7 research outputs found
Dynamic interplay between thalamic activity and Cajal-Retzius cells regulates the wiring of cortical layer 1
Cortical wiring relies on guidepost cells and activity-dependent processes that are thought to act sequentially. Here, we show that the construction of layer 1 (L1), a main site of top-down integration, is regulated by crosstalk between transient Cajal-Retzius cells (CRc) and spontaneous activity of the thalamus, a main driver of bottom-up information. While activity was known to regulate CRc migration and elimination, we found that prenatal spontaneous thalamic activity and NMDA receptors selectively control CRc early density, without affecting their demise. CRc density, in turn, regulates the distribution of upper layer interneurons and excitatory synapses, thereby drastically impairing the apical dendrite activity of output pyramidal neurons. In contrast, postnatal sensory-evoked activity had a limited impact on L1 and selectively perturbed basal dendrites synaptogenesis. Collectively, our study highlights a remarkable interplay between thalamic activity and CRc in L1 functional wiring, with major implications for our understanding of cortical development.We thank the IBENS Imaging Facility (France BioImaging, supported by ANR-10-INBS-04, ANR-10-LABX-54 MEMO LIFE, and ANR-11-IDEX-000-02 PSLâ Research University, âInvestments for the Futureâ). This work was supported by grants from the Spanish Ministry of Science, Innovation, and Universities (PGC2018-096631-B-I00) and the European Research Council (ERC-2014-CoG-647012) to G.L.-B. N.C. received funding from the Marie SkĆodowska-Curie individual fellowship under the European Unionâs Horizon 2020 research and innovation program (AXO-MATH, grant agreement no. 798326). F.G. received funding from the Agence Nationale de la Recherche (SyTune, ANR-21-CE37-0010), the European Research Council under the European Unionâs Horizon 2020 research and innovation program (NEUROGOAL, grant agreement no.677878), the Region Nouvelle-Aquitaine, and the University of Bordeaux. The Garel laboratory is supported by INSERM, CNRS, ANR-15-CE16-0003, ANR-19-CE16-0017-02, Investissements dâAvenir implemented by ANR-10-LABX-54 MEMO LIFE, ANR-11-IDEX-0001-02 PSLâ Research University, and the European Research Council (ERC-2013-CoG-616080, NImO). I.G. is a recipient of a fellowship from the French Ministry of Research and postdoctoral funding from Labex MemoLife, and S.G. is part of the Ecole des Neurosciences de Paris Ile-de-France network.Peer reviewe
Caractérisation fonctionnelle des projections de l'Amygdale vers les zones motrices du cortex frontal lors de l'action-sélection adaptative
Animals daily face complex situations that require adapted responses for surviving. The process of evaluating the available actions and selecting the one that appears the most relevant is called âaction-selectionâ. It requires prior building of a fine mental model that associate actions to their outcomes, often via a process of âreinforcement learningâ. Despite pieces of evidence about several brain regions with neural activity correlating with choice, the circuit and neuronal mechanisms that select actions remain discussed. Recent studies highlight the secondary motor cortex (MOs), at the interface of sensory integration and motor processing, as a credible candidate for computing action-selection. Indeed, neural activity states predicting choice have been unveiled in the MOs of rodents and its inactivation biases the selection of actions. These studies almost exclusively focused on expert animals but information about how actions are encoded in naive animals and during learning are still lacking. In a first study (Aime*, Augusto*, Kouskoff et al., 2020), we have highlighted that the MOs receives inputs from the Basolateral Amygdala (BLA), a structure known for its importance in associative learning. We have shown that BLA inputs to the MOs facilitate the discrimination of sounds associated to different outcomes in the context of associative fear learning. In a similar way, one could imagine that the BLA provides associative signals to help MOs discriminate actions with positive values. A major aim of the present doctoral work is the characterization of the role of these BLA- to-MOs projections during the learning of rewarding actions. To address this goal, we first developed a rewarding, self-driven action-selection paradigm for head-restrained mice allowing chronic two-photon microscopy of neuronal compartments through the different steps of learning. Using somatic calcium imaging and optogenetic, we have highlighted the implication of MOs in performing the task. Then, we have imaged and analyzed the activity of specific BLA boutons connecting to MOs over weeks of behavior, a technical challenge (because of the small size of boutons and weak signals) rarely undertaken so far. Altogether, the results presented in this thesis provide both novel evidences for the role of MOs in action-selection and for the importance of BLA to MOs projections for associative learningLes animaux sont confrontĂ©s quotidiennement Ă des situations complexes qui exigent des rĂ©ponses adaptĂ©es pour survivre. Le processus d'Ă©valuation des actions disponibles et de sĂ©lection de celle qui semble la plus pertinente est appelĂ© "action-sĂ©lection". Il nĂ©cessite la construction prĂ©alable d'un modĂšle mental fin qui associe les actions Ă leurs consĂ©quences, souvent par un processus d'apprentissage par renforcement. MalgrĂ© la collecte de donnĂ©es montrant des activitĂ©s neuronales en corrĂ©lation avec le choix dans plusieurs rĂ©gions du cerveau, le circuit et les mĂ©canismes neuronaux qui sĂ©lectionnent les actions restent discutĂ©s. Des Ă©tudes rĂ©centes mettent en Ă©vidence le cortex moteur secondaire (MOs), Ă l'interface de l'intĂ©gration sensorielle et du traitement moteur, comme un candidat crĂ©dible pour le calcul de lâaction-sĂ©lection. En effet, des Ă©tats d'activitĂ© neuronale prĂ©disant le choix ont Ă©tĂ© dĂ©voilĂ©s dans le MOs des rongeurs et son inactivation a pour effet de biaiser la sĂ©lection des actions. Ces Ă©tudes ont presque exclusivement portĂ© sur des animaux experts, ainsi les informations sur la maniĂšre dont les actions sont encodĂ©es chez les animaux naĂŻfs et pendant l'apprentissage font encore dĂ©faut. Dans une premiĂšre Ă©tude (Aime*, Augusto*, Kouskoff et al., 2020), nous avons soulignĂ© que le MOs reçoit des affĂ©rences de l'Amygdale BasolatĂ©rale (BLA), une structure connue pour son importance dans l'apprentissage associatif. Nous avons montrĂ© que les affĂ©rences de la BLA au MOs facilitent la discrimination de sons associĂ©s Ă diffĂ©rentes consĂ©quences dans un contexte dâapprentissage associatif de peur. De la mĂȘme maniĂšre, il est facile dâimaginer que la BLA puisse fournir des signaux associatifs au MOs afin dâaider Ă discriminer les actions ayant des valeurs positives.Un objectif majeur de cette Ă©tude doctorale est la caractĂ©risation du rĂŽle des projections de la BLA vers le MOs pendant l'apprentissage d'actions menant Ă une rĂ©compense. Pour atteindre cet objectif, nous avons d'abord dĂ©veloppĂ© un paradigme de sĂ©lection d'actions non guidĂ© menant Ă une rĂ©compense pour souris en tĂȘte restreinte. Cela nous permet, par microscopie Ă deux photons, lâacquisition chronique de compartiments neuronaux au cours des diffĂ©rentes Ă©tapes de l'apprentissage. A lâaide d'imagerie-calcique somatique et d'optogĂ©nĂ©tique, nous avons mis en Ă©vidence l'implication du MOs dans l'exĂ©cution de 10 cette tĂąche comportementale. Ensuite, nous avons Ă©galement imagĂ© et analysĂ© l'activitĂ© de boutons synaptiques de la BLA au sein du MOs au long des semaines de la tĂąche comportementale, un dĂ©fi technique (en raison de la taille des boutons et de la faible amplitude des signaux) rarement entrepris jusqu'Ă prĂ©sent. Dans l'ensemble, les rĂ©sultats prĂ©sentĂ©s dans cette thĂšse fournissent de nouvelles preuves du rĂŽle du MOs dans lâaction-sĂ©lection et de l'importance des projections de la BLA vers le MOs lors d'apprentissages associatifs
Functional characterization of Amygdala projections to motor related cortices during adaptive action-selection
Les animaux sont confrontĂ©s quotidiennement Ă des situations complexes qui exigent des rĂ©ponses adaptĂ©es pour survivre. Le processus d'Ă©valuation des actions disponibles et de sĂ©lection de celle qui semble la plus pertinente est appelĂ© "action-sĂ©lection". Il nĂ©cessite la construction prĂ©alable d'un modĂšle mental fin qui associe les actions Ă leurs consĂ©quences, souvent par un processus d'apprentissage par renforcement. MalgrĂ© la collecte de donnĂ©es montrant des activitĂ©s neuronales en corrĂ©lation avec le choix dans plusieurs rĂ©gions du cerveau, le circuit et les mĂ©canismes neuronaux qui sĂ©lectionnent les actions restent discutĂ©s. Des Ă©tudes rĂ©centes mettent en Ă©vidence le cortex moteur secondaire (MOs), Ă l'interface de l'intĂ©gration sensorielle et du traitement moteur, comme un candidat crĂ©dible pour le calcul de lâaction-sĂ©lection. En effet, des Ă©tats d'activitĂ© neuronale prĂ©disant le choix ont Ă©tĂ© dĂ©voilĂ©s dans le MOs des rongeurs et son inactivation a pour effet de biaiser la sĂ©lection des actions. Ces Ă©tudes ont presque exclusivement portĂ© sur des animaux experts, ainsi les informations sur la maniĂšre dont les actions sont encodĂ©es chez les animaux naĂŻfs et pendant l'apprentissage font encore dĂ©faut. Dans une premiĂšre Ă©tude (Aime*, Augusto*, Kouskoff et al., 2020), nous avons soulignĂ© que le MOs reçoit des affĂ©rences de l'Amygdale BasolatĂ©rale (BLA), une structure connue pour son importance dans l'apprentissage associatif. Nous avons montrĂ© que les affĂ©rences de la BLA au MOs facilitent la discrimination de sons associĂ©s Ă diffĂ©rentes consĂ©quences dans un contexte dâapprentissage associatif de peur. De la mĂȘme maniĂšre, il est facile dâimaginer que la BLA puisse fournir des signaux associatifs au MOs afin dâaider Ă discriminer les actions ayant des valeurs positives.Un objectif majeur de cette Ă©tude doctorale est la caractĂ©risation du rĂŽle des projections de la BLA vers le MOs pendant l'apprentissage d'actions menant Ă une rĂ©compense. Pour atteindre cet objectif, nous avons d'abord dĂ©veloppĂ© un paradigme de sĂ©lection d'actions non guidĂ© menant Ă une rĂ©compense pour souris en tĂȘte restreinte. Cela nous permet, par microscopie Ă deux photons, lâacquisition chronique de compartiments neuronaux au cours des diffĂ©rentes Ă©tapes de l'apprentissage. A lâaide d'imagerie-calcique somatique et d'optogĂ©nĂ©tique, nous avons mis en Ă©vidence l'implication du MOs dans l'exĂ©cution de 10 cette tĂąche comportementale. Ensuite, nous avons Ă©galement imagĂ© et analysĂ© l'activitĂ© de boutons synaptiques de la BLA au sein du MOs au long des semaines de la tĂąche comportementale, un dĂ©fi technique (en raison de la taille des boutons et de la faible amplitude des signaux) rarement entrepris jusqu'Ă prĂ©sent. Dans l'ensemble, les rĂ©sultats prĂ©sentĂ©s dans cette thĂšse fournissent de nouvelles preuves du rĂŽle du MOs dans lâaction-sĂ©lection et de l'importance des projections de la BLA vers le MOs lors d'apprentissages associatifs.Animals daily face complex situations that require adapted responses for surviving. The process of evaluating the available actions and selecting the one that appears the most relevant is called âaction-selectionâ. It requires prior building of a fine mental model that associate actions to their outcomes, often via a process of âreinforcement learningâ. Despite pieces of evidence about several brain regions with neural activity correlating with choice, the circuit and neuronal mechanisms that select actions remain discussed. Recent studies highlight the secondary motor cortex (MOs), at the interface of sensory integration and motor processing, as a credible candidate for computing action-selection. Indeed, neural activity states predicting choice have been unveiled in the MOs of rodents and its inactivation biases the selection of actions. These studies almost exclusively focused on expert animals but information about how actions are encoded in naive animals and during learning are still lacking. In a first study (Aime*, Augusto*, Kouskoff et al., 2020), we have highlighted that the MOs receives inputs from the Basolateral Amygdala (BLA), a structure known for its importance in associative learning. We have shown that BLA inputs to the MOs facilitate the discrimination of sounds associated to different outcomes in the context of associative fear learning. In a similar way, one could imagine that the BLA provides associative signals to help MOs discriminate actions with positive values. A major aim of the present doctoral work is the characterization of the role of these BLA- to-MOs projections during the learning of rewarding actions. To address this goal, we first developed a rewarding, self-driven action-selection paradigm for head-restrained mice allowing chronic two-photon microscopy of neuronal compartments through the different steps of learning. Using somatic calcium imaging and optogenetic, we have highlighted the implication of MOs in performing the task. Then, we have imaged and analyzed the activity of specific BLA boutons connecting to MOs over weeks of behavior, a technical challenge (because of the small size of boutons and weak signals) rarely undertaken so far. Altogether, the results presented in this thesis provide both novel evidences for the role of MOs in action-selection and for the importance of BLA to MOs projections for associative learnin
An increase in dendritic plateau potentials is associated with experience-dependent cortical map reorganization
Significance
Here we describe a mechanism for cortical map plasticity. Classically, representational map changes are thought to be driven by changes within cortico-cortical circuits, e.g., Hebbian plasticity of synaptic circuits that lost vs. maintained an excitatory drive from the first-order thalamus, possibly steered by neuromodulatory forces from deep brain regions. Our work provides evidence for an additional gating mechanism, provided by plateau potentials, which are driven by higher-order thalamic feedback. Higher-order thalamic neurons are characterized by broad receptive fields, and the plateau potentials that they evoke strongly facilitate long-term potentiation and elicit spikes. We show that these features combined constitute a powerful driving force for the fusion or expansion of sensory representations within cortical maps.</p
bioRxiv 569137; https://doi.org/10.1101/569137
bioRxiv 569137; doi: https://doi.org/10.1101/56913
Astroglial ER-mitochondria calcium transfer mediates endocannabinoid-dependent synaptic integration
International audienceIntracellular calcium signaling underlies the astroglial control of synaptic transmission and plasticity. Mitochondria-endoplasmic reticulum contacts (MERCs) are key determinants of calcium dynamics, but their functional impact on astroglial regulation of brain information processing is currently unexplored. We found that the activation of astrocyte mitochondrial-associated CB1 receptors (mtCB1) determines MERCs-dependent intracellular calcium signaling and synaptic integration. The stimulation of mtCB1 receptors promotes calcium transfer from the endoplasmic reticulum to mitochondria through a specific molecular cascade, involving the mitochondrial calcium uniporter (MCU). Physiologically, mtCB1-dependent mitochondrial calcium uptake determines the dynamics of cytosolic calcium events in astrocytes upon endocannabinoid mobilization. Accordingly, electrophysiological recordings in hippocampal slices showed that conditional genetic exclusion of mtCB1 receptors or dominant negative MCU expression in astrocytes blocks lateral synaptic potentiation, through which astrocytes integrate the activity of distant synapses. Altogether, these data reveal an endocannabinoid link between astroglial MERCs and the regulation of brain network functions
Astroglial ER-mitochondria calcium transfer mediates endocannabinoid-dependent synaptic integration
International audienceIntracellular calcium signaling underlies the astroglial control of synaptic transmission and plasticity. Mitochondria-endoplasmic reticulum contacts (MERCs) are key determinants of calcium dynamics, but their functional impact on astroglial regulation of brain information processing is unexplored. We found that the activation of astrocyte mitochondrial-associated type-1 cannabinoid (mtCB1) receptors determines MERC-dependent intracellular calcium signaling and synaptic integration. The stimulation of mtCB1 receptors promotes calcium transfer from the endoplasmic reticulum to mitochondria through a specific molecular cascade, involving the mitochondrial calcium uniporter (MCU). Physiologically, mtCB1-dependent mitochondrial calcium uptake determines the dynamics of cytosolic calcium events in astrocytes upon endocannabinoid mobilization. Accordingly, electrophysiological recordings in hippocampal slices showed that conditional genetic exclusion of mtCB1 receptors or dominant-negative MCU expression in astrocytes blocks lateral synaptic potentiation, through which astrocytes integrate the activity of distant synapses. Altogether, these data reveal an endocannabinoid link between astroglial MERCs and the regulation of brain network functions