Scientific interests
We use a combination of in vivo and in vitro techniques to study the basic physiological mechanisms triggered in the brain in response to exercise. In particular, we study protective mechanisms of exercise in stroke. We employ animal models to mimic human disease and/or use of medications. We investigate behavioral effects of diseases, drugs, and exercise, combined with histological examinations at the light, confocal or electron microscopic level. We also use primary cell cultures and established cell lines as experimental models for mechanistic studies.
The aim is to identify new therapeutic targets for the prevention/therapy of stroke and neurodegenerative disorders.
Teaching
Higher education and employment history
Education
- PhD in Neuroscience, University of Oslo, 2012
- Cand.pharm. (MScPharm) in Pharmacology, University of Oslo, 2003
Employment history
- Professor, Department of Pharmacy, University of Oslo, 2022-present
- Professor II, Lovisenberg diaconal college (LDH)/ Norway (20 %), 2023-present
- Associate Professor, Department of Pharmacy, University of Oslo, 2017–2022
- Associate Professor (20%), Department of Behavioural Sciences, OsloMet, 2017–2022
- Associate Professor, Department of Behavioural Sciences, HiOA (now OsloMet), 2016–2017
Tags:
Brain and nervous system,
Physical activity,
Diabetes,
Parkinson's disease,
Alzheimer's disease,
Neuroscience,
exercise
Publications
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Mjønes, Harald Stranger; Havik, Mona; Seferi, Gezime & Morland, Cecilie
(2026).
High-intensity interval exercise affects neurogenesis and angiogenesis differently in diabetic and non-diabetic mice.
Frontiers in Neuroscience.
ISSN 1662-4548.
20,
p. 1–12.
doi:
10.3389/fnins.2026.1927709.
Full text in Research Archive
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Kennedy, Lauritz Hagen; Morland, Cecilie; Narum, Martine; Bergersen, Linda Hildegard & Rinholm, Johanne Egge
(2025).
Lactate Receptor HCAR1 Affects Axonal Development and Contributes to Lactate’s Protection of Axons and Myelin in Experimental Neonatal Hypoglycemia.
eNeuro.
12(5).
doi:
10.1523/eneuro.0563-24.2025.
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Lactate plays an important role in brain energy metabolism. It contributes to normal brain development and to neuroprotection in diabetic hypoglycemia, but its role in neonatal hypoglycemia is unclear. Moreover, lactate can work as a signaling substance via the lactate receptor HCAR1 (Hydroxycarboxylic acid receptor 1). Recent studies indicate that HCAR1 is protective in mouse models of neonatal hypoxic ischemia and has a role in metabolic regulation in glial cells during hypoglycemia. Here we have studied potential impacts of HCAR1 on axonal and myelin development in the cerebral cortex and corpus callosum of young (P21) wild-type (WT) mice and HCAR1 KO mice and in cortical organotypic brain slice cultures. The HCAR1 KO mice showed lower axonal area relative to WT in both cortex and corpus callosum. However, the myelin area was unaffected by HCAR1 KO. Using particle and colocalization analysis, we show that HCAR1 KO predominantly reduces axonal size in unmyelinated axons. Using an organotypic brain slice model of neonatal hypoglycemia, we find that lactate protects both axonal and myelin development in hypoglycemia, partially via HCAR1. Lastly, live imaging with a pH-sensitive dye on acute cortical brain slices indicates that cellular lactate uptake is influenced by HCAR1. In conclusion, our findings support a role of HCAR1 in axonal development and in lactate’s protective effects in hypoglycemia.
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Lambertus, Marvin; Geiseler, Samuel Jakob & Morland, Cecilie
(2024).
High-intensity interval exercise is more efficient than medium intensity exercise at inducing neurogenesis.
Journal of Physiology.
ISSN 0022-3751.
602(24),
p. 7027–7042.
doi:
10.1113/JP287328.
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Boysen, Elin Sundby; Øderud, Tone; Strisland, Frode; Bull, Emilie Meyer; Dahl, Inger-Lise & Hassel, Bjørnar
[Show all 7 contributors for this article]
(2024).
Using heart rate monitoring to discover pain and discomfort in non-verbal persons with severe intellectual disability: Caregivers’ experiences.
Technology and Disability.
ISSN 1055-4181.
36(4),
p. 161–170.
doi:
10.3233/TAD-230029.
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BACKGROUND Non-verbal persons with intellectual disabilities (ID) may suffer from pain or discomfort, but caregivers may not notice this because of the communication difficulties. Previously, we conducted a study in which professional caregivers used heart rate (HR) monitoring to identify situations that cause acute pain or distress in the everyday life of non-verbal persons with ID. OBJECTIVE To explore professional caregivers’ experience with using HR monitors to better understand non-verbal persons with ID. METHODS Fifteen professional caregivers and 30 final-year students of social education were recruited as informants based on their experience with HR monitoring in non-verbal persons. The informants were interviewed, and they responded to a questionnaire with open-ended questions. The qualitative data were analysed thematically. RESULTS Caregivers reported that HR monitoring provided information about acute pain, acute or prolonged distress, occurrence of epileptic seizures, and the non-verbal persons’ preferences and dislikes. HR data had to be interpreted contextually to be meaningful. Some informants found HR monitoring time-consuming or the interpretation of HR data challenging due to multiple possible causes of increased HR. CONCLUSIONS Caregivers experience HR monitoring as a potentially important source of information that may help them better understand non-verbal persons with ID.
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Skauli, Nadia; Izadpanah, Negar Zohoorian; Banitalebi, Shervin; Geiseler, Samuel Jakob; Salameh, Maher & Shreyas, Rao
[Show all 9 contributors for this article]
(2024).
Aquaporin-4 deletion leads to reduced infarct volume and increased peri-infarct astrocyte reactivity in a mouse model of cortical stroke.
Journal of Physiology.
ISSN 0022-3751.
602(13),
p. 3151–3168.
doi:
10.1113/JP284099.
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Aquaporin-4 (AQP4) is the main water channel in brain and is enriched in perivascular astrocyte processes abutting brain microvessels. There is a rich literature on the role of AQP4 in experimental stroke. While its role in oedema formation following middle cerebral artery occlusion (MCAO) has been studied extensively, its specific impact on infarct volume remains unclear. This study investigated the effects of total and partial AQP4 deletion on infarct volume in mice subjected to distal medial cerebral artery (dMCAO) occlusion. Compared to MCAO, this model induces smaller infarcts confined to neocortex, and less oedema. We show that AQP4 deletion significantly reduced infarct volume as assessed 1 week after dMCAO, suggesting that the role of AQP4 in stroke goes beyond its effect on oedema formation and dissolution. The reduction in infarct volume was associated with increased astrocyte reactivity in the peri-infarct areas. No significant differences were observed in the number of microglia among the genotypes. These findings provide new insights in the role of AQP4 in ischaemic injury indicating that AQP4 affects both infarct volume and astrocyte reactivity in the peri-infarct zone.
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Seferi, Gezime; Mjønes, Harald Stranger; Havik, Mona; Reiersen, Herman; Dalen, Knut Tomas & Nordengen, Kaja
[Show all 7 contributors for this article]
(2024).
Distribution of lipid droplets in hippocampal neurons and microglia: impact of diabetes and exercise.
Life Science Alliance (LSA).
7(10).
doi:
10.26508/lsa.202302239.
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Neuroinflammation, aging, and neurodegenerative disorders are associated with excessive accumulation of neutral lipids in lipid droplets (LDs) in microglia. Type 2 diabetes mellitus (T2DM) may cause neuroinflammation and is a risk factor for neurodegenerative disorders. Here, we show that hippocampal pyramidal neurons contain smaller, more abundant LDs than their neighboring microglia. The density of LDs varied between pyramidal cells in adjacent subregions, with CA3 neurons containing more LDs than CA1 neurons. Within the CA3 region, a gradual increase in the LD content along the pyramidal layer from the hilus toward CA2 was observed. Interestingly, the high neuronal LD content correlated with less ramified microglial morphotypes. Using the db/db model of T2DM, we demonstrated that diabetes increased the number of LDs per microglial cell without affecting the neuronal LD density. High-intensity interval exercise induced smaller changes in the number of LDs in microglia but was not sufficient to counteract the diabetes-induced changes in LD accumulation. The changes observed in response to T2DM may contribute to the cerebral effects of T2DM and provide a mechanistic link between T2DM and neurodegenerative disorders.
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Øderud, Tone; Boysen, Elin Sundby; Strisland, Frode; Dahl, Inger-Lise; Bull, Emilie Meyer & Hassel, Bjørnar
[Show all 7 contributors for this article]
(2023).
Identifying pain and distress in non-verbal persons with intellectual disability: Professional caregivers' and parents' attitudes towards using wearable sensors.
Technology and Disability.
ISSN 1055-4181.
35(3),
p. 207–216.
doi:
10.3233/TAD-220390.
Full text in Research Archive
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BACKGROUND: Persons with severe intellectual disability (ID) may be non-verbal and unable to communicate pain or distress. Consequently, painful conditions may go undetected, and non-verbal persons with ID may not receive adequate care and treatment. OBJECTIVE: This study aims to explore how professional caregivers and parents identify pain and distress in non-verbal persons with ID, and their attitudes towards using wearable sensors to identify pain and distress in daily life situations. METHODS: Exploratory, mixed method study. Caregivers (83) answered an online questionnaire, and professional caregivers (18) and parents (7) were interviewed. RESULTS: Professional caregivers and parents recognise pain and distress from observations and behavioural signs that are often equivocal. They experience that this is inadequate to reliably detect pain and distress in non-verbal persons with ID. Professional caregivers and parents’ express frustration and fear that painful conditions may remain untreated. They are positive towards using wearable sensors on condition that sensors do not infringe on user autonomy and privacy. CONCLUSIONS: There is a need for sensors and methods that can objectively identify pain and distress and ensure adequate treatment, that may improve quality of life of non-verbal persons with ID.
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Geiseler, Samuel Jakob; Phan, Kimberly Dungdung; Brox, Camilla; Nguyen, Teresa Dang; Tartanoglu, Can Hicabi & Doosje, Hanne Lise
[Show all 9 contributors for this article]
(2023).
Pre-stroke exercise does not reduce atrophy in healthy young adult mice.
Neuroscience Letters.
ISSN 0304-3940.
814.
doi:
10.1016/j.neulet.2023.137447.
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Stroke is the main cause of acquired disability in adults. Exercise reduces the risk for stroke and protects against functional loss after stroke. An exercise-induced reduction in key risk factors probably contributes to the protective effect, but direct effects on the brain may also contribute to stroke protection. We previously reported that exercise increases angiogenesis and neurogenesis through activation of the lactate receptor HCA1. Here we exposed young adult wild-type mice and HCA1 knockout mice to interval exercise at high or medium intensity, or to intraperitoneal injections of L-lactate or saline for seven weeks before we induced experimental stroke by permanent occlusion of the distal medial cerebral artery (dMCA). The resulting cortical atrophy measured three weeks after stroke was unaffected by exercise or L-lactate pre-treatments, and independent of HCA1 activation. Our results suggest that the beneficial effect of exercise prior to stroke where no reperfusion occurs is limited in individuals who do not carry risk factors.
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Øverberg, Linda Thøring; Lugg, Elise Fritsch; Gaarder, Mona; Langhammer, Birgitta; Thommessen, Bente & Rønning, Ole Morten
[Show all 7 contributors for this article]
(2022).
Plasma levels of BDNF and EGF are reduced in acute stroke patients.
Heliyon.
8(6).
doi:
10.1016/j.heliyon.2022.e09661.
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Stroke affects almost 14 million people worldwide each year. It is the second leading cause of death and a major cause of acquired disability. The degree of initial impairment in cognitive and motor functions greatly affects the recovery, but idiosyncratic factors also contribute. These are largely unidentified, which contributes to making accurate prediction of recovery challenging. Release of soluble regulators of neurotoxicity, neuroprotection and repair are presumably essential. Here we measured plasma levels of known regulators of neuroprotection and repair in patients with mild acute ischemic stroke and compared them to the plasma levels in healthy age and gender matched controls. We found that the levels of BDNF and EGF were substantially lower in stroke patients than in healthy controls, while the levels of bFGF and irisin did not differ between the groups. The lower levels of growth factors highlight that during the acute phase of stroke, there is a mismatch between the need for neuroprotection and repair, and the brain's ability to induce these processes. Large individual differences in growth factor levels were seen among the stroke patients, but whether these can be used as predictors of long-term prognosis remains to be investigated.
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Morland, Cecilie & Nordengen, Kaja
(2022).
N-Acetyl-Aspartyl-Glutamate in Brain Health and Disease.
International Journal of Molecular Sciences.
ISSN 1661-6596.
23(3),
p. 1–16.
doi:
10.3390/ijms23031268.
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N-acetyl-aspartyl-glutamate (NAAG) is the most abundant dipeptide in the brain, where it acts as a neuromodulator of glutamatergic synapses by activating presynaptic metabotropic glutamate receptor 3 (mGluR3). Recent data suggest that NAAG is selectively localized to postsynaptic dendrites in glutamatergic synapses and that it works as a retrograde neurotransmitter. NAAG is released in response to glutamate and provides the postsynaptic neuron with a feedback mechanisms to inhibit excessive glutamate signaling. A key regulator of synaptically available NAAG is rapid degradation by the extracellular enzyme glutamate carboxypeptidase II (GCPII). Increasing endogenous NAAG—for instance by inhibiting GCPII—is a promising treatment option for many brain disorders where glutamatergic excitotoxicity plays a role. The main effect of NAAG occurs through increased mGluR3 activation and thereby reduced glutamate release. In the present review, we summarize the transmitter role of NAAG and discuss the involvement of NAAG in normal brain physiology. We further present the suggested roles of NAAG in various neurological and psychiatric diseases and discuss the therapeutic potential of strategies aiming to enhance NAAG levels.
Keywords: NAAG; retrograde neurotransmitter; glutamate carboxypeptidase II; Parkinson’s disease; Alzheimer’s disease; stroke; traumatic brain injury; pain; schizophrenia; epilepsy
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Cunnane, Stephen C.; Trushina, Eugenia; Morland, Cecilie; Prigione, Alessandro; Casadesus, Gemma & Andrews, Zane B
[Show all 27 contributors for this article]
(2020).
Brain energy rescue: an emerging therapeutic concept for neurodegenerative disorders of ageing.
Nature Reviews Drug Discovery.
ISSN 1474-1776.
19,
p. 609–633.
doi:
10.1038/s41573-020-0072-x.
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The brain requires a continuous supply of energy in the form of ATP, most of which is produced from glucose by oxidative phosphorylation in mitochondria, complemented by aerobic glycolysis in the cytoplasm. When glucose levels are limited, ketone bodies generated in the liver and lactate derived from exercising skeletal muscle can also become important energy substrates for the brain. In neurodegenerative disorders of ageing, brain glucose metabolism deteriorates in a progressive, region-specific and disease-specific manner — a problem that is best characterized in Alzheimer disease, where it begins presymptomatically. This Review discusses the status and prospects of therapeutic strategies for countering neurodegenerative disorders of ageing by improving, preserving or rescuing brain energetics. The approaches described include restoring oxidative phosphorylation and glycolysis, increasing insulin sensitivity, correcting mitochondrial dysfunction, ketone-based interventions, acting via hormones that modulate cerebral energetics, RNA therapeutics and complementary multimodal lifestyle changes.
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Hadzic, Alena; Nguyen, Teresa Dang; Hosoyamada, Makoto; Tomioka, Naoko H.; Bergersen, Linda Hildegard & Storm-Mathisen, Jon
[Show all 7 contributors for this article]
(2020).
The Lactate Receptor HCA1 Is Present in the Choroid Plexus, the Tela Choroidea, and the Neuroepithelial Lining of the Dorsal Part of the Third Ventricle.
International Journal of Molecular Sciences.
ISSN 1661-6596.
21(18).
doi:
10.3390/ijms21186457.
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The volume, composition, and movement of the cerebrospinal fluid (CSF) are important for brain physiology, pathology, and diagnostics. Nevertheless, few studies have focused on the main structure that produces CSF, the choroid plexus (CP). Due to the presence of monocarboxylate transporters (MCTs) in the CP, changes in blood and brain lactate levels are reflected in the CSF. A lactate receptor, the hydroxycarboxylic acid receptor 1 (HCA1), is present in the brain, but whether it is located in the CP or in other periventricular structures has not been studied. Here, we investigated the distribution of HCA1 in the cerebral ventricular system using monomeric red fluorescent protein (mRFP)-HCA1 reporter mice. The reporter signal was only detected in the dorsal part of the third ventricle, where strong mRFP-HCA1 labeling was present in cells of the CP, the tela choroidea, and the neuroepithelial ventricular lining. Co-labeling experiments identified these cells as fibroblasts (in the CP, the tela choroidea, and the ventricle lining) and ependymal cells (in the tela choroidea and the ventricle lining). Our data suggest that the HCA1-containing fibroblasts and ependymal cells have the ability to respond to alterations in CSF lactate in body–brain signaling, but also as a sign of neuropathology (e.g., stroke and Alzheimer’s disease biomarker).
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Lambertus, Marvin; Øverberg, Linda Thøring; Andersson, Krister Andreas; Hjelden, Malin Sørli; Hadzic, Alena & Haugen, Øyvind Pernell
[Show all 10 contributors for this article]
(2020).
L‐lactate induces neurogenesis in the mouse ventricular‐subventricular zone via the lactate receptor HCA1.
Acta Physiologica.
ISSN 1748-1708.
231(3).
doi:
10.1111/apha.13587.
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Aim: Adult neurogenesis occurs in two major niches in the brain: the subgranular zone of the hippocampal formation and the ventricular-subventricular zone. Neurogenesis in both niches is reduced in ageing and neurological disease involving dementia. Exercise can rescue memory by enhancing hippocampal neurogenesis, but whether exercise affects adult neurogenesis in the ventricular-subventricular zone remains unresolved. Previously, we reported that exercise induces angiogenesis through ac- tivation of the lactate receptor HCA1. The aim of the present study is to investigate HCA1-dependent effects on neurogenesis in the two main neurogenic niches. Methods: Wild-type and HCA1 knock-out mice received high intensity interval ex- ercise, subcutaneous injections of L-lactate, or saline injections, five days per week for seven weeks. Well-established markers for proliferating cells (Ki-67) and imma- ture neurons (doublecortin), were used to investigate neurogenesis in the subgranular zone and the ventricular-subventricular zone. Results: We demonstrated that neurogenesis in the ventricular-subventricular zone is enhanced by HCA1 activation: Treatment with exercise or lactate resulted in in- creased neurogenesis in wild-type, but not in HCA1 knock-out mice. In the subgranu- lar zone, neurogenesis was induced by exercise in both genotypes, but unaffected by lactate treatment. Conclusion: Our study demonstrates that neurogenesis in the two main neurogenic niches in the brain is regulated differently: Neurogenesis in both niches was induced by exercise, but only in the ventricular-subventricular zone was neurogenesis in- duced by lactate through HCA1 activation. This opens for a role of HCA1 in the physiological control of neurogenesis, and potentially in counteracting age-related cognitive decline.
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Nordengen, Kaja; Morland, Cecilie; Slusher, B.S. & Gundersen, Vidar
(2019).
Dendritic localization and exocytosis of NAAG in the rat hippocampus.
Cerebral Cortex.
ISSN 1047-3211.
doi:
10.1093/cercor/bhz176.
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While a lot is known about classical, anterograde neurotransmission, less is known about the mechanisms and molecules involved in retrograde neurotransmission. Our hypothesis is that N-acetylaspartylglutamate (NAAG), the most abundant dipeptide in the brain, may act as a retrograde transmitter in the brain. NAAG was predominantly localized in dendritic compartments of glutamatergic synapses in the intact hippocampus, where it was present in close proximity to synaptic-like vesicles. In acute hippocampal slices, NAAG was depleted from postsynaptic dendritic elements during neuronal stimulation induced by depolarizing concentrations of potassium or by exposure to glutamate receptor (GluR) agonists. The depletion was completely blocked by botulinum toxin B and strictly dependent on extracellular calcium, indicating exocytotic release. In contrast, there were low levels of NAAG and no effect by depolarization or GluR agonists in presynaptic glutamatergic terminals or GABAergic pre- and postsynaptic elements. Together these data suggest a possible role for NAAG as a retrograde signaling molecule at glutamatergic synapses via exocytotic release.
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Geiseler, Samuel & Morland, Cecilie
(2018).
The janus face of VEGF in stroke.
International Journal of Molecular Sciences.
ISSN 1661-6596.
19:1362(5),
p. 1–20.
doi:
10.3390/ijms19051362.
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The family of vascular endothelial growth factors (VEGFs) are known for their regulation ofvascularization. Inthebrain,VEGFsareimportantregulatorsofangiogenesis,neuroprotectionand neurogenesis. Dysregulation of VEGFs is involved in a large number of neurodegenerative diseases and acute neurological insults, including stroke. Stroke is the main cause of acquired disabilities, and normally results from an occlusion of a cerebral artery or a hemorrhage, both leading to focal ischemia. Neurons in the ischemic core rapidly undergo necrosis. Cells in the penumbra are exposed to ischemia, but may be rescued if adequate perfusion is restored in time. The neuroprotective and angiogenic effects of VEGFs would theoretically make VEGFs ideal candidates for drug therapy in stroke. However, contradictory to what one might expect, endogenously upregulated levels of VEGF as well as the administration of exogenous VEGF is detrimental in acute stroke. This is probably due to VEGF-mediated blood–brain-barrier breakdown and vascular leakage, leading to edema and increased intracranial pressure as well as neuroinflammation. The key to understanding this Janus face of VEGF function in stroke may lie in the timing; the harmful effect of VEGFs on vessel integrity is transient, as both VEGF preconditioning and increased VEGF after the acute phase has a neuroprotective effect. The present review discusses the multifaceted action of VEGFs in stroke prevention and therapy.
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Morland, Cecilie; Frøland, Anne-Sofie; Nguyen, Mi Mong Tran; Storm-Mathisen, Jon; Gundersen, Vidar & Rise, Frode
[Show all 7 contributors for this article]
(2018).
Propionate enters GABAergic neurons, inhibits GABA transaminase, causes GABA accumulation and lethargy in a model of propionic acidemia.
Biochemical Journal.
ISSN 0264-6021.
doi:
10.1042/BCJ20170814.
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Propionic acidemia is the accumulation of propionate in blood due to dysfunction of propionyl-CoA carboxylase. The condition causes lethargy and striatal degeneration with motor impairment in humans. How propionate exerts its toxic effect is unclear. Here, we show that intravenous administration of propionate causes dose-dependent propionate accumulation in the brain and transient lethargy in mice. Propionate, an inhibitor of histone deacetylase, entered GABAergic neurons, as could be seen from increased neuronal histone H4 acetylation in the striatum and neocortex. Propionate caused an increase in GABA (γ-amino butyric acid) levels in the brain, suggesting inhibition of GABA breakdown. In vitro propionate inhibited GABA transaminase with a Ki of ∼1 mmol/l. In isolated nerve endings, propionate caused increased release of GABA to the extracellular fluid. In vivo, propionate reduced cerebral glucose metabolism in both striatum and neocortex. We conclude that propionate-induced inhibition of GABA transaminase causes accumulation of GABA in the brain, leading to increased extracellular GABA concentration, which inhibits neuronal activity and causes lethargy. Propionate-mediated inhibition of neuronal GABA transaminase, an enzyme of the inner mitochondrial membrane, indicates entry of propionate into neuronal mitochondria. However, previous work has shown that neurons are unable to metabolize propionate oxidatively, leading us to conclude that propionyl-CoA synthetase is probably absent from neuronal mitochondria. Propionate-induced inhibition of energy metabolism in GABAergic neurons may render the striatum, in which >90% of the neurons are GABAergic, particularly vulnerable to degeneration in propionic acidemia.
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Morland, Cecilie; Andersson, Krister; Haugen, Øyvind Pernell; Hadzic, Alena; Kleppa, Liv & Gille, Andreas
[Show all 21 contributors for this article]
(2017).
Exercise induces cerebral VEGF and angiogenesis via the lactate receptor HCAR1.
Nature Communications.
8.
doi:
10.1038/ncomms15557.
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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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Morland, Cecilie; Pettersen, Mi Nguyen & Hassel, Bjørnar
(2016).
Hyperosmolar sodium chloride is toxic to cultured neurons and causes reduction of glucose metabolism and ATP levels, an increase in glutamate uptake, and a reduction in cytosolic calcium.
Neurotoxicology.
ISSN 0161-813X.
doi:
10.1016/j.neuro.2016.03.005.
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Elevation of serum sodium, hypernatremia, which may occur during dehydration or treatment with sodium chloride, may cause brain dysfunction and damage, but toxic mechanisms are poorly understood. We found that exposure to excess NaCl, 10–100 mmol/L, for 20 h caused cell death in cultured cerebellar granule cells (neurons). Toxicity was due to Na+, since substituting excess Na+ with choline reduced cell death to control levels, whereas gluconate instead of excess Cl− did not. Prior to cell death from hyperosmolar NaCl, glucose consumption and lactate formation were reduced, and intracellular aspartate levels were elevated, consistent with reduced glycolysis or glucose uptake. Concomitantly, the level of ATP became reduced. Pyruvate, 10 mmol/L, reduced NaCl-induced cell death. The extracellular levels of glutamate, taurine, and GABA were concentration-dependently reduced by excess NaCl; high-affinity glutamate uptake increased. High extracellular [Na+] caused reduction in intracellular free [Ca2+], but a similar effect was seen with mannitol, which was not neurotoxic. We suggest that inhibition of glucose metabolism with ensuing loss of ATP is a neurotoxic mechanism of hyperosmolar sodium, whereas increased uptake of extracellular neuroactive amino acids and reduced intracellular [Ca2+] may, if they occur in vivo, contribute to the cerebral dysfunction and delirium described in hypernatremia.
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Lauritzen, Knut Husø; Morland, Cecilie; Puchades, Maja Amedjkouh; Holm-Hansen, Signe; Hagelin, Else Marie Valbjørn & Lauritzen, Fredrik
[Show all 10 contributors for this article]
(2013).
Lactate Receptor Sites Link Neurotransmission, Neurovascular Coupling, and Brain Energy Metabolism.
Cerebral Cortex.
ISSN 1047-3211.
doi:
10.1093/cercor/bht136.
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The G-protein-coupled lactate receptor, GPR81 (HCA1), is known to promote lipid storage in adipocytes by downregulating cAMP levels. Here, we show that GPR81 is also present in the mammalian brain, including regions of the cerebral neocortex and hippocampus, where it can be activated by physiological concentrations of lactate and by the specific GPR81 agonist 3,5-dihydroxybenzoate to reduce cAMP. Cerebral GPR81 is concentrated on the synaptic membranes of excitatory synapses, with a postsynaptic predominance. GPR81 is also enriched at the blood-brain-barrier: the GPR81 densities at endothelial cell membranes are about twice the GPR81 density at membranes of perivascular astrocytic processes, but about one-seventh of that on synaptic membranes. There is only a slight signal in perisynaptic processes of astrocytes. In synaptic spines, as well as in adipocytes, GPR81 immunoreactivity is located on subplasmalemmal vesicular organelles, suggesting trafficking of the protein to and from the plasma membrane. The results indicate roles of lactate in brain signaling, including a neuronal glucose and glycogen saving response to the supply of lactate. We propose that lactate, through activation of GPR81 receptors, can act as a volume transmitter that links neuronal activity, cerebral energy metabolism and energy substrate availability.
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Larsson, Max; Morland, Cecilie; Poblete-Naredo, Irais; Biber, Jürg; Danbolt, Niels Christian & Gundersen, Vidar
(2011).
The Sodium-Dependent Inorganic Phosphate Transporter SLC34Al (NaPi-IIa) Is Not Localized in the Mouse Brain: A Case of Tissue-Specific Antigenic Cross-Reactivity.
Journal of Histochemistry and Cytochemistry.
ISSN 0022-1554.
59(9),
p. 807–812.
doi:
10.1369/0022155411411713.
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Holten, Aleksander Talgøy; Morland, Cecilie; Nordengen, Kaja & Gundersen, Vidar
(2008).
Vesicular Release of L- and D-Aspartate from Hippocampal Nerve Terminals: Immunogold Evidence.
Open Neuroscience Journal.
2,
p. 51–58.
doi:
10.2174/1874082000802010051.
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Morland, Cecilie; Henjum, Solveig; Iversen, Evy Grini; Skrede, Knut Kristian & Hassel, Bjørnar
(2007).
Evidence for a higher glycolytic than oxidative metabolic activity in white matter of rat brain.
Neurochemistry International.
ISSN 0197-0186.
doi:
10.1016/j.neuint.2007.01.003.
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Morland, Cecilie; Henjum, Solveig; Iversen, Evy Grini; Skrede, Knut Kristian & Hassel, Bjørnar
(2007).
Evidence for a higher glycolytic than oxidative metabolic activity in white matter of rat brain.
Neurochemistry International.
ISSN 0197-0186.
50(5),
p. 703–709.
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Morland, Cecilie; Boldingh, Karen A; Iversen, Evy Grini & Hassel, Bjørnar
(2004).
Valproate is neuroprotective against malonate toxicity in rat striatum: an association with augmentation of high-affinity glutamate uptake.
Journal of Cerebral Blood Flow and Metabolism.
ISSN 0271-678X.
doi:
10.1097/01.WCB.0000138666.25305.A7.
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The antiepileptic drug valproate (VPA) may be neuroprotective. We treated rats with VPA for 14 days (300 mg/kg twice daily) before intrastriatal injection of 1.5 μmol (1 M) of the succinate dehydrogenase inhibitor malonate. VPA-treated animals developed smaller lesions than control animals: 10 ± 2 mm3 versus 26 ± 8 mm3 (means ± SD; P = 10−4). Injection of NaCl that was equiosmolar with 1 M malonate caused lesions of only 1.2 ± 0.4 mm3 in control animals, whereas physiologic saline produced no lesion. VPA pretreatment reduced the malonate-induced extracellular accumulation of glutamate. This effect paralleled an increase in the striatal level of the glutamate transporter GLT, which augmented high-affinity glutamate uptake by 25%, as determined from the uptake of [3H] glutamate into striatal proteoliposomes. Malonate caused a 76% reduction in striatal adenosine triphosphate (ATP) content, but the glial, ATP-dependent formation of glutamine from radiolabeled glucose or glutamate was intact, indicating that glial ATP production supported uptake of glutamate. Striatal levels of HSP-70 and fos were reduced, and the levels of bcl-2 and phosphorylated extracellular signal-regulated kinase remained unaffected, but histone acetylation was increased by VPA treatment. The results suggest that augmentation of glutamate uptake may contribute importantly to VPA-mediated neuroprotection in striatum.
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Hassel, Bjørnar; Boldingh, Karen Astrid; Morland, Cecilie; Iversen, Evy Grini & Skrede, Knut Kristian
(2003).
Glutamate transport, glutamine synthetase and phosphate-activated glutaminase in rat CNS white matter. A quantitative study.
Journal of Neurochemistry.
ISSN 0022-3042.
doi:
10.1046/j.1471-4159.2003.01984.x.
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Geiseler, Samuel; Hadzic, Alena; Sajedi, Ghazal; Forbord, Karl Martin Frøseth & Morland, Cecilie
(2020).
Lactate injections are neuroprotective in stroke via HCAR1.
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Morland, Cecilie
(2019).
Forstå meg! -Bruk av pulsmåling som supplerende kommunikasjon hos personer med svært begrensede kommunikajsonsevner.
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Lambertus, Marvin & Morland, Cecilie
(2019).
The role of Lactate Receptor HCAR1 in Subventricular Zone Neurogenesis.
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Lambertus, Marvin; Seferi, Gezime; Øverberg, Linda Thøring & Morland, Cecilie
(2019).
Lactate receptor HCAR1 in cerebral insulin resistance and neurogenesis.
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Lambertus, Marvin; Sørli, Malin; Haugen, Øyvind Pernell; Andersson, Krister Andreas & Morland, Cecilie
(2018).
The effects of HCAR1 activation on the release of growth factors from pia mater fibroblasts.
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Andersson, Krister; Morland, Cecilie; Haugen, Øyvind Pernell; Hadzic, Alena; Kleppa, Liv & Gille, Andreas
[Show all 21 contributors for this article]
(2017).
Exercise benefits brain through the lactate receptor HCAR1, increasing VEGF and capillary density in hippocampus and cortex.
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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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Andersson, Krister; Morland, Cecilie; Haugen, Øyvind Pernell; Bergersen, Linda Hildegard & Storm-Mathisen, Jon
(2017).
Physical exercise promotes brain angiogenesis through a lactate receptor.
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Physical exercise can improve brain function and delay neurodegeneration, but the initial signal from muscle to brain is unknown. Here we show that the lactate receptor (HCAR1) is highly enriched in fibroblast-like cells that line and surround the pial blood vessels supplying the brain, and that activation of HCAR1 stimulates vascular endothelial growth factor A (VEGFA) levels and angiogenesis in hippocampus. High intensity interval exercise (five days weekly for seven weeks), as well as L-lactate injected subcutaneously to similarly increase blood lactate levels, caused a substantial increase in brain VEGFA protein and microvessel density in wild-type mice, but not in knockout mice lacking HCAR1. In contrast, skeletal muscle showed no vascular HCAR1 expression and no HCAR1 dependent change in vascularization induced by exercise or lactate. To our knowledge, this is the first demonstration that a substance released by exercising skeletal muscle induces supportive effects in brain through an identified receptor.
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Moretti, Laura; Stølen, Tomas; Wisløff, Ulrik; Storm-Mathisen, Jon; Bergersen, Linda Hildegard & Morland, Cecilie
(2016).
Effects of intrinsic fitness level on mitochondria during exercise.
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Narvesen, Cecilie; Boldingh, Karen A; Iversen, Evy Grini; Taubøll, Erik & Hassel, Bjørnar
(2003).
Valproate may be neuroprotective through various mechanisms.
Nevrodagene 2003..
p. 91–91.
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Phan, Kimberly Dungdung; Geiseler, Samuel & Morland, Cecilie
(2020).
The lactate receptor HCAR1 in the regulation of neurogenesis and angiogenesis during stroke.
Universitetet i Oslo.
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Millions of people suffer from stroke every year, being a leading cause of morbidity and mortality worldwide. The current pharmacological and endovascular therapies in stroke aim to restore cerebral blood flow, but are not suitable for many stroke patients due to a number of risk factors. With the limited post-stroke rehabilitation treatments available, prevention of stroke will continue to be an area of research with a large impact. One of the best preventive strategies in stroke is exercise, which has shown to reduce risk factors and improve brain function through direct effects in the brain. Trophic growth factors are elevated after exercise which enhances neurogenesis and angiogenesis, and have been suggested to exert the neuroprotective effects in the ischaemic brain. The lactate receptor (HCAR1) has recently shown to be highly enriched in fibroblasts in the meninges, particularly the pia mater. Furthermore, activation of these receptors by lactate injections or high-intensity exercise, enhance cerebral vascular endothelial growth factor A (VEGF-A) levels and angiogenesis, and perhaps also directly enhance neurogenesis. Since HCAR1 can be stimulated by circulating lactate arriving from the blood as a result of exercise, this may explain the underlying beneficial effects of exercise in stroke. The present study aimed to examine the HCAR1-induced vascularization and neurogenesis in response to exercise in the neuroprotection of stroke. Wild-type mice and HCAR1 knockout mice were subjected to high-intensity exercise (at levels known to significantly increase blood-lactate levels), medium-intensity exercise, or intraperitoneal injections of lactate or saline (control) daily for 5 consecutive days a week for 7 weeks in total. Following the treatments, focal ischaemia was induced by permanent coagulation of the distal middle cerebral artery, and the mice were allowed a 3-weeks recovery phase before being sacrificed by perfusion fixation to collect the brains. Whole cresyl violet-stained sections were analysed for comparison of infarct volume. Interestingly, no significant differences between the treatment groups or genotypes were found. Possible reasons for the lack of observed effects are presented. In conclusion, preventive and prolonged exercise preconditioning or lactate injections do not protect against ischaemia-induced cell death 3 weeks after stroke. Moreover, the outcome was independent of HCAR1-mediated effects. Overall, these findings provide new insights of the long-lasting effects (3 weeks after stroke induction) on the stroke outcome of exercise preconditioning and lactate treatment, through the lactate receptor HCAR1.
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Sajedi, Ghazal & Morland, Cecilie
(2019).
Effekter av laktat via laktatreseptor HCAR1 ved iskemisk hjerneslag.
Universitetet i Oslo.
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Bare et lite stopp i blodtilførsel til hjernen, for eksempel ved iskemisk hjerneslag, kan føre til celledød og nevrologiske skader. Laktat er vist å ha nevroprotektive effekter som beskytter nevroner mot iskemi. Under høyintensitetstrening skjer det en akkumulering av laktat i blodet, og laktat gjennom aktivering av hydroksykarboksylsyre reseptor 1 (HCAR1) induserer signalveier som kan være en del av de helsefremmende effektene av trening. I denne studien øker vi laktatkonsentrasjonen i blodet gjennom laktatinjeksjoner, og vi undersøker om laktat, gjennom aktivering av HCAR1, gir mindre lesjonsvolum etter et hjerneslag. Vi induserte hjerneslag i villtypemus som hadde HCAR1 (WT) og i HCAR1 knock-out mus (KO) ved permanent okklusjon av distal arteria cerebri media (MCA). Deretter injiserte vi laktat (200 mg/ml oppløst i 0,9% 1 M PBS; 2 g/kg kroppsvekt) eller natriumklorid (0,9%; 2 g/kg kroppsvekt) intraperitonealt 24 og 48 timer etter operasjonen. I dyr perfundert tre uker etter operasjonen så vi et signifikant mindre lesjonsvolum i WT-mus behandlet med laktat enn i WT-mus behandlet med natriumklorid. HCAR1 KO-mus tenderte til å ha mindre lesjoner enn WT musene, men i KO-musene ga laktatinjeksjoner ingen effekt på lesjonsstørrelsen. Vi indentifiserer dermed HCAR1 som en viktig reseptor ved hjerneslag, og et potensielt angrepspunkt for nye legemidler ved hjerneslag. Videre ønsket vi å undersøke om denne gunstige effekten av laktat kommer av økt nevrogenese og/eller angiogenese i hjernen. Vi analyserte tetthet av nevroblaster (DCX+ celler) i subgranulære sonen (SGZ) i hilus av gyrus dentatus (DG) og subventrikulære sonen (SVZ). For å undersøke graden av angiogenese så vi på kapillærtetthet i hilus av DG og rundt slagområdet. Det ble oppdaget forskjeller eller tendenser til forskjeller mellom gruppene, men vi fant ingen forskjeller som i seg selv kan forklare den store effekten av laktat på lesjonsvolum i WT-mus. Denne studien viser at laktat, gjennom aktivering av HCAR1, reduserer slagvolumet i WT-mus, men ikke i HCAR1 KO-mus. Selv om mekanismen fortsatt er ukjent, er effekten vi ser på slagvolum klinisk relevant. Laktatbehandlingen i denne studien ble gitt 24-48 timer etter indusert hjerneslag. Det representerer et tidsvindu der man har få eller ingen effektive behandlingsalternativer å tilby pasientene. Studien åpner for å teste ut HCAR1-agonister i behandling av hjerneslag.
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Published
Sep. 18, 2017 10:40 AM
- Last modified
Dec. 5, 2025 10:07 AM
