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.
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.
|Hsu, Alexander; Luebke, Jennifer I; Medalla, Maria (2017) Comparative ultrastructural features of excitatory synapses in the visual and frontal cortices of the adult mouse and monkey. J Comp Neurol 525:2175-2191|
|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|
|Rumbell, Timothy H; Dragulji?, Danel; Yadav, Aniruddha et al. (2016) Automated evolutionary optimization of ion channel conductances and kinetics in models of young and aged rhesus monkey pyramidal neurons. J Comput Neurosci 41:65-90|
|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|
|Coskren, Patrick J; Luebke, Jennifer I; Kabaso, Doron et al. (2015) Functional consequences of age-related morphologic changes to pyramidal neurons of the rhesus monkey prefrontal cortex. J Comput Neurosci 38:263-83|
|Steele, John W; Brautigam, Hannah; Short, Jennifer A et al. (2014) Early fear memory defects are associated with altered synaptic plasticity and molecular architecture in the TgCRND8 Alzheimer's disease mouse model. J Comp Neurol 522:2319-35|
|Dickstein, D L; Weaver, C M; Luebke, J I et al. (2013) Dendritic spine changes associated with normal aging. Neuroscience 251:21-32|
|Crimins, Johanna L; Pooler, Amy; Polydoro, Manuela et al. (2013) The intersection of amyloid ? and tau in glutamatergic synaptic dysfunction and collapse in Alzheimer's disease. Ageing Res Rev 12:757-63|
|Yadav, Aniruddha; Gao, Yuan Z; Rodriguez, Alfredo et al. (2012) Morphologic evidence for spatially clustered spines in apical dendrites of monkey neocortical pyramidal cells. J Comp Neurol 520:2888-902|
Showing the most recent 10 out of 18 publications