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.

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.