Synapses are the sites of information processing in the mammalian brain. While generation and persistence of synapses during learning make them potential substrate for circuit modification and memory storage, the molecular mechanisms underlying synaptic structural changes and synapse diversity remain to be elucidated. Dendritic spines are the postsynaptic sites for the majority of excitatory synapses in the brain. Using an innovative combination of in vivo two-photon imaging and retrospective Array Tomography, the goals of this proposal are to determine the molecular composition and local connectivity of learning-related synapses, and to reveal principles of circuit remodeling during learning. We propose three specific aims.
Aim 1 examines the protein expression of individual spines (postsynaptic structures of excitatory synapses) during the process of synaptogenesis. Such expression patterns will be compared with those of preexisting stable spines to determine the molecular signature of new spines formed during learning.
Aim 2 identifies the presynaptic partners for learning-associated new spines, and dissects how local circuits """"""""reweigh"""""""" or """"""""rewire"""""""" during learning.
Aim 3 investigates how spine dynamics of pyramidal neurons from different cortical layers respond to motor learning, and determines if new spines formed during learning receive unique presynaptic inputs. Successful completion of the research will not only provide critical insights into the biology of synapse formation and diversity, but also offer neuroscientists a novel tool box to highlight new connections formed in a brain's recent past. Discovering how synapses remodel during learning will build a foundation for future investigation of how synaptic structure/function is altered by pathologies associated with learning defects.

Public Health Relevance

Synapses are the fundamental units of neuronal plasticity. Abnormal synaptic morphology and functions are hallmarks of many neurological and psychiatric disorders. Combining live imaging with single synapse proteomic examination, this project investigates the molecular mechanisms underlying synaptogenesis during learning. Knowledge obtained from this study will open doors for possible future translational researches on normal learning processes and also neurological disorders that afflict memory in humans where direct in vivo imaging is not applicable.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
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Neurobiology of Learning and Memory Study Section (LAM)
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Asanuma, Chiiko
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University of California Santa Cruz
Schools of Arts and Sciences
Santa Cruz
United States
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Martin, P-M; Stanley, R E; Ross, A P et al. (2016) DIXDC1 contributes to psychiatric susceptibility by regulating dendritic spine and glutamatergic synapse density via GSK3 and Wnt/β-catenin signaling. Mol Psychiatry :
Burette, Alain; Collman, Forrest; Micheva, Kristina D et al. (2015) Knowing a synapse when you see one. Front Neuroanat 9:100
Zemmar, Ajmal; Weinmann, Oliver; Kellner, Yves et al. (2014) Neutralization of Nogo-A enhances synaptic plasticity in the rodent motor cortex and improves motor learning in vivo. J Neurosci 34:8685-98