Translational Neurobiology and Cognitive Neurophysiology Group – University of Copenhagen

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Projects in Translational Neurobiology and Cognitive Neurophysiology Group

Mechanisms of Brain Aging and brain markers for cognitive decline

The interplay in brain between neurons, astrocytes and vascular mural cells regulate brain blood flow and in turn energy supply to brain cells. Preserved energy supply is crucial for normal brain function and cognition and energy failure is a common cause of brain frailty and nerve cell death. The mechanism by which aging influences these processes is incompletely understood. We examine brain aging mechanisms using novel imaging techniques for rodents and humans, with focus on quantification of brain capillary function, oxygen delivery and use, and neuronal function. Our studies will provide a detailed understanding of how dysregulation of brain capillary function may trigger cognitive decline in aging, and will identify novel capillary-based avenues for repair. For human studies we examine a sample of the Metropolit 1953 Danish male birth cohort of approximately 600 males in whom screening for cognitive changes have already been undertaken 4 times over their life-course, while brain structure and function have been examined twice. We use this longitudinal approach to provide a trajectory of cognitive skills versus brain structure and function including cerebral rhythmic activity as indicated by electroencephalography (EEG), capillary flow and brain oxygen consumption at high temporal and spatial resolution as indicated by magnetic resonance imaging (MRI). The birth cohort is examined by genetic testing as well with focus on candidate genes for dementia, sleep patterns, mitochondrial function and inflammation. The repeated measurements with 5-years intervals in the same 600 males are likely to provide novel insights into age-related changes in brain function based on an increased understanding of the ability of test-persons to produce activity in defined neuronal networks of importance for information processing. Furthermore, exploration of the relation between cognitive skills and brain blood vessel function and oxygen supply will provide important information on brain energy, cognitive skills and brain frailty – a crucial factor for brain diseases in the elderly.

To advance a translational approach we carry out corresponding experiments in aged mice with focus on vascular mechanisms. Our novel studies in aged mice suggest that brain arterioles and capillaries are less sensitive to vasoactive stimuli than vessels of young adult mice. Our data suggest that this is due to a change of properties of brain mural cells, i.e. brain pericytes that control capillary flow. In addition, changes in glycosylation of the inner membrane of the brain endothelial cells may hamper not only flow, but also the diffusion of energy substrates across the blood-brain barrier. The cellular mechanisms by which these changes of function are accomplished will be examined in mouse models of aging and premature aging. We examine the interplay between the cellular elements of the brain neurovascular unit examined by a combination of 2-photon microscopy and optogenetics, and appropriate strains of transgenic mice. The express purpose is to identify cellular mechanisms that can be influenced by drugs and to rescue function and prevent frailty in the aged mice.

Completed PhD projects

  1. The dynamic brain - Activity patterns in cognitive ageing and during cerebral blood flow modulation. Naja Liv Hansen, 2014.
  2. GABAergic inhibition in the adult and aged brain. Sanne Barsballe Jessen, 2014.
  3. Salivary gland function as diagnostic tool for age-associated cognitive decline. Christiane Elisabeth Sørensen, 2016.
  4. Late Midlife Sleep and Circadian Pattern: Associations withTrajectories of Cognitive Development in Adulthood. Katja Linda Waller, 2017.
  5. Cognitive Ability and Steady-State Evoked Gamma Response. Anna Horwitz, 2017.
  6. Delirium in critical illness: Relation to EEG changes and systemic inflammation. Rikke Malte Nielsen, 2017.

Ongoing PhD projects

  1. Neurovascular coupling during cognitive auditory and visual processing. Nelly Richard, to be completed in 2018.
  2. Functional and structural connectivity changes in early cognitive aging. Kiyana Zarnani, to be completed in 2018.
  3. Cognitive processing during normal healthy aging compared to patients surviving delirium. Neuropsychological, EEG and structural brain correlates. Olalla Urdanibia Centelles, to be completed in 2020.
  4. Cell-based control of brain energy supply and use and changes with age. Matilda Dahlquist, to be completed in 2018.