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

Abstract

BackgroundIrritability, 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.MethodsWe 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.ResultsMice, 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.ConclusionOur 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.

Are reactions to frustrative nonreward in other animals a model for human anger? Neurobehavioral implications and therapeutic applications.

“…Additional FNR activation of septal nuclei in the low aggressive, but not high aggressive animals was consistent with the well-established aggression-inhibitory functions of the septum. Curiously, such results were not found in juvenile mice where FNR-related activation was distributed among numerous cortical and subcortical structures, including prelimbic (anterior) and dorsal components of the cingulate gyrus (Naik et al, 2023). Activation of the midbrain cuneiform nucleus found in this study most likely mediates FNR-induced locomotor activity.…”

Impact of Entertainment Industry on Perceived Quality of Life, Stress and Frustration Among Female Viewers

“…Because more frustrated people have. Quality of life effected more and more (Naik, Ma, Munyeshyaka, Leibenluft, & Li, 2023).…”

A New Paradigm to Investigate the Neuroscience of Irritability in Youth

“…In a recent issue of Biological Psychiatry: Global Open Science , Naik et al. ( 6 ) provide the scientific community with an elegant new behavioral paradigm to model frustration in juvenile mice, thus paving the way for the in-depth neural studies the field has long needed. Termed the alternate poking reward omission (APRO) task, this paradigm is as simple as it is robust.…”