Imaging serotonin reuptake in the living brain

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Science Translational Medicine  30 Nov 2016:
Vol. 8, Issue 367, pp. 367ec191
DOI: 10.1126/scitranslmed.aal2800

Traditional functional magnetic resonance imaging (fMRI) measures brain activity by detecting changes associated with blood flow in specific regions of the brain. Due to the noninvasive nature of this technique, fMRI has been employed to elucidate the neural substrates of behaviors in healthy volunteers and patients with various neuropsychiatric disorders. However, traditional fMRI does not detect changes in neurotransmitters, which are key chemical messengers that signal neurons to communicate with each other.

In a recent publication, Hai et al. reported their success in developing a molecular fMRI method that maps the neurotransmitter serotonin (5HT) as it is transported into neurons. These researchers designed and synthesized an imaging sensor, which is a protein that carries 5HT and releases the neurotransmitter at the moment of reuptake to neurons. Reuptake of 5HT is the reabsorption of a secreted 5HT by the neuron that originally produced and secreted it. Reuptake of 5HT is necessary for the neurotransmitter to be dissociated from the sensor and recycled. By exploiting the reuptake process, this imaging method allows for an unprecedented opportunity to map 5HT transport three-dimensionally in the living brain.

Using this novel molecular imaging technique, the authors demonstrated that 5HT removal from the imaging sensor varied spatially in different parts of the basal ganglia and anatomical regions nearby in rats, which suggested that there were multiple mechanisms of 5HT clearance. Furthermore, administration of fluoxetine, a selective 5HT reuptake inhibitor (SSRI), suppressed 5HT removal in septal subregions, whereas fluoxetine decreased reuptake in striatum. The region-specific effects of modulators of 5HT physiology provide tremendous insights into the mechanisms of actions of medications such as SSRIs.

This new molecular fMRI method is clearly an important neuroimaging tool for advancing the understanding of the mechanisms of actions of psychiatric medications modulating the 5HT system. Because of the presence of the blood-brain barrier, currently the sensor needs to be directly injected into the brain. Although this molecular imaging method has great promise in animal models, researchers will need to be able to deliver the sensor noninvasively to the brain to be useful in humans.

A. Hai et al., Molecular fMRI of serotonin transport. Neuron 92, 754–756 (2016). [Abstract]

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