Serotonin is often called the happy chemical as it has been well known, for over 40 years, to play a role in our wellbeing, as well as learning, sleep/wake cycles, appetite, and aggression. However, despite this knowledge, the specifics of how this neurotransmitter contributes to these effects are still not fully understood.
Researchers at the Medical University of Vienna set out to deepen our understanding of serotonin and its function by monitoring changes over time in the brains of mice using magnetic resonance imaging (MRI) and positron emission tomography (PET).
What Do We Know About Serotonin?
In the central nervous system, serotonin is used to transmit electrical impulses along our nerve fibers. When a signal is received, serotonin is released from the pre-synaptic neuron into the space between two neurons, the synaptic cleft, and binds to receptors on the post-synaptic neuron, passing on the signal. The serotonin transporter (SERT) then brings the serotonin back into the pre-synaptic neuron, ready for the next signal where the process can begin again.
Our understanding of this process and our knowledge that low levels of serotonin are associated with mental health disorders such as depression, anxiety, and substance abuse has led to the development of therapeutics that target the serotonergic system. For example, selective serotonin reuptake inhibitors (SSRIs) bind to the SERT and block the neurotransmitter from returning to the pre-synaptic neuron, increasing the levels of serotonin in the synaptic cleft. This class of drugs are among the most widely used for the treatment of depression and anxiety. However, this mechanism is only a snapshot of the purpose of serotonin and the overarching role this neurotransmitter plays in its many functions requires more investigation.
MRI and PET Can Help to Develop Our Understanding
One difficulty in developing our understanding of the role of serotonin is the translation of pre-clinical research, performed in animals, to the human patient. Methods that provide us with a wealth of information in pre-clinical research often involves sacrificing the animals and so cannot be performed with human patients to provide a comparison. Therefore, techniques that can be used in both situations have the potential to help bridge the gap from bench to bedside. Dr. Pollak and her team at the Medical University of Vienna used MRI and PET scans in their study, both of which can be used for pre-clinical and clinical studies.
MRI applies a strong external magnetic field, which enables a detailed anatomical image to be obtained non-invasively. PET is minimally invasive as it uses a radiotracer. This radiotracer accumulates in specific regions in the body, which can be monitored to provide functional, physiological information. These techniques are often used in combination to give a more detailed level of information.
Validating the PET Technique
The radiotracer [11C]DASB (3-amino-4-(2-dimethylanimomethylpenylsulfanyl)-benzonitrile) has been the most successful when investigating SERT and the serotonergic system for PET imaging in human studies. However, using [11C]DASB-PET for small-animal imaging, with mice, in particular, has proven challenging. Therefore, the group first set out to assess whether this technique could be utilized to determine SERT density in murine models.
MRI and [11C]DASB-PET scans were obtained from three groups of mice with varying levels of SERT. After imaging, the mice were sacrificed, and the pre-clinical method of western blotting was also performed to quantify the levels of SERT. The imaging and western blotting data gave comparable SERT densities in the regions of interest (ROI) – the hippocampus, striatum, thalamus and cortex – and validated that [11C]DASB-PET imaging can give a quantitative analysis of SERT density in mice.
MRI and PET Analysis Revealed a Reduction in SERT Density
Dr. Pollak and her team were then able to use this technique to asses the effect of chronic stress on SERT density in specific ROIs of the mouse brain. A cohort of mice were randomly split into two groups; one group was subjected to a long-term (57 days) corticosterone treatment, a model used to induce chronic stress, while the other, control, group was treated with regular drinking water. Both groups were scanned before and after treatment using a Bruker ICON™ from Bruker Biospin for MRI and a microPET Focus22 scanner. The data revealed significant reductions in SERT density in the ROIs after chronic corticosterone treatment when compared to the control group.
In parallel, the second cohort of mice were studied to assess the effects of chronic stress by monitoring their behavior using the novelty-suppressed feeding test (NSF), which measures a rodent’s aversion to eating in a new environment. As with the imaging cohort, the mice were split equally into a corticosterone treatment and a control group, and both groups were assessed before and after treatment. After treatment, the corticosterone group had a significantly higher aversion to eating compared to the control group, indicating depression-related anxiety behavior.
A Reduction in SERT Density is Linked to Depressive Behavior
From these data, the group were able to demonstrate that a reduction in SERT density in several areas of the brain is linked to depression-related anxiety behavior. This study is the first demonstration of dynamic changes in SERT density in a mouse model of chronic stress and is an important step forward in developing our understanding of the role of the serotonergic system. Dr. Pollak and her team believe that further work in this area, such as measuring the SERT density at several time points, will enable us to shed more light on the specifics of serotonin in its many functions.
References and Further Reading
- Reisinger S.N. et al. (2019). PET Imaging of the Mouse Brain Reveals a Dynamic Regulation of SERT Density in a Chronic Stress Model. Translational Psychiatry. Doi: https://doi.org/10.1038/s41398-019-0416-7