Institut de Neurociències (INc) - UAB Barcelona

Same drug can have opposite effects on memory according to sexual differences

Same drug can have opposite effects on memory according to sexual differences

An investigation led by the INc-UAB, carried out from the study of a drug that modifies the memory of fear, shows for the first time that the neural processes and behaviours related to the formation of memory can be opposite between male and female mice. The study, published in Nature Communications, has been developed in collaboration with other INc-UAB research groups and the IMIM. Read the article

03/05/2021

A research team from the Institut de Neurociències at the Universitat Autònoma de Barcelona (INc-UAB) has showed that inhibition through a drug of the Tac2 neuronal circuit, involved in the formation of the memory of fear, has opposite effects on the ability to remember aversive events in mice according to sex: it is reduced in male mice and increased in female mice.

Is the first time that a drug has been shown to produce this opposite effect on the memory of male and female mice. The study also evidences that opposing molecular mechanisms and behaviours can occur in memory formation depending on sex. The study has been published in Nature Communications.

The research group on Translational mechanisms of the memory of fear led by Raül Andero, professor and researcher at ICREA, has been studying the functioning of fear memory for years to find treatments for pathologies associated with traumatic experiences, such as post-traumatic stress and phobias.

The research team had identified that the Tac2 circuit, located in the amygdala, could be temporarily blocked by the effect of a drug they are studying. This drug, called Osanetant, was able to reduce the capacity to recall traumatic events in male mice. In the study published now, they discovered that this same drug produces the opposite effect in female mice, increasing their fear memory.

This opposite effect is explained by the fact that, in blocking the Tac2 pathway, the drug interacts with the neuronal receptors of two sex hormones: testosterone in males and estrogen in females. In addition, it has been observed that hormonal fluctuations during the oestrous cycle in female mice, equivalent to the menstrual cycle in women, vary the effects of the drug on the ability to remember aversive events.

''These results demonstrate the ability that hormones have to modulate the formation of fear memories, and show the need to consider sex differences and hormonal cycles in the design of pharmacological treatments for psychiatric disorders’’, says Antonio Florido, INc-UAB predoctoral researcher and first author of the article.

In the field of neurosciences, only one study in females is published for every 5.5 done in males. And research on Tac2 pathway has also been done mostly in males so far.

“Understanding how and why memory processes differ between sexes is key to designing treatments for fear disorders, especially considering that women are the ones who most often present these types of disorders. Some drugs that are already used may not have the expected effects on them”, says Raül Andero, the study coordinator. “Our findings may help raise awareness of the need to do research differentiating by sex and promote basic and clinical studies that include the female sex”, he adds.

The drug studied is not new, but it is safe for use in humans. However, at the moment it is not being used to treat any disease. Dr. Andero's group is now investigating its potential use in treating fear disorders differently by sex.

In this research, which has been carried out in collaboration with other INc-UAB research groups and the Hospital del Mar Medical Research Institute (IMIM), scientists show the importance of personalized medicine. "Mental health drugs that we have today, not only for memory-related disorders, are not specific enough and may be causing contrary effects to those desired", they conclude.

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How is long-term memory created and consolidated?

How is long-term memory created and consolidated?

Long-term memory is a brain mechanism that allows us to encode and retain an almost unlimited amount of information throughout our lifetime. Key proteins that activate protein synthesis, such as the a subunit of the eIF2 initiation factor (eIF2a), are involved in the process.

In this study, published in the journal Nature and made in mice, researchers identified those neural circuits and connections by which, in both health and disease conditions, eIF2a impairs learning and memory when bound to a phosphorus molecule (phosphorylated), but enhances them in their non-phosphorylated form.

The research team, in which Albert Quintana and Elisenda Sanz participated under the coordination of McGill University (Montreal, Canada), showed that eIF2a is involved in the formation of new long duration memories through its activity in two types of neurons in the hippocampus: excitatory neurons and neurons expressing somatostatin, a group of inhibitory neurons.

In parallel and autonomously, the reduction of eIF2a phosphorylation in these two subpopulations is enough to increase protein synthesis, strengthen connections between neurons, and improve long-term memory.

“To study these effects, we used a technique we had developed, that showed that the changes in the excitatory neurons during learning are similar to those observed by genetically preventing eIF2a phosphorylation in these neurons”, explains Elisenda Sanz. This is important because it validated the genetic model and allowed identifying the changes that learning produces at a transcriptional level.

"The existence of two autonomous processes for memory consolidation mediated by the non-phosphorylated form of eIF2a may respond to an evolutionary advantage in ensuring and regulating the duration of a given memory", says Albert Quintana.

The study is the first to analyze separately the role of excitatory and inhibitory neurons in the hippocampus in the consolidation of these types of memories, and helps to understand the creation and maintenance of memories phenomenon, which continues to belargely unknown.

Original article: Sharma, V., Sood, R., Khlaifia, A. et al. eIF2α controls memory consolidation via excitatory and somatostatin neurons. Nature (2020). https://doi.org/10.1038/s41586-020-2805-8

Biochemical alterations revealed in patients with Lesch-Nyhan disease

Biochemical alterations revealed in patients with Lesch-Nyhan disease

Lesch-Nyhan is a rare genetical disease, affecting 1 in 380,000 newborns. Patients suffer from overproduction of uric acid, anemia, severe neurological problems, and compulsive self-injurious behavior. The pathology is caused by a deficiency of HGprt, an enzyme that participates in the metabolism of purine nucleotides. Purines regulate many biological processes and are part of the basic structure of DNA and RNA. They can be synthesized in two different metabolic pathways: the de novo synthesis, from simple precursors, such as amino acids and folic acid derivatives; and the salvage pathway, a recycling system where HGprt participates, in which the cell saves energy. A HGprt deficiency causes the acceleration of the de novo synthesis pathway to try to compensate the system.

Since measuring the nucleotide concentration in the brain of a living patient is not feasible, scientists often use cell cultures. However, the studies conducted until now in Lesch-Nyhan patients' cultured cells have never revealed any abnormalities in their nucleotide content. In this work, led by José Manuel López from the INC-UAB, and in collaboration with H. A. Jinnah from Emory University in Atlanta, and Rosa Torres from the Hospital Universitario La Paz in Madrid, the researchers show that these alterations could not be detected because, in most laboratories, cells are maintained in mediums that have extremely higher levels of folic acid than physiological concentrations.

"Culture mediums usually have 100 times more folic acid than the levels found in blood. This is for cells to divide and grow faster in a culture plate, but it does not reproduce what happens in the body", explains José Manuel López.

In this study, published in PNAS, researchers used physiological levels of folic acid in their culture mediums and observed two important alterations in patients’ fibroblasts. Firstly, an accumulation of ZMP, an intermediate product in the de novo nucleotide synthesis that is potentially toxic; and secondly, a reduction in ATP, the most abundant purine nucleotide in cells, which is essential for obtaining energy. Researchers also found ZMP derivatives increased in the urine and cerebrospinal fluid of patients, concluding that the alterations detected in fibroblasts can also occur in the brain and in other tissues.

"We present cell culture conditions that allow for the study of the mechanisms involved in the development of this disease. Our study also suggests a possible treatment, since the alterations observed in the cultures are reversed with high levels of folic acid”, indicates José Manuel López.

According to the researchers, the study may have highly relevant consequences, since manipulating folic acid levels can be a valuable strategy to study the pathogenesis of this rare disease, for which there is no known treatment. The discovery could also have implications in the research of other diseases in which high concentrations of folic acid in the culture medium could be masking cellular alterations, such as those in which nucleotide metabolism is affected.

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