Publications by authors named "Edgar Soria-Gomez"

30 Publications

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Cannabinoid control of hippocampal functions: the where matters.

FEBS J 2021 May 11. Epub 2021 May 11.

Department of Neurosciences, Faculty of Medicine and Nursing, University of the Basque Country UPV/EHU, Leioa, Spain.

In the brain, hippocampal circuits are crucial for cognitive performance (e.g., memory) and deeply affected in pathological conditions (e.g., epilepsy, Alzheimer). Specialized molecular mechanisms regulate different cell types underlying hippocampal circuitries functions. Among them, cannabinoid receptors exhibit various roles depending on the cell type (e.g., neuron, glial cell) or subcellular organelle (e.g., mitochondria). Determining the site of action and precise mechanisms triggered by cannabinoid receptor activation at a local cellular and subcellular level helps us understand hippocampal pathophysiological states. In doing so, past and current research have advanced our knowledge of cannabinoid functions and proposed novel routes for potential therapeutics. By outlining these data in this work, we aim to showcase current findings and highlight the pathophysiological impact of the cannabinoid receptor type 1 (CB1) localization/activation in hippocampal circuits.
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http://dx.doi.org/10.1111/febs.15907DOI Listing
May 2021

Subcellular specificity of cannabinoid effects in striatonigral circuits.

Neuron 2021 05 25;109(9):1513-1526.e11. Epub 2021 Mar 25.

INSERM, U1215 NeuroCentre Magendie, Endocannabinoids and Neuroadaptation, Bordeaux, France; University of Bordeaux, Bordeaux, France.

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 (CB) receptors in the striatonigral circuit elicits both antinociception and catalepsy in mice. The decrease in nociception depends on the activation of plasma membrane-residing CB receptors (pmCB), leading to the inhibition of cytosolic PKA activity and substance P release. By contrast, mitochondrial-associated CB receptors (mtCB) 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 CB receptor signaling within striatonigral circuits determines multimodal control of behavior.
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http://dx.doi.org/10.1016/j.neuron.2021.03.007DOI Listing
May 2021

A Novel Cortical Mechanism for Top-Down Control of Water Intake.

Curr Biol 2020 12 8;30(23):4789-4798.e4. Epub 2020 Oct 8.

INSERM, U1215 NeuroCentre Magendie, 146 rue Léo Saignat, 33077 Bordeaux Cedex, France; University of Bordeaux, 146 rue Léo Saignat, 33000 Bordeaux, France. Electronic address:

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 (CB) modulate consummatory behaviors, such as feeding [16-26]. However, the role of CB receptors in the control of water intake is still a matter of debate [27-31]. Here, we show that endogenous activation of CB in cortical glutamatergic neurons of the ACC promotes water intake. Notably, presynaptic CB 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 CB 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.
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http://dx.doi.org/10.1016/j.cub.2020.09.011DOI Listing
December 2020

Specific Hippocampal Interneurons Shape Consolidation of Recognition Memory.

Cell Rep 2020 08;32(7):108046

INSERM U1215, NeuroCentre Magendie, Bordeaux 33300, France; University of Bordeaux, Bordeaux 33300, France; Ikerbasque-Basque Foundation for Science, Bilbao 48013, Spain; Department of Neuroscience, Faculty of Medicine and Nursing, University of the Basque Country (UPV/EHU) Leioa 48940, Spain; Achucarro Basque Center for Neuroscience, Leioa 48940, Spain. Electronic address:

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 (CBR)-expressing hippocampal interneurons determines episodic-like memory consolidation by linking dopamine D receptor (DR) signaling to GABAergic transmission. Mice lacking CBRs in D-positive cells (D-CB-KO) display impairment in long-term, but not short-term, novel object recognition memory (NOR). Re-expression of CBRs in hippocampal DR-positive cells rescues this NOR deficit. Learning induces an enhancement of in vivo hippocampal long-term potentiation (LTP), which is absent in mutant mice. CBR-mediated NOR and the associated LTP facilitation involve local control of GABAergic inhibition in a D-dependent manner. This study reveals that hippocampal CBR-/DR-expressing interneurons control NOR memory, identifying a mechanism linking the diversity of hippocampal interneurons to specific behavioral outcomes.
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http://dx.doi.org/10.1016/j.celrep.2020.108046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7443618PMC
August 2020

Special Issue "Olfaction: From Genes to Behavior".

Genes (Basel) 2020 06 15;11(6). Epub 2020 Jun 15.

Department of Neurosciences, University of the Basque Country UPV/EHU, 48940 Leioa, Spain.

The senses dictate how the brain represents the environment, and this representation is the basis of how we act in the world [...].
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http://dx.doi.org/10.3390/genes11060654DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7348778PMC
June 2020

Cannabinoid Control of Olfactory Processes: The Matters.

Genes (Basel) 2020 04 16;11(4). Epub 2020 Apr 16.

Department of Neurosciences, University of the Basque Country UPV/EHU, Barrio Sarriena s\n, 48940 Leioa, Spain.

Olfaction has a direct influence on behavior and cognitive processes. There are different neuromodulatory systems in olfactory circuits that control the sensory information flowing through the rest of the brain. The presence of the cannabinoid type-1 (CB1) receptor, (the main cannabinoid receptor in the brain), has been shown for more than 20 years in different brain olfactory areas. However, only over the last decade have we started to know the specific cellular mechanisms that link cannabinoid signaling to olfactory processing and the control of behavior. In this review, we aim to summarize and discuss our current knowledge about the presence of CB1 receptors, and the function of the endocannabinoid system in the regulation of different olfactory brain circuits and related behaviors.
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http://dx.doi.org/10.3390/genes11040431DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7230191PMC
April 2020

CB1 Receptors in the Anterior Piriform Cortex Control Odor Preference Memory.

Curr Biol 2019 08 18;29(15):2455-2464.e5. Epub 2019 Jul 18.

INSERM, U1215 NeuroCentre Magendie, 146 rue Léo Saignat, 33077 Bordeaux Cedex, France; University of Bordeaux, 146 rue Léo Saignat, 33000 Bordeaux, France. Electronic address:

The retrieval of odor-related memories shapes animal behavior. The anterior piriform cortex (aPC) is the largest part of the olfactory cortex, and it plays important roles in olfactory processing and memory. However, it is still unclear whether specific cellular mechanisms in the aPC control olfactory memory, depending on the appetitive or aversive nature of the stimuli involved. Cannabinoid-type 1 (CB1) receptors are present in the aPC (aPC-CB1), but their potential impact on olfactory memory was never explored. Here, we used a combination of behavioral, genetic, anatomical, and electrophysiological approaches to characterize the functions of aPC-CB1 receptors in the regulation of appetitive and aversive olfactory memory. Pharmacological blockade or genetic deletion of aPC-CB1 receptors specifically impaired the retrieval of conditioned odor preference (COP). Interestingly, expression of conditioned odor aversion (COA) was unaffected by local CB1 receptor blockade, indicating that the role of aPC endocannabinoid signaling is selective for retrieval of appetitive memory. Anatomical investigations revealed that CB1 receptors are highly expressed on aPC GABAergic interneurons, and ex vivo electrophysiological recordings showed that their pharmacological activation reduces miniature inhibitory post-synaptic currents (mIPSCs) onto aPC semilunar (SL), but not pyramidal principal neurons. COP retrieval, but not COA, was associated with a specific CB1-receptor-dependent decrease of mIPSCs in SL cells. Altogether, these data indicate that aPC-CB1 receptor-dependent mechanisms physiologically control the retrieval of olfactory memory, depending on odor valence and engaging modulation of local inhibitory transmission.
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http://dx.doi.org/10.1016/j.cub.2019.06.041DOI Listing
August 2019

The motivation for exercise over palatable food is dictated by cannabinoid type-1 receptors.

JCI Insight 2019 03 7;4(5). Epub 2019 Mar 7.

Endocannabinoids and NeuroAdaptation, NeuroCentre INSERM U1215, Bordeaux, France.

The lack of intrinsic motivation to engage in, and adhere to, physical exercise has major health consequences. However, the neurobiological bases of exercise motivation are still unknown. This study aimed at examining whether the endocannabinoid system (ECS) is involved in this process. To do so, we developed an operant conditioning paradigm wherein mice unlocked a running wheel with nose pokes. Using pharmacological tools and conditional mutants for cannabinoid type-1 (CB1) receptors, we provide evidence that CB1 receptors located on GABAergic neurons are both necessary and sufficient to positively control running motivation. Conversely, this receptor population proved dispensable for the modulation of running duration per rewarded sequence. Although the ECS mediated the motivation for another reward, namely palatable food, such a regulation was independent from CB1 receptors on GABAergic neurons. In addition, we report that the lack of CB1 receptors on GABAergic neurons decreases the preference for running over palatable food when mice were proposed an exclusive choice between the two rewards. Beyond providing a paradigm that enables motivation processes for exercise to be dissected either singly or in concurrence, this study is the first to our knowledge to identify a neurobiological mechanism that might contribute to sedentary behavior.
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http://dx.doi.org/10.1172/jci.insight.126190DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6483603PMC
March 2019

Hippocampal CB Receptors Control Incidental Associations.

Neuron 2018 09 30;99(6):1247-1259.e7. Epub 2018 Aug 30.

INSERM, U1215 NeuroCentre Magendie, 33000 Bordeaux, France; University of Bordeaux, 33000 Bordeaux, France. Electronic address:

By priming brain circuits, associations between low-salience stimuli often guide future behavioral choices through a process known as mediated or inferred learning. However, the precise neurobiological mechanisms of these incidental associations are largely unknown. Using sensory preconditioning procedures, we show that type 1 cannabinoid receptors (CBR) in hippocampal GABAergic neurons are necessary and sufficient for mediated but not direct learning. Deletion and re-expression of CBR in hippocampal GABAergic neurons abolishes and rescues mediated learning, respectively. Interestingly, paired presentations of low-salience sensory cues induce a specific protein synthesis-dependent enhancement of hippocampal CBR expression and facilitate long-term synaptic plasticity at inhibitory synapses. CBR blockade or chemogenetic manipulations of hippocampal GABAergic neurons upon preconditioning affect incidental associations, as revealed by impaired mediated learning. Thus, CBR-dependent control of inhibitory hippocampal neurotransmission mediates incidental associations, allowing future associative inference, a fundamental process for everyday life, which is altered in major neuropsychiatric diseases. VIDEO ABSTRACT.
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http://dx.doi.org/10.1016/j.neuron.2018.08.014DOI Listing
September 2018

Astroglial CB Receptors Determine Synaptic D-Serine Availability to Enable Recognition Memory.

Neuron 2018 06 17;98(5):935-944.e5. Epub 2018 May 17.

INSERM U1215, NeuroCentre Magendie, 33077 Bordeaux, France; University of Bordeaux, 33077 Bordeaux, France. Electronic address:

Bidirectional communication between neurons and astrocytes shapes synaptic plasticity and behavior. D-serine is a necessary co-agonist of synaptic N-methyl-D-aspartate receptors (NMDARs), but the physiological factors regulating its impact on memory processes are scantly known. We show that astroglial CB receptors are key determinants of object recognition memory by determining the availability of D-serine at hippocampal synapses. Mutant mice lacking CB receptors from astroglial cells (GFAP-CB-KO) displayed impaired object recognition memory and decreased in vivo and in vitro long-term potentiation (LTP) at CA3-CA1 hippocampal synapses. Activation of CB receptors increased intracellular astroglial Ca levels and extracellular levels of D-serine in hippocampal slices. Accordingly, GFAP-CB-KO displayed lower occupancy of the co-agonist binding site of synaptic hippocampal NMDARs. Finally, elevation of D-serine levels fully rescued LTP and memory impairments of GFAP-CB-KO mice. These data reveal a novel mechanism of in vivo astroglial control of memory and synaptic plasticity via the D-serine-dependent control of NMDARs.
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http://dx.doi.org/10.1016/j.neuron.2018.04.034DOI Listing
June 2018

Localization of the cannabinoid type-1 receptor in subcellular astrocyte compartments of mutant mouse hippocampus.

Glia 2018 07 26;66(7):1417-1431. Epub 2018 Feb 26.

Department of Neurosciences, University of the Basque Country UPV/EHU, Leioa, E-48940, Spain.

Astroglial type-1 cannabinoid (CB ) receptors are involved in synaptic transmission, plasticity and behavior by interfering with the so-called tripartite synapse formed by pre- and post-synaptic neuronal elements and surrounding astrocyte processes. However, little is known concerning the subcellular distribution of astroglial CB receptors. In particular, brain CB receptors are mostly localized at cells' plasmalemma, but recent evidence indicates their functional presence in mitochondrial membranes. Whether CB receptors are present in astroglial mitochondria has remained unknown. To investigate this issue, we included conditional knock-out mice lacking astroglial CB receptor expression specifically in glial fibrillary acidic protein (GFAP)-containing astrocytes (GFAP-CB -KO mice) and also generated genetic rescue mice to re-express CB receptors exclusively in astrocytes (GFAP-CB -RS). To better identify astroglial structures by immunoelectron microscopy, global CB knock-out (CB -KO) mice and wild-type (CB -WT) littermates were intra-hippocampally injected with an adeno-associated virus expressing humanized renilla green fluorescent protein (hrGFP) under the control of human GFAP promoter to generate GFAPhrGFP-CB -KO and -WT mice, respectively. Furthermore, double immunogold (for CB ) and immunoperoxidase (for GFAP or hrGFP) revealed that CB receptors are present in astroglial mitochondria from different hippocampal regions of CB -WT, GFAP-CB -RS and GFAPhrGFP-CB -WT mice. Only non-specific gold particles were detected in mouse hippocampi lacking CB receptors. Altogether, we demonstrated the existence of a precise molecular architecture of the CB receptor in astrocytes that will have to be taken into account in evaluating the functional activity of cannabinergic signaling at the tripartite synapse.
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http://dx.doi.org/10.1002/glia.23314DOI Listing
July 2018

Representation-mediated Aversion as a Model to Study Psychotic-like States in Mice.

Bio Protoc 2017 Jun;7(12)

INSERM, U1215 NeuroCentre Magendie, Bordeaux, France.

Several paradigms for rodent models of the cognitive and negative endophenotypes found in schizophrenic patients have been proposed. However, significant efforts are needed in order to study the pathophysiology of schizophrenia-related positive symptoms. Recently, it has been shown that these positive symptoms can be studied in rats by using representation-mediated learning. This learning measure the accuracy of mental representations of reality, also called 'reality testing'. Alterations in 'reality testing' performance can be an indication of an impairment in perception which is a clear hallmark of positive psychotic-like states. Thus, we describe here a mouse task adapted from previous findings based on a sensory preconditioning task. With this task, associations made between different neutral stimuli (, an odor and a taste) and subsequent selective devaluation of one of these stimuli have allowed us to study mental sensory representations. Thus, the interest of this task is that it can be used to model positive psychotic-like states in mice, as recently described.
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http://dx.doi.org/10.21769/BioProtoc.2358DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5662143PMC
June 2017

A cannabinoid link between mitochondria and memory.

Nature 2016 11 9;539(7630):555-559. Epub 2016 Nov 9.

INSERM U1215, NeuroCentre Magendie, Bordeaux 33077, France.

Cellular activity in the brain depends on the high energetic support provided by mitochondria, the cell organelles which use energy sources to generate ATP. Acute cannabinoid intoxication induces amnesia in humans and animals, and the activation of type-1 cannabinoid receptors present at brain mitochondria membranes (mtCB) can directly alter mitochondrial energetic activity. Although the pathological impact of chronic mitochondrial dysfunctions in the brain is well established, the involvement of acute modulation of mitochondrial activity in high brain functions, including learning and memory, is unknown. Here, we show that acute cannabinoid-induced memory impairment in mice requires activation of hippocampal mtCB receptors. Genetic exclusion of CB receptors from hippocampal mitochondria prevents cannabinoid-induced reduction of mitochondrial mobility, synaptic transmission and memory formation. mtCB receptors signal through intra-mitochondrial Gα protein activation and consequent inhibition of soluble-adenylyl cyclase (sAC). The resulting inhibition of protein kinase A (PKA)-dependent phosphorylation of specific subunits of the mitochondrial electron transport system eventually leads to decreased cellular respiration. Hippocampal inhibition of sAC activity or manipulation of intra-mitochondrial PKA signalling or phosphorylation of the Complex I subunit NDUFS2 inhibit bioenergetic and amnesic effects of cannabinoids. Thus, the G protein-coupled mtCB receptors regulate memory processes via modulation of mitochondrial energy metabolism. By directly linking mitochondrial activity to memory formation, these data reveal that bioenergetic processes are primary acute regulators of cognitive functions.
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http://dx.doi.org/10.1038/nature20127DOI Listing
November 2016

Cannabinoid receptor type-1: breaking the dogmas.

F1000Res 2016 24;5. Epub 2016 May 24.

Endocannabinoids and Neuroadaptation, INSERM U1215 NeuroCentre Magendie, Bordeaux, 33077, France; University of Bordeaux, Bordeaux, France.

The endocannabinoid system (ECS) is abundantly expressed in the brain. This system regulates a plethora of physiological functions and is composed of cannabinoid receptors, their endogenous ligands (endocannabinoids), and the enzymes involved in the metabolism of endocannabinoids. In this review, we highlight the new advances in cannabinoid signaling, focusing on a key component of the ECS, the type-1 cannabinoid receptor (CB 1). In recent years, the development of new imaging and molecular tools has demonstrated that this receptor can be distributed in many cell types (e.g., neuronal or glial cells) and intracellular compartments (e.g., mitochondria). Interestingly, cellular and molecular effects are differentially mediated by CB 1 receptors according to their specific localization (e.g., glutamatergic or GABAergic neurons). Moreover, this receptor is expressed in the periphery, where it can modulate periphery-brain connections. Finally, the better understanding of the CB 1 receptor structure led researchers to propose interesting and new allosteric modulators. Thus, the advances and the new directions of the CB 1 receptor field will provide new insights and better approaches to profit from its interesting therapeutic profile.
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http://dx.doi.org/10.12688/f1000research.8245.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4879932PMC
May 2016

Habenular CB1 Receptors Control the Expression of Aversive Memories.

Neuron 2015 Oct 24;88(2):306-13. Epub 2015 Sep 24.

INSERM, U862 NeuroCentre Magendie, Group Endocannabinoids and Neuroadaptation, Bordeaux 33077, France; University of Bordeaux, Bordeaux 33077, France. Electronic address:

Expression of aversive memories is key for survival, but the underlying brain mechanisms are not fully understood. Medial habenular (MHb) axons corelease glutamate and acetylcholine onto target postsynaptic interpeduncular (IPN) neurons, but their role in aversive memories has not been addressed so far. We found that cannabinoid type 1 receptors (CB1R), key regulators of aversive responses, are present at presynaptic terminals of MHb neurons in the IPN. Conditional deletion of CB1R from MHb neurons reduces fear-conditioned freezing and abolishes conditioned odor aversion in mice, without affecting neutral or appetitively motivated memories. Interestingly, local inhibition of nicotinic, but not glutamatergic receptors in the target region IPN before retrieval, rescues these phenotypes. Finally, optogenetic electrophysiological recordings of MHb-to-IPN circuitry revealed that blockade of CB1R specifically enhances cholinergic, but not glutamatergic, neurotransmission. Thus, presynaptic CB1R control expression of aversive memories by selectively modulating cholinergic transmission at MHb synapses in the IPN.
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http://dx.doi.org/10.1016/j.neuron.2015.08.035DOI Listing
October 2015

Dissecting the cannabinergic control of behavior: The where matters.

Bioessays 2015 Nov 11;37(11):1215-25. Epub 2015 Aug 11.

Group "Endocannabinoids and Neuroadaptation," NeuroCentre Magendie, INSERM U862, University of Bordeaux, Bordeaux, France.

The endocannabinoid system is the target of the main psychoactive component of the plant Cannabis sativa, the Δ(9)-tetrahydrocannabinol (THC). This system is composed by the cannabinoid receptors, the endogenous ligands, and the enzymes involved in their metabolic processes, which works both centrally and peripherally to regulate a plethora of physiological functions. This review aims at explaining how the site-specific actions of the endocannabinoid system impact on memory and feeding behavior through the cannabinoid receptors 1 (CB1 R). Centrally, CB1 R is widely distributed in many brain regions, different cell types (e.g. neuronal or glial cells) and intracellular compartments (e.g. mitochondria). Interestingly, cellular and molecular effects are differentially mediated by CB1 R according to their cell-type localization (e.g. glutamatergic or GABAergic neurons). Thus, understanding the cellular and subcellular function of CB1 R will provide new insights and aid the design of new compounds in cannabinoid-based medicine. Also watch the Video Abstract.
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http://dx.doi.org/10.1002/bies.201500046DOI Listing
November 2015

New insights on food intake control by olfactory processes: the emerging role of the endocannabinoid system.

Mol Cell Endocrinol 2014 Nov 27;397(1-2):59-66. Epub 2014 Sep 27.

INSERM, U862 NeuroCentre Magendie, Endocannabinoids and Neuroadaptation, Bordeaux, France.

The internal state of the organism is an important modulator of perception and behavior. The link between hunger, olfaction and feeding behavior is one of the clearest examples of these connections. At the neurobiological level, olfactory circuits are the targets of several signals (i.e. hormones and nutrients) involved in energy balance. This indicates that olfactory areas are potential sensors of the internal state of the organism. Thus, the aim of this manuscript is to review the literature showing the interplay between metabolic signals in olfactory circuits and its impact on food intake.
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http://dx.doi.org/10.1016/j.mce.2014.09.023DOI Listing
November 2014

A restricted population of CB1 cannabinoid receptors with neuroprotective activity.

Proc Natl Acad Sci U S A 2014 Jun 19;111(22):8257-62. Epub 2014 May 19.

Centro de Investigación Biomédica en Red Sobre Enfermedades Neurodegenerativas, Instituto Ramón y Cajal de Investigación Sanitaria, 28040 Madrid, Spain;Department of Biochemistry and Molecular Biology I, Instituto Universitario de Investigación Neuroquímica, Complutense University, 28040 Madrid, Spain;

The CB1 cannabinoid receptor, the main molecular target of endocannabinoids and cannabis active components, is the most abundant G protein-coupled receptor in the mammalian brain. Of note, CB1 receptors are expressed at the synapses of two opposing (i.e., GABAergic/inhibitory and glutamatergic/excitatory) neuronal populations, so the activation of one and/or another receptor population may conceivably evoke different effects. Despite the widely reported neuroprotective activity of the CB1 receptor in animal models, the precise pathophysiological relevance of those two CB1 receptor pools in neurodegenerative processes is unknown. Here, we first induced excitotoxic damage in the mouse brain by (i) administering quinolinic acid to conditional mutant animals lacking CB1 receptors selectively in GABAergic or glutamatergic neurons, and (ii) manipulating corticostriatal glutamatergic projections remotely with a designer receptor exclusively activated by designer drug pharmacogenetic approach. We next examined the alterations that occur in the R6/2 mouse, a well-established model of Huntington disease, upon (i) fully knocking out CB1 receptors, and (ii) deleting CB1 receptors selectively in corticostriatal glutamatergic or striatal GABAergic neurons. The data unequivocally identify the restricted population of CB1 receptors located on glutamatergic terminals as an indispensable player in the neuroprotective activity of (endo)cannabinoids, therefore suggesting that this precise receptor pool constitutes a promising target for neuroprotective therapeutic strategies.
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http://dx.doi.org/10.1073/pnas.1400988111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4050577PMC
June 2014

The endocannabinoid system controls food intake via olfactory processes.

Nat Neurosci 2014 Mar 9;17(3):407-15. Epub 2014 Feb 9.

1] INSERM, U862 NeuroCentre Magendie, Endocannabinoids and Neuroadaptation, Bordeaux, France. [2] University of Bordeaux, NeuroCentre Magendie U862, Bordeaux, France. [3].

Hunger arouses sensory perception, eventually leading to an increase in food intake, but the underlying mechanisms remain poorly understood. We found that cannabinoid type-1 (CB1) receptors promote food intake in fasted mice by increasing odor detection. CB1 receptors were abundantly expressed on axon terminals of centrifugal cortical glutamatergic neurons that project to inhibitory granule cells of the main olfactory bulb (MOB). Local pharmacological and genetic manipulations revealed that endocannabinoids and exogenous cannabinoids increased odor detection and food intake in fasted mice by decreasing excitatory drive from olfactory cortex areas to the MOB. Consistently, cannabinoid agonists dampened in vivo optogenetically stimulated excitatory transmission in the same circuit. Our data indicate that cortical feedback projections to the MOB crucially regulate food intake via CB1 receptor signaling, linking the feeling of hunger to stronger odor processing. Thus, CB1 receptor-dependent control of cortical feedback projections in olfactory circuits couples internal states to perception and behavior.
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http://dx.doi.org/10.1038/nn.3647DOI Listing
March 2014

Astroglial CB1 cannabinoid receptors regulate leptin signaling in mouse brain astrocytes.

Mol Metab 2013 9;2(4):393-404. Epub 2013 Aug 9.

INSERM, Neurocentre Magendie, Physiopathologie de la Plasticité Neuronale, U862, F-33000 Bordeaux, France ; University of Bordeaux, Neurocentre Magendie, Physiopathologie de la Plasticité Neuronale, U862, F-33000 Bordeaux, France ; Neuropharmacology, Institute of Neurosciences, Université Catholique de Louvain, Av. Hippocrate 54, B1.54.10-10, 1200 Bruxelles, Belgium.

Type-1 cannabinoid (CB1) and leptin (ObR) receptors regulate metabolic and astroglial functions, but the potential links between the two systems in astrocytes were not investigated so far. Genetic and pharmacological manipulations of CB1 receptor expression and activity in cultured cortical and hypothalamic astrocytes demonstrated that cannabinoid signaling controls the levels of ObR expression. Lack of CB1 receptors also markedly impaired leptin-mediated activation of signal transducers and activators of transcription 3 and 5 (STAT3 and STAT5) in astrocytes. In particular, CB1 deletion determined a basal overactivation of STAT5, thereby leading to the downregulation of ObR expression, and leptin failed to regulate STAT5-dependent glycogen storage in the absence of CB1 receptors. These results show that CB1 receptors directly interfere with leptin signaling and its ability to regulate glycogen storage, thereby representing a novel mechanism linking endocannabinoid and leptin signaling in the regulation of brain energy storage and neuronal functions.
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http://dx.doi.org/10.1016/j.molmet.2013.08.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3854987PMC
December 2013

Activation of the sympathetic nervous system mediates hypophagic and anxiety-like effects of CB₁ receptor blockade.

Proc Natl Acad Sci U S A 2013 Mar 4;110(12):4786-91. Epub 2013 Mar 4.

Department of Biochemistry and Molecular Biology I and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, School of Biology, Complutense University-Instituto Universitario de Investigación Neuroquímica, 28040 Madrid, Spain.

Complex interactions between periphery and the brain regulate food intake in mammals. Cannabinoid type-1 (CB1) receptor antagonists are potent hypophagic agents, but the sites where this acute action is exerted and the underlying mechanisms are not fully elucidated. To dissect the mechanisms underlying the hypophagic effect of CB1 receptor blockade, we combined the acute injection of the CB1 receptor antagonist rimonabant with the use of conditional CB1-knockout mice, as well as with pharmacological modulation of different central and peripheral circuits. Fasting/refeeding experiments revealed that CB1 receptor signaling in many specific brain neurons is dispensable for the acute hypophagic effects of rimonabant. CB1 receptor antagonist-induced hypophagia was fully abolished by peripheral blockade of β-adrenergic transmission, suggesting that this effect is mediated by increased activity of the sympathetic nervous system. Consistently, we found that rimonabant increases gastrointestinal metabolism via increased peripheral β-adrenergic receptor signaling in peripheral organs, including the gastrointestinal tract. Blockade of both visceral afferents and glutamatergic transmission in the nucleus tractus solitarii abolished rimonabant-induced hypophagia. Importantly, these mechanisms were specifically triggered by lipid-deprivation, revealing a nutrient-specific component acutely regulated by CB1 receptor blockade. Finally, peripheral blockade of sympathetic neurotransmission also blunted central effects of CB1 receptor blockade, such as fear responses and anxiety-like behaviors. These data demonstrate that, independently of their site of origin, important effects of CB1 receptor blockade are expressed via activation of peripheral sympathetic activity. Thus, CB1 receptors modulate bidirectional circuits between the periphery and the brain to regulate feeding and other behaviors.
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http://dx.doi.org/10.1073/pnas.1218573110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3607008PMC
March 2013

Striatal GABAergic and cortical glutamatergic neurons mediate contrasting effects of cannabinoids on cortical network synchrony.

Proc Natl Acad Sci U S A 2013 Jan 26;110(2):719-24. Epub 2012 Dec 26.

Department of Systems Neuroscience, Institut d'Investigacions Biomèdiques August Pi i Sunyer, 08016 Barcelona, Spain.

Activation of type 1 cannabinoid receptors (CB1R) decreases GABA and glutamate release in cortical and subcortical regions, with complex outcomes on cortical network activity. To date there have been few attempts to disentangle the region- and cell-specific mechanisms underlying the effects of cannabinoids on cortical network activity in vivo. Here we addressed this issue by combining in vivo electrophysiological recordings with local and systemic pharmacological manipulations in conditional mutant mice lacking CB1R expression in different neuronal populations. First we report that cannabinoids induce hypersynchronous thalamocortical oscillations while decreasing the amplitude of faster cortical oscillations. Then we demonstrate that CB1R at striatonigral synapses (basal ganglia direct pathway) mediate the thalamocortical hypersynchrony, whereas activation of CB1R expressed in cortical glutamatergic neurons decreases cortical synchrony. Finally we show that activation of CB1 expressed in cortical glutamatergic neurons limits the cannabinoid-induced thalamocortical hypersynchrony. By reporting that CB1R activations in cortical and subcortical regions have contrasting effects on cortical synchrony, our study bridges the gap between cellular and in vivo network effects of cannabinoids. Incidentally, the thalamocortical hypersynchrony we report suggests a potential mechanism to explain the sensory "high" experienced during recreational consumption of marijuana.
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http://dx.doi.org/10.1073/pnas.1217144110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3545808PMC
January 2013

Ventral tegmental area cannabinoid type-1 receptors control voluntary exercise performance.

Biol Psychiatry 2013 May 11;73(9):895-903. Epub 2012 Dec 11.

Institut National de la Santé et de la Recherche Médicale-INSERM, U862, NeuroCentre Magendie, Physiopathologie de la Plasticité Neuronale, Bordeaux, France.

Background: We have shown that the endogenous stimulation of cannabinoid type-1 (CB₁) receptors is a prerequisite for voluntary running in mice, but the precise mechanisms through which the endocannabinoid system exerts a tonic control on running performance remain unknown.

Methods: We analyzed the respective impacts of constitutive/conditional CB₁ receptor mutations and of CB₁ receptor blockade on wheel-running performance. We then assessed the consequences of ventral tegmental area (VTA) CB₁ receptor blockade on the wheel-running performances of wildtype (gamma-aminobutyric acid [GABA]-CB₁⁺/⁺) and mutant (GABA-CB₁⁻/⁻) mice for CB₁ receptors in brain GABA neurons. Using in vivo electrophysiology, the consequences of wheel running on VTA dopamine (DA) neuronal activity were examined in GABA-CB₁⁺/⁺ and GABA-CB₁⁻/⁻ mice.

Results: Conditional deletion of CB₁ receptors from brain GABA neurons, but not from several other neuronal populations or from astrocytes, decreased wheel-running performance in mice. The inhibitory consequences of either the systemic or the intra-VTA administration of CB1 receptor antagonists on running behavior were abolished in GABA-CB₁⁻/⁻ mice. The absence of CB1 receptors from GABAergic neurons led to a depression of VTA DA neuronal activity after acute/repeated wheel running.

Conclusions: This study provides evidence that CB₁ receptors on VTA GABAergic terminals exert a permissive control on rodent voluntary running performance. Furthermore, it is shown that CB₁ receptors located on GABAergic neurons impede negative consequences of voluntary exercise on VTA DA neuronal activity. These results position the endocannabinoid control of inhibitory transmission as a prerequisite for wheel-running performance in mice.
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http://dx.doi.org/10.1016/j.biopsych.2012.10.025DOI Listing
May 2013

Bimodal control of fear-coping strategies by CB₁ cannabinoid receptors.

J Neurosci 2012 May;32(21):7109-18

INSERM U862, NeuroCentre Magendie, 33076 Bordeaux, France.

To maximize their chances of survival, animals need to rapidly and efficiently respond to aversive situations. These responses can be classified as active or passive and depend on the specific nature of threats, but also on individual fear coping styles. In this study, we show that the control of excitatory and inhibitory brain neurons by type-1 cannabinoid (CB₁) receptors is a key determinant of fear coping strategies in mice. In classical fear conditioning, a switch between initially predominant passive fear responses (freezing) and active behaviors (escape attempts and risk assessment) develops over time. Constitutive genetic deletion of CB₁ receptors in CB₁⁻/⁻ mice disrupted this pattern by favoring passive responses. This phenotype can be ascribed to endocannabinoid control of excitatory neurons, because it was reproduced in conditional mutant mice lacking CB₁ receptors from cortical glutamatergic neurons. CB₁ receptor deletion from GABAergic brain neurons led to the opposite phenotype, characterized by the predominance of active coping. The CB₁ receptor agonist Δ⁹-tetrahydrocannabinol exerted a biphasic control of fear coping strategies, with lower and higher doses favoring active and passive responses, respectively. Finally, viral re-expression of CB₁ receptors in the amygdala of CB₁⁻/⁻ mice restored the normal switch between the two coping strategies. These data strongly suggest that CB₁ receptor signaling bimodally controls the spontaneous adoption of active or passive coping strategies in individuals. This primary function of the endocannabinoid system in shaping individual behavioral traits should be considered when studying the mechanisms of physiological and pathological fear.
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http://dx.doi.org/10.1523/JNEUROSCI.1054-12.2012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6622289PMC
May 2012

Mitochondrial CB₁ receptors regulate neuronal energy metabolism.

Nat Neurosci 2012 Mar 4;15(4):558-64. Epub 2012 Mar 4.

INSERM, Neurocentre Magendie, Physiopathologie de plasticité neuronale, Endocannabinoids and Neuroadaptation, U862, Bordeaux, France.

The mammalian brain is one of the organs with the highest energy demands, and mitochondria are key determinants of its functions. Here we show that the type-1 cannabinoid receptor (CB(1)) is present at the membranes of mouse neuronal mitochondria (mtCB(1)), where it directly controls cellular respiration and energy production. Through activation of mtCB(1) receptors, exogenous cannabinoids and in situ endocannabinoids decreased cyclic AMP concentration, protein kinase A activity, complex I enzymatic activity and respiration in neuronal mitochondria. In addition, intracellular CB(1) receptors and mitochondrial mechanisms contributed to endocannabinoid-dependent depolarization-induced suppression of inhibition in the hippocampus. Thus, mtCB(1) receptors directly modulate neuronal energy metabolism, revealing a new mechanism of action of G protein-coupled receptor signaling in the brain.
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http://dx.doi.org/10.1038/nn.3053DOI Listing
March 2012

Oleamide administered into the nucleus accumbens shell regulates feeding behaviour via CB1 and 5-HT2C receptors.

Int J Neuropsychopharmacol 2010 Oct 22;13(9):1247-54. Epub 2010 Jul 22.

Laboratorio de Canabinoides, Departamento de Fisiología, Facultad de Medicina, UNAM, México, DF, Mexico.

The central nervous system control of food intake has been extensively studied, hence, several neurotransmitter systems regulating this function are now clearly identified, for example, the endocannabinoid and serotoninergic systems. The former stimulates feeding while the latter inhibits it. Oleamide (Ole) is a cannabimimetic molecule affecting both systems. In this work, we tested the orexigenic and anorectic potential of Ole when administered into the nucleus accumbens shell (NAcS), a brain region that has been related to the orexigenic effects of cannabinoids. Additionally, we tested if Ole administered into this nucleus affects the activity of the hypothalamic nuclei involved in feeding behaviour, just as other cannabinoids do. We found a hyperphagic effect of Ole that is mediated through CB1 activation. The combination of Ole and the CB1 antagonist, AM251, produced a hypophagia that was fully blocked by SB212084, a 5-HT2C receptor antagonist. We also show that blockade of 5-HT2C and 5-HT2A receptors in the NAcS stimulates food intake. Finally, the combination of Ole and AM251 activates hypothalamic nuclei, an effect also blocked by SB242084. In conclusion, we show, for the first time, that Ole administered into the NAcS has a dual effect on feeding behaviour, acting through cannabinoid and serotonin receptors. These effects probably result from a downstream interaction with the hypothalamus.
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http://dx.doi.org/10.1017/S1461145710000702DOI Listing
October 2010

Intrahippocampal administration of anandamide increases REM sleep.

Neurosci Lett 2010 Apr 24;473(2):158-62. Epub 2010 Feb 24.

Grupo de Neurociencias, Depto. de Fisiología, Fac. de Medicina, UNAM, Mexico, D.F. 045 10, Mexico.

A nascent literature has postulated endocannabinoids (eCBs) as strong sleep-inducing lipids, particularly rapid-eye-movement sleep (REMs), nevertheless the exact mechanisms behind this effect remain to be determined. Anandamide and 2-arachidonyl glycerol, two of the most important eCBS, are synthesized in the hippocampus. This structure also expresses a high concentration of cannabinoid receptor 1 (CB1). Recent extensive literature supports eCBs as important regulators of hippocampal activity. It has also been shown that these molecules vary their expression on the hippocampus depending on the light-dark cycle. In this context we decided to analyze the effect of intrahippocampal administration of the eCB anandamide (ANA) on the sleep-waking cycle at two points of the light-dark cycle. Our data indicate that the administration of ANA directly into the hippocampus increases REMs in a dose dependent manner during the dark but not during the light phase of the cycle. The increase of REMs was blocked by the CB1 antagonist AM251. This effect was specific for the hippocampus since ANA administrations in the surrounding cortex did not elicit any change in REMs. These results support the idea of a direct relationship between hippocampal activity and sleep mechanisms by means of eCBs. The data presented here show, for the first time that eCBs administered into the hippocampus trigger REMs and support previous studies where chemical stimulation of limbic areas triggered sleep.
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http://dx.doi.org/10.1016/j.neulet.2010.02.044DOI Listing
April 2010

BCL-2 and BAX proteins expression throughout the light-dark cycle and modifications induced by sleep deprivation and rebound in adult rat brain.

J Neurosci Res 2009 May;87(7):1602-9

Grupo de Neurociencias, Depto. de Fisiología, Facultad de Medicina, Universidad Nacional Autónoma de México, D.F., Mexico.

It has been suggested that sleep has a restorative function; however, experimental support is limited. Hence, we investigated whether changes in the level of antiapoptotic BCL-2 protein and proapoptotic BAX protein occur during sleep deprivation (SD) and sleep rebound, and evaluated the spontaneous changes in these proteins, along the light-dark cycle, in the adult male Wistar rat. Estimations were made in the prefrontal cortex, hippocampus, striatum, and pons. We observed that BCL-2 exhibited diurnal variations in the prefrontal cortex and striatum, whereas BAX varied in the striatum and showed only small variations in the pons as measured by immunoblotting. The BCL-2/BAX ratio exhibited diurnal variations in the prefrontal cortex and striatum. BCL-2 and BAX levels were affected by 24 hr of total SD and 24 hr of sleep rebound. SD decreased the BCL-2/BAX ratio in the prefrontal cortex and pons. Sleep rebound increased the BCL-2/BAX ratio in the hippocampus. In conclusion, the BCL-2/BAX ratio is high during the dark phase as compared with the light phase in the prefrontal cortex and during the light phase as compared with the dark phase in the striatum. SD decreased the BCL-2/BAX ratio in the prefrontal cortex and pons, whereas sleep rebound increased it in the hippocampus. These changes point out structures in the brain that express these proteins as a response to the light-dark cycle. Similarly, SD and sleep rebound seem to change these proteins expression in some other brain structures, suggesting that cellular vulnerability might be altered by these changes.
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http://dx.doi.org/10.1002/jnr.21987DOI Listing
May 2009

Impairment of endocannabinoids activity in the dorsolateral striatum delays extinction of behavior in a procedural memory task in rats.

Neuropharmacology 2008 Jul 25;55(1):55-62. Epub 2008 Apr 25.

Grupo de Neurociencias, Departmento de Fisiología, Facultad de Medicina, UNAM, Laboratorio 601, Apartado Postal 70-250, Mexico City, D.F. 04510, Mexico.

The dorsolateral striatum (DLS) has been implicated in the learning of habits and procedural memories. Extinction of this kind of memories has been poorly studied. The DLS expresses high levels of the cannabinergic receptor one (CB1), and, lately, it has been suggested that the activation of CB1 in this structure is indispensable for long-term depression (LTD) development. We performed experiments in a T-maze and evaluated the effects of intrastriatal and intrahipocampal administration of the CB1 antagonist AM251 on extinction and on c-Fos expression. We also administered anandamide to evaluate if an artificial increase of endocannabinoids facilitates extinction. Our results indicate clearly a dose-response blockade of extinction induced by AM251 injected into the striatum but a facilitation of extinction when administered into the hippocampus. Anandamide did not induce any observable changes. AM251 effects were accompanied by an increase in c-Fos immunoreactivity in the DLS and its decrease in the hippocampal region, suggesting that the activation of CB1 in the striatum is necessary for the extinction of procedural memories. These findings could be important in some neurological conditions, such as obsessive-compulsive disorder in which striatal activity seems to be abnormal.
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http://dx.doi.org/10.1016/j.neuropharm.2008.04.013DOI Listing
July 2008

A potential function of endocannabinoids in the selection of a navigation strategy by rats.

Psychopharmacology (Berl) 2008 Jul 6;198(4):565-76. Epub 2007 Sep 6.

Grupo de Neurociencias, Depto. de Fisiología, Fac. de Medicina, UNAM, Apdo., Postal 70-250, Mexico, D.F., 04510, Mexico.

Rationale: One of the adaptive abilities of the brain is the generation of a strategy to optimize acquisition of information, i.e., learning. In this study, we explored the role of environmental conditions (the light-dark cycle) and of the endocannabinoid anandamide in rats to select a strategy to solve the Barnes maze (BM).

Objectives: To determine the effects of manipulating the cannabinergic system on a spatial task in relation to the light-dark cycle.

Materials And Methods: Rats received an intrahippocampal or intrastriatal administration of anandamide, AM251, or their combination at two different points of the light-dark cycle (1300 and 0100 hours), and their performance in the BM was evaluated. In addition, we determined the expression of the cannabinoid 1 receptor (CB1R) in the hippocampus and striatum throughout the light-dark cycle.

Results: Results indicate that rats solved the BM by using a spatial strategy during the light phase and a procedural (serial) strategy during the dark phase of the cycle. CB1R expression varied in the hippocampus, being higher at 1300 hours and lower at 0100 hours, whereas its expression remained unchanged in the striatum.

Conclusions: Changes in the brain, which include changes in the endocannabinoid system, prompt it to use different strategies (spatial and procedural, or others not evaluated in this study) to cope with the environmental demands. These cerebral changes are adaptive responses to the light-dark cycle.
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http://dx.doi.org/10.1007/s00213-007-0911-zDOI Listing
July 2008