Breaking barriers: a blood test to study gene expression in the brain

The released markers of activity (RMAs) is a non-invasive monitoring of gene expression in the brain with a simple blood test

Measuring gene expression at the brain level requires invasive techniques or less sensitive non-invasive methods. Released markers of activity (RMAs) represent a novel non-invasive approach for monitoring brain gene expression. Indeed, RMAs are synthetic serum markers that can be expressed at the central level but arrive in the blood enabling non-invasive monitoring of gene expression in the brain with a simple blood test.

How to track brain processes?

Unveiling the body’s inner processes through blood sampling is one of the main challenges of medical and pharmacological research. This is especially true when talking about brain processes that lack identifiable serum markers. Indeed, to fully understand what happens in the brain without invasive methods or post-mortem analyses, a revolutionary solution is needed. The method described by Lee and colleagues would enable to equipment of a tissue with the ability to release custom-made serum markers into the bloodstream in response to any physiological activity. With an approach like this, it could be possible to track numerous processes in a single sample, approaching the sensitivity of single-molecule detection.

Towards non-invasive brain monitoring: custom serum markers

Molecule transport from blood to the brain is limited by the blood-brain barrier (BBB). Most attempts to bypass this barrier have been made especially to deliver therapeutic molecules into the brain from the bloodstream. In 2001 Zhang and Pardige discovered that antibodies injected into the brain are quickly removed and this observation led to the realization that this process could be repurposed for monitoring brain physiology. Consequently, researchers decided to merge the Fc domain of an antibody with a readily detectable secreted reporter, expressed within the mouse brain. This marker could then be activated in response to any physiological change triggering gene expression, such as heightened neuronal activity.

The synthetic markers, named “release markers of activity” (RMAs), were easily detectable in the blood in high amounts through a simple plate reader assay. For example, the expression of RMAs could be linked to the Fos gene, whose expression is increased by neuronal activation, enabling the measurement of brain activity through a blood test.

RMAs open many future applications since the markers can be designed with different reporters and can be detected using detecting proteins in the blood. The RMA signal can be used to study any physiological process that results in gene expression. Moreover, this approach can be useful in longitudinal studies aiming to establish a sequence of events.

RMAs, due to the need for blood draw and their kinetics in crossing the BBB, are ideal for monitoring sustained changes like gene expression, disease development, cell division, or memory formation. However, rapid changes such as synaptic potential require integration over time and resultant gene expression changes for study with RMAs.

Further development of RMAs can facilitate the detection of various reporter types including luciferases, fluorescent proteins, or antibody tags.

This approach represents a precious tool for non-invasive brain gene expression studies.


By Maria Teresa Gallo, Department of Pharmacological and Biomolecular Sciences “Rodolfo Paoletti”, University of Milan.


Link and doi of the publication: