Faglige interesser
- Hjernen og nervesystemet
- Oligodendrocytter og myelin
- Metabolisme i hjernen
- Iskemisk hjerneskade
- Laktat
- Mitokondrier
- Endoplasmatisk retikulum
- Oksidativt stress
Undervisning
- Molekylærmedisin, fysiologi (MED1100 og MED2200)
- Reproduksjon (MED2200)
- Membraner og membrantransport (MED1100)
Emneord:
Hjernen og nervesystemet,
Myelin,
Energi,
Metabolisme,
Mitokondrier,
Hvit substans,
Laktat
Publikasjoner
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Kennedy, Lauritz Hagen & Rinholm, Johanne Egge
(2017).
Visualization and live imaging of oligodendrocyte organelles in organotypic brain slices using adeno-associated virus and confocal microscopy.
Journal of Visualized Experiments.
ISSN 1940-087X.
doi:
10.3791/56237.
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Morland, Cecilie; Andersson, Krister; Haugen, Øyvind Pernell; Hadzic, Alena; Kleppa, Liv & Gille, Andreas
[Vis alle 21 forfattere av denne artikkelen]
(2017).
Exercise induces cerebral VEGF and angiogenesis via the lactate receptor HCAR1.
Nature Communications.
ISSN 2041-1723.
8.
doi:
10.1038/ncomms15557.
Fulltekst i vitenarkiv
Vis sammendrag
Physical exercise can improve brain function and delay neurodegeneration; however, the initial signal from muscle to brain is unknown. Here we show that the lactate receptor
(HCAR1) is highly enriched in pial fibroblast-like cells that line the vessels supplying blood to the brain, and in pericyte-like cells along intracerebral microvessels. Activation of HCAR1 enhances cerebral vascular endothelial growth factor A (VEGFA) and cerebral angiogenesis. High-intensity interval exercise (5 days weekly for 7 weeks), as well as L-lactate subcutaneous injection that leads to an increase in blood lactate levels similar to exercise,
increases brain VEGFA protein and capillary density in wild-type mice, but not in knockout mice lacking HCAR1. In contrast, skeletal muscle shows no vascular HCAR1 expression and no HCAR1-dependent change in vascularization induced by exercise or lactate. Thus, we demonstrate that a substance released by exercising skeletal muscle induces supportive effects in brain through an identified receptor.
Editorial summary:
Physical exercise promotes brain angiogenesis through an unknown signalling cascade. Morland et al. identify the elusive muscle-brain communication and show that lactate produced by muscle activity binds to its receptor HCAR1 in brain vessel-surrounding cells, stimulating VEGF production and brain angiogenesis.
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Rinholm, Johanne Egge; Vervaeke, Koen Gerard Alois; Tadross, Michael; Tkachuk, Ariana; Kopek, Benjamin & Brown, Timothy A
[Vis alle 8 forfattere av denne artikkelen]
(2016).
Movement and structure of mitochondria in oligodendrocytes and their myelin sheaths.
Glia.
ISSN 0894-1491.
64(5),
s. 810–825.
doi:
10.1002/glia.22965.
Vis sammendrag
Mitochondria play several crucial roles in the life of oligodendrocytes. During development of the myelin sheath they are essential
providers of carbon skeletons and energy for lipid synthesis. During normal brain function their consumption of pyruvate will
be a key determinant of how much lactate is available for oligodendrocytes to export to power axonal function. Finally, during
calcium-overload induced pathology, as occurs in ischemia, mitochondria may buffer calcium or induce apoptosis. Despite their
important functions, very little is known of the properties of oligodendrocyte mitochondria, and mitochondria have never been
observed in the myelin sheaths. We have now used targeted expression of fluorescent mitochondrial markers to characterize
the location and movement of mitochondria within oligodendrocytes. We show for the first time that mitochondria are able to
enter and move within the myelin sheath. Within the myelin sheath the highest number of mitochondria was in the cytoplasmic
ridges along the sheath. Mitochondria moved more slowly than in neurons and, in contrast to their behavior in neurons and
astrocytes, their movement was increased rather than inhibited by glutamate activating NMDA receptors. By electron microscopy
we show that myelin sheath mitochondria have a low surface area of cristae, which suggests a low ATP production. These
data specify fundamental properties of the oxidative phosphorylation system in oligodendrocytes, the glial cells that enhance
cognition by speeding action potential propagation and provide metabolic support to axons.
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Ersland, Kari Merete; Håvik, Bjarte; Rinholm, Johanne Egge; Gundersen, Vidar; Stansberg, Christine & Steen, Vidar Martin
(2013).
LOC689986, a unique gene showing specific expression in restricted areas of the rodent neocortex.
BMC Neuroscience.
ISSN 1471-2202.
14.
doi:
10.1186/1471-2202-14-68.
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Rinholm, Johanne Egge; Hamilton, Nicola; Kessaris, Nicoletta; Richardson, William D.; Bergersen, Linda Hildegard & Attwell, David
(2011).
Regulation of Oligodendrocyte Development and Myelination by Glucose and Lactate.
Journal of Neuroscience.
ISSN 0270-6474.
31(2),
s. 538–548.
doi:
10.1523/JNEUROSCI.3516-10.2011.
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Jensen, Vidar; Rinholm, Johanne Egge; Johansen, Tine Jeanette; Medin, Tirill; Storm-Mathisen, Jon & Sagvolden, Terje
[Vis alle 8 forfattere av denne artikkelen]
(2009).
N-methyl-d-aspartate receptor subunit dysfunction at hippocampal glutamatergic synapses in an animal model of attention-deficit/hyperactivity disorder.
Neuroscience.
ISSN 0306-4522.
158(1),
s. 353–364.
doi:
10.1016/j.neuroscience.2008.05.016.
Vis sammendrag
Attention-deficit/hyperactivity disorder (ADHD) is the most common neurobehavioural disorder among children. ADHD children are hyperactive, impulsive and have problems with sustained attention. These cardinal features are also present in the best validated animal model of ADHD, the spontaneously hypertensive rat (SHR), which is derived from the Wistar Kyoto rat (WKY). Current theories of ADHD relate symptom development to factors that alter learning. N-methyl-d-aspartate receptor (NMDAR) dependent long term changes in synaptic efficacy in the mammalian CNS are thought to represent underlying cellular mechanisms for some forms of learning. We therefore hypothesized that synaptic abnormality in excitatory, glutamatergic synaptic transmission might contribute to the altered behavior in SHRs. We studied physiological and anatomical aspects of hippocampal CA3-to-CA1 synapses in age-matched SHR and WKY (controls). Electrophysiological analysis of these synapses showed reduced synaptic transmission (reduced field excitatory postsynaptic potential for a defined fiber volley size) in SHR, whereas short-term forms of synaptic plasticity, like paired-pulse facilitation, frequency facilitation, and delayed response enhancement were comparable in the two genotypes, and long-term potentiation (LTP) of synaptic transmission was of similar magnitude. However, LTP in SHR was significantly reduced (by 50%) by the NR2B specific blocker CP-101,606 (10 muM), whereas the blocker had no effect on LTP magnitude in the control rats. This indicates that the SHR has a functional predominance of NR2B, a feature characteristic of early developmental stages in these synapses. Quantitative immunofluorescence and electron microscopic postembedding immunogold cytochemistry of the three major NMDAR subunits (NR1, NR2A; and NR2B) in stratum radiatum spine synapses revealed no differences between SHR and WKY. The results indicate that functional impairments in glutamatergic synaptic transmission may be one of the underlying mechanisms leading to the abnormal behavior in SHR, and possibly in human ADHD
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MacAskill, Andrew F.; Rinholm, Johanne Egge; Twelvetrees, Alison E.; Arancibia-Carcamo, I. Lorena; Muir, James & Fransson, Asa
[Vis alle 9 forfattere av denne artikkelen]
(2009).
Miro1 is a calcium sensor for glutamate receptor-dependent localization of mitochondria at synapses.
Neuron.
ISSN 0896-6273.
61(4),
s. 541–555.
Vis sammendrag
Energy use, mainly to reverse ion movements in neurons, is a fundamental constraint on brain information processing. Trafficking of mitochondria to locations in neurons where there are large ion fluxes is essential for powering neural function. Mitochondrial trafficking is regulated by Ca2+ entry through ionotropic glutamate receptors, but the underlying mechanism is unknown. We show that the protein Miro1 links mitochondria to KIF5 motor proteins, allowing mitochondria to move along microtubules. This linkage is inhibited by micromolar levels of Ca2+ binding to Miro1. With the EF hand domains of Miro1 mutated to prevent Ca2+ binding, Miro1 could still facilitate mitochondrial motility, but mitochondrial stopping induced by glutamate or neuronal activity was blocked. Activating neuronal NMDA receptors with exogenous or synaptically released glutamate led to Miro1 positioning mitochondria at the postsynaptic side of synapses. Thus, Miro1 is a key determinant of how energy supply is matched to energy usage in neurons.
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Rinholm, Johanne Egge; Slettaløkken, Gunnar; Marcaggi, Paikan; Skare, Øivind; Storm-Mathisen, Jon & Bergersen, Linda Hildegard
(2007).
Subcellular localization of the glutamate transporters GLAST and GLT at the neuromuscular junction in rodents.
Neuroscience.
ISSN 0306-4522.
145.
doi:
10.1016/j.neuroscience.2006.12.041.
Se alle arbeider i Cristin
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Andersson, Krister; Morland, Cecilie; Haugen, Øyvind Pernell; Hadzic, Alena; Kleppa, Liv & Gille, Andreas
[Vis alle 21 forfattere av denne artikkelen]
(2017).
Exercise benefits brain through the lactate receptor HCAR1, increasing VEGF and capillary density in hippocampus and cortex.
Vis sammendrag
While physical exercise is known to improve brain function and delay neurodegeneration, the signal from muscle to brain has not been identified. We show here that the lactate receptor, hydroxycarboxylic acid receptor 1 (HCAR1 also known as GPR81), mediates exercise induced increase in the content of vascular endothelial growth factor A (VEGFA) and in capillary density in the hippocampus and cerebral cortex. Mice were subjected to high intensity interval exercise 5 days per week for 7 weeks. Increases in VEGFA and capillary density were observed in wild-type (wt) mice, but not in knockout (ko) mice lacking HCAR1. Subcutaneous injections of L-lactate 5 days per week for 7 weeks, to achieve intermittently high blood lactate levels comparable to those after exercise, reproduced the findings in wt mice. No changes were observed in ko mice. The intermittent nature of the stimulation may be important since continuously high extracellular lactate has previously been observed to down-regulate HCAR1. To our knowledge, the present finding is the first demonstration that a substance released by exercising skeletal muscle induces supportive effects in brain through an identified receptor. No changes in VEGFA or capillary density were observed in the cerebellar cortex. HCAR1 was highly expressed in pial fibroblast-like cells that line the vessels supplying blood to the brain, and in fibroblast-/pericyte-like cells along intracerebral microvessels. These cells are strategically placed to monitor changes in blood-born lactate as well as in brain extracellular lactate (which equilibrate across the vascular endothelium via monocarboxylate transporter 1). Skeletal muscle showed no vascular HCAR1 expression and no HCAR1-dependent change in vascularization induced by exercise or lactate. As VEGFA governs neuronal functions such as LTP as well as vascular growth, the increases may have direct effects on neurons as well as indirect effects through enhancement of vascularization. Both disturbed vascularization and impaired synaptic function are components of the pathogenesis in neurodegenerative dementias such as Alzheimer’s disease. The lactate receptor HCAR1 may prove a useful nutraceutical target for intervention in persons at risk for dementia who are unable to exercise sufficiently to achieve optimal HCAR1 stimulation through rises in blood lactate.
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Morland, Cecilie; Andersson, Krister; Haugen, Øyvind Pernell; Hadzic, Alena; Kleppa, Liv & Gille, Andreas
[Vis alle 18 forfattere av denne artikkelen]
(2016).
A novel mechanism for cerebral angiogenesis via lactate receptor HCAR1 at pial vessels.
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Morland, Cecilie; Andersson, Krister; Haugen, Øyvind Pernell; Hadzic, Alena; Kleppa, Liv & Gille, Andreas
[Vis alle 18 forfattere av denne artikkelen]
(2016).
Exercise induces cerebral angiogenesis via lactate receptor HCAR1 at pial vessels.
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Rinholm, Johanne Egge & Bergersen, Linda Hildegard
(2012).
The wrap that feeds neurons.
Nature.
ISSN 0028-0836.
487(7408),
s. 435–436.
doi:
10.1038/487435a.
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Rinholm, Johanne Egge; Hamilton, NB; Ianarelli, P; Kessaris, N; Richardson, WD & Bergersen, Linda Hildegard
[Vis alle 7 forfattere av denne artikkelen]
(2009).
LACTATE TRANSPORTERS IN DEVELOPING OLIGODENDROCYTES.
Glia.
ISSN 0894-1491.
57(13),
s. S113–S113.
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Publisert
2. juni 2021 10:07
- Sist endret
12. des. 2023 13:30