Area of Knowledge: PHYSICAL SCIENCES, MATHEMATICS AND ENGINEERING
Magnetic Resonance Imaging (MRI) is a well-known clinical diagnostic tool that provides detailed soft tissue anatomy without depth limitations. Functional Magnetic Resonance Imaging (fMRI) maps brain activity by detecting MRI signal changes linked to alterations in blood flow and oxygenation. Recently, metabolic MRI techniques, incl. hyperpolarization (HP) and deuterium metabolic imaging (DMI), have transformed disease diagnosis. They track biochemical reactions (metabolites) in vivo, enabling early diseases detection and therapy assessment at the cellular level.
Photopharmacology encompasses the development and applications of photoswitchable drugs, whose biological activity is regulated by illumination, to enhance the drugs’ pharmacological specificity with the ability to activate them on demand at selected locations. The first clinical trial of a photoswitchable drug in humans has completed phase 1b in 2023 to achieve vision restoration in patients of blindness. Others are expected to follow suit in fields like neuromodulation, where control over brain activity can be achieved with spatiotemporal precision and pharmacological specificity, or in cancer treatments, to selectively kill tumor cells without off-target adverse effects in other tissues.
This project will advance MRI techniques for fMRI, HP and DMI to investigate neuronal activity and metabolic changes upon administration and remote activation of photoswitchable drugs. We will correlate changes in electrical activity and metabolism of cortical neurons elicited by physiological stimuli and by drug photoswitching. We will obtain detailed spatiotemporal maps of brain activity using drugs targeting glutamate and GABAA receptors, which underlie the main excitatory and inhibitory pathways in mammalian neuronal circuits. These unprecedented fundamental capacities will be applied to address therapeutic challenges including sensory impairment and neuronal hyperexcitability pathologies like pain and epilepsy.
Job position description
Suitable candidates should hold a MSc in chemistry, biochemistry, bio(medical) engineering or physiology. They will receive support from experienced staff with multidisciplinary expertise in Marco-Rius and Gorostiza labs.
Envisioned tasks involve implementing state-of-the-art techniques like in vivo electrophysiology, fMRI, and neuromodulation with photoswitchable drugs to be used as gold standards:
Task 1. Electrophysiological determination of cortical responses in anesthetized wildtype mice elicited by (1) physiological stimuli, (2) the application photoswitchable drugs targeting glutamate and GABAA receptors (excitatory and inhibitory, respectively), and (3) invasive and noninvasive illumination of the drugs in different brain regions (6 months).
Task 2. fMRI determination (BOLD signal) of cortical responses elicited by physiological stimuli and by photoswitchable drugs with illumination. Correlation of electrode recordings and fMRI data, comparison of spatiotemporal resolution, and pharmacological specificity. Comparisons will be established also with the results of a parallel PhD project at IBEC that uses intravital multiphoton fluorescence microscopy imaging and drug photostimulation of brain cortical activity (6 months).
Task 3. HP-MR (pyruvate-to-lactate ratio) and DMI (glucose metabolism) determination of cortical responses elicited by physiological stimuli and by photoswitchable drugs with illumination. Cross-correlation of metabolic MR data with electrode recordings and fMRI data, comparison of spatiotemporal resolution, and metabolic pathway specificity (18 months).
Task 4. Proof-of-concept fMRI/metabolic MR for cortical activity and therapeutic interventions with photoswitchable drugs in sensory impairment, neuronal hyperexcitability, and hepatotoxicity. Rodents experiments will involve training for legal accreditation, surgical procedures (recording electrode and cortical window implantation), anesthesia, cannulation, euthanasia, and dissection (18 months).