Abstract
Background Irritability, which can be defined as proneness to anger that can reach a pathological extent, is one of the most common reasons youth present for psychiatric evaluation and care. Aberrant responses to frustrative non-reward (FNR, the response to omission of an expected reward) are central to the pathophysiology of irritability. FNR is a cross-species RDoC construct. The development of preclinical FNR models could advance mechanistic studies of the important, and relatively understudied, clinical phenomenon of irritability.
Methods We used FNR, a translational construct across species, as a conceptual framework for a novel behavioral paradigm (Alternate Poking Reward Omission, APRO) in mice. After APRO, mice were examined with a battery of behavioral tests to determine the effects of frustration. Also, whole brain imaging of c-Fos expression was used to identify brain regions activated by FNR.
Results Mice, regardless of sex, increased locomotion, and aggression towards conspecifics after APRO. There was no change in anxiety-like, depression-like, or non-aggressive social behaviors. APRO causes activation of 13 regions in the prelimbic, ACC, hippocampus, dorsal thalamus, cuneiform nucleus, pons, and pallidum areas, and 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 brain regions identified to be selectively activated by it lay the groundwork for further mechanistic studies of frustration and irritability in rodents.
Competing Interest Statement
The authors have declared no competing interest.