甘丙肽及其受体对睡眠觉醒周期的调控
作者：admin 来源：未知 日期：2021-04-12 08:36人气：
摘 要：
甘丙肽（GAL）及其受体（GalRs）广泛分布于中枢神经系统，参与多种生理功能调节。下丘脑前部腹外侧视前核（VLPO） 80%神经元含GAL并与γ-氨基丁酸共存，发出下行投射至多个觉醒核团，抑制结节乳头体核、中缝背核和蓝斑核神经元活动而促进睡眠。本研究回顾GAL-GalRs系统在中枢神经系统的发现，聚焦多项利用神经示踪、神经药理学、分子生物学、化学遗传和光遗传学等方法研究进展，证明VLPO GAL能神经元调控生理条件下慢波睡眠的产生和维持以及参与阿尔茨海默症、焦虑、抑郁、癫痫和成瘾等疾病及伴随睡眠障碍的机制，总结性地提出尚未清晰的问题和研究方向。
关键词：
甘丙肽 甘丙肽受体 腹外侧视前核 睡眠障碍 睡眠觉醒周期
Galanin and its receptors play a critical role in the regulation of the sleep-wake cycle
Cui Guang-fu Zheng Xin Chen Hai-lin Gao Jin-xian Xie Jun-fan Shao Yu-feng Hou Yi-ping
Department of Neuroscience, Anatomy, Histology and Embryology, Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, Lanzhou University;
Abstract：
Galanin(GAL) and its receptors(GalRs) exist widely in the central nervous system, and regulate multiple physiological functions. Approximately 80% of the neurons in the ventrolateral preoptic nucleus(VLPO) of anterior hypothalamus contain gamma-aminobutyric acid and GAL. These neurons project themselves to the major nuclei that promote wakefulness and then inhibit the neuronal activation of the tuberomammillary nucleus, dorsal raphe nucleus and locus coeruleus to produce sleep. The present short review expounded the historic and recent data about the discovery of GAL and GalRs, emphasizing the latest research using techniques such as neural circuit tracing, neuropharmacology, molecular biology, chemogenetic and optogenetic ways, to confirm that galaninergic neurons of VLPO help initiate and maintain slow-wave sleep. Moreover,several evidences also showed that GAL was involved in the pathological mechanism of sleep disturbance in subjects with Alzheimer's disease, anxiety, depression, epilepsy and addiction. We summarized the issues that are not yet clear and indicated the direction in future studies.
Keyword：
galanin; galanin receptors; ventrolateral preoptic nucleus; sleep disorder; sleep-wake cycle；
人生1/3时间在睡眠中度过，睡眠与神经发育[1]、突触生长[2]、记忆巩固[3]、代谢产物清除[4]等密切相关。睡眠与觉醒的产生和维持是由多个神经系统释放不同的神经递质参与完成，同时受控于内环境平衡（如睡眠压力）、节律（如昼夜节律）以及“非稳态负荷”影响（如行为应激）[5—6]，睡眠觉醒转换是通过脑内促醒与促眠神经递质及调质相互作用实现。近年发现脑内源性神经肽在睡眠觉醒周期调节中扮演重要角色，如orexin及其受体系统和神经肽S及其受体系统参与觉醒的产生与维持[7—8]，甘丙肽（galanin,GAL）及其受体（galanin receptors,Gal Rs）系统参与睡眠的产生与维持[9]。
GAL于1983年首次在猪小肠中被发现，因其N末端为甘氨酸，C末端为丙氨酸而命名。GAL具有29个氨基酸（人类、大猩猩和猕猴为30个氨基酸），其序列在不同物种间非常保守，其中N末端对生物学功能非常重要[10]。GAL的3种受体（Gal R1、Gal R2、Gal R3）均为G蛋白耦联受体，其中Gal R1、Gal R3通过激活Gi/o型G蛋白引起神经元超极化，而Gal R2通过激活Gq/11型G蛋白引起神经元去极化[11]。GAL、Gal Rs在哺乳类动物中枢和外周神经系统广泛存在，参与调节认知、焦虑、抑郁、癫痫和睡眠等[10]多种功能。GAL在睡眠觉醒周期和睡眠障碍调节中起重要作用，本研究简述GAL-Gal Rs系统调节睡眠觉醒周期生理和病理过程的研究进展，为睡眠研究和相关疾病治疗提供参考。
1 GAL在中枢神经系统分布
GAL及其m RNA在啮齿类、灵长类和人类的中枢神经系统中均能检测到。GAL在杏仁核、丘脑室旁核、下丘脑视上核和视前核、脑干（背侧中缝核（dorsal raphe nucleus,DRN）、导水管周围灰质、被盖核、蓝斑（locus coeruleus,LC））分布较多，而在背根神经节、基底前脑（basal forebrain,BF）、海马和大脑皮层（前额叶和岛叶）分布相对较少[12]。
GAL神经纤维在前额叶皮质、内侧杏仁核、海马齿状回、前嗅核、中央隔核外侧部、腹外侧乳头体核、下丘脑后部、外侧下丘脑（lateral hypothalamus,LH）、室旁核，导水管周围灰质、DRN、背侧臂旁核、LC均有大量分布；在小细胞、巨细胞和外侧网状核有中等数量的纤维；在脊髓感觉背根神经节和垂体后叶有少量分布[13]。
GAL常与其他多种神经递质或神经肽共存，例如在腹外侧视前核（ventrolateral preoptic nucleus,VLPO）与γ-氨基丁酸共表达，通过选择性下行投射抑制结节乳头核（tuberomammillary nucleus,TMN）、DRN、LC和中脑导水管中央灰质等单胺能上行觉醒核团，发挥促睡眠作用[8,14]。在BF、腹侧隔核和斜角带与乙酰胆碱（acetylcholine,ACh）共表达，投射到腹侧海马参与学习记忆调节[15]。在中脑腹侧被盖区与多巴胺（dopamine,DA）共表达通过抑制DA在伏隔核释放，降低吗啡成瘾引起的位置偏好[16]。在下丘脑与血管加压素共表达，经突触前膜Gal R1反馈性抑制其释放，参与体内渗透压调节[17]。在LC和DRN分别与5-羟色胺（5-hydroxytryptamine,5-HT）和去甲肾上腺素（norepinephrine,NE）共表达，参与抗抑郁和抗焦虑调节[18]。
2 Gal Rs在中枢神经系统分布
GAL对睡眠觉醒、情绪、学习记忆等生理功能的调节作用与Gal Rs分布有关。Skofitsh等[19]通过放射自显影技术标记发现在杏仁核、前额叶皮质、嗅球吻侧核、下丘脑（腹内侧下丘脑、乳头体前核、视前区和前下丘脑）、被盖核、背侧终纹床核均有125I-GAL密集结合位点。大鼠杏仁核传出纤维大多数能结合GAL，其投射区（如终纹床核、腹侧盖核、黑质致密部、导水管周围灰质、网状结构、背缝核和臂旁核）也有GAL结合位点[12]。
通过免疫组化和原位杂交等方法发现Gal R1在中枢神经系统（如终纹床核、基底外侧杏仁核、海马、下丘脑（室旁核、LH、TMN、腹内侧下丘脑）、中脑（导水管中央灰质、DRN、黑质、被盖）、伏隔核、脑桥延髓（外侧臂旁核、LC、脊髓三叉神经核、脑桥网状核）和基底神经节）均有大量分布[20]。Gal R2分布于海马齿状回、梨状皮层、下丘脑（室旁核、视前区）、黑质、导水管周围灰质、三叉神经感觉核和运动核[20]。Gal R3主要分布在外周组织（心脏、脾脏和睾丸），在中枢局限于下丘脑区域、穹窿下结构、BF、脑桥、延髓和脊髓背角，但在新皮层、纹状体、海马、丘脑和小脑几乎没有分布[21]。Gal Rs在情绪和睡眠觉醒调控相关核团均有分布，如LC、DRN、TMN、海马、基底外侧杏仁核和伏隔核，提示GAL可能通过Gal Rs调节情绪紊乱导致的睡眠障碍。
3 Gal Rs配体
GAL (1-29）作为内源性天然配体与3种受体均有较高亲和力，是非选择性Gal Rs激动剂，其N末端片段GAL (1-13）是受体结合的关键片段，保持亲本肽的高亲和力，常与其他一些生物活性分子以嵌合肽形式合成Gal Rs配体（M15、M35、M32、M40、M617、M871、M1145、M1153)[13]。目前大多数嵌合肽分子因对酶稳定性差和不能透过血脑屏障等原因，在实验和治疗中受到限制，因此各种非肽类配体逐渐增多（如Gal R1激动剂（Galnon、Galmic),Gal R1拮抗剂（Sch 202596),Gal R3拮抗剂（SNAP 37889,SNAP 398299,Gal R3ant))[13]。Gal Rs配体及效应见表1。
表1 Gal Rs配体及效应
多种Gal Rs拮抗剂和激动剂已应用于基础和临床研究，为进一步阐明其生理功能和疾病治疗靶点提供重要工具，例如AR-M1896用于抗惊厥研究[22],M1145、M871、M617用于情绪障碍研究[23]。另外Gal R2别构调节物CYM2503可协同内源性GAL增强抗癫痫效应[13]。
4 GAL对睡眠觉醒周期调节
4.1 GAL参与生理条件下睡眠觉醒调节
研究[14]发现VLPO中80%γ-氨基丁酸能神经元共表达GAL，并选择性下行投射到下丘脑后部TMN组胺能神经元的胞体和树突并形成靶连接，同时也投射向LC的NE能神经元和DRN的5-HT能神经元。根据VLPO与TMN神经解剖环路，Saper等[9]提出VLPO-TMN睡眠—觉醒相互转化的“跷跷板”调控模型被广泛认同。在睡眠过程中，VLPO通过GAL和γ-氨基丁酸能神经抑制TMN觉醒核团而促眠，觉醒核团活动性降低也使VL-PO神经元去抑制，进一步维持睡眠的稳定。
Gaus等[24]研究发现多数哺乳类包括人类存在VLPO睡眠环路，进一步利用Fos标记睡眠期VLPO活动神经元显示80%为GAL能，同时GAL神经元还延伸到VLPO扩展区。特异性细胞损毁VLPO动物表现出减少50%以上的慢波睡眠（slow-wave sleep,SWS）或称为非快速眼动睡眠和异相睡眠（paradoxical sleep,PS）或称为快速眼动睡眠，损毁密集投射向TMN的VLPO核心区显著减少SWS持续时间和脑电（electroencephalogram,EEG）δ波活动，并改变其片段发生次数，证明该连接环路调节觉醒与SWS时相的转换，而损毁主要投射向LC和DRN的VLPO扩展区导致PS减少，说明该投射主要参与PS控制[25]。随着人类年龄增加VLPO GAL神经元数量丢失，出现明显的睡眠片段化，同样现象在啮齿类动物和猫均有发现[24,26]。
通过光遗传（1～4 Hz）和化学遗传学技术激活投射向TMN的VLPO GAL神经元引起SWS增多，睡眠潜伏期缩短[27]，而更高频率光刺激（10Hz）可沉寂VLPO GAL神经元引起小鼠觉醒增加[28]。光激活投射到VLPO的背内侧下丘脑GAL神经元引起SWS增多，表明GAL-Gal Rs系统在睡眠觉醒周期调控中起重要作用[29]。
睡眠监测下选择性6 h剥夺大鼠PS发现下丘脑视前区GAL m RNA的表达增加，剥夺期间SWS向PS的转换频繁，而PS剥夺后恢复期GAL m RNA不再增加[30]，提示GAL表达与PS倾向密切相关。健康男性青年志愿者静脉注射GAL (4×50μg或4×150μg）出现类似睡眠剥夺后恢复期睡眠反跳第3阶段PS增加，低剂量（4×50μg）引起EEGδ和θ波能谱密度增强[31]。提示GAL与SWS、PS的调节有关。VLPO GAL敲除动物在睡眠剥夺后不出现恢复期SWS反跳和EEGδ波活动增强，表明GAL参与睡眠稳态平衡维持[32]。
研究[33]提示内源性促眠因子腺苷可激活VLPO GAL神经元，抑制TMN，诱导睡眠，持续性觉醒导致腺苷蓄积，经腺苷A2A受体激活VLPO Type-2（根据GAL和GABA神经元对5-HT应答（抑制或兴奋）分为Type-1与Type-2）神经元活动增强诱导睡眠，而Type-1神经元与睡眠维持相关。光刺激视黑素缺失（Opn4-/-）小鼠不能引起VLPO GAL神经元活动，提示VLPO GAL神经元是光促夜间活动动物睡眠环路的组成部分[34]。
在某些神经系统疾病及睡眠障碍中GAL和Gal Rs表达会发生显著变化，提示GAL-Gal Rs系统参与该病理过程。动物模型和基因编辑技术的应用使研究GAL在阿尔茨海默症（Alzheimer's disease,AD）、焦虑、抑郁、癫痫和成瘾等病理过程及睡眠障碍中的作用机理成为可能。
4.2 GAL参与AD及其睡眠障碍调节
AD与中隔—基底前脑ACh能神经元退化和海马体ACh能投射减少有关，而中隔—基底前脑复合体的ACh和GAL共表达神经元投射到海马体并参与AD的病理过程[35]。AD患者BF中GAL合成增多[36]，通过抑制ACh-GABA神经环路中GA-BA释放，使ACh神经元去抑制活动性增强或通过Gal R2直接激活ACh神经元，引起海马ACh释放增加[37]。GAL可拮抗β淀粉样蛋白沉积引起的神经毒性和学习能力损伤[38]。GAL还能维持AD模型动物BF ACh能神经元功能，延长其存活时间[39]，表明GAL在AD病理过程中起到保护和延缓病程进展作用。多导睡眠记录发现AD患者常伴有睡眠片段化、夜间睡眠时间减少、白天嗜睡和昼夜节律颠倒等睡眠障碍[40]，其原因与睡眠相关核团VLPO GAL神经元丢失有关[41]，而GAL合成释放增多是机体的补偿或保护机制[42]。提示GAL抗AD并改善其睡眠障碍，具有良好的临床应用前景。
4.3 GAL参与抑郁、焦虑及其睡眠障碍调节
随着社会生活节奏加快和工作学习压力增大，情绪障碍患者增加，其中抑郁症患者占很大比例。理论认为抑郁症的病因与脑内5-HT和NE功能失调有关[43]。利血平抑郁模型动物LC中GAL m RNA表达增加[44]。强迫游泳、糖水偏好、悬尾和开场等动物实验证明激活Gal R1、Gal R3可引起抑郁样行为，激活Gal R2能产生抗抑郁样行为作用。GAL还能够缓解急性应激反应和保护海马神经元发挥协同抗抑郁作用[45]。基因分析发现Gal R2基因表达量与近期生活压力呈负相关关系[46]，而中国汉族女性GAL基因（rs694066）多态性与重度抑郁障碍发生率呈正相关关系[47]，表明GAL、Gal R2参与人类的抗抑郁调节。抑郁患者睡眠障碍主要表现为PS增多，PS潜伏期缩短和睡眠片段化，GAL静脉注射可引起健康志愿者PS剥夺样作用[31]，并使抑郁患者PS睡眠潜伏期延长[48]。
中枢注射GAL可降低应激状态下小鼠血浆肾上腺皮质激素浓度，产生抗焦虑作用[49]。双侧中央杏仁核注射GAL可抑制育亨宾焦虑模型动物的焦虑样行为并可被Gal Rs拮抗剂M40所拮抗[50]。应用基因敲除（konckout,KO）研究发现GAL-KO、Gal R1-KO、Gal R2-KO小鼠均表现出焦虑样行为[51—52]，药理学实验发现Gal R3拮抗剂具有抗焦虑作用[53]，表明GAL通过不同机制调节焦虑和抑郁。GAL抗焦虑样睡眠的研究很少，未来需阐明GAL调节焦虑样睡眠的作用机制。GAL调节情绪的研究为新的抗抑郁和抗焦虑药物开发和临床应用提供依据[23]。
4.4 GAL参与其他疾病引起的睡眠障碍调节
癫痫患者常表现出睡眠时间减少、睡眠片段化和睡眠时相转换增加等睡眠障碍，SWS期可诱发癫痫发作，PS期可抑制癫痫脑区放电和癫痫样放电的传播[54]。颞叶癫痫模型大鼠发作期海马GAL m RNA表达上调，在齿状回注射GAL能够显著减少癫痫持续时间[55]，而海马Gal R1-KO小鼠则有自发癫痫现象[56]，表明GAL-Gal R1系统参与调控抑制癫痫发作和改善癫痫睡眠障碍的作用。
药物成瘾者多存在PS减少、浅睡眠增多、失眠、睡眠呼吸暂停和睡眠结构改变等睡眠障碍，原因与多巴胺受体长期受刺激有关[57]。绝大多数成瘾者出现的睡眠不足会减少多巴胺分泌从而使其更加依赖药物，使戒断更加困难。黑质—纹状体和腹侧被盖—伏隔核多巴胺能神经元胞体表达Gal R1[10,13],Gal R1-KO小鼠表现出更严重的吗啡戒断症状，表明GAL通过Gal R1拮抗吗啡成瘾引起的药物依赖和戒断症状[58]。结合GAL的促眠作用，推测GAL干预或激活Gal R1能够缓解吗啡依赖和戒断症状的同时改善睡眠障碍。
5 结语与展望
GAL-Gal Rs系统在睡眠觉醒周期转换和睡眠维持中发挥重要的调节作用，还参与多种伴随睡眠失调疾病的病理过程。虽然前期研究证明GAL与GABA共存于VLPO神经元并下行抑制性投射TMN、LC、DRN而促SWS，但各自功能的异同尚不明晰，调控SWS的条件和角色有待进一步明确。GAL-Gal Rs系统在睡眠觉醒周期生理与病理过程的作用靶点和机制需清晰，发现Gal Rs激动剂或拮抗剂在疾病治疗中的新用途也将成为未来工作的重点。
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