Cholinergic modulation of dentate gyrus processing through dynamic reconfiguration of inhibitory circuits

The dentate gyrus (DG) of the hippocampus plays a key role in memory formation, and it is known to be modulated by septal projections. By performing electrophysiology and optogenetics, we evaluated the role of cholinergic modulation in the processing of afferent inputs in the DG. We show that mature granule cells (GCs), but not adult-born immature neurons, have increased responses to afferent perforant path stimuli upon cholinergic modulation. This is due to a highly precise reconfiguration of inhibitory circuits, differentially affecting Parvalbumin and Somatostatin interneurons, resulting in a nicotinic-dependent perisomatic disinhibition of GCs. This circuit reorganization provides a mechanism by which mature GCs could escape the strong inhibition they receive, creating a window of opportunity for plasticity. Indeed, coincident activation of perforant path inputs with optogenetic release of acetylcholine produces a long-term potentiated response in GCs, essential for memory formation.Fil: Ogando, Mora. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigación en Biomedicina de Buenos Aires - Instituto Partner de la Sociedad Max Planck; ArgentinaFil: Pedroncini, Olivia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigación en Biomedicina de Buenos Aires - Instituto Partner de la Sociedad Max Planck; ArgentinaFil: Federman, Maria Noel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigación en Biomedicina de Buenos Aires - Instituto Partner de la Sociedad Max Planck; ArgentinaFil: Romano, Sebastián Alejo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigación en Biomedicina de Buenos Aires - Instituto Partner de la Sociedad Max Planck; ArgentinaFil: Brum, Luciano Ariel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Lanuza, Guillermo Marcos. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Refojo, Damian. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigación en Biomedicina de Buenos Aires - Instituto Partner de la Sociedad Max Planck; ArgentinaFil: Marin Burgin, Antonia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigación en Biomedicina de Buenos Aires - Instituto Partner de la Sociedad Max Planck; Argentin

Ascl1 Balances Neuronal versus Ependymal Fate in the Spinal Cord Central Canal

Generation of neuronal types at the right time, location, and number is essential for building a functional nervous system. Significant progress has been reached in understanding the mechanisms that govern neuronal diversity. Cerebrospinal fluid-contacting neurons (CSF-cNs), an intriguing spinal cord central canal population, are produced during advanced developmental stages, simultaneous with glial and ependymal cells. It is unknown how CSF-cNs are specified after the neurogenesis-to-gliogenesis switch. Here, we identify delayed Ascl1 expression in mouse spinal progenitors during the gliogenic phase as key in CSF-cN differentiation. With fate mappings and time-controlled deletions, we demonstrate that CSF-cNs derive from Ascl1-expressing cells and that Ascl1 triggers late neurogenesis in the amniote spinal cord. Ascl1 abrogation transforms prospective CSF-cN progenitors into ependymocytes. These results demonstrate that late spinal progenitors have the potential to produce neurons and that Ascl1 initiates CSF-cN differentiation, controlling the precise neuronal and nonneuronal composition of the spinal central canal.Fil: Di Bella, Daniela Jesica. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Fundación Instituto Leloir; ArgentinaFil: Carcagno, Abel Luis. Fundación Instituto Leloir; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Bartolomeu, M. Lucía. Fundación Instituto Leloir; ArgentinaFil: Pardi, Belén. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigación en Biomedicina de Buenos Aires - Instituto Partner de la Sociedad Max Planck; ArgentinaFil: Löhr, Heiko. University of Cologne; AlemaniaFil: Siegel, Nicole. Fundación Instituto Leloir; ArgentinaFil: Hammerschmidt, Matthias. University of Cologne; AlemaniaFil: Marin Burgin, Antonia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigación en Biomedicina de Buenos Aires - Instituto Partner de la Sociedad Max Planck; ArgentinaFil: Lanuza, Guillermo Marcos. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Fundación Instituto Leloir; Argentin

αSynuclein control of mitochondrial homeostasis in human-derived neurons is disrupted by mutations associated with Parkinson’s disease

The etiology of Parkinson’s disease (PD) converges on a common pathogenic pathway of mitochondrial defects in which α-Synuclein (αSyn) is thought to play a role. However, the mechanisms by which αSyn and its disease-associated allelic variants cause mitochondrial dysfunction remain unknown. Here, we analyzed mitochondrial axonal transport and morphology in human-derived neurons overexpressing wild-type (WT) αSyn or the mutated variants A30P or A53T, which are known to have differential lipid affinities. A53T αSyn was enriched in mitochondrial fractions, inducing significant mitochondrial transport defects and fragmentation, while milder defects were elicited by WT and A30P. We found that αSyn-mediated mitochondrial fragmentation was linked to expression levels in WT and A53T variants. Targeted delivery of WT and A53T αSyn to the outer mitochondrial membrane further increased fragmentation, whereas A30P did not. Genomic editing to disrupt the N-terminal domain of αSyn, which is important for membrane association, resulted in mitochondrial elongation without changes in fusion-fission protein levels, suggesting that αSyn plays a direct physiological role in mitochondrial size maintenance. Thus, we demonstrate that the association of αSyn with the mitochondria, which is modulated by protein mutation and dosage, influences mitochondrial transport and morphology, highlighting its relevance in a common pathway impaired in PD.Fil: Pozo Devoto, Victorio Martin. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia ; ArgentinaFil: Dimopoulos, Nicolás. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Alloatti, Matías. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia ; ArgentinaFil: Pardi, María Belén. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigación en Biomedicina de Buenos Aires - Instituto Partner de la Sociedad Max Planck; ArgentinaFil: Saez, Trinidad María de Los Milagros. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia ; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Otero, Maria Gabriela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia ; ArgentinaFil: Cromberg, Lucas Eneas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia ; ArgentinaFil: Marin Burgin, Antonia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigación en Biomedicina de Buenos Aires - Instituto Partner de la Sociedad Max Planck; ArgentinaFil: Scassa, Maria Elida. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia; ArgentinaFil: Stokin, Gorazd B.. Anne’s University Hospital; República ChecaFil: Schinder, Alejandro Fabián. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Sevlever, Gustavo. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia; ArgentinaFil: Falzone, Tomas Luis. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia ; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentin

Development of behaviors

Behavior requires functional muscles, but the development of behavior depends primarily on events within the nervous system. The pattern of development is similar in invertebrates and vertebrates. When nerve cells first appear, they are not yet connected with other cells, and hence they cannot produce behavior. However, once neurons start to form synapses, behaviors begin, although at first they may be simple. As the nervous system matures, several factors – including hormones, activity within the neurons, and input from the environment – modify the system and consequently the behavior produced, allowing it to become a more effective response to ongoing events.Fil: French, K.A.. University Of California. Department Of Neurobiology; Estados UnidosFil: Marin Burgin, Antonia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina. University Of California. Department Of Neurobiology; Estados Unido

Requirement of Adult-Born Neurons for Hippocampus-Dependent Learning

A fundamental question in the field of adult neurogenesis relies in addressing whether neurons generated in the adult dentate gyrus are needed for hippocampal function. Increasing evidence is accumulating in support of the notion that hippocampus-dependent behaviors activate new neurons and that those neurons are highly relevant for information processing. More specifically, immature new neurons under development that have unique functional characteristics begin to emerge as a highly relevant population in the dentate gyrus network. This review focuses on how hippocampus-dependent behaviors activate adult-born neurons and how modulation and ablation of adult hippocampal neurogenesis alter spatial and associative memory. While several contradictory findings emerge when analyzing the literature, evidence in favor of a relevant role of adult-born neurons in hippocampal function is compelling.Fil: Marin Burgin, Antonia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquimicas de Buenos Aires; Argentina. Fundación Instituto Leloir; ArgentinaFil: Schinder, Alejandro Fabian. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquimicas de Buenos Aires; Argentina. Fundación Instituto Leloir; Argentin

Adult-born granule cells improve stimulus encoding and discrimination in the dentate gyrus

Heterogeneity plays an important role in diversifying neural responses to support brain function. Adult neurogenesis provides the dentate gyrus with a heterogeneous population of granule cells (GCs) that were born and developed their properties at different times. Immature GCs have distinct intrinsic and synaptic properties than mature GCs and are needed for correct encoding and discrimination in spatial tasks. How immature GCs enhance the encoding of information to support these functions is not well understood. Here, we record the responses to fluctuating current injections of GCs of different ages to study how they encode stimuli. Immature GCs produce unreliable responses compared to mature GCs, exhibiting imprecise spike timings across repeated stimulation. We use a statistical model to describe the stimulus-response transformation performed by GCs of different ages. We fit this model to the data and obtain parameters that capture GCs encoding properties. Parameter values from this fit reflect the maturational differences of the population and indicate that immature GCs perform a differential encoding of stimuli. To study how this age heterogeneity influences encoding by a population, we perform stimulus decoding using populations that contain GCs of different ages. We find that, despite their individual unreliability, immature GCs enhance the fidelity of the signal encoded by the population and improve the discrimination of similar time dependent stimuli. Thus, the observed heterogeneity confers the population with enhanced encoding capabilities.Fil: Arribas, Diego Martín. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigación en Biomedicina de Buenos Aires - Instituto Partner de la Sociedad Max Planck; ArgentinaFil: Marin Burgin, Antonia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigación en Biomedicina de Buenos Aires - Instituto Partner de la Sociedad Max Planck; ArgentinaFil: Morelli, Luis Guillermo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigación en Biomedicina de Buenos Aires - Instituto Partner de la Sociedad Max Planck; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Física; Argentina. Max Planck Institute for Molecular Physiology; Alemani

From synapses to behavior: development of a sensory-motor circuit in the leech

The development of neuronal circuits has been advanced greatly by the use of imaging techniques that reveal the activity of neurons during the period when they are constructing synapses and forming circuits. This review focuses on experiments performed in leech embryos to characterize the development of a neuronal circuit that produces a simple segmental behavior called "local bending." The experiments combined electrophysiology, anatomy, and FRET-based voltage-sensitive dyes (VSDs). The VSDs offered two major advantages in these experiments: they allowed us to record simultaneously the activity of many neurons, and unlike other imaging techniques, they revealed inhibition as well as excitation. The results indicated that connections within the circuit are formed in a predictable sequence: initially neurons in the circuit are connected by electrical synapses, forming a network that itself generates an embryonic behavior and prefigures the adult circuit; later chemical synapses, including inhibitory connections, appear, "sculpting" the circuit to generate a different, mature behavior. In this developmental process, some of the electrical connections are completely replaced by chemical synapses, others are maintained into adulthood, and still others persist and share their targets with chemical synaptic connections.Fil: Marin Burgin, Antonia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina. University of California at San Diego; Estados UnidosFil: Kristan, William B.. University of California at San Diego; Estados UnidosFil: French, Kathleen A.. University of California at San Diego; Estados Unido

Widespread inhibition proportional to excitation controls the gain of a leech behavioral circuit

Changing gain in a neuronal system has important functional consequences, but the underlying mechanisms have been elusive. Models have suggested a variety of neuronal and systems properties to accomplish gain control. Here, we show that the gain of the neuronal network underlying local bending behavior in leeches depends on widespread inhibition. Using behavioral analysis, intracellular recordings, and voltage-sensitive dye imaging, we compared the effects of blocking just the known lateral inhibition with blocking all GABAergic inhibition. This revealed an additional source of inhibition, which was widespread and increased in proportion to increasing stimulus intensity. In a model of the input/output functions of the three-layered local bending network, we showed that inhibiting all interneurons in proportion to the stimulus strength produces the experimentally observed change in gain. This relatively simple mechanism for controlling behavioral gain could be prevalent in vertebrate as well as invertebrate nervous systems.Fil: Baca, Serapio M.. University of California at San Diego; Estados UnidosFil: Marin Burgin, Antonia. University of California at San Diego; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Wagenaar, Daniel A.. University of California at San Diego; Estados UnidosFil: Kristan, William B.. University of California at San Diego; Estados Unido

Input normalization by global feedforward inhibition expands cortical dynamic range

The cortex is sensitive to weak stimuli, but responds to stronger inputs without saturating. The mechanisms that enable this wide range of operation are not fully understood. We found that the amplitude of excitatory synaptic currents necessary to fire rodent pyramidal cells, the threshold excitatory current, increased with stimulus strength. Consequently, the relative contribution of individual afferents in firing a neuron was inversely proportional to the total number of active afferents. Feedforward inhibition, acting homogeneously across pyramidal cells, ensured that threshold excitatory currents increased with stimulus strength. In contrast, heterogeneities in the distribution of excitatory currents in the neuronal population determined the specific set of pyramidal cells recruited. Together, these mechanisms expand the range of afferent input strengths that neuronal populations can represent.Fil: Pouille, Frédéric. University Of California. Department Of Neurobiology; Estados UnidosFil: Marin Burgin, Antonia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina. University Of California. Department Of Neurobiology; Estados UnidosFil: Adesnik, Hillel. University Of California. Department Of Neurobiology; Estados UnidosFil: Atallah, Bassam V.. University Of California. Department Of Neurobiology; Estados UnidosFil: Scanziani, Massimo. University Of California. Department Of Neurobiology; Estados Unido

The late and dual origin of cerebrospinal fluid-contacting neurons in the mouse spinal cord.

Considerable progress has been made in understanding the mechanisms that control the production of specialized neuronal types. However, how the timing of differentiation contributes to neuronal diversity in the developing spinal cord is still a pending question. In this study, we show that cerebrospinal fluid-contacting neurons (CSF-cNs), an anatomically discrete cell type of the ependymal area, originate from surprisingly late neurogenic events in the ventral spinal cord. CSF-cNs are identified by the expression of the transcription factors Gata2 and Gata3, and the ionic channels Pkd2l1 and Pkd1l2. Contrasting with Gata2/3(+) V2b interneurons, differentiation of CSF-cNs is independent of Foxn4 and takes place during advanced developmental stages previously assumed to be exclusively gliogenic. CSF-cNs are produced from two distinct dorsoventral regions of the mouse spinal cord. Most CSF-cNs derive from progenitors circumscribed to the late-p2 and the oligodendrogenic (pOL) domains, whereas a second subset of CSF-cNs arises from cells bordering the floor plate. The development of these two subgroups of CSF-cNs is differentially controlled by Pax6, they adopt separate locations around the postnatal central canal and they display electrophysiological differences. Our results highlight that spatiotemporal mechanisms are instrumental in creating neural cell diversity in the ventral spinal cord to produce distinct classes of interneurons, motoneurons, CSF-cNs, glial cells and ependymal cells.Fil: Petracca, Yanina Lujan. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Sartoretti, María Micaela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Di Bella, Daniela Jesica. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Marin Burgin, Antonia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Carcagno, Abel Luis. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Schinder, Alejandro Fabian. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Lanuza, Guillermo Marcos. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentin