Synaptic plasticity in many different forms is widely recognized as essential to normal brain development, to homeostasis of the mature brain, and to our abilities to adapt to changing environments and injury and to learn. There is relatively little information, however, to link particular known forms of synaptic plasticity to particular forms or sites of behaviorally relevant brain circuit plasticity. This gap in our knowledge prevents us from efficiently pinpointing synapses of known functional relevance as we explore the molecular, synaptic, and circuit bases of memory and its disorders. The experiments proposed here will exploit unique advantages of the mouse whisker sensory system to explore basic mechanisms of neocortical synaptic plasticity. The work will apply a powerful new high-resolution proteomic imaging method called "array tomography" (AT) to measure molecular and structural characteristics of cortical synapse populations at the level of individual synapses. AT has unique abilities to resolve individual synapses in native circuit tissue context, to measure dozens of distinctive molecular markers (e.g., diverse receptor, transporter, signaling, scaffolding and adhesion proteins) at each synapse, and to do so with very high experimental throughput. Thus, AT can determine a high dimensional molecular signature for each individual synapse in very large populations and differentiate specific synapse subpopulations on the basis of such molecular signatures. The proposed research will develop and apply a novel AT-based screening strategy to search in an unbiased fashion for patterns of structural and molecular change occurring in specific mouse neocortical synapses in reaction to specific sensory adaptation and associative conditioning procedures.

Public Health Relevance

This research will apply a powerful new high-resolution proteomic imaging method called array tomography to pinpoint specific sites of synaptic plasticity associated with particular sensory adaptation and associative learning paradigms. The resulting new information on brain plasticity mechanisms will contribute to the development of improved drug treatments for neurodevelopmental and neurodegenerative disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS075252-04
Application #
8842414
Study Section
Neurodifferentiation, Plasticity, and Regeneration Study Section (NDPR)
Program Officer
Talley, Edmund M
Project Start
2011-07-01
Project End
2015-04-30
Budget Start
2014-05-01
Budget End
2015-04-30
Support Year
4
Fiscal Year
2014
Total Cost
$477,363
Indirect Cost
$175,761
Name
Stanford University
Department
Biophysics
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
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Micheva, Kristina D; Bruchez, Marcel P (2012) The gain in brain: novel imaging techniques and multiplexed proteomic imaging of brain tissue ultrastructure. Curr Opin Neurobiol 22:94-100
Kleinfeld, David; Bharioke, Arjun; Blinder, Pablo et al. (2011) Large-scale automated histology in the pursuit of connectomes. J Neurosci 31:16125-38