A New Behavioral Paradigm for Frustrative Non-reward Reveals a Global Change in Brain Networks by Frustration

BACKGROUND: Irritability, defined as proneness to anger, can reach a pathological extent. It is a defining symptom of Disruptive Mood Dysregulation Disorder (DMDD) and one of the most common reasons youth presents for psychiatric evaluation and care. Aberrant responses to frustrative non-reward (FNR, the response to omission of expected reward) are central to the pathophysiology of irritability. FNR is a translational construct to study irritability across species. The development of preclinical FNR models would advance mechanistic studies of the important and relatively understudied clinical phenomenon of irritability. METHODS: We used FNR as a conceptual framework to develop a novel mouse behavioral paradigm named Alternate Poking Reward Omission (APRO). After APRO, mice were examined with a battery of behavioral tests and processed for whole brain c-Fos imaging. FNR increases locomotion and aggression in mice regardless of sex. These behavioral changes resemble the symptoms observed in youth with severe irritability. There is no change in anxiety-like, depression-like, or non-aggressive social behaviors. FNR increases c-Fos+ neurons in 13 subregions of thalamus, iso-cortex and hippocampus including the prelimbic, ACC, hippocampus, dorsal thalamus, cuneiform nucleus, pons, and pallidum areas. FNR also shifts the brain network towards a more global processing mode. CONCLUSION: Our novel FNR paradigm produces a frustration effect and alters brain processing in ways resembling the symptoms and brain network reconfiguration observed in youth with severe irritability. The novel behavioral paradigm and identified brain regions lay the groundwork for further mechanistic studies of frustration and irritability in rodents.