Antagonistic neurons and pain signals

A central role in processing emotions has been ascribed to the almond shaped amygdala arranged in pairs in the brains of mammals. The amygdala ‘evaluates’ emotional memories, coordinates the phenomena of fear and ultimately decides on flight or fight reactions when we are confronted with danger. In addition to fear, it also influences emotions such as anger and joy as well as sexual drive and reproduction. In conjunction with the working group of Wulf Haubensak from the Research Institute of Molecular Pathology (IMP) in Vienna, the working group led by Prof. Dr. Andreas Hess, Chair of Pharmacology and Toxicology at FAU, has been investigating the influence of certain neurons in the amygdala on the representation of pain in other regions of the brain. The study was recently published online in the journal Communications Biology .

Two types of neurons

‘We have been able to prove that the amygdala is not only responsible for coordinating fear, but is also responsible for processing pain,’ says Prof. Andreas Hess. The messenger substances of neurons in the central nucleus of the amygdala lead to systemic changes in various regions of the brain and ultimately even to measurable changes in behaviour.

Anatomically, the amygdala consists of various nuclei. Two types of neurons were identified in the lateral area of the central amygdala. One type of neuron produces the enzyme protein kinase C δ (PKC δ+), which is important for cell communication, the other produces the neurotransmitter somatostatin (SST+). ‘Both neuron populations have an antagonistic effect and influence many other regions of the brain,’ explains Isabel Wank from the working group led by Prof. Andreas Hess from the Chair of Pharmacology and Toxicology at FAU. To find out if both types of neurons influence other regions of the brain such as the thalamus, they have to be deliberately switched on and off. To do so, the researchers used the established method of optogenetics. The DNA of mice was genetically modified in such as way that it produced light-sensitive proteins in the cells mentioned above. The function of these cells can then be influenced from the outside by exposure to light. Firstly, a fibre-optic light guide was implanted into the central amygdala of mice under anaesthetic. This then enabled the researchers to ‘activate’ the neurons with blue lasers. The neurons deactivated themselves automatically after a short period of time.

Decisive influence on processing pain

To produce images of the influence of the activated PKC and SST neurons on other regions of the brain, the researchers used non-invasive functional magnetic resonance imaging (fMRI). By using this technique, they were able to show which areas of the brain are modulated by both cell populations and to what extent this modulation affects the processing of moderate heat stimuli applied for a short time to the mouse’s hind paw. ‘Using these highly-sensitive methods yields a clear result, even with only a few animals,’ says Prof. Hess.

The results show that the activated PKC neurons of the amygdala cause other regions of the brain to process pain to a lesser extent. The modulation is carried out ‘bottom up’, from the old regions of the brain in evolutionary terms to the cortex. In contrast, the SST neurons tended to lead to stronger ‘processing’ of the pain top down from the cortex. As the researchers from Vienna were able to demonstrate, activating the neurons also leads to changes in behaviour in the animals in the experiment. Compared to wild-type mice, the mice with activated SST neurons had a tendency to pull their paws away more quickly from the heat source, whereas activated PKC neurons led to a slower reaction. The amygdala evidently has a decisive modulating influence on the processing of pain stimuli in the brain.

As yet, the results of this fundamental research cannot be directly transferred to humans. However, the use of functional magnetic resonance imaging seems very promising. ‘What we were able to demonstrate using fMRI in mice can be directly transferred to humans,’ says Prof. Hess. The role of damage to the amygdala could therefore be investigated using fMRI on patients in future.

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