%0 Journal Article
%T Unpredictable Mixed-Valence Outcomes Induce a Chronic and Reversible Generalized Anxiety-like Phenotype in Male Mice.
%A Crawford DW
%A Patel KR
%A Swiecka A
%A Bond J
%A Tiwari A
%A Plaisted NM
%A Rednam N
%A McKeen KM
%A Patel HM
%A Sharma P
%A Roslewicz E
%A Matzel LD
%J Biol Psychiatry Glob Open Sci
%V 4
%N 4
%D 2024 Jul
%M 38883866
暂无%R 10.1016/j.bpsgos.2024.100318
%X <B>UNASSIGNED: </B>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.<BR><B>UNASSIGNED: </B>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.<BR><B>UNASSIGNED: </B>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.<BR><B>UNASSIGNED: </B>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.<BR>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.