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Training Grant-
Biology of Aging

Corinna Burger

Corinna Burger

PhD, University of Colorado
Associate Professor, Department of Neurology

Elucidation of the Mechanisms of Successful Cognitive aging

The primary goal of my research program is to understand the molecular basis of cognition and aging. My early work identified Homer1c as one of the genes that is downregulated in aged rats that are learning-impaired in a spatial learning task compared to learning unimpaired aged animals. The first goal was to validate the role of this gene in learning at the functional level. First, we described for the first time the synaptic plasticity deficits of Homer1 knockout mice (H1-KO). Next, we introduced Homer1c into the hippocampus of Homer1 KO using Adeno-associated virus (rAAV) and for the first time we showed that gene targeting of Homer1c via rAAV was sufficient to rescue both the learning impairments and synaptic plasticity deficits of these animals.

Secondly, we devised a new learning paradigm that could be used before and after genetic manipulation to accurately classify aged rats as learning-impaired (AI) or superior learners (SL). Commonly used memory tests to segregate AI and SL result in long lasting memories and cannot be repeated in a short time (weeks). Therefore, in order to accomplish our goal of rescuing AI animals with Homer1c, we had to develop a behavioral task that could be forgotten in a couple of weeks. We showed that the Object Location Memory (OLM) task can be used to segregate aged rats into SL and AI, a novel finding in the aging field. Because SL and AI have been usually segregated using the more widely used Morris Water Maze task (MWM), we also had to demonstrate that individual performance in OLM correlates with performance in MWM. Again, these have been recognized as novel and exciting findings and this method in and of itself will impact the field of cognitive aging by facilitating the testing of pharmacological or genetic reagents for the treatment of neurodegenerative disorders.

Third, using this behavioral paradigm, we demonstrated for the first time that gene delivery of Homer1c into the hippocampus of aged learning-impaired rats rescues their learning deficits. These results are significant because they provide evidence for Homer1c as a potential gene target in the treatment of aged related memory impairment and they demonstrate the practical use of our behavioral paradigm to test the effects of genetic manipulations using a within-subjects behavioral design.

Finally, we started exploring the mechanisms underlying the behavioral benefits of environmental enrichment. For this, we housed young (2 month old) and old (18-month old) rats in environmentally enriched (EE), socially enriched (SE), or standard housing (SC) conditions and conducted tests of learning and memory formation. We demonstrate that animals that have been exposed to environmental enrichment demonstrate enhanced learning and memory enhanced hippocampal LTP relative to SE rats. Our results demonstrate that this LTP is dependent on group I metabotropic glutamate receptor mGluR5 signaling, activation of ERK and mTOR signaling cascades, and sustained phosphorylation of p70s6 kinase, thus providing a potential target mechanism for future studies of cognitive enhancement in the rodent.

Our work is now focusing on finding mechanisms of successful cognitive aging that might start early in life. We have found that young rats can be categorized into inferior and superior learners using sensitive behavioral tasks, and that performance on these tasks early in life is predictive of performance later in life. Furthermore, we have found that repeated training in this task selectively improves the performance of inferior learners, suggesting that behavioral training from an early age may provide a buffer against age-related cognitive decline.

Representative Publications
Cortese, G. P., Olin, A., O'Riordan, K., Hullinger, R., & Burger, C. (2018). Environmental enrichment improves hippocampal function in aged rats by enhancing learning and memory, LTP, and mGluR5-Homer1c activity. Neurobiology of Aging, 63, 1-11.
View publication via DOI: DOI:10.1016/j.neurobiolaging.2017.11.004

Cortese, G. P., & Burger, C. (2017). Neuroinflammatory challenges compromise neuronal function in the aging brain: Postoperative cognitive delirium and Alzheimer's disease. Behavioural Brain Research, 322(Pt B), 269-279.
View publication via DOI: DOI:10.1016/j.bbr.2016.08.027

Beckervordersandforth, R., Ebert, B., Schaffner, I., Moss, J., Fiebig, C., Shin, J., Moore, D.L., Ghosh, L., Trinchero, M.F., Stockburger, C., Friedland, K., Steib, K., von Wittgenstein, J., Keiner, S., Redecker, C., Holter, S.M., Xiang, W., Wurst, W., Ja (2017). Role of mitochondrial metabolism in the control of early lineage progression and aging phenotypes in adult hippocampal neurogenesis. Neuron, 93(3): 560-573.
View publication via DOI: DOI:10.1016/j.neuron.2016.12.017

Peng, Y., Kim, M. J., Hullinger, R., O'Riordan, K. J., Burger, C., Pehar, M., & Puglielli, L. (2016). Improved proteostasis in the secretory pathway rescues Alzheimer's disease in the mouse. Brain, 139, 937-952.
View publication via DOI: DOI:10.1093/brain/awv385

Li, M., Pehar, M., Liu, Y., Bhattacharyya, A., Zhang, S. C., O'Riordan, K. J., Burger, C., & Puglielli, L. (2015). The amyloid precursor protein (APP) intracellular domain regulates translation of p44, a short isoform of p53, through an IRES-dependent mechanism. Neurobiology of Aging, 36, 2725-2736.
View publication via DOI: DOI:10.1016/j.neurobiolaging.2015.06.021

Hullinger, R., & Burger, C. (2015). Learning impairments identified early in life are predictive of future impairments associated with aging. Behavioural Brain Research, 294, 224-233.
View publication via DOI: DOI:10.1016/j.bbr.2015.08.004

Hullinger, R., O'Riordan, K., & Burger, C. (2015). Environmental enrichment improves learning and memory and long-term potentiation in young adult rats through a mechanism requiring mGluR5 signaling and sustained activation of p70s6k. Neurobiology of Learning and Memory, 125, 126-134.
View publication via DOI: DOI:10.1016/j.nlm.2015.08.006

O'Riordan, K., Gerstein, H., Hullinger, R., & Burger, C. (2014). The role of Homer1c in metabotropic glutamate receptor-dependent long-term potentiation. Hippocampus, 24(1), 1-6.
View publication via DOI: DOI:10.1002/hipo.22222

Gerstein, H., Lindstrom, M. J., & Burger, C. (2013). Gene delivery of Homer1c rescues spatial learning in a rodent model of cognitive aging. Neurobiology of Aging, 34, 1963-1970.
View publication via DOI: DOI:10.1016/j.neurobiolaging.2013.02.006

Gerstein, H., Hullinger, R., Lindstrom, M. J., & Burger, C. (2013). A behavioral paradigm to evaluate hippocampal performance in aged rodents for pharmacological and genetic target validation. PLoS One, 8(5), e62360.
View publication via DOI: DOI:10.1371/journal.pone.0062360

Gerstein. H., O'Riordan, K., Osting, S., Schwarz, M., & Burger, C. (2012). Rescue of synaptic plasticity and spatial learning deficits in the hippocampus of Homer1 knockout mice by recombinant adeno-associated viral gene delivery of Homer1c. Neurobiology of Learning and Memory, 97, 17-29.
View publication via DOI: DOI:10.1016/j.nlm.2011.08.009

Westmark, P.R., Westmark, C.J., Wang, S., Levenson, J., O'Riordan, K.J., Burger, C., & Malter, J.S. (2010). Pin1 and PKMzeta sequentially control dendritic protein synthesis. Science Signaling, 3(112), ra18.
View publication via DOI: DOI:10.1126/scisignal.2000451

Pehar, M., O'Riordan, K.J., Burns-Cusato, M., Andrzejewski, M.E., del Alcazar, C.G., Burger, C., Scrable, H., & Puglielli, L. (2010). Altered longevity-assurance activity of p53:p44 in the mouse causes memory loss, neurodegeneration and premature death. Aging Cell, 9(2), 174-190.
View publication via DOI: DOI:10.1111/j.1474-9726.2010.00547.x

Burger, C., Lopez, M. C., Baker, H. V., Mandel, R. J., & Muzyczka, N (2008). Genome-wide analysis of aging and learning-related genes in the hippocampal dentate gyrus. Neurobiology of Learning and Memory, 89, 379-396..
View publication via DOI: DOI:10.1016/j.nlm.2007.11.006

Burger, C., Lopez, M. C., Feller, J. A., Baker, H. V., Muzyczka, N., & Mandel, R. J. (2007). Changes in transcription within the CA1 field of the hippocampus are associated with age related memory impairments. Neurobiology of Learning and Memory, 87(1), 21-41.
View publication via DOI: DOI:10.1016/j.nlm.2006.05.003

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