Age-related cognitive impairment imposes a very significant burden on a large number of elderly people. In addition, managing and preventing neurodegenerative disorders such as Alzheimer's disease (AD) will require a sophisticated understanding of the neurobiological determinants of age-related vulnerability of cortical circuits mediating cognition. The overarching hypothesis of this proposal 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. We will continue to investigate these issues in both rat and non-human primate (NHP) models. In all cases, the age-related alterations will be measured at the level of spine number, spine morphology, synapse morphology, and the Glutamate receptor (GluR) phenotype of axospinous synapses as determined by immunogold analyses. The natural variability in progression of cognitive aging across subjects will allow us to identify and differentiate synaptic characteristics related to both cognitive decline and successful aging in both animal models.
In Specific Aim 1, we will use high resolution, quantitative microscopy in brains from rhesus monkeys that have had extensive behavioral assessment to reveal the morphologic and molecular synaptic alterations in area 46 of prefrontal cortex (RFC) that mediate age-related impairment of cognitive functions dependent on PFC. We hypothesize that these alterations will affect efficacy of glutamatergic inputs to pyramidal cells as well as mechanisms of synaptic plasticity.
Specific Aim 2 will use the same behaviorally-characterized rhesus monkeys targeted in Specific Aim 1 to delineate the structural and molecular age-related synaptic alterations in hippocampus that predict decrements in the medial temporal lobe memory system, dentate gyrus (DG), CA1 and CAS will be analyzed, with particular attention in DG to the vulnerability of the entorhinal/DG circuit referred to as the perforant path. The aged NHPs will also be followed for menopausal status, allowing us to link our synaptic findings to the onset of natural menopause as well as cognitive status and chronological age.
Specific Aim 3 will use in vivo induction of LTP in young adult rats to establish a baseline of molecular plasticity of GluRs at the potentiated synapses. Then, age-related alterations that compromise synaptic plasticity will be delineated through similar experiments using LTP induction in aged impaired and unimpaired rats aimed at revealing key molecular mechanisms of compromised plasticity that impact spatial memory. These studies will provide critically important data from which to design interventions and judge their success in restoring or maintaining a youthful synaptic profile for humans with age-related cognitive impairment, and perhaps even early AD.
|Pereira, A C; Gray, J D; Kogan, J F et al. (2017) Age and Alzheimer's disease gene expression profiles reversed by the glutamate modulator riluzole. Mol Psychiatry 22:296-305|
|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|
Showing the most recent 10 out of 65 publications