bluuebunny/crossref_metadata_2025_split huggingface dataset:
Lasting N-Terminal Phosphorylation of c-Jun and Activation of c-Jun N-Terminal Kinases after Neuronal Injury
Authors: Herdegen Thomas , Claret Francois-Xavier , Kallunki Tuula , Martin-Villalba Ana , Winter Christine , Hunter Tony , Karin Michael 
Published: April 2018

Transcription factor c-Jun is proposed to control neuronal cell death and survival, but its activation by N-terminal phosphorylation and the underlying activity of the c-Jun N-terminal kinases (JNKs) remain to be elucidated in the adult mammalian brain. We generated a polyclonal antiserum that specifically recognizes c-Jun phosphorylated at its serine 73 (S73) residue after UV irradiation of 3T3 cells. Disruption of thec-junlocus in 3T3 cells abolished this reaction, and retransfection of the humanc-junat thec-jun−/−background restored it.The phospho-c-Jun antiserum was used to visualize N-terminally phosphorylated c-Jun in the adult rat brain with cellular resolution. Prolonged c-Jun S73 phosphorylation was detected in affected neurons up to 5 d after transient occlusion of medial cerebral artery or up to 50 d after transection of central nerve fiber tracts. After cerebral ischemia–reperfusion, phosphorylation of c-Jun was linked with induced expression of Fas-ligand (APO-1, CD95-ligand), whose gene is a putative c-Jun/AP-1 target, and with terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling (TUNEL) reactivity, a marker for apoptosis. After nerve fiber transection, however, lasting c-Jun phosphorylation occurred in axotomized neurons negative for Fas-ligand or TUNEL and regardless of degeneration or survival. In contrast to these lasting phosphorylation patterns, transient seizure activity by pentylenetetrazole provoked only a brief c-Jun phosphorylation and JNK activation.In extracts from ischemic or axotomized brain compartments, c-Jun phosphorylation correlated with enhanced long-term JNK activity, and in-gel kinase assays visualized proteins with sizes corresponding to JNK isoforms as the only c-Jun N-terminally phosphorylating enzymes.These results demonstrate that lasting c-Jun S73 phosphorylation and JNK activity are part of neuronal stress response after neurodegenerative disorders in the adult mammalian brain with Fas-ligand as a putative apoptotic effector.
Regulated Expression of the Cell Adhesion Glycoprotein F3 in Adult Hypothalamic Magnocellular Neurons
Authors: Pierre Karin , Rougon Geneviève , Allard Michèle , Bonhomme Renée , Gennarini Gianfranco , Poulain Dominique A. , Theodosis Dionysia. T. 
Published: April 2018

F3, a glycoprotein of the immunoglobulin superfamily implicated in axonal growth, occurs in oxytocin (OT)-secreting and vasopressin (AVP)-secreting neurons of the adult hypothalamo-neurohypophysial system (HNS) whose axons undergo morphological changes in response to stimulation. Immunocytochemistry and immunoblot analysis showed that during basal conditions of HNS secretion, there are higher levels of this glycosylphosphatidyl inositol-anchored protein in the neurohypophysis, where their axons terminate, than in the hypothalamic nuclei containing their somata. Physiological stimulation (lactation, osmotic challenge) reversed this pattern and resulted in upregulation of F3 expression, paralleling that of OT and AVP under these conditions.In situhybridization revealed that F3 expression in the hypothalamus is restricted to its magnocellular neurons and demonstrated a more than threefold increase in F3 mRNA levels in response to stimulation. Confocal and electron microscopy localized F3 in secretory granules in all neuronal compartments, a localization confirmed by detection of F3 immunoreactivity in granule-enriched fractions obtained by sucrose density gradient fractionation of rat neurohypophyses. F3 was not visible on any cell surface in the magnocellular nuclei. In contrast, in the neurohypophysis, it was present not only in secretory granules but also on the surface of axon terminals and glia and in extracellular spaces.Taken together, our observations reveal that the cell adhesion glycoprotein F3 is colocalized with neurohypophysial peptides in secretory granules. It follows, therefore, the regulated pathway of secretion in HNS neurons to be released by exocytosis at their axon terminals in the neurohypophysis, where it may intervene in activity-dependent structural axonal plasticity.
Contrast-Invariant Orientation Tuning in Cat Visual Cortex: Thalamocortical Input Tuning and Correlation-Based Intracortical Connectivity
Authors: Troyer Todd W. , Krukowski Anton E. , Priebe Nicholas J. , Miller Kenneth D. 
Published: April 2018

The origin of orientation selectivity in visual cortical responses is a central problem for understanding cerebral cortical circuitry. In cats, many experiments suggest that orientation selectivity arises from the arrangement of lateral geniculate nucleus (LGN) afferents to layer 4 simple cells. However, this explanation is not sufficient to account for the contrast invariance of orientation tuning.To understand contrast invariance, we first characterize the input to cat simple cells generated by the oriented arrangement of LGN afferents. We demonstrate that it has two components: a spatial-phase-specific component (i.e., one that depends on receptive field spatial phase), which is tuned for orientation, and a phase-nonspecific component, which is untuned. Both components grow with contrast.Second, we show that a correlation-based intracortical circuit, in which connectivity between cell pairs is determined by the correlation of their LGN inputs, is sufficient to achieve well tuned, contrast-invariant orientation tuning. This circuit generates both spatially opponent, “antiphase” inhibition (“push–pull”), and spatially matched, “same-phase” excitation. The inhibition, if sufficiently strong, suppresses the untuned input component and sharpens responses to the tuned component at all contrasts. The excitation amplifies tuned responses. This circuit agrees with experimental evidence showing spatial opponency between, and similar orientation tuning of, the excitatory and inhibitory inputs received by a simple cell. Orientation tuning is primarily input driven, accounting for the observed invariance of tuning width after removal of intracortical synaptic input, as well as for the dependence of orientation tuning on stimulus spatial frequency.The model differs from previous push–pull models in requiring dominant rather than balanced inhibition and in predicting that a population of layer 4 inhibitory neurons should respond in a contrast-dependent manner to stimuli of all orientations, although their tuning width may be similar to that of excitatory neurons. The model demonstrates that fundamental response properties of cortical layer 4 can be explained by circuitry expected to develop under correlation-based rules of synaptic plasticity, and shows how such circuitry allows the cortex to distinguish stimulus intensity from stimulus form.
TrkB and TrkC Signaling Are Required for Maturation and Synaptogenesis of Hippocampal Connections
Authors: Martı́nez Albert , Alcántara Soledad , Borrell Vı́ctor , Del Rı́o José A. , Blasi Joan , Otal Raquel , Campos Narciso , Boronat Albert , Barbacid Mariano , Silos-Santiago Inmaculada , Soriano Eduardo 
Published: April 2018

Recent studies have suggested a role for neurotrophins in the growth and refinement of neural connections, in dendritic growth, and in activity-dependent adult plasticity. To unravel the role of endogenous neurotrophins in the development of neural connections in the CNS, we studied the ontogeny of hippocampal afferents intrkB (−/−) andtrkC (−/−) mice. Injections of lipophilic tracers in the entorhinal cortex and hippocampus of newborn mutant mice showed that the ingrowth of entorhinal and commissural/associational afferents to the hippocampus was not affected by these mutations. Similarly, injections of biocytin in postnatal mutant mice (P10–P16) did not reveal major differences in the topographic patterns of hippocampal connections.In contrast, quantification of biocytin-filled axons showed that commissural and entorhinal afferents have a reduced number of axon collaterals (21–49%) and decreased densities of axonal varicosities (8–17%) in bothtrkB (−/−) andtrkC (−/−) mice. In addition, electron microscopic analyses showed thattrkB (−/−) andtrkC (−/−) mice have lower densities of synaptic contacts and important structural alterations of presynaptic boutons, such as decreased density of synaptic vesicles. Finally, immunocytochemical studies revealed a reduced expression of the synaptic-associated proteins responsible for synaptic vesicle exocytosis and neurotransmitter release (v-SNAREs and t-SNAREs), especially intrkB (−/−) mice. We conclude that neithertrkB nortrkC genes are essential for the ingrowth or layer-specific targeting of hippocampal connections, although the lack of these receptors results in reduced axonal arborization and synaptic density, which indicates a role for TrkB and TrkC receptors in the developmental regulation of synaptic inputs in the CNSin vivo. The data also suggest that the genes encoding for synaptic proteins may be targets of TrkB and TrkC signaling pathways.
Postnatal Development of Type I and Type II Hair Cells in the Mouse Utricle: Acquisition of Voltage-Gated Conductances and Differentiated Morphology
Authors: Rüsch Alfons , Lysakowski Anna , Eatock Ruth Anne 
Published: April 2018

The type I and type II hair cells of mature amniote vestibular organs have been classified according to their afferent nerve terminals: calyx and bouton, respectively. Mature type I and type II cells also have different complements of voltage-gated channels. Type I cells alone express a delayed rectifier, gK,L, that is activated at resting potential. We report that in mouse utricles this electrophysiological differentiation occurs during the first postnatal week. Whole-cell currents were recorded from hair cells in denervated organotypic cultures and in acutely excised epithelia. From postnatal day 1 (P1) to P3, most hair cells expressed a delayed rectifier that activated positive to resting potential and a fast inward rectifier, gK1. Between P4 and P8, many cells acquired the type I-specific conductance gK,Land/or a slow inward rectifier, gh. By P8, the percentages of cells expressing gK,Land ghwere at mature levels.To investigate whether the electrophysiological differentiation correlated with morphological changes, we fixed utricles at different times between P0 and P28. Ultrastructural criteria were developed to classify cells when calyces were not present, as in cultures and neonatal organs. The morphological and electrophysiological differentiation followed different time courses, converging by P28. At P0, when no hair cells expressed gK,L, 33% were classified as type I by ultrastructural criteria. By P28, ∼60% of hair cells in acute preparations received calyx terminals and expressed gK,L. Data from the denervated cultures showed that neither electrophysiological nor morphological differentiation depended on ongoing innervation.
Contributions of Pathway and Neuron to Preferential Motor Reinnervation
Authors: Brushart Thomas M. , Gerber Jonathan , Kessens Philip , Chen You-Gang , Royall Richard M. 
Published: April 2018

Motor axons regenerating after transection of mixed nerve preferentially reinnervate distal muscle branches, a process termed preferential motor reinnervation (PMR). Motor axon collaterals appear to enter both cutaneous and muscle Schwann cell tubes on a random basis. Double-labeling studies suggest that PMR is generated by pruning collaterals from cutaneous pathways while maintaining those in motor pathways (the “pruning hypothesis”). If all collaterals projecting to muscle are saved, then stimulation of regenerative sprouting should increase specificity by increasing the number of motoneurons with at least one collateral in a muscle pathway. In the current experiments, collateral sprouting is stimulated by crushing the nerve proximal to the repair site before suture, a maneuver that also conditions the neuron and predegenerates the distal pathway. Control experiments are performed to separate these effects from those of collateral generation.Experiments were performed on the rat femoral nerve and evaluated by exposing its terminal cutaneous and muscle branches to HRP or Fluoro-Gold. Crush proximal to the repair site increased motor axon collaterals at least fivefold and significantly increased the percentage of correctly projecting motoneurons, consistent with the pruning hypothesis. Conditioning the nerve with distal crushes before repair had no effect on specificity. A graft model was used to separate the effects of collateral generation and distal stump predegeneration. Previous crush of the proximal femoral nerve significantly increased the specificity of fresh graft reinnervation. Stimulation of regenerative collateral sprouting thus increased PMR, confirming the pruning hypothesis. However, this effect was overshadowed by the dramatic specificity with which predegenerated grafts were reinnervated by fresh uncrushed proximal axons. These unexpected effects of predegeneration on specificity could involve a variety of possible mechanisms and warrant further study because of their mechanistic and clinical implications.
Single-Cell RT-PCR and Functional Characterization of Ca2+Channels in Motoneurons of the Rat Facial Nucleus
Authors: Plant T. D. , Schirra C. , Katz E. , Uchitel O. D. , Konnerth A. 
Published: April 2018

Voltage-dependent Ca2+channels are a major pathway for Ca2+entry in neurons. We have studied the electrophysiological, pharmacological, and molecular properties of voltage-gated Ca2+channels in motoneurons of the rat facial nucleus in slices of the brainstem. Most facial motoneurons express both low voltage-activated (LVA) and high voltage-activated (HVA) Ca2+channel currents. The HVA current is composed of a number of pharmacologically separable components, including 30% of N-type and ∼5% of L-type. Despite the dominating role of P-type Ca2+channels in transmitter release at facial motoneuron terminals described in previous studies, these channels were not present in the cell body. Remarkably, most of the HVA current was carried through a new type of Ca2+channel that is resistant to toxin and dihydropyridine block but distinct from the R-type currents described in other neurons.Using reverse transcription followed by PCR amplification (RT-PCR) with a powerful set of primers designed to amplify all HVA subtypes of the α1-subunit, we identified a highly heterogeneous expression pattern of Ca2+channel α1-subunit mRNA in individual neurons consistent with the Ca2+current components found in the cell bodies and axon terminals. We detected mRNA for α1Ain 86% of neurons, α1Bin 59%, α1Cin 18%, α1Din 18%, and α1Ein 59%. Either α1Aor α1BmRNAs (or both) were present in all neurons, together with various other α1-subunit mRNAs. The most frequently occurring combination was α1Awith α1Band α1E. Taken together, these results demonstrate that the Ca2+channel pattern found in facial motoneurons is highly distinct from that found in other brainstem motoneurons.
Correlation-Based Development of Ocularly Matched Orientation and Ocular Dominance Maps: Determination of Required Input Activities
Authors: Erwin Ed , Miller Kenneth D. 
Published: April 2018

We extend previous models for separate development of ocular dominance and orientation selectivity in cortical layer 4 by exploring conditions permitting combined organization of both properties. These conditions are expressed in terms of functions describing the degree of correlation in the firing of two inputs from the lateral geniculate nucleus (LGN), as a function of their retinotopic separation and their “type” (ON center or OFF center and left eye or right eye).The development of ocular dominance requires that the correlations of an input with other inputs of the same eye be stronger than or equal to its correlations with inputs of the opposite eye and strictly stronger at small retinotopic separations. This must be true after summing correlations with inputs of both center types. The development of orientation-selective simple cells requires that (1) an input’s correlations with other inputs of the same center type be stronger than its correlations with inputs of the opposite center type at small retinotopic separation; and (2) this relationship reverse at larger retinotopic separations within an arbor radius (the radius over which LGN cells can project to a common cortical point). This must be true after summing correlations with inputs serving both eyes.For orientations to become matched in the two eyes, correlated activity within the receptive fields must be maximized by specific between-eye alignments of ON and OFF subregions. Thus the correlations between the eyes must differ depending on center type, and this difference must vary with retinotopic separation within an arbor radius.These principles are satisfied by a wide class of correlation functions. Combined development of ocularly matched orientation maps and ocular dominance maps can be achieved either simultaneously or sequentially. In the latter case, the model can produce a correlation between the locations of orientation map singularities and local ocular dominance peaks similar to that observed physiologically.The model’s main prediction is that the above correlations should exist among inputs to cortical layer 4 simple cells before vision. In addition, mature simple cells are predicted to have certain relationships between the locations of the ON and OFF subregions of the left and right eyes’ receptive fields.
An Oscillatory Short-Term Memory Buffer Model Can Account for Data on the Sternberg Task
Authors: Jensen Ole , Lisman John E. 
Published: April 2018

A limited number (7 ± 2) of items can be held in human short-term memory (STM). We have previously suggested that observed dual (theta and gamma) oscillations could underlie a multiplexing mechanism that enables a single network to actively store up to seven memories. Here we have asked whether models of this kind can account for the data on the Sternberg task, the most quantitative measurements of memory search available. We have found several variants of the oscillatory search model that account for the quantitative dependence of the reaction time distribution on the number of items (S) held in STM. The models differ on the issues of (1) whether theta frequency varies with S and (2) whether the phase of ongoing oscillations is reset by the probe. Using these models the frequencies of dual oscillations can be derived from psychophysical data. The derived values (fθ= 6–10 Hz ; fγ= 45–60 Hz) are in reasonable agreement with experimental values. The exhaustive nature of the serial search that has been inferred from psychophysical measurements can be plausibly explained by these oscillatory models. One argument against exhaustive serial search has been the existence of serial position effects. We find that these effects can be explained by short-term repetition priming in the context of serial scanning models. Our results strengthen the case for serial processing and point to experiments that discriminate between variants of the serial scanning process.
Spontaneous Network Activity Transiently Depresses Synaptic Transmission in the Embryonic Chick Spinal Cord
Authors: Fedirchuk Brent , Wenner Peter , Whelan Patrick J. , Ho Stephen , Tabak Joel , O’Donovan Michael J. 
Published: April 2018

We examined the effects of spontaneous or evoked episodes of rhythmic activity on synaptic transmission in several spinal pathways of embryonic day 9–12 chick embryos. We compared the amplitude of synaptic potentials evoked by stimulation of the ventrolateral funiculus (VLF), the dorsal or ventral roots, before and after episodes of activity. With the exception of the short-latency responses evoked by dorsal root stimulation, the potentials were briefly potentiated and then reduced for several minutes after an episode of rhythmic activity. Their amplitude progressively recovered in the interval between successive episodes. The lack of post-episode depression in the short-latency component of the dorsal root evoked responses is probably attributable to the absence of firing in cut muscle afferents during an episode of activity.The post-episode depression of VLF-evoked potentials was mimicked by prolonged stimulation of the VLF, subthreshold for an episode of activity. By contrast, antidromically induced motoneuron firing and the accompanying calcium entry did not depress VLF-evoked potentials recorded from the stimulated ventral root. In addition, post-episode depression of VLF-evoked synaptic currents was observed in voltage-clamped spinal neurons. Collectively, these findings suggest that somatic postsynaptic activity and calcium entry are not required for the depression. We propose instead that the mechanism may involve a form of long-lasting activity-induced synaptic depression, possibly a combination of transmitter depletion and ligand-induced changes in the postsynaptic current accompanying transmitter release. This activity-dependent depression appears to be an important mechanism underlying the occurrence of spontaneous activity in developing spinal networks.
Human Episodic Memory Retrieval Is Accompanied by a Neural Contiguity Effect
Authors: Folkerts Sarah , Rutishauser Ueli , Howard Marc W. 
Published: April 2018

Cognitive psychologists have long hypothesized that experiences are encoded in a temporal context that changes gradually over time. When an episodic memory is retrieved, the state of context is recovered—a jump back in time. We recorded from single units in the medial temporal lobe of epilepsy patients performing an item recognition task. The population vector changed gradually over minutes during presentation of the list. When a probe from the list was remembered with high confidence, the population vector reinstated the temporal context of the original presentation of that probe during study, a neural contiguity effect that provides a possible mechanism for behavioral contiguity effects. This pattern was only observed for well remembered probes; old probes that were not well remembered showed an anti-contiguity effect. These results constitute the first direct evidence that recovery of an episodic memory in humans is associated with retrieval of a gradually changing state of temporal context, a neural “jump back in time” that parallels the act of remembering.SIGNIFICANCE STATEMENTEpisodic memory is the ability to relive a specific experience from one's life. For decades, researchers have hypothesized that, unlike other forms of memory that can be described as simple associations between stimuli, episodic memory depends on the recovery of a neural representation of spatiotemporal context. During study of a sequence of stimuli, the brain state of epilepsy patients changed slowly over at least a minute. When the participant remembered a particular event from the list, this gradually changing state was recovered. This provides direct confirmation of the prediction from computational models of episodic memory. The resolution of this point means that the study of episodic memory can focus on the mechanisms by which this representation of spatiotemporal context is maintained and sometimes recovered.