This Project will continue its focus on signaling and plasticity as a basis for individual differences in aging outcomes. Against a background of largely preserved structural integrity, alterations in the function of neurons in the medial temporal lobe provide the most reliable indicators of cognitive abilities that depend on this circuitry. The background and preliminary data for this research plan indicate a basis for distinguishing two subpopulations of aged rats that each differ from young. Consistent with recent findings in other components of the overall research program, the CAS region of the hippocampus is particularly noteworthy as an area that undergoes pronounced alterations associated with cognitive impairment. A distinctive profile is also found in this region in aged animals with preserved cognitive function.
The Specific Aims of this project will 1) extend the regional analysis of broad molecular profiling in behaviorally characterized aged rats to a paradigm for measuring learning-activated transcription (Aim 2), and 2) assess the efficacy of interventions to gain control over the dysregulaton of cellular function in impaired aged rats and determine whether the such treatments normalize indicators in the molecular profile in both basal and learningactivated conditions along with improved behavioral outcomes (Aim 3). The purpose of studies using interventions based on data in the model is twofold, 1) to allow the test of specific scientific hypotheses, and 2) to examine new avenues into translation approaches for therapy. Test agents under study in the proposed work include 1) antiepileptics (valproate and ABT 769), 2) HDAC inhibitors (sodium butyrate and MS 275), and 3) agonists selective for GABA-A a5 receptors.
In Specific Aim 4 we will examine the basis for differential adaptive aging in rats that perform on a par with young adults. That work will explore a new hypothesis concerning alterations in middle-age that may serve an adaptive function in aging outcomes, both neuroprotective and behavioral. Such adaptations would be consistent with a switch in plasticity mechanisms observed in aged unimpaired rats. Finally, research under this project will examine whether signatures of neurocognitive aging in subregions of the hippocampal system in rats have a counterpart in aged monkey brains. Importantly those studies, similar to our research with aged rodents, will use brain tissue obtained from behaviorally characterized young and aged rhesus monkeys. We will ask questions that are based on the conditions of different aging outcomes in the rodent, including 1) overall profiles that relate to cognitive status in the aging primate (e.g. impaired and adaptive), 2) the status of specific genes that are markers of neurocognitive aging in the rodent (CAS and CA1 regions), and 3) pre- and post-synaptic gene expression patterns in arrays of dentate gyrus and entorhinal cortex that may serve as a basis for synaptic failure in the connections formed by the perforant path.
|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|
|Fletcher, Bonnie R; Hill, Gordon S; Long, Jeffrey M et al. (2014) A fine balance: Regulation of hippocampal Arc/Arg3.1 transcription, translation and degradation in a rat model of normal cognitive aging. Neurobiol Learn Mem 115:58-67|
|Koh, Ming Teng; Spiegel, Amy M; Gallagher, Michela (2014) Age-associated changes in hippocampal-dependent cognition in Diversity Outbred mice. Hippocampus 24:1300-7|
|Yang, Sunggu; Megill, Andrea; Ardiles, Alvaro O et al. (2013) Integrity of mGluR-LTD in the associative/commissural inputs to CA3 correlates with successful aging in rats. J Neurosci 33:12670-8|
|Spiegel, Amy M; Koh, Ming Teng; Vogt, Nicholas M et al. (2013) Hilar interneuron vulnerability distinguishes aged rats with memory impairment. J Comp Neurol 521:3508-23|
|Tomas Pereira, Ines; Coletta, Christopher E; Perez, Evelyn V et al. (2013) CREB-binding protein levels in the rat hippocampus fail to predict chronological or cognitive aging. Neurobiol Aging 34:832-44|
|Koh, Ming Teng; Rosenzweig-Lipson, Sharon; Gallagher, Michela (2013) Selective GABA(A) *5 positive allosteric modulators improve cognitive function in aged rats with memory impairment. Neuropharmacology 64:145-52|
|Agster, Kara L; Burwell, Rebecca D (2013) Hippocampal and subicular efferents and afferents of the perirhinal, postrhinal, and entorhinal cortices of the rat. Behav Brain Res 254:50-64|
|Castellano, James F; Fletcher, Bonnie R; Kelley-Bell, Bennett et al. (2012) Age-related memory impairment is associated with disrupted multivariate epigenetic coordination in the hippocampus. PLoS One 7:e33249|
|Shamy, Jul Lea; Habeck, Christian; Hof, Patrick R et al. (2011) Volumetric correlates of spatiotemporal working and recognition memory impairment in aged rhesus monkeys. Cereb Cortex 21:1559-73|
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