Neuropharmacology最新文献_第2页

Sex-specific changes in voluntary alcohol consumption and nucleus accumbens synaptic plasticity in C57BL/6J mice exposed to neonatal maternal separation 暴露于新生儿母体分离的 C57BL/6J 小鼠在自愿饮酒和核团突触可塑性方面的性别特异性变化

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2024-11-07 DOI: 10.1016/j.neuropharm.2024.110212

Giuseppe Talani , Francesca Biggio , Maria Cristina Mostallino , Elisabetta Batzu , Giovanni Biggio , Enrico Sanna

The long-term influence of early-life stress on brain neurophysiology has been extensively investigated using different animal models. Among these, repeated maternal separation (RMS) in rodents is one of the most commonly adopted. In this study, we elucidated the long-lasting effects of exposure to postnatal RMS in C57BL/6J adult mice on voluntary alcohol consumption and nucleus accumbens (NAc) neurophysiology. Mice were separated from their dam for 360 min daily from postnatal day 2 (PND2) to PND17, and experiments were then performed in adult (PND60) animals. In addition, as recent evidence showed that circulating estrogens may play a protective role against stress effects on brain function, including the organization and activation of neuronal structures, we also evaluated the effect of a single injection of β-estradiol 3-benzoate (EB) at PND2, which is known to disrupt male sex differentiation, in male RMS mice. The RMS exposure was associated with an increased voluntary alcohol consumption and preference in male mice, but not in female mice or male mice treated with a single injection of EB. Patch clamp experiments conducted in NAc medium spiny neurons (MSNs) revealed that excitatory but not inhibitory synaptic transmission and long-term plasticity of glutamatergic synapses were significantly impaired in male but not in female mice exposed to the RMS protocol. This effect was again prevented in RMS male mice treated with EB. Our findings strengthen the idea of a sex-dependent influence of early-life stress on long-lasting modifications in synaptic transmission and plasticity in brain areas involved in goal-directed behavior and alcohol intake.

人们利用不同的动物模型对早期生活压力对大脑神经生理学的长期影响进行了广泛研究。其中，啮齿类动物的重复母体分离（RMS）是最常用的模型之一。在这项研究中，我们阐明了C57BL/6J成年小鼠出生后暴露于RMS对自愿饮酒和伏隔核（NAc）神经生理学的长期影响。从出生后第2天（PND2）到第17天，每天将小鼠与母鼠分离360分钟，然后在成年（PND60）小鼠中进行实验。此外，最近有证据表明，循环中的雌激素可能对大脑功能（包括神经元结构的组织和激活）的应激效应起到保护作用，因此我们还评估了在雄性 RMS 小鼠出生后第 2 天单次注射 3-苯甲酸 β-雌二醇（EB）的影响。RMS 暴露与雄性小鼠的自愿酒精消耗量和偏好增加有关，但与雌性小鼠或单次注射 EB 的雄性小鼠无关。在 NAc 中刺神经元（MSNs）中进行的膜片钳实验显示，暴露于 RMS 方案的雄性小鼠（而非雌性小鼠）的兴奋性突触传递和谷氨酸能突触的长期可塑性显著受损，而抑制性突触传递和谷氨酸能突触的长期可塑性没有受损。用 EB 治疗的 RMS 雄性小鼠也能防止这种影响。我们的研究结果加强了这样一种观点，即早期生活压力对目标定向行为和酒精摄入相关脑区突触传递和可塑性的长期改变具有性别依赖性。

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引用次数: 0

Adenosine regulates depressive behavior in mice with chronic social defeat stress through gut microbiota 腺苷通过肠道微生物群调节慢性社会挫败应激小鼠的抑郁行为

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2024-11-06 DOI: 10.1016/j.neuropharm.2024.110209

Yao Huang , Yue You , Wei Wang , Yuan-Hao Chen , Hao Zhang , Qu-Peng Li , Le Liu , Kun Tong , Nan Sun , Jing-Ru Hao , Can Gao

Major depressive disorder (MDD) is recognized as the most prevalent affective disorder worldwide. Metagenomic studies increasingly support a critical role for dysbiosis of gut microbiota in the development of depression. Previous studies have demonstrated that adenosine alleviates gut dysbiosis, suggesting that elevating adenosine levels could be a novel intervention for MDD; however, the mechanisms underlying this effect remain unclear. This study utilized 16S rRNA gene sequencing, fecal microbiota transplantation (FMT) and ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) to test the hypothesis that increased adenosine alleviates depressive behaviors in male mice subjected to chronic social defeat stress (CSDS) through alterations to gut microbiota. The data showed that depression-susceptible (SUS) mice exhibited gut dysbiosis, and FMT from SUS mice increased depression-like behaviors in healthy recipients. In SUS mice, adenosine supplementation ameliorated both depression-like behaviors and abnormalities in gut microbiota, and co-administration of probiotics and adenosine not only mitigated depression-like behaviors but also enhanced gut barrier integrity. By including 83 depressed adolescents and 67 healthy controls, this study found that the level of short-chain fatty acids (SCFAs) in the depression group was reduced, this finding parallels reductions seen in SUS mice and in recipient mice after FMT from SUS donors. Conversely, supplementation with either adenosine or probiotics led increased SCFAs concentrations in the serum of SUS mice. These findings suggest that adenosine may alleviate depression-like behaviors in CSDS mice by modulating the gut microbiota. This effect is likely associated with increased serum SCFAs, metabolites produced by the gut microbiota, following adenosine supplementation.

This article is part of the Special Issue on "Personality Disorders".

重度抑郁症（MDD）被认为是全球最普遍的情感障碍。越来越多的元基因组研究表明，肠道微生物群失调在抑郁症的发病中起着至关重要的作用。以前的研究表明，腺苷能缓解肠道菌群失调，这表明提高腺苷水平可能是治疗 MDD 的一种新的干预措施；然而，这种作用的机制仍不清楚。本研究利用16S rRNA基因测序、粪便微生物群移植（FMT）和超高效液相色谱-串联质谱法（UPLC-MS/MS）测试了这样一个假设：增加腺苷含量可通过改变肠道微生物群来缓解遭受慢性社交失败压力（CSDS）的雄性小鼠的抑郁行为。数据显示，易患抑郁症（SUS）的小鼠表现出肠道菌群失调，而来自 SUS 小鼠的 FMT 会增加健康受试者的抑郁样行为。在 SUS 小鼠中，补充腺苷可改善抑郁样行为和肠道微生物群的异常，同时服用益生菌和腺苷不仅可减轻抑郁样行为，还能增强肠道屏障的完整性。通过纳入 83 名抑郁青少年和 67 名健康对照组，该研究发现抑郁组的短链脂肪酸（SCFAs）水平降低了，这一发现与 SUS 小鼠和从 SUS 供体接受 FMT 后的受体小鼠中看到的降低情况相似。相反，补充腺苷或益生菌会增加 SUS 小鼠血清中 SCFAs 的浓度。这些发现表明，腺苷可通过调节肠道微生物群来减轻 CSDS 小鼠的抑郁样行为。这种效果可能与补充腺苷后血清中SCFAs（肠道微生物群产生的代谢产物）的增加有关。

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引用次数: 0

Humanin attenuates metabolic, toxic, and traumatic neuropathic pain in mice by protecting against oxidative stress and increasing inflammatory cytokine 人参皂苷通过防止氧化应激和增加炎性细胞因子减轻小鼠的代谢性、毒性和创伤性神经病理性疼痛

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2024-11-05 DOI: 10.1016/j.neuropharm.2024.110207

Batuhan Bilgin , Munevver Gizem Hekim , Ferah Bulut , Muhammed Mirac Kelestemur , Muhammed Adam , Sibel Ozcan , Sinan Canpolat , Ahmet Ayar , Mete Ozcan

Neuropathic pain is associated with diverse etiologies, including sciatica, diabetes, and the use of chemotherapeutic agents. Despite the varied origins, mitochondrial dysfunction, oxidative stress, and inflammatory cytokines are recognized as key contributing factors in both the initiation and maintenance of neuropathic pain. The effects of the mitochondrial-derived peptide humanin on neuropathic pain, however, remain unclear, despite its demonstrated influence on these mechanisms in numerous disease models. This study aimed to evaluate the effects of humanin on pain behavior in murine models of metabolic (streptozotocin/STZ), toxic (oxaliplatin/OXA), traumatic (sciatic nerve cuffing/cuff), and neuropathic pain. A secondary objective was to assess whether humanin modulates oxidative damage and inflammatory cytokine levels in these neuropathic pain models.

Humanin (4 mg/kg) was administered intraperitoneally (i.p.) to BALB/c male mice with induced neuropathic pain over a period of 15 days, with pain thresholds assessed using hot plate, cold plate, and Von Frey tests. Serum levels of antioxidant enzymes, oxidative stress markers, and inflammatory/anti-inflammatory cytokines were measured via enzyme-linked immunosorbent assay (ELISA).

In neuropathic pain-induced mice, humanin administration resulted in a statistically significant increase in pain threshold values in the STZ + Humanin, OXA + Humanin, and cuff + Humanin groups compared to their respective control groups (P < 0.05) over 15 days. Furthermore, humanin treatment significantly elevated antioxidant enzyme levels and anti-inflammatory cytokine concentrations, while reducing oxidative stress markers and pro-inflammatory cytokine levels compared to control groups (P < 0.01).

These findings suggest that humanin exhibits therapeutic potential in the treatment of neuropathic pain induced by STZ, OXA, and cuff models. The ability of humanin to mitigate neuropathic pain through the suppression of oxidative stress and inflammatory cytokines indicates its promise as a novel therapeutic strategy.

神经性疼痛与多种病因有关，包括坐骨神经痛、糖尿病和化疗药物的使用。尽管病因多种多样，但线粒体功能障碍、氧化应激和炎性细胞因子被认为是导致神经性疼痛发生和维持的关键因素。然而，线粒体衍生肽 humanin 对神经病理性疼痛的影响仍不清楚，尽管它在许多疾病模型中都被证明对这些机制有影响。本研究旨在评估人肽对代谢性（链脲佐菌素/STZ）、毒性（奥沙利铂/OXA）和创伤性（坐骨神经袖带/袖套）神经病理性疼痛小鼠模型中疼痛行为的影响。次要目的是评估人胰岛素是否能调节这些神经病理性疼痛模型中的氧化损伤和炎性细胞因子水平。对诱发神经病理性疼痛的 BALB/c 雄性小鼠腹腔注射人参素（4 毫克/千克），为期 15 天，使用热板、冷板和 von Frey 试验评估疼痛阈值。通过酶联免疫吸附试验（ELISA）测定血清中抗氧化酶、氧化应激标记物和炎症/抗炎细胞因子的水平。在神经病理性疼痛诱导的小鼠中，与各自的对照组相比，服用人胰岛素 15 天后，STZ + 人胰岛素组、OXA + 人胰岛素组和袖套 + 人胰岛素组的疼痛阈值均有统计学意义的显著提高（P < 0.05）。此外，与对照组相比，人参皂苷治疗明显提高了抗氧化酶水平和抗炎细胞因子浓度，同时降低了氧化应激标记物和促炎细胞因子水平（P < 0.01）。这些研究结果表明，人参皂苷在治疗由 STZ、OXA 和袖套模型诱发的神经病理性疼痛方面具有治疗潜力。人参皂苷能够通过抑制氧化应激和炎症细胞因子减轻神经性疼痛，这表明它有望成为一种新型治疗策略。

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引用次数: 0

Asiatic acid alleviates subarachnoid hemorrhage-induced brain injury in rats by inhibiting ferroptosis of neurons via targeting acyl-coenzyme a oxidase 1 积雪草酸通过靶向酰辅酶A氧化酶1抑制神经元的铁凋亡，从而减轻蛛网膜下腔出血诱发的大鼠脑损伤。

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2024-11-03 DOI: 10.1016/j.neuropharm.2024.110208

Yukun Hu , Jingyu Gu , Xin Jin , Xiaoxiao Wu , Haiying Li , Lei Bai , Jiang Wu , Xiang Li Sr.

The occurrence of subarachnoid hemorrhage (SAH) can lead to brain injury, which is a fatal condition with limited effective clinical intervention strategies. The naturally occurring component Asiatic acid (AA), found in the tropical plant Centella asiatica, has been reported to possess neuroprotective properties. The objective of this study was to evaluate the neuroprotective effect of AA following SAH and investigate its potential mechanisms. The SAH model was established in male Sprague-Dawley (SD) rats through intravascular perforation, following a standardized protocol. The administration of AA was performed via gavage following SAH. A lentiviral vector was constructed and utilized for the knockdown of Acyl Coenzyme A Oxidase 1 (ACOX1) Firstly, AA treatment effectively improves brain neurological deficit, neuronal damage, and iron deposition induced by SAH. Furthermore, it has been demonstrated that AA directly interacts with ACOX1, which exhibits decreased expression in neurons following SAH. Additionally, our study reveals AA can reverse SAH-induced reduction in ACOX1 expression, concurrently ameliorating neuronal ferroptosis. This improvement is evidenced by reduced lipid peroxidation, including mitigated GSH depletion, decreased MDA production, and increased GPX4 content and activity. Also, AA enhances mitochondrial constriction while alleviating cristae disruption induced by SAH, providing crucial insights into its neuroprotective effects against neuronal ferroptosis in SAH. Moreover, when ACOX1 is knocked down, the neuroprotective effects of AA are weakened. Collectively, this study elucidated the neuroprotective effect of AA by inhibiting neuronal cell ferroptosis through targeting ACOX1. These findings suggest that AA holds promise as a potential therapeutic candidate for ameliorating SAH-induced brain injury.

蛛网膜下腔出血（SAH）可导致脑损伤，是一种致命的疾病，但有效的临床干预策略有限。据报道，热带植物积雪草中的天然成分积雪草酸（AA）具有神经保护作用。本研究的目的是评估 AA 在 SAH 后的神经保护作用并研究其潜在机制。按照标准化方案，通过血管内穿孔在雄性 Sprague-Dawley (SD) 大鼠中建立 SAH 模型。SAH 后通过灌胃给予 AA。首先，AA 能有效改善 SAH 引起的脑神经功能缺损、神经元损伤和铁沉积。此外，有研究表明 AA 可直接与 ACOX1 相互作用，而 ACOX1 在 SAH 后的神经元中表达减少。此外，我们的研究发现 AA 可以逆转 SAH 引起的 ACOX1 表达减少，同时改善神经元的铁沉积。这种改善体现在脂质过氧化的减少，包括 GSH 消耗的减轻、MDA 生成的减少以及 GPX4 含量和活性的增加。此外，AA 还能增强线粒体收缩，同时减轻 SAH 引起的嵴破坏，这为其在 SAH 中防止神经元铁骤变的神经保护作用提供了重要的启示。此外，当 ACOX1 被敲除时，AA 的神经保护作用会减弱。总之，本研究阐明了 AA 通过靶向 ACOX1 抑制神经元细胞铁嗜性的神经保护作用。这些发现表明，AA有望成为改善SAH诱导的脑损伤的潜在候选疗法。

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引用次数: 0

Microglia phagocytosis of PNNs mediates PV-positive interneuron dysfunction and associated gamma oscillations in neuroinflammation-induced cognitive impairment in mice 在神经炎症诱导的小鼠认知障碍中，小胶质细胞对 PNNs 的吞噬介导了 PV 阳性中间神经元功能障碍和相关的伽马振荡。

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2024-11-02 DOI: 10.1016/j.neuropharm.2024.110205

Kai Liu , Yu-zhu Gao , Xin-miao Wu , Xiao-yi Hu , Cui-na Shi , Qiu-li He , Hai-peng Wu , Hao Yao , Da-qing Ma , Jian-jun Yang , Mu-huo Ji

Neuroinflammation, characterized by activation of glial cells, plays a critical role in central nervous system disorders. However, the precise mechanisms of neuroinflammation contributing to cognitive impairment remain elusive. Perineuronal nets (PNNs) are extracellular matrixes that envelop the cell bodies and dendrites of parvalbumin (PV)-positive interneurons and may be mediated by apolipoprotein E (ApoE) gene. To investigate whether disruption of PNNs associated with ApoE is implicated in neuroinflammation-induced cognitive impairment, we established a neuroinflammation model by administering lipopolysaccharides (LPS) at 0.5 mg/kg for 7 consecutive days. Cognitive function was assessed using the open field, Y-maze, and novel object recognition tests, and neural oscillations were also recorded. Furthermore, differentially expressed genes in microglia within the hippocampus were identified through single-cell RNA sequencing analysis. Overexpression of hyaluronan and proteoglycan link protein 1 (Hapln1) and ApoE knockdown were carried out through adeno-associated virus (AAV) injection to C57BL/6J mice and CX3CR1-CreERT2 mice, respectively. It was found that LPS-induced neuroinflammation impaired cognitive function by reducing PNNs and PV-positive interneurons’ outputs, as well as disrupting gamma (γ) oscillations in the hippocampal CA1. Overexpression of Hapln1 was able to restore PV-positive interneurons and γ oscillations, ultimately alleviating the cognitive impairment. Mechanistically, LPS-triggered microglial activation leads to the phagocytosis of PNNs, a process influenced by ApoE. Notably, prevention of PNNs engulfment through targeting microglial ApoE in the CA1 improved cognitive impairment. Collectively, our study suggested that microglial phagocytosis of PNNs plays a key role in neuroinflammation-induced cognitive impairment, which is probably mediated by the ApoE.

以神经胶质细胞活化为特征的神经炎症在中枢神经系统疾病中起着至关重要的作用。然而，导致认知障碍的神经炎症的确切机制仍然难以捉摸。神经元周围网（PNNs）是包裹副发光素（PV）阳性中间神经元细胞体和树突的细胞外基质，可能由载脂蛋白 E（ApoE）基因介导。为了研究与载脂蛋白 E 相关的 PNNs 的破坏是否与神经炎症引起的认知障碍有关，我们建立了一个神经炎症模型，通过连续 7 天以 0.5 毫克/千克的剂量给药脂多糖（LPS）。认知功能通过开阔地、Y-迷宫和新物体识别测试进行评估，神经振荡也被记录下来。此外，还通过单细胞RNA测序分析确定了海马内小胶质细胞中的差异表达基因。通过向C57BL/6J小鼠和CX3CR1-CreERT2小鼠注射腺相关病毒（AAV），分别实现了透明质酸和蛋白多糖连接蛋白1（Hapln1）的过表达和载脂蛋白E的敲除。研究发现，LPS诱导的神经炎症会减少PNNs和PV阳性中间神经元的输出，并破坏海马CA1的伽马（γ）振荡，从而损害认知功能。过量表达Hapln1能够恢复PV阳性中间神经元和γ振荡，最终缓解认知障碍。从机制上讲，LPS 触发的小胶质细胞活化导致了 PNNs 的吞噬，这一过程受到载脂蛋白 E 的影响。值得注意的是，通过靶向 CA1 中的小胶质细胞载脂蛋白E来阻止 PNNs 吞噬，可以改善认知障碍。总之，我们的研究表明，小胶质细胞吞噬 PNNs 在神经炎症诱导的认知障碍中起着关键作用，而这可能是由载脂蛋白E介导的。

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引用次数: 0

Psilocybin reduces grooming in the SAPAP3 knockout mouse model of compulsive behaviour 迷幻药可减少 SAPAP3 基因敲除小鼠强迫行为模型中的梳理行为。

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2024-11-02 DOI: 10.1016/j.neuropharm.2024.110202

James J. Gattuso , Carey Wilson , Anthony J. Hannan , Thibault Renoir

Psilocybin is a serotonergic psychedelic compound which shows promise for treating compulsive behaviours. This is particularly pertinent as compulsive disorders require research into new pharmacological treatment options as the current frontline treatments such as selective serotonin reuptake inhibitors, require chronic administration, have significant side effects, and leave almost half of the clinical population refractory to treatment.

In this study, we investigated psilocybin administration in male and female SAPAP3 knockout (KO) mice, a well-validated mouse model of obsessive compulsive and related disorders. We assessed the effects of acute psilocybin (1 mg/kg, intraperitoneal) administration on head twitch and locomotor behaviour as well as anxiety- and compulsive-like behaviours at multiple time-points (1, 3 and 8 days post-injection).

While psilocybin did not have any effect on anxiety-like behaviours, we revealed that acute psilocybin administration led to enduring reductions in compulsive behaviour in male SAPAP3 KO mice and reduced grooming behaviour in female wild-type (WT) and SAPAP3 KO mice. We also found that psilocybin increased locomotion in WT littermates but not in SAPAP3 KO mice, suggesting in vivo serotonergic dysfunctions in KO animals. On the other hand, the typical head-twitch response following acute psilocybin (confirming its hallucinogenic-like effect at this dose) was observed in both genotypes.

Our novel findings suggest that acute psilocybin may have potential to reduce compulsive-like behaviours (up to 1 week after a single injection). Our study can inform future research directions as well as supporting the utility of psilocybin as a novel treatment option for compulsive disorders.

迷幻药是一种血清素能迷幻化合物，有望治疗强迫行为。这一点尤为重要，因为强迫症需要研究新的药物治疗方案，因为目前的一线治疗药物（如选择性 5-羟色胺再摄取抑制剂）需要长期用药，副作用大，而且几乎有一半的临床人群对治疗不耐受。在这项研究中，我们研究了在雄性和雌性 SAPAP3 基因敲除（KO）小鼠中服用迷幻药的情况。我们在多个时间点（注射后 1 天、3 天和 8 天）评估了急性服用迷幻药（1 毫克/千克，腹腔注射）对头部抽搐和运动行为以及焦虑和强迫行为的影响。虽然迷幻药对焦虑样行为没有任何影响，但我们发现，急性迷幻药注射会导致雄性 SAPAP3 KO 小鼠强迫行为的持续减少，以及雌性野生型（WT）和 SAPAP3 KO 小鼠梳理行为的减少。我们还发现，迷幻药能增加WT同窝小鼠的运动能力，但不能增加SAPAP3 KO小鼠的运动能力，这表明KO动物体内存在血清素能障碍。另一方面，两种基因型的小鼠在服用急性迷幻药后都出现了典型的头部抽搐反应（证实了该剂量下的致幻效应）。我们的新发现表明，急性西洛赛宾可能具有减少类似强迫症行为的潜力（单次注射后可持续一周）。我们的研究可以为未来的研究方向提供信息，并支持将迷幻药作为治疗强迫症的一种新方法。

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引用次数: 0

SARM1 deficiency induced depressive-like behavior via AMPKα/p-eEF2 axis to synapse dysfunction SARM1 缺乏通过 AMPKα/p-eEF2 轴与突触功能障碍诱发抑郁样行为

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2024-11-01 DOI: 10.1016/j.neuropharm.2024.110206

Weifen Li , Wenhui Zhu , Junhao Chen , Tahir Ali , Shupeng Li

Sterile Alpha and TIR Motif Containing 1 (SARM1) are proteins implicated in various neurological processes; however, their role in depression remains unexplored. This study investigated the contribution of SARM1 to depressive-like behaviors in a chronic stress-induced depression model and SARM1 knockout (KO) mice. Depressive-like behaviors were assessed using a battery of behavioral tests, including the Open Field Test (OFT), the Forced Swim Test (FST), the Sucrose Preference Test (SPT), and the Tail Suspension Test (TST). Mitochondrial energy metabolism alteration, cytokine level changes, and other related molecular signaling protein expression were evaluated using ELISA and western blotting techniques to investigate the underlying mechanisms. Behavioral assessments (OFT, FST, SPT, TST) revealed depressive-like phenotypes in SARM1 KO mice, accompanied by altered mitochondrial energy metabolism (NAD+, ATP) in the cortex. Intriguingly, SARM1 depletion led to peripheral inflammation, as evidenced by elevated cytokine levels in plasma but not in brain regions (cortex). In addition, we found dysregulated energy metabolism, AMPK signaling, and synaptic plasticity in the cortex of SARM1 KO mice. Notably, AICAR (Acadesine), an AMPK activator, ameliorated depressive-like behaviors and synaptic dysfunction, while Compound C, an AMPK inhibitor, reversed these effects. Additionally, NH125, an eEF2 kinase inhibitor, improved depressive-like behaviors in SARM1 KO mice. These findings demonstrate that SARM1 is critical in regulating depressive-like behaviours through the AMPKα/p-eEF2 signaling pathway. Targeting AMPK signaling and synaptic function may offer novel therapeutic avenues for depression.

不育α和TIR-Motif Containing 1（SARM1）是一种与多种神经过程有关的蛋白质，然而，它们在抑郁症中的作用仍有待探索。本研究调查了 SARM1 在慢性压力诱导的抑郁模型和 SARM1 基因敲除（KO）小鼠的抑郁样行为中的作用。抑郁样行为通过一系列行为测试进行评估，包括开阔地测试（OFT）、强迫游泳测试（FST）、蔗糖偏好测试（SPT）和尾悬吊测试（TST）。使用 ELISA 和 Western 印迹技术评估线粒体能量代谢的改变、细胞因子水平的变化以及其他相关分子信号蛋白的表达，以研究其潜在机制。行为评估（OFT、FST、SPT、TST）显示，SARM1 KO 小鼠具有类似抑郁症的表型，同时皮层线粒体能量代谢（NAD+、ATP）也发生了改变。耐人寻味的是，SARM1 的耗竭会导致外周炎症，表现为血浆中细胞因子水平的升高，而脑区（皮层）则没有。此外，我们还发现 SARM1 KO 小鼠大脑皮层的能量代谢、AMPK 信号传导和突触可塑性失调。值得注意的是，AMPK 激活剂 AICAR（Acadesine）能改善抑郁样行为和突触功能障碍，而 AMPK 抑制剂化合物 C 则能逆转这些影响。此外，eEF2 激酶抑制剂 NH125 也能改善 SARM1 KO 小鼠的抑郁样行为。这些研究结果表明，SARM1 在通过 AMPKα/p-eEF2 信号通路调节抑郁样行为方面起着关键作用。以 AMPK 信号传导和突触功能为靶点可能会为抑郁症提供新的治疗途径。

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引用次数: 0

Hippocampal SENP3 mediates chronic stress-induced depression-like behaviors by impairing the CREB-BDNF signaling 海马SENP3通过损害CREB-BDNF信号传导介导慢性压力诱导的抑郁样行为

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2024-10-31 DOI: 10.1016/j.neuropharm.2024.110203

Zhiwei Gao , Jie Peng , Yi Zhang , Zhuo Chen , Rongrong Song , Ze Song , Qijie Feng , Micona Sun , Haojie Zhu , Xu Lu , Rongrong Yang , Chao Huang

Impaired signaling between cyclic adenosine monophosphate response element binding protein (CREB) and brain-derived neurotrophic factor (BDNF) in the hippocampus is generally considered to be the cause of depression. The mechanisms underlying the impairment of CREB-BDNF signaling under stress conditions are largely unclear. Small ubiquitin-like modifier (SUMO) specific peptidase 3 (SENP3) is a molecule that can regulate SUMOylation of target proteins related to synaptic plasticity. Its dynamic changes have been reported to be associated with neuronal damage in various models of central nervous disorders such as cerebral ischemia and traumatic brain injury. However, its role in depression is completely unknown. This problem was addressed in the present study. Our results showed that chronic unpredictable stress (CUS) triggered a specific increase in SENP3 expression in the hippocampus of non-stressed mice. Overexpression of SENP3 in the hippocampus of non-stressed mice elicited depression-like behaviors in the tail suspension test, forced swimming test, and sucrose preference test, accompanied by impairment of the CREB-BDNF signaling cascade in the hippocampus. Conversely, genetic silencing of SENP3 in the hippocampus suppressed the development of depression-like behaviors. Furthermore, infusion of SENP3-shRNA into the hippocampus failed to suppress CUS-induced depression-like behaviors when mice received genetic silencing CREB or BDNF in the hippocampus or inhibition of the BDNF receptor by K252a. Taken together, these results suggest that abnormally elevated SENP3 in the hippocampus leads to the development of depression-like behavior by impairing the CREB-BDNF signaling cascade. SENP3 in the hippocampus could be a promising target for the development of new antidepressants.

海马中环磷酸腺苷反应元件结合蛋白（CREB）和脑源性神经营养因子（BDNF）之间的信号传导受损通常被认为是抑郁症的病因。在压力条件下，CREB-BDNF 信号转导受损的机制尚不清楚。小泛素样修饰物（SUMO）特异性肽酶 3（SENP3）是一种可以调节与突触可塑性相关的靶蛋白的 SUMO 化的分子。据报道，在脑缺血和脑外伤等各种中枢神经疾病模型中，其动态变化与神经元损伤有关。然而，它在抑郁症中的作用却完全未知。本研究解决了这一问题。我们的研究结果表明，慢性不可预知应激（CUS）会引发非应激小鼠海马中 SENP3 表达的特异性增加。在非应激小鼠的海马中过表达 SENP3 会在悬尾试验、强迫游泳试验和蔗糖偏好试验中引起抑郁样行为，并伴随着海马中 CREB-BDNF 信号级联的损伤。相反，在海马中基因沉默SENP3可抑制抑郁样行为的发生。此外，当小鼠接受海马CREB或BDNF基因沉默或K252a抑制BDNF受体时，将SENP3-shRNA注入海马也不能抑制CUS诱导的抑郁样行为。综上所述，这些结果表明，海马中异常升高的 SENP3 会损害 CREB-BDNF 信号级联，从而导致抑郁样行为的发生。海马中的 SENP3 可能是开发新型抗抑郁药物的一个有前途的靶点。

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引用次数: 0

Oxytocin alleviates high-fat diet-induced anxiety by decreasing glutamatergic synaptic transmission in the ventral dentate gyrus in adolescent mice 催产素通过减少青春期小鼠腹侧齿状回的谷氨酸能突触传递，缓解高脂饮食诱发的焦虑。

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2024-10-29 DOI: 10.1016/j.neuropharm.2024.110201

Xi Cao , Qiyuan Wang , Lina Zhang , Huichao Sun , Gang Xu , Xiao Chen , Zhihong Wu , Huibao Liu , Gaole Yuan , Jian Wu , Tao Liu

A high-fat diet (HFD)-induced obesity is associated with mental disorders in adolescence. However, the mechanisms underlying these associations remain unclear. In this study, we hypothesized that synaptic remodeling occurs in the ventral hippocampus (vHP) of obese mice. To investigate this, we established a postnatal model of HFD-induced obesity in mice and observed increased body weight, elevated plasma luteinizing hormone and testosterone levels, premature puberty, and enhanced anxiety-like behavior in male subjects. We also examined the effect of HFD on the c-Fos protein expression in the ventral dentate gyrus (vDG) and explored the influence of intracerebroventricular (i.c.v) oxytocin injections on HFD-induced anxiety. Our results indicated an increase in c-Fos-positive cells in the vDG following HFD consumption. Additionally, we recorded the spontaneous synaptic activity of miniature excitatory postsynaptic currents (mEPSCs) in the vDG. Notably, HFD resulted in an elevated mEPSC frequency without affecting mEPSC amplitude. Subsequently, investigations demonstrated that i.c.v oxytocin injections reversed anxiety-like behavior induced by HFD. Moreover, the application of oxytocin in a bath solution reduced the mEPSC frequency in the vDG. These findings suggest that postnatal HFD intake induces synaptic dysfunction in the vDG, associated with the hyperactivity of vDG neurons, potentially contributing to the anxiety-like behavior in juvenile obesity.

高脂饮食（HFD）导致的肥胖与青少年精神障碍有关。然而，这些关联的机制仍不清楚。在本研究中，我们假设肥胖小鼠的腹侧海马（vHP）发生了突触重塑。为了研究这一点，我们建立了一个高氟酸膳食诱导的小鼠产后肥胖模型，并观察到雄性受试者体重增加、血浆黄体生成素和睾酮水平升高、青春期提前以及焦虑样行为增强。我们还研究了高密度脂蛋白胆固醇对腹侧齿状回（vDG）c-Fos蛋白表达的影响，并探讨了脑室内注射催产素对高密度脂蛋白胆固醇诱发焦虑的影响。我们的研究结果表明，摄入高氟酸后，vDG 中的 c-Fos 阳性细胞有所增加。此外，我们还记录了vDG中微型兴奋性突触后电流（mEPSCs）的自发突触活动。值得注意的是，HFD 导致 mEPSC 频率升高，但不影响 mEPSC 振幅。随后的研究表明，静脉注射催产素可逆转高频分解诱导的焦虑样行为。此外，在浴液中注射催产素还能降低vDG中的mEPSC频率。这些研究结果表明，出生后摄入高氟酸诱导vDG突触功能障碍，与vDG神经元的过度活跃有关，可能导致青少年肥胖症中的焦虑样行为。

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引用次数: 0

Dopamine D3 receptor mediates natural and methamphetamine rewards via regulating the expression of miR-29c in the nucleus accumbens of mice 多巴胺D3受体通过调节小鼠脑核中miR-29c的表达介导天然和甲基苯丙胺奖励

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2024-10-28 DOI: 10.1016/j.neuropharm.2024.110200

Rui Wang , Li Zhu , Yunting Fan , Huiqing Du , Wei Han , Fanglin Guan , Yingjie Zhu , Tong Ni , Teng Chen

The dopamine D3 receptor (D3R), principally confined to the nucleus accumbens (NAc), is involved in regulating natural and drug rewards; however, the molecular mechanisms underlying the associated process remain unclear. Earlier research has reported the concurrent influence of D3R and miR-29c expressed in the NAc on methamphetamine (METH)-induced reward behaviors and microglial activation, hinting at regulatory roles in reward processing. Herein, we performed viral manipulation-mediating D3R/miR-29c overexpression and inhibition in the whole NAc in male D3R knockout and wild-type mice to investigate this potential relationship. Behavioral responses to the rewarding stimuli were assessed using sucrose preference score, METH-induced locomotor sensitization, and METH-induced conditioned place preference tests. Overall, we observed a notable decrease in the behavioral response to sucrose and METH in D3R-deficient mice, accompanied by the downregulation of miR-29c expression in the NAc. Diminished responses to those rewarding stimuli in D3R-deficient mice primarily stemmed from the reduction of GSK3β activity and subsequent down-regulation of miR-29c in the NAc. Microglial activation in the NAc mediates the effect of D3R-miR-29c deficiency on the reward effects of sucrose and METH. Pharmacological suppression of microglial activity rescued the reduced response in mice lacking D3R-miR-29c in the NAc. Overall, this study revealed the mechanism by which D3R regulates both natural and drug rewards via miR-29c in the murine NAc, highlighting the role of the NAc D3R-miR-29c pathway as a critical regulator of rewards, and providing new insights into the role of NAc D3R-miR-29c in encoding rewarding experiences.

多巴胺 D3 受体（D3R）主要局限于脑核（NAc），参与调节自然和药物奖赏；然而，相关过程的分子机制仍不清楚。早先的研究报道了在NAc中表达的D3R和miR-29c同时影响甲基苯丙胺（METH）诱导的奖赏行为和小胶质细胞活化，暗示了在奖赏处理过程中的调节作用。在此，我们对雄性D3R基因敲除小鼠和野生型小鼠的整个NAc进行了病毒操作介导的D3R/miR-29c过表达和抑制，以研究这种潜在的关系。我们使用蔗糖偏好评分、METH 诱导的运动敏化和 METH 诱导的条件性位置偏好测试评估了对奖赏刺激的行为反应。总体而言，我们观察到 D3R 缺陷小鼠对蔗糖和 METH 的行为反应明显降低，同时 NAc 中 miR-29c 的表达下调。D3R缺陷小鼠对这些奖赏刺激的反应减弱主要源于GSK3β活性的降低以及随后NAc中miR-29c的下调。NAc中的小胶质细胞活化介导了D3R-miR-29c缺陷对蔗糖和METH奖赏效应的影响。药物抑制小胶质细胞的活性可以挽救在NAc中缺乏D3R-miR-29c的小鼠的反应减弱。总之，本研究揭示了小鼠NAc中D3R通过miR-29c调节自然奖赏和药物奖赏的机制，突出了NAc D3R-miR-29c通路作为奖赏关键调节因子的作用，并为NAc D3R-miR-29c在编码奖赏体验中的作用提供了新的见解。

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引用次数: 0