Epigenetic memory: the Lamarckian brain

Abstract

Recent data support the view that epigenetic processes play a role in memory consolidation and help to transmit acquired memories even across generations in a Lamarckian manner. Drugs that target the epigenetic machinery were found to enhance memory function in rodents and ameliorate disease phenotypes in models for brain diseases such as Alzheimer's disease, Chorea Huntington, Depression or Schizophrenia. In this review, I will give an overview on the current knowledge of epigenetic processes in memory function and brain disease with a focus on Morbus Alzheimer as the most common neurodegenerative disease. I will address the question whether an epigenetic therapy could indeed be a suitable therapeutic avenue to treat brain diseases and discuss the necessary steps that should help to take neuroepigenetic research to the next level.

Figure 1. Epigenetic and non-coding RNA mechanisms

(1) DNA is wrapped around the nucleosome which consists of the four core histones (H). Histone tails are subjected to post-translational modification including acetylation and methylation, which give rise to the “histone-code” that affects gene expression. Histone acetylation and methylation are regulated by the counteracting activity of histone acetyltransferases (HATs) and histone-deacetylases (HDACs) or histone-methyltransferases (HMTs) and histone-demethylases (HDMs), respectively. (2) Methylation of DNA at the C-5 atom of cytosine is mediated by DNA-methyltransferases and often occurs in cytosine-guanine-rich regions of the genome (CpG islands). DNA-methylation is generally associated with gene silencing. DNA-hydroxymethylation is mediated by ten-eleven translocation proteins and also regulates gene expression. (3) Non-coding RNAs affect gene expression and protein function. The best-studied non-coding RNAs are micro RNAs (miRs) that catalyze gene silencing or inhibition of protein translation. These processes are key regulators of genome–environment interactions and provide to a cell the molecular tools to transform the variable combinations of genetic and environmental factors into long-term adaptive changes. There is now emerging evidence that the epigenome also regulates the consolidation of processed information into long-term memories.

Figure 2. Analyzing memory function in rodents

This image illustrates three commonly used tests to study memory formation in rodents. (A) The Morris water maze Test measures spatial reference memory that is highly hippocampus-dependent. A mouse or rat is placed in a pool that contains opaque water and an escape platform that is located underneath the water surface. During the training, the rodent learns to locate the hidden platform based on spatial orientation. Such memory is normally acquired gradually throughout multiple training sessions on subsequent days (e.g., 10 days of training). (B) The Pavlovian fear conditioning is used to assess associative memory. The rodent is allowed to explore the test box representing a novel context for about 3 min before it receives a mild electric foot shock. When placed back into the context 24 h later, the animal shows freezing, inborn behavior that rodents express in response to threatening situations. The amount of freezing is quantified and reflects learning ability. In contrast to the water maze, fear conditioning is successfully acquired after a single training session, and memory can be tested even 1 year later. (C) In the novel object recognition paradigm, the animal is habituated to the test arena and eventually presented with two objects that it explores equally. After a delay that can vary from minutes (short-term memory) to 24 h (long-term memory), the animal is re-exposed to the arena that now contains one novel object. Based on the previous training session, the animal remembers the object that has already been explored and will show a preference for the novel object. (D) To elucidate the mechanisms that underlie memory consolidation, a suitable approach is to subject animals to a training session and isolate afterward at distinct time points tissue for molecular analysis. Especially paradigms such as fear conditioning are often used since memory is acquired within a distinct time window after a single training session allowing for a “molecular snapshot” of memory consolidation. Based on such results, hypothesis can be formed and suitable gain- and loss-of-function mouse models are generated that are then again tested for memory function.

Figure 3. Understanding the epigenome of learning and memory

1. Experimental approaches to test memory function in model systems should be employed to define the epigenetic landscape of memory formation. Well-studied examples are mice that are subjected to hippocampus-dependent memory training such as contextual fear conditioning. 2. In order to understand how the epigenome shapes neuronal circuitries, it will be essential to isolate distinct cell types for epigenome analysis. This could be achieved in a meaningful manner via fluorescence-activated cell sorting of nuclei that will then be subjected to epigenome profiling using next-generation sequencing (NGS) approaches. 3. Bioinformatic analysis and computational modeling will be an essential tool to understand the molecular networks linked to memory formation in health and disease. 4. This will allow researchers to formulate novel hypothesis about the underlying mechanisms that shall then be tested using suitable models systems. For example, mutant mice that lack or overexpress the hub within a given network. The effect of such manipulation and the epigenetic network can then be tested again using cell-type-specific epigenome profiling.

Figure 4. The epigenome as a read out for life experience and disease risk

Throughout lifetime an organism is exposed to variable environmental stimuli that can initiate memory consolidation processes. On the basis of the existing data, it can be speculated that consolidation of such life experiences into memories critically involve long-term epigenetic changes. Such epigenetic signatures may even be transmitted to the next generation thereby influencing the phenotype of the coming generations. Part of such life experiences represents the interaction of genetic and non-genetic risk factors for brain diseases such as Alzheimer disease. I hypothesize that also such risk factors lead to a disease-specific epigenetic signature and a corresponding gene expression profile that may even affect disease risk in the next generation. As such epigenetic signatures may serve as bona fide biomarkers and therapeutic strategies to target, the epigenome may turn out to be more beneficial than directly targeting the multiple risk factors that are believed to contribute to disease pathogenesis.