One of the alluring aspects of examining the role of chromatin modifications in modulating transcription required for long-term memory processes is that these modifications may provide transient and potentially stable epigenetic marks in the service of activating and/or maintaining transcriptional processes. These in turn ultimately participate in the molecular mechanisms required for neuronal changes subserving long-lasting changes in behavior. As an epigenetic mechanism of transcriptional control, chromatin modification has been shown to participate in maintaining cellular memory (e.g. cell fate) and may underlie the strengthening and maintenance of synaptic connections required for long-term changes in behavior. Epigenetics has become central to several fields of neurobiology where researchers have found that regulation of chromatin modification has a significant role in epilepsy, drug addiction, depression, neurodegenerative diseases, and memory. A current hypothesis is that specific patterns of chromatin modification may have specific effects on cellular function and subsequent behavior. Recent research suggests that our epigenome changes as a function of time, potentially leading to a shift in chromatin structure that makes gene expression more difficult, and thus forming long-term memories more difficult. In this proposal, we will examine the role of histone deacetylase 3 (HDAC3) in regulating gene expression during memory formation in the aging rodent. We have identified an age at which aging rodents fail to form long-term memory for object location, which is a form of memory susceptible to age-dependent decline in humans. HDAC3 is a powerful enzyme that generates a repressive chromatin structure that inhibits gene expression. During memory formation in young rodents, HDAC3 is removed from specific genes, resulting in long-term memory formation. However, this mechanism fails in aging rodents. We hypothesize that in the aging brain, HDAC3 develops abnormal activity in repressing gene expression. Our preliminary data support this hypothesis by demonstrating that homozygous focal genetic deletion of Hdac3 in aging rodents completely restores their long-term memory formation for object location. To fully test this hypothesis, we propose two aims.
In aim 1 we will examine the role of HDAC3 in age-dependent long-term memory formation using genetically modified mice, viral approaches, and several behavioral tasks.
In aim 2, we will use next generation sequencing including chromatin immunoprecipitation (ChIP) sequencing and RNA sequencing to identify HDAC3 target genes and how those genes are regulated throughout the lifespan by examining a number of different ages. Results from these experiments would demonstrate that HDAC3 is a key regulator of memory formation in the aging brain, which would lead to a significant conceptual advance in our understanding of how epigenetic mechanisms function in the aged brain and also identify potential for novel therapeutic design.
Age-related cognitive decline is an important concern in the United States, as approximately 20% of the US population is expected to be age 65 or older by the year 2030. Understanding age-related memory impairments and developing new treatment strategies to improve memory and prolong healthy cognitive function are therefore becoming increasingly important as the population ages. This proposal will examine a key epigenetic mechanism that underlies memory formation, which may unlock a novel approach to ameliorating age-related memory dysfunction.
| Shu, Guanhua; Kramár, Enikö A; López, Alberto J et al. (2018) Deleting HDAC3 rescues long-term memory impairments induced by disruption of the neuron-specific chromatin remodeling subunit BAF53b. Learn Mem 25:109-114 |
| Kwapis, Janine L; Alaghband, Yasaman; Kramár, Enikö A et al. (2018) Epigenetic regulation of the circadian gene Per1 contributes to age-related changes in hippocampal memory. Nat Commun 9:3323 |
| Hemstedt, Thekla J; Lattal, K Matthew; Wood, Marcelo A (2017) Reconsolidation and extinction: Using epigenetic signatures to challenge conventional wisdom. Neurobiol Learn Mem 142:55-65 |
| Kwapis, Janine L; Alaghband, Yasaman; López, Alberto J et al. (2017) Context and Auditory Fear are Differentially Regulated by HDAC3 Activity in the Lateral and Basal Subnuclei of the Amygdala. Neuropsychopharmacology 42:1284-1294 |
