调控睡眠-觉醒的分子细胞和脑网络机制探讨

睡眠是影响人体健康的重要因素,睡眠失调易引起多种生理和心理疾病。睡眠稳态既受外界因素(昼夜变化、饮食和温度)影响,亦受内在系统(分子钟和促睡眠/觉醒神经元)调控。细胞内有CLOCK、PER、CRY、NPAS2和BMAL1等分子周期性变化控制生物节律;脑内有基底前脑、丘脑、下丘脑、脑桥和延髓等神经元群体特异性地抑制或促进睡眠与觉醒,各核团之间通过突触连接形成神经网络启动和维持觉醒、非快速眼动睡眠和快速眼动睡眠。睡眠障碍普遍存在,本综述将针对调控生物体睡眠-觉醒的分子、细胞和脑网络机制展开讨论,为防治睡眠障碍类疾病提供新的思路。     

下丘脑hypocretin神经元协调睡眠-觉醒功能

哺乳动物的生活实际上是由睡眠与觉醒、休息与活动、镇静与警戒组成的。上世纪早期的研究预示了在下丘脑后部有一促觉醒区 ,目前神经科学家已证实了上述预测。下丘脑的hypocretin(也称为orexin)神经元对于觉醒系统的调节起着决定性作用 ,该神经元的活动能使睡意减少 ,同时提高觉醒和警戒。Hypocretin神经元分泌兴奋性神经递质hypocretin 1和hypocretin 2 ,投射到参与睡眠 觉醒机制的脑干 ,脑干的这些结构各有自己主要的神经递质 (如缝核的 5 羟色胺、蓝斑的去甲肾上腺素、背侧被盖的乙酰胆碱、乳头结节核的组胺、内侧隔核与斜角带核的γ …     

基底外侧杏仁核对睡眠-觉醒的调节作用

采用多道睡眠描记方法,观察了基底外侧杏仁核在睡眠－觉醒调节中的作用。结果发现,电损毁双侧ＢＬＮ引起慢波睡眠和快波睡眠增加,觉醒减少;在双侧ＢＬＮ内注射选择性损毁神经元胸体剂量的红藻氨酸引起双相效应,注射ＫＡ后第１天出现失眠,自第３天开始,ＳＷＳ增多,Ｗ减少,但ＰＳ无显著变化。     

大鼠中脑腹侧被盖区在睡眠—觉醒调节中的作用

本实验在３１只清醒自由行动的雄性ＳＤ大鼠进行。结果如下：（１）以侧中脑腹侧被盖区（ＶＴＡ）微量注射３．３ｎｍｏｌ溴亭后第２－３ｈ觉醒时间显著增加（Ｐ＜０．０１）;６．６ｎｍｏｌ溴隐亭有类似效果;０．６６和１．３３ｎｍｏｌ溴隐亭无明显作用。（２）同样方法ＶＴＡ微量注射２ｎｍｏｌ和４ｎｍｏｌＳＣＨ２３３９０后第２－３ｈ觉醒时间明显减少（分别为Ｐ＜０．０１和Ｐ＜０．０５）,但注射３．４ｎｍｏｌ舒必利则无     

NO对大鼠睡眠-觉醒的调节

目的和方法：通过对大鼠侧脑室微量注射ＮＯＳ抑制剂Ｌ－ＮＡＭＥ及ＮＯ的前体Ｌ－精氨酸（Ｌ－Ａｒｇ）观察两种物质对大鼠睡眠－觉醒的影响。结果：注射１ｍｇ Ｌ－ＮＡＭＥ（５μＬ）后４ｈ觉醒（Ｗ）明显增加,尤以注射后第１￣２ｈ显著;４ｈ慢波睡眠（ＳＷＳ）明显减少,该效应同样以注射后第１￣２ｈ显著;异相睡眠（ＰＳ）无明显变化。小剂量Ｌ－ＮＡＭＥ（０．２ｍｇ,５μｌ）对大鼠的Ｗ、ＳＷＳ、ＰＳ无明显影响;同样方     

腺苷和睡眠觉醒调节

腺苷作为神经调质,调节多种神经生物学功能.随觉醒时间延长,动物脑内腺苷水平逐渐增高,在睡眠期显著降低.因此,腺苷被认为是调节睡眠的内稳态因子之一.腺苷受体(receptor,R)有A1R、A2AR、A2BR和A3R四种亚型,其中A1R和A2AR与诱导睡眠相关.激活A1R可抑制促觉醒神经元诱导睡眠,也可抑制促眠神经元导致...     

腹侧被盖区DA神经元调节睡眠—觉醒机制的探讨

本实验观察了微量注射γ－氨基丁酸（ＧＡＢＡ）和５－羟色胺（５－ＨＴ）于大鼠中脑腹侧被盖区（ＶＴＡ）对该部位多巴胺神经元活动的调节及其对睡眠觉醒的影响。实验观察到：ＶＴＡ注射ＧＡＢＡ（２５μｇ）和５－ＨＴ（２μｇ）,伏隔核（Ａｃｂ）内多巴胺（ＤＡ）代谢产物－双羟苯乙酸（ＤＯＰＡＣ）分别降低到注射前的６８．２％（Ｐ〈０．０１）和升高到１３６．１％（Ｐ〈０．０１）,并相应减少和增加觉醒。双侧Ａｃｂ注射Ｄ     

昼夜节律系统与成人昼夜节律睡眠觉醒障碍

昼夜节律是存在于所有生命体中、接近24小时的内源性生物节律。昼夜节律与社会或环境节律的长期不同步,会引起睡眠、情绪等一系列变化。本文阐述了昼夜节律系统与睡眠之间的联系,重点介绍成人昼夜节律睡眠觉醒障碍疾病的临床研究成果,以期加强临床医生对该病的认识和诊治。     

大鼠发育期睡眠/觉醒周期的神经调节

幼年期大鼠的睡眠/觉醒周期和成年期的有显著差异,最为显著的特点是快眼动(REM) 睡眠在24 小时内的百分比远多于其他任何年龄阶段,随着脑发育成熟而逐渐减少.与此同时,非快眼动(NREM) 睡眠和觉醒的百分比逐渐增加.后者与参与NREM睡眠和觉醒调节的神经元在发育早期的成熟程度较为一致.鉴于大鼠发育早期REM睡眠每日的百分比由最高开始逐渐降低,而触发和促进REM睡眠的胆碱能神经元各生化成分的活性则是由最低开始逐渐升高,此期的REM睡眠应该还有胆碱能以外的动力驱动.新近的资料表明,促肾上腺皮质激素释放因子(CRF)可能是幼年期REM睡眠的另一主要驱动力量.     

五羟色胺在睡眠-觉醒中作用

五羟色胺(5-hydroxytryptamine,5-HT)又称为血清素(serotonin)广泛存在于机体多种组织。神经系统内的五羟色胺属于单胺类神经递质,与很多生理功能有关,参与对摄食、性行为、神经内分泌、疼痛感知、学习记忆和情绪、睡眠-觉醒等生理过程的调控。新近基于电生理、神经化学、分子生物学和神经药理学研究方法发现,五羟色胺和睡眠觉醒过程特别是觉醒过程密切相关,在促进觉醒、抑制快动眼睡眠方面有重要作用。本文介绍了五羟色胺在睡眠-觉醒周期中作用研究的最新进展。     

Dopaminergic Regulation of Enkephalin Release

The effects of dopamine receptor stimulation on enkephalin release were evaluated in vitro and in vivo by measuring the changes in the levels of [Met5]enkephalin (YGGFM) and Tyr-Gly-Gly (YGG), a characteristic extracellular enkephalin metabolite produced under the action of enkephalinase. In rat striatal slices, D1-receptor agonists or antagonists did not modify enkephalin release. By contrast, D2-receptor agonists enhanced the potassium-induced release of YGGFM and YGG without affecting spontaneous release from nondepolarized slices. This response was prevented by the D2-receptor antagonists haloperidol and RIV 2093, the latter compound being more potent, which suggested the involvement of a putative D2-receptor subtype. Acute administration of apomorphine or selective D2-receptor agonists, but not that of a D1-receptor agonist, enhanced the steady-state level of YGG without affecting the YGGFM level in rat striatum. The effect was blocked selectively by D2-receptor antagonists which, administered alone, had no effect. These observations indicate that D2-receptor stimulation in vitro or in vivo facilitates enkephalin release from striatal neurons, but that endogenous dopamine does not exert any tonic influence upon the opioid peptide neuron activity under basal conditions. However, chronic administration of haloperidol resulted in increases in striatal YGGFM and YGG, an effect presumably reflecting a long-term adaptive process.     

Dopaminergic Regulation of Septohippocampal Cholinergic Neurons

Abstract: The extent to which acetylcholine (ACh) release in the hippocampus is regulated by dopaminergic mechanisms was assessed using in vivo microdialysis in freely moving rats. Systemic administration of the dopamine (DA) receptor agonist apomorphine (1.0 mg/kg) or the specific D₁ agonist CY 208–243 (1.0 mg/kg) increased microdialysate concentrations of ACh in the hippocampus. The D₂ receptor agonist quinpirole (0.5 mg/kg) produced a small but statistically significant decrease in hippocampal ACh release. d -Amphetamine (2.0 mg/kg) increased ACh release, an effect that was blocked by the D₁ receptor antagonist SCH 23390 (0.3 mg/kg) but not by the D₂ antagonist raclopride (1.0 mg/kg). These findings suggest that endogenous DA stimulates septo-hippocampal cholinergic neurons primarily via actions at D₁ receptors. In addition, these results are similar to previous findings regarding the dopaminergic regulation of cortical ACh release, and suggest that the anatomical continuum formed by basal forebrain cholinergic neurons that project to the cortex and hippocampus acts as a functional unit, at least with respect to its regulation by DA.     

Dopaminergic Regulation of Striatal Acetylcholine Release: The Critical Role of Acetylcholinesterase Inhibition

Abstract: This study examined the effects of different levels of acetylcholinesterase (AChE) inhibition on dopaminergic regulation of striatal acetylcholine (ACh) release as estimated by in vivo brain microdialysis. Systemic administration of d-amphetamine (2 or 10 mg/kg) increased the striatal output of ACh when the AChE inhibitor neostigmine (0.1 µM) was present in the perfusion fluid. In contrast, when the same experiments were conducted at 0.01 µM neostigmine, d-amphetamine failed to affect (2 mg/kg) or significantly decreased (10 mg/kg) striatal ACh output. The inhibitory action of the D₂ receptor agonist quinpirole (0.2 mg/kg) was significantly greater at 0.01 µM than at 0.1 µM neostigmine. Similarly, there was a nonsignificant trend for the D₂ antagonist raclopride (1 mg/kg) to stimulate ACh release to a greater extent at the low neostigmine concentration. In contrast, the stimulant effects of systemic administration of the D₁ agonist A-77636 (1.46 mg/kg) on striatal ACh release were the same at the two neostigmine concentrations. These results demonstrate that the concentration of an AChE inhibitor in the perfusion solution can quantitatively and even qualitatively influence the manner in which dopaminergic agents regulate ACh overflow in the striatum. On comparing the present results with earlier reports concerning the effects of d-amphetamine on tissue concentrations of ACh, it is tentatively concluded that a low neostigmine concentration is the more physiologically relevant condition. Under such conditions, at moderate doses d-amphetamine does not appear to alter striatal ACh release, with this likely being due to the opposing actions of D₁ and D₂ receptors. Nevertheless, until the endogenous interstitial concentrations of striatal ACh can be measured by other methods, the physiological relevance of ACh microdialysis studies in the striatum will remain uncertain.     

丙泊酚对认知的损伤及成瘾性研究进展

作为一种临床上常用的静脉麻醉药,丙泊酚主要用于诱导或维持全身麻醉,近年来随着临床实践及实验室研究发现,除了麻醉作用外,丙泊酚还有许多其他非麻醉效应。如在给药期间可导致认知功能的损伤,其机制可能涉及增强抑制性神经元的活性、抑制兴奋性神经元的活性、抑制某些神经递质如一氧化氮的产生等影响记忆的形成;同时该药一经临床使用,就有报道指出其可能存在潜在的成瘾性,而后续多数研究均提示其能够诱导奖赏效应的产生从而导致其成瘾及滥用。为更好的推动对丙泊酚认知功能损伤的机制及保护措施的研究、以及其成瘾机制及戒断方法的研究,本文就近年丙泊酚对认知功能损伤作用及潜在成瘾性的研究进展作一综述。     

Dopaminergic and Serotonergic Neurotransmission Systems Are Differentially Involved in Auditory Cortex Learning: A Long-Term Microdialysis Study of Metabolites

Abstract: Auditory cortex has been shown to be a site of widespread neuronal learning processes even in the context of simple auditory conditioning behavior. In view of their presumed role in determining behavioral and motivational relevance of incoming information we investigated whether the dopaminergic and serotonergic systems are involved in auditory cortex learning. Using a chronic brain microdialysis technique over 4 days, samples from auditory cortex were obtained before, during, and after daily footshock avoidance training simultaneously from trained gerbils and passive control animals or pseudotrained animals. Because of detection limits of dopamine and serotonin in auditory cortex, the response profiles of extracellular homovanillic acid as the metabolite of the dopaminergic system and of 5-hydroxyindoleacetic acid as the metabolite of the serotonergic system were determined from consecutive dialysis samples each day. The response of the dopaminergic system appeared to reflect the initial formation of the behaviorally relevant association exclusively during the first training day, whereas the serotonergic response appeared to correlate with the stress level of animals.     

多巴胺能药物对早期帕金森病患者睡眠障碍发生的影响

目的:探讨多巴胺能药物及其它因素与早期帕金森病患者睡眠障碍之间的关系。方法:选择84名早期帕金森病患者作为病例组,87名健康人作为对照组。采用帕金森病睡眠量表(PDSS)评价患者的睡眠状况。采用非条件Logistic回归分析早期帕金森病患者睡眠障碍的影响因素。结果:早期帕金森病组PDSS总评分显著低于对照组(P=0.000);HAMD评分则显著高于对照组(P=0.000)。早期帕金森病患者睡眠障碍的主要类型为失眠。使用多巴胺能药物(OR=5.50,95%CI:1.96-15.81)是早期帕金森病患者发生睡眠障碍的危险因素;而较低的HAMD评分(OR=0.35,95%CI:0.13-0.93)则显著降低其睡眠障碍风险。结论:早期帕金森病患者存在睡眠障碍,多巴胺能药物和抑郁可能促进和加重其睡眠障碍。     

Hypocretins: The Timing of Sleep and Waking

The appropriate time and place for sleep and waking are important factors for survival. Sleep and waking, rest and activity, flight and fight, feeding, and reproduction are all organized in relation to the day and night. A biological clock, the suprachiasmatic nucleus (SCN), synchronized by photic influences and other environmental cues, provides an endogenous timing signal that entrains circadian body rhythms and is complemented by a homeostatic sleep pressure factor. Cholinergic, catecholaminergic, serotonergic, and histaminergic nuclei control wakefulness and mutually interact with the SCN as well as sleep- and wake-promoting neurons in the hypothalamus to form a bistable switch that controlls the timing of behavioral state transitions. Hypocretin neurons integrate circadian-photic and nutritional-metabolic influences and act as a conductor in the aminergic orchestra. Their loss causes narcolepsy, a disease conferring the inability to separate sleep and waking. Their role in appetitive behavior, stress, and memory functions is important to our understanding of addiction and compulsion.     

老年稳定期精神分裂症患者睡眠障碍现状调查及对记忆功能的影响

摘要 目的：调查老年稳定期精神分裂症患者睡眠障碍现状,分析其影响因素,并分析老年稳定期精神分裂症患者睡眠障碍与记忆功能的关系。方法：选择2018年5月~2021年5月期间我院收治的100例老年稳定期精神分裂症患者。采用自制临床资料调查问卷采集患者临床资料,采用匹茨堡睡眠质量指数（PSQI）评价所有患者的睡眠状况,采用多维记忆评估量表（MMAS）评价所有患者的记忆功能,单因素及多因素Logistic回归分析老年稳定期精神分裂症患者睡眠障碍的影响因素。Pearson检验分析PSQI评分与记忆功能评分的相关性。结果：纳入的100例老年稳定期精神分裂症患者中,有68例发生睡眠障碍,睡眠障碍发生率为68.00%。根据患者有无睡眠障碍分为两组：睡眠障碍组（n=68）和无睡眠障碍组（n=32）。单因素分析结果显示：老年稳定期精神分裂症患者睡眠障碍与年龄、性别、户籍所在地、文化水平、婚姻状况、发病情况、收入情况有关（P<0.05）,而与精神症状无关（P>0.05）。多因素Logistic回归分析显示婚姻状况为未婚/离异/丧偶、户籍所在地为城镇、性别男、年龄>70岁、文化水平为中学、收入情况为无是老年稳定期精神分裂症患者睡眠障碍的危险因素（P＜0.05）。睡眠障碍组汉词记忆、汉词配对、图画记忆评分低于无睡眠障碍组,PSQI评分高于无睡眠障碍组（P<0.05）。老年稳定期精神分裂症伴睡眠障碍患者PSQI评分与汉词配对、图画记忆、汉词记忆评分呈负相关（P＜0.05）。结论：老年稳定期精神分裂症患者存在较高的睡眠障碍发生率,且受到年龄、性别、户籍所在地等多种因素的影响。睡眠障碍可影响患者记忆功能状况,睡眠障碍越严重,记忆功能越差。     

Neurotensin Regulation of Endogenous Acetylcholine Release from Rat Striatal Slices Is Independent of Dopaminergic Tone

The effects of neurotensin (NT) alone or in combination with the dopamine antagonist sulpiride were tested on the release of endogenous acetylcholine (ACh) from striatal slices. NT enhanced potassium (25 mM)-evoked ACh release from striatal slices in a dose-dependent manner. This effect was tetrodotoxin-insensitive, suggesting an action directly on cholinergic elements. The dopamine antagonist sulpiride (5 x 10(-5) M) significantly increased (63%) potassium-evoked ACh release from striatal slices; potassium-evoked ACh release was further increased (90%) in the presence of NT (10(-5) M) and sulpiride (5 x 10(-5) M). The second set of experiments tested the effects of 6-hydroxydopamine (6-OHDA) lesions of the substantia nigra on NT-induced increases of potassium-evoked ACh release. These lesions did not alter the NT regulation of potassium-evoked ACh release from striatal slices, but did significantly increase spontaneous (33%) and potassium-evoked (40%) ACh release from striatal slices. Striatal choline acetyltransferase activity was not affected by 6-OHDA lesions. In addition, following 6-OHDA lesions, sulpiride was ineffective in altering ACh release from striatal slices. Furthermore, evoked ACh release in the presence of the combination of NT and sulpiride was not different from that in the presence of NT alone. These results suggest that in the rat striatum, NT regulates cholinergic interneuron activity by interacting with NT receptors associated with cholinergic elements. Moreover, the NT modulation of cholinergic activity is independent of either an interaction of NT with D2 dopamine receptors or the sustained release of dopamine.     

Hypocretins: The Timing of Sleep and Waking

The appropriate time and place for sleep and waking are important factors for survival. Sleep and waking, rest and activity, flight and fight, feeding, and reproduction are all organized in relation to the day and night. A biological clock, the suprachiasmatic nucleus (SCN), synchronized by photic influences and other environmental cues, provides an endogenous timing signal that entrains circadian body rhythms and is complemented by a homeostatic sleep pressure factor. Cholinergic, catecholaminergic, serotonergic, and histaminergic nuclei control wakefulness and mutually interact with the SCN as well as sleep‐ and wake‐promoting neurons in the hypothalamus to form a bistable switch that controlls the timing of behavioral state transitions. Hypocretin neurons integrate circadian‐photic and nutritional‐metabolic influences and act as a conductor in the aminergic orchestra. Their loss causes narcolepsy, a disease conferring the inability to separate sleep and waking. Their role in appetitive behavior, stress, and memory functions is important to our understanding of addiction and compulsion.