Epigenetic Mechanisms for Long-Term Memory Acquisition and Maintenance
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Authors Gookin, Dylon Kyle
Publisher The University of Arizona.
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Abstract
In this review, we will explore the evidence that supports an epigenetic foundation for learning and memory. Through this, we will first review the basics of both learning and memory before delving into the foundational mechanisms for epigenetics. Understanding this, we will examine the evidence that suggest a link between epigenetics and long-term memory by observing two distinct directionalities: 1) the procession of learning into consolidation of a memory, and how this affects an organisms genetic code, and 2) the manifestation of change in behavior as a result of the aforementioned epigenetic changes to an organism’s DNA. Beyond this, lapses in our current understanding will be discussed, and suggestions for future work will be outlined.
Abbreviations
Deoxyribonucleic acid (DNA), brain-derived neurotrophic factor (BDNF), calcium/calmodulin- dependent protein kinase (CaMKII), N-methyl-D-aspartate receptor (NMDAR), α-amino-3- hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR), ribonucleic acid (RNA), post- translational modification (PTM), histone acetyltransferase (HAT), acetyl coenzyme A (acetyl- CoA), histone deacetylase (HDAC), histone methyltransferase (HMT), histone demethylase (HDM), protein phophotase (PP), cytosine-phosphate-guanine (CpG), DNA methyltransferase (DNMT).
Epigenetic Mechanisms for Long-Term Memory Maintenance 2
Introduction
With the exponential advent of new technologies, modern conversation often shifts to the importance of memory. Ten years ago, digital memory storage was just becoming a presence in modern day life, and just recently, technology was even revealed that allowed a micro-SD card to carry over 200GB of information. Even so, as our understanding of computer mechanics and digital memory storage improves, our understanding of organic memory is still a rough patchwork of ideas sewn together with some few threads of evidence.
The human brain is more capable of memory storage than any currently developed piece of technology, and rightfully so. Though we’ve made great lengths in understanding some of the neurological processes that can affect learning and memory, the mechanisms in place for an organic memory unit such as the brain are still far from being fully understood. Common thought is based around the idea that all of our memories are stored in our brain. Aside from the thousands of brain-injury case studies that one could dive through, it is more or less common knowledge that knowledge itself, and thus memory, are housed within the brain. Though this works for a lambent understanding of the learning and memory, this does not paint the entire picture.
Nothing in a living organism remains static. Old skin cells consistently flake off, only to be replaced by new ones, and even bone structure is constantly remodeled. Neurons within the brain do not usually die off. Even so, though the lifespan of an individual neuron might be enormous, the lifespan of the proteins that decorate each individual neuron simply cannot be. It is at this point that modern neuroscientists reach a troubling junction: somehow, the forever changing body of a living organism must remain constant enough to allow for long-term memory. It’s at this junction that the field of neuroepigenetics has been developed.
In spite of all the ways that a living organism can change, there is one thing guiding those changes: deoxyribose nucleic acid, or DNA. DNA is, at its core, responsible for the maintenance of all other functions of a living organism. It is what differentiates a human from a strawberry, it is what allows for the regeneration of skin cells, and when it is tweaked (such as with UV radiation), it can cause radical changes in an organisms make-up. Because of its static foundation but surprising malleability, neuroscientists are looking into how neurological structures and DNA work together to form and maintain long-term memory. Epigenetic Mechanisms for Long-Term Memory Maintenance 3
What is Learning and Memory
Definition
Part of the ambiguity underlying the conversation about learning and memory stems from its definition. From a psychologist’s perspective, memory can be defined as a behavioral change caused by an experience. Therefore, learning would be defined as a process for acquiring memories (Okano, Hirano, Balaban 2000). Though useful, this doesn’t account for the biological basis of memory. Several studies have determined that protein synthesis is necessary for the development of memory, so it is important to highlight this aspect when discussing memory in any aspect (Davis, Squire 1984). In order to consolidate both the psychological and biological aspect of memory, we can broadly define learning and memory as the lasting alterations in behavioral output in response to transient environmental input (Sweatt 2010; Zovkic 2013).
Types of Memory
The ambiguity in this definition allows for the blanket application for several types of memory. Memory is usually divided into distinct “types” based on memory content or longevity. We will primarily discuss long-term memory, a type based on longevity, but in order to understand what long-term memory is, it is important to understand how it differentiates from all other types of memory. Schacter and Tulving outlined various “memory systems” that served as the foundation for our current types of memory (1994). The majority of the studies that we will eventually discuss involve the development of long-term memory based on fear conditioning and spatial memory. Epigenetic Mechanisms for Long-Term Memory Maintenance 4
Table 1: Types of memory systems as defined by Schacter and Tulving (1994). Note that although some of these types of memory are frequently referenced, these systems of memory were developed in 1994, and have laid the groundwork for the understanding that there exists various types of memory.
Though Schacter and Tulving defined types of memory by their content, memory is also deconstructed into types based on the longevity of the memory itself. Cowan described, in his own review of memory types, the differences between long-term, short-term, and working memory (2009). Throughout his review, he concludes that working memory stands most distinct from both short term and long term memory, though the latter two are more ambiguous in difference. Working memory is the type of memory utilized for planning and carrying out behavior (Miller 1986). Short term memory, Cowan argues, is so similar to working memory that the two blend in definition except that the former reflects “faculties of the human mind that can hold a limited amount of information in a very accessible state” (Cowan 2009; Broadbent 1958; Atkinson, Shiffrin 1968). By this, Cowan means to differentiate working from short term memory by claiming that short term memory is capable of storage, whereas working is not. Long term memory is not vastly different from short-term except in their respective duration and capacity, where duration is the length of time a memory can be stored, and the capacity describes Epigenetic Mechanisms for Long-Term Memory Maintenance 5 the number of memorized “items” that can be “stored” (Cowan 1998). For the sake of this review, we will be focusing primarily on long-term memory. Many of the mechanisms of working memory and short term memory, such as duration, can be at least somewhat explained by the decay of proteins within neurons. Long term memory is not so easy to rationalize.
Biological Basis for Learning and Memory
With the types of memory distinguished, we explore the biological mechanisms in play that are responsible for memory formation, or learning. Until recently, we have understood that memory existed, and that it must be influenced by external stimuli, but there had been little work completed that verified this connection. Two studies published in 1973 were the first to establish a biological link between the outside world and a living brain, familiarly known as long term potentiation (LTP). Researchers were able to measure an increase in synaptic strength between two neurons after electrode stimulation in rabbits (Bliss 1973). Though this did not substantiate anything about memory, it proved that the brain could be, at least temporarily, modified in response to external stimuli. The connection to memory was first suggested in a review of this mechanism (Figure 1), when it was concluded that “if LTP is a substrate for memory it must be shown that is both necessary and sufficient” for it (Teyley, DiScenna 1987). At the time, there simply wasn’t enough evidence to verify the connection. Epigenetic Mechanisms for Long-Term Memory Maintenance 6
Figure 1: One variety of long-term potentiation (adapted from Kauer Malenka 2007): External stimuli results in action potential that opens voltage-gated calcium ion channels that provoke the release of glutamate, a neurotransmitter. -amino-3-hydroxy-5- methyl-4-isoxazole propionic acid receptor (AMPAR) activation via glutamate results in an influx of sodium ion (not pictured; Kandel 1991). Subsequent voltage relief removes the magnesium ion block from the N-methyl-D-aspartate receptor (NMDAR). Calcium ion influx via NMDAR activates calcium/calmodulin-dependent protein-kinase II (CaMKII), which results in AMPAR insertion into the postsynaptic cytoskeleton. This allows for a lower threshold of glutamate concentration for excitatory postsynaptic potential (EPSP). Also not pictured: CAMKII begins a signal transduction cascade that can result in the transcription and eventual production of additional AMPA receptors (Lynch 2004).
Today, however, we’ve made great strides toward doing just that. Nabavi et al. were able to generate a fear response based on memory solely by optigenetically initiating LTP (2014). Based on this research, we can now begin to cautiously develop a full length trace from external stimuli to the generation of a memory. Understanding how a memory can be formed from external stimuli allows us to question how these memories are maintained. It is at this point that we reach a problem.
The Problem with Long Term Memory
Verifying the relationship between the protein make-up of a neuron and memory bring us to one big question: If the specific proteins contained within neurons of the brain are at least partly responsible for memory, how are they maintained? We briefly addressed this issue early on: nothing in an organism is completely static. If protein synthesis is linked to memory Epigenetic Mechanisms for Long-Term Memory Maintenance 7 formation, as suggested by Nabavi et al., there must be a mechanism(s) in place to maintain said proteins, so as to ensure the subsequent maintenance of memory. It’s here that we will discuss the basic of epigenetics, to illuminate this area of ambiguity.
Epigenetics
Defining Epigenetics
Living organisms are incredibly complex organic machines. The proper coding for the construction and operation of these machines, or the genome, is DNA. DNA can be partially copied via transcription, and those copies allow for the translation of the individual proteins that make up the entirety of an organism. Structural changes to DNA, such as changes to the base pair organization, can have drastic and permanent consequences. Much of this is common knowledge at this point, but DNA can be influenced in ways other than through the direct modification of its organization. DNA can be manipulated without disturbing the sequence of base pairs via epigenetic mechanisms. These mechanisms manipulate the folding of molecules of DNA so as to inhibit or encourage the subsequent transcription and translation of individual genes. This additional layer of manipulation to the genome is known as the epigenome (Mazzio, Soliman 2011; Costa 2007).
DNA does not simply exist as a lump in the nucleus of a cell. Rather, it’s folded into a nucleoprotein complex called chromatin. Chromatin is constructed of several individual units called nucleosomes, which are composed of 147 base pairs of DNA wrapped around an octamer of alkaline histone proteins (Cooper 2000). The histones responsible for the composition of the nucleosomes are H2A, H2B, H3 and H4, (Quina et al. 2006). These individual nucleosomes can link together via another histone, H1, to form a long chain that, as stated, is called chromatin. This chromatin can assume two different forms, called euchromatin and heterochromatin, which respectively inhibit or encourage the attachment of transcription factors (Cooper 2000).
Epigenetic Mechanisms
There are several different factors that influence the conformational state of chromatin and the subsequent transcription (or lack thereof) of DNA. As previously stated, acidic DNA molecules bind to the alkaline histone molecules that are responsible for the tight coiling of DNA (Quina et al. 2006). However, altering the charge of these histones can interfere with the normal Epigenetic Mechanisms for Long-Term Memory Maintenance 8 interactions between histone molecules and DNA. This can result in the opening or closing of the chromatin conformation, and the respective promotion or inhibition of transcription. Aside from these post-translational modifications (PTMs) to histones, such as acetylation and methylation (figure 2) we will also discuss the direct methylation of DNA (figure 3), which is generally understood to suppress transcription.
Histone Acetylation
Of the two PTMs that we will be discussing, histone acetylation is the better characterized. Histone acetyltransferases (HATs) catalyze the transfer of an acetyl group from acetyl-coenzyme A (acetyl-CoA) to specific lysine side chains within a histone’s N-terminal tail region (Loidl 1994). This addition interferes with the positive charge of the lysine group, which degrades the intermolecular attraction that the histone shares with DNA and other histones (Hong et al. 1993). This subsequent weakening of the chromatin structure allows for the attack of transcription machinery (Luger, Richmond 1998). Acetylation can be reversed with the application of histone deacetylases (HDACs) and is often correlated with the repression of gene expression, which offers further evidence toward the relationship between transcription and histone acetylation (Ekwall 2005).
Histone Methylation
Though histone methylation is not as well characterized as histone acetylation, this does not mean that it is completely misunderstood. Histone methylation occurs via histone methyltransferases (HMTs) that selectively methylate side chains of the H3 histone. Similarly to acetylation, this influences the charge on the histone, which affects its interaction with DNA and other histones (Jenuwin, Allis 2001). However, there has been little progress in determining any consistence in how methylation affects the likelihood of transcription, as methylation has been indicated to both promote and repress transcription (Kouzarides 2002). Whereas acetylation tends to promote transcription in all scenarios, methylation, regardless of number, at the H3 lysine 4 will promote transcription. At the same time, di- and trimethylation at H3K9 can repress transcription when it occurs at H3K9. Demethylation of histones is not well studied at this point, though there is evidence to suggest that it is possible via JmjC-domain containing histone demethylases (Tsukada et al. 2006). Epigenetic Mechanisms for Long-Term Memory Maintenance 9
Figure 2: (adapted from Zovkic et al. 2013). Histone Modification: this visual model serves to outline the existing substrates responsible for histone modification. Histone acetyltransferases (HATs) acetylate histones. Histone deacetylases (HDACs) deacetylate histones. Histone methyltransferases (HMTs) methylate histones. Histone demethylase (HDMs) demethylate histones. Protein kinases (PKs) phosphorylate histones. Protein phosphatases (PPs) dephosphorylate histones. Heterochromatin – Repressed Transcription: Methylation is commonly understood to be responsible for binding the nucleosomes together, preventing transcription. Euchromatine – Active Transcription: Acetylation is understood to open up the histones, allowing transcription factors (TF) to bind to the DNA, allowing for transcription (Zovkic et al. 2013).
DNA Methylation
Though DNA methylation preferentially occurs at cytosine nucleotides that are residing adjacent to guanine nucleotides. When this kind of arrangement occurs within the genome with high frequency, it is known as a cytosine-phosphate-guanine (CpG) island, and is especially prone to methylation (Deaton, Bird 2011). Methylation occurs through the covalent transfer of a methyl group from S-Adenosylmethione (AdomMet or SAM) (Chiang et al. 1996). This transfer is catalyzed by DNA methyltransferases (DNMTs). Specifically speaking, DNMT1, DNMT3a and 3b are all responsible for de novo methylation of cytosine nucleotides, but DNMT3a and 3b have been determined necessary for DNA methylation maintenance (Chen et al. 2003; Rhee et al. 2002; Fuks et al. 2000). DNA methylation is understood to repress transcription by promoting the binding of histones into a closed, heterochromatin structure, which blocks transcriptional machinery (Iguchi-Ariga and Schaffner 1989. Aside from its own function, there is evidence to Epigenetic Mechanisms for Long-Term Memory Maintenance 10 suggest that methylation can recruit additional suppressors of transcription. HDACs, which we know to repress transcription via histone deacetylation, are recruited by a methyl CpG binding protein (MeCP2), which are elicited by the methyl groups of the DNA (Iguchi-Ariga and Schaffner 1989; Kass 1997). As a small aside, and in contrast to the normally understood function, DNA methylation can also promote transcription, when MeCP2s bind to CREB (Chahrour et al. 2008). DNA methylation is also reversible, though poorly understood in comparison to DNA methylation. The current mechanisms involves members of the Gadd45 family, TET family, and DNMT3a and 3b, in spite of the latter two being involved in DNA methylation (Zovkic et al. 2013; Wu, Zhang 2010; Ooi, Bestor 2008).
Figure 3: Visual representation of DNA methylation (adapted from Zovkic et al. 2013). From left to right: CpG islands: an example of a CpG island that is prone to methylation. The methylation of the cytosine promotes the recruitment of MeCP2, which then binds HDACs, which can repress transcription via deacetylation (Iguchi-Ariga and Schaffner 1989; Kass 1997). Cytosine Methylation: as shown, cytosine is methylated by DNMTs. Demethylation can take place via proteins from the TET family, the Gadd45 family, or even DNMTs. (Zovkic et al. 2013; Wu, Zhang 2010; Ooi, Bestor 2008).
Interference of Epigenetic Mechanisms
None of the above discussed mechanisms are exclusive, and often work synergistically or antagonistically in conjunction with one another, forming a “histone code” (Strahl, Allis 2000). As previously discussed, HDACs are responsible for deacetylating histones. The deacetylation allows for the charged surface of histones to retain their charge and bind the DNA, preventing transcription (Ekwall 2005). DNA methylation, which can inhibit transcription by itself, also recruits HDACs to further repress transcription (Iguchi-Ariga and Schaffner 1989; Kass 1997). In this way, both DNA methylation and histone deacetylation operate synergistically to oppose acetylation and subsequent DNA transcription. Based on this, it is important not to make Epigenetic Mechanisms for Long-Term Memory Maintenance 11 assumptions based on the isolated function of a single epigenetic mechanism, as they will realistically be operating in conjunction with several other factors in an in vivo setting (Zovkic et al. 2013).
Where Memory Meets Epigenetics
At this point, we have now reviewed the basic principles underlying learning and memory. Put shortly, it’s possible to draw a rudimentary trace from a stimulus and follow it through to some of the responsive biological changes that can take place within a neuron. Though we can use this trace to explain short term changes in the protein make up of specific neurons with the brain, it fails to account for the permanent changes that are predictably required for long term memory. We have also reviewed the primary epigenetic mechanisms in place that are responsible for long lasting changes to transcriptional promotion or repression. Though the specific results of various combinations of epigenetic modifications are still unclear, it is evident that these modifications can cause permanent changes in DNA conformation, and thus its tendency for transcription. By applying the epigenetic mechanisms for permanent modifications to protein production to the lapses in explanation for long-term memory, we can begin to discuss how memory could be maintained via epigenetics. Graff and Tsai developed a hypothetical mechanism based on these concepts (Figure 4). Epigenetic Mechanisms for Long-Term Memory Maintenance 12
Figure 4: Proposed mechanism for epigenetic basis of long-term memory (adapted from Graff, Tsai 2013). LTP initiates NMDAR enabled calcium influx, which activates calmodulin (not shown). Calmodulin activation facilitates the phosphorylation of CaMKII, which prompts the dissociation of MeCP2 from the promoter region of the gene coding for brain-derived neurotrophic factor (BDNF) (Graff, Tsai 2013), a protein implicated in memory development and maintenance (Bekinschtein 2013). BDNF is then transcribed for and translated, after which it triggers nitric oxide (NO) synthase (not shown), which nitrosylates HDAC2 (Graff, Tsai 2013). Nitrosylation of HDAC2 allows for the acetylation of the histones, leading to a euchromatin state (Graff, Tsai 2013). This open form of chromatin allows for the positive feedback production of BDNF (adapted from Graff, Tsai 2013).
The following section will evaluate several different studies that explore the connection between memory establishment and maintenance and epigenetics. For the sake of organization, we will first discuss several studies that observed the influence of memory development and maintenance on the epigenome. Following, we will discuss several studies that observed how changes in epigenetic post-translational changes correlated with changes in learning and memory retention.
Linking Memory to Epigenetic Changes Epigenetic Mechanisms for Long-Term Memory Maintenance 13
Generally speaking, the act of learning has been linked to several different epigenetic modifications of genes implicated in memory maintenance. Several researchers summarily determined that the act of learning led to increases and decreases in DNA methylation in the genes coding for brain-derived neurotrophic factor (BDNF) and calcineurin, two proteins hugely involved in learning and memory that we will discuss later on (Miller, Sweatt 2007; Lubin et al. 2008; Feng et al. 2010; Gupta et al. 2010; Miller et al. 2010; Munoz et al. 2010; Penner et al. 2011). We will also be discussing protein phosphatase 1 (PP1) in the next section, which is known to be a memory suppressor due to its role in increasing HDAC and HDM activity (Koshibu et al. 2009).
Beyond this general understanding however, there has been plenty of research that more specifically implicate links between various methods of learning (arguably implicating differences in types of memory) and changes in the epigenome. Much of this evidence demonstrates some specificity in epigenetic change across different types of learning, brain regions, and even brain subregions. Fear conditioning correlated with DNA methylation for the (PP1) gene and the subsequent decrease of said protein within the hippocampus (Miller, Sweatt 2007). It also is associated with increases in acetylation at H3K14, trimethylation at H3K4me3, and dimethylation at H3K9me2 (Levenson et al. 2004; Chwang et al. 2006; Gupta et al. 2010; Gupta-Agarwal et al. 2012). Additionally, fear conditioning is linked to an increase in de novo hippocampal DNMT for the promoter of the PP1 gene sequence (Miller, Sweatt 2007). As previously stated, however, the same type of learning can have different effects in different brain regions. For example, although fear conditioning is associated with histone modifications in both the amygdala and the hippocampus (Monsey et al. 2011) they differ in the specifics of these modifications, such as at the homer1 gene (Mehan et al. 2011). Some work in this relationship between epigenetics and memory has also been completed in discussion with other training methods, and even different subregions of a brain. H3 and H4 acetylation and H3K9 deacetylation took place in the CA1 subregion of the hippocampus, whereas the CA3 subregion only experienced H3 acetylation (Castellano et al. 2012).
Linking Epigenetic Mechanisms to Changes in Memory
The evidence demonstrating a link between epigenetic modifications and memory is much more difficult to substantiate. Rather than simply training and dissecting a specimen, it is Epigenetic Mechanisms for Long-Term Memory Maintenance 14 necessary to selectively modify and mark specific genes of the epigenome, which we simply do not have the technology to do at this point. Instead, most studies have revolved around inhibiting specific mechanisms and drawing inferences based on known relationships. For example, by inhibiting DNMT as a whole, tested individuals demonstrated memory deficits that were reversed by HDAC inhibitors (Miller et al. 2008; Maddox, Shafe 2011; Monsey et al. 2011). By this, we can be quick to assume that DNMT is thusly responsible for the memory deficits, but without a way to ensure the isolation of the effects of DNMT, there is no way to validate this claim.
There are countless other studies that review the minutiae of the material that we just discussed. In a separate review of the role of chromatin in the regulation of transcription, Barret and Wood compiled a list (Table 2) of several known memory effects due largely to acetylation and deacetylation (2008). Note that we are only able to trace the changes to specific histones as a result of training exercises, as we are not yet capable of manually and selectively inducing such changes.
Table 2: Adapted compilation from Barret and Wood (2008) of known effects of HDAC inhibitors on memory, and known histone PTMs in response to learning activities. b The different HDAC inhibitors that have been investigated with regard to their ability to enhance memory and synaptic plasticity (Barrett, Wood 2008). c The different histone residues and the post-translational modifications at that residue that have been implicated in being regulated during normal or enhanced memory. (Barrett, Wood 2008). Epigenetic Mechanisms for Long-Term Memory Maintenance 15
Conclusions and Future Directions
If there has been any doubt that the organic manifestation of memory could be any more complicated than digital storage, it has hopefully been quelled at this point. Rather than being coded as a series of ones and zeros, organic memory is stored via selectively and differentially modified genes. These genes are specific for different neurons within different subregions of different regions of every brain. The complexity of the matter borders on the inane, but we are slowly making headway into the mess.
The progress is slow, however. We need to acknowledge that there are simply too variables involved in the epigenetic basis of memory to work through the matter by hand. Additionally, we need to acknowledge that today’s technology is simply too rudimentary for an undertaking of this level of precision and magnitude. Before we can begin to make any kind of meaningful progress into decoding the patterns that underlie the relationship between epigenetics and memory, we need to find a way to selectively mark and inflict specific PTMs onto specific genes. From this point, we can begin to methodically evaluate the effects of specific PTMs on specific subregions and regions. From there, we can finally look more broadly, and determine the effects of specific PTMs on memory. It will be a long and arduous process, but we have already taken the first steps.
Epigenetic Mechanisms for Long-Term Memory Maintenance 16
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