L-LTP can be induced by a single train of stimulation in presence of protein-synthesis inhibitors

editorial reviewedEncoding of memories relies on modifications in the strength of the synapses connecting the different cells within a neuronal network. The selective increases in synaptic weight are thought to be biologically implemented by long-term potentiation (LTP). Classically, in area CA1 of hippocampal slices a single train at 100-Hz (1s) triggers a short-lasting LTP, which lasts 1-2 h and is independent of new protein synthesis, whereas multiple trains induce a long-lasting LTP, which lasts several hours and can be blocked by protein synthesis inhibitors. However, it has been repeatedly shown that the threshold and the features of these LTP depend on the history of the neurons, a phenomenon known as metaplasticity. We already demonstrated that slices recovery conditions modified the characteristics of LTP (Capron et al. 2006). By maintaining the slices in submersion during recovery, it was possible to induce a long-lasting LTP with a single train. Further investigations demonstrated that long-lasting LTP (more than 10 hours) can be induced by a very short stimulation (15 pulses) and that increasing the number of pulses increased just the level of potentiation. Moreover, this kind of LTP became nearly independent of new protein synthesis. In this case, synaptic tagging could not be observed anymore. The only way to impair this long-lasting potentiation was to increase the frequency of basal stimulation: stimulating the slices every 10 sec prevent the stabilization of LTP induced by one or 4 trains. But in this case again, synaptic tagging could not be observed. So, in vitro, de novo protein-synthesis dependence of LTP and synaptic tagging can only be observed in very specific conditions depending on the set-up used, the experimenter, the conditions of slices recovery, the composition of ACSF....This dramatically increases the difficulty for comparing the different results obtained in different labs and prevents rapid progress in the understanding of this phenomena. Grant acknowledgements: A.Villers is Research Fellow of F.R.S.-FNRS. L.Ris is Senior Research Associate of F.R.S.-FNRS. This investigation was supported by the Queen Elisabeth Fund for Medical Research

Neuroinflammatory processes induced during EAE also affect the hippocampus and its associated cognitive processes

editorial reviewedNeuroinflammatory processes induced during EAE also affect the hippocampus and its associated cognitive processes. Recent scientific advances have clearly demonstrated the important role of the immune system in the central nervous system (CNS). Specific immune responses take place within the brain and are not only involved in pathological events but also in normal brain functioning. An integrative network develops between neurons, glia and peripheral immune cells which actively interact to regulate many neuronal functions and ensure the proper brain functioning. This complex neuroimmune crosstalk is particularly implicated in the remodeling of synaptic circuits contributing to synaptic plasticity and memory function. Microglial cells represent the resident immune cells of the CNS, protecting the brain against various pathological insults. Their immune responses are tightly regulated to maintain CNS homeostasis and limit neurotoxic processes. However, under diseased conditions, the delicate balance between neuroprotective and neurodegenerative effects of immune responses can be rapidly disrupted due to an excessive or prolonged activation of immune and glial cells. This can result in the delivery of damage signals and the propagation of neuroinflammation leading eventually to neuronal alterations1. Synaptic plasticity is the ability of neurons to modulate the strength of their synaptic transmission. Different forms of synaptic plasticity exist such as the long-term potentiation (LTP). This process enables to modify neural circuits dynamic and ensures memory consolidation in the hippocampus. Immune processes are directly implicated in learning and memory and play a dual role. In the healthy brain, time-controlled immune responses including glial cells activation and cytokine production exert a positive effect on neural plasticity by increasing neuronal excitability. However, an excessive brain immune activation can induce a neuronal hyperexcitability state which is associated to disturbances in synaptic plasticity and memory2. Cognitive impairments are very common in many neuroinflammatory disorders. However, the mechanisms involved are still poorly understood because of the large diversity and complexity of immune responses that can be engaged3. This project aims to study the effects of neuroinflammation on neuronal network activity and synaptic plasticity in mouse hippocampus and to highlight the molecular and cellular inflammatory actors related to cognitive disorders. We are particularly interested in inflammatory processes developed during experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis induced by a specific autoimmune reaction against myelin sheaths of neurons leading to demyelination and motor disorders. We use EAE as a model of CNS chronic neuroinflammatory disease to analyze the possible implication of the NFκB pathway and glial cells in synaptic plasticity dysfunctions and in neuronal network functioning during neuroinflammatory diseases. The chronic course of EAE allows us to dissociate the different inflammatory steps of the disease (relapsing versus remitting stage) and to analyze more precisely their impact on cognition. Only few studies using EAE as an experimental model have analyzed the hippocampal integrity and they show conflicting results4-6. Hippocampal synaptic plasticity was analyzed during the course of EAE by ex vivo electrophysiological recordings (LTP) made on acute hippocampal slices from EAE mice. LTP measurements showed that the level of potentiation is higher at the peak of EAE but progressively decreases during the remission phase when motor symptoms improve. This suggests a time dependent impairment of hippocampal plastic potential during the EAE remission stage. A cognitive impairment was also demonstrated in vivo during this remission stage by evaluating the learning and memory capacities of remitting mice with contextual fear conditioning. Although myelin is the main target of the immune reaction during EAE, no modification of MBP expression was found by western-blotting and immunohistochemistry in mouse hippocampus at any stage of EAE. Besides the lack of demyelination, the structural integrity of the hippocampus was also unaffected during EAE as no atrophy, inflammatory infiltrates or dendritic area modification were found. However, our immunostainings and ELISA experiments revealed a higher glial activation and a production of inflammatory factors like IL1β or TNFα in the hippocampus of EAE mice. The number of both astrocytes and microglial cells follows the disease progression as it enhances at the peak of the disease and then decreases during the remission stage. So, although motor impairments are the main symptoms of EAE, we demonstrated that immune responses and neuroinflammation associated to EAE can also affect cognitive structures like hippocampus and can lead to cognitive impairments during the course of the disease. Taken together, our results suggest that, as no demyelination occurs, activated microglia and astrocytes could be linked to modifications of hippocampal synaptic plasticity during EAE and could therefore be important actors implicated in cognitive disorders related to neuroinflammation. The next step of the project will be to investigate the implication of the NFκB signaling pathway in the hippocampus during EAE thanks to an inducible adenoviral vector system which will allow us first to visualize the hippocampal NFκB expression and then to induce a negative feedback to inhibit its own activity. Summary for lay people Many neuroinflammatory diseases are characterized by cognitive impairments which are now a major problem in our society, becoming more and more common and disabling. This study will help to better understand how neuroinflammation can affect our memory processes. We will attempt to identify some inflammatory factors which could play a key role in cognitive disorders related to neuroinflammatory diseases. These one could then be the subject of further investigations for the development of new therapeutic approaches aimed at improving cognition in patients suffering from neuroinflammatory disorders. Beaucoup de maladies neuroinflammatoires sont caractérisées par des troubles cognitifs qui sont aujourd'hui un problème majeur dans notre société, devenant de plus en plus fréquent et invalidant. Cette étude aidera à mieux comprendre comment la neuroinflammation affecte nos processus de mémorisation. Nous tenterons d'identifier certains acteurs inflammatoires qui pourraient jouer un rôle clé dans les troubles cognitifs associés aux maladies neuroinflammatoires. Ceux-ci pourraient dès lors faire l'objet de futures recherches pour le développement de nouvelles approches thérapeutiques visant à améliorer la cognition chez les patients souffrant de troubles neuroinflammatoires

Study of the physiopathological roles of APP: implication in Alzheimer's disease and type 2 diabetes

editorial reviewedNowadays, there is evidence that brain glucose metabolism and Alzheimer's disease (AD) are linked. Patients suffering from type II diabetes present a higher risk to develop AD while in Alzheimer's disease patients the brain glucose metabolism is reduced, leading to a general hypometabolism. This abnormal glucose metabolism can already be observed in genetically predisposed people before the expression of any clinical sign. It is therefore very important to better understand the link between brain utilization of glucose and AD. On the other hand, while beta-amyloid aggregates are one of the principal hallmarks of the disease, all strategies targeting these aggregates have failed until now to prove their efficacy. Targeting the amyloid precursor protein (APP) itself and its role in brain metabolism could bring some new insights and lead to novel therapeutic strategies. Recent research showed that APP and peptides derived from its proteolytic cleavage are involved in cholesterol and ganglioside metabolism. Our hypothesis is that APP is involved in energy flux between the body and the brain. During ageing or in case of pathology such as insulin resistance, glucose availability can be reduced in the brain leading to a compensatory increase in the expression of APP. This compensatory increase could be the starting point of disruption of metabolic and neurotransmitter homeostasis leading to cognitive deficit. The aim of this project is to better understand the link between the expression and the processing of APP and brain glucose metabolism and its impact on neuronal activity and synaptic connections. This would provide new evidences in the pathological process of Alzheimer's disease and diabetes. Experiments were carried out on the hippocampus of transgenic mice B6.129S7 having 2 (+/+, WT), 1 (+/-, HT) or 0 (-/-, KO) allele of the APP gene allowing the study of three levels of APP expression. This model has the advantage of excluding the possible role of beta-amyloid aggregates because the endogenous murine form of the beta-amyloid peptide does not aggregate into oligomers and fibers. The expression of APP gene and protein was evaluated by genotyping and Western-Blotting respectively. The correlation between APP expression level and metabolic activity in the hippocampus was evaluated by 1H-NMR spectroscopy and has allowed to discriminate each genotype on the basis of their metabolic profile. We observed a decrease in the level of glucose in the hippocampus of KO mice compared to WT mice. Creatine and phosphocreatine were also reduced in APP KO mice compared to HT and WT whereas the level of GABA increases in the hippocampus of KO mice. The interesting thing is that heterozygote mice (HT) present an intermediate level of each of these metabolites. The physiological impact of the interaction between APP and glucose was studied by extracellular electrophysiological recordings of cell excitability and synaptic activity in acute hippocampal slices. Slices were incubated with three different concentrations of glucose in the aCSF to assess their sensitivity to hypoglycaemia (10mM, normoglycemia; 5mM, mild hypoglycaemia; 2.5mM, severe hypoglycaemia). Preliminary results showed that the reduction of glucose level from 10mM to 5mM induced a large decrease of the synaptic response in WT mice (50 % of reduction) while the decrease in synaptic activity was much less important in KO mice (30% of reduction). Here again heterozygote mice presented an intermediate phenotype (40% of reduction). The sensitivity to moderate hypoglycaemia seems to be correlated with the level of expression of APP in the hippocampus. Moreover a higher decrease in glucose supply (2.5mM) further reduced the synaptic response, indicating that a more pronounced glucose hypometabolism has more deleterious consequences on neural viability. Finally ageing also seems to have an effect on the hippocampus. Indeed, 6 month-old mice showed a decrease in synaptic activity and excitability compared to 6 week-old mice. As we observed a modification of the expression of GABA, we studied the effect of disinhibition on electrical activity by adding picrotoxin (PTX) to the aCSF. In the normoglycemic condition the intensity of the epileptiform activity was higher in KO mice than in the other two groups. When the glucose was reduced to 2.5mM, we observed an extinction of the fEPSP in most of the WT slices compared to the KO slices, where epileptiform activity was still high. Once again HT mice presented an intermediate phenotype. These preliminary results still need to be completed to better understand the mechanisms responsible of the establishment of Alzheimer's disease in order to stop them before the onset of clinical symptoms

Neuroinflammatory processes induced during EAE also affect the hippocampus and its associated cognitive processes

editorial reviewedRecent scientific advances have clearly demonstrated the important role of the immune system in the central nervous system (CNS). Specific immune responses take place within the brain and are not only involved in pathological events but also in normal brain functioning. An integrative network develops between neurons, glia and peripheral immune cells which actively interact to regulate many neuronal functions and ensure the proper brain functioning. This complex neuroimmune crosstalk is particularly implicated in the remodeling of synaptic circuits contributing to synaptic plasticity and memory function. Microglial cells represent the resident immune cells of the CNS, protecting the brain against various pathological insults. Their immune responses are tightly regulated to maintain CNS homeostasis and limit neurotoxic processes. However, under diseased conditions, the delicate balance between neuroprotective and neurodegenerative effects of immune responses can be rapidly disrupted due to an excessive or prolonged activation of immune and glial cells. This can result in the delivery of damage signals and the propagation of neuroinflammation leading eventually to neuronal alterations1. Synaptic plasticity is the ability of neurons to modulate the strength of their synaptic transmission. Different forms of synaptic plasticity exist such as the long-term potentiation (LTP). This process enables to modify neural circuits dynamic and ensures memory consolidation in the hippocampus. Immune processes are directly implicated in learning and memory and play a dual role. In the healthy brain, time-controlled immune responses including glial cells activation and cytokine production exert a positive effect on neural plasticity by increasing neuronal excitability. However, an excessive brain immune activation can induce a neuronal hyperexcitability state which is associated to disturbances in synaptic plasticity and memory2. Cognitive impairments are very common in many neuroinflammatory disorders. However, the mechanisms involved are still poorly understood because of the large diversity and complexity of immune responses that can be engaged3. This project aims to study the effects of neuroinflammation on neuronal network activity and synaptic plasticity in mouse hippocampus and to highlight the molecular and cellular inflammatory actors related to cognitive disorders. We are particularly interested in inflammatory processes developed during experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis induced by a specific autoimmune reaction against myelin sheaths of neurons leading to demyelination and motor disorders. We use EAE as a model of CNS chronic neuroinflammatory disease to analyze the possible implication of the NFκB pathway and glial cells in synaptic plasticity dysfunctions and in neuronal network functioning during neuroinflammatory diseases. The chronic course of EAE allows us to dissociate the different inflammatory steps of the disease (relapsing versus remitting stage) and to analyze more precisely their impact on cognition. Only few studies using EAE as an experimental model have analyzed the hippocampal integrity and they show conflicting results4-6. Hippocampal synaptic plasticity was analyzed during the course of EAE by ex vivo electrophysiological recordings (LTP) made on acute hippocampal slices from EAE mice. LTP measurements showed that the level of potentiation is higher at the peak of EAE but progressively decreases during the remission phase when motor symptoms improve. This suggests a time dependent impairment of hippocampal plastic potential during the EAE remission stage. A cognitive impairment was also demonstrated in vivo during this remission stage by evaluating the learning and memory capacities of remitting mice with contextual fear conditioning. Although myelin is the main target of the immune reaction during EAE, no modification of MBP expression was found by western-blotting and immunohistochemistry in mouse hippocampus at any stage of EAE. Besides the lack of demyelination, the structural integrity of the hippocampus was also unaffected during EAE as no atrophy, inflammatory infiltrates or dendritic area modification were found. However, our immunostainings and ELISA experiments revealed a higher glial activation and a production of inflammatory factors like IL1β or TNFα in the hippocampus of EAE mice. The number of both astrocytes and microglial cells follows the disease progression as it enhances at the peak of the disease and then decreases during the remission stage. So, although motor impairments are the main symptoms of EAE, we demonstrated that immune responses and neuroinflammation associated to EAE can also affect cognitive structures like hippocampus and can lead to cognitive impairments during the course of the disease. Taken together, our results suggest that, as no demyelination occurs, activated microglia and astrocytes could be linked to modifications of hippocampal synaptic plasticity during EAE and could therefore be important actors implicated in cognitive disorders related to neuroinflammation. The next step of the project will be to investigate the implication of the NFκB signaling pathway in the hippocampus during EAE thanks to an inducible adenoviral vector system which will allow us first to visualize the hippocampal NFκB expression and then to induce a negative feedback to inhibit its own activity

Proteins synthesized in dendrites can sustain local long-lasting long term potentiation (L-LTP) but cannot be captured by other synapses

editorial reviewedLong-term potentiation (LTP) is a lasting increase in synaptic strength induced by high frequency stimulation (HFS) of the related presynaptic fibers. In the CA1 region of mice hippocampal slices, a strong tetanic stimulation triggers a long-lasting long-term potentiation (L-LTP), which requires protein synthesis for the development of its late phase. It was first believed that all these proteins were synthesized in the soma. However, more recently, it was proved that translation of mRNAs could also take place in dendrites. Hence the first question asked here: is dendritic protein synthesis able to sustain an LTP lasting more than 2-3 hours? Here, L-LTP was elicited in hippocampal slices by delivering 4 trains of HFS to the Schaffer's collaterals while monitoring the resulting excitatory postsynaptic potential field (fEPSP) every 15 min for 8 hrs in the CA1 region. We took advantage of the fact that, in CA1 pyramidal cells, it is possible to sever the dendrites from their somas. So we were able to compare the LTP obtained on isolated dendrites to that observed on intact dendrites. We report that, in CA1 dendrites separated from their cellular bodies, a strong stimulation induces an L-LTP lasting as long as 8 hours and requiring dendritic protein synthesis. In intact slices, the late LTP elicited in one pathway by a strong stimulation can be captured by another pathway activated only by a weak stimulation. The current hypothesis is that a weak stimulation creates a synaptic tag which is able to capture plasticity-related proteins synthesized in the soma. The second question asked: can L-LTP induced in isolated dendrites be transferred to weakly activated synapses? We report that synaptic capture-mediated L-LTP cannot happen in isolated dendrites. Taken together, these results suggest that synaptic capture observed in intact slices is dependent on proteins produced through transcription and/or somatic translation

Development of an experimental model of traumatic brain injury using hippocampal slice cultures.

editorial reviewedThis paper discusses the design and performance of the time measurement technique and of the synchronization systems of the CMS hadron calorimeter. Time measurement performance results are presented from test beam data taken in the years 2004 and 2006. For hadronic showers of energy greater than 100 GeV, the timing resolution is measured to be about 1.2 ns. Time synchronization and out-of-time background rejection results are presented from the Cosmic Run At Four Tesla and LHC beam runs taken in the Autumn of 2008. The inter-channel synchronization is measured to be within 2 ns

Trace amine associate receptor 1 (TAAR1) as a new target for the treatment of cognitive dysfunction in Alzheimer disease

editorial reviewedAlzheimer disease (AD) is the main cause of dementia with approximately 27 million people affected worldwide. Beta-Amyloid peptide (Ab) is elevated in the brains of patients with AD and is believed to be causative in the disease process. Ab can reduce long-term potentiation (LTP), a form of synaptic plasticity that is closely associated with learning and memory [1]. LTP involves postsynaptic phosphorylation and glutamate receptor trafficking, particularly; it has been shown that amyloid can cause reduction of glutamatergic transmission and inhibition of synaptic plasticity via increased endocytosis of NMDA receptors. Trace Amines (TAs) are a family of endogenous compounds with strong structural similarity to the classical monoamine neurotransmitters. The molecular mechanism of the TAs involves binding to a novel G protein-coupled receptor, called TAAR (trace amine-associated receptor). TAAR1 is distributed in the CNS. Recently, it has been shown that selective activation of TAAR1 are able to reverse glutamatergic hypofunction induced by selective NMDA receptor antagonists suggesting that TAAR1 activation may enhance also glutamatergic function. There are several lines of evidence suggesting pro-cognitive action of TAAR1 agonists in various behavioral experimental protocols and there is evidence indicating that TAAR1 can modulate frontal cortex glutamate NMDA receptor- related functions. [2-5]. Objectives: 1. To study in vitro the role of TAAR1 agonists on basal cortical glutamatergic transmission and their beneficial effect on Ab-induced dysfunction. 2. To study, in vivo, the role of TAAR1 in cognitive dysfunction induced by Ab and the beneficial role of TAAR1 agonists on cognition in Alzheimer's mouse models. Methods: In vitro experiments were conducted on primary cortical cultures. Cortices of E17 embryo from TAAR1 and control mice were isolated and incubated for 14 days at 37 °C and 5% CO2. Cells were then stimulated with Ab 1-42 (1 µM, AnaSpec, USA), TAAR1 agonist (RO5256390, Sigma Aldrich, Belgium, 1 µM) or both 1hr at 37°C and NMDA surface expression was assessed using biotinylation assay and Western blots. In vivo studies were performed using 10-weeks mice ICV injected with: Ab 1-42 (3 µl), TAAR1 agonist (3µl) or both and vehicle treated controls. 7 days later, a series of behavioral tests were performed to evaluate the effects of Ab 1-42 and TAAR1 agonist, including Morris Water Maze (MWM), novel object recognition (NOR) and open field. Results: In vitro data showed that, as expected in WT mice, Ab 1-42 significantly decreased NMDA surface (NR1: -35± 2.6%; NR2A: -38± 1.8%; NR2B: -47± 4.2% ) expression while TAAR1 agonist promotes their membrane localization (NR1: +48±4.8%; NR2A: +67±3.5%; NR2B: +52±3.8% p<0.05, Student t test) on cortical cells. Conclusion: Altogether, our results showed that in vitro, TAAR1 agonist displayed the ability of increasing NMDA receptors surface expression, suggesting the possibility of displaying therapeutic effect on cognitive Ab induced impairments. Whether these effects are reproducible in vivo, are currently addressed. References [1] Selkoe DJ. Alzheimer's disease is a synaptic failure. Science 2002; 298(5594):789-91. [2] Guise KG, Shapiro ML. Medial Prefrontal Cortex Reduces Memory Interference by Modifying Hippocampal Encoding. Neuron. 2017 ; 5;94(1):183-192.e8. [3] Flores-Martínez E, Peña-Ortega F. Amyloid b Peptide-Induced Changes in Prefrontal Cortex Activity and Its Response to Hippocampal Input. Int J Pept. 2017; 7386809. [4] Banks PJ, Burroughs AC, Barker GR, Brown JT, Warburton EC, Bashir ZI. Disruption of hippocampal-prefrontal cortex activity by dopamine D2R-dependent LTD of NMDAR transmission. Proc Natl Acad Sci U S A. 2015; 1;112(35):11096-101. [5] Feld M, Krawczyk MC, Sol Fustiñana M, Blake MG, Baratti CM, Romano A, Boccia MM. Decrease of ERK/MAPK overactivation in prefrontal cortex reverses early memory deficit in a mouse model of Alzheimer's disease. J Alzheimers Dis. 2014;40(1):69-82

Dopamine Transporter Knock-out Rats an innovative animal model for dopamine related diseases

editorial reviewedHere, we present a newly developed strain of rats in which the gene encoding the dopamine transporter (DAT) has been disrupted (Dopamine Transporter Knockout rats [DAT-KO rats]). DAT-KO rats display functional hyperdopaminergia accompanied by pronounced spontaneous locomotor hyperactivity. Hyperactivity of DAT-KO rats can be counteracted by amphetamine, methylphenidate, and a few other compounds exerting inhibitory action on dopamine-dependent hyperactivity. DAT-KO rats also demonstrate cognitive deficits in working memory and sensorimotor gating tests, less propensity to develop compulsive behaviors, and strong dysregulation in frontostriatal BDNF function. These observations highlight the key role of DAT in the control of brain dopaminergic transmission. DAT-KO rats could provide a novel translational model for human diseases involving aberrant dopamine functions such as Attention Deficit with Hyperkinetic disorders, Parkinson’s disease and partly bipolar disorders

Muscle-to-brain communication in the context of obesity : impact of physical exercise

editorial reviewedExercise training (ET) has a positive effect on brain health. Although molecular mechanisms underlying ET benefits are still poorly understood, a cross-talk between skeletal muscle and brain has been described. During ET, muscle releases specific myokines among which potential regulators of hippocampal function, like Irisin. This exerkine is a PGC1α-dependant myokine released by cleavage of FNDC5. Also expressed in the brain, FNDC5 contributes to increase the level of brain-derived neurotrophic factor. However, the contribution of muscle-derived Irisin on cognitive function remains controversial, as the influence of obesity or ET modalities. The goal of our study is to determine (i) inter-relationships between FNDC5/Irisin pathway and cognition in function of ET modalities and (ii) whether muscle-to-brain crosstalk is altered in the context of obesity. To this aim, two ET modalities were compared in mice: spontaneous ET (environmental enrichment) and endurance ET (training sessions on a treadmill). Mice were fed either with a Low-Fat (LF) or an High-Fat (HF) diet. ET reduces weight gain and fasting glycaemia in obese mice. Environmental enrichment improves spatial learning and memory (Morris Water Maze test), particularly in obese animals. Irisin plasmatic level is enhanced by a HF diet and endurance ET. In muscles, FNDC5 protein level is also modified by ET and diet. In brain, ET improves BDNF protein level. In conclusion, ET modalities and obesity influence FNDC5/Irisin pathway and cognitive functions in mice. Further studies are necessary to understand the contribution of muscle-derived Irisin to ET effects

Muscle-to-Brain communication in the context of obesity: impact of physical exercise?

editorial reviewedMuscle-to-Brain communication in the context of obesity: impact of physical exercise? A. Delpierre (1), C. Deroux (2), L. Ris (2), A-E. Declèves (3), A. Legrand (1), A. Villers (2) and A. Tassin (1) (1) Lab. of Respiratory Physiology and Rehabilitation, UMONS (2) Lab. of Neurosciences, UMONS (3) Lab. of Metabolic and Molecular Biochemistry, UMONS Exercise training (ET) has a positive effect on brain health. During ET, skeletal muscle releases specific myokines among them potential regulators of hippocampal function, like Irisin, released by cleavage of FNDC5. Also expressed in the brain, FNDC5 contributes to increase the level of brain-derived neurotrophic factor (BDNF). However, the contribution of muscle-derived Irisin on cognitive function remains controversial, as well as the influence of obesity or ET modalities. The goal of our study is to determine (i) inter-relationships between FNDC5/Irisin pathway and cognition depending on ET modalities and (ii) whether muscle-to-brain crosstalk is altered in the context of obesity. Two ET modalities were compared in Low-Fat (LF) and High-Fat (HF) fed mice: volontary (enriched environment) and forced ET (endurant). Irisin plasmatic level is increased by ET, whatever ET modality or diet. As concern FNDC5, volontary ET is associated to an increased protein level in LF but not in HF mouse muscles while forced ET does not modify FNDC5 protein level in muscular or brain tissues. Enrichment in mice improves spatial learning and memory. However, the BDNF protein level is not modified by volontary ET in the cortex and hippocampus. Forced ET does not modify spatial learning and memory and BDNF protein level in the hippocampus. However, BDNF protein level is increased in the brain cortex by endurance- training and surprisingly, by HF diet. In conclusion, ET increases Irisin plasmatic level and enrichment improves cognitive function in mice. FNDC5 protein level depend on training modalities, is tissue-specific and influenced by diet.Etude translationnelle de la communication muscle-cerveau lors d’un reconditionnement musculaire appliqué dans un contexte d’obésité. - Sources privée