This RAISE project is jointly funded by the Chemistry of Life Processes Program in the Division of Chemistry, the Physics of Living Systems Program in the Division of Physics, the Cellular Dynamics and Function and the Molecular Biophysics Clusters in the Division of Molecular and Cellular Biosciences, the Neural Systems Cluster in the Division of Integrative Organismal Systems, the Division of Emerging Frontiers, the RAISE Program and the Office of Integrative Activities.
This award is funding Professors Peter Wolynes, Margaret Cheung, Michael Diehl and Herbert Levine at Rice University and M. Neal Waxham at University of Texas (UT) Health-Houston to investigate the molecular mechanisms of learning and memory. The initiation of learning begins with changes at neuronal synapses that can strengthen (or weaken) the response of the synapse. This process is termed synaptic plasticity. Stimuli that produce learning lead to structural changes of the post-synaptic dendritic spine. The initial events of memory and learning include a temporary rise in calcium concentrations and activation of a protein called calmodulin. The next step is activation of calmodulin-dependent enzyme, kinase II (CaMKII). At the same time, structural rearrangements occur in the actin cytoskeleton leading to an enlargement of the spine compartment. How these initial events lead to remodeling of the actin cytoskeleton is largely unknown. This project focuses on the events that lead to the changes in actin cytoskeleton. The research also addresses the question of how these structural changes in the actin cytoskeleton are used to maintain memory. State-of-the-art computational modeling is used to answer these questions. Modeling is applied at molecular and supra-molecular scales. The models examine molecular changes that bridge the time scales between the initial steps and start of synaptic plasticity. The computational modeling goes hand in hand with state-of-the-art structural and functional imaging and biochemical pathway analyses. The research allows graduate students and postdoctoral fellows to acquire specialized training in computer simulations and mathematical modeling of a subcellular system. The students and fellows acquire an understanding of the brain starting from a molecular level. The team of theoreticians and experimentalists working cooperatively on this problem strengthens the training process. This project is integrated into an outreach program to introduce undergraduate students from underrepresented groups to science by participating in the research.
This research project quantitatively characterizes the relevant molecular processes involved in the dynamical "tectonic" reorganization inside a dendritic spine involved in forming memories. It focuses on the actin cytoskeleton using computer simulations and experimental analyses at both molecular and supra-molecular scales. This study therefore contributes directly to understanding the role of mechanics and structure in synaptic plasticity and learning and memory. Explicitly, the hypothesis is that the transient effects from calcium influx create, in a CaMKII-dependent manner, changes in the spatial patterning of the actin structure. Such changes may be be stabilized by feedback loops with prion-like proteins. These stabilized structures may be a type of "structural engram" which then serves as long-term reservoir for maintaining enhanced synaptic strength in the postsynaptic neuron. Testing, modifying, and verifying this hypothesis may help point the way towards a more quantitatively-sophisticated approach to the first stages of learning and memory in the brain.
