Neuropharmacology最新文献_第7页

Repeated administration of the synthetic cannabinoid AKB48 induces serotonergic neuroadaptation in male and female mice: behavioural and immunohistochemical evidence 反复给药合成大麻素AKB48诱导雄性和雌性小鼠血清素能神经适应：行为和免疫组织化学证据

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2025-11-05 DOI: 10.1016/j.neuropharm.2025.110758

Giorgia Corli , Fabrizio De Luca , Sabrine Bilel , Marta Bassi , Elisa Roda , Rosa Maria Gaudio , Liana Fattore , Carlo Alessandro Locatelli , Matteo Marti

Background and purpose

In the last years, Synthetic Cannabinoids (SCBs) have established themselves as one of the largest and most popular groups of Novel Psychoactive Substances (NPS), being frequently detected in biological samples of patients involved in intoxication and death cases. To date, compelling evidence on the potential interaction between SCBs and non-cannabinoid neurotransmission systems has emerged, with reference to a high-level overlap between endocannabinoid and serotoninergic system. Their long-term effect on serotoninergic pathways is still to be elucidated.

Experimental approach

Using a behavioural and immunohistochemical approach, we investigated the neuroplasticity at 5-HT_2A serotoninergic receptors and serotonin transporter in the cerebellum and cortex induced by repeated AKB48 administration in male and female mice. Further, pharmacological response to the serotoninergic compounds 2C-I or 25I-NBOMe has been studied.

Key results

The repeated exposure to AKB48 results in a worsening effect on the visual sensorimotor, sensory gating, and motor reactivity response to synthetic hallucinogens, that appears to be generally more prolonged in male with respect to AKB48-treated female mice. Interestingly, the effect has been related to cerebellar and cortical neuroplasticity at serotoninergic neurotransmission system, that involves both 5-HT_2A and SERT, that occurs more markedly and rapidly in female with respect to male mice.

Conclusion and implications

This data highlight the interaction between SCBs and psychedelic drugs that may be relevant to their long-term effects and psychiatric sequelae potentially related to their consumption.

在过去的几年中，合成大麻素（SCBs）已经成为最大和最受欢迎的新型精神活性物质（NPS）群体之一，经常在涉及中毒和死亡病例的患者的生物样本中检测到。迄今为止，关于scb和非大麻素神经传递系统之间潜在相互作用的令人信服的证据已经出现，涉及内源性大麻素和5 -羟色胺能系统之间的高度重叠。它们对血清素能通路的长期影响仍有待阐明。实验方法：采用行为学和免疫组织化学方法，研究了反复给药AKB48对雌雄小鼠小脑和皮层5-HT2A 5-羟色胺能受体和5-羟色胺转运体的神经可塑性。此外，对血清素能化合物2C-I或25i - nome的药理学反应也进行了研究。反复暴露于AKB48导致视觉感觉运动、感觉门控和对合成致幻剂的运动反应反应的恶化，与AKB48处理的雌性小鼠相比，雄性小鼠的这种影响通常更长。有趣的是，这种效应与5-HT2A和SERT的5-羟色胺能神经传递系统的小脑和皮层神经可塑性有关，雌性小鼠比雄性小鼠发生得更明显、更迅速。结论和意义这些数据强调了scb和迷幻药物之间的相互作用，这可能与它们的长期影响和精神后遗症有关。

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引用次数: 0

Golexanolone affords sustained improvement of Parkinson's symptoms in rats by reducing microglia activation that restores the glutamate-GABA-dopamine pathway Golexanolone通过减少小胶质细胞的激活，恢复谷氨酸-氨基丁酸-多巴胺通路，持续改善大鼠帕金森症状

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2025-11-05 DOI: 10.1016/j.neuropharm.2025.110759

Maria A. Pedrosa , Gergana Mincheva , Mar Martinez-Garcia , Lola Vazquez , Thomas P. Blackburn , Magnus Doverskog , Marta Llansola , Vicente Felipo

Golexanolone improves motor and non-motor symptoms in the 6-OHDA rat model of Parkinson's disease (PD) and reduces neuroinflammation in the striatum, without inducing dyskinesias. To understand the underlying mechanisms, we hypothesized that activated microglia in substantia nigra (SN) have increased glutaminase and glutamate production; glutamate uptake by astrocytes induces GABA release and enhanced GABA_A receptors activation contributes to loss of tyrosine hydroxylase (TH) and dopamine. The study aims were to assess if: 1) the mechanisms proposed occur and are reversed by golexanolone; 2) improvement by golexanolone is maintained with pathological progression; 3) an earlier treatment start provides more beneficial effects.

Daily golexanolone treatment from one week after model induction by unilateral injection of 6-OHDA in male rats was performed. Motor function, fatigue and short-term memory were assessed after four and eight weeks. At three and nine weeks, TH, glutamate and dopamine, as well as glutaminase in microglia and GABA in astrocytes were analyzed.

6-OHDA rats show microglia activation in SN, with increased glutaminase and glutamate. Increased glutamate is associated with reduced GABA into astrocytes and increased extracellular GABA, which enhances GABA_A receptors activation in neurons, contributing to loss of TH and dopamine, and altering TrkB signaling. Golexanolone reduces activation of microglia at early and long time after 6-OHDA injection, reduces activation of the glutaminase-glutamate-GABA-TH-dopamine pathway at three weeks after surgery and preserves TrkB membrane expression associated with dopamine receptors, despite the loss of dopamine, at a longer time. Both mechanisms contribute to sustained improvement of fatigue and motor and cognitive functions.

Early treatment affords more beneficial effects than late treatment on PD symptoms. Golexanolone affords sustained improvement of PD symptoms in the rat model by reducing neuroinflammation, increasing dopaminergic signaling and therefore could be considered for clinical evaluation in patients with PD.

Golexanolone改善6-OHDA大鼠帕金森病（PD）模型的运动和非运动症状，减少纹状体的神经炎症，而不引起运动障碍。为了了解潜在的机制，我们假设激活的黑质（SN）小胶质细胞增加了谷氨酰胺酶和谷氨酸的产生；星形胶质细胞对谷氨酸的摄取诱导GABA释放，GABAA受体激活增强导致酪氨酸羟化酶（TH）和多巴胺的丧失。该研究的目的是评估：1)所提出的机制是否发生并被戈勒马诺酮逆转；2)戈勒马诺酮的改善随着病理进展而维持；3)越早开始治疗效果越好。雄性大鼠单侧注射6-羟色胺诱导模型1周后，每日给药戈莱诺酮。运动功能、疲劳和短期记忆在4周和8周后进行评估。在第3周和第9周时，分析TH、谷氨酸和多巴胺，以及小胶质细胞中的谷氨酰胺酶和星形胶质细胞中的GABA。6-OHDA大鼠SN出现小胶质细胞活化，谷氨酰胺酶和谷氨酸升高。谷氨酸的增加与GABA进入星形胶质细胞的减少和细胞外GABA的增加有关，这增强了GABAA受体在神经元中的激活，导致TH和多巴胺的丢失，并改变TrkB信号。Golexanolone在注射6-OHDA后的早期和长时间内降低了小胶质细胞的激活，在手术后3周降低了谷氨酰胺-谷氨酸- gaba - th -多巴胺通路的激活，并在更长的时间内保留了多巴胺受体相关的TrkB膜表达，尽管多巴胺丢失。这两种机制都有助于持续改善疲劳、运动和认知功能。早期治疗比晚期治疗对帕金森病症状更有利。Golexanolone通过减少神经炎症，增加多巴胺能信号传导，在大鼠模型中持续改善PD症状，因此可以考虑用于PD患者的临床评估。

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引用次数: 0

Multimodal relationships and multifactorial associations between oral microecological and neurodegenerative diseases 口腔微生态与神经退行性疾病之间的多模式关系和多因素关联。

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2025-11-04 DOI: 10.1016/j.neuropharm.2025.110760

Yi Zhou , Jiaxuan Li , Di Wang , Ling Peng , Keda Chen

Dysregulation of the oral microbiome can result in inflammation of the oral mucosa and is associated with the development and advancement of numerous local and systemic illnesses, including those triggered by viral infections. The review thoroughly examines how the IL-17/Th17 response contributes to both protective immunity and inflammation in the oral mucosa, as well as its role in the onset of neurodegenerative diseases. A theoretical structure is offered for the possible connections among immune cells and the bacteria in the mouth. Changes in the oral microbiome and its produced pro-inflammatory factors may serve as non-invasive biomarkers for the invasion of potential neurodegenerative pathogens, offering predictive and early warning value for the severity of neurodegenerative diseases. Studying the intricate connection between the oral microbiome and neurodegenerative diseases offers potential for innovative strategies in preventing and treating the advancement of such conditions. Additional investigation is needed to reveal the mechanisms behind this connection and offer important insights for upcoming clinical procedures.

口腔微生物组的失调可导致口腔黏膜的炎症，并与许多局部和全身性疾病的发展和进展有关，包括由病毒感染引发的疾病。这篇综述深入探讨了IL-17/Th17反应如何促进口腔黏膜的保护性免疫和炎症，以及它在神经退行性疾病发病中的作用。为免疫细胞与口腔细菌之间的可能联系提供了理论结构。口腔微生物组及其产生的促炎因子的变化可作为潜在神经退行性病原体侵袭的非侵入性生物标志物，为神经退行性疾病的严重程度提供预测和预警价值。研究口腔微生物组与神经退行性疾病之间的复杂联系，为预防和治疗这些疾病的进展提供了创新策略的潜力。需要进一步的研究来揭示这种联系背后的机制，并为即将到来的临床程序提供重要的见解。

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引用次数: 0

Hippocampal GPR17 down regulation ameliorates CMS-induced depression-like behaviors in mice 海马GPR17下调可改善小鼠cms诱导的抑郁样行为。

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2025-11-04 DOI: 10.1016/j.neuropharm.2025.110757

Zhi Xie , Bing Fan , Tian Tian Zhi , YangXia Wu , Yan Yang , Lei Wu , Xian Wu

Chronic stress is a significant pathogenic factor that contributes to the onset of depression. GPR17 has anti-inflammatory and anti-oxidative effects, but its role in depression is still unknown. In this study, we examined the role of GPR17 in mice exposed to chronic mild stress (CMS) and elucidated its underlying molecular mechanisms. We down-regulated hippocampal GPR17 by injecting LV-GPR17-shRNA or the GPR17 antagonist cangrelor into the DG region of the mouse hippocampus. To explore the role of GPR17 in the pathogenesis of depression, we employed behavioral, pathological, and biochemical experiments. We found that CMS-induced depression-like behaviors were associated with increased GPR17 expression in the hippocampus. Pharmacological activation of GPR17 in the hippocampus triggered depression-like behaviors in normal mice. Conversely, knockdown and inhibition of GPR17 alleviated depression-like behaviors induced by CMS in mice. Furthermore, knockdown and inhibition of GPR17 significantly suppressed CMS-induced activation of hippocampal glial cells and reduced inflammatory cytokine levels, alleviating neuroinflammation in mice. Additionally, knockdown and inhibition of GPR17 also promoted hippocampal neurogenesis and improved synaptic plasticity in CMS-exposed mice. In vitro, the GPR17 antagonist cangrelor increased the survival rate of corticosterone (CORT)-treated HT22 cells and upregulated the expression of synapse-associated proteins. Moreover, we found that the antidepressant-like effects of GPR17 modulation were mediated through the hippocampal BDNF/CREB/TrkB pathway. Our findings suggest that GPR17 may be a promising therapeutic target for depression.

慢性压力是导致抑郁症发病的重要致病因素。GPR17具有抗炎和抗氧化作用，但其在抑郁症中的作用尚不清楚。在这项研究中，我们研究了GPR17在慢性轻度应激（CMS）小鼠中的作用，并阐明了其潜在的分子机制。我们通过在小鼠海马DG区注射LV-GPR17-shRNA或GPR17拮抗剂angrelor来下调海马GPR17。为了探讨GPR17在抑郁症发病机制中的作用，我们采用了行为、病理和生化实验。我们发现cms诱导的抑郁样行为与海马中GPR17表达增加有关。正常小鼠海马区GPR17的药理激活可引发抑郁样行为。相反，GPR17的敲低和抑制可减轻小鼠CMS诱导的抑郁样行为。此外，GPR17的敲低和抑制可显著抑制cms诱导的海马胶质细胞活化，降低炎症细胞因子水平，减轻小鼠的神经炎症。此外，GPR17的敲低和抑制也促进了cms暴露小鼠的海马神经发生和突触可塑性的改善。在体外实验中，GPR17拮抗剂canrelor提高皮质酮（CORT）处理的HT22细胞的存活率，上调突触相关蛋白的表达。此外，我们发现GPR17调节的抗抑郁样作用是通过海马BDNF/CREB/TrkB通路介导的。我们的研究结果表明，GPR17可能是一个有希望的治疗抑郁症的靶点。

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引用次数: 0

Microdosing psilocybin and its effect on creativity: Lessons learned from three double-blind placebo controlled longitudinal trials 微剂量裸盖菇素及其对创造力的影响：来自三个双盲安慰剂对照纵向试验的经验教训。

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2025-11-02 DOI: 10.1016/j.neuropharm.2025.110732

Luisa Prochazkova , Josephine Marschall , Michiel van Elk , Ben D. Rifkin , Neil R. Schon , Donatella Fiacchino , George Fejer , Martin Kuchar , Bernhard Hommel

Background

Taking very small doses of psychedelics (LSD, truffles) over an extended period became prevalent in Western societies for its alleged cognitive benefit, including enhanced creativity. However, in the absence of robust, double-blind-controlled quantitative studies, such claims remain anecdotal.

Methods

Here we present results from 3 double-blind placebo-controlled longitudinal trials (one of which pre-registered) assessing the effects of microdosing psilocybin on convergent and divergent creativity in a well-controlled semi-naturalistic setting. To enhance statistical power and generalizability, data from all trials (N = 171) were pooled in a mega-analysis, resulting in one of the most robust laboratory-based studies on microdosing to date.

Results

We found that active microdosing increased the ratio of original responses (originality/fluency), indicating higher quality of divergent thinking in the active microdosing condition. The unadjusted originality score was significantly more pronounced in the active microdosing condition, but only when relative dosage (dose/weight of participants) was considered. Importantly, these effects survived controlling for dose guess and demographic biases. No effects of active microdosing were found for other divergent-thinking scores or convergent thinking.

Conclusion

The results suggest that the effects of truffle mirodosing are limited to the quality of divergent thinking. Moreover, our findings highlight the importance of controlling for placebo effects and prior psychedelic experience in assessing the impact of microdosing.

背景：长期服用小剂量的致幻剂（LSD，松露）在西方社会变得普遍，因为它据称对认知有好处，包括增强创造力。然而，由于缺乏强有力的双盲对照定量研究，这种说法仍然是道听途说。方法：在这里，我们展示了3个双盲安慰剂对照纵向试验的结果（其中一个是预先注册的），评估了在控制良好的半自然环境下，微剂量裸盖菇素对趋同和发散创造力的影响。为了提高统计能力和普遍性，我们将所有试验（N = 171）的数据汇总到一个大型分析中，得出了迄今为止最可靠的基于实验室的微剂量研究之一。结果：我们发现主动微剂量增加了原创反应的比率（原创性/流畅性），表明在主动微剂量条件下发散思维的质量更高。在主动微剂量条件下，未调整的原创性得分显著更明显，但仅在考虑相对剂量（参与者的剂量/体重）时才如此。重要的是，这些效应在控制剂量猜测和人口统计学偏差后仍然存在。没有发现主动微剂量对其他发散性思维得分或收敛性思维得分的影响。结论：松露剂量对发散性思维的影响是有限的。此外，我们的研究结果强调了在评估微剂量影响时控制安慰剂效应和先前迷幻经历的重要性。

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引用次数: 0

Glutamatergic neurons in the ventral hippocampal CA1 participate in the regulation of comorbidity of chronic pain and depression 海马腹侧CA1区谷氨酸能神经元参与慢性疼痛和抑郁共病的调节

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2025-10-31 DOI: 10.1016/j.neuropharm.2025.110755

Wei Meng , Yihang Lv , Zihan Ren , Weidong Zang , Songxue Su , Jing Cao , Cui Li

Background

Chronic pain and depression are highly comorbid conditions that pose a significant clinical challenge, yet the underlying neural circuitry mechanisms are poorly understood. The ventral hippocampal CA1 (vCA1) has been implicated in both pain and affective processing, but its specific role in this comorbidity remains unclear.

Methods

We combined immunofluorescence, whole-cell patch-clamp recordings, and pathway-specific chemogenetic and optogenetic manipulations to investigate the role of vCA1 glutamatergic neurons and their downstream targets in a chronic constriction injury (CCI) mouse model. Behavioral assays were used to assess nociceptive, depressive, and anxiety-related phenotypes.

Results

We observed reduced excitability of vCA1 and ventral dentate gyrus (vDG) neurons in the comorbidity model. Inhibition or ablation of vCA1 glutamatergic neurons in naïve mice induced both nociceptive hypersensitivity and depression-like behaviors, whereas suppression of vDG neurons elicited depression-like behaviors without altering nociceptive sensitivity. Conversely, optogenetic and chemogenetic activation of vCA1 glutamatergic neurons alleviated CCI-induced nociceptive hypersensitivity and depression behaviors. A functional divergence was identified in the downstream pathways of vCA1: projections to the nucleus accumbens (NAc) and thalamic reticular nucleus (TRN) selectively modulated nociceptive hypersensitivity, whereas projections to the lateral septum (LS) specifically regulated depression-like behaviors.

Conclusion

These findings establish vCA1 glutamatergic neurons as a critical hub in pain-depression comorbidity, and delineate distinct pathways that differentially govern nociceptive and depressive behaviors.

背景：慢性疼痛和抑郁是高度合并症，对临床构成重大挑战，但其潜在的神经回路机制尚不清楚。腹侧海马CA1 （vCA1）与疼痛和情感处理有关，但其在这种共病中的具体作用尚不清楚。方法：结合免疫荧光、全细胞膜片钳记录、途径特异性化学发生和光遗传学操作，研究vCA1谷氨酸能神经元及其下游靶点在慢性收缩性损伤（CCI）小鼠模型中的作用。行为分析用于评估伤害性、抑郁和焦虑相关表型。结果：在共病模型中，我们观察到vCA1和腹状齿状回（vDG）神经元的兴奋性降低。抑制或消蚀naïve小鼠的vCA1谷氨酸能神经元可诱导伤害性超敏反应和抑郁样行为，而抑制vDG神经元可诱导抑郁样行为，但不改变伤害性敏感性。相反，vCA1谷氨酸能神经元的光遗传学和化学遗传学激活可减轻cci诱导的伤害性超敏反应和抑郁行为。在vCA1的下游通路中发现了功能差异：对伏隔核（NAc）和丘脑网状核（TRN）的投射选择性地调节伤害性超敏反应，而对外侧隔（LS）的投射特异性地调节抑郁样行为。结论：这些发现证实了vCA1谷氨酸能神经元是疼痛-抑郁共病的关键中枢，并描绘了不同的通路，不同地控制伤害性和抑郁行为。

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引用次数: 0

Corrigendum to “Protective role of madecassoside from Centella asiatica against protein L-isoaspartyl methyltransferase deficiency-induced neurodegeneration” [Neuropharmacology 109834 (2023) DOI: 10.1016/j.neuropharm.2023.109834] “积雪草草皂苷对蛋白质l -异天冬氨酸甲基转移酶缺乏症诱导的神经变性的保护作用”[神经药理学109834 (2023)DOI: 10.1016/j.n neuromedicine .2023.109834]的更正。

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2025-10-31 DOI: 10.1016/j.neuropharm.2025.110735

Zicheng Ling , Sirui Zhou , Yancheng Zhou , Wanyu Zhong , Zhonghao Su , Zhenxia Qin

引用次数: 0

Indole-3-acetic acid exerts protective effects on sleep deprivation-induced cognitive impairment 吲哚-3-乙酸对睡眠剥夺引起的认知障碍有保护作用

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2025-10-30 DOI: 10.1016/j.neuropharm.2025.110747

Jiao Han , Linjuan Zhang , Yixuan Lyu , Yifang Zhai , Wei Wu , Yuhang Qin , Li Ma , Lixia Zhuo , Yuxi Guo , Xiaodan Wang , Feidi Wang , Linlin Jing , Jing Wang , Yan Li , Rongrong Yang

The gut microbiota and its metabolites have increasingly been recognized as crucial factors contributing to the cognitive deficits induced by sleep deprivation (SD), a condition characterized by diminished hippocampal neurogenesis. Nevertheless, the signaling pathways that integrate inputs from metabolites and gut endocrine hormones to influence neurobehavioral outcomes remain largely elusive. In the present study, the multiomics analysis demonstrated that SD led to a significant reduction in the levels of the microbial metabolite indole-3-acetic acid (IAA) in mice (male). Notably, oral administration of IAA effectively ameliorated cognitive impairments and restored intestinal integrity in SD mice. Mechanistically, IAA binds to the aryl hydrocarbon receptor (AhR) in enterochromaffin cells (ECs), thereby increasing the secretion of serotonin (5-hydroxytryptamine; 5-HT). 5-HT subsequently activates the vagus nerve via the 5-HT₃ receptor, which in turn stimulates hippocampal neuronal activity and promotes neurogenesis, ultimately alleviating cognitive impairments. These findings underscore the pivotal role of the gut-derived metabolite IAA in modulating hippocampal function through the gut–EC–vagus nerve–brain axis. Moreover, they provide perspectives on the mechanisms underlying SD-induced cognitive impairment, suggesting promising avenues for future therapeutic strategies.

肠道微生物群及其代谢物越来越被认为是导致睡眠剥夺（SD）引起的认知缺陷的关键因素，这种疾病的特征是海马神经发生减少。然而，整合代谢物和肠道内分泌激素输入来影响神经行为结果的信号通路在很大程度上仍然难以捉摸。在本研究中，多组学分析表明，SD导致小鼠（雄性）微生物代谢物吲哚-3-乙酸（IAA）水平显著降低。值得注意的是，口服IAA可有效改善SD小鼠的认知障碍并恢复肠道完整性。在机制上，IAA与肠染色质细胞（ECs）中的芳烃受体（AhR）结合，从而增加血清素（5-羟色胺；5-HT）的分泌。5-HT随后通过5-HT3受体激活迷走神经，进而刺激海马神经元活动，促进神经发生，最终减轻认知障碍。这些发现强调了肠源代谢物IAA在通过肠- ec -迷走神经-脑轴调节海马功能中的关键作用。此外，他们还为sd诱导的认知障碍的机制提供了观点，为未来的治疗策略提供了有希望的途径。

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引用次数: 0

Influence of social support on the acquisition of conditioned place aversion induced by chemical stimulation of the dorsal periaqueductal gray matter: a sex-dependent approach 社会支持对化学刺激背侧导水管周围灰质诱发的条件厌恶习得的影响：一种性别依赖的方法。

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2025-10-30 DOI: 10.1016/j.neuropharm.2025.110749

Alvaro Henrique Bernardo de Lima Silva, Pedro Henrique Azevedo de Oliveira, Joice Maria da Cunha, Janaina Menezes Zanoveli, Bruno Jacson Martynhak

Social support (SS) provided by conspecifics during an aversive situation can influence the processing of fear and anxiety responses. However, the effect of social support on the aversive response produced by stimulation of the dorsolateral periaqueductal gray matter (dPAG) have not yet been investigated. Therefore, we investigated in male and female rats the effect of chemical stimulation of the dPAG with N-methyl-D-aspartate (NMDA) on the acquisition of conditioned place aversion (CPA) and whether stimulation of dPAG would produce a persistent anxiety-like response, using for that the elevated plus maze (EPM) test. The effects of dPAG stimulation were evaluated in the presence or absence of social support (SS) provided by a non-familial, naïve conspecific. We found that during an aversive conditioning session, dPAG stimulation induced freezing behavior in both male and female rats, which was attenuated by the presence of SS. In the CPA test, dPAG stimulation induced aversion in both sexes, while the SS reversed CPA in males, but not in females. Despite this effect in female rats, SS induced a significant increase in appetitive ultrasonic vocalizations (USVs) and a decrease in aversive USVs, along with reduced anxiety-like behavior in both male and female rats. On the other hand, all these beneficial effects observed on the processing of aversive memory and anxiety-like response were not observed in the animals serving as SS providers, which is an aspect that needs to be better investigated. Our findings provide new insights into the role of the dPAG and social support (SS) in the acquisition of aversive responses and in the associated persistent anxiety-like behavior.

同种个体在厌恶情境下提供的社会支持会影响恐惧和焦虑反应的加工。然而，社会支持对刺激背外侧导水管周围灰质（dPAG）产生的厌恶反应的影响尚未得到研究。为此，我们采用升高+迷宫（EPM）实验，研究了n -甲基- d -天冬氨酸（NMDA）对雄性和雌性大鼠dPAG的化学刺激对条件厌恶（CPA）习得的影响，以及dPAG刺激是否会产生持续的焦虑样反应。在有或没有社会支持（SS）的情况下，对dPAG刺激的效果进行了评估，社会支持（SS）是由一个非家族性的naïve同种个体提供的。我们发现，在厌恶条件反射过程中，dPAG刺激诱导了雄性和雌性大鼠的冻结行为，这种行为被SS的存在所减弱。在CPA测试中，dPAG刺激诱导了雄性和雌性大鼠的厌恶行为，而SS在雄性大鼠中逆转了CPA，但在雌性大鼠中没有。尽管在雌性大鼠中有这种作用，但在雄性和雌性大鼠中，SS诱导了食欲超声发声（usv）的显著增加和厌恶超声发声（usv）的减少，以及焦虑样行为的减少。另一方面，这些对厌恶记忆加工和焦虑样反应的有益影响在作为SS提供者的动物中没有观察到，这是一个需要进一步研究的方面。我们的研究结果为dPAG和社会支持（SS）在厌恶反应的获得和相关的持续焦虑样行为中的作用提供了新的见解。

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引用次数: 0

Oral administration of indole-3-lactic acid alleviates activity-based anorexia in female mice 口服吲哚-3-乳酸减轻雌性小鼠活动性厌食症。

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2025-10-28 DOI: 10.1016/j.neuropharm.2025.110746

Xinyu Tang , Jingyu Wang , Jinge Sun , Zhiying Jin , Xin Qian , Jianxin Zhao , Wei Chen , Peijun Tian

Anorexia nervosa (AN) is a severe psychiatric disorder characterized by extreme dietary restriction, pronounced weight loss, and disturbed energy metabolism. In recent years, increasing attention has been given to the role of the gut microbiota and its tryptophan-derived metabolites in modulating host neural function and feeding behavior via the gut–brain axis. Indole-3-lactic acid (ILA), one of the major tryptophan metabolites produced by the gut microbiota has been shown to exert neuroprotective and anti-inflammatory effects. However, its role in central appetite regulation remains unclear. In this study, we systematically evaluated the therapeutic potential and underlying mechanisms of ILA using an activity-based anorexia (ABA) mouse model. Oral administration of ILA significantly mitigated weight loss, reduced food intake, and hyperactivity in ABA mice. Pharmacokinetic analysis revealed that ILA was efficiently absorbed from the gastrointestinal tract, crossed the blood–brain barrier, and maintained a relatively stable concentration in the brain. Transcriptomic profiling of the hypothalamus identified 457 differentially expressed genes (DEGs), which were significantly enriched in pathways related to neuroactive ligand–receptor interactions, PI3K-Akt signaling, and MAPK signaling. Notably, the expression of the orexigenic neuropeptide Qrfp and its receptor Gpr103 was markedly upregulated following ILA treatment. These findings were further validated in vitro and in vivo, confirming that ILA activates the Qrfp–Gpr103 signaling axis. Additionally, ILA significantly restored dopamine and serotonin (5-HT) levels in the striatum of ABA mice. Collectively, our results demonstrate that ILA, as a microbiota-derived tryptophan metabolite, holds promise for improving energy deficits through modulation of central neural circuits, suggesting its potential as an adjunctive intervention for anorexia nervosa and related metabolic disorders.

神经性厌食症（Anorexia neurosa， AN）是一种严重的精神疾病，其特征是极度限制饮食、体重明显减轻和能量代谢紊乱。近年来，肠道菌群及其色氨酸衍生代谢物通过肠-脑轴调节宿主神经功能和摄食行为的作用越来越受到关注。吲哚-3-乳酸（ILA）是肠道微生物群产生的主要色氨酸代谢物之一，已被证明具有神经保护和抗炎作用。然而，它在食欲中枢调节中的作用尚不清楚。在这项研究中，我们使用基于活动的厌食症（ABA）小鼠模型系统地评估了ILA的治疗潜力和潜在机制。口服ILA可显著减轻ABA小鼠的体重减轻、减少食物摄入和多动症。药代动力学分析表明，ILA从胃肠道被有效吸收，穿过血脑屏障，并在脑内保持相对稳定的浓度。下丘脑的转录组学分析鉴定出457个差异表达基因（deg），这些基因在神经活性配体-受体相互作用、PI3K-Akt信号传导和MAPK信号传导相关的通路中显著富集。值得注意的是，在ILA治疗后，产氧神经肽Qrfp及其受体Gpr103的表达明显上调。这些发现在体外和体内得到了进一步的验证，证实了ILA激活了Qrfp-Gpr103信号轴。此外，ILA显著恢复ABA小鼠纹状体中多巴胺和5-羟色胺（5-HT）水平。总的来说，我们的研究结果表明，ILA作为一种微生物衍生的色氨酸代谢物，有望通过调节中枢神经回路来改善能量不足，这表明它有可能作为神经性厌食症和相关代谢疾病的辅助干预手段。

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