Our overarching hypothesis is that selective synaptic alterations in cortical glutamatergic systems occur with aging, compromising both synapse number and the molecular and morphologic components of plasticity required for learning and memory, thereby contributing to age-related cognitive impairment The current Specific Aims are: 1) To determine the age-related morphologic and molecular alterations in pyramidal cells and axospinous synapses in area 46 of dorsolateral prefrontal cortex (dlPFC) in rhesus monkey and their contribution to cognitive aging; 2) To determine the age-related synaptic alterations in rhesus monkey hippocampus and the degree to which they predict decrements in the medial temporal lobe memory system; and 3) To identify changes in synaptic GluR profiles induced by LTP in young and aged rats, how they are altered in aging, and how such age-related alterations relate to memory performance mediated by hippocampus. We have made extensive progress in all three Specific Aims, and have revealed fundamental differences in the nature of synaptic aging between hippocampus and dIPFC as well as differences in the indices that are predictive of cognitive performance mediated by each region. In addition, we have revealed that the small, thin, highly plastic spines are vulnerable in dIPFC, whereas the mushroom spines are unaffected by aging. The MERIT extension will allow us to pursue these reflections of selective vulnerability in synaptic aging comprehensively, as well as pursue several new directions. First, with extended time we will be able to determine the molecular profile of vulnerable vs. resistant spine classes in dIPFC to provide a basis for therapeutic strategies. Second, we will have access to two additional cohorts of young and aged rhesus monkeys with structural and functional imaging built in to the design, and differential rearing conditions as a variable for one of the cohorts. Third, we have now developed the capacity to dramatically expand our neuronal reconstruction and spine analysis to additional neocortical regions, allowing for a comprehensive analysis of selective synaptic vulnerability across the neocortex. Fourth, we will expand our molecular targets to include links to both tau pathology and actin polymerization to provide a more mechanistic basis for alterations in neuronal/synaptic structure and plasticity. Fifth, we will expand our rat analyses to include PFC to test the hypothesis that the synaptic and circuit mechanisms in the PFC age similarly and can impair homologous cognitive functions across species. In all cases, we will expand our capacity to provide novel therapeutic targets based on molecular underpinnings of synaptic aging.
This project is designed to reveal the synaptic basis for age-related cognitive decline. The emerging data will provide a framework for both behavioral and pharmaceutical therapies to protect against age-related cognitive decline. This is important for non-Alzheimer's Disease cognitive decline as well as Alzheimer's Disease since the synaptic alterations that we identify very likely occur in the human brain as well, leaving neurons vulnerable to the degenerative cascade embodied by Alzheimer's Disease.
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|Hara, Yuko; Yuk, Frank; Puri, Rishi et al. (2016) Estrogen Restores Multisynaptic Boutons in the Dorsolateral Prefrontal Cortex while Promoting Working Memory in Aged Rhesus Monkeys. J Neurosci 36:901-10|
|Hara, Yuko; Waters, Elizabeth M; McEwen, Bruce S et al. (2015) Estrogen Effects on Cognitive and Synaptic Health Over the Lifecourse. Physiol Rev 95:785-807|
|Morrison, John H; Baxter, Mark G (2014) Synaptic health. JAMA Psychiatry 71:835-7|
|Young, M E; Ohm, D T; Dumitriu, D et al. (2014) Differential effects of aging on dendritic spines in visual cortex and prefrontal cortex of the rhesus monkey. Neuroscience 274:33-43|
|Hara, Yuko; Yuk, Frank; Puri, Rishi et al. (2014) Presynaptic mitochondrial morphology in monkey prefrontal cortex correlates with working memory and is improved with estrogen treatment. Proc Natl Acad Sci U S A 111:486-91|
|Pereira, Ana C; Lambert, Hilary K; Grossman, Yael S et al. (2014) Glutamatergic regulation prevents hippocampal-dependent age-related cognitive decline through dendritic spine clustering. Proc Natl Acad Sci U S A 111:18733-8|
|Bloss, Erik B; Puri, Rishi; Yuk, Frank et al. (2013) Morphological and molecular changes in aging rat prelimbic prefrontal cortical synapses. Neurobiol Aging 34:200-10|
|Wang, Min; Yang, Yang; Wang, Ching-Jung et al. (2013) NMDA receptors subserve persistent neuronal firing during working memory in dorsolateral prefrontal cortex. Neuron 77:736-49|
|Ohm, Daniel T; Bloss, Erik B; Janssen, William G et al. (2012) Clinically relevant hormone treatments fail to induce spinogenesis in prefrontal cortex of aged female rhesus monkeys. J Neurosci 32:11700-5|
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