Electrical Compartmentalization in Neurons

The dendritic tree of neurons plays an important role in information processing in the brain. While it is thought that dendrites require independent subunits to perform most of their computations, it is still not understood how they compartmentalize into functional subunits. Here, we show how these subunits can be deduced from the properties of dendrites. We devised a formalism that links the dendritic arborization to an impedance-based tree graph and show how the topology of this graph reveals independent subunits. This analysis reveals that cooperativity between synapses decreases slowly with increasing electrical separation and thus that few independent subunits coexist. We nevertheless find that balanced inputs or shunting inhibition can modify this topology and increase the number and size of the subunits in a context-dependent manner. We also find that this dynamic recompartmentalization can enable branch-specific learning of stimulus features. Analysis of dendritic patch-clamp recording experiments confirmed our theoretical predictions.Peer reviewe

Hippocampal Memory Recovery After Acute Stress: A Behavioral, Morphological and Molecular Study

Indexación: Scopus.Laboratory of Neuroplasticity and Neurogenetics, Department of Biochemistry and Molecular Biology, Faculty of Chemistry and Pharmaceutical Sciences, Universidad de Chile, Santiago, Chile, 2Laboratorio Farmacología del Comportamiento, ICBM, Facultad de Medicina, Universidad de Chile, Santiago, Chile, 3Department of Kinesiology, Faculty of Health Sciences, Universidad Católica del Maule, Talca, Chile, 4Facultad de Psicología, Universidad de Talca, Talca, Chile, 5Instituto de Ciencias Biomédicas, Facultad de Ciencias de la Salud, Universidad Autónoma de Chile, Santiago, Chile, 6Escuela de Química y Farmacia, Facultad de Medicina, Universidad Andres Bello, Santiago, Chile.This study was supported by the following grants: Fondo Nacional de Desarrollo Científico y Tecnológico (FONDECYT) 1120528 (JLF), Fondo Central de Investigación, Universidad de Chile ENL025/16 (JLF).Several studies have shown that a single exposure to stress may improve or impair learning and memory processes, depending on the timing in which the stress event occurs with relation to the acquisition phase. However, to date there is no information about the molecular changes that occur at the synapse during the stress-induced memory modification and after a recovery period. In particular, there are no studies that have evaluated—at the same time—the temporality of stress and stress recovery period in hippocampal short-term memory and the effects on dendritic spine morphology, along with variations in N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunits. The aim of our study was to take a multidimensional approach to investigate concomitant behavioral, morphological and molecular changes induced by a single restraint stress exposure (2.5 h) and a recovery period of 6 and 24 h in rats. We found that acute stress elicited a reduced preference to explore an object placed in a novel position (a hippocampal-dependent task). These changes were accompanied by increased activity of LIM kinase I (LIMK; an actin-remodeling protein) and increased levels of NR2A subunits of NMDA receptors. After 6 h of recovery from stress, rats showed similar preference to explore an object placed in a novel or familiar position, but density of immature spines increased in secondary CA1 apical dendrites, along with a transient rise in GluA2 AMPA receptor subunits. After 24 h of recovery from stress, the animals showed a preference to explore an object placed in a novel position, which was accompanied by a normalization of NMDA and AMPA receptor subunits to control values. Our data suggest that acute stress produces reversible molecular and behavioral changes 24 h after stress, allowing a full reestablishment of hippocampal-related memory. Further studies need to be conducted to deepen our understanding of these changes and their reciprocal interactions.Adaptive stress responses are a promising avenue to develop interventions aiming at restoring hippocampal function impaired by repetitive stress exposure. © 2018 Aguayo, Tejos-Bravo, Díaz-Véliz, Pacheco, García-Rojo, Corrales, Olave, Aliaga, Ulloa, Avalos, Román-Albasini, Rojas and Fiedler.https://www.frontiersin.org/articles/10.3389/fnmol.2018.00283/ful

The NMDA receptor GluN2C subunit controls cortical excitatoryinhibitory balance, neuronal oscillations and cognitive function

Despite strong evidence for NMDA receptor (NMDAR) hypofunction as an underlying factor for cognitive disorders, the precise roles of various NMDAR subtypes remains unknown. The GluN2Ccontaining NMDARs exhibit unique biophysical properties and expression pattern, and lower expression of GluN2C subunit has been reported in postmortem brains from schizophrenia patients. We found that loss of GluN2C subunit leads to a shift in cortical excitatory-inhibitory balance towards greater inhibition. Specifically, pyramidal neurons in the medial prefrontal cortex (mPFC) of GluN2C knockout mice have reduced mEPSC frequency and dendritic spine density and a contrasting higher frequency of mIPSCs. In addition a greater number of perisomatic GAD67 puncta was observed suggesting a potential increase in parvalbumin interneuron inputs. At a network level the GluN2C knockout mice were found to have a more robust increase in power of oscillations in response to NMDAR blocker MK- 801. Furthermore, GluN2C heterozygous and knockout mice exhibited abnormalities in cognition and sensorimotor gating. Our results demonstrate that loss of GluN2C subunit leads to cortical excitatoryinhibitory imbalance and abnormal neuronal oscillations associated with neurodevelopmental disorders

MicroRNA Profiling and Bioinformatics Target Analysis in Dorsal Hippocampus of Chronically Stressed Rats: Relevance to Depression Pathophysiology

Indexación: Scopus.1Laboratory of Neuroplasticity and Neurogenetics, Faculty of Chemical and Pharmaceutical Sciences, Department of Biochemistry and Molecular Biology, Universidad de Chile, Santiago, Chile, 2National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Durham, NC, United States, 3Centro de Genómica y Bioinformática, Facultad de Ciencias, Universidad Mayor, Santiago, Chile, 4Millennium Institute for Integrative Biology (iBio), FONDAP Center for Genome Regulation, Departamento de Genética Molecular y Microbiología, Pontificia Universidad Católica de Chile, Santiago, Chile, 5Department of Kinesiology, Faculty of Health Sciences, Universidad Católica del Maule, Talca, Chile, 6Escuela de Química y Farmacia, Facultad de Medicina, Universidad Andres Bello, Santiago, Chile.This study was supported by the following grants: FONDECYT 1120528 (JLF), Fondo Central de Investigación, Universidad de Chile ENL025/16 (JLF), ES090079 (JAC). Research in RG and EV laboratories is funded by Instituto Milenio iBio – Iniciativa Científica Milenio MINECON.Studies conducted in rodents subjected to chronic stress and some observations in humans after psychosocial stress, have allowed to establish a link between stress and the susceptibility to many complex diseases, including mood disorders. The studies in rodents have revealed that chronic exposure to stress negatively affects synaptic plasticity by triggering changes in the production of trophic factors, subunit levels of glutamate ionotropic receptors, neuron morphology, and neurogenesis in the adult hippocampus. These modifications may account for the impairment in learning and memory processes observed in chronically stressed animals. It is plausible then, that stress modifies the interplay between signal transduction cascades and gene expression regulation in the hippocampus, therefore leading to altered neuroplasticity and functioning of neural circuits. Considering that miRNAs play an important role in post-transcriptional-regulation of gene expression and participate in several hippocampus-dependent functions; we evaluated the consequences of chronic stress on the expression of miRNAs in dorsal (anterior) portion of the hippocampus, which participates in memory formation in rodents. Here, we show that male rats exposed to daily restraint stress (2.5 h/day) during 7 and 14 days display a differential profile of miRNA levels in dorsal hippocampus and remarkably, we found that some of these miRNAs belong to the miR-379-410 cluster. We confirmed a rise in miR-92a and miR-485 levels after 14 days of stress by qPCR, an effect that was not mimicked by chronic administration of corticosterone (14 days). Our in silico study identified the top-10 biological functions influenced by miR-92a, nine of which were shared with miR-485: Nervous system development and function, Tissue development, Behavior, Embryonic development, Organ development, Organismal development, Organismal survival, Tissue morphology, and Organ morphology. Furthermore, our in silico study provided a landscape of potential miRNA-92a and miR-485 targets, along with relevant canonical pathways related to axonal guidance signaling and cAMP signaling, which may influence the functioning of several neuroplastic substrates in dorsal hippocampus. Additionally, the combined effect of miR-92a and miR-485 on transcription factors, along with histone-modifying enzymes, may have a functional relevance by producing changes in gene regulatory networks that modify the neuroplastic capacity of the adult dorsal hippocampus under stress. © 2018 Muñoz-Llanos, García-Pérez, Xu, Tejos-Bravo, Vidal, Moyano, Gutiérrez, Aguayo, Pacheco, García-Rojo, Aliaga, Rojas, Cidlowski and Fiedler.https://www.frontiersin.org/articles/10.3389/fnmol.2018.00251/ful

Ultrastructural Distribution of the 7 Nicotinic Acetylcholine Receptor Subunit in Rat Hippocampus

Acetylcholine (ACh) is an important neurotransmitter in the mammalian brain; it is implicated in arousal, learning, and other cognitive functions. Recent studies indicate that nicotinic receptors contribute to these cholinergic effects, in addition to the established role of muscarinic receptors. In the hippocampus, where cholinergic involvement in learning and memory is particularly well documented, 7 nicotinic acetylcholine receptor subunits (7 nAChRs) are highly expressed, but their precise ultrastructural localization has not been determined. Here, we describe the results of immunogold labeling of serial ultrathin sections through stratum radiatum of area CA1 in the rat. Using both anti-7 nAChR immunolabeling and -bungarotoxin binding, we find that 7 nAChRs are present at nearly all synapses in CA1 stratum radiatum, with immunolabeling present at both presynaptic and postsynaptic elements. Morphological considerations and double immunolabeling indicate that GABAergic as well as glutamatergic synapses bear 7 nAChRs, at densities approaching those observed for glutamate receptors in CA1 stratum radiatum. Postsynaptically, 7 nAChRs often are distributed at dendritic spines in a perisynaptic annulus. In the postsynaptic cytoplasm, immunolabeling is associated with spine apparatus and other membranous structures, suggesting that 7 nAChRs may undergo dynamic regulation, with insertion into the synapse and subsequent internalization. The widespread and substantial expression of 7 nAChRs at synapses in the hippocampus is consistent with an important role in mediating and/or modulating synaptic transmission, plasticity, and neurodegeneration

Cortical region interactions and the functional role of apical dendrites

The basal and distal apical dendrites of pyramidal cells occupy distinct cortical layers and are targeted by axons originating in different cortical regions. Hence, apical and basal dendrites receive information from distinct sources. Physiological evidence suggests that this anatomically observed segregation of input sources may have functional significance. This possibility has been explored in various connectionist models that employ neurons with functionally distinct apical and basal compartments. A neuron in which separate sets of inputs can be integrated independently has the potential to operate in a variety of ways which are not possible for the conventional model of a neuron in which all inputs are treated equally. This article thus considers how functionally distinct apical and basal dendrites can contribute to the information processing capacities of single neurons and, in particular, how information from different cortical regions could have disparate affects on neural activity and learning

Mutant huntingtin enhances activation of dendritic Kv4 K+ channels in striatal spiny projection neurons

Huntington\u27s disease (HD) is initially characterized by an inability to suppress unwanted movements, a deficit attributable to impaired synaptic activation of striatal indirect pathway spiny projection neurons (iSPNs). To better understand the mechanisms underlying this deficit, striatal neurons in ex vivo brain slices from mouse genetic models of HD were studied using electrophysiological, optical and biochemical approaches. Distal dendrites of iSPNs from symptomatic HD mice were hypoexcitable, a change that was attributable to increased association of dendritic Kv4 potassium channels with auxiliary KChIP subunits. This association was negatively modulated by TrkB receptor signaling. Dendritic excitability of HD iSPNs was rescued by knocking-down expression of Kv4 channels, by disrupting KChIP binding, by restoring TrkB receptor signaling or by lowering mutant-Htt (mHtt) levels with a zinc finger protein. Collectively, these studies demonstrate that mHtt induces reversible alterations in the dendritic excitability of iSPNs that could contribute to the motor symptoms of HD

The dendritic density field of a cortical pyramidal cell

Much is known about the computation in individual neurons in the cortical column. Also, the selective connectivity between many cortical neuron types has been studied in great detail. However, due to the complexity of this microcircuitry its functional role within the cortical column remains a mystery. Some of the wiring behavior between neurons can be interpreted directly from their particular dendritic and axonal shapes. Here, I describe the dendritic density field (DDF) as one key element that remains to be better understood. I sketch an approach to relate DDFs in general to their underlying potential connectivity schemes. As an example, I show how the characteristic shape of a cortical pyramidal cell appears as a direct consequence of connecting inputs arranged in two separate parallel layers

IRX-2, a Novel Immunotherapeutic, Enhances Functions of Human Dendritic Cells

Background: In a recent phase II clinical trial for HNSCC patients, IRX-2, a cell-derived biologic, promoted T-cell infiltration into the tumor and prolonged overall survival. Mechanisms responsible for these IRX-2-mediated effects are unknown. We hypothesized that IRX-2 enhanced tumor antigen-(TA)-specific immunity by up-regulating functions of dendritic cells (DC). Methodology/Principal Findings: Monocyte-derived DC obtained from 18 HNSCC patients and 12 healthy donors were matured using IRX-2 or a mix of TNF-α, IL-1β and IL-6 ("conv. mix"). Multicolor flow cytometry was used to study the DC phenotype and antigen processing machinery (APM) component expression. ELISPOT and cytotoxicity assays were used to evaluate tumor-reactive cytotoxic T lymphocytes (CTL). IL-12p70 and IL-10 production by DC was measured by Luminex® and DC migration toward CCL21 was tested in transwell migration assays. IRX-2-matured DC functions were compared with those of conv. mix-matured DC. IRX-2-matured DC expressed higher levels (p<0.05) of CD11c, CD40, CCR7 as well as LMP2, TAP1, TAP2 and tapasin than conv. mix-matured DC. IRX-2-matured DC migrated significantly better towards CCL21, produced more IL-12p70 and had a higher IL12p70/IL-10 ratio than conv. mix-matured DC (p<0.05 for all). IRX-2-matured DC carried a higher density of tumor antigen-derived peptides, and CTL primed with these DC mediated higher cytotoxicity against tumor targets (p<0.05) compared to the conv. mix-matured DC. Conclusion: Excellent ability of IRX-2 to induce ex vivo DC maturation in HNSCC patients explains, in part, its clinical benefits and emphasizes its utility in ex vivo maturation of DC generated for therapy. © 2013 Schilling et al

Modeling Reverse-Phi Motion-Selective Neurons in Cortex: Double Synaptic-Veto Mechanism

Reverse-phi motion is the illusory reversal of perceived direction of movement when the stimulus contrast is reversed in successive frames. Livingstone, Tsao, and Conway (2000) showed that direction-selective cells in striate cortex of the alert macaque monkey showed reversed excitatory and inhibitory regions when two different contrast bars were flashed sequentially during a two-bar interaction analysis. While correlation or motion energy models predict the reverse-phi response, it is unclear how neurons can accomplish this. We carried out detailed biophysical simulations of a direction-selective cell model implementing a synaptic shunting scheme. Our results suggest that a simple synaptic-veto mechanism with strong direction selectivity for normal motion cannot account for the observed reverse-phi motion effect. Given the nature of reverse-phi motion, a direct interaction between the ON and OFF pathway, missing in the original shunting-inhibition model, it is essential to account for the reversal of response. We here propose a double synaptic-veto mechanism in which ON excitatory synapses are gated by both delayed ON inhibition at their null side and delayed OFF inhibition at their preferred side. The converse applies to OFF excitatory synapses. Mapping this scheme onto the dendrites of a direction-selective neuron permits the model to respond best to normal motion in its preferred direction and to reverse-phi motion in its null direction. Two-bar interaction maps showed reversed excitation and inhibition regions when two different contrast bars are presented