Project Details
Projekt
13C Magnetic Resonance Spectroscopy to Investigate the Effects of Chronic Alcohol Exposure on Neurometabolism in the In Vivo Mouse Brain
Applicant
Dr. Markus Sack
Subject Area
Medical Physics, Biomedical Technology
Biochemistry
Biochemistry
Term
from 2019 to 2024
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 410108683
This application for a Research Fellowship proposes to apply dynamic in vivo 13C Magnetic Resonance Spectroscopy (MRS) in mice to investigate the effects of chronic alcohol exposure on neurometabolism during acute withdrawal. Alcohol use disorder (AUD) is a chronic relapsing disease characterized by recurrent compulsive alcohol abuse despite significant alcohol-related behavioral, cognitive, physiological, and social problems (American Psychiatric Association, 2013). AUD can be considered the world's biggest addiction problem. Harmful use of alcohol is estimated to lead to 5.9% of all deaths, 5.1% of the global burden of disease, and has been demonstrated to have a causal relationship with over 200 adverse health conditions (World Health Organization, 2014). In AUD, excessive glutamatergic neurotransmission has long been implicated in the acute withdrawal syndrome (AWS), a potentially lethal set of symptoms including seizures, hallucinations, and delirium tremens. Numerous microdialysis studies in animals demonstrated increased glutamate levels that correspond with the intensity of the withdrawal symptomatology and we were able to provide direct evidence for increased glutamate markers in humans and animals. A main finding was a strongly increased glutamate/glutamine (Glu/Gln) ratio in the rat brain during the first three days of withdrawal suggesting increased turnover via the Glu-Gln cycle. Knowledge about the central Glu-Gln dynamics during AWS may increase our understanding of the neurotoxic actions of alcohol and may provide access points to prevent it.13C MRS was proven to be a non-invasive powerful tool to investigate the compartmentalized cerebral metabolism and neurotransmitter cycling by the quantitative calculation of metabolic flux rates in humans and animals. It provides unique insides into the dynamics of neurometabolites, e.g. the Glu-Gln cycle, and thus can help to gain a deeper understanding of the Glu-Gln dynamics during AWS.Mouse brain 13C MRS in vivo is challenging and rarely used, although it is promising in mouse models. The few in vivo studies suffer from a comparatively large voxel covering mostly the whole brain or at least several brain regions limiting their use in preclinical studies. Our institute is equipped with state-of-the-art hardware and with the proposed project we could overcome this limitation and demonstrate the feasibility to investigate functional dynamics of the Glu-Gln cycle in vivo on the level of discrete and well-defined brain structures.The objective of this project is to further improve our 13C MRS methods with the goal to apply them in a study investigating the effects of chronic alcohol consumption during acute alcohol withdrawal on brain glucose metabolism in mice in vivo.
DFG Programme
Research Grants
