Aging is associated with declining function across a broad spectrum of behavioral and biological measures. This component of the program project will pursue neuropsychological studies aimed at determining the nature and range of cognitive deficits associated with aging, and electrophysiological studies aimed at characterizing hippocampal integrative processing at multiple levels. Direct collaborations with other members of the project will pursue specific program project objectives: PROGRAM OBJECTIVE #1: To assess the differential vulnerability of cortical and subcortical neurons associated with aging, we will characterize the range of decline in hippocampal-dependent memory function and dissociate deficits in hippocampal-dependent memory performance from impairments in cognitive abilities associated with prefrontal cortex function. In collaboration Rapp, we will correlate age-related changes in neuron number in the medial and orbital prefrontal cortex with declines in performance on spatial and odor-guided memory performance that are differentially dependent on these brain areas. PROGRAM OBJECTIVE #2: To assess the structural integrity of the hippocampus we will characterize age-related changes in neurophysiological function in terms of (1) qualitative and quantitative differences in neural coding by single neurons and neural ensembles during spatial information processing and their plasticity in response to task alterations, and (2) septo-hippocampal integration reflected in synchronization of afferent information processing with the hippocampal theta rhythm during exploratory behavior. In collaboration with Rapp we will correlate changes in cholinergic and noncholinergic cell number with age-related decline in septo-hippocampal integration. PROGRAM OBJECTIVE #3: To assess functional alterations in signal transduction pathways we will employ a newly developed behavioral- electrophysiological paradigm for producing learning-related alterations in synaptic efficacy in specific hippocampal pathways. In collaborations with Gallagher and Wolfe we will correlate postranslational PKC and glutamate receptor phosphorylation in the hippocampus with age-related decline in acquisition and decay of learning related synaptic plasticity. Each of these experiments is designed to test specific hypotheses about the nature of age related cognitive decline: that aging associated with decline in prefrontal- as well as hippocampal-dependent cognitive functions, and that at least some aspect of age-related cognitive involves loss of basal forebrain regulation of hippocampal processing, and consequent limitations in the range of stimuli encoded, the flexibility of representations in response to change, and the plasticity of hippocampal synaptic mechanisms.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
3P01AG009973-08S1
Application #
6098306
Study Section
Project Start
1998-09-30
Project End
1999-08-31
Budget Start
1997-10-01
Budget End
1998-09-30
Support Year
8
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Type
DUNS #
045911138
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Haberman, Rebecca P; Koh, Ming Teng; Gallagher, Michela (2017) Heightened cortical excitability in aged rodents with memory impairment. Neurobiol Aging 54:144-151
Haberman, Rebecca P; Branch, Audrey; Gallagher, Michela (2017) Targeting Neural Hyperactivity as a Treatment to Stem Progression of Late-Onset Alzheimer's Disease. Neurotherapeutics 14:662-676
Posada-Duque, Rafael Andrés; Ramirez, Omar; Härtel, Steffen et al. (2017) CDK5 downregulation enhances synaptic plasticity. Cell Mol Life Sci 74:153-172
Gu, Yu; Tran, Trinh; Murase, Sachiko et al. (2016) Neuregulin-Dependent Regulation of Fast-Spiking Interneuron Excitability Controls the Timing of the Critical Period. J Neurosci 36:10285-10295
Wang, Hui; Ardiles, Alvaro O; Yang, Sunggu et al. (2016) Metabotropic Glutamate Receptors Induce a Form of LTP Controlled by Translation and Arc Signaling in the Hippocampus. J Neurosci 36:1723-9
Robitsek, Jonathan; Ratner, Marcia H; Stewart, Tara et al. (2015) Combined administration of levetiracetam and valproic acid attenuates age-related hyperactivity of CA3 place cells, reduces place field area, and increases spatial information content in aged rat hippocampus. Hippocampus 25:1541-55
Tomás Pereira, Inês; Gallagher, Michela; Rapp, Peter R (2015) Head west or left, east or right: interactions between memory systems in neurocognitive aging. Neurobiol Aging 36:3067-3078
Gallagher, Michela; Burwell, Rebecca; Burchinal, Margaret (2015) Severity of spatial learning impairment in aging: Development of a learning index for performance in the Morris water maze. Behav Neurosci 129:540-8
Mayse, Jeffrey D; Nelson, Geoffrey M; Avila, Irene et al. (2015) Basal forebrain neuronal inhibition enables rapid behavioral stopping. Nat Neurosci 18:1501-8
Castellano, James F; Fletcher, Bonnie R; Patzke, Holger et al. (2014) Reassessing the effects of histone deacetylase inhibitors on hippocampal memory and cognitive aging. Hippocampus 24:1006-16

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