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  • KAUST Research Workshop on

    Innovative Technologies to

    Study Brain Energy Metabolism


    April 9 - 11, 2018

    King Abdullah University of Science and Technology, Kingdom of Saudi Arabia

​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​About

Brain energy metabolism is altered in most neuropsychiatric and neurodegenerative disorders
not to mention ischemic conditions and stroke. It is also at the basis of functional brain imaging
techniques that detect signals of metabolic or vascular origin. It is therefore crucial to understand
the cellular and molecular basis of brain energy metabolism to assess its relevance for information
processing, for brain disorders and for the development of novel therapeutic targets.

Organizers

Professor Bruno Weber

University of Zurich, Switzerland

Professor Luis Felipe Barros

Centro de Estudios Cientificos, Chile

Professor Pierre Magistretti

King Abdullah University of Science & Technology, Saudi Arabia

Schedule

  • MondayApril 9
  • TuesdayApril 10
  • WednesdayApril 11
8:15 AM

Registration

9:00 AM

Welcome Address & Introductory remarks

Welcome Address & Introductory remarks by Professor Pierre Magistretti, Dean of the Biological and Environmental Science and Engineering Division, KAUST

Professor Pierre Magistretti
King Abdullah University of Science & Technology, Saudi Arabia
9:20 AM

"Neuron-glia metabolic coupling: the cornerstone of brain energetics"

Session 1: Brain energy metabolism: A cellular perspective

Professor Pierre Magistretti
King Abdullah University of Science & Technology, Saudi Arabia
9:55 AM

Lecture Klaus-Armin Nave

Session 1: Brain energy metabolism: A cellular perspective

10:35 AM

Coffee Break

10:55 AM

"Viral vector tools for selective inhibition of lactate release from astrocytes"

Session 1: Brain energy metabolism: A cellular perspective

11:25 AM

"Impairing long-term memory by inhibiting brain glycogenolysis: a 3D-ulstrastructure study"

Session 1: Brain energy metabolism: A cellular perspective

Professor Andrea Falqui
King Abdullah University of Science & Technology, Saudi Arabia
11:55 AM

General discussion

12:15 PM

Lunch break

2:00 PM

"Energy metabolism is coupled to physiologic mitochondrial ros production in neurons and astrocytes"

Session 2: Brain energy metabolism: A mitochondrial perspective

2:40 PM

"Mitochondrial CB1 receptors: a tool to study the role of brain bioenergetics in behavior"

Session 2: Brain energy metabolism: A mitochondrial perspective

Professor Giovanni Marsicano
NeuroCentre Magendie, Bordeaux, France
3:20 PM

Coffee Break

3:40 PM

"The Role of the Mitochondrial Genome in Aging"

Session 2: Brain energy metabolism: A mitochondrial perspective

Professor José Antonio Enríquez
Spanish National Centre for Cardiovascular Research, Madrid
4:20 PM

"Neuron-specific disruption of the mitochondrial pyruvate carrier 1 leads to neuronal hyperexcitability in-vivo"

Session 2: Brain energy metabolism: A mitochondrial perspective

5:00 PM

General discussion

8:45 AM

"3D volumetric Ca²+ imaging of astrocytes reveals novel properties of brain networks"

9:25 AM

"The complex two-way conversation between energy and signaling as visualized with genetically-encoded nanosensors"

Session 3: Imaging Brain Metabolism: Spatial and Temporal Domains

Professor Luis Felipe Barros
Centro de Estudios Cientificos, Chile
10:05 AM

Coffee Break

10:25 AM

"Decoding Microdomain Calcium Signals in Astrocytes"

Session 3: Imaging Brain Metabolism: Spatial and Temporal Domains

Professor Amit Agarwal
Universität Heidelberg, Germany
11:05 AM

"Glia-neuron interaction in the light of in vivo two-photon imaging"

Session 3: Imaging Brain Metabolism: Spatial and Temporal Domains

Professor Bruno Weber
University of Zurich, Switzerland
11:45 AM

General Discussion

12:05 PM

Poster Session

University Library - Seaview Area Level 2

1:10 PM

Lunch break

1:45 PM

"Oxygen Microscopy in the Brain"

Session 4: Novel Imaging Techniques and Modeling

2:25 PM

"Neuroanatomical basis of brain energy metabolism in the mammalian brain"

Session 4: Novel Imaging Techniques and Modeling

Dr. Corrado Calì
King Abdullah University of Science & Technology, Saudi Arabia
2:55 PM

"Interactive Visualization for Neuroscience"

Session 4: Novel Imaging Techniques and Modeling

Professor Markus Hadwiger
King Abdullah University of Science & Technology, Saudi Arabia
3:25 PM

"Label free microscopy for quantitative assessment of biophysical data: cell growth and metabolism"

Session 4: Novel Imaging Techniques and Modeling

Professor Christian Depeursinge
King Abdullah University of Science & Technology, Saudi Arabia
3:55 PM

Coffee Break

4:10 PM

"Modelling the metabolic cost of information at synapses and brain energy metabolism"

Session 4: Novel Imaging Techniques and Modeling

Professor Renaud Jolivet
CERN & University of Geneva, Switzerland
4:40 PM

"Chemical kinetic insights into brain lactate metabolism"

Session 4: Novel Imaging Techniques and Modeling

Professor Mani Sarathy
King Abdullah University of Science & Technology, Saudi Arabia
5:10 PM

"Quantitative phase-digital holographic microscopy: a promising imaging technique to explore cell dynamics and metabolism"

Session 4: Novel Imaging Techniques and Modeling

Professor Pierre Marquet
Cervo Brain Research Center, Université Laval, Canada
5:50 PM

"The New Leica FALCON – Fast Lifetime Contrast for Imaging of Brain Structure and Function"

Session 4: Novel Imaging Techniques and Modeling

6:05 PM

Alejandro San Martin - Development of Optogenetics Tools to Measure Metabolic Flux at Subcellular Resolution in Intact Cells

Metabolites are the nodes of a complex network which is highly conserved throughout life. Understanding of local fluxes within the metabolic grid is constrained by technological limitations, mainly spatiotemporal resolution. For example, it has been known for a while that the first enzyme of glycolysis is attached to mitochondria, but we do not know what is the functional meaning of this location. Current models of cellular metabolism assume that all mitochondria in a cell behave equally. Yet mitochondria within a given cell differ in terms of morphology, age, location, connectivity, motility, and crosstalk with plasma membrane and organelles. Are they all similar in terms of their metabolism? Technologies are emerging that are capable of measuring metabolites with subcellular resolution in living cells. Genetically-encoded nanosensors are proteins build by the fusion of a ligand binding moiety with a fluorescent protein. The binding of the test molecule produces a conformational change that affect the spectroscopy properties of the fluorescent partner. Being genetically-encoded, they can be expressed in single-cells and targeted to subcellular localizations such as mitochondria. Here we introduce PyronicSF, a single-wavelength nanosensor for pyruvate. This sensor undergoes a maximal fluorescent change of 250% and detects pyruvate between 0.03 and 12 mM, spanning the physiological range in mammalian cells. PyronicSF was insensitive to pH and a panel of molecules structurally related to pyruvate. In combination with pharmacological inhibition of the mitochondrial pyruvate carrier (MPC) it was possible to obtain real-time, reversible measurements of the rate of pyruvate consumption in single mitochondria. Our results show that it is possible to characterize metabolic flux in individual organelles. We envisage that single-mitochondria pyruvate consumption measurements will allow to go deep into the understanding of how subcellular localization, morphology, aging and motility can modulate mitochondrial function.

6:15 PM

Eloise de Tredern - A glial involvement at the somatic level during long term memory consolidation in Drosophila melanogaster

High level cognitive tasks such as long-term memory formation require transcriptional regulations and de novo protein synthesis in the soma. Still, in this compartment, it is unknown if and how neuronal metabolism is regulated and sustained by glia, as it is well demonstrated at the level of the axon and the synapse (Bélanger et al., Cell Metabolism, 2011). In the model organism Drosophila melanogaster, five glial subtypes populate the central nervous system (Kremer et al., Glia, 2017). The brain is enclosed inside the equivalent of the brain-blood barrier, composed by perineurial and subperineurial glia. Axons and dendrites – the neuropil - are localized at the centre of the brain, while neuronal somas are segregated at the periphery. Astrocyte-like glia extend multiple processes deep into the neuropil, while ensheathing glia enwrap neuropil structures. In the periphery of the brain, cortex glial cells envelop each neuronal soma individually. Thanks to the diverse and precise genetic tools available in this model, we expressed the dominant thermosensitive allele of dynamin specifically in these different glial subtypes. By transferring flies at restrictive temperature, it allowed us to block exocytosis in the targeted glial cells in a spatiotemporally defined window. Using this approach, we showed that cortex glial cells were involved very early in olfactory memory formation, and specifically in long-term memory. Mushroom bodies are the integrative structures involved in associative memory in the fly brain. We now study if cortex glia could be activated by a signal derived from mushroom-body neurons, which are cholinergic (Barnstedt et al., Neuron, 2016). Data from feeding experiments indirectly suggest that, once activated, cortex glia would support neuronal cell bodies metabolism, but the pathways involved still need to be more precisely deciphered.

6:30 PM

Roman Serrat - Modulation of Astroglial Calcium Signaling by Mitochondrial Type 1 Cannabinoid Receptor

Mitochondrial Ca2+ plays a critical physiological role in cellular energy metabolism and signalling, and its overload contributes to various pathological conditions including neuronal apoptotic death in neurological diseases. It is known that the type-1 cannabinoid receptor (CB1) is present at the mitochondria (mtCB1) and the activation of these receptors decreases cellular respiration and dysregulates memory processes. Data from our lab now show that the CB1 receptor is also present in the mitochondria of astrocytes and can regulate energy production in this cell context. However, it is still not clear whether mtCB1 participates in the synaptic effect of CB1 in astrocytes and if this is mediated by the reported decrease in ATP production or by a regulation in the Ca2+ buffering capacity of mitochondria. Using confocal microscopy in isolated astrocytes transfected with a genetically encoded Ca2+ indicator (GCAMP6s) targeted to mitochondria and a cytosolic Ca2+ sensor (RCAMP2), we have shown that CB1 activation by the specific agonist WIN 55,212-2 leads to an increase of Ca2+ in both compartments. Conversely, a mutant CB1 that it is not addressed to mitochondria (DN22-CB1) only affects cytosolic Ca2+. These results demonstrate that mtCB1 receptor regulates Ca2+ levels in the mitochondria. The inhibitor of soluble adenylyl cyclase (sAC) KH7, that blocks mtCB1-dependent respiration, does not affect cannabinoid-induced increase of mitochondrial Ca2+ in astrocytes, suggesting that this effect of mtCB1 might be independent from cellular respiration. Moreover, the inhibitors of the IP3 receptor located in the endoplasmic reticulum (ER) 2-APB and Xestospongin C blocked the WIN-dependent mitochondrial Ca2+ increase, suggesting that the ER is the source responsible for the increase of Ca2+ in the mitochondria. To investigate if these “in vitro” experiments are reproducible in an “in vivo” model, the somatosensory cortex of WT mice was infected with AAV viruses expressing the mitochondrial GCAMP6s sensor under the astroglial promoter GFAP and the activity of mitochondrial Ca2+ monitored using a 2-photon microscopy in anesthetized animals. Preliminary results show that the intraperitoneal injection of the CB1 agonist THC increases the % of activated mitochondria particles. To conclude, this work shows that mtCB1 regulates Ca2+ levels in the mitochondria of astrocytes, representing a potential novel mechanism by which astroglial CB1 receptors could control astroglial functions and synaptic plasticity.

6:40 PM

General Discussion

2:30 PM

"An upregulation of energy metabolism in the Drosophila mushroom body triggers long-term memory formation"

3:10 PM

"Astrocytes as CNS metabolic sensors"

Session 5: Model Systems and Pathology

3:50 PM

Coffee Break

4:10 PM

"Metabolic coupling between glial networks and neural circuits in the neuroendocrine hypothalamus"

Session 5: Model Systems and Pathology

Dr. Jerome Clasadonte
Jean-Pierre Aubert Research Center, Lille, France
4:50 PM

"Glycolysis-derived L-serine in astrocytes contributes to cognitive deficits in Alzheimer's disease"

Session 5: Model Systems and Pathology

Professor Gilles Bonvento
CEA - François Jacob Institute of Biology, France
5:30 PM

General Discussion

5:50 PM

Concluding Remarks

by Professor Pierre Magistretti

Professor Pierre Magistretti
King Abdullah University of Science & Technology, Saudi Arabia

Speakers

Professor Alexander Guorine

University College London, UK

Professor Amit Agarwal

Universität Heidelberg, Germany

Professor Andrea Falqui

King Abdullah University of Science & Technology, Saudi Arabia

Professor Andrea Volterra

University of Lausanne, Switzerland

Professor Anja Teschemacher

University of Bristol, UK

Professor Bruno Weber

University of Zurich, Switzerland

Professor Christian Depeursinge

King Abdullah University of Science & Technology, Saudi Arabia

Dr. Corrado Calì

King Abdullah University of Science & Technology, Saudi Arabia

Professor Gilles Bonvento

CEA - François Jacob Institute of Biology, France

Professor Giovanni Marsicano

NeuroCentre Magendie, Bordeaux, France

Professor Jean-Claude Martinou

University of Geneva, Switzerland

Dr. Jerome Clasadonte

Jean-Pierre Aubert Research Center, Lille, France

Professor José Antonio Enríquez

Spanish National Centre for Cardiovascular Research, Madrid

Professor Juan Pedro Bolaños

University of Salamanca, Spain

Professor Klaus-Armin Nave

Max Planck Institute for Experimental Medicine, Göttingen, Germany

Professor Luis Felipe Barros

Centro de Estudios Cientificos, Chile

Professor Mani Sarathy

King Abdullah University of Science & Technology, Saudi Arabia

Professor Markus Hadwiger

King Abdullah University of Science & Technology, Saudi Arabia

Professor Pierre Magistretti

King Abdullah University of Science & Technology, Saudi Arabia

Professor Pierre Marquet

Cervo Brain Research Center, Université Laval, Canada

Professor Pierre-Yves Placais

CNRS, ESPCI Paris, France

Professor Renaud Jolivet

CERN & University of Geneva, Switzerland

Professor Sergei Vinogradov

University of Pennsylvania, USA