41,523 research outputs found
Comprehensive Monosynaptic Rabies Virus Mapping of Host Connectivity with Neural Progenitor Grafts after Spinal Cord Injury.
Neural progenitor cells grafted to sites of spinal cord injury have supported electrophysiological and functional recovery in several studies. Mechanisms associated with graft-related improvements in outcome appear dependent on functional synaptic integration of graft and host systems, although the extent and diversity of synaptic integration of grafts with hosts are unknown. Using transgenic mouse spinal neural progenitor cell grafts expressing the TVA and G-protein components of the modified rabies virus system, we initiated monosynaptic tracing strictly from graft neurons placed in sites of cervical spinal cord injury. We find that graft neurons receive synaptic inputs from virtually every known host system that normally innervates the spinal cord, including numerous cortical, brainstem, spinal cord, and dorsal root ganglia inputs. Thus, implanted neural progenitor cells receive an extensive range of host neural inputs to the injury site, potentially enabling functional restoration across multiple systems
NMDA Currents Modulate the Synaptic InputâOutput Functions of Neurons in the Dorsal Nucleus of the Lateral Lemniscus in Mongolian Gerbils
Neurons in the dorsal nucleus of the lateral lemniscus (DNLL) receive excitatory and inhibitory inputs from the superior olivary complex (SOC) and convey GABAergic inhibition to the contralateral DNLL and the inferior colliculi. Unlike the fast glycinergic inhibition in the SOC, this GABAergic inhibition outlasts auditory stimulation by tens of milliseconds. Two mechanisms have been postulated to explain this persistent inhibition. One, an âintegration-basedâ mechanism, suggests that postsynaptic excitatory integration in DNLL neurons generates prolonged activity, and the other favors the synaptic time course of the DNLL output itself. The feasibility of the integration-based mechanism was tested in vitro in DNLL neurons of Mongolian gerbils by quantifying the cellular excitability and synaptic inputâoutput functions (IO-Fs). All neurons were sustained firing and generated a near monotonic IO-F on current injections. From synaptic stimulations, we estimate that activation of approximately five fibers, each on average liberating âź18 vesicles, is sufficient to trigger a single postsynaptic action potential. A strong single pulse of afferent fiber stimulation triggered multiple postsynaptic action potentials. The steepness of the synaptic IO-F was dependent on the synaptic NMDA component. The synaptic NMDA receptor current defines the slope of the synaptic IO-F by enhancing the temporal and spatial EPSP summation. Blocking this NMDA-dependent amplification during postsynaptic integration of train stimulations resulted into a âź20% reduction of the decay time course of the GABAergic inhibition. Thus, our data show that the NMDA-dependent amplification of the postsynaptic activity contributes to the GABAergic persistent inhibition generated by DNLL neurons
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
Rosetta Brains: A Strategy for Molecularly-Annotated Connectomics
We propose a neural connectomics strategy called Fluorescent In-Situ
Sequencing of Barcoded Individual Neuronal Connections (FISSEQ-BOINC),
leveraging fluorescent in situ nucleic acid sequencing in fixed tissue
(FISSEQ). FISSEQ-BOINC exhibits different properties from BOINC, which relies
on bulk nucleic acid sequencing. FISSEQ-BOINC could become a scalable approach
for mapping whole-mammalian-brain connectomes with rich molecular annotations
Network structure determines patterns of network reorganization during adult neurogenesis
New cells are generated throughout life and integrate into the hippocampus
via the process of adult neurogenesis. Epileptogenic brain injury induces many
structural changes in the hippocampus, including the death of interneurons and
altered connectivity patterns. The pathological neurogenic niche is associated
with aberrant neurogenesis, though the role of the network-level changes in
development of epilepsy is not well understood. In this paper, we use
computational simulations to investigate the effect of network environment on
structural and functional outcomes of neurogenesis. We find that small-world
networks with external stimulus are able to be augmented by activity-seeking
neurons in a manner that enhances activity at the stimulated sites without
altering the network as a whole. However, when inhibition is decreased or
connectivity patterns are changed, new cells are both less responsive to
stimulus and the new cells are more likely to drive the network into bursting
dynamics. Our results suggest that network-level changes caused by
epileptogenic injury can create an environment where neurogenic reorganization
can induce or intensify epileptic dynamics and abnormal integration of new
cells.Comment: 28 pages, 10 figure
Statistical mechanics of neocortical interactions: large-scale EEG influences on molecular processes
Recent calculations further supports the premise that large-scale synchronous
firings of neurons may affect molecular processes. The context is scalp
electroencephalography (EEG) during short-term memory (STM) tasks. The
mechanism considered is (SI units)
coupling, where is the momenta of free waves
the charge of in units of the electron charge, and
the magnetic vector potential of current from
neuronal minicolumnar firings considered as wires, giving rise to EEG. Data has
processed using multiple graphs to identify sections of data to which
spline-Laplacian transformations are applied, to fit the statistical mechanics
of neocortical interactions (SMNI) model to EEG data, sensitive to synaptic
interactions subject to modification by waves.Comment: Accepted for publication in Journal of Theoretical Biolog
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NMDAR-Activated PP1 Dephosphorylates GluN2B to Modulate NMDAR Synaptic Content.
In mature neurons, postsynaptic N-methyl-D-aspartate receptors (NMDARs) are segregated into two populations, synaptic and extrasynaptic, which differ in localization, function, and associated intracellular cascades. These two pools are connected via lateral diffusion, and receptor exchange between them modulates synaptic NMDAR content. Here, we identify the phosphorylation of the PDZ-ligand of the GluN2B subunit of NMDARs (at S1480) as a critical determinant in dynamically controlling NMDAR synaptic content. We find that phosphorylation of GluN2B at S1480 maintains NMDARs at extrasynaptic membranes as part of a protein complex containing protein phosphatase 1 (PP1). Global activation of NMDARs leads to the activation of PP1, which mediates dephosphorylation of GluN2B at S1480 to promote an increase in synaptic NMDAR content. Thus, PP1-mediated dephosphorylation of the GluN2B PDZ-ligand modulates the synaptic expression of NMDARs in mature neurons in an activity-dependent manner, a process with profound consequences for synaptic and structural plasticity, metaplasticity, and synaptic neurotransmission
Gated rotation mechanism of site-specific recombination by ĎC31 integrase
Integrases, such as that of the Streptomyces temperate bacteriophage ĎC31, promote site-specific recombination between DNA sequences in the bacteriophage and bacterial genomes to integrate or excise the phage DNA. ĎC31 integrase belongs to the serine recombinase family, a large group of structurally related enzymes with diverse biological functions. It has been proposed that serine integrases use a âsubunit rotationâ mechanism to exchange DNA strands after double-strand DNA cleavage at the two recombining att sites, and that many rounds of subunit rotation can occur before the strands are religated. We have analyzed the mechanism of ĎC31 integrase-mediated recombination in a topologically constrained experimental system using hybrid âphesâ recombination sites, each of which comprises a ĎC31 att site positioned adjacent to a regulatory sequence recognized by Tn3 resolvase. The topologies of reaction products from circular substrates containing two phes sites support a right-handed subunit rotation mechanism for catalysis of both integrative and excisive recombination. Strand exchange usually terminates after a single round of 180° rotation. However, multiple processive â360° rotationâ rounds of strand exchange can be observed, if the recombining sites have nonidentical base pairs at their centers. We propose that a regulatory âgatingâ mechanism normally blocks multiple rounds of strand exchange and triggers product release after a single round
Maintenance of cell type-specific connectivity and circuit function requires Tao kinase
Sensory circuits are typically established during early development, yet how circuit specificity and function are maintained during organismal growth has not been elucidated. To gain insight we quantitatively investigated synaptic growth and connectivity in the Drosophila nociceptive network during larval development. We show that connectivity between primary nociceptors and their downstream neurons scales with animal size. We further identified the conserved Ste20-like kinase Tao as a negative regulator of synaptic growth required for maintenance of circuit specificity and connectivity. Loss of Tao kinase resulted in exuberant postsynaptic specializations and aberrant connectivity during larval growth. Using functional imaging and behavioral analysis we show that loss of Tao-induced ectopic synapses with inappropriate partner neurons are functional and alter behavioral responses in a connection-specific manner. Our data show that fine-tuning of synaptic growth by Tao kinase is required for maintaining specificity and behavioral output of the neuronal network during animal growth
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