Mouse Model of Chronic Social Stress‐Induced Excessive Pavlovian Aversion Learning‐Memory

Abstract 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)