INSPIRE: Memory Storage by Variable-size Stable Structures

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The mechanism of memory is one the major mysteries of biology. Recent work suggests that as a result of learning synapses grow and that the size of the synapse is what stores the components of memories. The aim of the proposed work is to visualize directly this growth process in brain tissue using a newly developed super-resolution microscope, and to understand why such structures have stable size once learning has occurred. Instability would result is loss of memory, so evolution is thought to have favored ways of maximizing stability. To gain insight into the mechanism of stability, physical and computational model systems will be used. If the principles that underlie stability in the face of variable size can be understood, the outcome of this work could open the door to a new era in nanotechnology in which these principles could be utilized, leading potentially to novel solutions to problems in self-assembly. Additional contributions of this project include the organization and instruction of a course in the scientific programming language, MATLAB, in an enrichment course for students from groups under-represented in science and technology, and the opportunity for US trainees to participate in an international collaboration. This proposal focuses on supramolecular structures that do not have fixed size but can exist in multiple different sizes, all of which are stable. Thus, if a stimulus causes the transition from one stable state to another, the structure has information storage capability (memory). The investigators termed this type of structure variable-size stable structures (VSSS). Interest in VSSS arises from two seemingly unrelated fields: neuroscience and the physics of nanostructures. The molecular basis of memory is one the most fundamental unsolved problems in neuroscience. Evidence strongly suggests that synapses grow to encode memory. Thus, memory storage in the brain appears to be a structural problem, and efforts need to be made to understand the structural principles that make memory storage possible. The project integrates cutting-edge optical microscopy with theoretical modeling. Utilizing a newly-available super-resolution microscope, the investigators will make the first effort to observe synaptic growth during synaptic plasticity in real time. The goal of the theoretical efforts is to develop a physical theory of VSSS and evaluate different models, including ones that have emerged from the study of synapses. Questions to be addressed include: (i) The importance of cooperative interactions among multiple components to generating stable yet kinetically accessible and reconfigurable assemblages. (ii) Design principles that lead to self-terminating assembly, such as growth by finite-size modules. (iii) Mechanisms by which nonequilibrium energy consumption changes the limits of VSSS. An ultimate goal is a generalized theory for nonequilibrium self-assembly capable of describing VSSS. This project is jointly funded by the Neural Systems Cluster in the Division of Integrative Organismal Systems and by the Physics of Living Systems Program in the Physics Division.