539 research outputs found

    Parallel Computational Subunits in Dentate Granule Cells Generate Multiple Place Fields

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    A fundamental question in understanding neuronal computations is how dendritic events influence the output of the neuron. Different forms of integration of neighbouring and distributed synaptic inputs, isolated dendritic spikes and local regulation of synaptic efficacy suggest that individual dendritic branches may function as independent computational subunits. In the present paper, we study how these local computations influence the output of the neuron. Using a simple cascade model, we demonstrate that triggering somatic firing by a relatively small dendritic branch requires the amplification of local events by dendritic spiking and synaptic plasticity. The moderately branching dendritic tree of granule cells seems optimal for this computation since larger dendritic trees favor local plasticity by isolating dendritic compartments, while reliable detection of individual dendritic spikes in the soma requires a low branch number. Finally, we demonstrate that these parallel dendritic computations could contribute to the generation of multiple independent place fields of hippocampal granule cells

    Dendritic integration in hippocampal dentate gyrus granule cells

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    Hippocampal granule cells are critical relay stations to transfer spatial information from the entorhinal cortex into the hippocampus proper. Therefore, the integrative properties of the small-caliber granule cell dendrites were examined in this thesis, using a combination of dual somato-dendritic patch-clamp recordings and two-photon glutamate uncaging. These experiments revealed unusual integrative properties that differ substantially from other principal neurons. Due to a strong dendritic voltage attenuation, the impact of individual synapses on granule cell output is low. At the same time, integration is linear, only weakly affected by input synchrony, and is independent of the spatial location of input sites. These integrative properties can enhance contrast in the generation of place-specific firing maps from entorhinal inputs and contribute to the sparse representation of space in the dentate gyrus

    Fast-spiking parvalbumin^+ GABAergic interneurons: From cellular design to microcircuit function

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    The success story of fast-spiking, parvalbumin-positive (PV+) GABAergic interneurons (GABA, γ-aminobutyric acid) in the mammalian central nervous system is noteworthy. In 1995, the properties of these interneurons were completely unknown. Twenty years later, thanks to the massive use of subcellular patch-clamp techniques, simultaneous multiple-cell recording, optogenetics, in vivo measurements, and computational approaches, our knowledge about PV+ interneurons became more extensive than for several types of pyramidal neurons. These findings have implications beyond the “small world” of basic research on GABAergic cells. For example, the results provide a first proof of principle that neuroscientists might be able to close the gaps between the molecular, cellular, network, and behavioral levels, representing one of the main challenges at the present time. Furthermore, the results may form the basis for PV+ interneurons as therapeutic targets for brain disease in the future. However, much needs to be learned about the basic function of these interneurons before clinical neuroscientists will be able to use PV+ interneurons for therapeutic purposes

    Slow Inhibition and Inhibitory Recruitment in the Hippocampal Dentate Gyrus

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    L’hippocampe joue un rĂŽle central dans la navigation spatiale, la mĂ©moire et l’organisation spatio-temporelle des souvenirs. Ces fonctions sont maintenues par la capacitĂ© du gyrus dentĂ© (GD) de sĂ©paration des patrons d'activitĂ© neuronales. Le GD est situĂ© Ă  l’entrĂ©e de la formation hippocampique oĂč il reconnaĂźt la prĂ©sence de nouveaux motifs parmi la densitĂ© de signaux affĂ©rant arrivant par la voie entorhinale (voie perforante). Le codage parcimonieux est la marque distinctive du GD. Ce type de codage est le rĂ©sultat de la faible excitabilitĂ© intrinsĂšque des cellules granulaires (CGs) en combinaison avec une inhibition locale prĂ©dominante. En particulier, l’inhibition de type « feedforward » ou circuit inhibiteur antĂ©rograde, est engagĂ©e par la voie perforante en mĂȘme temps que les CGs. Ainsi les interneurones du circuit antĂ©rograde fournissent des signaux GABAergique aux CGs de maniĂšre presque simultanĂ©e qu’elles reçoivent les signaux glutamatergiques. Cette thĂšse est centrĂ©e sur l’étude des interactions entre ces signaux excitateurs de la voie entorhinale et les signaux inhibiteurs provenant des interneurones rĂ©sidant dans le GD et ceci dans le contexte du codage parcimonieux et le patron de dĂ©charge en rafale caractĂ©ristique des cellules granulaires. Nous avons adressĂ© les relations entre les projections entorhinales et le rĂ©seau inhibitoire antĂ©rograde du GD en faisant des enregistrements Ă©lectrophysiologiques des CG pendant que la voie perforante est stimulĂ©e de maniĂšre Ă©lectrique ou optogĂ©nĂ©tique. Nous avons dĂ©couvert un nouvel mĂ©canisme d’inhibition qui apparait Ă  dĂ©lais dans les CGs suite Ă  une stimulation dans les frĂ©quences gamma. Ce mĂ©canisme induit une hyperpolarisation de longue durĂ©e (HLD) et d’une amplitude prononce. Cette longue hyperpolarisation est particuliĂšrement prolongĂ©e et dĂ©passe la durĂ©e d’autres types d’inhibition transitoire lente dĂ©crits chez les CGs. L’induction de HLD crĂ©e une fenĂȘtre temporaire de faible excitabilitĂ© suite Ă  laquelle le patron de dĂ©charge des CGs et l’intĂ©gration d’autres signaux excitateurs sont altĂ©rĂ©s de maniĂšre transitoire. Nous avons donc conclu que l’activitĂ© inhibitrice antĂ©rograde joue un rĂŽle central dans les processus de codage dans le GD. Cependant, alors qu’il existe une multitude d’études dĂ©crivant les interneurones qui font partie de ce circuit inhibiteur, la question de comment ces cellules sont recrutĂ©es par la voie entorhinale reste quelque peu explorĂ©e. Pour apprendre plus Ă  ce sujet, nous avons enregistrĂ© des interneurones rĂ©sidant iii dans la couche molĂ©culaire du GD tout en stimulant la voie perforante de maniĂšre optogĂ©nĂ©tique. Cette mĂ©thode de stimulation nous a permis d’induire la libĂ©ration de glutamate endogĂšne des terminales entorhinales et ainsi d’observer le recrutement purement synaptique d’interneurones. De maniĂšre surprenante, les rĂ©sultats de cette expĂ©rience dĂ©montrent un faible taux d’activation des interneurones, accompagnĂ© d’un tout aussi faible nombre total de potentiels d’action Ă©mis en rĂ©ponse Ă  la stimulation mĂȘme Ă  haute frĂ©quence. Ce constat semble contre-intuitif Ă©tant donnĂ© qu’en gĂ©nĂ©rale on assume qu’une forte activitĂ© inhibitrice est requise pour le maintien du codage parcimonieux. Tout de mĂȘme, l’analyse des patrons de dĂ©charge des interneurones qui ont Ă©tĂ© activĂ©s a fait ressortir la prĂ©Ă©minence de trois grands types: dĂ©charge prĂ©coce, retardĂ©e ou rĂ©guliĂšre par rapport le dĂ©but des pulses lumineux. Les rĂ©sultats obtenus durant cette thĂšse mettent la lumiĂšre sur l’important consĂ©quences fonctionnelles des interactions synaptique et polysynaptique de nature transitoire dans les rĂ©seaux neuronaux. Nous aimerions aussi souligner l’effet prononcĂ© de l’inhibition Ă  court terme du type prolongĂ©e sur l’excitabilitĂ© des neurones et leurs capacitĂ©s d’émettre des potentiels d’action. De plus que cet effet est encore plus prononcĂ© dans le cas de HLD dont la durĂ©e dĂ©passe souvent la seconde et altĂšre l’intĂ©gration d’autres signaux arrivants simultanĂ©ment. Donc on croit que les effets de HLD se traduisent au niveau du rĂ©seaux neuronal du GD comme une composante cruciale pour le codage parcimonieux. En effet, ce type de codage semble ĂȘtre la marque distinctive de cette rĂ©gion Ă©tant donnĂ© que nous avons aussi observĂ© un faible niveau d’activation chez les interneurones. Cependant, le manque d’activitĂ© accrue du rĂ©seau inhibiteur antĂ©rograde peut ĂȘtre compensĂ© par le maintien d’un gradient GABAergique constant Ă  travers le GD via l’alternance des trois modes de dĂ©charges des interneurones. En conclusion, il semble que le codage parcimonieux dans le GD peut ĂȘtre prĂ©servĂ© mĂȘme en absence d’activitĂ© soutenue du rĂ©seau inhibiteur antĂ©rograde et ceci grĂące Ă  des mĂ©canismes alternatives d’inhibition prolongĂ©e Ă  court terme.The hippocampus is implicated in spatial navigation, the generation and recall of memories, as well as their spatio-temporal organization. These functions are supported by the processes of pattern separation that occurs in the dentate gyrus (DG). Situated at the entry of the hippocampal formation, the DG is well placed to detect and sort novelty patterns amongst the high-density excitatory signals that arrive via the entorhinal cortex (EC). A hallmark of the DG is sparse encoding that is enabled by a combination of low intrinsic excitability of the principal cells and local inhibition. Feedforward inhibition (FFI) is recruited directly by the EC and simultaneously with the granule cells (GCs). Therefore, FFI provides fast GABA release and shapes input integration at the millisecond time scale. This thesis aimed to investigate the interplay of entorhinal excitatory signals with GCs and interneurons, from the FFI in the DG, in the framework of sparse encoding and GC’s characteristic burst firing. We addressed the long-range excitation – local inhibitory network interactions using electrophysiological recordings of GCs – while applying an electrical or optogenetic stimulation of the perforant path (PP) in the DG. We discovered and described a novel delayed-onset inhibitory post synaptic potential (IPSP) in GCs, following PP stimulation in the gamma frequency range. Most importantly, the IPSP was characterized by a large amplitude and prolonged decay, outlasting previously described slow inhibitory events in GCs. The long-lasting hyperpolarization (LLH) caused by the slow IPSPs generates a low excitability time window, alters the GCs firing pattern, and interferes with other stimuli that arrive simultaneously. FFI is therefore a key player in the computational processes that occurs in the DG. However, while many studies have been dedicated to the description of the various types of the interneurons from the FFI, the question of how these cells are synaptically recruited by the EC remains not entirely elucidated. We tackled this problem by recording from interneurons in the DG molecular layer during PP-specific optogenetic stimulation. Light-driven activation of the EC terminals enabled a purely synaptic recruitment of interneurons via endogenous glutamate release. We found that this method of stimulation recruits only a subset of interneurons. In addition, the total number of action potentials (AP) was surprisingly low even at high frequency stimulation. This result is counterintuitive, as strong and persistent inhibitory signals are assumed to restrict GC v activation and maintain sparseness. However, amongst the early firing interneurons, late and regular spiking patterns were clearly distinguishable. Interestingly, some interneurons expressed LLH similar to the GCs, arguing that it could be a commonly used mechanism for regulation of excitability across the hippocampal network. In summary, we show that slow inhibition can result in a prolonged hyperpolarization that significantly alters concurrent input’s integration. We believe that these interactions contribute to important computational processes such as sparse encoding. Interestingly, sparseness seems to be the hallmark of the DG, as we observed a rather low activation of the interneuron network as well. However, the alternating firing of ML-INs could compensate the lack of persistent activity by the continuous GABA release across the DG. Taken together these results offer an insight into a mechanism of feedforward inhibition serving as a sparse neural code generator in the DG

    Normal And Epilepsy-Associated Pathologic Function Of The Dentate Gyrus

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    The dentate gyrus plays critical roles both in cognitive processing and in regulating propagation of pathological, synchronous activity through the limbic system. The cellular and circuit mechanisms underlying these diverse functions overlap extensively. At the cellular level, the intrinsic properties of dentate granule cells combine to make these neurons fundamentally reluctant to activate, one of their hallmark traits. At the circuit level, the dentate gyrus is one of the more heavily inhibited regions of the brain, with powerful feedforward and feedback GABAergic inhibition dominating responses to afferent activation. In pathologic states such as epilepsy, disease-associated alterations within the dentate gyrus combine to compromise this circuit’s regulatory properties, culminating in a collapse of its normal function. Through the use of dynamic circuit imaging and electrophysiological brain slice recordings, pharmacology, immunohistochemistry, and a pilocarpine model of epilepsy, I characterize the emergence of dentate granule cell firing properties during brain development and then examine how the circuit’s normal activation properties become corrupted as epilepsy develops. I find that, in the perinatal brain, dentate granule cells activate in large numbers. As animals mature, these cells become less excitable and activate in extremely sparse populations in a precise, repeatable, frequency-dependent manner. This sparse activation is mediated by local circuit inhibition and not by alterations in afferent innervation of granule cells. Later, in a pilocarpine model of epilepsy, I demonstrate that normally sparse granule cell activation is massively enhanced during both epilepsy development and expression. This augmentation in excitability is mediated primarily by local disinhibition, and the mechanistic cause of this compromised inhibitory function varies over time following epileptogenic injury. My results implicate a reduction in chloride ion extrusion as a mechanism compromising inhibitory function and contributing to granule cell hyperactivation specifically during early epilepsy development. In contrast, we demonstrate that sparse dentate granule cell activation in chronically epileptic mice is rescued by glutamine application, implicating compromised GABA synthesis as a mechanism of disinhibition in chronic epilepsy. We conclude that compromised feedforward inhibition within the local circuit is the predominant mediator of the massive dentate gyrus circuit hyperactivation evident in animals during and following epilepsy development

    Steep, Spatially Graded Recruitment of Feedback Inhibition by Sparse Dentate Granule Cell Activity

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    The dentate gyrus of the hippocampus is thought to subserve important physiological functions, such as 'pattern separation'. In chronic temporal lobe epilepsy, the dentate gyrus constitutes a strong inhibitory gate for the propagation of seizure activity into the hippocampus proper. Both examples are thought to depend critically on a steep recruitment of feedback inhibition by active dentate granule cells. Here, I used two complementary experimental approaches to quantitatively investigate the recruitment of feedback inhibition in the dentate gyrus. I showed that the activity of approximately 4% of granule cells suffices to recruit maximal feedback inhibition within the local circuit. Furthermore, the inhibition elicited by a local population of granule cells is distributed non-uniformly over the extent of the granule cell layer. Locally and remotely activated inhibition differ in several key aspects, namely their amplitude, recruitment, latency and kinetic properties. Finally, I show that net feedback inhibition facilitates during repetitive stimulation. Taken together, these data provide the first quantitative functional description of a canonical feedback inhibitory microcircuit motif. They establish that sparse granule cell activity, within the range observed in-vivo, steeply recruits spatially and temporally graded feedback inhibition

    Ablation of BAF170 in developing and postnatal dentate gyrus affects neural stem cell proliferation, differentiation, and learning

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    The BAF chromatin remodeling complex plays an essential role in brain development. However its function in postnatal neurogenesis in hippocampus is still unknown. Here, we show that in postnatal dentate gyrus (DG), the BAF170 subunit of the complex is expressed in radial glial-like (RGL) progenitors and in cell types involved in subsequent steps of adult neurogenesis including mature astrocytes. Conditional deletion of BAF170 during cortical late neurogenesis as well as during adult brain neurogenesis depletes the pool of RGL cells in DG, and promotes terminal astrocyte differentiation. These derangements are accompanied by distinct behavioral deficits, as reflected by an impaired accuracy of place responding in the Morris water maze test, during both hidden platform as well as reversal learning. Inducible deletion of BAF170 in DG during adult brain neurogenesis resulted in mild spatial learning deficits, having a more pronounced effect on spatial learning during the reversal test. These findings demonstrate involvement of BAF170-dependent chromatin remodeling in hippocampal neurogenesis and cognition and suggest a specific role of adult neurogenesis in DG in adaptive behavior
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