心理科学进展, 2019, 27(2): 312-321 doi: 10.3724/SP.J.1042.2019.00312

研究前沿

心理韧性及其神经机制:来自非人类动物模型的证据

刘浩然1, 张晨风1, 杨莉,1,2

1华南师范大学心理学院

2华南师范大学脑科学与康复医学研究院, 广州 510631

The neural mechanism underlying resilience

LIU Haoran1, ZHANG Chenfeng1, YANG Li,1,2

1 School of Psychology, South China Normal University, Guangzhou 510631, China

2 Institute for Brain Research and Rehabilitation, South China Normal University, Guangzhou 510631, China

通讯作者: 杨莉, E-mail: yang_li@m.scnu.edu.cn

收稿日期: 2017-11-13   网络出版日期: 2019-02-15

基金资助: * 国家自然科学基金.  31771219
广州市科技创新基金.  201607010320
华南师范大学心理学院研究生科研创新基金资助.  hsxly2017005

Received: 2017-11-13   Online: 2019-02-15

摘要

心理韧性是指个体对不幸、逆境或挫折等压力情形的有效适应。以非人类动物为模型的心理韧性研究一般改称心理韧性为“抗逆力”, 本文也将沿用“抗逆力”来区分不同物种的韧性研究。近年来采用非人类动物模型对抗逆力神经机制的探索取得了重要进展, 内侧前额叶、海马、奖赏环路等脑区及其投射均参与调控抗逆力的表现, 操控其神经环路的影响与所面对的压力形式有关, 并且高抗动物拥有特异性适应机制。鉴于人类研究的伦理及实验手段等原因, 抗逆力的研究将为人类的韧性研究提供重要参考。

关键词: 心理韧性/抗逆力 ; 压力适应 ; 奖赏环路 ; 神经机制

Abstract

The resilience refers to the effective adaptation of individuals to stress circumstances. Of note, two different Chinese terms were used in this review to distinguish “resilience” in between humans and animals. Numerous studies have shown that medial prefrontal cortex, hippocampus and other brain areas involved in reward circuits mediate resilience. In addition, the adaptive brain mechanisms may differ in susceptible individuals compared to resilient ones. In combination with the ethical and experimental findings in humans, the results from animal research toward understanding the mechanism of resilience will provide important reference and neural basis to improve human resilience.

Keywords: resilience ; stress adaptation ; reward circuits ; neural mechanism

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本文引用格式

刘浩然, 张晨风, 杨莉. (2019). 心理韧性及其神经机制:来自非人类动物模型的证据 . 心理科学进展, 27(2), 312-321

LIU Haoran, ZHANG Chenfeng, YANG Li. (2019). The neural mechanism underlying resilience. Advances in Psychological Science, 27(2), 312-321

心理韧性(resilience), 又叫压力韧性(stress resilience), 是指个体对不幸、逆境或挫折等压力情形的有效适应, 使个体在压力中也能保持正常的心理和生理机能, 远离精神疾病(比如, 抑郁症, 创伤后应激障碍)的侵袭(Feder, Nestler, & Charney, 2009; Russo, Murrough, Han, Charney, & Nestler, 2012)。在压力下, 个体仅仅维持正常的认知以及行为反应, 避免严重的负性伤害的心理韧性反应被称为消极韧性(passive resilience), 而除了避免受到伤害之外, 个体还获得了新的成长与积极发展, 这种韧性反应被称为积极韧性(active resilience) (Russo et al., 2012)。

随着心理韧性研究的侧重点不同, 在不同时间、不同地点也被译为心理弹性、韧性、复原力、抗逆力以及压弹(席居哲, 左志宏, Wei, 2012; 于肖楠, 张建新, 2005), 并且以非人类哺乳动物为研究对象的心理韧性研究往往称之为“抗逆力”或“抗挫力”, 但译法的万变不离其本质——不同情形的压力源以及对压力积极、有效的适应(Fletcher & Sarkar, 2013)。

20世纪70年代, 一些经历了磨难却依然成长发育良好的儿童引起了心理学家和精神病学家的关注, 研究者对其背后机制的探索开启了心理韧性的研究(Masten, 2001)。早期的心理韧性研究主要关注不同韧性个体所具有的特征差异, 主要研究对象是有过苦难生活经历的青少年。20世纪90年代后, 研究者已经不再满足于探究不同韧性的不同行为表型, 转向理解个体对压力情形的具体适应过程, 尤其是对其神经机制的研究成为新的焦点。

心理韧性研究的演变不仅受社会环境改变的影响, 更受益于研究技术革新的直接推动, 导致新的研究范式不断出现。传统的心理韧性研究主要针对人类, 并以问卷调查和访谈为主要研究手段, 优点是有助于直接对心理韧性的行为表型进行概括性的描述, 并探讨心理韧性与其他行为变量之间的关系, 比如心理韧性可以削弱负性生活事件对抑郁的负面影响(朱清 等, 2012); 缺点是不同的问卷对心理韧性的构念界定不统一, 而且无法探知心理韧性的神经生物学基础。fMRI (functional magnetic resonance imaging)技术为代表的脑成像研究范式被广泛应用后, 众多心理学家尝试无创性探索心理韧性的脑机制, 逐渐发现右侧中部和上部额叶脑回(frontal gyri)、右侧脑岛(right insula)和前扣带回(anterior cingulate cortex, ACC)等脑区都参与调控高低心理韧性的不同表现(Burt et al., 2016; Johnson et al., 2014), 但由于fMRI目前固有的技术瓶颈, 研究者无法在比参与脑区更微观的层面上有效探究其功能活动。得益于心理韧性的非人类动物模型和光遗传等技术的应用, 近年来, 动物模型抗逆力神经环路机制的研究极大地拓展了对心理韧性机制的探索。研究发现内侧前额叶(medial prefrontal cortex, mPFC)、海马(hippocampus)以及腹侧被盖区(ventral tegmental area, VTA)-伏隔核(nucleus accumbens, NAc)环路都参与调控抗逆力, 并且这些脑区或神经环路在高抗(resilient)个体和易感(susceptible)个体上功能有所不同。此外也有针对低心理韧性或抗逆力的极端表现形式, 比如抑郁症、焦虑症、PTSD等压力相关的精神疾病的神经机理研究(Alves et al., 2017; Feder et al., 2009; A. Friedman, 2014)。

回顾国内有关心理韧性或抗逆力的综述, 多是围绕心理韧性的概念界定、影响因素、作用机制及模型的构建展开(刘伟伟, 汪海彬, 李梅, 黄丽, 2017; 马伟娜, 桑标, 洪灵敏, 2008; 于肖楠, 张建新, 2005), 缺乏生理机制上的研究支持。虽然2009年以来国外对于“resilience”的综述就已开始依据其脑机制阐述行为表型的变化(Feder et al., 2009), Scott J Russo、Minghu Han等人从分子水平到脑区整体活动水平介绍了“resilience”的神经生物学机制(Han & Nestler, 2017; Russo et al., 2012), 但鉴于心理韧性研究的快速发展, 有关其神经环路水平以及新的潜在干预靶点的研究, 依然缺乏及时的综述。本文对心理韧性的神经机制, 尤其是可能参与心理韧性调控的神经环路进行了系统阐述, 希望给与相关研究者新的视角和启发。

1 抗逆力的主要非人类动物模型

与调查问卷的研究范式相比, 抗逆力的非人类动物模型范式中对概念的界定比较统一:在压力情形下显示出较少负性反应的动物被认为是高抗个体(Ergang et al., 2015; Feder et al., 2009; Krishnan et al., 2007; Steimer & Driscoll, 2005)。动物模型的应用大大推动了对抗逆力神经机制的认识。2007年Krishnan等人的研究第一次深入到分子层面, 系统性地揭示了高抗动物和易感动物在神经机制上的不同, 以及由此导致的神经元电位、脑区活动和行为表现上的巨大差异(Krishnan et al., 2007)。2014年Friedman等人第一次揭示了不同于易感动物、特异性存在于高抗动物的神经机制(Allyson K. Friedman et al., 2014), 提示高抗神经机制不同于易感神经机制, 改善心理韧性或抗逆力不仅要着力于逆转负性伤害, 更要关注高抗机制本身的培育。在日益增多的抗逆力研究中, 慢性社交挫败压力模型(chronic social defeat stress, CSDS)、慢性温和应激模型(chronic mild stress, CMS)是两种应用较为广泛的抗逆力动物模型。

1.1 CSDS

CSDS是应用最为广泛的抗逆力动物模型, 借助CSDS, 2007年Krishnan等人第一次从分子层面阐述抗逆力的机制(Krishnan et al., 2007)。以C57BL/6小鼠为例, CSDS主要由3个阶段组成, 首先是挑选凶猛的CD-1大鼠, 然后使小鼠和大鼠处于同一环境中进行社交互动(由于天性和领地意识, 大鼠会攻击小鼠), 最后利用社交测试、糖水偏好测试(sucrose preference test)检测小鼠是否出现社交躲避(social avoidance)症状(Golden, Covington, Berton, & Russo, 2011), 以区分出高抗和易感两组小鼠进行深入研究。CSDS的核心是利用来自凶猛大鼠的压力源对小鼠进行压力性刺激, 从而模拟人类遭受巨大社交压力时的情境, 但需要注意的一点是, 大鼠的挑选至关重要, 过于凶猛、易造成小鼠机体损伤的和过于温和、与小鼠和睦相处的大鼠都应该被排除。

通过CSDS筛选出的高抗和易感小鼠在脑机制上存在着显著的差异。研究发现, 小鼠NAc包含中型多棘神经元(medium spiny neuron), 神经元上分布着密集的多巴胺受体亚型D1和D2, 经受CSDS之后, 二者的活动强度显著影响着小鼠的抗逆力表现。增强的D1活动有助于小鼠表现出高抗行为, 而使用化学遗传学方法抑制二者的活动将导致小鼠抑郁(Francis et al., 2015)。这项研究说明CSDS可以显著影响抗逆力相关的神经机制变化, 而NAc上的D1、D2受体可能是干预抗逆力的潜在靶点。除了应用于抗逆力的研究外, CSDS更多地被应用于抑郁情绪及抑郁症的研究。CSDS可诱发小鼠的焦虑和抑郁状态且能够维持24小时以上, 是一个被公认的、区分度良好的抑郁症建模方法(Iñiguez et al., 2014)。

1.2 CMS

CMS也被称为不可预见性慢性温和应激模型(unpredictable chronic mild stress, UCMS), 源于20世纪80年代Paul Willner及其同事有关临床抑郁症的研究(Hill, Hellemans, Verma, Gorzalka, & Weinberg, 2012)。除了应用于抗逆力研究之外, CMS也是抑郁症、焦虑症等压力相关疾病的良好建模方法。CMS的过程是对动物施加多种温和的(不会造成明显的机体组织损伤)、不可预见的压力性刺激, 并且间歇性地持续刺激10天~8周, 最后以旷场测试、高架十字迷宫测试、糖水偏好测试、水迷宫测试等方法测量其抑郁焦虑状态、奖赏行为以及空间记忆学习能力等指标, 将小鼠区分出不同抗逆力水平的组, 以进行下一步研究(Chang & Grace, 2014)。根据不同的研究目的, 可对小鼠施加的刺激包括足底电击、鼠笼倾斜45°、剥夺水和食物、24小时照明、每15分钟进行光暗环境交替等方式, 并且随机施加, 以确保刺激的不可预见性。

CMS相对于其他抗逆力范式的优点是可选用的刺激多种多样, 贴合现实, 这也是其被广泛应用于各类研究的原因, 但需要注意的是, 对于啮齿类动物, CMS的影响可能存在性别差异, 比如CMS之后的雄性大鼠呈现出稳定的糖水偏好减弱等抑郁样(depression-like)行为, 但雌性小鼠这些行为表征却并不稳定, 在不同的研究中甚至呈现矛盾的现象, 所以有研究者建议不要将糖水偏好测试的结果作为区分雌性大鼠抗逆力的指标(Franceschelli, Herchick, Thelen, Papadopoulou- Daifoti, & Pitychoutis, 2014)。

1.3 其他模型

CSDS、CMS之外, 还有许多其他的抗逆力动物模型。比如, 早期生活压力(early life stress)模型中, 使幼年的小鼠与父母短时间的分离, 从而影响小鼠长大后的不同抗逆力水平(Santarelli et al., 2017), 目前的研究对早期生活压力的影响并无定论, 但可以肯定的是, 与父母分离的时间长短以及分离时小鼠的年龄大小对小鼠成长的影响至关重要。习得性无助(learned helplessness, LH)模型, 对动物长时间施加不可躲避的足底电击或其他类似刺激, 将导致一部分动物在能够躲避电击的情况下放弃躲避而承受电击(Berton et al., 2007; Brachman et al., 2016), 相应的那些始终积极应对电击的动物就是高抗组, 值得注意的是, 这种模型所导致的脑机制变化容易与恐惧情绪混淆。上述所有模型都需要比较长的压力刺激训练和测试阶段, 而有一些模型可以省略训练阶段, 直接测试动物的某些指标, 进而区分出不同抗逆力水平的个体。比如急性应激(acute stress)模型, 根据动物在急性压力刺激下的反应来判定其抗逆力水平(El Yacoubi et al., 2003)——可根据小鼠在悬尾测试和强迫游泳中的表现直接区分出高、低抗逆力组, 但急性压力下的动物反应不能简单地归因于抗逆力的高低, 因此这类模型较少被采用。

2 心理韧性或抗逆力的神经机制

近10年来, 心理韧性或抗逆力的神经机制研究取得了巨大进步, 人们已经不满足于心理韧性或抗逆力有关脑区的探索, 其脑区间的环路机制成为了新的研究热点、重点。一种复杂的高级认知或情感行为绝不仅仅由某个或某些脑区独立调控, 脑区之间的连接、投射对行为的最终表现同样至关重要。

2.1 不同心理韧性或抗逆力的脑区活动差异

2.1.1 mPFC的活动强弱影响心理韧性的高低

近年来以人类、非人类哺乳动物等物种的研究都证明了不同心理韧性或抗逆力拥有不同的神经机制。采用多种动物模型(CSDS、CMS等)的研究发现, 相对于对照组小鼠, 易感小鼠的腹侧mPFC的神经活动以及表示神经元活动水平高低的早期蛋白基因表达(比如, c-Fos蛋白)都更低(Covington et al., 2010), 通过光遗传增加mPFC的活动将逆转易感小鼠表现出的多种负性行为, 并且此结果与针对抑郁症患者的一些临床研究结果一致(Adamec, Toth, Haller, Halasz, & Blundell, 2012; Covington et al., 2010)。这些结果说明mPFC可能是不同抗逆力神经机制差异的重要脑区, 其活动的减弱可能导致小鼠抗逆力下降, 增强其活动有助于改善负性行为并提高抗逆力。

也有研究认为mPFC活动增强将导致抗逆力降低。通过深部脑刺激(deep brain stimulation)抑制mPFC的活动将缓解抑郁个体或小鼠的负性症状(Covington et al., 2010; Warden et al., 2012), 并且采用LH动物模型的研究发现, 增强驱动mPFC神经元的兴奋性突触输入将使小鼠易患习得性无助, 并导致高抗小鼠转变为易感小鼠(Wang, Perova, Arenkiel, & Li, 2014)。在一些抑郁症、PTSD患者身上也发现了与此一致的结果(Drevets, Savitz, & Trimble, 2008; Hamani et al., 2011)。

我们认为, mPFC以貌似矛盾的方式影响抗逆力水平的原因可能是实验范式的不同。CSDS等范式给动物施加的压力时长远大于LH, 并且压力形式也不同, CSDS主要是来源于凶猛的CD1大鼠的社交、生存环境方面的慢性长期压力, 而LH主要是在对抗负性刺激(如电击)时的急性应激压力, 虽然二者最终都会反映在其抗逆力表现上, 但脑应对不同压力刺激的方式有差异。此外, 也有动物实验表明, 对于不同的、特定的压力形式下, mPFC的不同亚区对抗逆力有着不同的调控作用(Adamec et al., 2012; Ressler & Mayberg, 2007)。所以, 深入了解不同物种、不同实验范式的心理韧性或抗逆力研究, 继而进行系统性的整合是未来不可避免的研究方向。

2.1.2 奖赏环路所含脑区是介导心理韧性的核心结构

虽然动物实验表明mPFC对不同抗逆力的调控十分重要, 但根据近年来的相关研究, 与抗逆力关联最为密切的脑区是奖赏环路(reward circuits)。奖赏环路是指与奖赏及厌恶有关的脑区及其组成的脑环路, 主要包括ACC、腹侧纹状体(ventral striatum)、眶额皮层(orbital frontal cortex)、腹侧苍白球(ventral pallidum)以及中脑多巴胺系统等众多脑区(Haber & Knutson, 2010)。近年来中脑五羟色胺系统的核心脑区中缝背核(dorsal raphe nucleus, DRN)也被证明与奖赏相关行为有关(Haber & Knutson, 2010; Li et al., 2016; Liu et al., 2014; Wang et al., 2017)。奖赏环路中的海马、NAc、VTA、DRN与心理韧性或抗逆力关系最为密切。

VTA和NAc是近年来抗逆力研究中最受关注的两个脑区。VTA的多巴胺能神经元有两种动作电位发放模式:低频率的紧张性发放(tonic firing)和高频率的相位性发放(phasic firing) (Grace, West, Ash, Moore, & Floresco, 2003), 光遗传激发多巴胺能神经元相位性发放, 而非紧张性发放, 可以迅速使CSDS模型小鼠展现出社交回避增加、糖水偏好减弱等易感现象(Razzoli, Andreoli, Michielin, Quarta, & Sokal, 2011)。NAc是VTA的主要投射脑区之一, 阻断NAc的AMPA受体可以提高抗逆力, 并且NAc的基因表达模式(如Dnmt3a基因)影响着小鼠抗逆力的性别差异(Hodes et al., 2015; Vialou et al., 2010)。虽然VTA和NAc的功能活动参与调控抗逆力, 但目前对VTA所接收的神经输入以及NAc的下行功能环路如何介导抗逆力依然缺乏有说服力的研究。

2.1.3 海马参与调控抗逆力

海马的体积、投射连接、受体类型都可能参与抗逆力的调控。海马直接或间接地和压力的效应器“下丘脑-垂体-肾上腺轴(hypothalamic-pituitary- adrenal (HPA) axis)”形成多突触连接, 并且主要通过糖皮质激素受体(glucocorticoid receptors)和盐皮质激素受体(mineralocorticoid receptors)对HPA轴的压力反应进行负反馈调节(Franklin, Saab, & Mansuy, 2012; Levone, Cryan, & O'Leary, 2015)。fMRI研究证明, 对于经受了CSDS之后的小鼠, 其海马CA3区的体积与社交回避的严重程度呈负相关, 并且类似的结构变化在海马与VTA、海马与扣带回、海马与下丘脑之间同步发生(Anacker et al., 2016), 说明海马可能与其他脑区协作来调控抗逆力, 但有关人类抑郁情绪的研究得到了与动物研究不一致的结果。相对于健康人群, 抑郁被试的海马体积反而更小(MacQueen et al., 2003)。跨物种的差异、压力刺激形式的不同可能是这一矛盾的结果的原因之一, 并且人类适应压力的过程可能导致结果的多样化。一项长达两年的纵向研究显示, 不论是陷入抑郁情绪的被试还是健康被试, 其生活中遭受的负性压力事件数量都与海马体积正相关(Zannas et al., 2013)。所以, 压力对海马体积的影响是多种复杂因素的共同结果, 还可能存在着物种间的差异。但尤其需要注意的是, 仅仅通过脑区整体层面的研究只能得到海马与压力的相关关系, 得益于无创性研究手段的进步, 未来的心理韧性研究会在更微观的水平上阐述其因果关系。此外, 抗逆力的研究还发现, 分布于海马的不同亚型的GABAB受体、5-HT受体亚型5-HT1A对抗逆力的行为表现有着不同的作用, 单一性的敲除这些不同亚型的受体都会使小鼠展现出易感相关的负性行为(Mineur et al., 2015; O’Leary et al., 2014)。

上述研究侧重从海马的解剖结构角度评估对抗逆力的影响, 目前仍缺少从功能连接角度开展的研究, 比如在活体动物上直接使用光遗传技术干预上述受体参与的神经投射, 以判断这些受体亚型对于正常功能的意义。

结合海马和mPFC不同亚区的研究, 说明仅仅观测脑区的整体活动对阐明心理韧性或抗逆力的神经机制是远远不够的, 脑区内部的不同亚区、受体的不同亚型, 还有脑区内部不同的神经递质变化都可能产生不同的调控作用, 而深入阐释脑区内更精准的活动机制主要取决于研究技术的进步。

2.2 抗逆力的脑环路机制

2.2.1 mPFC的下行环路

mPFC向中脑、后脑以及脑干等区域有着广泛的投射(图1), 并且可以抑制压力导致的HPA轴反应, 避免适应不良(Diorio, Viau, & Meaney, 1993; Franklin et al., 2012; Wang et al., 2014)。mPFC的谷氨酸能神经元投射至外侧缰核(lateral habenula, LHb), 利用光遗传技术特异性激活此通路导致小鼠产生抑郁样反应(Li et al., 2011; Warden et al., 2012), 激活mPFC投射至杏仁核(amygdala)的GABA能神经元也会产生类似效果(Martinez et al., 2013; Moscarello & LeDoux, 2013), 说明mPFC的谷氨酸能和GABA能输出都通过调控其下行脑区而影响抗逆力相关的行为表现, 但目前尚不清楚不同递质介导的行为表型间的关系。此外, mPFC投射至DRN的谷氨酸能神经元被激发后却提高了小鼠的高抗表现(Warden et al., 2012), 因此, 同一脑区对不同下行脑区发出的投射对抗逆力可能有不同的调控作用, 一种调控作用的实现取决于特定类型神经元在特定脑区间的活动, 对同一脑区进行结构上的细分并对其神经输入与输出进行整体性的干预才有望更有效地改善抗逆力的行为表现。需要指出的是, 以上研究都是以小鼠为研究对象, 目前还缺乏以人类或非人灵长类为被试的心理韧性的神经环路研究。

图1

图1   小鼠抗逆力的神经环路图。激活或抑制两个脑区之间的投射可以调控小鼠的抗逆力行为表型(修改自Russo & Nestler, 2013)。


2.2.2 海马-NAc

以不同形式干预动物的海马向NAc的投射对抗逆力有不同的调控作用。采用CSDS模型的小鼠研究表明, 相比于对照组, 高抗小鼠的腹侧海马(ventral hippocampus, vHIP)活动减弱, 易感小鼠却没有显著差异(Bagot et al., 2015)。利用光遗传技术激活腹侧海马投射至NAc的谷氨酸能神经元, 结果发现小鼠的抗逆力发生变化:当光遗传长时间抑制vHIP-NAc环路时, 小鼠的抗逆力增高, 而短时间急剧增强vHIP-NAc环路活动却效果相反, 并且这种效果仅仅存在于vHIP-NAc环路, 以同样的方式干预mPFC-NAc或基底外侧杏仁核(basolateral amygdala)-NAc环路都不会产生类似的行为反应(Bagot et al., 2015)。这些结果说明, 同一神经环路以不同形式被激活可能产生不同的调控作用, 时间因素不可忽略。

2.2.3 VTA-NAc

如前所述, VTA的多巴胺能神经元的动作电位不同发放模式影响小鼠抗逆力的高低, 进一步研究发现, 通过光遗传激活VTA投射至NAc的多巴胺能神经元相位性发放导致小鼠更加易感, 而激活mPFC投射至NAc的环路却不会产生类似的效果(Razzoli et al., 2011), 这说明VTA-NAc环路对于动物抗逆力的调控可能有着不可取代的独特作用, 但对于遭受同样CSDS刺激的大鼠, 其VTA发放频率并未增加, 由此看来VTA的电生理活动与抗逆力的关系可能存在物种特异性。此外, 对于采用CMS模型的小鼠, 光遗传激活其VTA多巴胺能神经元相位性发放改善了小鼠原有的抑郁样行为(Tye et al., 2013), 因此, VTA多巴胺能神经元的活动与压力适应行为间并非固定的一一对应关系, 最终的压力适应结果取决于压力形式、神经元发放类型及压力激活的脑神经环路等多种因素的整合。

VTA从其他脑区接收的神经输入同样可以影响小鼠的行为表现。蓝斑(locus coeruleus)与VTA存在着直接的解剖上的连接(Chandler, Lamperski, & Waterhouse, 2013)和复杂的功能传继(Guiard, El Mansari, & Blier, 2008), 比如去甲肾上腺素能神经元(noradrenergic neurons), 抑制蓝斑投射至VTA的去甲肾上腺素能神经元通路, 结果导致CSDS压力下的小鼠抗逆力更高, 并且该通路被抑制后VTA投射至NAc的多巴胺能神经元活动也会减弱(Isingrini et al., 2016)。此外, 传统的抑郁症治疗主要围绕着5-HT系统以及奖赏相关脑区, 去甲肾上腺素能神经元调控抗逆力的发现为人类抑郁症的治疗提供了新的可能性靶点。这一研究显示了VTA上游脑区对VTA、NAc两大抗逆力相关脑区的重要调控作用, 但这一机制的发现目前仅仅局限于CSDS类似的慢性压力模型, 在急性压力情境中蓝斑的调控作用是否依然有效尚待探索。

2.3 高抗动物可能具备特异神经特征

近年来, 对于不同抗逆力的动物, 针对以VTA-NAc为代表的多巴胺能系统的研究揭示出高抗动物拥有着不同于易感动物以及正常群体的特异性机制。研究表明, 不论是在体记录还是体外记录, 采用CSDS模型的易感小鼠, 其VTA多巴胺能神经元的动作电位发放频率都显著增高, 而高抗小鼠则保持正常, 并且VTA多巴胺能神经元的发放频率与社交回避的严重程度正相关(Cao et al., 2010; Feder et al., 2009; Krishnan et al., 2007)。长期使用抗抑郁药物氟西汀(fluoxetine)对易感小鼠进行治疗或光遗传激活其VTA多巴胺能神经元, 最后完全逆转了本有的多种负性伤害和行为反应, 但急性、短期的氟西汀治疗则没有该效果(Cao et al., 2010; Chaudhury et al., 2013)。这些研究虽然说明了高抗性有着不同于易感动物的神经机制变化, 但结果之间存在矛盾:为何易感小鼠相比于高抗小鼠VTA发放频率更高, 但使用光遗传进一步兴奋其VTA活动却改善了其本有的负性伤害?Friedman等人后续的一项研究在更微观的层面上解释了这一脑区整体活动的矛盾现象(Allyson K. Friedman et al., 2014)。Friedman等人发现, 相比于对照组, 易感小鼠VTA多巴胺能神经元过度活跃(hyperactivity)并伴随着神经元中超极化激活的阳离子电流显著增大, 其中钾(K+)通道电流的增大十分重要, 但令人意外的是, 高抗小鼠VTA多巴胺能神经元中超极化电流更大(Allyson K. Friedman et al., 2014)。进一步研究发现, 高抗小鼠VTA多巴胺能神经元中更大的超极化电流会导致多巴胺能神经元更高频率的发放, 但高抗小鼠神经元中增大的K+电流会同时诱发自我调整机制(self-tuning mechanism), 使过度活跃的神经发放回归正常。进一步增大易感小鼠的超极化电流或光遗传进一步增强其VTA多巴胺能神经元发放, 结果发现其本有的抑郁样行为被有效改善, 从而为自我调整机制提供了证据(Allyson K. Friedman et al., 2014)。后来的研究也得到了和自我调整机制相一致的结果。为易感小鼠注射一种慢电压激活的K+通道(KCNQ)开放剂(opener)瑞替加滨(retigabine), 导致其VTA多巴胺能神经元KCNQ过表达, 结果使其本有的神经元过度发放回归正常、抑郁样行为也被有效改善(Allyson K Friedman et al., 2016)。这些研究说明, KCNQ可能作为改善人类心理韧性的新靶点。但更为重要的是, 这些研究论证了一个新观点:高抗和易感动物并非是压力适应的两个极端, 改善或逆转易感个体的负性表现并不等同于高抗或达到了普遍的正常水准, 高抗个体在特定压力情形下的适应有其独特的机制。

在高抗动物拥有特异性神经机制的论点提出之前, 有学者以人类为研究对象提出了类似观点。于肖楠和张建新在论述“resilience”译法时认为, 心理韧性不仅意味着个体能在重大创伤或应激之后恢复最初的状态, 更强调个体在挫折后的成长和新生, 这也是resilience被译为“韧性”的最大原因(于肖楠, 张建新, 2005), 但这种观点的根据是中国文化以及一些行为层面的证据。从2012年研究者第一次依据神经机制方面的证据, 提出“高抗动物可能有着不同于易感以及正常群体的独特机制” (Russo et al., 2012), 到2014年高抗的特异性神经机制被明确揭示, 围绕该论点的探讨越来越多, 这不仅为改善心理韧性的干预疗法提供了新思路, 也为相关精神障碍药物的开发提供了新的潜在靶点。

3 总结与展望

压力对人类身心健康、认知能力以及情绪稳定有巨大的影响, 并且在保护个体远离压力相关的精神疾病方面具有重要作用(McEwen et al., 2015), 其行为表现与众多高级认知机能或情绪有关, 比如认知重评(Cognitive reappraisal)、乐观主义(optimism)、积极的处理策略(active coping strategies)等(Feder et al., 2009), 最终导致其神经机制异常复杂也是情理之中。早期的韧性研究主要关注于高韧性与易感性的差异, 近些年的研究则转向理解心理韧性对压力的具体适应过程, 从而寻找更好的改善手段以及对压力相关疾病的治疗方法。2010年以来, 依据抗逆力动物模型的研究, 提出了“高抗动物可能有着不同于易感以及正常群体的独特机制”的观点, 同时揭示了去甲肾上腺素能神经元、KCNQ等潜在的药物靶点, 使人们对心理韧性的压力适应机制有了更加清晰的认识。在取得显著进展的同时, 有一些问题还需要被注意, 并在未来着力进行解决。

首先, 目前有关心理韧性神经机制的研究大多以非人类哺乳动物为研究对象, 以人类为直接研究对象、针对其韧性的神经机制的研究还比较少。虽然非人类哺乳动物与人类有着进化上共享的神经机制, 但并非简单的对应关系, 抗逆力研究得出的、被广泛承认的结果应该如何迁移到人类身上, 进而拓展对人类心理韧性神经机制的认识, 这仍然是一大问题。fMRI、深部脑刺激、脑磁图等无创探索人类神经活动的技术, 与神经科学众多有创但十分有力的方法结合, 将是解决这一问题的有效途径。再次, 运用多种抗逆力动物模型得出的结果存在着自相矛盾的现象, 整合并制定抗逆力研究的统一标准是十分必要的。最后, 也是最关键的问题, 既然单纯的逆转易感所表现出来的负性伤害并不等同于高抗, 那么从生理机制的角度出发, 如何看待高抗与易感的关系将对如何改善心理韧性或抗逆力的尝试产生重要影响。未来应整合多方技术与资源, 对这些问题进行更具生态效度的探究。

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URL     PMID:26422005      [本文引用: 1]

We examined the neurobiological mechanisms underlying stress susceptibility using structural magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI) to determine neuroanatomical differences between stress-susceptible and resilient mice. We also examined synchronized anatomical differences between brain regions to gain insight into the plasticity of neural networks underlying stress susceptibility. C57/Bl6 mice underwent 10 days of social defeat stress and were subsequently tested for social avoidance. For MRI, brains of stressed (susceptible n=11, resilient n=8) and control (n=12) mice were imaged ex vivo at 56碌m resolution using a T2-weighted sequence. We tested for behavior-structure correlations by regressing social avoidance z-scores against local brain volume. For DTI, brains were scanned with a diffusion-weighted fast-spin echo sequence at 78渭m isotropic voxels. Structural covariance was assessed by correlating local volume between brain regions. Social avoidance correlated negatively with local volume of the cingulate cortex, nucleus accumbens, thalamus, raph茅 nuclei and bed nucleus of the stria terminals. Social avoidance correlated positively with volume of the ventral tegmental area (VTA), habenula, periaqueductal grey, cerebellum, hypothalamus, and hippocampal CA3. Fractional anisotropy (FA) was increased in the hypothalamus and hippocampal CA3. We observed synchronized anatomical differences between the VTA and cingulate cortex, the hippocampus and VTA, hippocampus and cingulate cortex, and hippocampus and hypothalamus. These correlations revealed different structural covariance between brain regions in susceptible and resilient mice. Stress-integrative brain regions shape the neural architecture underlying individual differences in susceptibility and resilience to chronic stress.

Bagot R. C., Parise E. M., Peñna C. J., Zhang H-X., Maze I., Chaudhury D., .. Nestler E. J . ( 2015).

Ventral hippocampal afferents to the nucleus accumbens regulate susceptibility to depression

Nature Communications, 6, 7062.

URL     PMID:4430111      [本文引用: 2]

Enhanced glutamatergic transmission in the nucleus accumbens (NAc), a region critical for reward and motivation, has been implicated in the pathophysiology of depression; however, the afferent source of this increased glutamate tone is not known. The NAc receives glutamatergic inputs from the medial prefrontal cortex (mPFC), ventral hippocampus (vHIP) and basolateral amygdala (AMY). Here, we demonstrate that glutamatergic vHIP afferents to NAc regulate susceptibility to chronic social defeat stress (CSDS). We observe reduced activity in vHIP in mice resilient to CSDS. Furthermore, attenuation of vHIP-NAc transmission by optogenetic induction of long-term depression is pro-resilient, whereas acute enhancement of this input is pro-susceptible. This effect is specific to vHIP afferents to the NAc, as optogenetic stimulation of either mPFC or AMY afferents to the NAc is pro-resilient. These data indicate that vHIP afferents to NAc uniquely regulate susceptibility to CSDS, highlighting an important, novel circuit-specific mechanism in depression. Enhanced glutamatergic transmission in the nucleus accumbens (NAc) has been implicated in the pathophysiology of depression, yet the underlying source is not known. Here, the authors demonstrate a unique role for ventral hippocampal-NAc glutamatergic projections in regulating depression-like behaviour.

Berton O., Covington H. E., Ebner K., Tsankova N. M., Carle T. L., Ulery P., .. Nestler E. J . ( 2007).

Induction of delta FosB in the periaqueductal gray by stress promotes active coping responses

Neuron, 56( 3), 574-574.

URL     PMID:17640529      [本文引用: 1]

We analyzed the influence of the transcription factor ΔFosB on learned helplessness, an animal model of affective disorder wherein a subset of mice exposed to inescapable stress (IS) develop a deficit in escape behavior. Repeated IS induces ΔFosB in the ventrolateral periaqueductal gray (vlPAG), and levels of the protein are highly predictive of an individual's subsequent behavorial deficit—with the strongest ΔFosB induction observed in the most resilient animals. Induction of ΔFosB by IS predominates in substance P-positive neurons in the vlPAG, and the substance P gene, a direct target for ΔFosB, is downregulated upon ΔFosB induction. Local overexpression of ΔFosB in the vlPAG using viral-mediated gene transfer dramatically reduces depression-like behaviors and inhibits stress-induced release of substance P. These results indicate that IS-induced accumulation of ΔFosB in the vlPAG desensitizes substance P neurons enriched in this area and opposes behavioral despair by promoting active defense responses.

Brachman R. A., McGowan J. C., Perusini J. N., Lim S. C., Pham T. H., Faye C., .. Denny C. A . ( 2016).

Ketamine as a prophylactic against stress-induced depressive-like behavior

Biological Psychiatry, 79( 9), 776-786.

URL     PMID:4633406      [本文引用: 1]

Stress exposure is one of the greatest risk factors for psychiatric illnesses like major depressive disorder and posttraumatic stress disorder. However, not all individuals exposed to stress develop affective disorders. Stress resilience, the ability to experience stress without developing persistent psychopathology, varies from individual to individual. Enhancing stress resilience in at-risk populations could potentially protect against stress-induced psychiatric disorders. Despite this fact, no resilience-enhancing pharmaceuticals have been identified. Using a chronic social defeat (SD) stress model, learned helplessness (LH), and a chronic corticosterone (CORT) model in mice, we tested if ketamine could protect against depressive-like behavior. Mice were administered a single dose of saline or ketamine and then 1 week later were subjected to 2 weeks of SD, LH training, or 3 weeks of CORT. SD robustly and reliably induced depressive-like behavior in control mice. Mice treated with prophylactic ketamine were protected against the deleterious effects of SD in the forced swim test and in the dominant interaction test. We confirmed these effects in LH and the CORT model. In the LH model, latency to escape was increased following training, and this effect was prevented by ketamine. In the CORT model, a single dose of ketamine blocked stress-induced behavior in the forced swim test, novelty suppressed feeding paradigm, and the sucrose splash test. These data show that ketamine can induce persistent stress resilience and, therefore, may be useful in protecting against stress-induced disorders.

Burt K. B., Whelan R., Conrod P. J., Banaschewski T., Barker G. J., Bokde A. L. W., .. Consortium I . ( 2016).

Structural brain correlates of adolescent resilience

Journal of Child Psychology and Psychiatry, 57( 11), 1287-1296.

URL     PMID:27079174      [本文引用: 1]

Abstract BackgroundDespite calls for integration of neurobiological methods into research on youth resilience (high competence despite high adversity), we know little about structural brain correlates of resilient functioning. The aim of the current study was to test for brain regions uniquely associated with positive functioning in the context of adversity, using detailed phenotypic classification. Methods1,870 European adolescents ( M age02=0214.5602years, SD age02=020.4402years, 51.5% female) underwent MRI scanning and completed behavioral and psychological measures of stressful life events, academic competence, social competence, rule-abiding conduct, personality, and alcohol use. ResultsThe interaction of competence and adversity identified two regions centered on the right middle and superior frontal gyri; grey matter volumes in these regions were larger in adolescents experiencing adversity who showed positive adaptation. Differences in these regions among competence/adversity subgroups were maintained after controlling for several covariates and were robust to alternative operationalization decisions for key constructs. ConclusionsWe demonstrate structural brain correlates of adolescent resilience, and suggest that right prefrontal structures are implicated in adaptive functioning for youth who have experienced adversity.

Cao J.-L., Covington H. E., Friedman A. K., Wilkinson M. B., Walsh J. J., Cooper D. C., .. Han M.-H . ( 2010).

Mesolimbic dopamine neurons in the brain reward circuit mediate susceptibility to social defeat and antidepressant action

Journal Of Neuroscience, 30( 49), 16453-16458.

URL     [本文引用: 2]

Chandler D. J., Lamperski C. S., & Waterhouse B. D . ( 2013).

Identification and distribution of projections from monoaminergic and cholinergic nuclei to functionally differentiated subregions of prefrontal cortex

Brain Research, 1522, 38-58.

URL     PMID:23665053      [本文引用: 1]

61Nucleus basalis cells innervate multiple prefrontal cortical subregions.61VTA cells typically innervate a single prefrontal cortical subregion.61DRN neurons typically innervate a single prefrontal cortical subregion.61LC neurons typically innervate a single prefrontal cortical subregion.

Chang C-H. & Grace, A.A . ( 2014).

Amygdala-ventral pallidum pathway decreases dopamine activity after chronic mild stress in rats

Biological Psychiatry, 76( 3), 223-230.

URL     PMID:24209776      [本文引用: 1]

Major depressive disorder affects more than 15% of the population across their lifespan. In this study, we used the well-characterized unpredictable chronic mild stress (CMS) model of depression to examine this condition. Sprague-Dawley rats were presented randomly with mild stressors for 4 weeks, with body weight and sucrose intake monitored weekly. Locomotor activity and elevated plus maze test/forced swim test were conducted on Week 5; ventral tegmental area dopamine (DA) neuron activity was assessed within 1 week after the behavioral test with three indices: DA neuron population activity (defined as the number of spontaneously firing DA neurons); mean firing rate; and percent burst firing (i.e., the proportion of action potentials occurring in bursts). Consistent with previous studies, we found that, compared with control subjects, rats that underwent the CMS procedure were slower in gaining body weight and developed anxiety- and despair-like behavior. We now report a significant decrease in DA neuron population activity of CMS rats, and this decrease is restored by pharmacologically attenuating the activity of either the basolateral nucleus of the amygdala (BLA) or the ventral pallidum (VP). Moreover, pharmacological activation of the amygdala in nonstressed rats decreases DA neuron population activity similar to that with CMS, which is reversed by blocking the BLA-VP pathway. The CMS rat depression model is associated with a BLA-VP-ventral tegmental area inhibition of DA neuron activity. This information can provide insight into the circuitry underlying major depressive disorder and serve as a template for refining therapeutic approaches to this disorder.

Chaudhury D., Walsh J. J., Friedman A. K., Juarez B., Ku S. M., Koo J. W., .. Han M-H . ( 2013).

Rapid regulation of depression-related behaviours by control of midbrain dopamine neurons

Nature, 49( 7433), 532-536.

URL     PMID:3554860      [本文引用: 1]

Ventral tegmental area(VTA) dopamine neurons in the brain's reward circuit have a crucial role in mediating stress responses(1-4), including determining susceptibility versus resilience to social-stress-induced behavioural abnormalities(5). VTA dopamine neurons show two in vivo patterns of firing: low frequency tonic firing and high frequency phasic firing(6-8). Phasic firing of the neurons, which is well known to encode reward signals(6,7,9), is upregulated by repeated social-defeat stress, a highly validated mouse model of depression(5,8,10-13). Surprisingly, this pathophysiological effect is seen in susceptible mice only, with no apparent change in firing rate in resilient individuals(5,8). However, direct evidence-in real time-linking dopamine neuron phasic firing in promoting the susceptible (depression-like) phenotype is lacking. Here we took advantage of the temporal precision and cell-type and projection-pathway specificity of optogenetics to show that enhanced phasic firing of these neurons mediates susceptibility to social-defeat stress in freely behaving mice. We show that optogenetic induction of phasic, but not tonic, firing in VTA dopamine neurons of mice undergoing a subthreshold social-defeat paradigm rapidly induced a susceptible phenotype as measured by social avoidance and decreased sucrose preference. Optogenetic phasic stimulation of these neurons also quickly induced a susceptible phenotype in previously resilient mice that had been subjected to repeated social-defeat stress. Furthermore, we show differences in projection-pathway specificity in promoting stress susceptibility: phasic activation of VTA neurons projecting to the nucleus accumbens (NAc), but not to the medial prefrontal cortex (mPFC), induced susceptibility to social-defeat stress. Conversely, optogenetic inhibition of the VTA-NAc projection induced resilience, whereas inhibition of the VTA-mPFC projection promoted susceptibility. Overall, these studies reveal novel firing-pattern-and neural-circuit-specific mechanisms of depression.

Covington. H. E., Lobo M. K., Maze I., Vialou V., Hyman J. M., Zaman S., .. Nestler E. J . ( 2010).

Antidepressant effect of optogenetic stimulation of the medial prefrontal cortex

Journal of Neuroscience, 30( 48), 16082-16090.

URL     [本文引用: 3]

Diorio D., Viau V., & Meaney M. J . ( 1993).

The role of the medial prefrontal cortex (cingulate gyrus) in the regulation of hypothalamic-pituitary-adrenal responses to stress

The Journal of Neuroscience, 13( 9), 3839-3847.

URL     PMID:8396170      [本文引用: 1]

Abstract In the studies reported here we have examined the role of the medial prefrontal cortex (MpFC) in regulating hypothalamic-pituitary-adrenal (HPA) activity under basal and stressful conditions. In preliminary studies we characterized corticosteroid receptor binding in the rat MpFC. The results revealed high-affinity (Kd approximately 1 nM) binding with a moderate capacity (42.9 +/- 3 fmol/mg) for 3H-aldosterone (with a 50-fold excess of cold RU28362; mineralocorticoid receptor) and high-affinity (Kd approximately 0.5-1.0 nM) binding with higher capacity (183.2 +/- 22 fmol/mg) for 3H-RU 28362 (glucocorticoid receptor). Lesions of the MpFC (cingulate gyrus) significantly increased plasma levels of both adrenocorticotropin (ACTH) and corticosterone (CORT) in response to a 20 min restraint stress. The same lesions had no effect on hormone levels following a 2.5 min exposure to ether. Implants of crystalline CORT into the same region of the MpFC produced a significant decrease in plasma levels of both ACTH and CORT with restraint stress, but again, there was no effect with ether stress. Neither MpFC lesions nor CORT implants had any consistent effect on A.M. or P.M. levels of plasma ACTH or CORT. Manipulations of MpFC function were not associated with changes in the clearance rate for CORT or in corticosteroid receptor densities in the pituitary, hypothalamus, hippocampus, or amygdala. Taken together, these findings suggest that MpFC is a target site for the negative-feedback effects of glucocorticoids on stress-induced HPA activity, and that this effect is dependent upon the nature of the stress.

Drevets W. C., Savitz J., & Trimble M . ( 2008).

The subgenual anterior cingulate cortex in mood disorders

CNS Spectr, 13( 8), 663-681.

URL     [本文引用: 1]

El Yacoubi M., Bouali S., Popa D., Naudon L., Leroux- Nicollet I., Hamon M., .. Vaugeois J. M . ( 2003).

Behavioral, neurochemical, and electrophysiological characterization of a genetic mouse model of depression

Proc Natl Acad Sci USA, 100( 10), 6227-6232.

URL     PMID:12732720      [本文引用: 1]

Depression is a multifactorial illness and genetic factors play a role in its etiology. The understanding of its physiopathology relies on the availability of experimental models potentially mimicking the disease. Here we describe a model built up by selective breeding of mice with strikingly different responses in the tail suspension test, a stress paradigm aimed at screening potential antidepressants. Indeed, "helpless" mice are essentially immobile in the tail suspension test, as well as the Porsolt forced-swim test, and they show reduced consumption of a palatable 2% sucrose solution. In addition, helpless mice exhibit sleep-wakefulness alterations resembling those classically observed in depressed patients, notably a lighter and more fragmented sleep, with an increased pressure of rapid eye movement sleep. Compared with "nonhelpless" mice, they display higher basal seric corticosterone levels and lower serotonin metabolism index in the hippocampus. Remarkably, serotonin1A autoreceptor stimulation induces larger hypothermia and inhibition of serotoninergic neuronal firing in the nucleus raphe dorsalis in helpless than in nonhelpless mice. Thus, helpless mice exhibit a decrease in serotoninergic tone, which evokes that associated with endogenous depression in humans. Finally, both the behavioral impairments and the serotoninergic dysfunction can be improved by chronic treatment with the antidepressant fluoxetine. The helpless line of mice may provide an opportunity to approach genes influencing susceptibility to depression and to investigate neurophysiological and neurochemical substrates underlying antidepressant effects.

Ergang P., Vodička M., Soták M., Klusoňová P., Behuliak M., Řeháková L., .. Pácha J . ( 2015).

Differential impact of stress on hypothalamic-pituitary-adrenal axis: Gene expression changes in Lewis and Fisher rats

Psychoneuroendocrinology, 53, 49-59.

URL     PMID:25591115      [本文引用: 1]

The aim of the present work was to study the influence of variable stress on the expression of 11尾-hydroxysteroid dehydrogenase type 1 (11HSD1) and the neuropeptides corticotropin-releasing hormone (CRH), urocortins 2 and 3(UCN2, UCN3), arginine vasopressin (AVP), oxytocin (OXT) and adenylate cyclase-activating polypeptide (PACAP) in two inbred rat strains: stress hypo-responsive Lewis (LEW) and hyper-responsive Fisher 344 (F344) rats. We found site-specific and strain-dependent differences in the basal and stress-stimulated expression of 11HSD1, CRH, UCN2, UCN3 and PACAP. In LEW rats, stress upregulated 11HSD1 in the prefrontal cortex and lateral amygdala, whereas in F344 rats 11HSD1 was upregulated in the central amygdala and hippocampal CA2 and ventral but not dorsal CA1 region; no effect was observed in the paraventricular nucleus, pituitary gland and adrenal cortex of both strains. The expression of glucocorticoid receptors did not parallel the upregulation of 11HSD1. Stress also stimulated the expression of paraventricular OXT, CRH, UCN3 and PACAP in both strains but amygdalar CRH only in LEW and UCN2/UCN3 in F344 rats, respectively. The upregulation of PACAP and CRH was paralleled only by increased expression of PACAP receptor PAC1 but not CRH receptor type 1. These observations provide evidence that inbred F344 and LEW rats exhibit not only the well-known phenotypic differences in the activity of the HPA axis but also strain- and stress-dependent differences in the expression of genes encoding 11HSD1 and neuropeptides associated with the HPA axis activity. Moreover, the differences in 11HSD1 expression suggest different local concentration of corticosterone and access to GR in canonical and noncanonical structures of the HPA axis.

Feder A., Nestler E. J., & Charney D. S . ( 2009).

Psychobiology and molecular genetics of resilience

Nature Reviews Neuroscience, 10( 6), 446-457.

URL     [本文引用: 6]

Fletcher D. & Sarkar, M. ( 2013).

Psychological resilience: A review and critique of definitions, concepts, and theory

European Psychologist, 18( 1), 12-23.

URL     [本文引用: 1]

Franceschelli A., Herchick S., Thelen C., Papadopoulou- Daifoti Z., & Pitychoutis P. M . ( 2014).

Sex differences in the chronic mild stress model of depression

Behavioural Pharmacology, 25( 5-6), 372-383.

URL     PMID:25025701      [本文引用: 1]

Abstract A large volume of clinical and experimental evidence documents sex differences in brain anatomy, chemistry, and function, as well as in stress and drug responses. The chronic mild stress model (CMS) is one of the most extensively investigated animal models of chronic stress. However, only a limited number of studies have been conducted in female rodents despite the markedly higher prevalence of major depression among women. Herein, we review CMS studies conducted in rats and mice of both sexes and further discuss intriguing sex-dependent behavioral and neurobiological findings. The PubMed literature search engine was used to find and collect all relevant articles analyzed in this review. Specifically, a multitermed search was performed with 'chronic mild stress', 'chronic unpredictable stress' and 'chronic variable stress' as base terms and 'sex', 'gender', 'females' and 'depression' as secondary terms in various combinations. Male and female rodents appear to be differentially affected by CMS application, depending on the behavioral, physiological, and neurobiological indices that are being measured. Importantly, the CMS paradigm, despite its limitations, has been successfully used to assess a constellation of interdisciplinary research questions in the sex differences field and has served as a 'silver bullet' in assessing the role of sex in the neurobiology of major depression.

Francis T. C., Chandra R., Friend D. M., Finkel E., Dayrit G., Miranda J., .. Lobo M. K . ( 2015).

Nucleus accumbens medium spiny neuron subtypes mediate depression-related outcomes to social defeat stress

Biological Psychiatry, 77( 3), 212-222.

URL     PMID:25173629      [本文引用: 1]

The nucleus accumbens is a critical mediator of depression-related outcomes to social defeat stress. Previous studies demonstrate distinct neuroplasticity adaptations in the two medium spiny neuron (MSN) subtypes, those enriched in dopamine receptor D1 versus dopamine receptor D2, in reward and reinforcement leading to opposing roles for these MSNs in these behaviors. However, the distinct roles of nucleus accumbens MSN subtypes, in depression, remain poorly understood. Using whole-cell patch clamp electrophysiology, we examined excitatory input to MSN subtypes and intrinsic excitability measures in D1-green fluorescent protein and D2-green fluorescent protein bacterial artificial chromosome transgenic mice that underwent chronic social defeat stress (CSDS). Optogenetic and pharmacogenetic approaches were used to bidirectionally alter firing of D1-MSNs or D2-MSNs after CSDS or before a subthreshold social defeat stress in D1-Cre or D2-Cre bacterial artificial chromosome transgenic mice. We demonstrate that the frequency of excitatory synaptic input is decreased in D1-MSNs and increased in D2-MSNs in mice displaying depression-like behaviors after CSDS. Enhancing activity in D1-MSNs results in resilient behavioral outcomes, while inhibition of these MSNs induces depression-like outcomes after CSDS. Bidirectional modulation of D2-MSNs does not alter behavioral responses to CSDS; however, repeated activation of D2-MSNs in stress na ve mice induces social avoidance following subthreshold social defeat stress. Our studies uncover novel functions of MSN subtypes in depression-like outcomes. Notably, bidirectional alteration of D1-MSN activity promotes opposite behavioral outcomes to chronic social stress. Therefore, targeting D1-MSN activity may provide novel treatment strategies for depression or other affective disorders.

Franklin T. B., Saab B. J., & Mansuy I. M . ( 2012).

Neural mechanisms of stress resilience and vulnerability

Neuron, 75( 5), 747-761.

URL     [本文引用: 2]

Friedman, A. ( 2014).

Jump-starting natural resilience reverses stress susceptibility

Science, 346( 6209), 555.

URL     PMID:25359955      [本文引用: 1]

Novel therapy for treating depression Author: Allyson Friedman

Friedman A. K., Juarez B., Ku S. M., Zhang H., Calizo R. C., Walsh J. J., .. Dietz D. M . ( 2016).

KCNQ channel openers reverse depressive symptoms via an active resilience mechanism

Nature Communications, 7, 11671.

URL     PMID:27216573      [本文引用: 1]

Less than half of patients suffering from major depressive disorder, a leading cause of disability worldwide, achieve remission with current antidepressants, making it imperative to develop more effective treatment. A new therapeutic direction is emerging from the increased understanding of natural resilience as an active stress-coping process. It is known that potassium (K+) channels in the ventral tegmental area (VTA) are an active mediator of resilience. However, no druggable targets have been identified to potentiate active resilience mechanisms. In the chronic social defeat stress model of depression, we report that KCNQ-type K+channel openers, including FDA-approved drug retigabine (ezogabine), show antidepressant efficacy. We demonstrate that overexpression of KCNQ channels in the VTA dopaminergic neurons and either local infusion or systemic administration of retigabine normalized neuronal hyperactivity and depressive behaviours. These findings identify KCNQ as a target for conceptually novel antidepressants that function through the potentiation of active resilience mechanisms. Potassium channels in the ventral tegmental area are known to regulate resilience against stress-induced depression. Here, the authors show over expression of KCNQ3 channels in VTA dopaminergic neurons or treatment with KCNQ channel openers normalizes depressive behaviours in mouse models.

Friedman A. K., Walsh J. J., Juarez B., Ku S. M., Chaudhury D., Wang J., .. Han M.-H . ( 2014).

Enhancing depression mechanisms in midbrain dopamine neurons achieves homeostatic resilience

Science, 344( 6181), 313-319.

URL     [本文引用: 4]

Golden S. A., Covington Ⅲ H. E., Berton O., & Russo S. J . ( 2011).

A standardized protocol for repeated social defeat stress in mice

Nat Protoc, 6( 8), 1183-1191.

URL     PMID:21799487      [本文引用: 1]

A major impediment to novel drug development has been the paucity of animal models that accurately reflect symptoms of affective disorders. In animal models, prolonged social stress has proven to be useful in understanding the molecular mechanisms underlying affective-like disorders. When considering experimental approaches for studying depression, social defeat stress, in particular, has been shown to have excellent etiological, predictive, discriminative and face validity. Described here is a protocol whereby C57BL/6J mice that are repeatedly subjected to bouts of social defeat by a larger and aggressive CD-1 mouse results in the development of a clear depressive-like syndrome, characterized by enduring deficits in social interactions. Specifically, the protocol consists of three important stages, beginning with the selection of aggressive CD-1 mice, followed by agonistic social confrontations between the CD-1 and C57BL/6J mice, and concluding with the confirmation of social avoidance in subordinate C57BL/6J mice. The automated detection of social avoidance allows a marked increase in throughput, reproducibility and quantitative analysis. This protocol is highly adaptable, but in its most common form it requires 3-4 weeks for completion.

Grace A. A., West A., Ash B., Moore H., & Floresco S. B . ( 2003).

Tonic versus phasic DA release in the nucleus accumbens is differentially regulated by pathways that selectively alter DA neuron spontaneous activity and burst firing

Schizophrenia Research, 60( 1), 106-107.

URL     [本文引用: 1]

Background: Reports relating phenylalanine kinetics and metabolism to psychiatric disorders led us to undertake the comprehensive screening of the phenylalanine hydroxylase (PAH) coding region and functional testing of discovered mutations in a sample of psychiatric patients and healthy control subjects. Methods: Genomic DNA from psychiatric patients and control subjects was assayed for sequence variants in all PAH coding regions and splice junctions. In vivo functional analysis of mutations was conducted by assessing the kinetics and conversion to tyrosine of a standardized phenylalanine dose and by measuring fasting pterin levels. Results: A known missense mutation was observed in a schizoaffective subject, and a novel missense mutation was discovered in four subjects with schizophrenia and one normal subject. The schizoaffective patient heterozygous for the known A403V mutation showed the lowest rate of phenylalanine kinetics and lowest conversion to tyrosine in the patient sample. The four schizophrenic patients heterozygous for the novel K274E mutation showed significantly decreased phenylalanine kinetics, reduced conversion to tyrosine, and increased synthesis of the PAH cofactor tetrahydrobiopterin compared with schizophrenic subjects without the mutation. Conclusions: The study findings suggest that larger scale studies are warranted to test the relationship of the PAH genotype with a psychiatric phenotype. (C) 2003 Society, of Biological Psychiatry.

Guiard B. P., El Mansari M., & Blier P . ( 2008).

Cross-talk between dopaminergic and noradrenergic systems in the rat ventral tegmental area, locus ceruleus, and dorsal hippocampus

Molecular Pharmacology, 74( 5), 1463-1475.

URL     [本文引用: 1]

Haber S.N., & Knutson, B. ( 2010).

The Reward Circuit: Linking Primate Anatomy and Human Imaging

Neuropsychopharmacology, 35( 1), 4-26.

URL     [本文引用: 2]

Hamani C., Mayberg H., Stone S., Laxton A., Haber S., & Lozano A. M . ( 2011).

The subcallosal cingulate gyrus in the context of major depression

Biological Psychiatry, 69( 4), 301-308.

URL     PMID:21145043      [本文引用: 1]

The subcallosal cingulate gyrus (SCG), including Brodmann area 25 and parts of 24 and 32, is the portion of the cingulum that lies ventral to the corpus callosum. It constitutes an important node in a network that includes cortical structures, the limbic system, thalamus, hypothalamus, and brainstem nuclei. Imaging studies have shown abnormal SCG metabolic activity in patients with depression, a pattern that is reversed by various antidepressant therapies. The involvement of the SCG in mechanisms of depression and its emerging potential role as a surgical target for deep brain stimulation has focused recent interest in this area. We review anatomic and histologic attributes of the SCG and the morphologic and imaging changes observed in depression. Particular attention is given to the regional and downstream structures that could be influenced by the application of deep brain stimulation in this region.

Han M.-H. & Nestler, E.J . ( 2017).

Neural substrates of depression and resilience

Neurotherapeutics, 14( 3), 677-686.

URL     PMID:28397115      [本文引用: 1]

There is an urgent need for more effective medications to treat major depressive disorder, as fewer than half of depressed patients achieve full remission and many are not responsive with currently available antidepressant medications or psychotherapy. It is known that prolonged stressful events are an important risk factor for major depressive disorder. However, there are prominent individual variations in response to stress: a relatively small proportion of people (10-20%) experiencing prolonged stress develop stress-related psychiatric disorders, including depression (susceptibility to stress), whereas most stress-exposed individuals maintain normal psychological functioning (resilience to stress). There have been growing efforts to investigate the neural basis of susceptibility versus resilience to depression. An accumulating body of evidence is revealing the genetic, epigenetic, and neurophysiological mechanisms that underlie stress susceptibility, as well as the active mechanisms that underlie the resilience phenotype. In this review, we discuss, mainly based on our own work, key pathological mechanisms of susceptibility that are identified as potential therapeutic targets for depression treatment. We also review novel mechanisms that promote natural resilience as an alternative strategy to achieve treatment efficacy. These studies are opening new avenues to develop conceptually novel therapeutic strategies for depression treatment.

Hill M. N., Hellemans K. G. C., Verma P., Gorzalka B. B., & Weinberg J . ( 2012).

Neurobiology of chronic mild stress: Parallels to major depression

Neuroscience & Biobehavioral Reviews, 36( 9), 2085-2117.

URL     PMID:22776763      [本文引用: 1]

The chronic mild (or unpredictable/variable) stress (CMS) model was developed as an animal model of depression more than 20 years ago. The foundation of this model was that following long-term exposure to a series of mild, but unpredictable stressors, animals would develop a state of impaired reward salience that was akin to the anhedonia observed in major depressive disorder. In the time since its inception, this model has also been used for a variety of studies examining neurobiological variables that are associated with depression, despite the fact that this model has never been critically examined to validate that the neurobiological changes induced by CMS are parallel to those documented in depressive disorder. The aim of the current review is to summarize the current state of knowledge regarding the effects of chronic mild stress on neurobiological variables, such as neurochemistry, neurochemical receptor expression and functionality, neurotrophin expression and cellular plasticity. These findings are then compared to those of clinical research examining common variables in populations with depressive disorders to determine if the changes observed following chronic mild stress are in fact consistent with those observed in major depression. We conclude that the chronic mild stress paradigm: (1) evokes an array of neurobiological changes that mirror those seen in depressive disorders and (2) may be a suitable tool to investigate novel systems that could be disturbed in depression, and thus aid in the development of novel targets for the treatment of depression.

Hodes G. E., Pfau M. L., Purushothaman I., Ahn H. F., Golden S. A., Christoffel D. J., .. Russo S. J . ( 2015).

Sex differences in nucleus accumbens transcriptome profiles associated with susceptibility versus resilience to subchronic variable stress

Journal of Neuroscience, 35( 50), 16362-16376.

URL     PMID:4679819      [本文引用: 1]

Depression and anxiety disorders are more prevalent in females, but the majority of research in animal models, the first step in finding new treatments, has focused predominantly on males. Here we report that exposure to subchronic variable stress (SCVS) induces depression-associated behaviors in female mice, whereas males are resilient as they do not develop these behavioral abnormalities. In concert with these different behavioral responses, transcriptional analysis of nucleus accumbens (NAc), a major brain reward region, by use of RNA sequencing (RNA-seq) revealed markedly different patterns of stress regulation of gene expression between the sexes. Among the genes displaying sex differences was DNA methyltransferase 3a (Dnmt3a), which shows a greater induction in females after SCVS. Interestingly, Dnmt3a expression levels were increased in the NAc of depressed humans, an effect seen in both males and females. Local overexpression of Dnmt3a in NAc rendered male mice more susceptible to SCVS, whereas Dnmt3a knock-out in this region rendered females more resilient, directly implicating this gene in stress responses. Associated with this enhanced resilience of female mice upon NAc knock-out of Dnmt3a was a partial shift of the NAc female transcriptome toward the male pattern after SCVS. These data indicate that males and females undergo different patterns of transcriptional regulation in response to stress and that a DNA methyltransferase in NAc contributes to sex differences in stress vulnerability.SIGNIFICANCE STATEMENT Women have a higher incidence of depression than men. However, preclinical models, the first step in developing new diagnostics and therapeutics, have been performed mainly on male subjects. Using a stress-based animal model of depression that causes behavioral effects in females but not males, we demonstrate a sex-specific transcriptional profile in brain reward circuitry. This transcriptional profile can be altered by removal of an epigenetic mechanism, which normally suppresses DNA transcription, creating a hybrid male/female transcriptional pattern. Removal of this epigenetic mechanism also induces behavioral resilience to stress in females. These findings shed new light onto molecular factors controlling sex differences in stress response.

Iñiguez S. D., Riggs L. M., Nieto S. J., Dayrit G., Zamora N. N., Shawhan K. L., .. Warren B. L . ( 2014).

Social defeat stress induces a depression-like phenotype in adolescent male c57BL/6 mice

Stress-the International Journal on the Biology of Stress, 17( 3), 247-255.

URL     PMID:5534169      [本文引用: 1]

Exposure to stress is highly correlated with the emergence of mood-related illnesses. Because major depressive disorder often emerges in adolescence, we assessed the effects of social defeat stress on responses to depressive-like behaviors in juvenile mice. To do this, postnatal day (PD) 35 male c57BL/6 mice were exposed to 10 days of social defeat stress (PD35-44), while control mice were handled daily. Twenty-four hours after the last episode of defeat (PD45), separate groups of mice were tested in the social interaction, forced swimming, sucrose preference, and elevated plus-maze behavioral assays (n = 7 12 per group). Also, we examined body weight gain across days of social defeat and levels of blood serum corticosterone 40 min after the last episode of defeat stress. Our data indicates that defeated mice exhibited a depressive-like phenotype as inferred from increased social avoidance, increased immobility in the forced swim test, and reduced sucrose preference (a measure of anhedonia), when compared to non-defeated controls. Defeated mice also displayed an anxiogenic-like phenotype when tested on the elevated plus-maze. Lastly, stressed mice displayed lower body weight gain, along with increased blood serum corticosterone levels, when compared to non-stressed controls. Overall, we show that in adolescent male c57BL/6 mice, social defeat stress induces a depression- and anxiety-like phenotype 24 h after the last episode of stress. These data suggest that the social defeat paradigm may be used to examine the etiology of stress-induced mood-related disorders during adolescence.

Isingrini E., Perret L., Rainer Q., Amilhon B., Guma E., Tanti A., .. Giros B . ( 2016).

Resilience to chronic stress is mediated by noradrenergic regulation of dopamine neurons

Nature Neuroscience, 19( 4), 560-563.

URL     PMID:26878672      [本文引用: 1]

Abstract Dopamine (DA) neurons in the ventral tegmental area (VTA) help mediate stress susceptibility and resilience. However, upstream mechanisms controlling these neurons remain unknown. Noradrenergic (NE) neurons in the locus coeruleus, implicated in the pathophysiology of depression, have direct connections within the VTA. Here we demonstrate that NE neurons regulate vulnerability to social defeat through inhibitory control of VTA DA neurons.

Johnson D. C., Thom N. J., Stanley E. A., Haase L., Simmons A. N., Shih P. A., .. Paulus M. P . ( 2014).

Modifying resilience mechanisms in at-risk individuals: A controlled study of mindfulness training in Marines preparing for deployment

Am J Psychiatry, 171( 8), 844-853.

URL     [本文引用: 1]

Krishnan V., Han M-H., Graham D. L., Berton O., Renthal W., Russo S. J., .. Nestler E. J . ( 2007).

Molecular adaptations underlying susceptibility and resistance to social defeat in brain reward regions

Cell, 131( 2), 391-404.

URL     PMID:17956738      [本文引用: 4]

While stressful life events are an important cause of psychopathology, most individuals exposed to adversity maintain normal psychological functioning. The molecular mechanisms underlying such resilience are poorly understood. Here, we demonstrate that an inbred population of mice subjected to social defeat can be separated into susceptible and unsusceptible subpopulations that differ along several behavioral and physiological domains. By a combination of molecular and electrophysiological techniques, we identify signature adaptations within the mesolimbic dopamine circuit that are uniquely associated with vulnerability or insusceptibility. We show that molecular recapitulations of three prototypical adaptations associated with the unsusceptible phenotype are each sufficient to promote resistant behavior. Our results validate a multidisciplinary approach to examine the neurobiological mechanisms of variations in stress resistance, and illustrate the importance of plasticity within the brain's reward circuits in actively maintaining an emotional homeostasis.

Levone B. R., Cryan J. F., & O'Leary O. F . ( 2015).

Role of adult hippocampal neurogenesis in stress resilience

Neurobiology of Stress, 1, 147-155.

URL     PMID:4721321      [本文引用: 1]

61Ablation of adult hippocampal NG can affect stress susceptibility.61Increased hippocampal NG is associated with both susceptibility and resilience.61Adult hippocampal NG can influence stress-induced alterations in HPA-axis activity.61Behavioural effects of some but not all antidepressants are neurogenesis-dependent.61Stress and antidepressants can affect NG preferentially in the ventral hippocampus.

Li B., Piriz J., Mirrione M., Chung C., Proulx C. D., Schulz D., .. Malinow R . ( 2011).

Synaptic potentiation onto habenula neurons in the learned helplessness model of depression

Nature, 470( 7335), 535-539.

URL     PMID:21350486      [本文引用: 1]

The cellular basis of depressive disorders is poorly understood(1). Recent studies in monkeys indicate that neurons in the lateral habenula (LHb), a nucleus that mediates communication between forebrain and midbrain structures, can increase their activity when an animal fails to receive an expected positive reward or receives a stimulus that predicts aversive conditions (that is, disappointment or anticipation of a negative outcome)(2-4). LHb neurons project to, and modulate, dopamine-rich regions, such as the ventral tegmental area (VTA)(2,5), that control reward-seeking behaviour(6) and participate in depressive disorders(7). Here we show that in two learned helplessness models of depression, excitatory synapses onto LHb neurons projecting to the VTA are potentiated. Synaptic potentiation correlates with an animal's helplessness behaviour and is due to an enhanced presynaptic release probability. Depleting transmitter release by repeated electrical stimulation of LHb afferents, using a protocol that can be effective for patients who are depressed(8,9), markedly suppresses synaptic drive onto VTA-projecting LHb neurons in brain slices and can significantly reduce learned helplessness behaviour in rats. Our results indicate that increased presynaptic action onto LHb neurons contributes to the rodent learned helplessness model of depression.

Li Y., Zhong W. X., Wang D. Q., Feng Q. R., Liu Z. X., Zhou J. F., .. Luo M. M . ( 2016).

Serotonin neurons in the dorsal raphe nucleus encode reward signals

Nature Communications, 7, 10503.

URL     PMID:26818705      [本文引用: 1]

The dorsal raphe nucleus (DRN) is involved in organizing reward-related behaviours; however, it remains unclear how genetically defined neurons in the DRN of a freely behaving animal respond to various natural rewards. Here we addressed this question using fibre photometry and single-unit recording from serotonin (5-HT) neurons and GABA neurons in the DRN of behaving mice. Rewards including sucrose, food, sex and social interaction rapidly activate 5-HT neurons, but aversive stimuli including quinine and footshock do not. Both expected and unexpected rewards activate 5-HT neurons. After mice learn to wait for sucrose delivery, most 5-HT neurons fire tonically during waiting and then phasically on reward acquisition. Finally, GABA neurons are activated by aversive stimuli but inhibited when mice seek rewards. Thus, DRN 5-HT neurons positively encode a wide range of reward signals during anticipatory and consummatory phases of reward responses. Moreover, GABA neurons play a complementary role in reward processing. How neurons in the dorsal raphe nucleus (DRN) respond to reward related behaviours is not known. Here, Li and colleagues report that DRN serotoninergic neurons are phasically activated by rewards such as sex, food and sucrose, and tonically activated during reward anticipation, while GABAergic neurons respond to punishment.

Liu Z. X., Zhou J. F., Li Y., Hu F., Lu Y., Ma M., .. Luo M. M . ( 2014).

Dorsal raphe neurons signal reward through 5-HT and glutamate

Neuron, 81( 6), 1360-1374.

URL     PMID:4411946      [本文引用: 1]

The dorsal raphe nucleus (DRN) is the key brain center of 5-HT neurons. It has been debated whether DRN neurons signal punishment or reward. Liu et02al. report that activating DRN Pet-1 neurons reinforces mouse behaviors and guides rapid learning by a mechanism involving 5-HT and glutamate.

MacQueen G. M., Campbell S., McEwen B. S., Macdonald K., Amano S., Joffe R. T., .. Young L. T . ( 2003).

Course of illness, hippocampal function, and hippocampal volume in major depression

Proceedings of the National Academy of Sciences of the United States of Anerica, 100( 3), 1387-1392.

URL     PMID:12552118      [本文引用: 1]

Studies have examined hippocampal function and volume in depressed subjects, but none have systematically compared never-treated first-episode patients with those who have had multiple episodes. We sought to compare hippocampal function, as assessed by performance on hippocampal-dependent recollection memory tests, and hippocampal volumes, as measured in a 1.5-T magnetic resonance imager, in depressed subjects experiencing a postpubertal onset of depression. Twenty never-treated depressed subjects in a first episode of depression were compared with matched healthy control subjects. Seventeen depressed subjects with multiple past episodes of depression were also compared with matched healthy controls and to the first-episode patients. Both first- and multiple-episode depressed groups had hippocampal dysfunction apparent on several tests of recollection memory; only depressed subjects with multiple depressive episodes had hippocampal volume reductions. Curve-fitting analysis revealed a significant logarithmic association between illness duration and hippocampal volume. Reductions in hippocampal volume may not antedate illness onset, but volume may decrease at the greatest rate in the early years after illness onset.

Martinez R. C. R., Gupta N., Lázaro-Muñoz G., Sears R. M., Kim S., Moscarello J. M., .. Cain C. K . ( 2013).

Active vs. reactive threat responding is associated with differential c-Fos expression in specific regions of amygdala and prefrontal cortex

Learning & Memory, 20( 8), 446-452.

URL     PMID:23869027      [本文引用: 1]

Active avoidance (AA) is an important paradigm for studying mechanisms of aversive instrumental learning, pathological anxiety, and active coping. Unfortunately, AA neurocircuits are poorly understood, partly because behavior is highly variable and reflects a competition between Pavlovian reactions and instrumental actions. Here we exploited the behavioral differences between good and poor avoiders to elucidate the AA neurocircuit. Rats received Sidman AA training and expression of the activity-dependent immediate-early gene c-fos was measured after a shock-free AA test. Six brain regions with known or putative roles in AA were evaluated: amygdala, periaqueductal gray, nucleus accumbens, dorsal striatum, prefrontal cortex (PFC), and hippocampus. Good avoiders showed little Pavlovian freezing and high AA rates at test, the opposite of poor avoiders. Although c-Fos activation was observed throughout the brain, differential activation was found only in subregions of amygdala and PFC. Interestingly, c-Fos correlated with avoidance and freezing in only five of 20 distinct areas evaluated: lateral amygdala, central amygdala, medial amygdala, basal amygdala, and infralimbic PFC. Thus, activity in specific amygdala-PFC circuits likely mediates the competition between instrumental actions and Pavlovian reactions after AA training. Individual differences in AA behavior, long considered a nuisance by researchers, may be the key to elucidating the AA neurocircuit and understanding pathological response profiles.

Masten A.S . ( 2001).

Ordinary magic: Resilience processes in development

American Psychologist, 56( 3), 227-238.

URL     [本文引用: 1]

McEwen B. S., Bowles N. P., Gray J. D., Hill M. N., Hunter R. G., Karatsoreos I. N., & Nasca C . ( 2015).

Mechanisms of stress in the brain

Nature Neuroscience, 18( 10), 1353-1363.

URL     PMID:26404710      [本文引用: 1]

The brain perceives and adapts to stressors via multiple interacting molecular mechanisms involving the cell surface, cytoskeleton and epigenetic regulation resulting in structural remodeling, with continually changing gene expression. Understanding mechanisms of plasticity and vulnerability facilitate development of intervention for anxiety and depressive disorders as well as age-related cognitive decline.

Mineur Y. S., Einstein E. B., Bentham M. P., Wigestrand M. B., Blakeman S., Newbold S. A., & Picciotto M. R . ( 2015).

Expression of the 5-HT1A serotonin receptor in the hippocampus is required for social stress resilience and the antidepressant-like effects induced by the nicotinic partial agonist cytisine

Neuropsychopharmacology, 40( 4), 938-946.

URL     PMID:25288485      [本文引用: 1]

Nicotinic acetylcholine receptor (nAChR) blockers potentiate the effects of selective serotonin reuptake inhibitors (SSRIs) in some treatment-resistant patients; however, it is not known whether these effects are independent, or whether the two neurotransmitter systems act synergistically. We first determined that the SSRI fluoxetine and the nicotinic partial agonist cytisine have synergistic effects in a mouse model of antidepressant efficacy, whereas serotonin depletion blocked the effects of cytisine. Using a pharmacological approach, we found that the 5-HT1A agonist 8-OH-DPAT also potentiated the antidepressant-like effects of cytisine, suggesting that this subtype might mediate the interaction between the serotonergic and cholinergic systems. The 5-HT1A receptors are located both presynaptically and postsynaptically. We therefore knocked down 5-HT1A receptors in either the dorsal raphe (presynaptic autoreceptors) or the hippocampus (a brain area with high expression of 5-HT1A heteroreceptors sensitive to cholinergic effects on affective behaviors). Knockdown of 5-HT1A receptors in hippocampus, but not dorsal raphe, significantly decreased the antidepressant-like effect of cytisine. This study suggests that serotonin signaling through postsynaptic 5-HT1A receptors in the hippocampus is critical for the antidepressant-like effects of a cholinergic drug and begins to elucidate the molecular mechanisms underlying interactions between the serotonergic and cholinergic systems related to mood disorders.

Moscarello J.M., & LeDoux, J.E . ( 2013).

Active avoidance learning requires prefrontal suppression of amygdala- mediated defensive reactions

Journal Of Neuroscience, 33( 9), 3815-3823.

URL     PMID:23447593      [本文引用: 1]

Signaled active avoidance (AA) paradigms train subjects to prevent an aversive outcome by performing a learned behavior during the presentation of a conditioned cue. This complex form of conditioning involves pavlovian and instrumental components, which produce competing behavioral responses that must be reconciled for the subject to successfully avoid an aversive stimulus. In signaled AA paradigm for rat, we tested the hypothesis that the instrumental component of AA training recruits infralimbic prefrontal cortex (ilPFC) to inhibit central amygdala (CeA)-mediated Pavlovian reactions. Pretraining lesions of ilPFC increased conditioned freezing while causing a corresponding decrease in avoidance; lesions of CeA produced opposite effects, reducing freezing and facilitating avoidance behavior. Pharmacological inactivation experiments demonstrated that ilPFC is relevant to both acquisition and expression phases of AA learning. Inactivation experiments also revealed that AA produces an ilPFC-mediated diminution of pavlovian reactions that extends beyond the training context, even when the conditioned stimulus is presented in an environment that does not allow the avoidance response. Finally, injection of a protein synthesis inhibitor into either ilPFC or CeA impaired or facilitated AA, respectively, showing that avoidance training produces two opposing memory traces in these regions. These data support a model in which AA learning recruits ilPFC to inhibit CeA-mediated defense behaviors, leading to a robust suppression of freezing that generalizes across environments. Thus, ilPFC functions as an inhibitory interface, allowing instrumental control over an aversive outcome to attenuate the expression of freezing and other reactions to conditioned threat.

O’Leary O. F., Felice D., Galimberti S., Savignac H. M., Bravo J. A., Crowley T., .. Cryan J. F . ( 2014).

GABAB (1) receptor subunit isoforms differentially regulate stress resilience

Proceedings of the National Academy of Sciences of the United States of America, 111( 42), 15232-15237.

URL     PMID:25288769      [本文引用: 1]

Abstract Stressful life events increase the susceptibility to developing psychiatric disorders such as depression; however, many individuals are resilient to such negative effects of stress. Determining the neurobiology underlying this resilience is instrumental to the development of novel and more effective treatments for stress-related psychiatric disorders. GABAB receptors are emerging therapeutic targets for the treatment of stress-related disorders such as depression. These receptors are predominantly expressed as heterodimers of a GABAB(2) subunit with either a GABAB(1a) or a GABAB(1b) subunit. Here we show that mice lacking the GABAB(1b) receptor isoform are more resilient to both early-life stress and chronic psychosocial stress in adulthood, whereas mice lacking GABAB(1a) receptors are more susceptible to stress-induced anhedonia and social avoidance compared with wild-type mice. In addition, increased hippocampal expression of the GABAB(1b) receptor subunit is associated with a depression-like phenotype in the helpless H/Rouen genetic mouse model of depression. Stress resilience in GABAB(1b) (-/-) mice is coupled with increased proliferation and survival of newly born cells in the adult ventral hippocampus and increased stress-induced c-Fos activation in the hippocampus following early-life stress. Taken together, the data suggest that GABAB(1) receptor subunit isoforms differentially regulate the deleterious effects of stress and, thus, may be important therapeutic targets for the treatment of depression.

Razzoli M., Andreoli M., Michielin F., Quarta D., & Sokal D. M . ( 2011).

Increased phasic activity of VTA dopamine neurons in mice 3 weeks after repeated social defeat

Behavioural Brain Research, 218( 1), 253-257.

URL     [本文引用: 2]

Ressler K.J., & Mayberg, H.S . ( 2007).

Targeting abnormal neural circuits in mood and anxiety disorders: From the laboratory to the clinic

Nature Neuroscience, 10( 9), 1116-1124.

URL     [本文引用: 1]

Russo S. J., Murrough J. W., Han M. H., Charney D. S., & Nestler E. J . ( 2012).

Neurobiology of resilience

Nature Neuroscience, 15( 11), 1475-1484.

URL     [本文引用: 4]

Russo S.J., & Nestler, E.J . ( 2013).

The brain reward circuitry in mood disorders

Nature Reviews Neuroscience, 14( 9), 609-625.

[本文引用: 1]

Santarelli S., Zimmermann C., Kalideris G., Lesuis S. L., Arloth J., Uribe A., .. Schmidt M. V . ( 2017).

An adverse early life environment can enhance stress resilience in adulthood

Psychoneuroendocrinology, 78, 213-221.

URL     PMID:28219813      [本文引用: 1]

Chronic stress is a major risk factor for depression. Interestingly, not all individuals develop psychopathology after chronic stress exposure. In contrast to the prevailing view that stress effects are cumulative and increase stress vulnerability throughout life, the match/mismatch hypothesis of psychiatric disorders. The match/mismatch hypothesis proposes that individuals who experience moderate levels of early life psychosocial stress can acquire resilience to renewed stress exposure later in life. Here, we have tested this hypothesis by comparing the developmental effects of 2 opposite early life conditions, when followed by 2 opposite adult environments. Male Balb/c mice were exposed to either adverse early life conditions (limited nesting and bedding material) or a supportive rearing environment (early handling). At adulthood, the animals of each group were either housed with an ovariectomized female (supportive environment) or underwent chronic social defeat stress (socially adverse environment) for 3 weeks. At the end of the adult manipulations, all of the animals were returned to standard housing conditions. Then, we compared the neuroendocrine, behavioral and molecular effects of the interaction between early and adult environment. Our study shows that early life adversity does not necessarily result in increased vulnerability to stress. Specific endophenotypes, like hypothalamic-pituitary-adrenal axis activity, anxiety-related behavior and glucocorticoid receptor expression levels in the hippocampus were not significantly altered when adversity is experienced during early life and in adulthood, and are mainly affected by either early life or adult life adversity alone. Overall our data support the notion that being raised in a stressful environment prepares the offspring to better cope with a challenging adult environment and emphasize the role of early life experiences in shaping adult responsiveness to stress.

Steimer T. & Driscoll, P. ( 2005).

Inter-individual vs line/strain differences in psychogenetically selected Roman High-(RHA) and Low-(RLA) Avoidance rats: Neuroendocrine and behavioural aspects

Neuroscience & Biobehavioral Reviews, 29( 1), 99-112.

URL     PMID:0029399112      [本文引用: 1]

Inter-individual differences in neuroendocrine and behavioural responses to environmental challenges will be considered within the context of psychogenetic selection, using the Roman High-(RHA) and Low-(RLA) Avoidance rat lines as an example. We assume that the selected genotypes, by interacting with environmental factors, determine specific ‘biobehavioural profiles’. Practical and theoretical problems regarding the measurement of inter-individual vs line/strain differences, the definition of ‘traits’ vs experimental variables, and possible correlations between physiological and behavioural parameters will be discussed. We will argue that environmental influences are the main cause of inter-individual variability, and that the genotype only constitutes a ‘blueprint’ from which typical biobehavioural profiles are established, notably under the influence of early environmental factors. These biobehavioural profiles may correspond in part to human categories known as ‘types’, ‘temperaments’ or ‘personality traits’. Within each category (including those which can be obtained by psychogenetic selection), more individual personality traits can evolve, notably as a result of social interactions and particular life events.

Tye K. M., Mirzabekov J. J., Warden M. R., Ferenczi E. A., Tsai H. C., Finkelstein J., .. Deisseroth K . ( 2013).

Dopamine neurons modulate neural encoding and expression of depression-related behaviour

Nature, 493( 7433), 537-541.

URL     PMID:4160519      [本文引用: 1]

Major depression is characterized by diverse debilitating symptoms that include hopelessness and anhedonia(1). Dopamine neurons involved in reward and motivation(2-9) are among many neural populations that have been hypothesized to be relevant(10), and certain antidepressant treatments, including medications and brain stimulation therapies, can influence the complex dopamine system. Until now it has not been possible to test this hypothesis directly, even in animal models, as existing therapeutic interventions are unable to specifically target dopamine neurons. Here we investigated directly the causal contributions of defined dopamine neurons to multidimensional depression-like phenotypes induced by chronic mild stress, by integrating behavioural, pharmacological, optogenetic and electrophysiological methods in freely moving rodents. We found that bidirectional control (inhibition or excitation) of specified midbrain dopamine neurons immediately and bidirectionally modulates (induces or relieves) multiple independent depression symptoms caused by chronic stress. By probing the circuit implementation of these effects, we observed that optogenetic recruitment of these dopamine neurons potently alters the neural encoding of depression-related behaviours in the downstream nucleus accumbens of freely moving rodents, suggesting that processes affecting depression symptoms may involve alterations in the neural encoding of action in limbic circuitry.

Vialou V., Robison A. J., Laplant Q. C., Covington Ⅲ H. E., Dietz D. M., Ohnishi Y. N., .. Nestler E. J . ( 2010).

DeltaFosB in brain reward circuits mediates resilience to stress and antidepressant responses

Nature Neuroscience, 13( 6), 745-752.

URL     PMID:20473292      [本文引用: 1]

Abstract In contrast with the many studies of stress effects on the brain, relatively little is known about the molecular mechanisms of resilience, the ability of some individuals to escape the deleterious effects of stress. We found that the transcription factor DeltaFosB mediates an essential mechanism of resilience in mice. Induction of DeltaFosB in the nucleus accumbens, an important brain reward-associated region, in response to chronic social defeat stress was both necessary and sufficient for resilience. DeltaFosB induction was also required for the standard antidepressant fluoxetine to reverse behavioral pathology induced by social defeat. DeltaFosB produced these effects through induction of the GluR2 AMPA glutamate receptor subunit, which decreased the responsiveness of nucleus accumbens neurons to glutamate, and through other synaptic proteins. Together, these findings establish a previously unknown molecular pathway underlying both resilience and antidepressant action.

Wang D. Q., Li Y., Feng Q. R., Guo Q. C., Zhou J. F., & Luo M. M . ( 2017).

Learning shapes the aversion and reward responses of lateral habenula neurons

Elife, 6, e23045.

URL     PMID:28561735      [本文引用: 1]

10.7554/eLife.23045.001The lateral habenula (LHb) is believed to encode negative motivational values. It remains unknown how LHb neurons respond to various stressors and how learning shapes their responses. Here, we used fiber-photometry and electrophysiology to track LHb neuronal activity in freely-behaving mice. Bitterness, pain, and social attack by aggressors intensively excite LHb neurons. Aversive Pavlovian conditioning induced activation by the aversion-predicting cue in a few trials. The experience of social defeat also conditioned excitatory responses to previously neutral social stimuli. In contrast, fiber photometry and single-unit recordings revealed that sucrose reward inhibited LHb neurons and often produced excitatory rebound. It required prolonged conditioning and high reward probability to induce inhibition by reward-predicting cues. Therefore, LHb neurons can bidirectionally process a diverse array of aversive and reward signals. Importantly, their responses are dynamically shaped by learning, suggesting that the LHb participates in experience-dependent selection of behavioral responses to stressors and rewards.DOI: http://dx.doi.org/10.7554/eLife.23045.001

Wang M., Perova Z., Arenkiel B. R., & Li B . ( 2014).

Synaptic modifications in the medial prefrontal cortex in susceptibility and resilience to stress

Journal Of Neuroscience, 34( 22), 7485-7492.

URL     PMID:4035514      [本文引用: 2]

When facing stress, most individuals are resilient whereas others are prone to developing mood disorders. The brain mechanisms underlying such divergent behavioral responses remain unclear. Here we used the learned helplessness procedure in mice to examine the role of the medial prefrontal cortex (mPFC), a brain region highly implicated in both clinical and animal models of depression, in adaptive and maladaptive behavioral responses to stress. We found that uncontrollable and inescapable stress induced behavioral state-dependent changes in the excitatory synapses onto a subset of mPFC neurons: those that were activated during behavioral responses as indicated by their expression of the activity reporter c-Fos. Whereas synaptic potentiation was linked to learned helplessness, a depression-like behavior, synaptic weakening, was associated with resilience to stress. Notably, enhancing the activity of mPFC neurons using a chemical-genetic method was sufficient to convert the resilient behavior into helplessness. Our results provide direct evidence that mPFC dysfunction is linked to maladaptive behavioral responses to stress, and suggest that enhanced excitatory synaptic drive onto mPFC neurons may underlie the previously reported hyperactivity of this brain region in depression.

Warden M. R., Selimbeyoglu A., Mirzabekov J. J., Lo M., Thompson K. R., Kim S-Y., .. Deisseroth K . ( 2012).

A prefrontal cortex-brainstem neuronal projection that controls response to behavioural challenge

Nature, 492( 7429), 428-432.

URL     PMID:23160494      [本文引用: 3]

The prefrontal cortex () is thought to participate in high-level control of the generation of (including the decision to execute actions); indeed, imaging and lesion studies in beings have revealed that dysfunction can lead to either impulsive states with increased tendency to initiate action, or to amotivational states characterized by symptoms such as reduced activity, hopelessness and depressed mood. Considering the opposite valence of these two phenotypes as well as the broad complexity of other tasks attributed to , we sought to elucidate the circuitry that favours effortful behavioural responses to challenging situations. Here we develop and use a quantitative method for the continuous assessment and control of active response to a behavioural challenge, synchronized with single-unit electrophysiology and optogenetics in freely moving . In recording from the medial (mPFC), we observed that many neurons were not simply movement-related in their spike-firing patterns but instead were selectively modulated from moment to moment, according to the animal's decision to act in a challenging situation. Surprisingly, we next found that direct activation of principal neurons in the mPFC had no detectable causal effect on this . We tested whether this could be causally mediated by only a subclass of mPFC cells defined by specific downstream wiring. Indeed, by leveraging optogenetic projection-targeting to control cells with specific efferent wiring patterns, we found that selective activation of those mPFC cells projecting to the brainstem dorsal raphe (DRN), a serotonergic implicated in , induced a profound, rapid and reversible effect on selection of the active behavioural state. These results may be of importance in understanding the neural circuitry underlying normal and pathological patterns of action selection and motivation in .

Zannas A. S., McQuoid D. R., Payne M. E., Steffens D. C., MacFall J. R., Ashley-Koch A., & Taylor W. D . ( 2013).

Negative life stress and longitudinal hippocampal volume changes in older adults with and without depression

Journal of Psychiatric Research, 47( 6), 829-834.

URL     PMID:23478048      [本文引用: 1]

Major depressive disorder is associated with smaller hippocampal volumes but the mechanisms underlying this relationship are unclear. To examine the effect of environmental influences, we examined the relationship between self-reported stressors and two-year change in hippocampal volume. Seventy elderly nondepressed subjects and eighty-nine elderly depressed subjects were followed for two years. The number of negative stressful life events (nSLE), perceived stress levels, and cranial MRI were obtained at baseline and at the two-year assessment. For secondary analyses, subjects provided blood for 5-HTTLPR polymorphism genotyping. After controlling for covariates including presence or absence of depression, greater numbers of baseline nSLEs were significantly associated with greater baseline hippocampal volumes bilaterally. Greater numbers of baseline nSLEs were also associated with reduction in hippocampal volume over two years in the right but not the left hemisphere. Neither perceived stress levels nor changes in stress measures were significantly associated with hippocampal volume measures. However, in secondary analyses, we found that increases in perceived stress over time was associated with volume reduction of the left hippocampus, but only in 5-HTTLPR L/L homozygotes. Our findings suggest different short- and long-term effects of negative life stressors on hippocampal volumes in older adults. These effects appear independent on the presence or absence of depression. Furthermore, these effects may be moderated by genetic polymorphisms in key neurotransmitter systems. These novel findings have important implications for understanding environmental influences on brain aging.

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