Memory plots: an hidden broker, an hormone beyond suspicion

Memoria: un ormone insospettato, un mediatore nascosto

The problem of memory loss motivates researchers to try to better understand how the brain works, how memories are consolidated and how and why we lose them. Being able to maintain our memories allows us to maintain a sense of selfishness and orientation in the world, understanding how to prevent chronic memory loss is a top priority in neuroscience. Recently, a team of researchers from the University of Toronto, Mississauga, Ontario, Canada, in collaboration with colleagues from the United States and the United Kingdom, studied the role of a particular protein in memory formation. Their results have been published in the Cell Reports magazine. Senior researcher Iva Zovkic and her team conducted their study on mice, focusing specifically on a protein called histone H2A.Z. This type of protein binds to DNA, helping it to maintain its structure within cells. Dr. Zovkic and the group worked with young and elderly mice to understand how the H2A.Z protein was involved with memory formation and suppression. As part of their experiment, the researchers placed the mice in a new box, in order to force them to become familiar with an unknown environment. So, to be able to test how the protein worked in the context of memory formation, the animals were exposed to a negative stimulus while they were in the box.

In this way, the mice formed an association between the new environment and the bad experience they had been exposed to. The second time the scientists put them in the box, the now cautious rats refused to move and explore, as they normally would. Half an hour after the mice had been exposed to the negative stimulus, Zovkic and colleagues evaluated the animals’ brains for possible variations in the way H2A.Z binds to DNA. They revealed that in young mice, fear training was associated with an “overwhelming” reduction of H2A histones and DNA bonds in 3,048 points on the genes with which proteins normally bind, as well as an increase in ties in only 25 points. . The same applies to older mice, who have experienced a reduction in bonds to 2,901 places and an increase to only 9 points after fear training. This, the researchers explain, means that fewer links between the H2A.Z protein and DNA are associated with memory formation, allowing mice to remember their negative experience. The researchers also noted that the levels of H2A.Z were dependent on the age of the animals. Therefore, the protein was found at higher levels in the hippocampus of elderly mice, which is a region of the brain strongly associated with memory formation.

Based on these observations, Zovkic and his team have inferred that the higher H2A.Z levels are, the more likely that memory formation and storage will be hindered. Thus, if advancing age correlates with more H2A.Z bonds, this could explain age-related memory loss. The next step from here, the researchers say, will be to test their theory on very old rats. If their ideas are confirmed by further studies, the researchers plan to go ahead and study the effects of H2A.Z in humans, whose bodies also produce this protein. “We have thousands of experiences every day, but we only remember the things that are somehow important to us, “notes Zovkic. “This experiment used a very simple learning experience to illustrate that H2A.Z apparently serves to suppress memory, and the removal of this protein seems to allow the formation of long-lasting memories. Identify H2A.Z as a unique protein that is involved with memory and increases with aging, it could be a big problem for the creation of genetic or pharmaceutical therapies for age-related cognitive decline and dementia This is because histone H2A.Z is a relatively therapeutic target specific”.

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New research was conducted by scientists led by dr. Gerard Karsenty, president of the Department of Genetics and Development at the Columbia University Medical Center in New York, to understand the role of a protein apparently foreign to the brain in memory. Previous research, co-signed by Dr. Karsenty, has shown that osteocalcin – which is a hormone produced by bone cells – satisfies a number of metabolic functions in the human body and influences spatial learning, memory and the birth of new neurons in mice. In addition, another study conducted by Dr. Karsenty showed that injections with osteocalcin can restore muscle function in elderly mice, bringing it to the same levels as those of their young colleagues. Explain how this led to new research: “We also observed that the hormone rapidly decreases in humans during early adulthood, which raises an important question: can memory loss be reversed by restoring this hormone to youthful levels?”

To answer this question, Dr. Karsenty and colleagues conducted a series of experiments on elderly mice. In one experiment, 16-month-old mice received continuous infusions of osteocalcin in the blood over a 2-month period. The researchers also took blood plasma from young mice that did not have enough of the hormone, he added osteocalcin and injected it into elderly mice. They also reduced osteocalcin levels of young normal mice by adding anti-osteocalcin antibodies to their blood plasma. After subjecting the rodents to memory tests, the researchers found that hormone blood infusions improved the memory of the mice. In fact, osteocalcin seemed to increase the memory of mice to levels equivalent to those of young mice. In addition, osteocalcin-boosted plasma transfusion from mice with osteocalcin deficiency to elderly mice has also significantly improved the latter’s performance in memory tests. In contrast, mice that received a plasma transfusion from mice lacking osteocalcin did not perform better on memory tests, and young mice whose levels of osteocalcin were artificially decreased were worse than their normal counterparts.

Scientists also note that the hormone seemed to “reduce anxious behavior” in aging mice. Overall, the results of the experiments suggested a resounding “yes” in response to the initial question that stimulated the research of scientists. Encouragingly, the rodents did not present toxic side effects resulting from the administration of osteocalcin. “It’s a protein in our body, so it should be safe,” says Dr. Karsenty. “But of course, we must conduct more research to translate our findings into clinical use for human beings.” The team also wondered if they could identify a neuronal receptor for osteocalcin. To do this, they genetically designed a mouse model in which the rodents “switched off” the GPR158 receptor. These receptors are found in the hippocampus, which is the area of ​​the brain responsible for creating and storing new memories. Thus, the researchers administered osteocalcin infusions to these rodents. Unlike active GPR158 mice, the researchers did not see memory improvements in mice that had de-activated these receptors.

Therefore, besides the bones and the regulation of insulin secretion (only very recently discovered), circulating osteocalcin also has a non-endocrine but more central function. Probably on the bones regulates calcium to make the skeleton stand up; in the brain would make “stand the memories up”….

  • a cura del Dr. Gianfrancesco Cormaci, PhD, specialista in Biochimica Clinica

Pubblicazioni scientifiche

Stefanelli G et al., Zovkic IB. Cell Rep. 2018 Jan 30; 22(5):1124-1131.

Khrimian L et al., Karsenty G. J Exp Med. 2017 Oct 2; 214(10):2859-2873.

Orlandi C et al. J Biol Chem. 2015 May 29; 290(22):13622-39.

Zovkic IB et al. Nature. 2014 Nov 27; 515(7528):582-86.

Patel N, Itakura T et al. PLoS One. 2013; 8(2):e57843.

Informazioni su Dott. Gianfrancesco Cormaci 1326 Articoli
- Laurea in Medicina e Chirurgia nel 1998 (MD Degree in 1998) - Specialista in Biochimica Clinica nel 2002 (Clinical Biochemistry specialty in 2002) - Dottorato in Neurobiologia nel 2006 (Neurobiology PhD in 2006) - Ha soggiornato negli Stati Uniti, Baltimora (MD) come ricercatore alle dipendenze del National Institute on Drug Abuse (NIDA/NIH) e poi alla Johns Hopkins University, dal 2004 al 2008. - Dal 2009 si occupa di Medicina personalizzata. - Detentore di un brevetto sulla preparazione di prodotti gluten-free a partire da regolare farina di frumento immunologicamente neutralizzata (owner of a patent concerning the production of bakery gluten-free products, starting from regular wheat flour). - Autore di un libro riguardante la salute e l'alimentazione, con approfondimenti su come questa condizioni tutti i sistemi corporei. - Autore di articoli su informazione medica, salute e benessere sui siti web salutesicilia.com e medicomunicare.it