Preclinical Laboratory, Adult Psychiatry and Psychotherapy, University Hospital of Psychiatry and University of Zurich, Zurich, Switzerland.
Zurich Neuroscience Center, University of Zurich and ETH Zurich, Switzerland.
Curr Protoc. 2024 Mar;4(3):e1008. doi: 10.1002/cpz1.1008.
Increased experience of aversive stimuli/events is a psychological-neurobiological state of major importance in psychiatry. It occurs commonly in generalized anxiety disorder, post-traumatic stress disorder, and major depression. A sustained period of exposure to threat (chronic stressor) is a common risk factor, and a major symptom is generalized excessive perception of, and reactivity to, aversive stimuli. In rodents, Pavlovian aversion learning and memory (PAL, PAM), quantified in terms of the conditioned defensive behavior freezing, is an extensively studied behavioral paradigm, and well understood in terms of underlying neural circuitry. In mice, chronic social stress (CSS) is a 15-day resident-intruder paradigm in which C57BL/6 adult males are exposed continuously and distally to dominant-aggressive CD-1 male mice (sustained threat) interspersed with a brief daily period of proximal attack (acute threat). To ensure that physical wounding is minimized, proximal attacks are limited to 30 to 60 s/day and lower incisor teeth of CD-1 mice are blunted. Control (comparison) mice are maintained in littermate pairs. The CSS and CD-1 mice are maintained in distal contact during subsequent behavioral testing. For PAL, CSS and control (CON) mice are placed in a conditioning chamber (context) and exposed to a tone [conditioned stimulus (CS)] and mild, brief foot shock [unconditioned stimulus (US)]. For PAM, mice are placed in the same context and presented with CS repetitions. The CSS mice acquire (learn) and express (memory) a higher level of freezing than CON mice, indicating that CSS leads to generalized hypersensitivity to aversion, i.e., chronic social aversion leads to increased aversion salience of foot shock. Distinctive features of the model include the following: high reproducibility; rare, mild wounding only; male specificity; absence of "susceptible" vs "resilient" subgroups; behavioral effects dependent on continued presence of CD-1 mice; and preclinical validation of novel compounds for normalizing aversion hypersensitivity with accurate feedforward prediction of efficacy in human patients. © 2024 The Authors. Current Protocols published by Wiley Periodicals LLC. Basic Protocol 1: Chronic social stress (CSS) Basic Protocol 2: Pavlovian aversion learning and memory (PALM).
增加对厌恶刺激/事件的体验是精神病学中一个非常重要的心理-神经生物学状态。它常见于广泛性焦虑症、创伤后应激障碍和重度抑郁症。持续暴露于威胁（慢性应激源）是一个常见的风险因素，主要症状是对厌恶刺激的普遍过度感知和反应。在啮齿动物中，条件性回避学习和记忆（PAL、PAM），以条件性防御行为冻结的定量表示，是一种广泛研究的行为范式，并且其潜在的神经回路也得到了很好的理解。在小鼠中，慢性社交应激（CSS）是一种为期 15 天的居民入侵者范式，其中 C57BL/6 成年雄性小鼠持续且远距离暴露于优势攻击性 CD-1 雄性小鼠（持续威胁），中间穿插短暂的每日近端攻击（急性威胁）。为了确保尽量减少身体创伤，近端攻击限制在每天 30 到 60 秒，并且 CD-1 小鼠的下切牙被钝化。对照（比较）小鼠保持在同窝配对中。CSS 和 CD-1 小鼠在随后的行为测试中保持远距离接触。对于 PAL，CSS 和对照（CON）小鼠被放置在一个 conditioning 室（context）中，并暴露于一个音调[条件刺激（CS）]和温和的、短暂的足部电击[非条件刺激（US）]。对于 PAM，小鼠被放置在相同的 context 中，并呈现 CS 重复。CSS 小鼠比 CON 小鼠获得（学习）和表达（记忆）更高水平的冻结，这表明 CSS 导致对厌恶的普遍过敏，即慢性社交厌恶导致足部电击的厌恶显着性增加。该模型的独特特征包括以下几点：高重现性；罕见、轻度创伤；雄性特异性；没有“易感”与“抗敏”亚组；行为效应取决于 CD-1 小鼠的持续存在；以及新型化合物用于正常化厌恶过敏的临床前验证，具有对人类患者疗效的准确前馈预测。© 2024 作者。Wiley Periodicals LLC 出版的《当代协议》。基础方案 1：慢性社交应激（CSS）基础方案 2：条件性回避学习和记忆（PALM）。
