Cognitive decline in normal aging is accompanied by morphologic changes on many scales, and in rhesus monkeys, by single cell electrophysiological changes such as altered firing rates and synaptic responses. A subset of 'successful agers'can maintain both normal cognitive function and normal single-cell electrophysiology, suggesting some form of adaptive compensation for morphologic dystrophy at the cellular level. To date, no mechanistic understanding of these cellular changes, nor the inferred compensatory mechanisms, exists. The goal of this unique multidisciplinary project is to develop innovative computational technologies for identifying causal mechanisms underlying the cognitive decline that accompanies aging and neurodegeneration. Based upon these mechanisms, this project will design quantitatively precise strategies for compensating or reversing these changes, to restore a given cellular-level function to normal levels.
Three Specific Aims will address this broad objective: (1) To reconstruct the morphology, including dendritic spines, of electrophysiologically characterized young and aged layer 3 (L3) pyramidal cells from the prefrontal cortex of rhesus monkeys that have underwent behavioral testing;(2) To develop morphologically accurate compartment models of young and aged L3 pyramidal cells while developing novel parameter optimization tools;and (3) To predict compensatory mechanisms for restoring normal function in aged or dystrophic neurons using newly-designed sensitivity-analysis techniques. Public dissemination of the 3D morphology and physiology of young and aged neurons from behaviorally characterized primates will provide a unique database for the general neuroscience community to begin to address important cellular and system-level questions. Dissemination of all modeling and analysis software will provide the computational community with efficient tools to apply and extend these techniques. Such studies will generate crucial insight into the cellular bases of aging- and neurodegenerative disease-related changes in cognitive function. The development of novel technologies to predict mechanisms that can compensate for specific morphologic changes to restore a given cellular level function, has far-reaching implications for designing therapeutic interventions for many human diseases.

Public Health Relevance

This project develops and validates novel computational methods for predicting compensatory strategies to reverse the effects of pathologic changes accompanying normal aging and neurodegenerative disorders. Such technologies have far-reaching implications for designing therapeutic interventions in brain diseases. Public distribution of the software that implements these technologies and of the reconstructed neuron morphologies and electrophysiological data from cognitively characterized animals is an invaluable resource to the general neuroscience community.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG035071-04
Application #
8528441
Study Section
Special Emphasis Panel (ZRG1-NT-B (09))
Program Officer
Wise, Bradley C
Project Start
2010-09-30
Project End
2015-05-31
Budget Start
2013-09-01
Budget End
2014-05-31
Support Year
4
Fiscal Year
2013
Total Cost
$350,840
Indirect Cost
$75,759
Name
Icahn School of Medicine at Mount Sinai
Department
Neurosciences
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
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Medalla, Maria; Gilman, Joshua P; Wang, Jing-Yi et al. (2017) Strength and Diversity of Inhibitory Signaling Differentiates Primate Anterior Cingulate from Lateral Prefrontal Cortex. J Neurosci 37:4717-4734
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Medalla, Maria; Luebke, Jennifer I (2015) Diversity of glutamatergic synaptic strength in lateral prefrontal versus primary visual cortices in the rhesus monkey. J Neurosci 35:112-27
Luebke, Jennifer I; Medalla, Maria; Amatrudo, Joseph M et al. (2015) Age-related changes to layer 3 pyramidal cells in the rhesus monkey visual cortex. Cereb Cortex 25:1454-68
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