Anterior cingulate cortex projections to the dorsal medial striatum underlie insomnia associated with chronic pain

doi:10.1016/j.neuron.2024.01.014

Neuron

Volume 112, Issue 8, 17 April 2024, Pages 1328-1341.e4
第112卷，第8期，2024年4月17日，第1328-1341.e4页

https://doi.org/10.1016/j.neuron.2024.01.014 Get rights and content 获取权利和内容

Referred to by 提到

Anterior cingulate cortex and insomnia: A cingulate-striatum connection
前扣带皮层与失眠：扣带-纹状体的联系

Neuron, Volume 112, Issue 8, 17 April 2024, Pages 1202-1204
神经元，第112卷，第8期，2024年4月17日，第1202-1204页

Qi-Yu Chen, Min Zhuo 陈启宇，卓敏

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Highlights 亮点

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ACC pyramidal neurons (PNs) are selectively activated during chronic-pain-induced insomnia
ACC锥体神经元（PN）在慢性疼痛诱导的失眠中被选择性激活
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Lesion of ACC PNs abolishes chronic-pain-induced insomnia
ACC PN的损伤消除了慢性疼痛引起的失眠
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Hyperactive ACC PNs control chronic-pain-induced insomnia via the DMS pathway
过度活跃的ACC PN通过DMS途径控制慢性疼痛诱导的失眠
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Enhanced plasticity of ACC PNs to DMS D1R-MSNs mediates insomnia
ACC PN对DMS D1 R-MSNs的可塑性增强介导失眠

Summary 总结

Chronic pain often leads to the development of sleep disturbances. However, the precise neural circuit mechanisms responsible for sleep disorders in chronic pain have remained largely unknown. Here, we present compelling evidence that hyperactivity of pyramidal neurons (PNs) in the anterior cingulate cortex (ACC) drives insomnia in a mouse model of nerve-injury-induced chronic pain. After nerve injury, ACC PNs displayed spontaneous hyperactivity selectively in periods of insomnia. We then show that ACC PNs were both necessary for developing chronic-pain-induced insomnia and sufficient to mimic sleep loss in naive mice. Importantly, combining optogenetics and electrophysiological recordings, we found that the ACC projection to the dorsal medial striatum (DMS) underlies chronic-pain-induced insomnia through enhanced activity and plasticity of ACC-DMS dopamine D1R neuron synapses. Our findings shed light on the pivotal role of ACC PNs in developing chronic-pain-induced sleep disorders.
慢性疼痛往往会导致睡眠障碍的发展。然而，负责慢性疼痛中睡眠障碍的精确神经回路机制在很大程度上仍然未知。在这里，我们提出了令人信服的证据表明，在神经损伤诱导的慢性疼痛的小鼠模型中，前扣带皮层（ACC）中的锥体神经元（PN）的过度活跃会导致失眠。在神经损伤后，ACC PN在失眠期间选择性地显示自发性过度活跃。然后，我们表明，ACC PN是发展慢性疼痛诱导的失眠症所必需的，并且足以模拟幼稚小鼠的睡眠丧失。重要的是，结合光遗传学和电生理记录，我们发现ACC投射到背内侧纹状体（DMS）的基础慢性疼痛诱导的失眠通过ACC-DMS多巴胺D1 R神经元突触的活性和可塑性增强。我们的研究结果揭示了ACC PN在慢性疼痛诱导的睡眠障碍中的关键作用。

Graphical abstract 图形摘要

Keywords 关键词

sleep

chronic pain

anterior cingulate cortex

striatum

dopamine

insomnia

pyramidal neurons

calcium imaging

dopamine D1 receptor

dopamine D2 receptor

慢性睡眠痛前扣带皮层纹状体多巴胺失眠锥体神经元钙成像多巴胺D1受体多巴胺D2受体

Introduction 介绍

Approximately 20% of the general population suffers from chronic pain,¹ with significant comorbidity of depression,²^,³^,⁴ poor memory,⁵^,⁶ and sleep disturbance.⁷^,⁸ Sleep complaints are present in 67%–88% of chronic pain patients, and at least 50% meet the criteria for insomnia.⁹ Chronic-pain-induced insomnia not only intensifies pain but also impairs memory¹⁰^,¹¹ and increases the risk of depression,¹² highlighting the need to address this comorbidity to improve overall patient outcomes. Despite the significant impact of chronic-pain-induced insomnia on patients, there has been limited research exploring the neuronal circuits underlying this phenomenon. Additionally, it remains unclear how the sleep-wake regulating circuits are affected by chronic pain and further mediate insomnia.
大约20%的普通人群患有慢性疼痛， ¹ 具有抑郁症的显著共病， ² ³ ⁴ 记忆力差， ⁵ ⁶ 和睡眠障碍。67%-88%的慢性疼痛患者存在睡眠问题，至少50%的患者符合失眠标准。 ⁹ 慢性疼痛引起的失眠不仅会加剧疼痛，还会损害记忆 ¹⁰ ¹¹ 并增加抑郁症的风险， ¹² 强调需要解决这种并发症以改善患者的整体预后。尽管慢性疼痛引起的失眠对患者有显著影响，但探索这种现象背后的神经回路的研究有限。此外，尚不清楚睡眠-觉醒调节回路如何受到慢性疼痛的影响并进一步介导失眠。

As the input of basal ganglia, the dorsal medial striatum (DMS) plays a key role in sleep-wake regulation.¹³^,¹⁴^,¹⁵ The two distinct populations of neurons play opposite roles in sleep-wake control: dopamine D1 receptor (D1R)-expressing medium spiny neurons (MSNs) promote wakefulness,¹⁴ whereas dopamine D2 receptor (D2R)-MSNs promote sleep.¹⁵ Interestingly, as one of the major inputs to the DMS, the anterior cingulate cortex (ACC) is reliably activated in chronic pain models and necessary for the processing of pain affect.¹⁶^,¹⁷^,¹⁸ Pyramidal neurons (PNs) within the ACC have been shown to control features of mechanical allodynia in neuropathic pain models.¹⁹ Besides, optogenetic activation of ACC corticospinal projections results in mechanical hypersensitivity, whereas inhibition produces acute analgesia.²⁰ Although the ACC was not treated as a wake-promoting center, recent evidence indicates that the ACC is involved in modulating wakefulness within specific contexts, such as a novel environment²¹ and depression,²² suggesting that heightened activity among ACC PNs may contribute to insomnia associated with chronic pain. However, whether the ACC-DMS circuit is involved in chronic-pain-induced insomnia and how chronic pain reshapes ACC PNs to DMS MSNs projections are unknown. We hypothesized that ACC PNs control chronic-pain-induced insomnia through enhanced synaptic connections to DMS D1R-MSNs.
背内侧纹状体（DMS）作为基底神经节的输入，在睡眠-觉醒调节中起着关键作用。 ¹³ ¹⁴ ¹⁵ 两种不同的神经元群体在睡眠-觉醒控制中起着相反的作用：多巴胺D1受体（D1 R）表达的中型多刺神经元（MSN）促进觉醒，而多巴胺D2受体（D2 R）-MSN促进睡眠。#4有趣的是，作为DMS的主要输入之一，前扣带皮层（ACC）在慢性疼痛模型中被可靠地激活，并且对于疼痛影响的处理是必要的。在神经病理性疼痛模型中，ACC内的锥体神经元（PN）已被证明控制机械异常性疼痛的特征。此外，ACC皮质脊髓投射的光遗传激活导致机械超敏反应，而抑制产生急性镇痛。尽管前扣带回并没有被当作一个促进觉醒的中心，但最近的证据表明，前扣带回参与了特定环境下的觉醒调节，例如新环境 ²¹ 和抑郁症 ²² ，这表明前扣带回PN之间的活动增强可能导致与慢性疼痛相关的失眠。然而，ACC-DMS回路是否参与慢性疼痛引起的失眠，以及慢性疼痛如何重塑ACC PN到DMS MSNs投射尚不清楚。我们假设ACC PN通过增强与DMS D1 R-MSNs的突触连接来控制慢性疼痛诱导的失眠。

To test our hypothesis, we conduct imaging studies in live animals and confirm that hyperactivity of ACC PNs is mainly associated with insomnia in chronic pain mice caused by nerve injury. Next, through gain- and loss-of-function experiments, we establish that ACC PNs play a causal role in regulating chronic-pain-induced insomnia through the ACC-DMS pathway. Using optogenetics-assisted slice electrophysiology, we further examine the synaptic plasticity of ACC-DMS D1R-MSNs/D2R-MSNs synapses following nerve injury. We find that the chronic-pain-induced hyperactivity of ACC PNs is reflected in the synaptic dynamics of D1R-MSNs rather than D2R-MSNs. Lastly, inhibition of DMS D1R-MSNs reverses chronic-pain-induced insomnia. Collectively, these studies demonstrate that the ACC PNs underlie insomnia associated with chronic neuropathic pain conditions, highlighting the ACC PN-DMS pathway as a potential target for therapeutic interventions aimed at addressing insomnia associated with chronic pain.
为了验证我们的假设，我们在活体动物中进行成像研究，并证实ACC PN的过度活跃主要与神经损伤引起的慢性疼痛小鼠的失眠有关。接下来，通过功能获得和丧失实验，我们确定ACC PN通过ACC-DMS通路在调节慢性疼痛诱导的失眠中发挥因果作用。使用光遗传学辅助切片电生理学，我们进一步检查神经损伤后ACC-DMS D1 R-MSNs/D2 R-MSNs突触的突触可塑性。我们发现，慢性疼痛引起的ACC PN的过度活跃反映在D1 R-MSNs而不是D2 R-MSNs的突触动力学。最后，DMS D1 R-MSN的抑制逆转了慢性疼痛引起的失眠。总的来说，这些研究表明，ACC PN是与慢性神经性疼痛状况相关的失眠的基础，突出了ACC PN-DMS通路作为旨在解决与慢性疼痛相关的失眠的治疗干预的潜在靶点。

Results 结果

Aberrant activation of ACC PNs in chronic-pain-induced insomnia
慢性疼痛性失眠症患者ACC神经元的异常激活

To establish the presence of chronic-pain-induced sleep disorders, we initially assessed the quantity of sleep-wake patterns in a mouse model of neuropathic pain induced by partial sciatic nerve ligation (PSNL) (Figures S1A–S1C). The PSNL model is widely recognized as a reliable and established method for inducing chronic pain and subsequent insomnia, as demonstrated in our previous studies.²³^,²⁴^,²⁵ In this study, we observed a significant increase in wakefulness during ZT0–ZT2 (07:00–09:00) in PSNL mice compared with the sham group (Figures S1D and S1E). Conversely, the sham mice exhibited a shorter latency to non-rapid eye movement (NREM) sleep onset and a longer mean duration of NREM sleep, without a difference in electroencephalogram (EEG) power density or episode number of NREM sleep during this time period (Figures S1F–S1J). These results confirm sleep disorders in PSNL mice.
为了确定慢性疼痛诱导的睡眠障碍的存在，我们最初评估了通过部分坐骨神经结扎（PSNL）诱导的神经性疼痛的小鼠模型中的睡眠-觉醒模式的数量（图S1 A-S1 C）。PSNL模型被广泛认为是诱导慢性疼痛和随后的失眠的可靠和成熟的方法，正如我们以前的研究所证明的那样。在该研究中，我们观察到与假手术组相比，PSNL小鼠在ZT 0-ZT 2（07：00-09：00）期间的觉醒显著增加（图S1 D和S1 E）。相反，假手术小鼠表现出较短的非快速眼动（NREM）睡眠开始的潜伏期和较长的NREM睡眠的平均持续时间，在该时间段期间脑电图（EEG）功率密度或NREM睡眠的发作次数没有差异（图S1 F-S1 J）。这些结果证实了PSNL小鼠的睡眠障碍。

Using in vivo calcium imaging and c-Fos labeling, previous studies reported that ACC PNs are activated in mice with chronic pain,¹⁶^,¹⁷^,²⁶ but it is unclear whether ACC PNs are selectively activated in chronic-pain-induced insomnia. Initially, we recorded the dynamic calcium activity of ACC PNs during two specific time intervals, ZT0–ZT2 (07:00–09:00) and ZT12–ZT14 (19:00–21:00), prior to PSNL surgery (refer to “base”). Subsequently, PSNL was applied to these mice, and after a 7-day period, we recorded the calcium activity of ACC PNs again at the same time points (refer to “PSNL,” Figures 1A–1C; Video S1). To investigate whether ACC PNs are specifically active due to chronic pain or chronic-pain-induced insomnia, we chose the time intervals of 07:00–09:00, corresponding to the insomnia phase in PSNL mice, and 19:00–21:00, when both naive and PSNL mice are awake (Figure S1D). Interestingly, we observed an increase in the calcium activity of ACC PNs only during the insomnia phase (07:00–09:00), not during the physiologically active phase (19:00–21:00), when compared with naive mice (Figures 1D and 1E). Furthermore, during sleep loss in the light phase, we noted that a substantial portion (62%) of ACC PNs show elevated calcium activity compared with their activity before PSNL surgery (Figure 1F). In contrast, during the initial 2 h of the dark phase when both sham and PSNL mice were awake, only 21% of ACC PNs in PSNL mice exhibited increased calcium activity (Figure 1F). These findings suggest that ACC PNs are abnormally activated specifically during chronic-pain-induced insomnia in PSNL mice.
使用体内钙成像和c-Fos标记，先前的研究报道了ACC PN在慢性疼痛小鼠中被激活， ¹⁶ ¹⁷ ²⁶ 但尚不清楚ACC PN是否在慢性疼痛诱导的失眠中被选择性激活。最初，我们记录了在PSNL手术之前的两个特定时间间隔ZT 0-ZT 2（07：00-09：00）和ZT 12-ZT 14（19：00-21：00）期间ACC PN的动态钙活性（参见“基础”）。随后，将PSNL应用于这些小鼠，7天后，我们在相同时间点再次记录ACC PN的钙活性（参见“PSNL”，图1A-1C;视频S1）。为了研究ACC PN是否由于慢性疼痛或慢性疼痛诱导的失眠而特别活跃，我们选择了07：00-09：00的时间间隔，对应于PSNL小鼠中的失眠期，以及19：00-21：00，当幼稚和PSNL小鼠都清醒时（图S1 D）。有趣的是，当与幼稚小鼠相比时，我们观察到ACC PN的钙活性仅在失眠期（07：00-09：00）期间增加，而在生理活性期（19：00-21：00）期间没有增加（图1D和1 E）。此外，在睡眠丧失的轻阶段，我们注意到，相当大一部分（62%）的ACC PN显示出升高的钙活性相比，他们的活动PSNL手术前（图1F）。相比之下，在黑暗阶段的最初2小时期间，当假手术小鼠和PSNL小鼠都清醒时，PSNL小鼠中仅21%的ACC PN表现出钙活性增加（图1F）。这些发现表明，ACC PN异常激活，特别是在慢性疼痛引起的失眠PSNL小鼠。

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Video S1. In vivo calcium imaging of ACC PNs, related to Figure 1.

To further affirm the selective activation of ACC PNs by chronic-pain-induced insomnia, we examined whether the ACC PNs’ activity remained elevated when exposed to hypnotics (diazepam), analgesics (morphine), or a combined analgesic and hypnotic compound (gabapentin) (Figures 1G and 1H). Initially, we established that there are more active ACC PNs in chronic-pain-induced insomnia mice (PSNL) compared with naive mice (base, Figure 1I). Interestingly, we found that treatment with either diazepam or morphine did not significantly decrease the number of active PNs in the ACC compared with chronic-pain-induced insomnia mice (PSNL) without drug treatment (Figure 1I). Remarkably, gabapentin treatment significantly decreased the number of active PNs in the ACC, comparable to the levels observed in naive mice (Figure 1I). We further assessed the calcium activity of single-unit ACC PNs during chronic-pain-induced insomnia (PSNL) and after treatment with diazepam, morphine, or gabapentin (Figure 1J). Consistently, the calcium activity of ACC PNs was only reduced by gabapentin treatment (Figure 1K). These results provide additional evidence supporting the notion that ACC PNs are specifically activated by chronic-pain-induced insomnia.
为了进一步证实慢性疼痛诱导的失眠对ACC PN的选择性激活，我们检查了当暴露于催眠药（地西泮）、镇痛药（吗啡）或联合的镇痛和催眠化合物（加巴喷丁）时ACC PN的活性是否保持升高（图1G和1H）。最初，我们确定了与幼稚小鼠相比，慢性疼痛诱导的失眠小鼠（PSNL）中存在更多活性ACC PN（基础，图1I）。有趣的是，我们发现，与没有药物治疗的慢性疼痛诱导的失眠小鼠（PSNL）相比，用地西泮或吗啡治疗并没有显著减少ACC中活性PN的数量（图1I）。值得注意的是，加巴喷丁治疗显著降低了ACC中活性PN的数量，与在幼稚小鼠中观察到的水平相当（图1I）。我们进一步评估了慢性疼痛诱导的失眠（PSNL）期间和地西泮、吗啡或加巴喷丁治疗后单单位ACC PN的钙活性（图1J）。一致地，ACC PN的钙活性仅通过加巴喷丁处理降低（图1K）。这些结果提供了额外的证据支持ACC PN是由慢性疼痛引起的失眠特异性激活的观点。

To investigate the aberrant activity of ACC PNs, we conducted electrophysiological recordings to examine the excitatory inputs to ACC PNs. ACC PNs were labeled by injecting AAV-DIO-mCherry into the ACC of CaMKII-Cre mice (Figures S2A and S2B). Acute brain tissues were collected during 07:00–09:00 and 19:00–21:00 in both PSNL and sham mice to align with the conducted calcium imaging procedures. Remarkably, we observed a significant increase in the frequency, but not the amplitude, of miniature excitatory postsynaptic currents (mEPSCs) in ACC PNs from brain tissues collected during 07:00–09:00 in PSNL mice (Figures S2C–S2E) compared with sham mice. However, there was no such difference observed during 19:00–21:00 (Figures S2F–S2H). These findings suggest an elevated presynaptic excitatory input to ACC PNs specifically during chronic-pain-induced insomnia. Taken together, these results show that the hyperactivity of ACC PNs is selectively related to chronic-pain-induced insomnia.
为了研究ACC PN的异常活动，我们进行了电生理记录，以检查对ACC PN的兴奋性输入。通过将AAV-DIO-mCherry注射到CaMKII-Cre小鼠的ACC中来标记ACC PN（图S2 A和S2 B）。在07：00-09：00和19：00-21：00期间收集PSNL和假手术小鼠的急性脑组织，以与进行的钙成像程序一致。值得注意的是，与假手术小鼠相比，我们观察到来自PSNL小鼠中07：00-09：00期间收集的脑组织的ACC PN中的微型兴奋性突触后电流（mEPSC）的频率显著增加，但幅度没有显著增加（图S2 C-S2 E）。然而，在19：00-21：00期间未观察到此类差异（图S2 F-S2 H）。这些发现表明，在慢性疼痛引起的失眠症，特别是突触前兴奋性输入到ACC PNs。总之，这些结果表明，ACC PN的过度活跃是选择性相关的慢性疼痛引起的失眠。

ACC PNs are required for chronic-pain-induced insomnia
慢性疼痛引起的失眠需要ACC PN

Although the correlation of hyperactivity of ACC PNs and chronic-pain-induced insomnia has been indicated by in vivo calcium imaging, the causal role is unclear. To demonstrate the necessity of ACC PNs in chronic-pain-induced insomnia, we ablated ACC PNs by cell-type-specific caspase-3 expression. AAV-hSyn-DIO-caspase-3 (mixed with AAV-hSyn-DIO-EGFP) was injected into the ACC of CaMKII-Cre mice, and AAV-hSyn-DIO-EGFP was injected as the control (Figure 2A). GFP-positive neurons were ablated in the ACC by caspase-3 (Figure 2B). Von Frey mechanical thresholds and sleep duration were assessed 3 weeks after virus injection in pain-free (naive) mice, prior to the application of PSNL in both GFP-control and caspase-3 mice. 1 week after PSNL, the same GFP-control and caspase-3 mice were re-evaluated for mechanical thresholds and sleep duration. The ablation of ACC PNs only resulted in elevated hind paw withdrawal thresholds in mice subjected to PSNL, but not in naive mice (Figure 2C). Importantly, the mechanical pain thresholds in PSNL mice with ACC PN ablation only showed a partial restoration toward baseline levels, suggesting that the elimination of ACC PNs relieved, but did not completely alleviate, mechanical allodynia in PSNL mice. Strikingly, EEG/electromyogram (EMG) recordings showed that ablation of ACC PNs completely abolished chronic-pain-induced insomnia in PSNL mice, decreasing the time of wakefulness in the first 2 h after light on (ZT0–ZT2), 12-h (ZT0–ZT12) and 24-h periods (ZT0–ZT24), and increasing NREM sleep for 2 and 24 h (ZT0–ZT24) after light on (Figures 2D and 2F). Interestingly, lesions of ACC PNs slightly decreased wakefulness in the dark phase of naive mice (Figures 2E and 2F), suggesting that ACC PNs may be involved in maintaining wakefulness. Surprisingly, unilateral lesion of ACC PNs, either contralateral or ipsilateral to sciatic nerve ligation, only resulted in a partial alleviation of insomnia in PSNL mice (Figure S3), probably due to diverse input pathways to the bilateral ACC. Taken together, these results show that chronic-pain-induced sleep loss may rely on ACC PNs in PSNL mice.
尽管体内钙成像表明ACC PN的过度活跃与慢性疼痛引起的失眠相关，但因果关系尚不清楚。为了证明ACC PN在慢性疼痛诱导的失眠中的必要性，我们通过细胞类型特异性caspase-3表达来消融ACC PN。将AAV-hSyn-DIO-caspase-3（与AAV-hSyn-DIO-EGFP混合）注射到CaMKII-Cre小鼠的ACC中，并且注射AAV-hSyn-DIO-EGFP作为对照（图2A）。通过半胱天冬酶-3消融ACC中的GFP阳性神经元（图2B）。在GFP对照和半胱天冬酶-3小鼠中应用PSNL之前，在无痛（未处理）小鼠中注射病毒后3周评估Von Frey机械阈值和睡眠持续时间。PSNL后1周，重新评估相同的GFP对照和半胱天冬酶-3小鼠的机械阈值和睡眠持续时间。ACC PN的消融仅导致经历PSNL的小鼠中后爪缩回阈值升高，但在未处理小鼠中不升高（图2C）。重要的是，ACC PN消融的PSNL小鼠的机械疼痛阈值仅显示出向基线水平的部分恢复，表明ACC PN的消除缓解了PSNL小鼠的机械异常性疼痛，但没有完全缓解。引人注目的是，EEG/肌电图（EMG）记录显示，ACC PN的消融完全消除了PSNL小鼠中慢性疼痛诱导的失眠，减少了光照后前2小时（ZT 0-ZT 2）、12小时（ZT 0-ZT 12）和24小时（ZT 0-ZT 24）的觉醒时间，并增加了光照后2小时和24小时（ZT 0-ZT 24）的NREM睡眠（图2D和2F）。有趣的是，ACC PN的损伤轻微降低了幼稚小鼠在黑暗期的觉醒（图2 E和2F），表明ACC PN可能参与维持觉醒。令人惊讶的是，对侧或同侧坐骨神经结扎的ACC PN的单侧损伤仅导致PSNL小鼠中失眠的部分缓解（图S3），这可能是由于双侧ACC的不同输入途径。总之，这些结果表明慢性疼痛诱导的睡眠丧失可能依赖于PSNL小鼠中的ACC PN。

Activation of ACC PNs is sufficient to induce sleep loss in naive mice
ACC PN的激活足以诱导幼稚小鼠的睡眠丧失

To further explore the causal role of hyperactivity of ACC PNs and chronic-pain-induced sleep disorders, we employed chemogenetics to mimic the aberrant activation of ACC PNs after PSNL. AAV-hSyn-DIO-hM3Dq-mCherry was bilaterally injected into the ACC of CaMKII-Cre naive (pain-free) mice (Figures 3A and 3B). Chemogenetic activation was validated by c-Fos labeling (Figure 3C). Activation of ACC PNs by clozapine-N-oxide (CNO) administration only slightly decreased mechanical pain thresholds, without a statistical significance (p = 0.10, Figure 3D), but significantly increased wakefulness for 4 h in CaMKII-Cre naive mice (Figures 3E–3G). Specifically, chemogenetic activation of ACC PNs induced an 85.5% increase in wakefulness and a 52.4% decrease in NREM sleep (07:00–11:00, Figures 3F and 3G), mimicking the difficulty of falling asleep in chronic pain mice. EEG power spectra of NREM sleep showed no difference in EEG power in NREM sleep or wakefulness from 07:00 to 11:00 (Figures 3H and 3I). As a control, chemogenetic activation of ACC PNs in the dark phase only slightly increased time of wakefulness when mice are physiologically awake (Figures S4A–S4C), suggesting that activation of ACC PNs does not robustly promote wakefulness in the dark phase. The same dosage of CNO (1 mg/kg) treatment in mCherry control mice did not change mechanical pain thresholds or sleep (Figures S4D–S4F). These results indicate that activation of ACC PNs in naive mice mimics chronic-pain-induced insomnia but not allodynia.
为了进一步探讨ACC PN过度活跃和慢性疼痛诱导的睡眠障碍的因果关系，我们采用化学遗传学来模拟PSNL后ACC PN的异常激活。将AAV-hSyn-DIO-hM 3Dq-mCherry双侧注射到CaMKII-Cre未处理（无痛）小鼠的ACC中（图3A和3B）。通过c-Fos标记验证化学发生激活（图3C）。通过施用氯氮平-N-氧化物（CNO）激活ACC PN仅略微降低机械疼痛阈值，没有统计学显著性（p = 0.10，图3D），但显著增加CaMKII-Cre未处理小鼠的觉醒4小时（图3E-3G）。具体地，ACC PN的化学发生活化诱导觉醒增加85.5%和NREM睡眠减少52.4%（07：00-11：00，图3F和3G），模拟慢性疼痛小鼠入睡的困难。 NREM睡眠的EEG功率谱显示从07：00至11：00 NREM睡眠或觉醒中的EEG功率没有差异（图3 H和3 I）。作为对照，当小鼠生理上清醒时，在黑暗阶段中ACC PN的化学发生活化仅略微增加觉醒时间（图S4 A-S4 C），表明ACC PN的活化在黑暗阶段中不会稳健地促进觉醒。在mCherry对照小鼠中相同剂量的CNO（lmg/kg）治疗不改变机械疼痛阈值或睡眠（图S4 D至图S4 F）。这些结果表明，在幼稚小鼠中ACC PN的激活模拟慢性疼痛诱导的失眠，但不是异常性疼痛。

Taken together, the hyperactivity of ACC PNs plays a key role in controlling chronic-pain-induced insomnia in PSNL mice.
总之，ACC PN的过度活跃在控制PSNL小鼠慢性疼痛诱导的失眠中起着关键作用。

Hyperactivity of ACC PNs increases wakefulness through the DMS pathway
ACC PN的过度活跃通过DMS途径增加觉醒

The ACC is not treated as a dominant sleep-wake regulation region; thus, it is unclear how hyperactivity of ACC PNs induced insomnia in chronic pain. The most intense output of ACC PNs is the DMS, which plays a curial role in sleep-wake regulation.¹⁴^,¹⁵ To confirm the functional connection of ACC PNs and DMS neurons, we optogenetically mapped ACC-DMS connections by electrophysiological recordings in brain slices of CaMKII-Cre mice (Figure S5A). Optogenetic stimulation of terminals of ACC PNs was applied in the DMS and responses from DMS neurons were recorded. The DMS neurons displayed typical morphology and electrophysiological properties of MSNs (Figures S5B and S5C). In total, 26 DMS MSNs were recorded and all neurons responded to blue light stimulation with spikes in the cell-attached mode (Figure S5D). The light-evoked EPSCs were blocked by α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) antagonist NBQX and N-methyl-D-aspartate receptor (NMDAR) antagonist APV (Figure S5E). The mean latency was less than 5 ms (Figure S5F), indicating direct excitatory connections between ACC PNs and DMS MSNs.
ACC没有被视为一个占主导地位的睡眠-觉醒调节区域，因此，目前还不清楚如何过度活跃的ACC PN引起失眠的慢性疼痛。ACC PNs最强的输出是DMS，它在睡眠-觉醒调节中起着重要作用。为了确认ACC PN和DMS神经元的功能连接，我们通过CaMKII-Cre小鼠脑切片中的电生理记录来光遗传学地映射ACC-DMS连接（图S5 A）。在DMS中应用ACC PN终末的光遗传刺激，并记录DMS神经元的反应。DMS神经元显示出MSN的典型形态和电生理特性（图S5 B和S5 C）。总共记录了26个DMS MSN，并且所有神经元都以细胞附着模式对具有尖峰的蓝光刺激作出响应（图S5 D）。光诱发的EPSC被α-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体（AMPAR）拮抗剂NBQX和N-甲基-D-天冬氨酸受体（NMDAR）拮抗剂APV阻断（图S5 E）。平均潜伏期小于5 ms（图S5 F），表明ACC PN和DMS MSN之间的直接兴奋性连接。

To elucidate the ACC-DMS circuit in mediating wakefulness, we optogenetically stimulated the ACC-DMS pathway in vivo (Figures 4A and 4B). Optogenetic activation of ACC-DMS projections slightly decreased mechanical pain thresholds without statistical difference in naive mice (Figure 4C). However, blue light stimulation in the DMS frequency- and latency-dependently induced transitions from NREM sleep to wakefulness, while no significant changes were observed following yellow light stimulation as a control (Figures 4D and 4E). Chronic stimulation of the ACC-DMS circuit for 1 h (10 s ON/20 s OFF for 120 cycles) increased time of wakefulness by 280%, while NREM and REM sleep were decreased compared with yellow light controls (Figures 4F and 4G). Opto-stimulation in mCherry control mice did not change mechanical pain thresholds or sleep (Figures S4G–S4I). In addition to ACC-DMS projections, ACC-nucleus accumbens (NAc) projections are implicated in the regulation of chronic pain.²⁶ Nevertheless, optogenetic stimulation of ACC-NAc projections did not induce wakefulness (Figures S6).
为了阐明介导觉醒的ACC-DMS回路，我们在体内光遗传学刺激ACC-DMS途径（图4A和4 B）。ACC-DMS投射的光遗传激活略微降低了机械疼痛阈值，而在幼稚小鼠中没有统计学差异（图4C）。然而，DMS频率和潜伏期依赖性的蓝光刺激诱导从NREM睡眠到觉醒的转变，而在作为对照的黄光刺激后没有观察到显著变化（图4D和4 E）。与黄光对照相比，ACC-DMS回路的慢性刺激1小时（10秒开启/20秒关闭，120个循环）使觉醒时间增加280%，而NREM和REM睡眠减少（图4F和4G）。mCherry对照小鼠中的光刺激不改变机械疼痛阈值或睡眠（图S4 G-S4 I）。除了ACC-DMS投射之外，ACC-丘脑核（NAc）投射涉及慢性疼痛的调节。然而，ACC-NAc投射的光遗传学刺激不诱导觉醒（图S6）。

To demonstrate the necessity of ACC-DMS projections in controlling chronic-pain-induced insomnia, we selectively inhibited DMS-projecting ACC neurons by chemogenetics in PSNL mice (Figures 4H and 4I). Chemogenetic inhibition of DMS-projecting ACC neurons was validated by c-Fos labeling (Figures 4J and 4K). Strikingly, inhibition of DMS-projecting ACC neurons restored sleep loss and increased mean duration of NREM sleep in PSNL mice (Figures 4L–4N), but only slightly increased mechanical pain thresholds in PSNL mice (Figure 4O), without affecting locomotion (Figure 4P). These results indicate that hyperactivity of DMS-projecting ACC neurons induces insomnia in PSNL mice.
为了证明ACC-DMS投射在控制慢性疼痛诱导的失眠中的必要性，我们在PSNL小鼠中通过化学遗传学选择性地抑制投射DMS的ACC神经元（图4 H和4 I）。通过c-Fos标记验证DMS投射ACC神经元的化学发生抑制（图4J和4K）。引人注目的是，对投射DMS的ACC神经元的抑制恢复了PSNL小鼠的睡眠丧失并增加了NREM睡眠的平均持续时间（图4L-4 N），但仅略微增加了PSNL小鼠的机械疼痛阈值（图4 O），而不影响运动（图4P）。这些结果表明，在PSNL小鼠中，投射DMS的ACC神经元的过度活跃诱导失眠。

Increased excitability of DMS D1R-MSNs in chronic pain
慢性疼痛中DMS D1 R-MSN的兴奋性增加

In the DMS, two distinct populations of MSNs, namely the D1R-MSNs and D2R-MSNs, control arousal and sleep, respectively.¹⁴^,¹⁵ To explore how DMS MSNs mediate chronic-pain-induced insomnia, we measured the activity and synaptic plasticity of DMS D1R-MSNs and D2R-MSNs in chronic pain mice by in vitro electrophysiologic recording. We subjected transgenic mice expressing GFP in D2R-MSNs (D2R-EGFP mice) to identify D2R-MSNs, whereas DMS cells lacking GFP but exhibiting typical morphology and electrophysiological characteristics of MSNs were identified as D1R-MSNs (Figure 5A). Compared with the sham mice, the intrinsic excitability of D1R-MSNs, but not D2R-MSNs, was distinctly increased in PSNL mice (Figures 5B–5D). To assess the membrane excitability of D1R-MSNs in the PSNL mice, the spontaneous EPSCs (sEPSCs) and mEPSCs of postsynaptic AMPARs were analyzed. Notably, the amplitude of sEPSCs and mEPSCs was simultaneously increased in the D1R-MSNs of PSNL mice (Figures 5E, 5F, 5H, and 5I), indicating an increase in the numbers or functions of postsynaptic AMPARs of D1R-MSNs. More importantly, the frequency of sEPSCs and mEPSCs was also increased in D1R-MSNs in PSNL mice, indicating that chronic pain enhances the release of presynaptic glutamate to D1R-MSNs (Figures 5G and 5J). By contrast, neither frequency nor amplitude of sEPSCs and mEPSCs was changed in D2R-MSNs after PSNL (Figures S5G–S5L). These results suggest that chronic pain significantly increases the presynaptic excitatory inputs to DMS D1R-MSNs and changed postsynaptic AMPARs in PSNL mice.
在DMS中，两个不同的MSN群体，即D1 R-MSN和D2 R-MSN，分别控制唤醒和睡眠。 ¹⁴ ¹⁵ 为了探讨DMS MSNs如何介导慢性疼痛诱导的失眠，我们通过体外电生理记录测量了慢性疼痛小鼠DMS D1 R-MSNs和D2 R-MSNs的活性和突触可塑性。我们对在D2 R-MSN中表达GFP的转基因小鼠（D2 R-EGFP小鼠）进行实验以鉴定D2 R-MSN，而缺乏GFP但表现出MSN的典型形态和电生理学特征的DMS细胞被鉴定为D1 R-MSN（图5A）。与假手术小鼠相比，在PSNL小鼠中，D1 R-MSN而不是D2 R-MSN的内在兴奋性明显增加（图5 B-5D）。为了评估PSNL小鼠中D1 R-MSN的膜兴奋性，分析了突触后AMPAR的自发EPSC（sEPSC）和mEPSC。值得注意的是，在PSNL小鼠的D1 R-MSN中sEPSC和mEPSC的幅度同时增加（图5E、5 F、5 H和5I），表明D1 R-MSN的突触后AMPAR的数量或功能增加。更重要的是，在PSNL小鼠的D1 R-MSN中sEPSC和mEPSC的频率也增加，表明慢性疼痛增强了突触前谷氨酸向D1 R-MSN的释放（图5G和5 J）。相比之下，在PSNL后，D2 R-MSN中sEPSC和mEPSC的频率和振幅均未改变（图S5 G-S5 L）。这些结果表明，慢性疼痛显着增加突触前兴奋性输入DMS D1 R-MSNs和改变突触后AMPAR在PSNL小鼠。

Increased synaptic plasticity of ACC-DMS D1R-MSNs in chronic pain
慢性疼痛中ACC-DMS D1 R-MSN的突触可塑性增加

Next, we tested whether PSNL-increased presynaptic glutamate inputs to DMS D1R-MSNs are from ACC PNs. We first investigated the long-term potentiation (LTP) in ACC PNs to DMS MSNs’ synapses to determine whether chronic pain would contribute to the changes in corticostriatal synaptic plasticity in PSNL mice. High-frequency stimulation was applied in the ACC using an electrode to trigger LTP in DMS MSNs in acute slices from D2R-EGFP mice, 7–14 days after sham/PSNL administration (Figures 6A and 6B). In PSNL mice, AMPAR-dependent LTP increased in DMS D1R-MSNs but reduced in D2R-MSNs (Figures 6C and 6D), indicating increased plasticity of ACC PNs-DMS D1R-MSNs. Simultaneously, the increased LTP in D1R-MSNs was associated with a reduction in the paired-pulse ratio (PPR) (Figure 6E), indicating that the presynaptic ACC glutamate release probability was increased in PSNL mice. In contrast, the increased PPR of D2R-MSNs may be responsible for the decreased LTP in PSNL mice (Figure 6F).
接下来，我们测试了PSNL增加的突触前谷氨酸对DMS D1 R-MSNs的输入是否来自ACC PN。我们首先研究了PSNL小鼠ACC PNs到DMS MSNs突触的长时程增强（LTP），以确定慢性疼痛是否会导致皮质纹状体突触可塑性的变化。在假手术/PSNL施用后7-14天，使用电极在ACC中施加高频刺激以触发来自D2 R-EGFP小鼠的急性切片中DMS MSN中的LTP（图6A和6 B）。在PSNL小鼠中，AMPAR依赖性LTP在DMS D1 R-MSN中增加，但在D2 R-MSN中减少（图6C和6D），表明ACC PNs-DMS D1 R-MSN的可塑性增加。同时，D1 R-MSN中LTP的增加与成对脉冲比（PPR）的降低相关（图6 E），表明PSNL小鼠中突触前ACC谷氨酸释放概率增加。相比之下，D2 R-MSN的PPR增加可能是PSNL小鼠中LTP降低的原因（图6 F）。

In addition to the adaptation of AMPARs and presynaptic neurotransmitters, NMDARs are also important elements in pain signaling.²⁷^,²⁸ Thus, we checked the ratio of NMDAR-mediated excitatory currents to AMPAR-mediated EPSCs (NMDAR/AMPAR ratio) by using optogenetic approaches to examine the specific glutamatergic afferents of ACC PNs to DMS MSNs. AAV-based tracing confirmed the morphological associations of ACC PNs and DMS D1R-/D2R-MSNs (Figures 6G and 6H). We, therefore, injected AAV-CaMKII-ChR2-mCherry into the ACC and stimulated ACC-DMS terminals with blue light to induce NMDAR/AMPAR currents. As a result, the NMDAR/AMPAR ratio was significantly higher in D1R-MSNs from PSNL mice but was not changed in D2R-MSNs (Figures 6I and 6J), suggesting that chronic pain increased NMDAR-mediated synaptic transmission in D1R-MSNs. These results thus far suggested that the adaptation of AMPARs, presynaptic neurotransmitters, and NMDARs provide a molecular basis for the changes in corticostriatal synaptic plasticity in chronic pain.
除了AMPAR和突触前神经递质的适应外，NMDAR也是疼痛信号传导的重要元件。因此，我们通过使用光遗传学方法检查ACC PN到DMS MSN的特异性神经元传入，检查了NMDAR介导的兴奋性电流与AMPAR介导的EPSC的比率（NMDAR/AMPAR比率）。基于AAV的追踪证实了ACC PN和DMS D1 R-/D2 R-MSN的形态学关联（图6 G和6 H）。因此，我们将AAV-CaMK II-ChR 2-mCherry注射到ACC中，并用蓝光刺激ACC-DMS末端以诱导NMDAR/AMPAR电流。结果，NMDAR/AMPAR比率在来自PSNL小鼠的D1 R-MSN中显著更高，但在D2 R-MSN中没有变化（图6 I和6 J），表明慢性疼痛增加了D1 R-MSN中NMDAR介导的突触传递。这些结果表明，AMPAR、突触前神经递质和NMDAR的适应为慢性疼痛中皮质纹状体突触可塑性的变化提供了分子基础。

Furthermore, we evaluated whether synaptic plasticity occurred at the onset of neuropathic pain in PSNL mice. Slices were prepared from animals 3–4 days after PSNL, and AMPAR-dependent LTP and PPR were measured in these mice. In contrast to the changes found 7–14 days after PSNL, none of these measures were changed in the early phase (3–4 days) of the neuropathic pain onset (Figures S7A–S7H). Together, these results indicate that chronic pain progressively induced significant synaptic plasticity of ACC-DMS D1R-MSNs synapse.
此外，我们评估了PSNL小鼠神经病理性疼痛发作时是否发生突触可塑性。从PSNL后3-4天的动物制备切片，并在这些小鼠中测量AMPAR依赖性LTP和PPR。与PSNL后7-14天发现的变化相反，在神经性疼痛发作的早期阶段（3-4天），这些测量值都没有变化（图S7 A-S7 H）。总之，这些结果表明慢性疼痛进行性诱导ACC-DMS D1 R-MSN突触的显著突触可塑性。

DMS D1R-MSNs mediate chronic-pain-induced insomnia
DMS D1 R-MSN介导慢性疼痛诱导的失眠

To determine whether activation of DMS D1R-MSNs is necessary for chronic-pain-induced insomnia, we injected AAV-DIO-hM4Di-mCherry into the DMS to silence D1R-MSNs selectively (Figures 7A and 7B). The inhibitory effect was validated by slice electrophysiological recordings (Figure 7C). Interestingly, we observed only a trend toward increased mechanical thresholds in PSNL mice when inhibiting DMS D1R-MSNs, without a statistical significance (Figure 7D). Importantly, chemogenetic inhibition of D1R-MSNs in the DMS decreased wakefulness for 2 h after CNO administration (07:00–09:00), concomitant with an increase in NREM sleep in PSNL, but not naive, mice as compared with vehicle controls (Figures 7E and 7F). These results indicate that inhibition of DMS D1R-MSNs partially blocked chronic-pain-induced insomnia.
为了确定DMS D1 R-MSN的激活是否是慢性疼痛诱导的失眠所必需的，我们将AAV-DIO-hM 4Di-mCherry注射到DMS中以选择性地沉默D1 R-MSN（图7A和7 B）。通过切片电生理记录验证抑制作用（图7 C）。有趣的是，当抑制DMS D1 R-MSN时，我们仅观察到PSNL小鼠中机械阈值增加的趋势，而没有统计学显著性（图7 D）。重要的是，与媒介物对照相比，DMS中D1 R-MSNs的化学发生抑制在CNO施用后减少觉醒2小时（07：00-09：00），伴随着PSNL小鼠中NREM睡眠的增加，但不伴随着幼稚小鼠中NREM睡眠的增加（图7 E和7 F）。这些结果表明，DMS D1 R-MSN的抑制部分阻断了慢性疼痛诱导的失眠。

Discussion 讨论

More than half of patients with chronic pain complain of sleep loss, but neural circuits underlying chronic-pain-induced sleep disorders are poorly understood. In this study, we revealed that the hyperactivity of ACC PNs plays a key role in chronic-pain-induced insomnia through DMS projections (Figure S7I). Hyperactivity of ACC PNs occurred selectively during periods of chronic-pain-induced insomnia, as demonstrated by in vivo calcium imaging. Furthermore, cell-type-selective ablation of ACC PNs in PSNL mice and chemogenetic activation of ACC PNs in the naive mice demonstrated that hyperactivity of ACC PNs is sufficient and necessary for chronic-pain-induced insomnia. Importantly, we dissected the ACC PNs to DMS pathway in regulating chronic-pain-induced insomnia and found enhanced plasticity of ACC-DMS D1R-MSNs in PSNL mice. We further demonstrated that inhibition of DMS D1R-MSNs alleviates chronic-pain-induced insomnia. Our findings address a long-standing gap in the understanding of how chronic pain induces sleep disorders by showing that ACC PN hyperactivity selectively controls chronic-pain-induced insomnia via reshaping the plasticity of ACC PNs to DMS D1R-MSNs synapses.
超过一半的慢性疼痛患者抱怨睡眠不足，但对慢性疼痛引起的睡眠障碍的神经回路知之甚少。在这项研究中，我们揭示了ACC PN的过度活跃通过DMS投射在慢性疼痛诱导的失眠中起关键作用（图S7 I）。体内钙离子成像显示，在慢性疼痛引起的失眠期间，ACC PN选择性过度活跃。此外，在PSNL小鼠中ACC PN的细胞类型选择性消融和在幼稚小鼠中ACC PN的化学发生激活证明了ACC PN的过度活跃对于慢性疼痛诱导的失眠是充分和必要的。重要的是，我们剖析了调节慢性疼痛诱导的失眠症的ACC PNs到DMS通路，并发现PSNL小鼠中ACC-DMS D1 R-MSNs的可塑性增强。我们进一步证明了DMS D1 R-MSN的抑制可减轻慢性疼痛诱导的失眠。我们的研究结果解决了长期存在的理解慢性疼痛如何诱导睡眠障碍的差距，表明ACC PN多动通过重塑ACC PN到DMS D1 R-MSNs突触的可塑性来选择性地控制慢性疼痛诱导的失眠。

Our study identifies a central cortical region that specifically controls chronic-pain-induced insomnia. First, activity of ACC PNs was specifically increased in chronic-pain-induced insomnia, while reducing pain sensitivity or increasing sleep alone could not reverse the hyperactivity of ACC PNs during insomnia in PSNL mice. Second, when ACC PNs were ablated, chronic-pain-induced insomnia was completely blocked, while the mechanical pain thresholds remained lower than those of mice without chronic pain. Third, activation of ACC PNs in naive mice induced sleep loss but did not decrease mechanical pain thresholds. These results highlight the crucial involvement of ACC PNs in insomnia specifically associated with chronic pain. Notably, analgesics such as morphine and gabapentin exhibit intricate mechanisms in influencing the activity of ACC PNs, potentially extending beyond the realm of insomnia induced by chronic pain. It will be interesting to test the activity of ACC PNs during treatment with peripheral analgesics in future studies. The ACC is known to be one of the most consistently activated brain regions in response to chronic pain, and it also regulates pain sensitivity and affective behaviors,²⁹^,³⁰ receiving numerous excitatory afferents from cortical areas, the basal forebrain, thalamus, hypothalamus, and the monoaminergic centers in the brainstem.³¹ This intricate network may contribute to the overactivation of ACC PNs in a chronic pain state.
我们的研究确定了一个中央皮层区域，专门控制慢性疼痛引起的失眠。首先，ACC PN的活性在慢性疼痛诱导的失眠中特异性增加，而单独降低疼痛敏感性或增加睡眠不能逆转PSNL小鼠失眠期间ACC PN的过度活跃。其次，当ACC PN被消融时，慢性疼痛诱导的失眠被完全阻断，而机械疼痛阈值仍然低于没有慢性疼痛的小鼠。第三，在未处理的小鼠中激活ACC PN诱导睡眠丧失，但不降低机械痛阈值。这些结果强调了ACC PN在失眠中的重要作用，特别是与慢性疼痛相关。值得注意的是，镇痛药如吗啡和加巴喷丁在影响ACC PN的活性方面表现出复杂的机制，可能超出慢性疼痛引起的失眠的范围。在未来的研究中，检测外周镇痛药治疗期间ACC PN的活性将是有趣的。已知ACC是响应慢性疼痛最持续激活的脑区之一，并且它还调节疼痛敏感性和情感行为， ²⁹ ³⁰ 接收来自皮质区、基底前脑、丘脑、下丘脑和脑干中的单胺能中心的许多兴奋性传入。 ³¹ 这个复杂的网络可能导致慢性疼痛状态下ACC PN的过度激活。

The ACC sends the densest output to the DMS, which modulates action,³² motivation, and decision-making.³³ DMS D1R-MSNs and D2R-MSNs are innervated by ACC PNs, but our results showed that hyperactivity of ACC PNs in chronic pain selectively increases excitatory connections with DMS D1R-MSNs, resulting in increased sEPSCs and mEPSCs, LTP, and the NMDAR/AMPAR ratio and decreased PPR in DMS D1R-MSNs, while D2R-MSNs were lacking these changes. Interestingly, the NAc in the ventral striatum also receives glutamatergic ACC inputs and controls the social transfer of pain.²⁶ Lower mEPSCs, with a reduced AMPAR/NMDAR ratio from cortical stimulation, are found specifically in NAc D2R-MSNs in neuropathic pain model mice.³⁴ Moreover, decreased excitatory synaptic transmission in NAc D2R-MSNs is required for decreased motivation during chronic pain.³⁵ These findings indicate that the ACC-NAc pathway may be more central to the regulation of emotional aspects, whereas the ACC-DMS pathway appears to be selectively involved in insomnia in the context of chronic pain.
ACC将拒绝输出发送到DMS，DMS调节行动， ³² 动机和决策。 ³³ DMS D1 R-MSNs和D2 R-MSNs由ACC PN支配，但我们的结果表明，慢性疼痛中ACC PN的过度活跃选择性地增加了与DMS D1 R-MSNs的兴奋性连接，导致DMS D1 R-MSNs中sEPSC和mEPSC、LTP和NMDAR/AMPAR比率增加以及PPR降低，而D2 R-MSNs缺乏这些变化。有趣的是，腹侧纹状体中的NAc也接受神经元能ACC输入，并控制疼痛的社会转移。 ²⁶ 在神经性疼痛模型小鼠的NAc D2 R-MSN中特异性地发现较低的mEPSC，其具有来自皮质刺激的降低的AMPAR/NMDAR比率。此外，NAc D2 R-MSN中兴奋性突触传递的减少是慢性疼痛期间动机减少所必需的。这些发现表明，ACC-NAc通路可能对情绪方面的调节更为重要，而ACC-DMS通路似乎选择性地参与慢性疼痛背景下的失眠。

Our finding that chemogenetic inhibition of DMS D1R-MSNs did not completely block chronic-pain-induced insomnia could be due to incomplete manipulation of the DMS D1R-MSN population or diffuse network effects. In recent decades, several wake-promoting brain regions were found to be directly activated during chronic pain, such as the locus coeruleus,³⁶^,³⁷^,³⁸ dorsal raphe,⁴^,³⁹ and parabrachial nuclei (PB).⁴⁰ For example, activation of glutamatergic lateral PB neurons induces neuropathic pain-like behavior⁴¹^,⁴²^,⁴³ and promotes wakefulness.⁴⁴^,⁴⁵^,⁴⁶ However, it remains uncertain whether neurons in these brain regions activated by chronic pain also specifically regulate insomnia. Furthermore, chronic pain mice do not exhibit heightened wakefulness during the dark phase, mirroring the behavior of chronic pain patients who do not display increased activity during the daytime. This implies that chronic-pain-induced insomnia may not be directly regulated by these physiologically powerful wake-promoting neurons. Therefore, further investigation is needed to determine whether these wake-promoting neurons specifically become activated in chronic pain. It is also important to explore whether the loss of function in these regions can fully block insomnia without affecting pain sensitivity.
我们发现DMS D1 R-MSN的化学发生抑制不能完全阻断慢性疼痛诱导的失眠可能是由于DMS D1 R-MSN群体的不完全操纵或扩散网络效应。近几十年来，一些促进唤醒的脑区被发现在慢性疼痛期间被直接激活，例如蓝斑、 ³⁶ ³⁷ ³⁸ 中缝背核、 ⁴ ³⁹ 和臂旁核（PB）。 ⁴⁰ 例如，多巴胺能外侧PB神经元的激活诱导神经性疼痛样行为 ⁴¹ ⁴² ⁴³ 并促进觉醒。 ⁴⁴ ⁴⁵ ⁴⁶ 然而，仍然不确定这些大脑区域中被慢性疼痛激活的神经元是否也专门调节失眠。此外，慢性疼痛小鼠在黑暗阶段没有表现出高度的觉醒，反映了慢性疼痛患者在白天没有表现出增加的活动的行为。这意味着慢性疼痛引起的失眠可能不直接由这些生理上强大的唤醒促进神经元调节。因此，需要进一步的研究来确定这些促进唤醒的神经元是否在慢性疼痛中被激活。同样重要的是要探索这些区域的功能丧失是否可以完全阻止失眠而不影响疼痛敏感性。

In chronic pain conditions, two distinct types of ACC neurons—GABAergic neurons and glutamatergic neurons—are both activated but play different roles in pain processing. ACC GABAergic neurons primarily regulate nociceptive hypersensitivity in conditions of low cortical activity.²⁴ Furthermore, sleep disturbances in a neuropathic-pain-like condition in the mouse are associated with altered GABAergic transmission in the cingulate cortex.⁴⁷ The interactions and local connections between these two types of neurons are likely more complex than simple direct activation or inhibition. Notably, certain GABAergic neurons can inhibit other GABAergic interneurons, leading to disinhibition of glutamatergic neurons.⁴⁸ This intricate balance between ACC GABAergic and glutamatergic neurons is crucial for normal physiological functioning. However, disruptions to this delicate balance can potentially result in allodynia, accompanied by symptoms such as insomnia and depression. Understanding these complex interactions between ACC GABAergic and glutamatergic neurons is vital for unraveling the mechanisms underlying chronic-pain-related symptoms.⁴⁹
在慢性疼痛条件下，两种不同类型的ACC神经元-GABA能神经元和多巴胺能神经元-都被激活，但在疼痛处理中发挥不同的作用。ACC GABA能神经元主要在皮质活动低的情况下调节伤害性超敏反应。此外，小鼠神经病理性疼痛样状态下的睡眠障碍与扣带皮层中GABA能传递的改变有关。#1这两种类型的神经元之间的相互作用和局部连接可能比简单的直接激活或抑制更复杂。值得注意的是，某些GABA能神经元可以抑制其他GABA能中间神经元，导致多巴胺能神经元的去抑制。ACC GABA能神经元和谷氨酸能神经元之间的这种复杂平衡对于正常的生理功能至关重要。然而，破坏这种微妙的平衡可能会导致异常性疼痛，并伴有失眠和抑郁等症状。了解ACC GABA能和谷氨酸能神经元之间的这些复杂的相互作用对于解开慢性疼痛相关症状的机制至关重要。 ⁴⁹

In summary, our study provides valuable insights into chronic-pain-induced insomnia and highlights the specific involvement of ACC PNs and the ACC-DMS D1R-MSNs’ synapse plasticity.
总之，我们的研究为慢性疼痛引起的失眠提供了有价值的见解，并强调了ACC PN和ACC-DMS D1 R-MSN的突触可塑性的具体参与。

STAR★Methods 星星★方法

Key resources table 关键资源表

REAGENT or RESOURCE 试剂或资源	SOURCE	IDENTIFIER
Antibodies 抗体
Rabbit polyclonal anti-Fos 兔抗Fos多克隆抗体	Millipore	Cat#ABE457; RRID: 目录号ABE 457; RRID： AB_2631318
Alexa Fluor 647 Donkey anti-Rabbit Alexa Fluor 647驴抗兔	Jackson ImmunoResearch 杰克逊免疫研究	Cat#: 711-606-152; RRID: AB_2340625 目录号：711-606-152; RRID：AB_2340625
Bacterial and virus strains 细菌和病毒株
AAV2/9-hSyn-DIO-hM3Dq-mCherry	Taitool Bioscience 泰图生物科技	Cat #S0192-9 目录号S 0192 -9
AAV2/9-hSyn-DIO-hM4Di-mCherry	Taitool Bioscience 泰图生物科技	Cat #S0193-9 目录号S 0193 -9
AAV9-hSyn-DIO-hChR2(H134R)-mCherry AAV9-hSyn-DIO-hChR2（H134R）-mCherry	Taitool Bioscience 泰图生物科技	Cat #S0165-9 目录号S 0165 -9
AAV9-hSyn-CaMKII-hChR2(H134R)-eYFP AAV9-hSyn-CaMKII-hChR2（H134R）-eYFP	Brain VTA 脑VTA	Cat #PT0296 目录号PT 0296
AAV9-hSyn-CaMKII-hChR2(H134R)-mCherry AAV9-hSyn-CaMKII-hChR2（H134R）-mCherry	Brain VTA 脑VTA	Cat #PT0296 目录号PT 0296
AAV2/9-CAG-DIO-Caspase-3	Taitool Bioscience 泰图生物科技	Cat # S0236-1 目录号S 0236 -1
AAV2/9-hSyn-DIO-eGFP	Taitool Bioscience 泰图生物科技	Cat # S0789-9 目录号S 0789 -9
AAV2/9-hSyn-DIO-mCherry	Taitool Bioscience 泰图生物科技	Cat #S0240-9 目录号S 0240 -9
AAV2/9-hSyn-FLEX-GCaMP6f	Taitool Bioscience 泰图生物科技	Cat #S0227-9 目录号S 0227 -9
scAAV2/2-Retro-hSyn-Cre-pA scAAV 2/2-逆转录-hSyn-Cre-pA	Taitool Bioscience 泰图生物科技	Cat #S0292-2R 目录号S 0292 - 2 R
Chemicals, peptides, and recombinant proteins 化学品、多肽和重组蛋白
NBQX	Tocris	Cat #0373 目录号0373
D-APV	Tocris	Cat #0106 目录号0106
biocytin	Sigma	Cat #B4261 目录号B4261
Clozapine-N-oxide 氯氮平-n-氧化物	LKT Laboratories LKT实验室	Cat #C4759 目录号C4759
Diazepam 安定	Tianjin Pharmaceutical Co., Ltd., China 天津医药股份有限公司有限公司，中国	N/A
Gabapentin	Chongqing Sai Wei Pharmaceutical Co. Ltd. , China 中国重庆赛威制药有限公司	N/A
Morphine 吗啡	Shenyang NO.1 Pharmaceutical Co., Ltd., China 沈阳第一制药有限公司有限公司，中国	N/A
Experimental models: Organisms/strains 实验模型：微生物/菌株
Mouse: CaMKII-Cre mice 小鼠：CaMKII-Cre小鼠	Jackson laboratory 杰克逊实验室	JAX stock #017535 JAX库存编号017535
Mouse: D1R-Cre mice 小鼠：D1 R-Cre小鼠 B6.FVB(Cg)-Tg(Drd1a-Cre) B6.FVB（Cg）-Tg（Drd1a-Cre）	Mutant Mouse Resource Research Centers 突变小鼠资源研究中心	Dr. Jiang-Fan Chen 博士陈江帆
D2R-eGFP mice D2 R-eGFP小鼠	Jackson Laboratory (USA) 杰克逊实验室（美国）	JAX stock #030537 JAX库存编号030537
D1R-tdTomato mice D1 R-tdTomato小鼠	Jackson Laboratory (USA) 杰克逊实验室（美国）	JAX stock #016204 JAX库存编号016204
Software and algorithms 软件和算法
SleepSign	Kissei Comtec 基赛康姆泰克	RRID: SCR_018200 RRID：SCR_018200
Spike2 Software Spike 2软件	Cambridge Electronic Design 剑桥电子设计	RRID: SCR_000903 RRID：SCR_000903
nVista 3	Inscopix Insopix	RRID:SCR_11286205 RRID：SCR_11286205
MATLAB R2014b	Mathworks	RRID:SCR_001622 RRID：SCR_001622
Igor Pro	Wavemetrics	RRID: SCR_000325 RRID：SCR_000325
FIJI	ImageJ	RRID: SCR_002285 RRID：SCR_002285
pClamp 10.3	Molecular Devices	RRID: SCR_011323 RRID：SCR_011323
Olympus FluoView	Olympus 奥林巴斯	RRID: SCR_014215 RRID：SCR_014215
GraphPad Prism 8.0	Graphpad	RRID:SCR_002798 RRID：SCR_002798
Adobe Illustrator	Adobe Systems	RRID: SCR_010279 RRID：SCR_010279
Other 其他
microtome 切片机	Leica 徕卡	Cat #CM1950 目录号CM 1950
vibratome	Leica 徕卡	Cat#VT1200 目录号VT 1200
pipette puller 吸管拔出器	Narishige	Cat #PC-10 目录号PC-10

Resource availability 资源可用性

Lead contact 引线触点

Further information and requests for resources and reagents should be directed to and will be fulfilled by the Lead Contact, Ya-Dong Li (yadlee@126.com).
有关资源和试剂的更多信息和请求，请发送至主要联系人Ya-Dong Li（yadlee@126.com），并由其完成。

Materials availability 材料可用性

This study did not generate new unique reagents.
本研究未生成新的独特试剂。

Data and code availability
数据和代码可用性

•
All data reported in this paper will be shared by the lead contact upon request.
本文中报告的所有数据将根据要求由主要联系人共享。
•
This paper does not report original code.
本文没有报告原始代码。
•
Any additional information required to reanalyze the data reported in this paper is available from the lead contact upon request.
如需重新分析本文中报告的数据所需的任何其他信息，可向主要联系人索取。

Experimental model and study participant details
实验模型和研究参与者详细信息

Experimental animals 实验动物

Male and female mice with a body weight of 22–26 g (10–14 weeks old) were used in this study, but gender difference was not evaluated in this study. CaMKII-Cre mice (10–14 weeks old) were obtained from the Jackson Laboratory (Stock No: 017535). D1R-Cre (B6.FVB(Cg)-Tg(Drd1a-Cre) EY266Gsat/Mmucd, GENSAT) mice (10–14 weeks old) were kindly provided by Jiang-Fan Chen (Wenzhou Medical University). D1R-tdTomato mice (10–14 weeks old) were kindly provided by Ji Hu (ShanghaiTech University). D2R-EGFP mice (10–14 weeks old) were obtained from the Institute of Neuroscience, Chinese Academy of Science, Shanghai. The animals were maintained at room temperature (22 ± 0.5°C) and controlled humidity (60 ± 2%) under a 12-h light/12-h dark cycle (lights on at 07:00) and provided food and water ad libitum. No immune deficiencies or other health problems were observed in these lines, and all animals were experimentally and drug-naive before use. All experimental protocols were approved by the Medical Experimental Animal Administrative Committee of Fudan University.
本研究中使用体重为22-26 g（10-14周龄）的雄性和雌性小鼠，但本研究中未评价性别差异。CaMKII-Cre小鼠（10-14周龄）获自杰克逊实验室（库存号：017535）。D1 R-Cre（B6.FVB（Cg）-Tg（Drd 1a-Cre）EY 266 Gsat/Mmucd，GENSAT）小鼠（10-14周龄）由Jiang-Fan Chen（温州医科大学）友情提供。D1 R-tdTomato小鼠（10-14周龄）由Ji Hu（上海科技大学）友好提供。D2 R-EGFP小鼠（10-14周龄）获自中国科学院神经科学研究所，上海。将动物保持在室温（22 ± 0.5 ℃）和受控湿度（60 ± 2%）下，12小时光照/12小时黑暗循环（07：00开灯），并随意提供食物和水。在这些品系中未观察到免疫缺陷或其他健康问题，并且所有动物在使用前均为实验和药物初治动物。所有实验方案均经复旦大学医学实验动物管理委员会批准。

Method details 方法详情

EEG/EMG electrode-implantation surgery
EEG/EMG电极植入手术

Mice were anesthetized under 1.5−2.0% isoflurane in oxygen at a flow rate of 0.8 L/min and implanted with EEG and electromyogram (EMG) electrodes for polysomnographic recordings. Two stainless-steel screws were installed through the skull over the parietal and frontal cortices according to the brain atlas, which served as EEG electrodes. Two insulated, stainless-steel, Teflon-coated wire EMG electrodes were bilaterally inserted into the trapezius muscles. All the electrodes were gathered into a micro-connector and fixed to the skull with dental cement.
将小鼠在含1.5 - 2.0%异氟烷的氧气中以0.8 L/min的流速麻醉，并植入EEG和肌电图（EMG）电极进行多导睡眠图记录。根据脑图谱，将两个不锈钢螺钉穿过颅骨安装在顶叶和额叶皮质上，作为EEG电极。两个绝缘的不锈钢，聚四氟乙烯涂层的电线EMG电极被两侧插入到肌肉。所有的电极都被收集到一个微型连接器中，并用牙科粘固剂固定在头骨上。

Virus injection and fiber implantation
病毒注射和纤维植入

Under anesthesia, mice were placed in a stereotaxic frame (RWD, Shenzhen, China). AAVs were injected by a fine glass electrode with a 15–20 μm tip containing virus was inserted bilaterally into the ACC (AP +0.7mm; ML ±0.3 mm; DV -1.8 mm) or DMS (AP +0.7/1.1 mm; ML ±1.25 mm; DV -2.5 mm). A total of 100 nL virus was delivered into each site over a 10-min period via nitrogen-gas pulses using an air-compression system. For AAV-DIO-hM4Di-mCherry injection, 2 injections in each striatum and 4 injections in total for each mouse. The needle was left in place for 10 min to permit diffusion. For optogenetic stimulation of ACC-DMS terminals, bilateral optic fibers (diameters = 200 um) were planted above the DMS (AP +0.7 mm; ML ±1.25 mm; DV -2.2 mm). Mice that received injections were used for experiments at least 2 weeks after viral injection.
在麻醉下，将小鼠置于立体定位框架（RWD，Shenzhen，China）中。通过具有15-20 μm尖端的精细玻璃电极注射AAV，将含有病毒的尖端双侧插入ACC（AP +0.7mm; ML ± 0.3mm; DV-1.8mm）或DMS（AP +0.7/1.1mm; ML ± 1.25mm; DV-2.5mm）。使用空气压缩系统，通过氮气脉冲在10分钟内将总计100 nL病毒输送到每个部位。对于AAV-DIO-hM 4Di-mCherry注射，在每个纹状体中注射2次，并且对于每只小鼠总共注射4次。将针留在原位10分钟以允许扩散。对于ACC-DMS末端的光遗传学刺激，将双侧光纤（直径= 200 μ π ι）种植在DMS上方（AP +0.7mm; ML ± 1.25mm; DV-2.2mm）。接受注射的小鼠在病毒注射后至少2周用于实验。

EEG recordings and analysis
EEG记录和分析

EEG recording and analysis were performed as described previously.⁵⁰^,⁵¹ EEG and EMG signals were first amplified and filtered (EEG, 0.5–25 Hz; EMG, 20–200 Hz). All signals were digitized at 128 Hz and collected with Vital Recorder software (Kissei Comtec, Nagano, Japan). The raw EEG signal was passed through band-pass filters, which allowed the following frequency bands to be separated and displayed individually on four additional channels: delta (0.5–4 Hz), theta (4–8 Hz), alpha (8–12 Hz), and beta (12–20 Hz). The average peak-to-peak amplitude was automatically computed for each frequency band by SleepSign software. Absolute power spectra of the EEG signals were computed every 4 s from 0–25 Hz in steps of 0.25 Hz. For sleep amount analysis (conducted by SleepSign according to standard criteria⁵²^,⁵³). All scoring was automatic based on EEG and EMG waveforms in 4 s epochs. We defined wakefulness as desynchronized EEG and high levels of EMG activity, NREM sleep as synchronized, high-amplitude, low-frequency (0.5–4 Hz) EEG signals in the absence of motor activity, and REM sleep as having pronounced theta like (6–8 Hz) EEG activity and muscle atonia. Vigilance states assigned by SleepSign (Kissei Comtec, Nagano, Japan) were examined visually and manually corrected after automatic scoring.
如前所述进行EEG记录和分析。 ⁵⁰ ⁵¹ EEG和EMG信号首先被放大和滤波（EEG，0.5-25 Hz; EMG，20-200 Hz）。所有信号在128 Hz下数字化，并用Vital Recorder软件（Kissei Comtec，Nagano，Japan）收集。原始EEG信号通过带通滤波器，其允许以下频带被分离并在四个附加通道上单独显示：delta（0.5-4 Hz）、theta（4-8 Hz）、alpha（8-12 Hz）和beta（12-20 Hz）。通过SleepSign软件自动计算每个频带的平均峰间振幅。EEG信号的绝对功率谱以0.25 Hz的步长从0-25 Hz每4 s计算一次。用于睡眠量分析（由SleepSign根据标准标准 ⁵² ⁵³ 进行）。所有评分均基于4s时相的EEG和EMG波形自动进行。我们将觉醒定义为去兴奋化的EEG和高水平的EMG活动，将NREM睡眠定义为在没有运动活动的情况下同步的、高振幅的、低频（0.5-4 Hz）的EEG信号，并且将REM睡眠定义为具有明显的θ样（6- 8Hz）EEG活动和肌肉张力减退。目视检查SleepSign（Kissei Comtec，Nagano，Japan）指定的警戒状态，并在自动评分后手动纠正。

Neuropathic pain model and measurement of mechanical allodynia
神经病理性疼痛模型及机械性痛觉超敏的测定

Under anesthesia, mice received partial sciatic nerve injury (PSNL) and sham operation. Briefly, the right sciatic nerve was exposed and one-third to half of the nerve trunk was tightly ligated using a 6–0 silk suture. For the sham operation, the nerve was exposed without ligation. PSNL or sham mice were placed in separate home cages during the recovery period. and mechanical allodynia was measured as the hind paw-withdrawal response to von Frey-hair stimulation. The paw was touched with one of series of 8 von Frey filaments with logarithmically incremental hair stiffness (0.07, 0.16, 0.4, 0.6, 1.0, 1.4, 2.0, and 4.0 g). The von Frey filament was pressed perpendicular to the plantar surface with enough force to cause slight buckling, and was held for an additional 6 to 8 seconds. Stimuli were presented after various intervals (several seconds). Clear paw withdrawal, shaking, or licking was considered nociceptive responses. The hair force was increased or decreased according to the response. Ambulation was considered an ambiguous response, and in such cases, the stimulus was repeated.
在麻醉状态下，小鼠接受部分坐骨神经损伤（PSNL）和假手术。简单地说，暴露右侧坐骨神经，并使用6-0丝线将神经干的三分之一至一半紧紧结扎。对于假手术，暴露神经而不结扎。在恢复期间，将PSNL或假手术小鼠置于单独的饲养笼中。机械性异常性疼痛测量为对von Frey-毛发刺激的后爪缩回反应。用一系列8根von Frey细丝中的一根接触爪，所述细丝具有几何学上递增的毛发硬度（0.07、0.16、0.4、0.6、1.0、1.4、2.0和4.0 g）。用足够的力垂直于足底表面按压von Frey细丝以引起轻微屈曲，并保持另外6至8秒。在不同的间隔（几秒钟）后呈现刺激。明显的缩爪、摇晃或舔被认为是伤害性反应。根据反应的不同，增加或减少毛力。Ambassador被认为是一种模糊的反应，在这种情况下，刺激被重复。

Immunohistochemistry 免疫组

For immunostaining of c-Fos and mCherry, mice were deeply anesthetized with 4% isoflurane and then perfused intracardially with 20 mL phosphate-buffered saline followed by 40 mL 4% paraformaldehyde (PFA). Brains were post-fixed for 24 h in 4% PFA and then transferred to 30% sucrose in PB at 4°C until they sank. Coronal sections (30 μm) were cut on a freezing microtome (CM1950, Leica, Germany). The floating sections were washed in PBS and incubated with a rabbit polyclonal antibody against c-Fos (1:5,000 dilution; Millipore) in PBS with 0.3% Tween-20 (PBST) for 48 h at 4°C on an agitator. After washing, sections were incubated with a 647-donkey anti-rabbit secondary antibody solution (1:1000) in 0.1% PBST for 2 h at 24 °C. For biocytin staining after whole-cell patch-clamp recordings, slices containing biocytin-loaded cells were fixed in 4% PFA and were then washed in PBS. Streptavidin conjugated to Alexa 647 (1:1000; Invitrogen Molecular Probes, USA) were used. Images were captured with Olympus confocal microscopy (FV3000, Olympus, Japan). Cell counting was performed on FIJI.
对于c-Fos和mCherry的免疫染色，用4%异氟烷深度麻醉小鼠，然后用20 mL磷酸盐缓冲盐水心内灌注，然后用40 mL 4%多聚甲醛（PFA）灌注。将脑在4%PFA中后固定24小时，然后在4°C下转移至PB中的30%蔗糖中，直到它们下沉。在冷冻切片机（CM 1950，Leica，德国）上切割冠状切片（30 μm）。将漂浮切片在PBS中洗涤，并在4°C下在搅拌器上与含0.3%Tween-20的PBS（PBST）中的针对c-Fos的兔多克隆抗体（1：5，000稀释; Millipore）孵育48小时。洗涤后，将切片与647-驴抗兔二抗溶液（1：1000）的0.1%PBST溶液在24 ℃下孵育2 h。对于全细胞膜片钳记录后的生物胞素染色，将含有生物胞素负载的细胞的切片固定在4%PFA中，然后在PBS中洗涤。使用与Alexa 647（1：1000; Invitrogen Molecular Probes，USA）缀合的链霉亲和素。用Olympus共聚焦显微镜（FV3000，Olympus，Japan）捕获图像。在FIJI上进行细胞计数。

Electrophysiology 电生理

Brain slice preparation 脑片制备

Acute slices of the ACC and the DMS were prepared from D2R-EGFP mice or AAV virus-injected CaMKII-Cre mice. Mice were anesthetized with chloral hydrate and transcardially perfused with ice-cold cutting artificial cerebrospinal fluid (ACSF) containing (in mM): 213 sucrose, 2.5 KCl, 1.25 NaH2PO4, 26 NaHCO₃, 10 glucose, 2 Na-Pyruvate, 0.4 ascorbic acid, 3 MgSO4, 0.1 CaCl₂ (pH 7.3 when carbogenated with 95% O₂ and 5% CO₂). Brains were rapidly removed and sliced in coronal slices (300 μm thick) in ice-cold cutting ACSF using a vibrating microtome (VT 1200S, Leica). Slices containing the DMS or ACC were transferred to recording ACSF containing (in mM): 119 NaCl, 2.5 KCl, 1.25 NaH2PO4, 1 MgSO4, 2 CaCl2, 26 NaHCO3, and 25 Glucose. Slices were incubated at 32°C for 30 min and then stored at room temperature until used for patch clamp recordings (1–5 h). The extracellular ACSF was saturated with 95% O2/5% CO2 to maintain oxygenation and a pH ∼7.435.
ACC和DMS的急性切片由D2 R-EGFP小鼠或AAV病毒注射的CaMKII-Cre小鼠制备。用水合氯醛麻醉小鼠，并经心脏灌注冰冷切割人工脑脊液（ACSF），其含有（以mM计）：213蔗糖，2.5 KCl，1.25 NaH 2 PO 4，26 NaHCO ₃ ，10葡萄糖，2丙酮酸钠，0.4抗坏血酸，3 MgSO 4，0.1 CaCl ₂ （当用95%O ₂ 和5%CO ₂ 碳化时，pH 7.3）。快速取出脑，并使用振动切片机（VT 1200 S，Leica）在冰冷切割ACSF中进行冠状切片（300 μm厚）。将含有DMS或ACC的切片转移至记录ACSF，其含有（以mM计）：119 NaCl、2.5 KCl、1.25 NaH 2 PO 4、1 MgSO 4、2 CaCl 2、26 NaHCO 3和25葡萄糖。将切片在32°C下孵育30分钟，然后在室温下储存直至用于膜片钳记录（1-5小时）。细胞外ACSF用95%O2/5%CO2饱和以维持氧合和pH = 7.435。

Whole-cell recordings ex vivo
离体全细胞记录

Slices were visualized using a combination of fluorescence and infrared differential interference contrast (IR-DIC) video microscopy using a fixed-stage upright microscope (BX51WI, Olympus) equipped with a water immersion lens (40×/0.8 W) and an IR-sensitive CCD camera (IR1000, DAGE MTI). The recording chamber was superfused with carbogen-saturated warm (30–32°C) ACSF at a flow rate of 2–3 ml min⁻¹. Picrotoxin (100 μM) was added to block GABA_A receptor-mediated IPSCs. mEPSCs were measured in voltage clamp at a holding potential of −70 mV and in the presence of 500 nM tetrodotoxin (TTX, to block voltage-gated sodium currents) and 25 μM d-(-)−2-amino-5-phosphonopentanoic acid (d-APV, to block NMDA receptor EPSCs). All drugs were dissolved in ACSF. Series resistance (Rs) compensation was not used. Therefore, cells with Rs changes over 25% were discarded.
使用配备有水浸透镜（40×/0.8 W）和IR敏感CCD相机（IR 1000，DAGE MTI）的固定台直立显微镜（BX 51 WI，Olympus），使用荧光和红外微分干涉对比（IR-DIC）视频显微镜的组合使切片可视化。记录室用碳饱和的温（30-32 ℃）ACSF以2-3 ml/min的流速灌注 ⁻¹ 。加入印防己毒素（100 μM）以阻断GABA _A 受体介导的IPSC。mEPSC在电压钳中测量，保持电位为−70 mV，存在500 nM河豚毒素（TTX，阻断电压门控钠电流）和25 μM d-（-）−2-氨基-5-膦酰基戊酸（d-APV，阻断NMDA受体EPSC）。所有药物均溶于ACSF中。未使用串联电阻（Rs）补偿。因此，丢弃Rs变化超过25%的细胞。

Recordings were conducted in the cell-attached or whole-cell configuration using a Multiclamp 700B amplifier (Molecular Devices), a Digidata 1440A interface and Clampex 10.3 software (Molecular Devices). Optical stimulation was delivered to slices via an optical fiber (200 μm core, Thorlabs, Newton, USA) coupled to a 470 nm diode-pumped solid-state continuous-wave laser system (OEM Laser Systems Salt Lake City, USA). Stimulation consisted of either a single 1 ms pulse or trains of 1 ms pulses delivered at 10 Hz. The output of the laser was <2 mW. Recording electrodes (3–7 MΩ) were filled with an internal solution consisting of (in mM): 105 potassium gluconate, 30 KCl, 4 ATP-Mg, 10 phosphocreatine, 0.3 EGTA, 0.3 GTP-Na, 10 HEPES (pH 7.3, 295–310 mOsm). The internal solution also contained 0.2% biocytin. For mEPSCs and NMDAR/AMPAR ratio recording, electrodes (3–7 MΩ) filled with 120 CsMeSO4, 15 CsCl, 8 NaCl, 10 HEPES, 0.2 EGTA, 10 TEA-Cl, 4 Mg2+ATP, 0.3 NaGTP, and 5 QX-314 were used. Random recordings were obtained from neurons in the dorsal medial striatum expressing eGFP and from neurons in the region of the ACC expressing mCherry. MSN electrophysiological properties closely resembled those reported in earlier studies, including the presence of a slow ramping subthreshold depolarization in response to low-magnitude positive current injections, a hyperpolarized resting potential, inward rectification, and prominent spike after-hyperpolarization. MSNs were also characterized by a small to medium cellular body size (10–15 μm in diameter) and a radially oriented large dendritic tree covered by spines, confirmed by posthoc biocytin staining. To record evoked action potential firings, current injection steps were generated using Clampex software (Molecular Devices). After the cells had stabilized for 3 minutes and then the range of 0 to +400 pA, 50 pA increments/steps were chosen to elicit action potential spikes in DMS neurons.
使用Multiclamp 700 B放大器（Molecular Devices）、Digidata 1440 A接口和Clampex 10.3软件（Molecular Devices）在细胞附着或全细胞配置中进行记录。通过与470 nm二极管泵浦固态连续波激光系统（OEM Laser Systems湖城USA）耦合的光纤（200 μm芯，Thorlabs，Newton，USA）将光学刺激传递到切片。刺激由单个1 ms脉冲或以10 Hz输送的1 ms脉冲串组成。激光器的输出<2 mW。记录电极（3-7 MΩ）填充有由以下组成的内部溶液（以mM计）：105葡萄糖酸钾、30 KCl、4 ATP-Mg、10磷酸肌酸、0.3 EGTA、0.3 GTP-Na、10 HEPES（pH 7.3，295-310 mOsm）。内部溶液还含有0.2%生物胞素。对于mEPSC和NMDAR/AMPAR比率记录，使用填充有120 CsMeSO 4、15 CsCl、8 NaCl、10 HEPES、0.2 EGTA、10 TEA-Cl、4 Mg 2 +ATP、0.3 NaGTP和5 QX-314的电极（3-7 MΩ）。从表达eGFP的背内侧纹状体中的神经元和表达mCherry的ACC区域中的神经元获得随机记录。MSN的电生理特性与早期研究中报道的非常相似，包括对低幅度正电流注入的缓慢斜坡阈下去极化、超极化静息电位、内向整流和突出的尖峰后超极化的存在。MSN的特征还在于小到中等的细胞体大小（直径10-15 μm）和被棘覆盖的放射状定向的大树突树，通过事后生物胞素染色证实。为了记录诱发的动作电位放电，使用Clampex软件（Molecular Devices）生成电流注射步骤。在细胞稳定3分钟后，然后在0至+400 pA的范围内，选择50 pA增量/步长以引发DMS神经元中的动作电位尖峰。

For long-term potentiation (LTP) and paired-pulse ratio (PPR) experiments using electrical stimulation, a tungsten bipolar electrode (WPI) was placed in layer V/VI of the ACC close to the callosum, AMPAR-mediated EPSCs were induced by repetitive stimulations at 0.5 Hz, and neurons were voltage-clamped at -70 mV. Picrotoxin (100 μM) was always present to block GABA_A receptor-mediated inhibitory synaptic currents in all experiments. The amplitudes of eEPSCs were adjusted to between 50-150 pA to obtain a baseline. Paired pulse ratio with a 50-ms interstimulus interval was recorded before the LTP recording. Recordings were rejected if input resistance changed by more than 30% during recordings. After 10 min of recording stable responses, high-frequency stimulation (HFS: 4 trains of stimuli spaced at 10-s intervals, with each train containing bursts of 100 spikes at 100 Hz) was delivered. Summary LTP graphs were constructed by normalizing data in 30s epochs to the mean value of the baseline EPSCs.
对于使用电刺激的长时程增强（LTP）和成对脉冲比（PPR）实验，将钨双极电极（WPI）放置在靠近胼胝体的ACC的V/VI层中，通过0.5Hz的重复刺激诱导AMPAR介导的EPSC，并将神经元电压钳位在-70mV。在所有实验中，始终存在印防己毒素（100 μM）以阻断GABA _A 受体介导的抑制性突触电流。将eEPSC的振幅调节至50-150 pA之间以获得基线。在记录LTP之前，记录具有50 ms刺激间隔的成对脉冲比。如果记录期间输入电阻变化超过30%，则拒绝记录。在记录稳定反应10分钟后，递送高频刺激（HFS：以10秒间隔间隔的4列刺激，每列包含100 Hz的100个尖峰的脉冲串）。通过将30秒时期的数据标准化为基线EPSC的平均值来构建总结LTP图。

For recording the AMPA receptor/NMDA receptors current ratios, EPSCs of DMS D1/D2R-MSNs were evoked by ChR2 stimulation using 473-nm light pulses (1 ms, 0.33-Hz LED, CoolLED), and were recorded in voltage clamp. The AMPA-mediated currents were recorded at a holding potential of -70 mV, and the NMDAR-mediated current was recorded at +40 mV.
为了记录AMPA受体/NMDA受体电流比，使用473-nm光脉冲（1 ms，0.33-Hz LED，CoolLED）通过ChR 2刺激诱发DMS D1/D2 R-MSN的EPSC，并在电压钳中记录。AMPA介导的电流在-70 mV的保持电位下记录，NMDAR介导的电流在+40 mV下记录。

In vivo calcium imaging and analysis
体内钙成像和分析

To record the calcium dynamic in ACC PNs, we first injected AAV-DIO-GCaMP6f into the ACC of CaMKII-Cre mice. After 2 weeks, a gradient refractive index (GRIN) lens (length: 2 mm, core 6 diameter: 0.6 mm) was implanted in the same position under the monitor of the imaging software (Inscopix, nVista 3.0) to display incoming fluorescence. After a week, the recording was taken by a single photon miniature fluorescence microscope (Inscopix nVista) attached to a baseplate positioned atop the GRIN lens to get the best focal plane. Both the GRIN lens and baseplate were fixed to the skull with dental cement. All imaging sessions were conducted in mice freely behaving in their home cage. At the session onset, the microscope was attached to a skull-mounted baseplate and mice were rested in their home cage for 20 min. Calcium images were recorded with the nVista® software (Inscopix, Inc) at a sample rate of 10 frames s^-1, and under 10% LED blue radiance power. Continuous imaging periods lasted 10 min for each mouse in light phase 07:00-09:00 and dark phase 19:00-21:00, and the same mouse was repeated recording 7 days after PSNL. The same PSNL mice were treated by diazepam (6 mg/kg), gabapentin (100 mg/kg) and morphine (1 mg/kg) with an interval of 3 days to wash out. Raw imaging data were processed using the Inscopix Data Processing software (Inscopix DPS®, Inc.). AUC for each cell was calculated. Only PNs had calcium activity before and after PSNL surgery were compared, and activated PNs had at least a 20% increase in AUC, while deactivated PNs have a 20% decrease.
为了记录ACC PN中的钙动力学，我们首先将AAV-DIO-GCaMP 6 f注射到CaMKII-Cre小鼠的ACC中。2周后，在成像软件（Insopix，nVista 3.0）的监视器下，将梯度折射率（GRIN）透镜（长度：2 mm，芯6直径：0.6 mm）植入相同位置，以显示传入荧光。一周后，通过连接到位于GRIN透镜顶部的基板上的单光子微型荧光显微镜（Insopix nVista）进行记录，以获得最佳焦平面。GRIN透镜和基板都用牙科粘固剂固定在颅骨上。所有成像阶段均在其饲养笼中自由活动的小鼠中进行。在实验开始时，将显微镜连接到安装在颅骨上的基板上，并将小鼠在其饲养笼中休息20 min。使用nVista®软件（Insopix，Inc）以10帧s ^-1 的采样率和10% LED蓝色辐射功率记录钙图像。光相07：00-09：00、暗相19：00-21：00连续成像10 min，同一只小鼠在PSNL后7 d重复记录。用地西泮（6 mg/kg）、加巴喷丁（100 mg/kg）和吗啡（1 mg/kg）处理相同的PSNL小鼠，间隔3天进行洗脱。使用Insopix数据处理软件（Insopix DPS®，Inc.）处理原始成像数据。计算每个细胞的AUC。仅比较PSNL手术前后具有钙活性的PN，并且活化的PN具有至少20%的AUC增加，而失活的PN具有20%的降低。

Locomotion in open field test
旷场运动试验

The open field test apparatus was a Plexiglas-squared arena (45 × 45 cm²) with gray walls (40 cm high) and an open roof, which was located in a sound-attenuated and dimly illuminated room. Mice were gently placed in the center of the field, and movement was recorded for 5 min with a video-tracking system. Locomotion was analyzed by EthoVision XT (Noldus).
开放场测试装置是具有灰色墙壁（40 cm高）和开放屋顶的Plexiglas-squared竞技场（45 × 45 cm ² ），其位于声音衰减和昏暗照明的房间中。将小鼠轻轻放置在视野的中心，并用视频跟踪系统记录运动5分钟。通过动物运动轨迹跟踪系统（Noldus）分析运动。

Quantification and statistical analysis
定量和统计分析

Data are expressed as the mean ± standard error of the mean (SEM). No statistical methods were used to pre-determine sample sizes but our sample sizes are similar to those reported in previous publications.⁵⁰^,⁵¹^,⁵⁴^,⁵⁵^,⁵⁶^,⁵⁷ Animals or data points were not excluded and each experiment was repeated 2 times. Data analysis was performed blinded to the conditions of the experiments. Statistical significance was assessed using two-tailed Student’s t-tests to compare two groups. One-way, two-way, or repeated-measures ANOVAs were used to compare multiple groups, with pairwise comparisons made using a Tukey post-hoc test. Statistical details can be found in figure legends. A two-tailed P-value < 0.05 was considered statistically significant. All data were analyzed using Prism 8 software.
数据表示为平均值±平均值的标准误差（SEM）。未使用统计学方法来预先确定样本量，但我们的样本量与先前出版物中报告的样本量相似。不排除动物或数据点，每个实验重复2次。在对实验条件不知情的情况下进行数据分析。使用双尾Student t检验评估统计学显著性以比较两组。使用单因素、双因素或重复测量ANOVA比较多个组，使用Tukey事后检验进行成对比较。统计详情见图例。双尾P值< 0.05被认为具有统计学显著性。使用Prism 8软件分析所有数据。

Acknowledgments 致谢

This study was supported by the STI2030-Major Project (2021ZD0203400 to Z.-L.H.); the National Natural Science Foundation of China (32371028 to Y.-D.L., 32300822 to Y.-J.L., 82020108014 and 32070984 to Z.-L.H., and 82071491 and 31871072 to W.-M.Q.); the Shanghai Municipal Science and Technology Major Project (2018SHZDZX01 to Z.-L.H.); the ZJLab Program for Shanghai Outstanding Academic Leaders (to Z.-L.H.); the Shanghai Center for Brain Science and Brain-Inspired Technology and Lingang Laboratory & National Key Laboratory of Human Factors Engineering Joint Grant (LG-TKN-202203-01 to Z.-L.H.); Shanghai Municipal Health Commission (202340046 to Y.-D.L.); and the Shanghai Jiao Tong University 2030 Initiative (to Y.-D.L.). M.L. was supported by the Japan Society for the Promotion of Science (JP21H02802 and JP22K21351); the Japan Agency for Medical Research and Development (AMED) Moonshot Programme (JP21zf0127005); and the World Premier International Research Center Initiative (WPI) of the Ministry of Education, Culture, Sports, Science and Technology (MEXT).
本研究得到了STI 2030重大项目（2021 ZD 0203400 to Z.- L.H.）;国家自然科学基金委员会（32371028）D.L.，32300822至Y.- J.L.，82020108014和32070984，Z.- LH和82071491和31871072，W.- M.Q.）;上海市科技重大专项（2018 SHZDZX 01-Z.- L.H.）; ZJLab上海市优秀学术带头人计划（至Z.- L.H.）;上海脑科学与脑启发技术研究中心与临港实验室、人因工程国家重点实验室联合资助（LG-TKN-202203-01 to Z.- L.H.）;上海市卫生健康委员会（202340046至Y.- D. L.）;和上海交通大学2030年倡议（向Y.- D. L.）。M.L. 该项目得到了日本科学促进协会（JP 21 H 02802和JP 22 K 21351）、日本医学研究开发机构（AMED）登月计划（JP 21 zf 0127005）和文部科学省（MEXT）世界一流国际研究中心倡议（WPI）的支持。

Author contributions 作者贡献

Y.-D.L., Z.-L.L., and Z.-L.H. designed the experiments; Z.-L.H. and W.-M.Q. provided mentorship of the project; Y.-D.L., Y.-J.L., W.-K.S., and Z.-K.C. performed the in vivo experiments; J.G., Y.-J.L., and Z.-L.L. collected and analyzed electrophysiological data; L.W. helped with electrophysiological analysis; Y.-D.L., Y.-J.L., and Z.-L.H. wrote the manuscript with assistance from Z.-L.L., W.-M.Q., W.-K.S., M.L., and A.C.; and all of the authors discussed the manuscript.
Y.- D.L.，Z.- L. L.，Z.- L.H.设计实验; Z.- L.H. W.-智商提供项目指导; Y.- D.L.，Y.- J.L.，W.-- K. S.，Z.- K.C.进行体内实验; J.G.，Y.- J.L.，Z.- L.L.收集和分析电生理数据; L.W.帮助进行电生理分析; Y.- D.L.，Y.- J.L.，Z.- L.H.在Z的帮助下完成了手稿。L. L.，W.--智商，W.-- K. S.，M.L.，A. C.;所有的作者都在讨论手稿

Declaration of interests 申报利益

The authors declare no competing interests.
作者声明没有利益冲突。

Supplemental information 补充信息

What’s this? 这是什么？

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G.E.Simon，M.VonKorff，M.Piccinelli，C.Fullerton，J.Ormel
An international study of the relation between somatic symptoms and depression
躯体症状与抑郁症关系的国际研究
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L.A. McWilliams, R.D. Goodwin, B.J. Cox
L.A.McWilliams，R.D.Goodwin，B.J.考克斯
Depression and anxiety associated with three pain conditions: results from a nationally representative sample
与三种疼痛状况相关的抑郁和焦虑：来自全国代表性样本的结果
Pain, 111 (2004), pp. 77-83
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查看PDF查看文章CrossRefView in Scopus谷歌学术
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A neural circuit for comorbid depressive symptoms in chronic pain
慢性疼痛中抑郁症状共病的神经回路
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M.C. Bushnell, M. Ceko, L.A. Low
M.C.Bushnell、M.Ceko、L.A.Low
Cognitive and emotional control of pain and its disruption in chronic pain
疼痛的认知和情绪控制及其在慢性疼痛中的破坏
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ScopusGoogle Scholar中的CrossRefView
6
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疼痛通路中的学习和记忆
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查看PDF查看文章在Scopus中查看谷歌学术
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M. Haack，N. Simpson，N. Sethna，S. Kaur，J. Mullington
Sleep deficiency and chronic pain: potential underlying mechanisms and clinical implications
睡眠不足与慢性疼痛：潜在的潜在机制和临床意义
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Assessing and Managing Sleep Disturbance in Patients with Chronic Pain
慢性疼痛患者睡眠障碍的评估和管理
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查看PDF查看文章在Scopus中查看谷歌学术
9
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P.H.Finan、B.R.Goodin、M.T.Smith
The association of sleep and pain: an update and a path forward
睡眠与疼痛的关联：更新和前进的道路
J. Pain, 14 (2013), pp. 1539-1552
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查看PDF查看文章在Scopus中查看谷歌学术
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The Effect of Insomnia on Neuropsychological Functioning in Patients with Comorbid Symptoms of Pain, Fatigue, and Mood Disorders
胰岛素对疼痛、疲劳和情绪障碍共病患者神经心理功能的影响
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Chronic Pain, Sleep, and Cognition in Older Adults With Insomnia: A Daily Multilevel Analysis
老年痴呆患者的慢性疼痛、睡眠和认知：每日多水平分析
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Anterior cingulate cortex and insomnia: A cingulate-striatum connection
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2024, Acta Pharmacologica Sinica

⁷: These authors contributed equally

⁸: Lead contact

View Abstract

[1] 1
A.M. Elliott, B.H. Smith, K.I. Penny, W.C. Smith, W.A. Chambers
A.M.Elliott、B.H.Smith、K.I.Penny、W.C.Smith、W.A.Chambers
The epidemiology of chronic pain in the community
社区慢性疼痛的流行病学
Lancet, 354 (1999), pp. 1248-1252
Lancet，354（1999），pp. 1248-1252
View PDF View article View in Scopus Google Scholar
查看PDF查看文章在Scopus中查看谷歌学术

[2] 2
G.E. Simon, M. VonKorff, M. Piccinelli, C. Fullerton, J. Ormel
G.E.Simon，M.VonKorff，M.Piccinelli，C.Fullerton，J.Ormel
An international study of the relation between somatic symptoms and depression
躯体症状与抑郁症关系的国际研究
N. Engl. J. Med., 341 (1999), pp. 1329-1335
N. Engl. J. Med.，341（1999），pp. 1329-1335
View in Scopus Google Scholar
在ScopusGoogle Scholar中查看

[3] 3
L.A. McWilliams, R.D. Goodwin, B.J. Cox
L.A.McWilliams，R.D.Goodwin，B.J.考克斯
Depression and anxiety associated with three pain conditions: results from a nationally representative sample
与三种疼痛状况相关的抑郁和焦虑：来自全国代表性样本的结果
Pain, 111 (2004), pp. 77-83
Pain，111（2004），pp. 77-83
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查看PDF查看文章CrossRefView in Scopus谷歌学术

[4] 4
W. Zhou, Y. Jin, Q. Meng, X. Zhu, T. Bai, Y. Tian, Y. Mao, L. Wang, W. Xie, H. Zhong, et al.
W.Zhou，Y.Jin，Q.Meng，X.Zhu，T.Bai，Y.Tian，Y.Mao，L.Wang，W.Xie，H.Zhong，et al.
A neural circuit for comorbid depressive symptoms in chronic pain
慢性疼痛中抑郁症状共病的神经回路
Nat. Neurosci., 22 (2019), pp. 1649-1658
Nat. Neurosci.，22（2019），pp. 1649-1658
CrossRef Google Scholar CrossRefGoogle学术

[5] 5
M.C. Bushnell, M. Ceko, L.A. Low
M.C.Bushnell、M.Ceko、L.A.Low
Cognitive and emotional control of pain and its disruption in chronic pain
疼痛的认知和情绪控制及其在慢性疼痛中的破坏
Nat. Rev. Neurosci., 14 (2013), pp. 502-511
Nat. Rev. Neurosci.，14（2013），pp. 502-511
CrossRef View in Scopus Google Scholar
ScopusGoogle Scholar中的CrossRefView

[6] 6
J. Sandkühler
Learning and memory in pain pathways
疼痛通路中的学习和记忆
Pain, 88 (2000), pp. 113-118
Pain，88（2000），pp. 113-118
View PDF View article View in Scopus Google Scholar
查看PDF查看文章在Scopus中查看谷歌学术

[7] 7
M. Haack, N. Simpson, N. Sethna, S. Kaur, J. Mullington
M. Haack，N. Simpson，N. Sethna，S. Kaur，J. Mullington
Sleep deficiency and chronic pain: potential underlying mechanisms and clinical implications
睡眠不足与慢性疼痛：潜在的潜在机制和临床意义
Neuropsychopharmacology, 45 (2020), pp. 205-216
Neuropsychopharmacology，45（2020），pp. 205-216
CrossRef View in Scopus Google Scholar
ScopusGoogle Scholar中的CrossRefView

[8] 8
M.D. Cheatle, S. Foster, A. Pinkett, M. Lesneski, D. Qu, L. Dhingra
M.D.Cheatle、S.Foster、A.Pinkett、M.Lesneski、D.Qu、L.Dhingra
Assessing and Managing Sleep Disturbance in Patients with Chronic Pain
慢性疼痛患者睡眠障碍的评估和管理
Anesthesiol. Clin., 34 (2016), pp. 379-393
麻醉剂。临床，34（2016），pp. 379-393
View PDF View article View in Scopus Google Scholar
查看PDF查看文章在Scopus中查看谷歌学术

[9] 9
P.H. Finan, B.R. Goodin, M.T. Smith
P.H.Finan、B.R.Goodin、M.T.Smith
The association of sleep and pain: an update and a path forward
睡眠与疼痛的关联：更新和前进的道路
J. Pain, 14 (2013), pp. 1539-1552
J. Pain，14（2013），pp. 1539-1552
View PDF View article View in Scopus Google Scholar
查看PDF查看文章在Scopus中查看谷歌学术

[10] 10
J. Aasvik, T.C. Stiles, A. Woodhouse, P. Borchgrevink, N. Inge Landrø
J.Aasvik，T.C.Stiles，A.Woodhouse，P.Borchgrevink，N.Inge Landravik
The Effect of Insomnia on Neuropsychological Functioning in Patients with Comorbid Symptoms of Pain, Fatigue, and Mood Disorders
胰岛素对疼痛、疲劳和情绪障碍共病患者神经心理功能的影响
Arch. Clin. Neuropsychol., 33 (2018), pp. 14-23
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A.F. Curtis, J.M. Williams, K.J.M. McCoy, C.S. McCrae
A.F.Curtis，J.M.威廉姆斯，K.J.M.麦考伊，C.S.麦克雷
Chronic Pain, Sleep, and Cognition in Older Adults With Insomnia: A Daily Multilevel Analysis
老年痴呆患者的慢性疼痛、睡眠和认知：每日多水平分析
J. Clin. Sleep Med., 14 (2018), pp. 1765-1772
临床睡眠医学杂志，14（2018），pp. 1765-1772
CrossRef View in Scopus Google Scholar
ScopusGoogle Scholar中的CrossRefView

[12] 12
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Neuron

Article 文章Anterior cingulate cortex projections to the dorsal medial striatum underlie insomnia associated with chronic pain前扣带皮层向背内侧纹状体的投射是慢性疼痛相关失眠的基础

Highlights 亮点

Summary 总结

Graphical abstract 图形摘要

Keywords 关键词

Introduction 介绍

Results 结果

Aberrant activation of ACC PNs in chronic-pain-induced insomnia慢性疼痛性失眠症患者ACC神经元的异常激活

ACC PNs are required for chronic-pain-induced insomnia慢性疼痛引起的失眠需要ACC PN

Activation of ACC PNs is sufficient to induce sleep loss in naive miceACC PN的激活足以诱导幼稚小鼠的睡眠丧失

Hyperactivity of ACC PNs increases wakefulness through the DMS pathwayACC PN的过度活跃通过DMS途径增加觉醒

Increased excitability of DMS D1R-MSNs in chronic pain慢性疼痛中DMS D1 R-MSN的兴奋性增加

Increased synaptic plasticity of ACC-DMS D1R-MSNs in chronic pain慢性疼痛中ACC-DMS D1 R-MSN的突触可塑性增加

DMS D1R-MSNs mediate chronic-pain-induced insomniaDMS D1 R-MSN介导慢性疼痛诱导的失眠