From individual receptors to whole brain function

The team of Dirk Jancke (left) and Stefan Herlitze (right) collaborated on many of the research projects underlying the review. Credits: RUB, Marquard

In the brain, over 100 molecular substances act as transmitters that control communication pathways between nerve cells through thousands of different receptor types. In a review, an international research team discusses how activation of specific neuronal receptors affects the neural network in the brain. The authors of Ruhr-University of Bochum (RUB), Pompeu Fabra University of Barcelona, ​​and Oxford University present concepts for quantifying receptor-specific modulation of brain conditions. They have also developed computer models that can predict the effects of individual receptor types on brain activity.

In addition, researchers show how to experimentally validate and improve computer-based predictions. They hope this will lead to new ways to diagnose and treat mental illness. They report on their research and the current state of research in a state-of-the-art review of the FEBS journal published by the Federation of European Biochemical Societies in April 2021.

Simulation of the dynamics of the state of the brain in a computer model

Much is already known about the molecular structure of nerve receptors. However, researchers know little about how individual receptor types alter the overall dynamics of the brain’s network. To simulate this in a computer model, the research team edited data from three different imaging techniques. Information about the anatomical connections of the brain recorded on diffusion-weighted magnetic resonance imaging. Information about participants’ resting activity obtained from measurements using functional magnetic resonance imaging, or fMRI for short. Distribution of receptor types recorded by positron emission tomography. Using this input, researchers were able to create individual receptors for each subject, reflecting the overall distribution of receptor types in the brain.

This allowed researchers to simulate the interactions between neurons that depend on the activation of individual receptor types in computer models. For example, they effectively activated serotonin receptor 5-HT2A and observed the following changes in the in silico model brain: “The activity pattern was surprisingly similar to what was observed on the scanner after the subject was given psychedelic or LSD, both of which are psychedelic substances that specifically bind to 5-HT2A receptors,” Bohum Optics said. Associate Professor Dirk Jancke, who is responsible for imaging, explains. Lab, lead author of review articles. Therefore, computer models were able to predict changes in the overall dynamics of the brain after activation of a single receptor type.

Experimental prediction testing

Pharmacological substances are usually not specific to just one type of receptor. Another drawback is that it cannot be used to locally activate neurons in a targeted manner. This means that more complex predictions and tests on human subjects are possible only to a limited extent.

Therefore, the authors propose to use optogenetic methods to refine the hypotheses and test them in animal experiments. A research group led by Professor Stefan Herlitze, co-author of RUB’s Department of General Zoology and Neurobiology, is one of the pioneers of this technology. Viral vectors are used to instruct cells to produce a particular protein. With this technique, genetically modified mice can be made to produce, for example, photoactivated receptors and proteins that fluoresce when nerve cells are active.

In previous studies, the authors used this method for the first time to show how serotonin affects visual information processing. “Our results suggest that 5-HT2A receptors suppress current visual input,” explains Dirk Jancke. “Therefore, external stimuli are less important to the brain, and at the same time, the processes that occur inside are relatively amplified. Hallucinations may be due to the fact that this imbalance has become too strong.”

Prognosis, diagnostic and therapeutic potential

Psychiatric disorders are often based on dysfunction of the transmission system and, as a result, changes in the activation of various receptors. This is associated with specific modulations of brain condition and can manifest itself in subtle changes in the dynamics of extensively intertwined neuronal networks in the brain. Through their research, scientists hope to use biomarkers to initiate new concepts, better diagnose and treat mental disorders more specifically. “Conceivable are specific pharmacological therapies and stimulatory techniques combined with concomitant psychiatric treatments that help learn new situations for re-adjusting pathological brain conditions,” says Yanke. I will.

How Serotonin Balances Communication in the Brain

For more information:
Dirk Jancke et al. Bridging the gap between single-receptor activity and whole-brain dynamics, FEBS Journal (2021). DOI: 10.1111 / febs.15855

Provided by Ruhr-Universitaet-Bochum

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From individual receptors to whole brain function

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