To fully understand changes in cognitive function during aging, it is necessary to understand how hormones that decline with age normally regulate and maintain structural and functional plasticity and resilience of the adult brain. Estradiol (E) is the best-studied hormone with respect to protection from cognitive decline and effects of stroke and risk for Alzheimer's disease in women. Yet, we are only beginning to understand how the aging brain responds to E at the cellular, molecular and anatomical levels and how E regulated plasticity changes with age. A major new direction in E action is the investigation of """"""""non-genomic""""""""signaling pathways by which E influences the functions of many cells in the brain and other organs. These pathways affect cell survival, cytoskeletal reorganization, protein synthesis, among other processes, as part of maintaining 'healthy brain cell functions"""""""" but they can be lost or severely impaired as the brain ages. The main objective of this project in support of the overall Program Project, focusing on hippocampus, is three-fold: first, to carry out in vitro studies of the E molecular mechanisms underiying E regulation of """"""""non-genomic"""""""" signaling processes;second, to determine the relevance of these pathways to such spine synapse formation and maturation (SSF/IVI) via immunocytochemical and ultrastructural studies on the adult rat hippocampus;third, to determine the relevance of these pathways to the loss with aging of E effects as spine synapse formation and maturation (SSF/M)using in vitro and in vivo approaches. In carrying out these goals, collaborative studies within the PPG will determine the relevance of these mechanisms to the studies of the age-related decline in cognitive as well as neuroendocrine function in the aging rat and primate brain which are being studied in other components of this program project. Our central hypothesis is that age-related failure of E treatment to increase the number of synapses in CAI region of the hippocampus may be due to changes in the molecular profile of axospinous synapses with respect to signaling pathway that participate in spine synapse formation and maturation (SSF/M) in response to E. To achieve this, we intend to, first, determine the signaling pathways and estrogen receptor involvement in NR2B phosphorylation and if aging results in a reduction of pNR2b in synaptic compartments;second, to determine how E activates the key signaling pathway, PISK-kinase, in the dendritic spine, and when and where this activation is lost in dendritic spines of the aging brain;third, to determine the role of the actin regulating protein, cortactin, in SSF/M and the rate- limiting role of cortactin in the age-related loss of E-induced SSF/M. Knowledge gained in these studies will focus preventative therapies on the key age-sensitive signaling pathways and molecules.

Public Health Relevance

Age-related cognitive decline is a serious problem. To fully understand changes in cognitive function during aging, we must understand how hormones that decline with age normally regulate and maintain structural and functional plasticity and resilience of the adult brain. We study actions of estradiol (E), known to protect from cognitive decline and effects of stroke and risk for Alzheimer's disease in women;knowledge gained in these studies will focus preventative therapies on the key age-sensitive signaling pathways and molecules.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
5P01AG016765-12
Application #
8376627
Study Section
Special Emphasis Panel (ZAG1-ZIJ-9)
Project Start
Project End
Budget Start
2012-03-01
Budget End
2013-02-28
Support Year
12
Fiscal Year
2012
Total Cost
$316,423
Indirect Cost
Name
Icahn School of Medicine at Mount Sinai
Department
Type
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
Baxter, Mark G; Santistevan, Anthony C; Bliss-Moreau, Eliza et al. (2018) Timing of cyclic estradiol treatment differentially affects cognition in aged female rhesus monkeys. Behav Neurosci 132:213-223
Crimins, Johanna L; Puri, Rishi; Calakos, Katina C et al. (2018) Synaptic distributions of pS214-tau in rhesus monkey prefrontal cortex are associated with spine density, but not with cognitive decline. J Comp Neurol :
Milham, Michael P; Ai, Lei; Koo, Bonhwang et al. (2018) An Open Resource for Non-human Primate Imaging. Neuron 100:61-74.e2
Motley, Sarah E; Grossman, Yael S; Janssen, William G M et al. (2018) Selective Loss of Thin Spines in Area 7a of the Primate Intraparietal Sulcus Predicts Age-Related Working Memory Impairment. J Neurosci 38:10467-10478
Bliss-Moreau, Eliza; Baxter, Mark G (2018) Estradiol treatment in a nonhuman primate model of menopause preserves affective reactivity. Behav Neurosci 132:224-229
Garcia, Alexandra N; Depena, Christina; Bezner, Kelsey et al. (2018) The timing and duration of estradiol treatment in a rat model of the perimenopause: Influences on social behavior and the neuromolecular phenotype. Horm Behav 97:75-84
Beckman, Danielle; Baxter, Mark G; Morrison, John H (2018) Future directions in animal models of Alzheimer's disease. J Neurosci Res 96:1829-1830
McEwen, Bruce S; Milner, Teresa A (2017) Understanding the broad influence of sex hormones and sex differences in the brain. J Neurosci Res 95:24-39
Nutsch, Victoria L; Bell, Margaret R; Will, Ryan G et al. (2017) Aging and estradiol effects on gene expression in the medial preoptic area, bed nucleus of the stria terminalis, and posterodorsal medial amygdala of male rats. Mol Cell Endocrinol 442:153-164
Garcia, Alexandra N; Bezner, Kelsey; Depena, Christina et al. (2017) The effects of long-term estradiol treatment on social behavior and gene expression in adult female rats. Horm Behav 87:145-154

Showing the most recent 10 out of 132 publications