Purpose. This FOA issued by the National Institute on Aging (NIA) invites applications for the study of factors regulating neuroplasticity with a particular emphasis on the age-dependent changes in the functions of dendrites, spines and synapses of key cell types in regions of brain especially vulnerable in Alzheimers disease (AD), and in models (in vitro and in vivo) of aging and of AD.Neuroplasticity refers to the changes in both structure and function of the brain that occur in response to experiential stimuli.This ability of the brain to reorganize itself is critical both in normal development and learning, and it is no less important in aging and neurodegenerative disorders. The decline of cognitive functions in aging and disease, especially those functions that rely upon the medial temporal lobe and prefrontal cortex, appears to stem, at least in part, from selective changes in synaptic function and integrity.This initiative solicits research to investigate the factors regulating synaptic plasticity and dysfunction and selective neuronal vulnerability with aging and in certain neurodegenerative disorders such as AD using in vitro and in vivo models. Mechanism of Support. This FOA will utilize the R01 grant mechanism. Funds Available and Anticipated Number of Awards.Awards issued under this FOA are contingent upon the availability of funds and the submission of a meritorious application. Budget and Project Period. The total project period for an application submitted in response to this funding opportunity may not exceed 5 years. Applicants for an R01 award are not limited in dollars but need to reflect the actual needs of the proposed project. Application Research Plan Component Length: The R01 application Research Plan component of the PHS398 (Items 2-5) may not exceed 25 pages, including tables, graphs, figures, diagrams, and charts (see also http://grants.nih.gov/grants/funding/funding_program.htm). Eligible Institutions/Organizations. Institutions/organizations listed in Section III, 1.A. are eligible to apply. Eligible Project Directors/Principal Investigators (PDs/PIs). Includes individuals with the skills, knowledge, and resources necessary to carry out the proposed research are invited to work with their institution/organization to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH support. Number of PDs/PIs. More than one PD/PI (i.e., multiple PDs/PIs), may be designated on the application. Number of Applications. Applicants may submit more than one application, provided that each application is scientifically distinct. Resubmissions.Applicants may submit a resubmission application, but such application must include an Introduction addressing the previous peer review critique (Summary Statement). See new NIH policy on resubmission (amended) applications (NOT-OD-09-003, NOT-OD-09-016). Renewals. Applicants may submit a renewal application.