| 1. |
- Barg, Sebastian, et al.
(författare)
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Delay between fusion pore opening and peptide release from large dense-core vesicles in neuroendocrine cells.
- 2002
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Ingår i: Neuron. - 0896-6273 .- 1097-4199. ; 33:2, s. 287-299
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Tidskriftsartikel (refereegranskat)abstract
- Peptidergic neurotransmission is slow compared to that mediated by classical neurotransmitters. We have studied exocytotic membrane fusion and cargo release by simultaneous capacitance measurements and confocal imaging of single secretory vesicles in neuroendocrine cells. Depletion of the readily releasable pool (RRP) correlated with exocytosis of 10%-20% of the docked vesicles. Some remaining vesicles became releasable after recovery of RRP. Expansion of the fusion pore, seen as an increase in luminal pH, occurred after approximately 0.3 s, and peptide release was delayed by another 1-10 s. We conclude that (1) RRP refilling involves chemical modification of vesicles already in place, (2) the release of large neuropeptides via the fusion pore is negligible and only proceeds after complete fusion, and (3) sluggish peptidergic transmission reflects the time course of vesicle emptying.
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| 2. |
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| 3. |
- Jensen, Jimmy, et al.
(författare)
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Direct activation of the ventral striatum in anticipation of aversive stimuli.
- 2003
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Ingår i: Neuron. - 0896-6273 .- 1097-4199. ; 40:6, s. 1251-1257
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Tidskriftsartikel (refereegranskat)abstract
- The brain "reward" system, centered on the limbic ventral striatum, plays a critical role in the response to pleasure and pain. The ventral striatum is activated in animal and human studies during anticipation of appetitive/pleasurable events, but its role in aversive/painful events is less clear. Here we present data from three human fMRI studies based on aversive conditioning using unpleasant cutaneous electrical stimulation and show that the ventral striatum is reliably activated. This activation is observed during anticipation and is not a consequence of relief after the aversive event. Further, the ventral striatum is activated in anticipation regardless of whether there is an opportunity to avoid the aversive stimulus or not. Our data suggest that the ventral striatum, a crucial element of the brain "reward" system, is directly activated in anticipation of aversive stimuli.
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| 4. |
- Kullander, Klas, et al.
(författare)
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Kinase-dependent and kinase-independent functions of EphA4 receptors in major axon tract formation in vivo
- 2001
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Ingår i: Neuron. - 0896-6273 .- 1097-4199. ; 29:1, s. 73-84
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Tidskriftsartikel (refereegranskat)abstract
- The EphA4 receptor tyrosine kinase regulates the formation of the corticospinal tract (CST), a pathway controlling voluntary movements, and of the anterior commissure (AC), connecting the neocortical temporal lobes. To study EphA4 kinase signaling in these processes, we generated mice expressing mutant EphA4 receptors either lacking kinase activity or with severely downregulated kinase activity. We demonstrate that EphA4 is required for CST formation as a receptor for which it requires an active kinase domain. In contrast, the formation of the AC is rescued by kinase-dead EphA4, suggesting that in this structure EphA4 acts as a ligand for which its kinase activity is not required. Unexpectedly, the cytoplasmic sterile-alpha motif (SAM) domain is not required for EphA4 functions. Our findings establish both kinase-dependent and kinase-independent functions of EphA4 in the formation of major axon tracts.
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| 5. |
- Larsson, HP, et al.
(författare)
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A conserved glutamate is important for slow inactivation in K+ channels
- 2000
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Ingår i: Neuron. - : Elsevier Science B.V., Amsterdam.. - 0896-6273 .- 1097-4199. ; 27:3, s. 573-583
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Tidskriftsartikel (refereegranskat)abstract
- Voltage-gated ion channels undergo slow inactivation during prolonged depolarizations. We investigated the role of a conserved glutamate at the extracellular end of segment 5 (S5) in slow inactivation by mutating it to a cysteine (E418C in Shaker). We could lock the channel in two different conformations by disulfide-linking 418C to two different cysteines, introduced in the Pore-S6 (P-S6) loop. Our results suggest that E418 is normally stabilizing the open conformation of the slow inactivation gate by forming hydrogen bonds with the P-S6 loop. Breaking these bonds allows the P-S6 loop to rotate, which closes the slow inactivation gate. Our results also suggest a mechanism of how the movement of the voltage sensor can induce slow inactivation by destabilizing these bonds.
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| 6. |
- Allan, D.W., et al.
(författare)
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Regulators acting in combinatorial codes also act independently in single differentiating neurons
- 2005
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Ingår i: Neuron. - : Elsevier BV. - 0896-6273 .- 1097-4199. ; 45:5, s. 689-700
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Tidskriftsartikel (refereegranskat)abstract
- In the Drosophila ventral nerve cord, a small number of neurons express the LIM-homeodomain gene apterous (ap). These ap neurons can be subdivided based upon axon pathfinding and their expression of neuropeptidergic markers. ap, the zinc finger gene squeeze, the bHLH gene dimmed, and the BMP pathway are all required for proper specification of these cells. Here, using several ap neuron terminal differentiation markers, we have resolved how each of these factors contributes to ap neuron diversity. We find that these factors interact genetically and biochemically in subtype-specific combinatorial codes to determine certain defining aspects of ap neuron subtype identity. However, we also find that ap, dimmed, and squeeze additionally act independently of one another to specify certain other defining aspects of ap neuron subtype identity. Therefore, within single neurons, we show that single regulators acting in numerous molecular contexts differentially specify multiple subtype-specific traits. Copyright ©2005 by Elsevier Inc.
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| 11. |
- Arthur-Farraj, Peter J., et al.
(författare)
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c-Jun Reprograms Schwann Cells of Injured Nerves to Generate a Repair Cell Essential for Regeneration
- 2012
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Ingår i: Neuron. - : Elsevier BV. - 0896-6273 .- 1097-4199. ; 75:4, s. 633-647
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Tidskriftsartikel (refereegranskat)abstract
- The radical response of peripheral nerves to injury (Wallerian degeneration) is the cornerstone of nerve repair. We show that activation of the transcription factor c-Jun in Schwann cells is a global regulator of Wallerian degeneration. c-Jun governs major aspects of the injury response, determines the expression of trophic factors, adhesion molecules, the formation of regeneration tracks and myelin clearance and controls the distinctive regenerative potential of peripheral nerves. A key function of c-Jun is the activation of a repair program in Schwann cells and the creation of a cell specialized to support regeneration. We show that absence of c-Jun results in the formation of a dysfunctional repair cell, striking failure of functional recovery, and neuronal death. We conclude that a single glial transcription factor is essential for restoration of damaged nerves, acting to control the transdifferentiation of myelin and Remak Schwann cells to dedicated repair cells in damaged tissue.
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| 12. |
- Barbier, Estelle, et al.
(författare)
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mTORC and ProSAPiP1: How Alcohol Changes Synapses of Reward Circuitry
- 2017
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Ingår i: Neuron. - : CELL PRESS. - 0896-6273 .- 1097-4199. ; 96:1
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Alcohol addiction is characterized by broad and persistent changes in brain function, but the underlying neural adaptations remain largely unknown. In this issue of Neuron, Laguesse et al. (2017) describe a neural mechanism through which long-term alcohol exposure induces structural and synaptic adaptations that promote excessive alcohol use.
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| 13. |
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| 15. |
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| 16. |
- Beets, Isabel, et al.
(författare)
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Natural Variation in a Dendritic Scaffold Protein Remodels Experience-Dependent Plasticity by Altering Neuropeptide Expression
- 2020
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Ingår i: Neuron. - : Elsevier. - 0896-6273 .- 1097-4199. ; 105:1, s. 106-121
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Tidskriftsartikel (refereegranskat)abstract
- The extent to which behavior is shaped by experience varies between individuals. Genetic differences contribute to this variation, but the neural mechanisms are not understood. Here, we dissect natural variation in the behavioral flexibility of two Caenorhabditis elegans wild strains. In one strain, a memory of exposure to 21% O2 suppresses CO2-evoked locomotory arousal; in the other, CO2 evokes arousal regardless of previous O2 experience. We map that variation to a polymorphic dendritic scaffold protein, ARCP-1, expressed in sensory neurons. ARCP-1 binds the Ca2+-dependent phosphodiesterase PDE-1 and co-localizes PDE-1 with molecular sensors for CO2 at dendritic ends. Reducing ARCP-1 or PDE-1 activity promotes CO2 escape by altering neuropeptide expression in the BAG CO2 sensors. Variation in ARCP-1 alters behavioral plasticity in multiple paradigms. Our findings are reminiscent of genetic accommodation, an evolutionary process by which phenotypic flexibility in response to environmental variation is reset by genetic change.
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| 17. |
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| 18. |
- Bergmann, O., et al.
(författare)
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The Age of Olfactory Bulb Neurons in Humans
- 2012
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Ingår i: Neuron. - : Elsevier BV. - 0896-6273 .- 1097-4199. ; 74:4, s. 634-639
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Tidskriftsartikel (refereegranskat)abstract
- Continuous turnover of neurons in the olfactory bulb is implicated in several key aspects of olfaction. There is a dramatic decline postnatally in the number of migratory neuroblasts en route to the olfactory bulb in humans, and it has been unclear to what extent the small number of neuroblasts at later stages contributes new neurons to the olfactory bulb. We have assessed the age of olfactory bulb neurons in humans by measuring the levels of nuclear bomb test-derived C-14 in genomic DNA. We report that C-14 concentrations correspond to the atmospheric levels at the time of birth of the individuals, establishing that there is very limited, if any, postnatal neurogenesis in the human olfactory bulb. This identifies a fundamental difference in the plasticity of the human brain compared to other mammals.
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| 19. |
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| 21. |
- Brincat, Scott L., et al.
(författare)
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Interhemispheric transfer of working memories
- 2021
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Ingår i: Neuron. - : Elsevier BV. - 0896-6273 .- 1097-4199. ; 109:6, s. 1055-1066
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Tidskriftsartikel (refereegranskat)abstract
- Visual working memory (WM) storage is largely independent between the left and right visual hemifields/cerebral hemispheres, yet somehow WM feels seamless. We studied how WM is integrated across hemifields by recording neural activity bilaterally from lateral prefrontal cortex. An instructed saccade during the WM delay shifted the remembered location from one hemifield to the other. Before the shift, spike rates and oscillatory power showed clear signatures of memory laterality. After the shift, the lateralization inverted, consistent with transfer of the memory trace from one hemisphere to the other. Transferred traces initially used different neural ensembles from feedforward-induced ones, but they converged at the end of the delay. Around the time of transfer, synchrony between the two prefrontal hemispheres peaked in theta and beta frequencies, with a directionality consistent with memory trace transfer. This illustrates how dynamics between the two cortical hemispheres can stitch together WM traces across visual hemifields.
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| 22. |
- Broomand, Amir, et al.
(författare)
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Large-Scale Movement within the Voltage-Sensor Paddle of a Potassium Channel-Support for a Helical-Screw Motion
- 2008
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Ingår i: Neuron. - : Elsevier BV. - 0896-6273 .- 1097-4199. ; 59:5, s. 770-777
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Tidskriftsartikel (refereegranskat)abstract
- The size of the movement and the molecular identity of the moving parts of the voltage sensor of a voltage-gated ion channel are debated. In the helical-screw model, the positively charged fourth transmembrane segment S4 slides and rotates along negative counter charges in S2 and S3, while in the paddle model, S4 carries the extracellular part of S3 (S3b) as a cargo. Here, we show that S4 slides 16-26 Å along S3b. We introduced pairs of cysteines in S4 and S3b of the Shaker K channel to make disulfide bonds. Residue 325 in S3b makes close and state-dependent contacts with a long stretch of residues in S4. A disulfide bond between 325 and 360 was formed in the closed state, while a bond between 325 and 366 was formed in the open state. These data are not compatible with the voltage-sensor paddle model, but support the helical-screw model. © 2008 Elsevier Inc. All rights reserved.
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| 23. |
- Bulovaite, Edita, et al.
(författare)
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A brain atlas of synapse protein lifetime across the mouse lifespan
- 2022
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Ingår i: Neuron. - : Elsevier BV. - 0896-6273 .- 1097-4199. ; 110:24, s. 4057-
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Tidskriftsartikel (refereegranskat)abstract
- The lifetime of proteins in synapses is important for their signaling, maintenance, and remodeling, and for memory duration. We quantified the lifetime of endogenous PSD95, an abundant postsynaptic protein in excitatory synapses, at single-synapse resolution across the mouse brain and lifespan, generating the Protein Lifetime Synaptome Atlas. Excitatory synapses have a wide range of PSD95 lifetimes extending from hours to several months, with distinct spatial distributions in dendrites, neurons, and brain regions. Synapses with short protein lifetimes are enriched in young animals and in brain regions controlling innate behaviors, whereas synapses with long protein lifetimes accumulate during development, are enriched in the cortex and CA1 where memories are stored, and are preferentially preserved in old age. Synapse protein lifetime increases throughout the brain in a mouse model of autism and schizophrenia. Protein lifetime adds a further layer to synapse diversity and enriches prevailing concepts in brain development, aging, and disease.
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| 24. |
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| 25. |
- Cowgill, John, et al.
(författare)
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Structure and dynamics of differential ligand binding in the human ρ-type GABAA receptor
- 2023
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Ingår i: Neuron. - : Elsevier BV. - 0896-6273 .- 1097-4199. ; 111:21, s. 5-3450
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Tidskriftsartikel (refereegranskat)abstract
- The neurotransmitter γ-aminobutyric acid (GABA) drives critical inhibitory processes in and beyond the nervous system, partly via ionotropic type-A receptors (GABAARs). Pharmacological properties of ρ-type GABAARs are particularly distinctive, yet the structural basis for their specialization remains unclear. Here, we present cryo-EM structures of a lipid-embedded human ρ1 GABAAR, including a partial intracellular domain, under apo, inhibited, and desensitized conditions. An apparent resting state, determined first in the absence of modulators, was recapitulated with the specific inhibitor (1,2,5,6-tetrahydropyridin-4-yl)methylphosphinic acid and blocker picrotoxin and provided a rationale for bicuculline insensitivity. Comparative structures, mutant recordings, and molecular simulations with and without GABA further explained the sensitized but slower activation of ρ1 relative to canonical subtypes. Combining GABA with picrotoxin also captured an apparent uncoupled intermediate state. This work reveals structural mechanisms of gating and modulation with applications to ρ-specific pharmaceutical design and to our biophysical understanding of ligand-gated ion channels.
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