Epigenetic upregulation of hippocampal CXCL12 contributes to context spatial memory-associated morphine conditioning

Liu, Guanxi; Wei, Jia-You; Li, Meng; Shi, Wei; Song, Liang-Huan; Shang, Li; Zhu, Shi-Qi; Xin, Wenjun; Zhang, Xueqin

doi:10.1016/j.bbi.2019.11.009

Cited by 7 publications

(5 citation statements)

References 41 publications

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“…Rat model of CPPs was established by conditioning with morphine (7.5 mg/kg × 5 days) according to our previous studies (Fig. 4A) ( 2 , 17 ). On day 6, the rats displayed a significant place preference to morphine-paired white chamber (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Subsequently, the intensive rewarding property of opioid is voluntarily associated with the environmental contexts in which morphine is experienced, which promotes the formation of drug-associated environmental memory ( 1 ). While the sense of rewarding generally follows each opiate intake, our previous study showed that only the repeated association between the rewarding and environmental cue initiated the formation of drug-related environmental memory ( 2 ). These results implied the different neural circuits processing rewarding and the formation of drug-related environmental memory.…”

Section: Introductionmentioning

confidence: 99%

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IPAC integrates rewarding and environmental memory during the acquisition of morphine CPP

Liu,

Liao,

Liu

et al. 2023

Sci. Adv.

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The association between rewarding and drug-related memory is a leading factor for the formation of addiction, yet the neural circuits underlying the association remain unclear. Here, we showed that the interstitial nucleus of the posterior limb of the anterior commissure (IPAC) integrated rewarding and environmental memory information by two different receiving projections from ventral tegmental area (VTA) and nucleus accumbens shell region (NAcSh) to mediate the acquisition of morphine conditioned place preference (CPP). A projection from the VTA GABAergic neurons (VTA GABA ) to the IPAC lateral region GABAergic neurons (IPACL GABA ) mediated the effect of morphine rewarding, whereas the pathway from NAcSh dopamine receptor 1–expressing neurons (NAcSh D1 ) to the IPAC medial region GABAergic neurons (IPACM GABA ) was involved in the acquisition of environmental memory. These findings demonstrated that the distinct IPAC circuits VTA GABA → IPACL GABA and NAcSh D1R → IPACM GABA were attributable to the rewarding and environmental memory during the acquisition of morphine CPP, respectively, and provided the circuit-based potential targets for preventing and treating opioid addiction.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

IPAC integrates rewarding and environmental memory during the acquisition of morphine CPP

Liu,

Liao,

Liu

et al. 2023

Sci. Adv.

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“…JAK2/STAT3 signaling is a critical pathway that regulates decidualization in response to estrogen and progesterone [27]. In addition, STAT3 signaling regulates the expression of CXCL12 [47] and TGF-β[48], cell factors secreted by DSCs to recruit and educate dNKs. In our study, we found that JAK2/STAT3 signaling was activated during decidualization and inhibited when UCHL1 was blocked by an inhibitor or shRNA.…”

Section: Discussionmentioning

confidence: 99%

Deficiency of UCHL1 results in insufficient decidualization accompanied by impaired dNK modulation and eventually miscarriage

Zhang,

Xue,

Huang

et al. 2024

Preprint

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Background Miscarriage is a frustrating complication of pregnancy that is common in women of reproductive age. Insufficient decidualization which not only impairs embryo implantation but disturbs the fetomaternal immune-tolerance, has been widely regarded as a major cause of miscarriage; however, the underlying mechanisms resulting in decidual impairment are largely unknown. Methods With informed consent, decidual tissue from patients with spontaneous abortion or normal pregnant women were collected to detect the expression profile of UCHL1. Human endometrial stromal cells (HESCs) were used to explore the roles of UCHL1 in decidualization and dNK modulation, as well as the mechanisms involved. C57/BL6 female mice (7–10 weeks old) were used to construct pregnancy model or artificially induced decidualization model to evaluate the effect of UCHL1 on mice decidualization and pregnancy outcome. Results The Ubiquitin C-terminal hydrolase L1 (UCHL1), as a deubiquitinating enzyme, was significantly downregulated in decidua from patients with miscarriage, along with impaired decidualization and decreased dNKs. Blockage of UCHL1 led to insufficient decidualization and resultant decreased expression of cytokines CXCL12, IL-15, TGF-β which were critical for generation of decidual NK cells (dNKs), whereas UCHL1 overexpression enhanced decidualization accompanied by increase of dNKs. Mechanistically, the promotion of UCHL1 on decidualization was dependent on its deubiquitinating activity, and intervention of UCHL1 inhibited the activation of JAK2/STAT3 signaling pathway, resulting in aberrant decidualization and decreased production of cytokines associated with dNKs modulation. Furthermore, we found that inhibition of UCHL1 also disrupted the decidualization in mice and causing adverse pregnancy outcome eventually. Conclusions UCHL1 plays significant roles in decidualization and dNKs modulation during pregnancy in both human and mice, and its deficiency indicates a poor pregnancy outcome due to defective decidualization, which makes UCHL1 to be a potential target for the diagnosis and treatment of miscarriage.

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“…The JAK2/STAT3 signaling pathway emerges as a pivotal regulator of decidualization in response to estrogen and progesterone [ 26 ]. In addition, STAT3 signaling regulates the expression of CXCL12 [ 48 ] and TGF-β [ 49 ], cell factors secreted by DSCs to recruit and educate dNKs. In our study, we found that JAK2/STAT3 signaling was activated during decidualization and inhibited when UCHL1 was blocked by an inhibitor or shRNA.…”

Section: Discussionmentioning

confidence: 99%

Deficiency of UCHL1 results in insufficient decidualization accompanied by impaired dNK modulation and eventually miscarriage

Zhang,

Xue,

Huang

et al. 2024

J Transl Med

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Background Miscarriage is a frustrating complication of pregnancy that is common among women of reproductive age. Insufficient decidualization which not only impairs embryo implantation but disturbs fetomaternal immune-tolerance, has been widely regarded as a major cause of miscarriage; however, the underlying mechanisms resulting in decidual impairment are largely unknown. Methods With informed consent, decidual tissue from patients with spontaneous abortion or normal pregnant women was collected to detect the expression profile of UCHL1. Human endometrial stromal cells (HESCs) were used to explore the roles of UCHL1 in decidualization and dNK modulation, as well as the mechanisms involved. C57/BL6 female mice (7–10 weeks old) were used to construct pregnancy model or artificially induced decidualization model to evaluate the effect of UCHL1 on mice decidualization and pregnancy outcome. Results The Ubiquitin C-terminal hydrolase L1 (UCHL1), as a deubiquitinating enzyme, was significantly downregulated in decidua from patients with miscarriage, along with impaired decidualization and decreased dNKs. Blockage of UCHL1 led to insufficient decidualization and resultant decreased expression of cytokines CXCL12, IL-15, TGF-β which were critical for generation of decidual NK cells (dNKs), whereas UCHL1 overexpression enhanced decidualization accompanied by increase in dNKs. Mechanistically, the promotion of UCHL1 on decidualization was dependent on its deubiquitinating activity, and intervention of UCHL1 inhibited the activation of JAK2/STAT3 signaling pathway, resulting in aberrant decidualization and decreased production of cytokines associated with dNKs modulation. Furthermore, we found that inhibition of UCHL1 also disrupted the decidualization in mice and eventually caused adverse pregnancy outcome. Conclusions UCHL1 plays significant roles in decidualization and dNKs modulation during pregnancy in both humans and mice. Its deficiency indicates a poor pregnancy outcome due to defective decidualization, making UCHL1 a potential target for the diagnosis and treatment of miscarriage. Graphical Abstract

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Epigenetic upregulation of hippocampal CXCL12 contributes to context spatial memory-associated morphine conditioning

Cited by 7 publications

References 41 publications

IPAC integrates rewarding and environmental memory during the acquisition of morphine CPP

IPAC integrates rewarding and environmental memory during the acquisition of morphine CPP

Deficiency of UCHL1 results in insufficient decidualization accompanied by impaired dNK modulation and eventually miscarriage

Deficiency of UCHL1 results in insufficient decidualization accompanied by impaired dNK modulation and eventually miscarriage

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