SummaryOur mood often fluctuates without warning. Recent accounts propose that these fluctuations might be preceded by changes in how we process reward. According to this view, the degree to which reward improves our mood reflects not only characteristics of the reward itself (e.g., its magnitude) but also how receptive to reward we happen to be. Differences in receptivity to reward have been suggested to play an important role in the emergence of mood episodes in psychiatric disorders [1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16]. However, despite substantial theory, the relationship between reward processing and daily fluctuations of mood has yet to be tested directly. In particular, it is unclear whether the extent to which people respond to reward changes from day to day and whether such changes are followed by corresponding shifts in mood. Here, we use a novel mobile-phone platform with dense data sampling and wearable heart-rate and electroencephalographic sensors to examine mood and reward processing over an extended period of one week. Subjects regularly performed a trial-and-error choice task in which different choices were probabilistically rewarded. Subjects’ choices revealed two complementary learning processes, one fast and one slow. Reward prediction errors [17, 18] indicative of these two processes were decodable from subjects’ physiological responses. Strikingly, more accurate decodability of prediction-error signals reflective of the fast process predicted improvement in subjects’ mood several hours later, whereas more accurate decodability of the slow process’ signals predicted better mood a whole day later. We conclude that real-life mood fluctuations follow changes in responsivity to reward at multiple timescales.

To assess the behavioural effects of prolonged motor practice in healthy volunteers, and the specific impact of inhibiting different motor-related brain regions in the late phase of motor learning using continuous theta burst transcranial magnetic stimulation (cTBS). Methods: Twelve subjects trained their non-dominant arm in eight arm motor tasks (Arm Ability Training, AAT) once a day for three weeks (16 sessions). During the last four days, training was performed before and after applying cTBS to either M1, S1, SMA, or PMC. Results: The AAT induced substantial and robust motor learning for the trained arm with variations across tasks. Considerable motor learning was also observed in the non-trained dominant arm with remarkably similar variations across tasks, suggesting that practise improved common underlying sensorimotor capacities (abilities) in addition to effector-specific effects. When applied after prolonged training, inhibitory cTBS showed no detrimental effects on motor performance/learning; M1 cTBS even improved performance in a labyrinth task. Conclusions: Prolonged training with the non-dominant arm led to profound motor learning across abilities with transfer to the non-trained dominant arm. Unlike during early stages of motor learning, no detrimental effect of cTBS over M1, S1, PMC, or SMA could be substantiated after prolonged motor practice.

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Neurodevelopmental disorders encompass a group of debilitating diseases presenting with motor and cognitive dysfunction, with variable age of onset and disease severity. Advances in genetic diagnostic tools have facilitated the identification of several monogenic chromatin remodeling diseases that cause Neurodevelopmental disorders. Chromatin remodelers play a key role in the neuro-epigenetic landscape and regulation of brain development; it is therefore not surprising that mutations, leading to loss of protein function, result in aberrant neurodevelopment. Heterozygous, usually de novo mutations in histone lysine methyltransferases have been described in patients leading to haploinsufficiency, dysregulated protein levels and impaired protein function. Studies in animal models and patient-derived cell lines, have highlighted the role of histone lysine methyltransferases in the regulation of cell self-renewal, cell fate specification and apoptosis. To date, in depth studies of histone lysine methyltransferases in oncology have provided strong evidence of histone lysine methyltransferase dysregulation as a determinant of cancer progression and drug resistance. As a result, histone lysine methyltransferases have become an important therapeutic target for the treatment of different cancer forms. Despite recent advances, we still lack knowledge about the role of histone lysine methyltransferases in neuronal development. This has hampered both the study and development of precision therapies for histone lysine methyltransferases-related Neurodevelopmental disorders. In this review, we will discuss the current knowledge of the role of histone lysine methyltransferases in neuronal development and disease progression. We will also discuss how RNA-based technologies using small-activating RNAs could potentially provide a novel therapeutic approach for the future treatment of histone lysine methyltransferase haploinsufficiency in these Neurodevelopmental disorders, and how they could be first tested in state-of-the-art patient-derived neuronal models.