Unpredictable Mixed-Valence Outcomes Induce a Chronic and Reversible Generalized Anxiety-like Phenotype in Male Mice.

Background: Clinical anxiety is a generalized state characterized by feelings of apprehensive expectation and is distinct from momentary responses such as fear or stress. In contrast, most laboratory tests of anxiety focus on acute responses to momentary stressors. Methods: Apprehensive expectation was induced by subjecting mice (for 18 days) to manipulations in which a running response (experiment 1) or a conditioned stimulus (experiment 2) were unpredictably paired with reward (food) or punishment (footshock). Before this treatment, the mice were tested in an open field and light/dark box to assess momentary responses that are asserted to reflect state anxiety. After treatment, the mice were assessed for state anxiety in an elevated plus maze, social interaction test, startle response test, intrusive object burying test, and stress-induced corticosterone elevations. In experiment 3, we treated mice similarly to experiment 1, but after mixed-valence training, some mice received either no additional training, additional mixed-valence training, or were shifted to consistent (predictable) reinforcement with food. Results: We consistently observed an increase in anxiety-like behaviors after the experience with mixed-valence unpredictable reinforcement. This generalized anxiety persisted for at least 4 weeks after the mixed-valence training and could be reversed if the mixed-valence training was followed by predictable reinforcement with food. Conclusions: Results indicate that experience with unpredictable reward/punishment can induce a chronic state analogous to generalized anxiety that can be mitigated by exposure to stable, predictable conditions. This learned apprehension protocol provides a conceptually valid model for the study of the etiology and treatment of anxiety in laboratory animals.

Anxiety disorders have a complex etiology that is difficult to study in laboratory animals because most laboratory manipulations do not induce a chronic, generalized condition analogous to the clinical disorder. Here, laboratory mice developed approach-avoidance conflicts when a response was unpredictably rewarded or punished. These conditions (but not predictable outcomes) promoted a long-lasting general increase in a range of behaviors and stress hormones that reflect underlying anxiety, and remedial exposure to predictable conditions of reward and punishment ameliorated the generalized state. These results represent the development of a conceptually valid animal model for the study of anxiety and suggest conditions that can contribute to the etiology and treatment of anxiety.

Negative attributes of mixed-valence memories strengthen over long retention intervals and the degree of enhancement is predicted by individual differences in state anxiety.

Memories are multifaceted and can simultaneously contain positive and negative attributes. Here, we report that negative attributes of a mixed-valence memory dominate long-term recall. To induce a mixed-valence memory, running responses were randomly reinforced with either food (∼83% of trials) or footshock (∼17% of trials), or a noise conditioned stimulus (CS) was followed randomly with either food (∼80% of trials) or footshock (∼20% of trials). Control animals were consistently reinforced with only food. Mixed-valence training promoted unstable behavior (e.g., erratic approach and withdrawal from the food cup) and moderate levels of fear during the training regimens. After a 20-day retention interval, animals that were consistently reinforced with food exhibited intact approach responding, and similar responding was observed if animals were food deprived or satiated (i.e., the response was insensitive to motivation). However, animals that experienced the mixed-valence training expressed significantly enhanced and stable fear (consistent immobility) relative to the end of training, regardless of whether animals were food deprived or not, suggesting that fear transitioned to a state that was insensitive to motivation. The degree of fear expressed during long-term retention was predicted by measures of state anxiety obtained prior to the training, indicating that the enhancement of fear across the retention interval was related to individual differences in basal "anxiety." These results suggest that negative attributes of memories dominate long-term recall, particularly in animals expressing an anxious phenotype, and these observations have direct implications for the chronic nature of anxiety disorders and the exacerbation of fear that accompanies posttraumatic stress disorder. (PsycInfo Database Record (c) 2023 APA, all rights reserved).