A New Behavioral Paradigm for Frustrative Nonreward in Juvenile Mice.

Background: Irritability, defined as proneness to anger, can reach a pathological extent. It is a defining symptom of disruptive mood dysregulation disorder and one of the most common reasons youths present for psychiatric evaluation and care. Aberrant responses to frustrative nonreward (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. Juvenile mice were exposed to alternate poking reward omission and then examined with a battery of behavioral tests to determine the behavioral effect of FNR. Results: FNR increased locomotion and aggression regardless of sex. These behavioral changes elicited by FNR resemble the symptoms observed in youth with severe irritability. FNR had no effect on anxiety-like, depression-like, or nonaggressive social behaviors. Conclusions: Our alternate poking reward omission paradigm effectively elevated aggression and locomotion in juvenile mice. These frustration effects are directly related to behavioral symptoms of youth with severe irritability. Our novel behavioral paradigm lays the groundwork for further mechanistic studies of frustration and irritability in rodents.

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.

Oligodendroglia are emerging players in several forms of learning and memory.

Synaptic plasticity is the fundamental cellular mechanism of learning and memory, but recent research reveals that myelin-forming glia, oligodendrocytes (OL), are also involved. They contribute in ways that synaptic plasticity cannot, and the findings have not been integrated into the established conceptual framework used in the field of learning and memory. OLs and their progenitors are involved in long-term memory, memory consolidation, working memory, and recall in associative learning. They also contribute to short-term memory and non-associative learning by affecting synaptic transmission, intrinsic excitability of axons, and neural oscillations. Oligodendroglial involvement expands the field beyond synaptic plasticity to system-wide network function, where precise spike time arrival and neural oscillations are critical in information processing, storage, and retrieval.