Unraveling the mechanisms of stress responses

Operation center for the body, unlimited inspiration for poets and artists and one of the most complex machines in nature, the human brain still keeps many mysteries around its functioning. And there they are, researchers from across the spectrum of neuroscience, trying to find out what secrets are hidden behind its mechanisms and structure on a microscopic scale.

Now, the Molecular Neurobiology group of the Buenos Aires Biomedicine Research Institute (IbioBA) in Argentina, attached to the National Council for Scientific and Technical Research (CONICET) of Argentina and linked to the Max Planck Society was able to identify the role that a molecule in particular, called circTulp4, has on emotional behavior. This is a key study, since the molecular mechanisms that give rise to emotional disorders are still unknown and in a huge proportion, experts say, the existing medication has very little or even no effect on patients.

In the study, published in the academic journal Science Advances, the researchers were able to observe that this molecule, a type of circular RNA abundantly present in the nervous system, functions as a promoter of synaptic neurotransmission, that is, the basis of communication. between neurons.

“A few years ago, our group contributed in a study led by a colleague from Berlin to the identification of an enormous amount of circular RNAs in the brain. In that study, we found that circTulp4 is one of the most abundant circular RNAs in the brain, and that it is even present in the synapses themselves, which are specialized compartments that mediate communication between neurons. Due to these characteristics, its abundance and its strategic location, we decided to choose it to explore its function,” Damián Refojo, head of the research group and, also, director of the IBioBA, told the CTyS-UNLaM Agency.

In a context of high incidence of anxiety disorders, Refojo explains, the discovery marks the potential of circular RNAs as relevant actors in the regulation of complex behaviors. Furthermore, it provides keys to the understanding of psychiatric disorders whose pathological bases are still not well known, which prevents, for the moment, having better therapeutic tools.

That something is stressful, the researchers explain, implies that it is perceived as dangerous. Usually, these threatening events or situations trigger the launch of a stress response. And, although this adaptive response is beneficial for the people who experience it, since it prepares the organism to escape or face said dangers, in some cases these processes are triggered in an excessive way in magnitude or time, or are triggered in the face of stimuli that They do not represent a real danger.

“Today, in our daily lives we are subjected to countless stressful situations, so those people who have sustained oversized stress responses are more predisposed to developing different psychiatric disorders such as depression or anxiety disorders,” highlights Sebastián Giusti, doctor in Biological Sciences and part of the work team, in dialogue with the CTyS-UNLaM Agency.

Sebastián Giusti in the laboratory. (Photo: Verónica Tello)

In the research, Giusti says, they developed genetically modified mice to eliminate the presence of this molecule, circTulp4. “By studying these mice, we found that circTulp4 regulates the sensitivity of the brain circuits that process the stress response,” details the CONICET researcher. In other words, circTulp4 allows ‘fine tuning’ of the response, so that it is not executed when the stimuli are not intense enough to represent a danger to the animal. “This is the first time, in this way, that a circular RNA has been shown to participate in the regulation of the stress response.” (Source: Nicolás Camargo Lescano / CTyS-UNLam Agency)