Ph.D., Biochemistry and Molecular Biology, Harvard University,
Research in the Abel lab focuses on the molecular mechanisms of memory storage and the molecular basis of neurodevelopmental and psychiatric disorders. Dr. Abel has been a leader in applying molecular and genetic approaches to define how neural circuits mediate behavior, making creative use of genetically modified mouse lines to study the biological basis of behavior. The three main areas of research in the Abel lab all derive from an interest in the ways in which information is stored in the brain. First, we have been examining the molecular and epigenetic mechanisms of long-term memory. We have identified ways to enhance memory, and we are seeking to define the molecular substrates underlying this cognitive enhancement with the hope that this will lead to novel therapeutic approaches for the debilitating cognitive impairments that accompany many neurological, psychiatric and neurodevelopmental disorders. Second, we have been examining the role of sleep in memory storage, defining the molecular mechanisms by which sleep deprivation impairs hippocampus-dependent memory. Recent work in the Abel lab has revealed that sleep deprivation alters synaptic connectivity in the hippocampus. Third, we are examining mouse models of schizophrenia and autism. We have recently identified male-specific deficits in reward learning in mouse models of autism, providing a potential way to explain the well-known male bias of this neurodevelopmental disorder.
Molecular Mechanisms of Long-Term Memory Storage
Each neuron contains thousands of synapses, each of which needs to be independently modifiable by experience. Work in the Abel lab suggests that localized signaling mediated by scaffolding proteins generates synapse-specific activation of biochemical pathways that mediate long-term memory storage. Beginning as a postdoctoral fellow, Dr. Abel pioneered genetic approaches to define the role of the cAMP signaling and protein kinase A in hippocampal synaptic plasticity and memory. Most recently, his lab has focused on spatial compartmentalization of PKA signaling via a large family of A-kinase anchoring proteins (AKAPs), which restrict PKA and other signaling molecules to specific subcellular locations such as the plasma membrane where they interact with receptors, adenylyl cyclases, and ion channels. This research includes computational approaches to model spatially restricted signaling along with genetic and pharmacological approaches.
How are memories stored for months and even years in neural circuits in the brain? Recent work by the Abel lab has suggested that epigenetic modifications that act during development to define cell fate provide a biochemical mechanism for long-term memory storage. Histone acetylation, an activating epigenetic mark, plays a critical role in long-term memory. Decreasing histone acetylation by genetic deletion of the histone acetyltransferase CREB-binding protein (CBP) in the hippocampus reduces long-term memory performance, whereas increasing histone acetylation by pharmacological inhibition of histone deacetylases (HDACs) or genetic deletion of the co-repressor SIN3a enhances long-term memory. We have found the Nr4a family of genes is downstream of CBP-mediated histone acetylation and required for the enhancement of memory by HDAC inhibition. We are studying the transcriptional regulators mediating long-term memory through mouse models and the genetic targets of histone acetylation using genome-wide techniques.
Sleep and Memory
Sleep facilitates the formation of hippocampus-dependent memories and brief periods of sleep deprivation are detrimental to memory consolidation. Additionally, sleep is regulated by many of the same molecular processes that contribute to memory storage. The Abel lab uses a combination of molecular, genetic, and viral approaches to elucidate the machinery underlying sleep-associated long-term memory consolidation. Specifically, we have found sleep deprivation induces a cascade of changes in cAMP signaling and protein synthesis. We have also defined the role of gliotransmission in mediating the impact of sleep deprivation on memory and cognition. Given that in today’s society people obtain insufficient sleep, which in turn results in deleterious effects on cognitive function, our studies are critical to understand the molecular and cellular changes induced by sleep and sleep deprivation and their impact on memory consolidation.
The Molecular Basis of Neurodevelopmental and Psychiatric Disorders
Cognitive deficits accompany many neurological, psychiatric and neurodevelopmental disorders. The Abel lab is interested in using mouse models to understand the structural, behavioral, and genetic underpinnings of schizophrenia and autism spectrum disorder. In an effort to model autism spectrum disorder, we have conducted an extensive study of behavioral phenotypes in several mouse models. Our studies in operant learning tasks have revealed deficits in motivation and reward-based learning, processes that are mediated by the basal ganglia. Our investigation of striatal-based behaviors and learning may provide unique insights into the basis of autism spectrum disorder, revealing the importance of deficits in the neural circuitry that mediates reward. With these translational approaches, we hope to identify novel targets for the development of new therapeutics to treat psychiatric and neurodevelopmental disorders.
Peixoto, L., Wimmer, M., Poplawski, S., Tudor, J. C., Kenworthy, C. A., Liu, S., Mizuno, K., Garcia, B. A., Zhang, N. R., Giese, K. P. and Abel, T. (2015). Memory acquisition and retrieval impact different epigenetic processes that regulate gene expression. BMC Genomics. 16: S5.
Peixoto, L., Risso, D., Poplaswki, S., Wimmer, M., Speed, T., Wood, M., and Abel, T. (2015). How data analysis affects power, reproducibility and biological insight of RNA-seq studies in complex datasets. Nucleic Acids Research 43: 7664-7674.
Havekes, R., Bruinenberg, V., Tudor, J. C., Ferri, S., Baumann, A., Meerlo, P. and Abel, T. (2014). Transiently increasing cAMP levels selectively in hippocampal excitatory neurons during sleep deprivation prevents memory deficits caused by sleep loss. Journal of Neuroscience. 34: 15715-21.
Patel, T. P., Gullotti, D. M., Hernandez, P., O’Brien, W. T., Capehart, B., Morrison III, B., Bass, C., Eberwine, J. E., Abel, T. and Meaney, D. F. (2014). An open-source toolbox for automated phenotyping of mice in behavioral tasks. Frontiers in Behavioral Neuroscience. 8: 349.
Hawk, J. D., Bookout, A. L., Poplawski, S. G., Bridi, M., Rao, A. J., Sulewski, M. E., Kroener, B. T., Mangelsdorf, D. J. and Abel, T. (2012). Nr4a nuclear receptors support memory enhancement by histone deacetylase inhibitors. Journal of Clinical Investigation. 122: 3593-3602.
Havekes, R., Huang, T., Nie, T., Canton, D., Park, A. J., Day, J.P., Guercio, L., Grimes, Q., Luczak, V., Gelman, I. H., Baillie, G.S., Scott, J. D. and Abel, T. (2012). Gravin orchestrates PKA and beta2-adrenergic receptor signaling critical for synaptic plasticity and memory. Journal of Neuroscience. 32:18137-18149.
Vecsey, C. G., Baille, G., Jaganath, D., Havekes, R., Daniels, A., Wimmer, M., Huang, T., Brown, K., Li, X.-Y., Descalzi, G., Kim, S. S., Chen, T., Shang, Y.-Z., Zhuo, M., Houslay, M. D. and Abel, T. (2009). Sleep deprivation impairs cAMP signaling in the hippocampus. Nature 461: 1122-1125.
To search PubMed for publications by Ted Abel, click here.
Biology/BIBB 251, Molecular and Cellular Neurobiology (with Marc Schmidt)
Biology 442/NGG 575, Neurobiology of Learning and Memory
Biology 488/NGG 578, Advanced Topics in Behavioral Genetics (with Maja Bucan)
To see Ted Abel's Google Scholar citations, click here.
To find out more about the Biological Basis of Behavior Program at Penn, click here.
To find out more about the Neurobehavior Testing Core at Penn, click here.
To find out more about the Neurobiology of Learning and Memory Journal (Elsevier), click here.