Periodic Reporting for period 2 - BrainPlay (The self-teaching brain) Reporting period: 2021-02-01 to 2022-07-31 Summary of the context and overall objectives of the project The BrainPlay consortium initiated a far-reaching and diverse investigation into the neural mechanisms of play. We defined avenue of investigation of the self-teaching brain and confronted the problem from various angles. We investigate the neurobiology of animal play (Brecht group), the human play (Bavelier group), the theory of self-teaching (Gütig group) and the synaptic foundations of self-teaching (Schmitz group). These different lines of research are not separate, but are highly integrated. Highlights of our current work include: the identification of midbrain mechanism of play control (joint investigation of Brecht and Schmitz groups), analysis of human play behavior in large video game data sets (Bavelier group), extension of the theory of synaptic plasticity (Gütig group) and analysis of glycinergic transmission and developmental changes in synapses related to the loss of playfulness in older animals (Schmitz group). Besides the group-specific efforts, there are numerous joint lines of research, for example major efforts in the comparative analysis of play. Our efforts have resulted in high-profile publications and our results have found a broad reception in news coverage and the lay audience. Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far We will report the work separately for each group even though our research effort is integrated. More details can be found in other parts of our report.1. Brecht GroupIn the second reporting period the work of the Brecht lab focused on the comparative analysis of play & ticklishness and on the search for subcortical drivers for play. The search for subcortical play generators is inspired by decade-old lesion evidence suggesting that play develops and persists even after removal of the cortex. Our efforts on subcortical play generators evolve in close collaboration with the Schmitz group; such efforts have led to the identification of candidate structures for subcortical play control, more specifically the lateral columns of the peri-aquaeductal gray. 2. Bavelier GroupOur characterization of human play and its neural bases is proceeding as we have completed the analysis of the determinants of play behavior in a large data set from the video game League of Legend, optimizing a way to contrast high and low flow states while playing video games and implementing EEG and fMRI data collection contrasting those states. Furthermore, noting that play is associated with a reduction in stress, we are comparing the impact of different forms of play on alleviating anxiety in adolescents. 3. Gütig GroupThe Gütig lab focused on theories of synaptic plasticity and learning in spiking neural networks. In preparations of the physiological characterization of synaptic plasticity in playing brains the Gütig lab has advanced these theories on several important frontiers, including conductance-based neuron models, plastic synaptic dynamic and maximal margin learning. Moreover important extensions of the theoretical framework towards neuronal self-timing, unsupervised learning and non-gradient-based changes in internal representations have been successfully devised. 4. Schmitz GroupThe long-term goal of Schmitz group work is to determine cellular underpinnings of playfulness. To do so, the Schmitz group made major advances in paving the way for cellular/synaptic analysis of play circuits. These efforts included the establishment of electrophysiological recordings in slices from the Peri-Aqueductal Gray (PAG). There is a striking difference in play-behaviour in young versus old animals. The group started to test for physiological differences in the two groups. The group finds significant differences in excitability and IPSC-Gly. Finally, the Schmitz group investigated the cellular biology of playful and non-playful animals. Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far) The entire research agenda of our consortium goes beyond the state of the art. What is new is the joining of forces between animal and human neurobiologists, cellular physiology and theo-retical neuroscience to unravel the mysteries of play. Our research effort has already greatly al-tered our understanding of play. Novel human-animal play paradigms have revealed astounding play abilities of rats. The theoretical framework for understanding synaptic modifications during learning has been extended, personal determinants of play behaviour have been determined and subcortical drivers of play behavior have been identified. Yet, with all that, key neural de-terminants of play are still unknown and we envision to resolve such questions and that the BrainPlay consortium will enlighten us about the self-teaching brain.