SleepLess Project: Imaging synaptic plasticity in therapeutic sleep deprivation for major depression

SleepLess Project: Imaging synaptic plasticity in therapeutic sleep deprivation for major depression

About the project

Patients with major depression benefit from therapeutic sleep deprivation. The causality of this clinically effective therapeutic measure is unknown and the underlying molecular mechanisms remain elusive. We hypothesize that prolonged wakefulness is associated with an increase in synaptic strength, and that the synaptic dysregulation is affecting long term potentiation in patients with major depression. The aim of the project is to examine the synaptic basis of the antidepressant effect of therapeutic sleep deprivation by Positron Emission Tomography (PET) imaging of the synaptic vesicle protein 2A (SV2A) as a measure of synaptic density in patients and healthy subjects as well as animal models of depression. Since both anesthesia and sleep are subject to compromise biologically valid outcomes when studying the synaptic basis of therapeutic sleep deprivation, we developed a fully quantitative PET imaging method for awake animals.

We propose that synaptic density determined with PET has the power to become a biomarker for the success of therapeutic sleep deprivation and thus providing means for future stratifications of different therapies in major depression. Identifying and understanding the mechanisms that mediate the effects of sleep restriction is necessary to develop effective interventions. This project will test a model that can be used to improve schedule design.

Methodological aspects

Neuroreceptor PET studies are commonly analyzed by applying tracer kinetic models to the PET data, with the distribution volume (VT) or the binding potential (BP) as the outcome measure. Both reflect the densities of target proteins in a brain region of interest. A tracer kinetic model requires quantitative PET image data. We have therefore worked with our partner from the Molecular Imaging Center Antwerp to improve and assess the image quality and quantitative accuracy for PET scans of freely moving, awake animals, with motion correction based on radioactive point sources.

Partners

• Molecular Imaging Center Antwerp, University of Antwerp, Wilrijk, Belgium
• McGill University, Douglas Hospital Research Center, McGill Centre for Studies in Aging, Translational Neuroimaging Laboratory, Montreal, Canada

Funding

This project is funded under the umbrella of the ERA-NET NEURON JTC 2017 ‘Synaptic Dysfunction’.

More on the SleepLess Project: www.sleepless.pet