How do you remember?

Memory processes like formation, maintenance and consolidation have been the subjects of extensive research and, as a result, we know quite a bit about them. And just when we thought that we are getting a pretty clear picture of the memory tableau and all that is left is a little bit of dusting around the edges and getting rid of the pink elephant in the middle of the room, here comes a new player that muddies the waters again.

DNA methylation. The attaching of a methyl group (CH3) to the DNA’s cytosine by a DNA methyltransferase (Dnmt) was considered until very recently a process reserved for the immature cells in helping them meet their final fate. In other words, DNA methylation plays a role in cell differentiation by suppressing gene expression. It has other roles in X-chromosome inactivation and cancer, but it was not suspected to play a role in memory until this decade.

Oliveira (2016) gives us a nice review of the role(s) of DNA methylation in memory formation and maintenance. First, we encounter the pharmacological studies that found that injecting Dnmt inhibitors in various parts of the brain in various species disrupted memory formation or maintenance. Next, we see the genetic studies, where mice Dnmt knock-downs and knock-outs also show impaired memory formation and maintenance. Finally, knowing which genes’ transcription is essential for memory, the researcher takes us through several papers that examine the DNA de novo methylation and demethylation of these genes in response to learning events and its role in alternative splicing.

Based on these here available data, the author proposes that activity induced DNA methylation serves two roles in memory: to “on the one hand, generate a primed and more permissive epigenome state that could facilitate future transcriptional responses and on the other hand, directly regulate the expression of genes that set the strength of the neuronal network connectivity, this way altering the probability of reactivation of the same network” (p. 590).

Here you go; another morsel of actual science brought to your fingertips by yours truly.

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Reference: Oliveira AM (Oct 2016, Epub 15 Sep 2016). DNA methylation: a permissive mark in memory formation and maintenance. Learning & Memory,  23(10): 587-593. PMID: 27634149, DOI: 10.1101/lm.042739.116. ARTICLE

By Neuronicus, 22 September 2016

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One parent’s gene better than the other’s

Not all people with the same bad genetic makeup that predisposes them to a particular disease go and develop that disease or, at any rate, not with the same severity and prognosis. The question is why? After all, they have the same genes…

Here comes a study that answers that very important question. Eloy et al. (2016) looked at the most common pediatric eye cancer (1 in 15,000) called retinoblastoma (Rb). In the hereditary form of this cancer, the disease occurs if the child carries mutant (i.e. bad) copies of the RB1 tumour suppressor gene located on chromosome 13 (13q14). These copies, called alleles, are inherited by the child from the mother or from the father. But some children with this genetic disadvantage do not develop Rb. They should, so why not?

The authors studied 57 families with Rb history. They took blood and tumour samples from the participants and then did a bunch of genetic tests: DNA, RNA, and methylation analyses.

They found out that when the RB1 gene is inherited from the mother, the child has only 9.7% chances of developing Rb, but when the gene is inherited from the father the child has only 67.5% chances of developing Rb.

The mechanism for this different outcomes may reside in the differential methylation of the gene. Methylation is a chemical process that suppresses the expression of a gene, meaning that less protein is produced from that gene. The maternal gene had less methylation, meaning that more protein was produced, which was able to offer some protection against the cancer. Seems counter-intuitive, you’d think less bad protein is a good thing, but there is a long and complicated explanation for that, which, in a very simplified form, posits that other events influence the function of the resultant protein.

Again, epigenetics seem to offer explanations for pesky genetic inheritance questions. Epigenetic processes, like DNA methylation, are modalities through which traits can be inherited that are not coded in the DNA itself.

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Reference: Eloy P, Dehainault C, Sefta M, Aerts I, Doz F, Cassoux N, Lumbroso le Rouic L, Stoppa-Lyonnet D, Radvanyi F, Millot GA, Gauthier-Villars M, & Houdayer C (29 Feb 2016). A Parent-of-Origin Effect Impacts the Phenotype in Low Penetrance Retinoblastoma Families Segregating the c.1981C>T/p.Arg661Trp Mutation of RB1. PLoS Genetics, 12(2):e1005888. eCollection 2016. PMID: 26925970, PMCID: PMC4771840, DOI: 10.1371/journal.pgen.1005888. ARTICLE | FREE FULLTEXT PDF

By Neuronicus, 24 July 2016

Fructose bad effects reversed by DHA, an omega-3 fatty acid

Despite alarm signals raised by various groups and organizations regarding the dangers of the presence of sugars – particularly fructose derived from corn syrup – in almost every food in the markets, only in the past decade there has been some serious evidence against high consumption of fructose.

A bitter-sweet (sic!) paper comes from Meng et al. (2016) who, in addition to showing some bad things that fructose does to brain and body, it also shows some rescue from its deleterious effects by DHA (docosahexaenoic acid), an omega-3 fatty acid.

The authors had 3 groups of rodents: one group got fructose in their water for 6 weeks, another group got fructose and DHA, and another group got their normal chow. The amount of fructose was calculated to be ecologically valid, meaning that they fed the animals the equivalent of 1 litre soda bottle per day (130 g of sugar for a 60 Kg human).

The rats that got fructose had worse learning and memory performance at a maze test compared to the other two groups.

The rats that got fructose had altered gene expression in two brain areas: hypothalamus (involved in metabolism) and hippocampus (involved in learning and memory) compared to the other two groups.

The rats that got fructose had bad metabolic changes that are precursors for Type 2 diabetes, obesity and other metabolic disorders (high blood glucose, triglycerides, insulin, and insulin resistance index) compared to the other two groups.

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The genetic analyses that the researchers did (sequencing the RNA and analyzing the DNA methylation) revealed a whole slew of the genes that had been affected by the fructose treatment. So, they did some computer work that involved Bayesian modeling  and gene library searching and they selected two genes (Bgn and Fmod) out of almost a thousand possible candidates who seemed to be the drivers of these changes. Then, they engineered mice that lacked these genes. The resultant mice had the same metabolic changes as the rats that got fructose, but… their learning and memory was even better than that of the normals? I must have missed something here. EDIT: Well… yes and no. Please read the comment below from the Principal Investigator of the study.

It is an ok paper, done by the collaboration of 7 laboratories from 3 countries. But there are a few things that bother me, as a neuroscientist, about it. First is the behavior of the genetic knock-outs. Do they really learn faster? The behavioral results are not addressed in the discussion. Granted, a genetic knockout deletes that gene everywhere in the brain and in the body, whereas the genetic alterations induced by fructose are almost certainly location-specific.

Which brings me to the second bother: nowhere in the paper (including the supplemental materials, yeas, I went through those) are any brain pictures or diagrams or anything that can tell us which nuclei of the hypothalamus the samples came from. Hypothalamus is a relatively small structure with drastically different functional nuclei very close to one another. For example, the medial preoptic nucleus that deals with sexual hormones is just above the suprachiasmatic nucleus that deals with circadian rhythms and near the preoptic is the anterior nucleus that deals mainly with thermoregulation. The nuclei that deal with hunger and satiety (the lateral and the ventromedial nucleus, respectively) are located in different parts of the hypothalamus. In short, it would matter very much where they got their samples from because the transcriptome and methylome would differ substantially from nucleus to nucleus. Hippocampus is not so complicated as that, but it also has areas with specialized functions. So maybe they messed up the identification of the two genes Bgn and Fmod as drivers of the changes; after all, they found almost 1 000 genes altered by fructose. And that mess-up might have been derived by their blind hypothalamic and hippocampal sampling. EDIT: They didn’t mess up,  per se. Turns out there were technical difficulties of extracting enough nucleic acids from specific parts of hypothalamus for analyses. I told you them nuclei are small…

Anyway, the good news comes from the first experiment, where DHA reverses the bad effects of fructose. Yeay! As a side note, the fructose from corn syrup is metabolized differently than the fructose from fruits. So you are far better off consuming the equivalent amount on fructose from a litre of soda in fruits. And DHA comes either manufactured from algae or extracted from cold-water oceanic fish oils (but not farmed fish, apparently).

If anybody that read the paper has some info that can help clarify my “bothers”, please do so in the Comment section below. The other media outlets covering this paper do not mention anything about the knockouts. Thanks! EDIT: The last author of the paper, Dr. Yang, was very kind and clarified a bit of my “bothers” in the Comments section. Thanks again!

Reference: Meng Q, Ying Z, Noble E, Zhao Y, Agrawal R, Mikhail A, Zhuang Y, Tyagi E, Zhang Q, Lee J-H, Morselli M, Orozco L, Guo W, Kilts TM, Zhu J, Zhang B, Pellegrini M, Xiao X, Young MF, Gomez-Pinilla F, Yang X (2016). Systems Nutrigenomics Reveals Brain Gene Networks Linking Metabolic and Brain Disorders. EBioMedicine, doi: 10.1016/j.ebiom.2016.04.008. Article | FREE fulltext PDF | Supplementals | Science Daily cover | NeuroscienceNews cover

By Neuronicus, 24 April 2016

Golf & Grapes OR Grandkids (but not both!)

Pesticides may be bad for you, but they are devastating for your great grandchildren, because there will be no great great grandchildren. Photo Credit: JetsandZeppelins from Flickr under CC BY 2.0 license
Pesticides may be bad for you, but they are devastating for your great grandchildren, because there will be no great great grandchildren. Photo Credit: JetsandZeppelins from Flickr under CC BY 2.0 license

Transgenerational epigenetic inheritance (TGI) refers to the inheritance of a trait from one generation to another without altering the DNA code (normally, evolution is driven by changes in the DNA itself). Instead, it happens by modifying the proteins that wrap around the DNA, the histones; these histones, in turn, control what genes will be expressed and when. Until a decade ago, TGI was considered impossible, nay, a scientific heresy since it had too close of a resemblance to Lamarckian evolution. But, true to its guiding principles, the scientific endeavor had to bite the bullet in front of amassing evidence and accept the fact that it may have been a kernel of truth to the so called ‘soft inheritance’.

Anway et al.’s paper was one of the first to promote the concept, ten years ago. They exposed pregnant rats to the pesticides vinclozolin or methoxychlor (only vinclozolin is still used widely in U.S.A. and several EU countries, particularly in agriculture, wine production, and turf maintenance; methoxychlor was banned in the early noughts). The authors found out that more than 90% of the male offspring had “increased incidence of male infertility”. These effects were transferred through the male germ line to nearly all males of all subsequent generations examined” up to great great grandsons, inclusively (Anway et al., 2005). (I don’t want to speculate how they managed to breed the low fertility males…). That doesn’t mean that the F5 generation was OK (the great great great gransons); it means that they stopped investigating after the F4 generation (or they couldn’t breed the F4s). Moreover, the mechanism of inheritance seems to be altered methylation of the DNA histones of the male germline, and not alteration of the DNA itself. Females were affected too, but they didn’t have enough data on that experiment (the Ph.D. student that did the work had to graduate sometime…).

Although the authors used higher amounts of pesticides than they suspected back then, in 2005, to be found in the environment, the study still gives pause for thought. After all, it has been 10 years since this paper plus the previous 20 years of use of the stuff. And no, you cannot get rid of it by washing your grapes and vegetables really thoroughly.

Reference: Anway, M. D., Cupp, A. S., Uzumcu, M., & Skinner, M. K. (3 June 2005). Epigenetic transgenerational actions of endocrine disruptors and male fertility. Science, 308(5727): 1466-1469. DOI:10.1126/science.1108190. Article + Science Cover + FREE PDF

by Neuronicus, 25 September 2015