Les publications

IF du Neurocentre

985 publications

* equal contribution
Les IF indiqués ont été collectés par le Web of Sciences en Juin 2021

14/07/2021 | Nature   IF 50
Dynamical prefrontal population coding during defensive behaviours.
Jercog D, Winke N, Sung K, Fernandez MM, Francioni C, Rajot D, Courtin J, Chaudun F, Jercog PE, Valerio S, Herry C
doi: 10.1038/s41586-021-03726-6

Coping with threatening situations requires both identifying stimuli that predict danger and selecting adaptive behavioural responses to survive(1). The dorsomedial prefrontal cortex (dmPFC) is a critical structure that is involved in the regulation of threat-related behaviour(2-4). However, it is unclear how threat-predicting stimuli and defensive behaviours are associated within prefrontal networks to successfully drive adaptive responses. Here we used a combination of extracellular recordings, neuronal decoding approaches, pharmacological and optogenetic manipulations to show that, in mice, threat representations and the initiation of avoidance behaviour are dynamically encoded in the overall population activity of dmPFC neurons. Our data indicate that although dmPFC population activity at stimulus onset encodes sustained threat representations driven by the amygdala, it does not predict action outcome. By contrast, transient dmPFC population activity before the initiation of action reliably predicts avoided from non-avoided trials. Accordingly, optogenetic inhibition of prefrontal activity constrained the selection of adaptive defensive responses in a time-dependent manner. These results reveal that the adaptive selection of defensive responses relies on a dynamic process of information linking threats with defensive actions, unfolding within prefrontal networks.

13/07/2021 | Cell Rep   IF 9.4
Probing the polarity of spontaneous perisomatic GABAergic synaptic transmission in the mouse CA3 circuit in vivo.
Dubanet O, Ferreira Gomes Da Silva A, Frick A, Hirase H, Beyeler A, Leinekugel X
doi: 10.1016/j.celrep.2021.109381

The hypothesis that reversed, excitatory GABA may be involved in various brain pathologies, including epileptogenesis, is appealing but controversial because of the technical difficulty of probing endogenous GABAergic synaptic function in vivo. We overcome this challenge by non-invasive extracellular recording of neuronal firing responses to optogenetically evoked and spontaneously occurring inhibitory perisomatic GABAergic field potentials, generated by individual parvalbumin interneurons on their target pyramidal cells. Our direct probing of GABAergic transmission suggests a rather anecdotal participation of excitatory GABA in two specific models of epileptogenesis in the mouse CA3 circuit in vivo, even though this does not preclude its expression in other brain areas or pathological conditions. Our approach allows the detection of distinct alterations of inhibition during spontaneous activity in vivo, with high sensitivity. It represents a promising tool for the investigation of excitatory GABA in different pathological conditions that may affect the hippocampal circuit.

06/07/2021 | Nat Commun   IF 14.9
Central amygdala micro-circuits mediate fear extinction.
Whittle N, Fadok J, MacPherson KP, Nguyen R, Botta P, Wolff SBE, Müller C, Herry C, Tovote P, Holmes A, Singewald N, Lüthi A, Ciocchi S
doi: 10.1038/s41467-021-24068-x

Fear extinction is an adaptive process whereby defensive responses are attenuated following repeated experience of prior fear-related stimuli without harm. The formation of extinction memories involves interactions between various corticolimbic structures, resulting in reduced central amygdala (CEA) output. Recent studies show, however, the CEA is not merely an output relay of fear responses but contains multiple neuronal subpopulations that interact to calibrate levels of fear responding. Here, by integrating behavioural, in vivo electrophysiological, anatomical and optogenetic approaches in mice we demonstrate that fear extinction produces reversible, stimulus- and context-specific changes in neuronal responses to conditioned stimuli in functionally and genetically defined cell types in the lateral (CEl) and medial (CEm) CEA. Moreover, we show these alterations are absent when extinction is deficient and that selective silencing of protein kinase C delta-expressing (PKCδ) CEl neurons impairs fear extinction. Our findings identify CEA inhibitory microcircuits that act as critical elements within the brain networks mediating fear extinction.

30/06/2021 | Neuron   IF 17.2
Nicotine inhibits the VTA-to-amygdala dopamine pathway to promote anxiety.
Nguyen C, Mondoloni S, Le Borgne T, Centeno I, Come M, Jehl J, Solie C, Reynolds LM, Durand-de Cuttoli R, Tolu S, Valverde S, Didienne S, Hannesse B, Fiancette JF, Pons S, Maskos U, Deroche-Gamonet V, Dalkara D, Hardelin JP, Mourot A, Marti F, Faure P
doi: 10.1016/j.neuron.2021.06.013

Nicotine stimulates dopamine (DA) neurons of the ventral tegmental area (VTA) to establish and maintain reinforcement. Nicotine also induces anxiety through an as yet unknown circuitry. We found that nicotine injection drives opposite functional responses of two distinct populations of VTA DA neurons with anatomically segregated projections: it activates neurons that project to the nucleus accumbens (NAc), whereas it inhibits neurons that project to the amygdala nuclei (Amg). We further show that nicotine mediates anxiety-like behavior by acting on beta2-subunit-containing nicotinic acetylcholine receptors of the VTA. Finally, using optogenetics, we bidirectionally manipulate the VTA-NAc and VTA-Amg pathways to dissociate their contributions to anxiety-like behavior. We show that inhibition of VTA-Amg DA neurons mediates anxiety-like behavior, while their activation prevents the anxiogenic effects of nicotine. These distinct subpopulations of VTA DA neurons with opposite responses to nicotine may differentially drive the anxiogenic and the reinforcing effects of nicotine.

19/06/2021 | Neuropharmacology   IF 5.3
CB1R-dependent regulation of astrocyte physiology and astrocyte-neuron interactions.
Covelo A, Eraso-Pichot A, Fernández-Moncada I, Serrat R, Marsicano G
doi: 10.1016/j.neuropharm.2021.108678

The endocannabinoid system (ECS) is involved in a variety of brain functions, mainly through the activation of the type-1 cannabinoid receptors (CB1R). CB1R are highly expressed throughout the brain at different structural, cellular and subcellular locations and its activity and expression levels have a direct impact in synaptic activity and behavior. In the last few decades, astrocytes have arisen as active players of brain physiology through their participation in the tripartite synapse and through their metabolic interaction with neurons. Here, we discuss some of the mechanisms by which astroglial CB1R at different subcellular locations, regulate astrocyte calcium signals and have an impact on gliotransmission and metabolic regulation. In addition, we discuss evidence pointing at astrocytes as potential important sources of endocannabinoid synthesis and release. Thus, we summarize recent findings that add further complexity and establish that the ECS is a fundamental effector of astrocyte functions in the brain.

Translational research on post-traumatic stress disorder (PTSD) has produced limited improvements in clinical practice. Fear conditioning (FC) is one of the dominant animal models of PTSD. In fact, FC is used in many different ways to model PTSD. The variety of FC-based models is ill defined, creating confusion and conceptual vagueness, which in turn impedes translation into the clinic. This article takes a historical and conceptual approach to provide a comprehensive picture of current research and help reorient the research focus. This work historically reviews the variety of models that have emerged from the initial association of PTSD with FC, highlighting conceptual pitfalls that have limited the translation of animal research into clinical advances. We then provide some guidance on how future translational research could benefit from conceptual and technological improvements to translate basic findings in patients. This objective will require transdisciplinary approaches and should involve physicians, engineers, philosophers, and neuroscientists.

Hippocampal adult neurogenesis has been associated to many cognitive, emotional, and behavioral functions and dysfunctions, and its status as a selected effect or an 'appendix of the brain' has been debated. In this review, we propose to understand hippocampal neurogenesis as the process underlying the 'Baldwin effect', a particular situation in evolution where fitness does not rely on the natural selection of genetic traits, but on 'ontogenetic adaptation' to a changing environment. This supports the view that a strong distinction between developmental and adult hippocampal neurogenesis is made. We propose that their functions are the constitution and the lifelong adaptation, respectively, of a basic repertoire of cognitive and emotional behaviors. This lifelong adaptation occurs through new forms of binding, i.e., association or dissociation of more basic elements. This distinction further suggests that a difference is made between developmental vulnerability (or resilience), stemming from dysfunctional (or highly functional) developmental hippocampal neurogenesis, and adult vulnerability (or resilience), stemming from dysfunctional (or highly functional) adult hippocampal neurogenesis. According to this hypothesis, developmental and adult vulnerability are distinct risk factors for various mental disorders in adults. This framework suggests new avenues for research on hippocampal neurogenesis and its implication in mental disorders.

10/05/2021 | Nat Commun   IF 14.9
Breathing-driven prefrontal oscillations regulate maintenance of conditioned-fear evoked freezing independently of initiation.
Bagur S, Lefort JM, Lacroix MM, de Lavilléon G, Herry C, Chouvaeff M, Billand C, Geoffroy H, Benchenane K
doi: 10.1038/s41467-021-22798-6

Brain-body interactions are thought to be essential in emotions but their physiological basis remains poorly understood. In mice, regular 4 Hz breathing appears during freezing after cue-fear conditioning. Here we show that the olfactory bulb (OB) transmits this rhythm to the dorsomedial prefrontal cortex (dmPFC) where it organizes neural activity. Reduction of the respiratory-related 4 Hz oscillation, via bulbectomy or optogenetic perturbation of the OB, reduces freezing. Behavioural modelling shows that this is due to a specific reduction in freezing maintenance without impacting its initiation, thus dissociating these two phenomena. dmPFC LFP and firing patterns support the region's specific function in freezing maintenance. In particular, population analysis reveals that network activity tracks 4 Hz power dynamics during freezing and reaches a stable state at 4 Hz peak that lasts until freezing termination. These results provide a potential mechanism and a functional role for bodily feedback in emotions and therefore shed light on the historical James-Cannon debate.

05/2021 | nat metab   IF 13.5
Central anorexigenic actions of bile acids are mediated by TGR5.
Perino A, Velázquez-Villegas LA, Bresciani N, Sun Y, Huang Q, Fénelon VS, Castellanos-Jankiewicz A, Zizzari P, Bruschetta G, Jin S, Baleisyte A, Gioiello A, Pellicciari R, Ivanisevic J, Schneider BL, Diano S, Cota D, Schoonjans K
doi: 10.1038/s42255-021-00398-4

Bile acids (BAs) are signalling molecules that mediate various cellular responses in both physiological and pathological processes. Several studies report that BAs can be detected in the brain(1), yet their physiological role in the central nervous system is still largely unknown. Here we show that postprandial BAs can reach the brain and activate a negative-feedback loop controlling satiety in response to physiological feeding via TGR5, a G-protein-coupled receptor activated by multiple conjugated and unconjugated BAs(2) and an established regulator of peripheral metabolism(3-8). Notably, peripheral or central administration of a BA mix or a TGR5-specific BA mimetic (INT-777) exerted an anorexigenic effect in wild-type mice, while whole-body, neuron-specific or agouti-related peptide neuronal TGR5 deletion caused a significant increase in food intake. Accordingly, orexigenic peptide expression and secretion were reduced after short-term TGR5 activation. In vitro studies demonstrated that activation of the Rho-ROCK-actin-remodelling pathway decreases orexigenic agouti-related peptide/neuropeptide Y (AgRP/NPY) release in a TGR5-dependent manner. Taken together, these data identify a signalling cascade by which BAs exert acute effects at the transition between fasting and feeding and prime the switch towards satiety, unveiling a previously unrecognized role of physiological feedback mediated by BAs in the central nervous system.

27/04/2021 | Sci Rep   IF 4.4
Early loss of Scribble affects cortical development, interhemispheric connectivity and psychomotor activity.
Ezan J, Moreau MM, Mamo TM, Shimbo M, Decroo M, Richter M, Peyroutou R, Rachel R, Tissir F, de Anda FC, Sans N, Montcouquiol M
doi: 10.1038/s41598-021-88147-1

Neurodevelopmental disorders arise from combined defects in processes including cell proliferation, differentiation, migration and commissure formation. The evolutionarily conserved tumor-suppressor protein Scribble (Scrib) serves as a nexus to transduce signals for the establishment of apicobasal and planar cell polarity during these processes. Human SCRIB gene mutations are associated with neural tube defects and this gene is located in the minimal critical region deleted in the rare Verheij syndrome. In this study, we generated brain-specific conditional cKO mouse mutants and assessed the impact of the Scrib deletion on brain morphogenesis and behavior. We showed that embryonic deletion of Scrib in the telencephalon leads to cortical thickness reduction (microcephaly) and partial corpus callosum and hippocampal commissure agenesis. We correlated these phenotypes with a disruption in various developmental mechanisms of corticogenesis including neurogenesis, neuronal migration and axonal connectivity. Finally, we show that Scrib cKO mice have psychomotor deficits such as locomotor activity impairment and memory alterations. Altogether, our results show that Scrib is essential for early brain development due to its role in several developmental cellular mechanisms that could underlie some of the deficits observed in complex neurodevelopmental pathologies.

19/04/2021 | Cell Metab   IF 27.3
Hypothalamic bile acid-TGR5 signaling protects from obesity.
Castellanos-Jankiewicz A, Guzman-Quevedo O, Fenelon VS, Zizzari P, Quarta C, Bellocchio L, Tailleux A, Charton J, Fernandois D, Henricsson M, Piveteau C, Simon V, Allard C, Quemener S, Guinot V, Hennuyer N, Perino A, Duveau A, Maitre M, Leste-Lasserre T, Clark S, Dupuy N, Cannich A, Gonzales D, Deprez B, Mithieux G, Dombrowicz D, Backhed F, Prevot V, Marsicano G, Staels B, Schoonjans K, Cota D
doi: 10.1016/j.cmet.2021.04.009

Bile acids (BAs) improve metabolism and exert anti-obesity effects through the activation of the Takeda G protein-coupled receptor 5 (TGR5) in peripheral tissues. TGR5 is also found in the brain hypothalamus, but whether hypothalamic BA signaling is implicated in body weight control and obesity pathophysiology remains unknown. Here we show that hypothalamic BA content is reduced in diet-induced obese mice. Central administration of BAs or a specific TGR5 agonist in these animals decreases body weight and fat mass by activating the sympathetic nervous system, thereby promoting negative energy balance. Conversely, genetic downregulation of hypothalamic TGR5 expression in the mediobasal hypothalamus favors the development of obesity and worsens established obesity by blunting sympathetic activity. Lastly, hypothalamic TGR5 signaling is required for the anti-obesity action of dietary BA supplementation. Together, these findings identify hypothalamic TGR5 signaling as a key mediator of a top-down neural mechanism that counteracts diet-induced obesity.

27/03/2021 | bull math biol   IF 1.8
Patient-Specific Modelling of Blood Coagulation.
Ratto N, Bouchnita A, Chelle P, Marion M, Panteleev M, Nechipurenko D, Tardy-Poncet B, Volpert V
doi: 10.1007/s11538-021-00890-8

Blood coagulation represents one of the most studied processes in biomedical modelling. However, clinical applications of this modelling remain limited because of the complexity of this process and because of large inter-patient variation of the concentrations of blood factors, kinetic constants and physiological conditions. Determination of some of these patients-specific parameters is experimentally possible, but it would be related to excessive time and material costs impossible in clinical practice. We propose in this work a methodological approach to patient-specific modelling of blood coagulation. It begins with conventional thrombin generation tests allowing the determination of parameters of a reduced kinetic model. Next, this model is used to study spatial distributions of blood factors and blood coagulation in flow, and to evaluate the results of medical treatment of blood coagulation disorders.

23/03/2021 | hepatology   IF 17.4
Proteomic profiling of hepatocellular adenomas paves the way to new diagnostic and prognostic approaches.
Dourthe C, Julien C, Di Tommaso S, Dupuy JW, Dugot-Senant N, Brochard A, Le Bail B, Blanc JF, Chiche L, Balabaud C, Bioulac-Sage P, Saltel F, Raymond AA
doi: 10.1002/hep.31826

BACKGROUND AND AIMS: Through an exploratory proteomic approach based on typical hepatocellular adenomas (HCA), we previously identified a new diagnostic biomarker for a distinctive subtype of HCA with high risk of bleeding, already validated on a multicenter cohort. We hypothesized that the whole protein expression deregulation profile could deliver much more informative data for tumors characterization. Therefore, we pursued our analysis with the characterization of HCAs proteomic profiles, evaluating their correspondence with the established genotype/phenotype classification and assessing whether they could provide added diagnosis and prognosis values. APPROACH & RESULTS: From a collection of 260 cases, we selected 52 typical cases of all different subgroups on which we built the first HCA proteomics database. Combining laser microdissection and mass spectrometry based proteomic analysis, we compared the relative protein abundances between tumoral (T) and non-tumoral (NT) liver tissues from each patient and we defined specific proteomic profile of each HCA sub-groups. Next, we built a matching algorithm comparing proteomic profile extracted from a patient with our reference HCA database. Proteomic profiles allowed HCA classification and made diagnosis possible, even for complexes cases with immunohistological or genomic analysis that did not lead to a formal conclusion. Despite a well-established pathomolecular classification, clinical practices have not substantially changed and HCA management link to the assessment of the malignant transformation risk remains delicate for many surgeons. That's why we also identified and validated a proteomic profile that directly evaluate malignant transformation risk regardless of HCA subtype. CONCLUSIONS: This pioneering work proposes a proteomic-based machine learning tool, operational on fixed biopsies, that can improve diagnosis and prognosis and therefore patient management for HCA.

19/03/2021 | Nat Commun   IF 14.9
Adult-born neurons immature during learning are necessary for remote memory reconsolidation in rats.
Lods M, Pacary E, Mazier W, Farrugia F, Mortessagne P, Masachs N, Charrier V, Massa F, Cota D, Ferreira G, Abrous DN, Tronel S
doi: 10.1038/s41467-021-22069-4

Memory reconsolidation, the process by which memories are again stabilized after being reactivated, has strengthened the idea that memory stabilization is a highly plastic process. To date, the molecular and cellular bases of reconsolidation have been extensively investigated particularly within the hippocampus. However, the role of adult neurogenesis in memory reconsolidation is unclear. Here, we combined functional imaging, retroviral and chemogenetic approaches in rats to tag and manipulate different populations of rat adult-born neurons. We find that both mature and immature adult-born neurons are activated by remote memory retrieval. However, only specific silencing of the adult-born neurons immature during learning impairs remote memory retrieval-induced reconsolidation. Hence, our findings show that adult-born neurons immature during learning are required for the maintenance and update of remote memory reconsolidation.

19/03/2021 | Neuron   IF 17.2
Subcellular specificity of cannabinoid effects in striatonigral circuits.
Soria-Gomez E, Pagano Zottola AC, Mariani Y, Desprez T, Barresi M, Bonilla-Del Rio I, Muguruza C, Le Bon-Jego M, Julio-Kalajzic F, Flynn R, Terral G, Fernandez-Moncada I, Robin LM, Oliveira da Cruz JF, Corinti S, Amer YO, Goncalves J, Varilh M, Cannich A, Redon B, Zhao Z, Leste-Lasserre T, Vincent P, Tolentino-Cortes T, Busquets-Garcia A, Puente N, Bains JS, Hebert-Chatelain E, Barreda-Gomez G, Chaouloff F, Lohman AW, Callado LF, Grandes P, Baufreton J, Marsicano G, Bellocchio L
doi: 10.1016/j.neuron.2021.03.007

Recent advances in neuroscience have positioned brain circuits as key units in controlling behavior, implying that their positive or negative modulation necessarily leads to specific behavioral outcomes. However, emerging evidence suggests that the activation or inhibition of specific brain circuits can actually produce multimodal behavioral outcomes. This study shows that activation of a receptor at different subcellular locations in the same neuronal circuit can determine distinct behaviors. Pharmacological activation of type 1 cannabinoid (CB1) receptors in the striatonigral circuit elicits both antinociception and catalepsy in mice. The decrease in nociception depends on the activation of plasma membrane-residing CB1 receptors (pmCB1), leading to the inhibition of cytosolic PKA activity and substance P release. By contrast, mitochondrial-associated CB1 receptors (mtCB1) located at the same terminals mediate cannabinoid-induced catalepsy through the decrease in intra-mitochondrial PKA-dependent cellular respiration and synaptic transmission. Thus, subcellular-specific CB1 receptor signaling within striatonigral circuits determines multimodal control of behavior.

18/03/2021 | Nat Neurosci   IF 24.9
Spinal astroglial cannabinoid receptors control pathological tremor.
Carlsen EMM, Falk S, Skupio U, Robin L, Zottola ACP, Marsicano G, Perrier JF
doi: 10.1038/s41593-021-00818-4

Cannabinoids reduce tremor associated with motor disorders induced by injuries and neurodegenerative disease. Here we show that this effect is mediated by cannabinoid receptors on astrocytes in the ventral horn of the spinal cord, where alternating limb movements are initiated. We first demonstrate that tremor is reduced in a mouse model of essential tremor after intrathecal injection of the cannabinoid analog WIN55,212-2. We investigate the underlying mechanism using electrophysiological recordings in spinal cord slices and show that endocannabinoids released from depolarized interneurons activate astrocytic cannabinoid receptors, causing an increase in intracellular Ca(2+), subsequent release of purines and inhibition of excitatory neurotransmission. Finally, we show that the anti-tremor action of WIN55,212-2 in the spinal cords of mice is suppressed after knocking out CB1 receptors in astrocytes. Our data suggest that cannabinoids reduce tremor via their action on spinal astrocytes.

15/03/2021 | Transl Psychiatry   IF 6.2
Inhibition of mTOR signaling by genetic removal of p70 S6 kinase 1 increases anxiety-like behavior in mice.
Koehl M, Ladeveze E, Catania C, Cota D, Abrous DN
doi: 10.1038/s41398-020-01187-5

The mechanistic target of rapamycin (mTOR) is a ubiquitously expressed kinase that acts through two complexes, mTORC1 and mTORC2, to regulate protein homeostasis, as well as long lasting forms of synaptic and behavioral plasticity. Alteration of the mTOR pathway is classically involved in neurodegenerative disorders, and it has been linked to dysregulation of cognitive functions and affective states. However, information concerning the specific involvement of the p70 S6 kinase 1 (S6K1), a downstream target of the mTORC1 pathway, in learning and memory processes and in the regulation of affective states remains scant. To fill this gap, we exposed adult male mice lacking S6K1 to a battery of behavioral tests aimed at measuring their learning and memory capabilities by evaluating reference memory and flexibility with the Morris water maze, and associative memory using the contextual fear conditioning task. We also studied their anxiety-like and depression-like behaviors by, respectively, performing elevated plus maze, open field, light-dark emergence tests, and sucrose preference and forced swim tests. We found that deleting S6K1 leads to a robust anxious phenotype concomitant with associative learning deficits; these symptoms are associated with a reduction of adult neurogenesis and neuronal atrophy in the hippocampus. Collectively, these results provide grounds for the understanding of anxiety reports after treatments with mTOR inhibitors and will be critical for developing novel compounds targeting anxiety.

03/2021 | Nat Neurosci   IF 24.9
Reactive astrocyte nomenclature, definitions, and future directions.
Escartin C, Galea E, Lakatos A, O'Callaghan JP, Petzold GC, Serrano-Pozo A, Steinhauser C, Volterra A, Carmignoto G, Agarwal A, Allen NJ, Araque A, Barbeito L, Barzilai A, Bergles DE, Bonvento G, Butt AM, Chen WT, Cohen-Salmon M, Cunningham C, Deneen B, De Strooper B, Diaz-Castro B, Farina C, Freeman M, Gallo V, Goldman JE, Goldman SA, Gotz M, Gutierrez A, Haydon PG, Heiland DH, Hol EM, Holt MG, Iino M, Kastanenka KV, Kettenmann H, Khakh BS, Koizumi S, Lee CJ, Liddelow SA, MacVicar BA, Magistretti P, Messing A, Mishra A, Molofsky AV, Murai KK, Norris CM, Okada S, Oliet SHR, Oliveira JF, Panatier A, Parpura V, Pekna M, Pekny M, Pellerin L, Perea G, Perez-Nievas BG, Pfrieger FW, Poskanzer KE, Quintana FJ, Ransohoff RM, Riquelme-Perez M, Robel S, Rose CR, Rothstein JD, Rouach N, Rowitch DH, Semyanov A, Sirko S, Sontheimer H, Swanson RA, Vitorica J, Wanner IB, Wood LB, Wu J, Zheng B, Zimmer ER, Zorec R, Sofroniew MV, Verkhratsky A
doi: 10.1038/s41593-020-00783-4

Reactive astrocytes are astrocytes undergoing morphological, molecular, and functional remodeling in response to injury, disease, or infection of the CNS. Although this remodeling was first described over a century ago, uncertainties and controversies remain regarding the contribution of reactive astrocytes to CNS diseases, repair, and aging. It is also unclear whether fixed categories of reactive astrocytes exist and, if so, how to identify them. We point out the shortcomings of binary divisions of reactive astrocytes into good-vs-bad, neurotoxic-vs-neuroprotective or A1-vs-A2. We advocate, instead, that research on reactive astrocytes include assessment of multiple molecular and functional parameters-preferably in vivo-plus multivariate statistics and determination of impact on pathological hallmarks in relevant models. These guidelines may spur the discovery of astrocyte-based biomarkers as well as astrocyte-targeting therapies that abrogate detrimental actions of reactive astrocytes, potentiate their neuro- and glioprotective actions, and restore or augment their homeostatic, modulatory, and defensive functions.

25/02/2021 | nat metab   IF 13.5
POMC neuronal heterogeneity in energy balance and beyond: an integrated view.
Quarta C, Claret M, Zeltser LM, Williams KW, Yeo GSH, Tschop MH, Diano S, Bruning JC, Cota D
doi: 10.1038/s42255-021-00345-3

Hypothalamic AgRP and POMC neurons are conventionally viewed as the yin and yang of the body's energy status, since they act in an opposite manner to modulate appetite and systemic energy metabolism. However, although AgRP neurons' functions are comparatively well understood, a unifying theory of how POMC neuronal cells operate has remained elusive, probably due to their high level of heterogeneity, which suggests that their physiological roles might be more complex than initially thought. In this Perspective, we propose a conceptual framework that integrates POMC neuronal heterogeneity with appetite regulation, whole-body metabolic physiology and the development of obesity. We highlight emerging evidence indicating that POMC neurons respond to distinct combinations of interoceptive signals and food-related cues to fine-tune divergent metabolic pathways and behaviours necessary for survival. The new framework we propose reflects the high degree of developmental plasticity of this neuronal population and may enable progress towards understanding of both the aetiology and treatment of metabolic disorders.

28/01/2021 | Mol Psychiatry   IF 16
PAI-1 protein is a key molecular effector in the transition from normal to PTSD-like fear memory.
Bouarab C*, Lacarriere V*, Vallee M, Leroux A, Guette C, Mennesson M, Marighetto A, Desmedt A*, Piazza PV*, Revest JM*
doi: 10.1038/s41380-021-01024-1

Moderate stress increases memory and facilitates adaptation. In contrast, intense stress can induce pathological memories as observed in post-traumatic stress disorders (PTSD). A shift in the balance between the expression of tPA and PAI-1 proteins is responsible for this transition. In conditions of moderate stress, glucocorticoid hormones increase the expression of the tPA protein in the hippocampal brain region which by triggering the Erk1/2(MAPK) signaling cascade strengthens memory. When stress is particularly intense, very high levels of glucocorticoid hormones then increase the production of PAI-1 protein, which by blocking the activity of tPA induces PTSD-like memories. PAI-1 levels after trauma could be a predictive biomarker of the subsequent appearance of PTSD and pharmacological inhibition of PAI-1 activity a new therapeutic approach to this debilitating condition.

11/01/2021 | Metabolism   IF 8.7
Elafibranor improves diet-induced nonalcoholic steatohepatitis associated with heart failure with preserved ejection fraction in Golden Syrian hamsters.
Briand F, Maupoint J, Brousseau E, Breyner N, Bouchet M, Costard C, Leste-Lasserre T, Petitjean M, Chen L, Chabrat A, Richard V, Burcelin R, Dubroca C, Sulpice T
doi: 10.1016/j.metabol.2021.154707

BACKGROUND: Cardiovascular disease is the leading cause of deaths in nonalcoholic steatohepatitis (NASH) patients. Mouse models, while widely used for drug development, do not fully replicate human NASH nor integrate the associated cardiac dysfunction, i.e. heart failure with preserved ejection fraction (HFpEF). To overcome these limitations, we established a nutritional hamster model developing both NASH and HFpEF. We then evaluated the effects of the dual peroxisome proliferator activated receptor alpha/delta agonist elafibranor developed for the treatment of NASH patients. METHODS: Male Golden Syrian hamsters were fed for 10 to 20weeks with a free choice diet, which presents hamsters with a choice between control chow diet with normal drinking water or a high fat/high cholesterol diet with 10% fructose enriched drinking water. Biochemistry, histology and echocardiography analysis were performed to characterize NASH and HFpEF. Once the model was validated, elafibranor was evaluated at 15mg/kg/day orally QD for 5weeks. RESULTS: Hamsters fed a free choice diet for up to 20weeks developed NASH, including hepatocyte ballooning (as confirmed with cytokeratin-18 immunostaining), bridging fibrosis, and a severe diastolic dysfunction with restrictive profile, but preserved ejection fraction. Elafibranor resolved NASH, with significant reduction in ballooning and fibrosis scores, and improved diastolic dysfunction with significant reduction in E/A and E/E' ratios. CONCLUSION: Our data demonstrate that the free choice diet induced NASH hamster model replicates the human phenotype and will be useful for validating novel drug candidates for the treatment of NASH and associated HFpEF.

2021 | Prog Brain Res   IF 2.5
Multiple facets of serotonergic modulation.
Beyeler A, Ju A, Chagraoui A, Cuvelle L, Teixeira M, Di Giovanni G, De Deurwaerdere P
doi: 10.1016/bs.pbr.2021.02.002

The serotonergic system of the central nervous system (CNS) has been implicated in a broad range of physiological functions and behaviors, such as cognition, mood, social interaction, sexual behavior, feeding behavior, sleep-wake cycle and thermoregulation. Serotonin (5-hydroxytryptamine, 5-HT) establishes a plethora of interactions with neurochemical systems in the CNS via its numerous 5-HT receptors and autoreceptors. The facets of this control are multiple if we consider the molecular actors playing a role in the autoregulation of 5-HT neuron activity including the 5-HT1A, 5-HT1B, 5-HT1D, 5-HT2B, 5-HT7 receptors as well as the serotonin transporter. Moreover, extrinsic loops involving other neurotransmitters giving the other 5-HT receptors the possibility to impact 5-HT neuron activity. Grasping the complexity of these interactions is essential for the development of a variety of therapeutic strategies for cognitive defects and mood disorders. Presently we can illustrate the plurality of the mechanisms and only conceive that these 5-HT controls are likely not uniform in terms of regional and neuronal distribution. Our understanding of the specific expression patterns of these receptors on specific circuits and neuronal populations are progressing and will expand our comprehension of the function and interaction of these receptors with other chemical systems. Thus, the development of new approaches profiling the expression of 5-HT receptors and autoreceptors should reveal additional facets of the 5-HT controls of neurochemical systems in the CNS.

03/11/2020 | Diabetes   IF 7.7
CB1 and GLP-1 Receptors Cross-Talk Provides New Therapies for Obesity.
Zizzari P, He R, Falk S, Bellocchio L, Allard C, Clark S, Lest, Quarta C
doi: 10.2337/db20-0162

GLP-1 receptor (GLP-1R) agonists effectively improve glycemia and body weight in patients with type 2 diabetes and obesity, but have limited weight-lowering efficacy and minimal insulin sensitizing action. In preclinical models, peripherally-restricted cannabinoid-1 receptor (CB1R) inhibitors, which are devoid of the neuropsychiatric side-effects observed with brain-penetrant CB1R blockers, ameliorate obesity and its multiple metabolic complications. Using mouse models with genetic loss of CB1R or GLP-1R, we demonstrate that these two metabolic receptors modulate food intake and body weight via reciprocal functional interactions. In diet-induced obese mice, the co-administration of a peripheral CB1R inhibitor with long-acting GLP-1R agonists achieves greater reduction in body weight and fat mass than monotherapies, by promoting negative energy balance. This co-treatment also results in larger improvements in systemic and hepatic insulin action, systemic dyslipidemia, and reduction of hepatic steatosis. Thus, peripheral CB1R blockade may allow safely potentiating the anti-obesity and anti-diabetic effects of currently available GLP-1R agonists.

05/10/2020 | Addict Biol   IF 4.1
Exercise craving potentiates excitatory inputs to ventral tegmental area dopaminergic neurons.
Medrano MC, Hurel I, Mesguich E, Redon B, Stevens C, Georges F, Melis M, Marsicano G, Chaouloff F
doi: 10.1111/adb.12967

Physical exercise, which can be addictogenic on its own, is considered a therapeutic alternative for drug craving. Exercise might thus share with drugs the ability to strengthen excitatory synapses onto ventral tegmental area (VTA) dopaminergic neurones, as assessed by the ratio of AMPA receptor (AMPAR)-mediated excitatory postsynaptic currents (EPSCs) to NMDA receptor (NMDAR)-mediated EPSCs. As did acute cocaine, amphetamine, or Delta(9) -tetrahydrocannabinol (THC) pretreatments, an acute 1-h wheel-running session increased the AMPAR/NMDAR ratio in VTA dopaminergic neurones. To dissect the respective influences of wheel-running seeking and performance, mice went through an operant protocol wherein wheel-running was conditioned by nose poking under fixed ratio schedules of reinforcement. Conditioned wheel-running increased the AMPAR/NMDAR ratio to a higher extent than free wheel-running, doing so although running performance was lower in the former paradigm than in the latter. Thus, the cue-reward association, rather than reward consumption, played a major role in this increase. The AMPAR/NMDAR ratio returned to baseline levels in mice that had extinguished the cued-running motivated task, but it increased after a cue-induced reinstatement session. The amplitude of this increase correlated with the intensity of exercise craving, as assessed by individual nose poke scores. Finally, cue-induced reinstatement of running seeking proved insensitive to acute cocaine or THC pretreatments. Our study reveals for the first time that the drive for exercise bears synaptic influences on VTA dopaminergic neurones which are reminiscent of drug actions. Whether these influences play a role in the therapeutic effects of exercise in human drug craving remains to be established.

03/10/2020 | Aging Cell   IF 7.2
Age-related impairment of declarative memory: linking memorization of temporal associations to GluN2B redistribution in dorsal CA1.
Al Abed AS, Sellami A, Potier M, Ducourneau EG, Gerbeaud-Lassau P, Brayda-Bruno L, Lamothe V, Sans N, Desmedt A, Vanhoutte P, Bennetau-Pelissero C, Trifilieff P, Marighetto A
doi: 10.1111/acel.13243

GluN2B subunits of NMDA receptors have been proposed as a target for treating age-related memory decline. They are indeed considered as crucial for hippocampal synaptic plasticity and hippocampus-dependent memory formation, which are both altered in aging. Because a synaptic enrichment in GluN2B is associated with hippocampal LTP in vitro, a similar mechanism is expected to occur during memory formation. We show instead that a reduction of GluN2B synaptic localization induced by a single-session learning in dorsal CA1 apical dendrites is predictive of efficient memorization of a temporal association. Furthermore, synaptic accumulation of GluN2B, rather than insufficient synaptic localization of these subunits, is causally involved in the age-related impairment of memory. These challenging data identify extra-synaptic redistribution of GluN2B-containing NMDAR induced by learning as a molecular signature of memory formation and indicate that modulating GluN2B synaptic localization might represent a useful therapeutic strategy in cognitive aging.

30/09/2020 | Curr Biol   IF 9.6
A Novel Cortical Mechanism for Top-Down Control of Water Intake.
Zhao Z, Soria-Gomez E, Varilh M, Covelo A, Julio-Kalajzic F, Cannich A, Castiglione A, Vanhoutte L, Duveau A, Zizzari P, Beyeler A, Cota D, Bellocchio L, Busquets-Garcia A, Marsicano G
doi: 10.1016/j.cub.2020.09.011

Water intake is crucial for maintaining body fluid homeostasis and animals' survival [1-4]. In the brain, complex processes trigger thirst and drinking behavior [1-5]. The anterior wall of the third ventricle formed by the subfornical organ (SFO), the median preoptic nucleus, and the organum vasculosum of the lamina terminalis (OVLT) constitute the primary structures sensing thirst signals and modulating water intake [6-10]. These subcortical regions are connected with the neocortex [11]. In particular, insular and anterior cingulate cortices (IC and ACC, respectively) have been shown to receive indirect innervations from the SFO and OVLT in rats [11] and to be involved in the control of water intake [12-15]. Type-1 cannabinoid receptors (CB1) modulate consummatory behaviors, such as feeding [16-26]. However, the role of CB1 receptors in the control of water intake is still a matter of debate [27-31]. Here, we show that endogenous activation of CB1 in cortical glutamatergic neurons of the ACC promotes water intake. Notably, presynaptic CB1 receptors of ACC glutamatergic neurons are abundantly located in the basolateral amygdala (BLA), a key area in the regulation of water intake. The selective expression of CB1 receptors in the ACC-to-BLA-projecting neurons is sufficient to stimulate drinking behavior. Moreover, chemogenetic stimulation of these projecting neurons suppresses drinking behavior, further supporting the role of this neuronal population in the control of water intake. Altogether, these data reveal a novel cortico-amygdalar mechanism involved in the regulation of drinking behavior.

26/09/2020 | autophagy   IF 9.8
Cannabinoid-induced motor dysfunction via autophagy inhibition.
Blazquez C, Ruiz-Calvo A, Bajo-Graneras R, Baufreton JM, Resel E, Varilh M, Pagano Zottola AC, Mariani Y, Cannich A, Rodriguez-Navarro JA, Marsicano G, Galve-Roperh I, Bellocchio L, Guzman M
doi: 10.1080/15548627.2020.1827560

The recreational and medical use of cannabis is largely increasing worldwide. Cannabis use, however, can cause adverse side effects, so conducting innovative studies aimed to understand and potentially reduce cannabis-evoked harms is important. Previous research conducted on cultured neural cells had supported that CNR1/CB1R (cannabinoid receptor 1), the main molecular target of cannabis, affects macroautophagy/autophagy. However, it was not known whether CNR1 controls autophagy in the brain in vivo, and, eventually, what the functional consequences of a potential CNR1-autophagy connection could be. We have now found that Delta(9)-tetrahydrocannabinol (THC), the major intoxicating constituent of cannabis, impairs autophagy in the mouse striatum. Administration of autophagy activators (specifically, the rapalog temsirolimus and the disaccharide trehalose) rescues THC-induced autophagy inhibition and motor dyscoordination. The combination of various genetic strategies in vivo supports the idea that CNR1 molecules located on neurons belonging to the direct (striatonigral) pathway are required for the autophagy- and motor-impairing activity of THC. By identifying autophagy as a mechanistic link between THC and motor performance, our findings may open a new conceptual view on how cannabis acts in the brain.

21/09/2020 | Prog Neuropsychopharmacol Biol Psychiatry   IF 4.4
Cannabis and exercise: Effects of Delta(9)-tetrahydrocannabinol on preference and motivation for wheel-running in mice.
Hurel I, Muguruza C, Redon B, Marsicano G, Chaouloff F
doi: 10.1016/j.pnpbp.2020.110117

Recent surveys have revealed close links between cannabis and exercise. Specifically, cannabis usage before and/or after exercise is an increasingly common habit primarily aimed at boosting exercise pleasure, motivation, and performance whilst facilitating post-exercise recovery. However, whether these beliefs reflect the true impact of cannabis on these aspects of exercise is unknown. This study has thus examined the effects of cannabis' main psychoactive ingredient, namely Delta(9)-tetrahydrocannabinol (THC), on (i) mouse wheel-running preference and performance and (ii) running motivation and seeking behaviour. Wheel-running preference and performance were investigated using a T-maze with free and locked wheels located at the extremity of either arm. Running motivation and seeking were assessed by a cued-running operant task wherein wheel-running was conditioned by nose poking. Moreover, because THC targets cannabinoid type 1 (CB1) receptors, i.e. receptors previously documented to control running motivation, this study also assessed the role of these receptors in running preference, performance, and craving-like behaviour. Whilst acute blockade or genetic deletion of CB1 receptors decreased running preference and performance in the T-maze, THC proved ineffective on either variable. The failure of THC to affect running variables in the T-maze extended to running motivation, as assessed by cued-running under a progressive ratio (PR) reinforcement schedule. This ineffectiveness of THC was not related to the treatment protocol because it successfully increased motivation for palatable food. Although craving-like behaviour, as indexed by a cue-induced reinstatement of running seeking, was found to depend on CB1 receptors, THC again proved ineffective. Neither running motivation nor running seeking were affected when CB1 receptors were further stimulated by increasing the levels of the endocannabinoid 2-arachidonoylglycerol. These results, which suggest that the drive for running is insensitive to the acute stimulation of CB1 receptors, raise the hypothesis that cannabis is devoid of effect on exercise motivation. Future investigation using chronic administration of THC, with and without other cannabis ingredients (e.g. cannabidiol), is however required before conclusions can be drawn.

21/09/2020 | Neuron   IF 14.4
LTP Induction Boosts Glutamate Spillover by Driving Withdrawal of Perisynaptic Astroglia.
Henneberger C*, Bard L*, Panatier A*, Reynolds JP, Kopach O, Medvedev NI, Minge D, Herde MK, Anders S, Kraev I, Heller JP, Rama S, Zheng K, Jensen TP, Sanchez-Romero I, Jackson CJ, Janovjak H, Ottersen OP, Nagelhus EA, Oliet SHR, Stewart MG*, Nagerl V*, Rusakov DA*
doi: 10.1016/j.neuron.2020.08.030

Extrasynaptic actions of glutamate are limited by high-affinity transporters expressed by perisynaptic astroglial processes (PAPs): this helps maintain point-to-point transmission in excitatory circuits. Memory formation in the brain is associated with synaptic remodeling, but how this affects PAPs and therefore extrasynaptic glutamate actions is poorly understood. Here, we used advanced imaging methods, in situ and in

Serotonin2B receptor (5-HT2BR) antagonists inhibit cocaine-induced hyperlocomotion independently of changes of accumbal dopamine (DA) release. Given the tight relationship between accumbal DA activity and locomotion, and the inhibitory role of medial prefrontal cortex (mPFC) DA on subcortical DA neurotransmission and DA-dependent behaviors, it has been suggested that the suppressive effect of 5-HT2BR antagonists on cocaine-induced hyperlocomotion may result from an activation of mPFC DA outflow which would subsequently inhibit accumbal DA neurotransmission. Here, we tested this hypothesis by means of the two selective 5-HT2BR antagonists, RS 127445 and LY 266097, using a combination of neurochemical, behavioral and cellular approaches in male rats. The intraperitoneal (i.p.) administration of RS 127445 (0.16 mg/kg) or LY 266097 (0.63 mg/kg) potentiated cocaine (10 mg/kg, i.p.)-induced mPFC DA outflow. The suppressant effect of RS 127445 on cocaine-induced hyperlocomotion was no longer observed in rats with local 6-OHDA lesions in the mPFC. Also, RS 127445 blocked cocaine-induced changes of accumbal glycogen synthase kinase (GSK) 3beta phosphorylation, a postsynaptic cellular marker of DA neurotransmission. Finally, in keeping with the location of 5-HT2BRs on GABAergic interneurons in the dorsal raphe nucleus (DRN), the intra-DRN perfusion of the GABAAR antagonist bicuculline (100 muM) prevented the effect of the systemic or local (1 muM, intra-DRN) administration of RS 127445 on cocaine-induced mPFC DA outflow. Likewise, intra-DRN bicuculline injection (0.1 mug/0.2 mul) prevented the effect of the systemic RS 127445 administration on cocaine-induced hyperlocomotion and GSK3beta phosphorylation. These results show that DRN 5-HT2BR blockade suppresses cocaine-induced hyperlocomotion by potentiation of cocaine-induced DA outflow in the mPFC and the subsequent inhibition of accumbal DA neurotransmission.

10/09/2020 | BioRxiv
The atypical Rho GTPase Rnd2 is critical for dentate granule neuron development and anxiety-like behavior during adult but not neonatal neurogenesis
Kerloch T, Farrugia F, Maitre M, Terral G, Koehl M, Heng JI, Blanchard M, Doat H, Leste-Lasserre T, Goron A, Gonzales D, Guillemot F, Abrous DN, Pacary E

24/08/2020 | Nat Commun   IF 12.1
Preventing and treating PTSD-like memory by trauma contextualization.
Al Abed AS, Ducourneau EG, Bouarab C, Sellami A, Marighetto A, Desmedt A
doi: 10.1038/s41467-020-18002-w

Post-traumatic stress disorder (PTSD) is characterized by emotional hypermnesia on which preclinical studies focus so far. While this hypermnesia relates to salient traumatic cues, partial amnesia for the traumatic context can also be observed. Here, we show in mice that contextual amnesia is causally involved in PTSD-like memory formation, and that treating the amnesia by re-exposure to all trauma-related cues cures PTSD-like hypermnesia. These findings open a therapeutic perspective based on trauma contextualization and the underlying hippocampal mechanisms.

19/08/2020 | Mol Psychiatry   IF 12.4
Brexpiprazole blocks post-traumatic stress disorder-like memory while promoting normal fear memory.
Ducourneau EG, Guette C, Perrot D, Mondesir M, Mombereau C, Arnt J, Desmedt A*, Piazza PV*
doi: 10.1038/s41380-020-0852-z

A cardinal feature of post-traumatic stress disorder (PTSD) is a long-lasting paradoxical alteration of memory with hypermnesia for salient traumatic cues and amnesia for peri-traumatic contextual cues. So far, pharmacological therapeutic approach of this stress-related disorder is poorly developed mainly because of the lack of animal model for this paradoxical memory alteration. Using a model that precisely recapitulates the two memory components of PTSD in mice, we tested if brexpiprazole, a new antipsychotic drug with pro-cognitive effects in rodents, may persistently prevent the expression of PTSD-like memory induced by injection of corticosterone immediately after fear conditioning. Acute administration of brexpiprazole (0.3 mg/kg) 7 days' post-trauma first blocks the expression of the maladaptive fear memory for a salient but irrelevant trauma-related cue. In addition, it enhances (with superior efficacy when compared to diazepam, prazosin, and escitalopram) memory for the traumatic context, correct predictor of the threat. This beneficial effect of brexpiprazole is overall maintained 1 week after treatment. In contrast brexpiprazole fully spares normal/adaptive cued fear memory, showing that the effect of this drug is specific to an abnormal/maladaptive (PTSD-like) fear memory of a salient cue. Finally, this treatment not only promotes the switch from PTSD-like to normal fear memory, but also normalizes most of the alterations in the hippocampal-amygdalar network activation associated with PTSD-like memory, as measured by C-Fos expression. Altogether, these preclinical data indicate that brexpiprazole could represent a new pharmacological treatment of PTSD promoting the normalization of traumatic memory.

18/08/2020 | Cell Rep   IF 8.1
Specific Hippocampal Interneurons Shape Consolidation of Recognition Memory.
Oliveira da Cruz JF, Busquets-Garcia A, Zhao Z, Varilh M, Lavanco G, Bellocchio L, Robin L, Cannich A, Julio-Kalajzic F, Leste-Lasserre T, Maitre M, Drago F, Marsicano G, Soria-Gomez E
doi: 10.1016/j.celrep.2020.108046

A complex array of inhibitory interneurons tightly controls hippocampal activity, but how such diversity specifically affects memory processes is not well understood. We find that a small subclass of type 1 cannabinoid receptor (CB1R)-expressing hippocampal interneurons determines episodic-like memory consolidation by linking dopamine D1 receptor (D1R) signaling to GABAergic transmission. Mice lacking CB1Rs in D1-positive cells (D1-CB1-KO) display impairment in long-term, but not short-term, novel object recognition memory (NOR). Re-expression of CB1Rs in hippocampal D1R-positive cells rescues this NOR deficit. Learning induces an enhancement of in vivo hippocampal long-term potentiation (LTP), which is absent in mutant mice. CB1R-mediated NOR and the associated LTP facilitation involve local control of GABAergic inhibition in a D1-dependent manner. This study reveals that hippocampal CB1R-/D1R-expressing interneurons control NOR memory, identifying a mechanism linking the diversity of hippocampal interneurons to specific behavioral outcomes.

10/08/2020 | eLife   IF 7.1
Inhibition of striatonigral autophagy as a link between cannabinoid intoxication and impairment of motor coordination.
Blazquez C, Ruiz-Calvo A, Bajo-Graneras R, Baufreton JM, Resel E, Varilh M, Pagano Zottola AC, Mariani Y, Cannich A, Rodriguez-Navarro JA, Marsicano G, Galve-Roperh I, Bellocchio L, Guzman M
doi: 10.7554/eLife.56811

The use of cannabis is rapidly expanding worldwide. Thus, innovative studies aimed to identify, understand and potentially reduce cannabis-evoked harms are warranted. Here, we found that Delta(9)-tetrahydrocannabinol, the psychoactive ingredient of cannabis, disrupts autophagy selectively in the striatum, a brain area that controls motor behavior, both in vitro and in vivo. Boosting autophagy, either pharmacologically (with temsirolimus) or by dietary intervention (with trehalose), rescued the Delta(9)-tetrahydrocannabinol-induced impairment of motor coordination in mice. The combination of conditional knockout mouse models and viral vector-mediated autophagy-modulating strategies in vivo showed that cannabinoid CB1 receptors located on neurons belonging to the direct (striatonigral) pathway are required for the motor-impairing activity of Delta(9)-tetrahydrocannabinol by inhibiting local autophagy. Taken together, these findings identify inhibition of autophagy as an unprecedented mechanistic link between cannabinoids and motor performance, and suggest that activators of autophagy might be considered as potential therapeutic tools to treat specific cannabinoid-evoked behavioral alterations.

03/08/2020 | Addict Biol   IF 4.1
Sex-dependent pharmacological profiles of the synthetic cannabinoid MMB-Fubinaca.
Oliveira da Cruz JF, Ioannidou C, Pagano Zottola AC, Muguruza C, Gomez-Sotres P, Fernandez M, Callado LF, Marsicano G, Busquets-Garcia A
doi: 10.1111/adb.12940

Synthetic cannabinoids have emerged as novel psychoactive substances with damaging consequences for public health. They exhibit high affinity at the cannabinoid type-1 (CB1 ) receptor and produce similar and often more potent effects as other CB1 receptor agonists. However, we are still far from a complete pharmacological understanding of these compounds. In this study, by using behavioral, molecular, pharmacological, and electrophysiological approaches, we aimed at characterizing several in vitro and in vivo pharmacological effects of the synthetic cannabinoid MMB-Fubinaca (also known as AMB-Fubinaca or FUB-AMB), a particular synthetic cannabinoid. MMB-Fubinaca stimulates CB1 receptor-mediated functional coupling to G-proteins in mouse and human brain preparations in a similar manner as the CB1 receptor agonist WIN55,512-2 but with a much greater potency. Both drugs similarly activate the CB1 receptor-dependent extracellular signal-regulated kinase (ERK) pathway. Notably, in vivo administration of MMB-Fubinaca in mice induced greater behavioral and electrophysiological effects in male than in female mice in a CB1 receptor-dependent manner. Overall, these data provide a solid pharmacological profiling of the effects of MMB-Fubinaca and important information about the mechanisms of action underlying its harmful impact in humans. At the same time, they reinforce the significant sexual dimorphism of cannabinoid actions, which will have to be taken into account in future animal and clinical studies.

08/07/2020 | Nature   IF 42.8
Glucose metabolism links astroglial mitochondria to cannabinoid effects.
Jimenez-Blasco D, Busquets-Garcia A, Hebert-Chatelain E, Serrat R, Vicente-Gutierrez C, Ioannidou C, G, Marsicano G
doi: 10.1038/s41586-020-2470-y

Astrocytes take up glucose from the bloodstream to provide energy to the brain, thereby allowing neuronal activity and behavioural responses(1-5). By contrast, astrocytes are under neuronal control through specific neurotransmitter receptors(5-7). However, whether the activation of astroglial receptors can directly regulate cellular glucose metabolism to eventually modulate behavioural responses is unclear. Here we show that activation of mouse astroglial type-1 cannabinoid receptors associated with mitochondrial membranes (mtCB(1)) hampers the metabolism of glucose and the production of lactate in the brain, resulting in altered neuronal functions and, in turn, impaired behavioural responses in social interaction assays. Specifically, activation of astroglial mtCB(1) receptors reduces the phosphorylation of the mitochondrial complex I subunit NDUFS4, which decreases the stability and activity of complex I. This leads to a reduction in the generation of reactive oxygen species by astrocytes and affects the glycolytic production of lactate through the hypoxia-inducible factor 1 pathway, eventually resulting in neuronal redox stress and impairment of behavioural responses in social interaction assays. Genetic and pharmacological correction of each of these effects abolishes the effect of cannabinoid treatment on the observed behaviour. These findings suggest that mtCB(1) receptor signalling can directly regulate astroglial glucose metabolism to fine-tune neuronal activity and behaviour in mice.

The serotonin (5-HT) system is the target of multiple anxiolytics, including Buspirone, which is a partial agonist of the serotonin 1A receptor (5-HT1A). Similarly, ligands of the serotonin 2A receptor (5-HT2A) were shown to alter anxiety level. The 5-HT1A and 2A receptors are widely expressed across the brain, but the target region(s) underlying the influence of those receptors on anxiety remain unknown. Interestingly, recent studies in human and non-human primates have shown that the 5-HT1A and 5-HT2A binding potentials within the insular cortex (insula) are correlated to anxiety. As an initial step to define the function of 5-HT transmission in the insula, we quantified the proportion of specific neuronal populations of the insula expressing 5-HT1A or 5-HT2A. We analyzed seven neural populations, including three defined by a molecular marker (putative glutamate, GABA or parvalbumin), and four defined by their projections to different downstream targets. First, we found that more than 70% of putative glutamatergic neurons, and only 30% of GABAergic neurons express the 5-HT1A. Second, within insular projection neurons, 5-HT1A is highly expressed (75-80%) in the populations targeting one sub-nuclei of the amygdala (central or basolateral), or targeting the rostral or caudal sections of the lateral hypothalamus (LH). Similarly, 70% of putative glutamatergic neurons and only 30% of insular GABAergic neurons contain 5-HT2A. Finally, the 5-HT2A is present in a majority of insula-amygdala and insula-LH projection neurons (73-82%). These observations suggest that most glutamatergic neurons can respond to 5-HT through 5-HT1A or 5-HT2A in the insula, and that 5-HT directly affects a limited number of GABAergic neurons. This study defines a molecular and neuroanatomical map of the 5-HT system within the insular cortex, providing ground knowledge to identify the potential role of serotonergic modulation of selective insular populations in anxiety.

29/06/2020 | Aging Cell   IF 7.2
Responsiveness of dentate neurons generated throughout adult life is associated with resilience to cognitive aging.
Montaron MF, Charrier V, Blin N, Garcia P, Abrous DN
doi: 10.1111/acel.13161

During aging, some individuals are resilient to the decline of cognitive functions whereas others are vulnerable. These inter-individual differences in memory abilities have been associated with differences in the rate of hippocampal neurogenesis measured in elderlies. Whether the maintenance of the functionality of neurons generated throughout adult life is linked to resilience to cognitive aging remains completely unexplored. Using the immediate early gene Zif268, we analyzed the activation of dentate granule neurons born in adult (3-month-old), middle-aged (12-month-old), or senescent (18-month-old) rats (n = 96) in response to learning when animals reached 21 months of age. The activation of neurons born during the developmental period was also examined. We show that adult-born neurons can survive up to 19 months and that neurons generated 4, 10, or 19 months before learning, but not developmentally born neurons, are activated in senescent rats with good learning abilities. In contrast, aged rats with bad learning abilities do not exhibit activity-dependent regulation of newborn cells, whatever their birthdate. In conclusion, we propose that resilience to cognitive aging is associated with responsiveness of neurons born during adult life. These data add to our current knowledge by showing that the aging of memory abilities stems not only from the number but also from the responsiveness of adult-born neurons.

20/06/2020 | bio protoc
An Alternative Maze to Assess Novel Object Recognition in Mice.
Da Cruz JFO, Gomis-Gonzalez M, Maldonado R, Marsicano G, Ozaita A, Busquets-Garcia A
doi: 10.21769/BioProtoc.3651

The novel object recognition (NOR) task is a behavioral test commonly used to evaluate episodic-like declarative memory and it relies on the innate tendency of rodents to explore novelty. Here we present a maze used to evaluate NOR memory in mice that reduces the time of the assay while improving reliability of the measurements by increasing the exploratory behavior. This memory test, being performed in a two-arms maze, is suitable for several strains of mice (including inbreed and outbreed) and does not require extended training sessions allowing an accurate temporal assessment of memory formation. This particular maze increases the mouse exploration time and reduces variability compared to other arenas used before to assess NOR. As both long- and short-term NOR memory can be easily and accurately quantified using this paradigm, this improved methodology can be easily applied to study pharmacological, genetic or age-related modulation of cognitive function.

09/06/2020 | Neuroendocrinology   IF 4.3
Calcitonin gene-related peptide-induced phosphorylation of STAT3 in arcuate neurons is a link in the metabolic benefits of portal glucose.
Soty M, Vily-Petit J, Castellanos-Jankiewicz A, Guzman-Quevedo O, Raffin M, Clark S, Silva M, Gautier-Stein A, Cota D, Mithieux G
doi: 10.1159/000509230

INTRODUCTION: Intestinal gluconeogenesis exerts metabolic benefits in energy homeostasis via the neural sensing of portal glucose. OBJECTIVE: The aim of this work was to determine central mechanisms involved in the effects of intestinal gluconeogenesis (IGN) on the control of energy homeostasis. METHODS: We investigated the effects of glucose infusion into the portal vein, at a rate that mimics IGN, in conscious wild-type, leptin-deficient ob/ob and CGRP-/- mice. RESULTS: We report that portal glucose infusion decreases food intake and plasma glucose and induces in the hypothalamic arcuate nucleus (ARC) the phosphorylation of STAT3, the classic intracellular messenger of leptin signaling. This notably takes place in POMC-expressing neurons. STAT3-phosphorylation does not require leptin, since portal glucose effects are observed in leptin-deficient (ob/ob) mice. We hypothesized that the portal glucose effects could require calcitonin gene-related peptide (CGRP), a neuromediator previously suggested to suppress hunger. In line with this hypothesis, neither the metabolic benefits nor the phosphorylation of STAT3 in the ARC take place upon portal glucose infusion in CGRP-deficient mice. Moreover, intracerebroventricular injection of CGRP activates hypothalamic phosphorylation of STAT3 in mice, and CGRP does the same in hypothalamic cells. Finally, no metabolic benefit of dietary fibers (known to depend on the induction of IGN), takes place in CGRP deficient mice. CONCLUSIONS: CGRP-induced phosphorylation of STAT3 in the ARC is part of the neural chain determining the hunger-modulating and glucose-lowering effects of IGN/portal glucose. CONCLUSIONS: CGRP-induced phosphorylation of STAT3 in the ARC is part of the neural chain determining the hunger-modulating and glucose-lowering effects of IGN/portal glucose.

09/06/2020 | Cell Rep   IF 8.1
Vangl2 in the Dentate Network Modulates Pattern Separation and Pattern Completion.
Robert BJA, Moreau MM, Dos Santos Carvalho S, Barthet G, Racca C, Bhouri M, Quiedeville A, Garret M, Atchama B, Al Abed AS, Guette C, Henderson DJ, Desmedt A, Mulle C, Marighetto A, Montcouquiol M, Sans N
doi: 10.1016/j.celrep.2020.107743

The organization of spatial information, including pattern completion and pattern separation processes, relies on the hippocampal circuits, yet the molecular and cellular mechanisms underlying these two processes are elusive. Here, we find that loss of Vangl2, a core PCP gene, results in opposite effects on pattern completion and pattern separation processes. Mechanistically, we show that Vangl2 loss maintains young postmitotic granule cells in an immature state, providing increased cellular input for pattern separation. The genetic ablation of Vangl2 disrupts granule cell morpho-functional maturation and further prevents CaMKII and GluA1 phosphorylation, disrupting the stabilization of AMPA receptors. As a functional consequence, LTP at lateral perforant path-GC synapses is impaired, leading to defects in pattern completion behavior. In conclusion, we show that Vangl2 exerts a bimodal regulation on young and mature GCs, and its disruption leads to an imbalance in hippocampus-dependent pattern completion and separation processes.

06/2020 | hepatol commun
ASS1 Overexpression: A Hallmark of Sonic Hedgehog Hepatocellular Adenomas; Recommendations for Clinical Practice.
Sala M, Gonzales D, Leste-Lasserre T, Dugot-Senant N, Paradis V, Di Tommaso S, Dupuy JW, Pitard V, Dourthe C, Sciarra A, Sempoux C, Ferrell LD, Clouston AD, Miller G, Yeh MM, Thung S, Gouw ASH, Quaglia A, Han J, Huan J, Fan C, Crawford J, Nakanuma Y, Harada K, le Bail B, Castain C, Frulio N, Trillaud H, Possenti L, Blanc JF, Chiche L, Laurent C, Balabaud C, Bioulac-Sage P, Raymond AA, Saltel F
doi: 10.1002/hep4.1514

Until recently, 10% of hepatocellular adenomas (HCAs) remained unclassified (UHCA). Among the UHCAs, the sonic hedgehog HCA (shHCA) was defined by focal deletions that fuse the promoter of Inhibin beta E chain with GLI1. Prostaglandin D2 synthase was proposed as immunomarker. In parallel, our previous work using proteomic analysis showed that most UHCAs constitute a homogeneous subtype associated with overexpression of argininosuccinate synthase (ASS1). To clarify the use of ASS1 in the HCA classification and avoid misinterpretations of the immunohistochemical staining, the aims of this work were to study (1) the link between shHCA and ASS1 overexpression and (2) the clinical relevance of ASS1 overexpression for diagnosis. Molecular, proteomic, and immunohistochemical analyses were performed in UHCA cases of the Bordeaux series. The clinico-pathological features, including ASS1 immunohistochemical labeling, were analyzed on a large international series of 67 cases. ASS1 overexpression and the shHCA subgroup were superimposed in 15 cases studied by molecular analysis, establishing ASS1 overexpression as a hallmark of shHCA. Moreover, the ASS1 immunomarker was better than prostaglandin D2 synthase and only found positive in 7 of 22 shHCAs. Of the 67 UHCA cases, 58 (85.3%) overexpressed ASS1, four cases were ASS1 negative, and in five cases ASS1 was noncontributory. Proteomic analysis performed in the case of doubtful interpretation of ASS1 overexpression, especially on biopsies, can be a support to interpret such cases. ASS1 overexpression is a specific hallmark of shHCA known to be at high risk of bleeding. Therefore, ASS1 is an additional tool for HCA classification and clinical diagnosis.

22/05/2020 | Nutrients   IF 4.5
Effects of a High-Protein Diet on Cardiometabolic Health, Vascular Function, and Endocannabinoids-A PREVIEW Study.
Tischmann L, Drummen M, Joris PJ, Gatta-Cherifi B, Raben A, Fogelholm M, Matias I, Cota D, Mensink RP, Westerterp-Plantenga MS, Adam TC
doi: 10.3390/nu12051512

An unfavorable lipid profile and being overweight are known mediators in the development of cardiovascular disease (CVD) risk. The effect of diet, particularly high in protein, remains under discussion. Therefore, this study examines the effects of a high-protein (HP) diet on cardiometabolic health and vascular function (i.e., endothelial function, arterial stiffness, and retinal microvascular structure), and the possible association with plasma endocannabinoids and endocannabinoid-related compounds in overweight participants. Thirty-eight participants (64.5 +/- 5.9 (mean +/- SD) years; body mass index (BMI) 28.9 +/- 4.0 kg/m(2)) were measured for 48 h in a respiration chamber after body-weight maintenance for approximately 34 months following weight reduction. Diets with either a HP (n = 20) or moderate protein (MP; n = 18) content (25%/45%/30% vs. 15%/55%/30% protein/carbohydrate/fat) were provided in energy balance. Validated markers for cardiometabolic health (i.e., office blood pressure (BP) and serum lipoprotein concentrations) and vascular function (i.e., brachial artery flow-mediated vasodilation, pulse wave analysis and velocity, and retinal microvascular calibers) were measured before and after those 48 h. Additionally, 24 h ambulatory BP, plasma anandamide (AEA), 2-arachidonoylglycerol (2-AG), oleoylethanolamide (OEA), palmitoylethanolamide (PEA), and pregnenolone (PREG) were analyzed throughout the day. Office and ambulatory BP, serum lipoprotein concentrations, and vascular function markers were not different between the groups. Only heart rate (HR) was higher in the HP group. HR was positively associated with OEA, while OEA and PEA were also positively associated with total cholesterol (TC) and low-density lipoprotein (LDL) cholesterol concentrations. Vascular function markers were not associated with endocannabinoids (or endocannabinoid-related substances). In conclusion, the HP diet did not affect cardiometabolic health and vascular function in overweight participants after completing a weight-loss intervention. Furthermore, our data indicate a possible association between OEA and PEA with TC and LDL cholesterol.

18/05/2020 | Nat Commun   IF 12.1
Author Correction: Structural basis of astrocytic Ca(2+) signals at tripartite synapses.
Arizono M, Inavalli VVGK, Panatier A, Pfeiffer T, Angibaud J, Levet F, Veer MJTT, Stobart J, Bellocchio L, Mikoshiba K, Marsicano G, Weber B, Oliet SHR, Nagerl UV
doi: 10.1038/s41467-020-16453-9

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

18/05/2020 | Cereb Cortex   IF 5
Sox11 is an Activity-Regulated Gene with Dentate-Gyrus-Specific Expression Upon General Neural Activation.
von Wittgenstein J, Zheng F, Wittmann MT,Balta EA, Ferrazzi F, Schaffner I, Haberle BM, Valero-Aracama MJ,, Koehl M, Miranda CJ, Kaspar BK, Ekici AB, Reis A,, Abrous DN, Alzheimer C, Lie DC
doi: 10.1093/cercor/bhz338

Neuronal activity initiates transcriptional programs that shape long-term changes in plasticity. Although neuron subtypes differ in their plasticity response, most activity-dependent transcription factors (TFs) are broadly expressed across neuron subtypes and brain regions. Thus, how region- and neuronal subtype-specific plasticity are established on the transcriptional level remains poorly understood. We report that in young adult (i.e., 6-8

01/05/2020 | Neuroscience   IF 3.1
Synaptic Functions of Type-1 Cannabinoid Receptors in Inhibitory Circuits of the Anterior Piriform Cortex.
Terral G, Varilh M, Cannich A, Massa F, Ferreira G, Marsicano G
doi: 10.1016/j.neuroscience.2020.03.002

In the olfactory system, the endocannabinoid system (ECS) regulates sensory perception and memory. A major structure involved in these processes is the anterior piriform cortex (aPC), but the impact of ECS signaling in aPC circuitry is still scantly characterized. Using ex vivo patch clamp experiments in mice and neuroanatomical approaches, we show that the two major forms of ECS-dependent synaptic plasticity, namely depolarization-dependent suppression of inhibition (DSI) and long-term depression of inhibitory transmission (iLTD) are present in the aPC. Interestingly, iLTD expression depends on layer localization of the inhibitory neurons associated with the expression of the neuropeptide cholecystokinin. Conversely, the decrease of inhibitory transmission induced by exogenous cannabinoid agonists or DSI do not seem to be impacted by these factors. Altogether, these results indicate that CB1 receptors exert an anatomically specific and differential control of inhibitory plasticity in the aPC, likely involved in spatiotemporal regulation of olfactory processes.

05/2020 | sci adv   IF 13.1
Identification of distinct pathological signatures induced by patient-derived alpha-synuclein structures in nonhuman primates.
Bourdenx M, Nioche A, Dovero S, Arotcarena ML, Camus S, Porras G, Thiolat ML, Rougier NP, Prigent A, Aubert P, Bohic S, Sandt C, Laferriere F, Doudnikoff E, Kruse N, Mollenhauer B, Novello S, Morari M, Leste-Lasserre T, Damas IT, Goillandeau M, Perier C, Estrada C, Garcia-Carrillo N, Recasens A, Vaikath NN, El-Agnaf OMA, Herrero MT, Derkinderen P, Vila M, Obeso JA, Dehay B, Bezard E
doi: 10.1126/sciadv.aaz9165

Dopaminergic neuronal cell death, associated with intracellular alpha-synuclein (alpha-syn)-rich protein aggregates [termed 'Lewy bodies' (LBs)], is a well-established characteristic of Parkinson's disease (PD). Much evidence, accumulated from multiple experimental models, has suggested that alpha-syn plays a role in PD pathogenesis, not only as a trigger of pathology but also as a mediator of disease progression through pathological spreading. Here, we have used a machine learning-based approach to identify unique signatures of neurodegeneration in monkeys induced by distinct alpha-syn pathogenic structures derived from patients with PD. Unexpectedly, our results show that, in nonhuman primates, a small amount of singular alpha-syn aggregates is as toxic as larger amyloid fibrils present in the LBs, thus reinforcing the need for preclinical research in this species. Furthermore, our results provide evidence supporting the true multifactorial nature of PD, as multiple causes can induce a similar outcome regarding dopaminergic neurodegeneration.

25/04/2020 | J Clin Endocrinol Metab   IF 5.4
Role of endocannabinoids in energy balance regulation in participants in the post-obese state - a PREVIEW study.
Drummen M, Tischmann L, Gatta-Cherifi B, Cota D, Matias I, Raben A, Adam T, Westerterp-Plantenga M
doi: 10.1210/clinem/dgaa193

CONTEXT: Endocannabinoids are suggested to play a role in energy balance regulation. OBJECTIVE: We aimed to investigate associations of endocannabinoid concentrations during the day with energy balance and adiposity and interactions with 2 diets differing in protein content in participants in the post-obese phase with pre-diabetes. DESIGN AND PARTICIPANTS: Participants (n=38) were individually fed in energy balance with a medium protein (MP: 15:55:30% of energy from Protein:Carbohydrate:Fat) or high protein diet (HP: 25:45:30% energy from P:C:F) for 48-hours in a respiration chamber. MAIN OUTCOME MEASURES: Associations between energy balance, energy expenditure, RQ and endocannabinoid concentrations during the day were assessed. RESULTS: Plasma-concentrations of anandamide (AEA), oleoylethanolamide (OEA), palmitoyethanolamide (PEA), and pregnenolone (PREG) significantly decreased during the day. This decrease was inversely related to BMI (AEA) or body-fat (%) (PEA; OEA). The lowest RQ value, before lunch, was inversely associated with concentrations of AEA and PEA before lunch. AUC of concentrations of AEA, 2-AG, PEA, and OEA were positively related to body-fat% (p<0.05). The HP and MP groups showed no differences in concentrations of AEA, OEA, PEA, and PREG, but the AUC of 2-arachidonoylglycerol (2-AG) was significantly higher in the HP vs. the MP group. CONCLUSIONS: In energy balance, only the endocannabinoid 2-AG changed in relation to protein level of the diet, while the endocannabinoid AEA, and endocannabinoid-related compounds OEA and PEA reflected the gradual energy intake matching energy expenditure over the day.