Cognitive impairment in normal aging and neurodegenerative disease is accompanied by altered morphologies on multiple scales: from the fine-grained geometry of individual spines to the global topologies of multi-neuron and vasculature networks that are distorted by space-occupying histopathologic lesions. A mechanistic understanding of the role of these structural changes in producing the observed cognitive deficits requires accurate 3D representations of neuronal morphology, and realistic biophysical modeling that can directly relate structural changes on multiple scales to altered neuronal firing patterns. To date however, no tools capable of resolving, digitizing and analyzing neuronal morphology on both local and global scales, and in true 3D, have been available. The central goal of this project is development of an automated analysis system for digitization, 3D reconstruction and geometric analysis of detailed and accurate neuronal morphology, capable of handling morphologic details on scales spanning local spine geometry through complex tree topology to the gross spatial arrangement of multi-neuron networks. As a specific example we will analyze morphologic changes in a Tg2576 mouse model of Alzheimer's disease (AD), in which amyloid deposition, altered cortical microvasculature and neural abnormalities provide easily identifiable examples of pathologic lesions.
Four Specific Aims will address this broad objective: (1) To develop a semi-automated system for 3D tree extraction and spine analysis from laser scanning microscopy (LSM) imaged data, with sub-voxel resolution for accurate neuronal morphometry at the finest scales; (2) to image and digitize in 3D individual neurons, multineuron and vasculature networks, and senile plaques from human and Tg2576 mouse models of AD; (3) to develop tools for global analysis of spatially complex cellular structures in 3D; (4) to distribute and maintain all software, and develop a database-driven web repository for distribution of digitized neurons and networks. By providing true 3D morphometry of complex neural structures on multiple scales, the tools developed in this study will enable future multiscale biophysical modeling studies capable of testing hypothesized mechanisms by which altered dendritic structure, spine geometry and network branching patterns in normal aging and neurodegenerative disease determine pathologies of working memory and cognitive function. Such studies will provide crucial insight into general mechanisms of memory induction and maintenance that underlie normal cognitive function, its dysfunction in diseased states, and potential mechanisms for its restoration. ? ?

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-MDCN-K (55))
Program Officer
Cavelier, German
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Mount Sinai School of Medicine
Schools of Medicine
New York
United States
Zip Code
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
Dickstein, D L; Weaver, C M; Luebke, J I et al. (2013) Dendritic spine changes associated with normal aging. Neuroscience 251:21-32
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
Reilly, James E; Hanson, Hugo H; Fernandez-Monreal, Monica et al. (2011) Characterization of MSB synapses in dissociated hippocampal culture with simultaneous pre- and postsynaptic live microscopy. PLoS One 6:e26478
Dumitriu, Dani; Rodriguez, Alfredo; Morrison, John H (2011) High-throughput, detailed, cell-specific neuroanatomy of dendritic spines using microinjection and confocal microscopy. Nat Protoc 6:1391-411
Dickstein, Dara L; Brautigam, Hannah; Stockton Jr, Steven D et al. (2010) Changes in dendritic complexity and spine morphology in transgenic mice expressing human wild-type tau. Brain Struct Funct 214:161-79
Luebke, Jennifer I; Weaver, Christina M; Rocher, Anne B et al. (2010) Dendritic vulnerability in neurodegenerative disease: insights from analyses of cortical pyramidal neurons in transgenic mouse models. Brain Struct Funct 214:181-99
Kabaso, Doron; Coskren, Patrick J; Henry, Bruce I et al. (2009) The electrotonic structure of pyramidal neurons contributing to prefrontal cortical circuits in macaque monkeys is significantly altered in aging. Cereb Cortex 19:2248-68
Langlands, T A M; Henry, B I; Wearne, S L (2009) Fractional cable equation models for anomalous electrodiffusion in nerve cells: infinite domain solutions. J Math Biol 59:761-808

Showing the most recent 10 out of 15 publications