The biochemical signaling mechanisms underlying the sustenance and perpetuation of long-lasting, experience-dependent functional change in the CNS remain mysterious. Although several appealing potential mechanisms in this context have been identified, including CaMKII autophosphorylation, PKM-zeta production, and AMPA receptor auto-regulation, transcription-regulating mechanisms have received little attention to date. This Project will investigate the hypothesis that a potent transcription-regulating mechanism, altered DNA methylation, might serve as a lasting signal in the hippocampus and cortex to subserve persisting alterations in gene expression, cellular properties, and circuit function. We will test this idea by executing two Specific Aims that test important predictions of the concept.
In Specific Aim 1 we will test the hypothesis that DNA methylation controls arc gene expression and hippocampal place field stability in vivo. Prior results have demonstrated that application of a variety of DNMT inhibitors, and conditional deletion of the DNMT 1 and 3A genes, leads to deficits in hippocampal LTP and deficits in hippocampus-dependent long-term contextual learning. However, it is not known how the deficits in hippocampal plasticity lead to memory deficits in the behaving animal. In this Aim we will investigate the role of DNA methylation at the cellular and systems level by investigating experience-driven long-term and short-term changes in DNA methylation in specific hippocampal neuronal subtypes using both immunohistochemistry and laser-capture dissection. In additional studies we will investigate the capacity of DNA methylation to regulate hippocampal arc gene expression, and by investigating the capacity of DNA methylation to control the formation and stabilization of hippocampal place cell firing patterns.
In Specific Aim 2 we will test the hypothesis that DNA methylation controls the storage of remote memory in the anterior cingulate cortex. Recent work from several laboratories has demonstrated that remote, i.e. very long-lasting, contextual memories are consolidated and stored in the anterior cingulate cortex. It is intriguing to consider that lasting changes in DNA methylation might contribute to stabilization of remote memory in the cortex, and in this Aim we will test whether remote memory formation is associated with altered DNA methylation in the anterior cingulate cortex, and whether disrupting cortical DNA methylation leads to remote memory destabilization.

Public Health Relevance

The study of the signaling mechanisms that contribute to long-lasting behavioral change will lead to the identification of novel neuropharmacological targets for drug development, and will contribute to a better general understanding of regulation of neurobehavioral function. This Project will specifically be relevant to the idea that drugs affecting gene expression may potentially be useful therapies for memory dysfunction and for facilitating long-term behavioral modification.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH091122-03
Application #
8449935
Study Section
Neurobiology of Learning and Memory Study Section (LAM)
Program Officer
Osborn, Bettina D
Project Start
2011-06-03
Project End
2016-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
3
Fiscal Year
2013
Total Cost
$351,600
Indirect Cost
$111,600
Name
University of Alabama Birmingham
Department
Neurosciences
Type
Schools of Medicine
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294
Guzman-Karlsson, Mikael C; Meadows, Jarrod P; Gavin, Cristin F et al. (2014) Transcriptional and epigenetic regulation of Hebbian and non-Hebbian plasticity. Neuropharmacology 80:3-17
Zovkic, Iva B; Paulukaitis, Brynna S; Day, Jeremy J et al. (2014) Histone H2A.Z subunit exchange controls consolidation of recent and remote memory. Nature 515:582-6
Lithner, Christina Unger; Lacor, Pascale N; Zhao, Wei-Qin et al. (2013) Disruption of neocortical histone H3 homeostasis by soluble A?: implications for Alzheimer's disease. Neurobiol Aging 34:2081-90
Day, Jeremy J; Childs, Daniel; Guzman-Karlsson, Mikael C et al. (2013) DNA methylation regulates associative reward learning. Nat Neurosci 16:1445-52
Kaas, Garrett A; Zhong, Chun; Eason, Dawn E et al. (2013) TET1 controls CNS 5-methylcytosine hydroxylation, active DNA demethylation, gene transcription, and memory formation. Neuron 79:1086-93
Almonte, Antoine G; Qadri, Laura H; Sultan, Faraz A et al. (2013) Protease-activated receptor-1 modulates hippocampal memory formation and synaptic plasticity. J Neurochem 124:109-22
Zovkic, Iva B; Sweatt, J David (2013) Epigenetic mechanisms in learned fear: implications for PTSD. Neuropsychopharmacology 38:77-93
Zovkic, Iva B; Guzman-Karlsson, Mikael C; Sweatt, J David (2013) Epigenetic regulation of memory formation and maintenance. Learn Mem 20:61-74
Rahn, Elizabeth J; Guzman-Karlsson, Mikael C; David Sweatt, J (2013) Cellular, molecular, and epigenetic mechanisms in non-associative conditioning: implications for pain and memory. Neurobiol Learn Mem 105:133-50
Sweatt, J David (2013) The emerging field of neuroepigenetics. Neuron 80:624-32

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