Is It Really In Your Genes? The Case for DNA Dependent Long Term Memory Storage

Stuebs J

Published on: 2019-10-24

Abstract

In the past century, studies on memory have made considerable advances in elucidating the mechanisms by which memory is stored. One of the most prominent explanations of long term memory storage is the theory of synaptic connectivity. However, it still remains unclear how synaptic connectivity is capable of storing memory engrams for up to a lifetime. The current review discusses alternative, DNA dependent mechanisms of memory storage and explains how epigenetic mechanisms of memory storage, namely DNA methylation and histone acetylation may be capable of encoding and storing memory in a more stable, long term fashion than synaptic connectivity alone.

Keywords

DNA; Storing memory; DNA Methylation and Histone

Introduction

The question of where and how memories are stored, has puzzled philosophers and scientists, such as Plato, for millennia [1]. Up until a century ago scientists were still debating whether memories are stored in the brain or in the ‘mind’ [2,3]. Compared to how slowly our understanding of the locus of memory has progressed between [2,3], the past century has made immense advances to further our understanding of the memory. Some of the biggest advances that have been made in the past century is our understanding that learning and memory seems to happen through the formation of synaptic connectivity as described by the likes of Hebb (1949) and Kandel [4]. However, recent evidence suggests that learning and memory consolidation in simple organisms can take place without the presence of synaptic plasticity [5]. To account for this, supplementary hypotheses have been developed suggesting that memory might be maintained and stored via epigenetic mechanism that are responsible for changes to Deoxyribonucleic acid (DNA) expression and protein synthesis. In the remainder of this paper I will be discussing the proposed mechanisms behind these hypotheses and the evidence for and against DNA expression as a means of memory storage.

Mechanisms of Epigenetic Memory Encoding

Epigenetic changes defined by non-heritable, but potentially stable changes to DNA and/or chromatin structure [4], have long been theorized to underlie learning and memory consolidation. These complex and poorly understood biochemical changes facilitate amongst others, the activation of plasticity promoting genes (e.g. brain-derived neuro trophic factor (BDNF) and reel in) and the repression of plasticity suppressing genes (protein phosphatase 1 (PP1)) [2,6]. Arguably, the two most important epigenetic transcriptional mechanisms involved in memory consolidation are DNA methylation and histone acetylation [4]. These mechanisms have been found to not only lead to memory facilitating gene readout, but also to facilitate memory maintenance and long term storage [4].

DNA Methylation

DNA methylation, which usually occurs at the cytosine–phosphate–guanine (CpG) sites within the DNA, is generated by either of two possible DNA methyl transferees’ (DNMTs); de novo DNMTs or maintenance DNMTs, which are responsible for methylating un methylated cytosine’s and strands of hemi-methylated DNA, respectively. During the methylation process, methyl groups are donated by S-adenosy l methionine, which lead to long lasting changes of the DNA segment without changing DNA sequencing [7]. This process is marked by several advantages that make it ideal for memory storage: (1) Its effects are stable and long lasting – by utilizing maintenance DNMTs, the DNA methylation process is capable of guiding its own inheritance following DNA replication, as well as restoring methylation in de methylated DNA strands [7]; (2) DNA methylation is activity dependent and evoked in response to learning dependent cascades following behavioral experiences [4]; (3) DNA methylation is highly specific and can be localized to a single exon within the DNA strand, thereby facilitating a range of different changes within the gene [4]. Over the past decades, countless animal studies including aplysia and rodents have linked loci specific, acute DNA (de)methylation to stimulus dependent learning [8,9]. Additional studies have found that DNA methylation of prefrontal cortex (PFC) the calcineurin (CaN) genes persists up to at least 30 days after a single associative learning experience in rats [3], and pharmacological inhibition of methylation was associated with impaired memory. This suggests that DNA methylation is involved not only in memory consolidation, but also in long term memory (LTM) storage.

Histone Acetylation

Histones are basic proteins that form the main component of chromatin which is responsible for DNA packaging [4]. Their versatility enables them to diversity act on chromatin structure and DNA expression and transcription [7]. As opposed to DNA methylation, histone acetylation does not ideally fit the criteria for LTM storage. While, similar to DNA methylation, histone acetylation has been found to be activity dependent in reaction to learning experiences [4], histone acetylation is not always precise in its locality, as simple changes to histones and the subsequent chromatin structure at one part of the structure will likely translate to changes in other parts of the structure too [4]. Additionally, histone acetylation is often found to be short lived and unstable in the changes they promote in gene expression [4]. Based on this evidence it might be assumed that histone acetylation could only be involved in memory consolidation, but not in LTM storage. Nevertheless, several studies have discovered a role of histone acetylation in LTM storage. For example, histone de acetylation inhibitors have been found to counter memory impairments in elderly mice and mice with induced neural atrophy [10,11].

DNA And Long Term Memory Storage

The evidence presented above supports the notion that DNA methylation and histone acetylation are involved in LTM formation and storage, however, it remains unclear exactly how these mechanisms facilitate LTM storage. As touched upon above, methylating processes are thought to facilitate plasticity promoting genes BDNF and reel in by via DNA de methylation, and to impede plasticity suppressing gene PP1, which in turn facilitates synaptic plasticity and long- term potentiation (LTP) [7]. However, this explanation requires the assumption that memories are stored through synaptic connectivity and LTP. Additionally, this explanation alone does not account for the fact that studies have observed associative learning LTM in the absence of synaptic connectivity and LTP [5,12]. In a recent study, Ryan and colleagues (2015) provided evidence suggesting that memory storage of fear conditioning does not rely on synaptic connectivity, but instead on engram cells within the hippocampus. In their experiment, Ryan and colleagues (2015) used blue light signals and electric stimulation to induce light dependent fear learning in a group of Channel rhodopsin–2 (ChR2) labeled mice. Shortly after the learning phase the mice were injected with the protein synthesis inhibitor anisomycin to induce retrograde amnesia. Further testing showed that anisomycin treated mice did no longer exhibit signs of fear conditioning in response to the previously conditioned stimuli. Additionally, anisomycin treated mice showed decreased dendritic spine density and limited synaptic connectivity in the engram specific ChR2 labeled cells. Interestingly, ontogenetic stimulation of ChR2-labeled engram cells in hippocampal CA1, in the lateral amygdala, and dentate gyros lead to activation of the conditioned fear response at initiation of the conditioned stimulus [12]. This suggests that synaptic plasticity is likely necessary for memory integration, however, memory storage is likely dependent on other mechanisms within memory specific engram cells [13]. Because engram cell-specific structural and functional plasticity is also protein synthesis dependent, it might be suggested that other mechanisms are at play to enable LTM storage, even at the absence of cell specific protein synthesis. Could it be that learning dependent DNA methylation might have created a template for the relevant learning dependent protein synthesis needed for memory storage. In fact, it has long been suggested that DNA methylation might be a key player in memory dependent protein synthesis that may explain how some memories can last a lifetime while many memory dependent proteins have a turnover rate of just hours [7,4].

Further evidence for the hypothesis that the template for memory specific engram proteins may be stored via DNA transcription mechanisms, comes from a revolutionary study recently published by Bédécarrats et al. (2018). In their study, Bédécarrats and colleagues (2018) extracted noncoding RNA (ncRNA) from long term sensitized aplasia California and injected it into habituated, naive animals. The findings showed that 24 hours after ncRNA injection, aplasia, who had previously habituated to siphon touches, now exhibited sensitized behaviors to being touched, and their siphon-withdrawal response was significantly stronger compared to controls who were injected with the ncRNA of non-sensitized aplasia [5]. It remains unclear whether these findings are indicative of explicit memory engram transfer of the learned siphon touch response, or whether the sensitized response is rather attributable to an overall increased sensitivity to stress due to epigenetic changes, in line with mechanisms observed in countless species including humans [14,15]. Despite these limitations, Bédécarrats and colleagues’ findings lend strong support to the hypothesis that LTM might be stored via DNA transcription.

Discussion

The aim of the current review was to discuss the currently proposed epigenetic mechanisms that facilitate LTM storage and the current the evidence for and against DNA transcription as a means of memory storage. As evidenced by this paper, there have been extensive advances in the field of memory research in the past decade, and emerging evidence continuously sheds new light on our understanding of the neurobiological mechanisms of learning and memory. It is my opinion that at this stage we can safely assume that the epigenetic mechanisms discussed above do play an important role in the consolidation and storage of memory, however, more research needs to be done to elucidate the specific mechanisms. At this stage, our understanding of the field and our ability to research it is impaired by the methodological and ethical obstacles that are associated with the relatively invasive methods needed to research biological mechanisms of memory. For example, many of the imaging       methods used to investigate protein synthesis and biochemical changes in the brain require for the test animals to be sacrificed, so that extended study of the same individuals remains difficult. Additionally, these ethical and methodological implications make it impossible to study human subjects, and thus the study of memory storage is limited to investigating long-term behavioral and associative memories, which are arguably less complex than the episodic and semantic memories scientist and philosophers have pondered about for millennia [1]. Despite these shortcomings, there is reason for optimism. Advances in biomedical research methods, such as from the in vivo ChR2 cell-labeling and stimulation methods used by Ryan et al. (2015), are constantly being made, and future methods are likely to further elucidate the seats of memory storage.

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