Albert Gjedde Group – University of Copenhagen

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Research

Molecular Neurobiology of Aging and Consciousness (MNAC)

CPINE: infrastructure facility founded at the DNP on the basis of a grant from the Ministry of Science. CPINE hosts a 9.4 Tesla magnet for in-vivo and in-vitro animal studies.

The group explores the rise and fall of human consciousness as functions of brain energy metabolism and neurotransmission during development, aging, and neurodegeneration. In collaboration with the COMA research Unit, University of Liège (Belgium), MNAC studies brain metabolism and cerebral functioning in patients in the minimally conscious and persistent vegetative state. The MNAC links the BRAINlab to the Center of Healthy Aging at Copenhagen University, CFIN at Aarhus University, and CMBN at the University of Oslo.

Neuroenergetics Unit

The Neuroenergetics Unit of the Brain Research and Integrative Neuroscience (BRAIN) laboratory at the Department of Neuroscience and Pharmacology is devoted to the study of brain energy turnover. Neuroenergetics is a topic in neuroscience concerned with the relations of energy turnover to conscious activity in the mammalian brain. Energy signifies the ability of a machine to do work. Neuroenergetics deals with the mechanisms responsible for brain work. Mammalian brain supports energy metabolism almost entirely by oxidation of glucose to carbon dioxide. A substantial fraction of the oxidative metabolism is directed towards the oxidative rephosphorylation of ADP to ATP, while the remainder is shared between the generation of reactive oxygen and nitrogen species (RONS) and the generation of heat. The fraction of oxygen consumption directed towards ATP production is the Oxidative Phosphorylation Index (OPI). ATP is the biochemical energy currency of the mammalian brain and the rate of breakdown of this molecule is a measure of the energy turnover associated with specific biochemical pathways.. Thus, the majority of the ATP is regenerated by oxidative metabolism and a smaller fraction is regenerated by means of aerobic glycolysis.

Remarkably, the magnitude of the ATP-associated energy turnover is unknown in the intact mammalian brain. The main reason for this state of ignorance is the fact that the magnitude of the OPI is not known with certainty in vivo, although some estimates place the value in the range of 0.5 to 0.75 (Gjedde et al. 2011). Among other consequences, this means that measures of oxygen and glucose consumption are imperfect indicators of energy turnover and brain work. The process known as aerobic glycolysis causes a small fraction of the glucose normally to be lost to the circulation as lactate. The mechanism responsible for this loss is the near-equilibrium reaction between pyruvate and lactate, which maintains a gradient of lactate concentration from brain tissue to the circulation, and the presence of transporters in the brain capillary endothelium enable the facilitated diffusion of lactate in proportion to this gradient. The extent of this loss defines the oxidative fraction of the metabolism, normally expressed as the value of the Oxygen-Glucose Index (OGI). Neither the magnitudes of the fraction of glucose and oxygen consumption directed towards ATP regeneration, nor the fraction of glucose consumption directed towards lactate, are known with certainty in the human brain as a whole or in its diverse regions.

As a measure of the degree of oxidation of glucose to carbon dioxide, the theoretical OGI value of 6 signifies complete oxidation of glucose. The most commonly cited value for human brain is lower, however, and close to 5.4 (Gjedde 2007), consistent with loss of 10% of phosphorylated glucose to the circulation as lactic acid molecules. Together, the OPI and the OGI define an ATP-Glucose Index (AGI), which is simply the product of the respective OPI and OGI values of 0.75 and 5.4, or 4, indicating that only two thirds of the glucose molecules metabolized in brain support the biochemical work of the brain. The fate of the energy held in the remaining third of the glucose molecules. Some is held in expanding structures of the neuronal networks but most undoubtedly is dissipated as heat. One possibility explored in the current investigations of neuroenergetics is whether or not the heat generated by the oxidative metabolism of the brain plays a role in molecular reconfigurations responsible for conscious brain functions. The key to heat generation in the brain (and elsewhere in the body) is the uncoupling of the electron chain reactions in mitochondria from the oxidative phosphorylation of ATP. It is the degree of uncoupling and hence of heat generation that is unknown in mammalian brains. Uncoupling is effected by proteins that dissipate the hydrogen ion gradient across the inner membrane of mitochondria. Several uncoupling proteins (UCP1-5) exist in different locations of the body, from UCP1 in the thyroid to UCP2 everywhere, UCP3 in skeletal muscle, and UCP4 in brain.

The extent of oxidative metabolism is important for several reasons. Uncoupling may serve to regulate production of RONS, prevent obesity, and promote healthy aging (Dalgaard 2011), and activation of neuronal functions is now thought to involve some reduction of relative oxidation, measurable as declines of the OGI as well as of the oxygen extraction fraction (OEF) (Raichle et al. 2010). Both indices are indicative of increased uncoupling, because changes of the OGI commonly are inversely correlated with changes of blood flow, i.e., when blood flow increases, the OGI tends to decline. In fact, reductions of the OGI and the OEF are so fundamental to certain interpretations of functional brain imaging results that the common measure of the OEF, the blood-oxygenation-level-dependent (BOLD) signal from functional magnetic resonance imaging (fMRI), universally is used as the most generally accepted index of functional activation of brain regions. An entire network of neuronal connections in brain, devoted to an assumed basic or "default" activity, has been defined as the parts of the brain where the OEF commonly is close to 0.40. The default activity is a hypothetical mode of brain operation in regions in a state characterized by the absence of goal-directed activity (Gusnard et al. 2001). The default mode is the activity to which the brain supposedly defaults when the individual's attention is not directed towards a specific external stimulus, which in turn generates a new state of reduced oxidation.

Previous assessments of the OGI depended on the determinations of arteriovenous deficits (AV-deficits) of oxygen, glucose and lactate. The AV-deficit of lactate normally is negative (signifying efflux from brain), but the magnitude of all AV-deficits for the brain are in doubt because the venous outflow is contaminated by admixture of venous blood from head and neck regions. The most direct measure of the OGI and hence of the loss of glucose as lactate therefore requires simultaneous measurements of regional oxygen and glucose consumption rates, but such measurements generally have yet not been reported.