a novel pathway in which endogenous opioids recruited by acute stress predominantly activate μR GABA to depress GABAergic inhibitory effects on CA1 pyramidal neurons, which subsequently alters the E/I balance in the hippocampus and results in impairment of memory retrieval.

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Section: Animalsmentioning

confidence: 99%

Hippocampal µ-opioid receptors on GABAergic neurons mediate stress-induced impairment of memory retrieval

Shi

Fan²,

Qiao³

et al. 2019

Mol Psychiatry

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show abstract

“…Recent research has shown that endocannabinoid ligands and their receptors are critical in neurotransmission, appetite control, emotions, pain perception, and immune responses. (10)(11)(12) There are two known cannabinoid receptors (CB1 and CB2) that belong to the G protein-coupled receptor superfamily and share 44% identity. CB1 exists principally on central and peripheral neurons, and it is closely related to the psychoactive effects of cannabinoids.…”

Section: Introductionmentioning

confidence: 99%

Cannabinoid Receptor 2 Agonist Prevents Local and Systemic Inflammatory Bone Destruction in Rheumatoid Arthritis

Zhu

Bai

et al. 2018

Journal of Bone and Mineral Research

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Cannabinoid receptor 2 (CB2) has been implicated as an important clinical regulator of inflammation and malignant osteolysis. Here, we observed that CB2 expression was markedly higher in the collagen‐induced arthritis (CIA) mice synovium and bone tissues than in the noninflamed synovium and bone tissues. The CB2 selective agonist (JWH133) but not antagonist (SR144528) suppressed CIA in mice without toxic effects, as demonstrated by the decreased synovial hyperplasia, inflammatory responses, cartilage damage, and periarticular and systemic bone destruction. JWH133 treatment decreased the infiltration of pro‐inflammatory M1‐like macrophages and repolarized macrophages from the M1 to M2 phenotype. Similarly, activation of CB2 increased the expression of anti‐inflammatory cytokine interleukin (IL)‐10 and reduced the expression of pro‐inflammatory cytokines, including tumor necrosis factor‐α (TNF‐α), IL‐1β, and IL‐6. In addition, JWH133 treatment attenuated osteoclast formation and osteoclastic bone resorption, and reduced the expression of receptor activators of the nuclear factor‐κB (NF‐κB) ligand (RANKL), matrix metallopeptidase‐9 (MMP‐9), tartrate‐resistant acid phosphatase (TRAP), cathepsin K (CTSK), and nuclear factor of activated T‐cells 1 (NFAT‐1) in CIA mice and osteoclast precursors, which were obviously blocked by pretreatment with SR144528. Mechanistically, JWH133 inhibited RANKL‐induced NF‐κB activation in the osteoclast precursors. We found that JWH133 ameliorates pathologic bone destruction in CIA mice via the inhibition of osteoclastogenesis and modulation of inflammatory responses, thereby highlighting its potential as a treatment for human rheumatoid arthritis. © 2018 American Society for Bone and Mineral Research.

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“…Different neuron types in the tuberomammillary nucleus and LH are implicated in the sleep/wakefulness regulation (Saito et al, 2018). The PeF receives inputs from circadian rhythm messages of the SCh to promote waking (Zhong et al, 2017). The stimulation of thalamic-ZI projections induce a sleep-like state , and a GABAergic subpopulation of neurons in the ZI can promote sleep (Liu K. et al, 2017).…”

Section: Sleeping and Arousalmentioning

confidence: 99%

Monosynaptic Input Mapping of Diencephalic Projections to the Cerebrospinal Fluid-Contacting Nucleus in the Rat

et al. 2020

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Objective: To investigate the projections the cerebrospinal fluid-contacting (CSFcontacting) nucleus receives from the diencephalon and to speculate on the functional significance of these connections. Methods:The retrograde tracer cholera toxin B subunit (CB) was injected into the CSF-contacting nucleus in SD rats according to the experimental formula of the stereotaxic coordinates. Animals were perfused 7-10 days after the injection, and the diencephalon was sliced at 40 µm with a freezing microtome. CB-immunofluorescence was performed on all diencephalic sections. The features of CB-positive neuron distribution in the diencephalon were observed with a fluorescence microscope. Results:The retrograde labeled CB-positive neurons were found in the epithalamus, subthalamus, and hypothalamus. Three functional diencephalic areas including 43 sub-regions revealed projections to the CSF-contacting nucleus. The CB-positive neurons were distributed in different density ranges: sparse, moderate, and dense.Conclusion: Based on the connectivity patterns of the CSF-contacting nucleus that receives anatomical inputs from the diencephalon, we preliminarily assume that the CSF-contacting nucleus participates in homeostasis regulation, visceral activity, stress, emotion, pain and addiction, and sleeping and arousal. The present study firstly illustrates the broad projections of the CSF-contacting nucleus from the diencephalon, which implies the complicated functions of the nucleus especially for the unique roles of coordination in neural and body fluids regulations.

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Endocannabinoid signaling in hypothalamic circuits regulates arousal from general anesthesia in mice

Cited by 45 publications

References 55 publications

Hippocampal µ-opioid receptors on GABAergic neurons mediate stress-induced impairment of memory retrieval

Hippocampal µ-opioid receptors on GABAergic neurons mediate stress-induced impairment of memory retrieval

Cannabinoid Receptor 2 Agonist Prevents Local and Systemic Inflammatory Bone Destruction in Rheumatoid Arthritis

Monosynaptic Input Mapping of Diencephalic Projections to the Cerebrospinal Fluid-Contacting Nucleus in the Rat

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