Periodic Reporting for period 3 - SynapSeek (Learning the shape of synaptic plasticity rules for neuronal architectures and function through machine learning.) Reporting period: 2022-02-01 to 2023-07-31 Summary of the context and overall objectives of the project How do we learn to dance, play an instrument, or a game as complex as chess or go? How do we make a memory? The common answer to these questions is “through synaptic plasticity”, through changing the synaptic connectivity of neural circuits so that representative brain activity can be reliably triggered. Such connectivity changes are governed by rules, i.e. synaptic mechanisms which monitor the activity of their environment and stereotypically strengthen or weaken synapses accordingly. The shape and mode of operation of these rules is still largely unknown: For the more than hundred different connection types in cortical circuits, only a handful of rules has been described at all. Similarly, testing observed rules in simulations of cortical function has only seen limited success. Our slow progress is due to the extraordinary difficulty of measuring and observing synapses without interference.Here, we follow a new approach. We are utilizing the growing power of machine learning methods to deduce synaptic plasticity rules directly. Newly developed search algorithms and sheer computational power allow us to integrate published data and infer synaptic rules in silico. We (1) develop a new mathematical expression of synaptic plasticity rules, experimentally appropriate and flexible enough to be implemented in a Machine Learning framework, dubbed SYNAPSEEK. We then (2) apply SYNAPSEEK to deduce the rules for building various neural structures with increasing complexity. Finally (3), we incorporate additional, experimental constraints to SYNAPSEEK to develop synaptic rules that shape network function as much as its structure. Our work establishes, for the first time, canonical sets of synaptic plasticity rules, based on the circuit structure they must produce, and the function they are meant to support. SYNAPSEEK promises wide ranging applications, from a basic understanding of cortical development to better protocols for Deep Brain Stimulation. Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far The project continues to proceed very much as envisioned and we continue to make good progress on the realization of all Aims. In particular, we have seen the continued success of our framework framework in analysing and modifying synaptic plasticity rules with ML methods (Aim 1). Further, we have begun to test and expand our techniques to infer plasticity rules in spiking networks as well, i.e. we started to fulfil the expectations of Aim 2 and 3, as hoped. Our work up to the end of period 3 has led to 10 poster presentations (NCCD’19, COSYNE ’20,21,22,23, Neuromatch ’20, CNS2023, NeurIPS20,23, IST retreat ’20, Oxford Neuroscience symposium ’19). Additionally, we have submitted 4 manuscripts for publication at NEURIPS 20,23 (which was accepted in Period 4, at the time of writing this report), eLife, Plos Comp.Neurosc. and others. We have started new work, on Aim 3, including experimental data to constrain our automated search methods. We have successfully hired two graduate students, and two postdocs. We have submitted three more abstracts to Cosyne 2024, for which we are currently awaiting the decision. 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 project is developing as expected and we are happy to report that we have substantially expanded the boundaries of the state of the art, such that our current methods are the most cutting-edge approaches to finding new plasticity rules. We are very optimistic that most of the Aims as described in the original grant can be fulfilled. We have experienced a slow down in progress due to covid and the relocation of the lab, but as of January 2022 we are picking up speed in Austria and making good progress on several fronts.