bluuebunny/crossref_metadata_2025_split huggingface dataset:
Immunological Instability of Persistent Adenovirus Vectors in the Brain: Peripheral Exposure to Vector Leads to Renewed Inflammation, Reduced Gene Expression, and Demyelination
Authors: Byrnes Andrew P. , MacLaren Robert E. , Charlton Harry M. 
Published: April 2018

Nonreplicating adenovirus vectors are being developed as vehicles for the delivery of therapeutic genesin vivo. Whereas in many organs an antiviral T cell response eliminates the vector and damages local tissue, when adenovirus vectors are injected into the brain the subsequent immune attack can be ineffective, allowing the vector to persist.In the present study, E1-deleted human adenovirus vectors were injected into the caudate nucleus of rats. Two months later, expression of protein from the vector was still evident and little inflammation was seen. A subcutaneous injection of adenovirus vector at this time, however, led within 2 weeks to severe mononuclear inflammation and microglial activation in the caudate. This caused local demyelination and a decrease in detectable protein expression from the vector. Interestingly, intense microglial activation and numerous lymphocytes and monocytes were also seen in brain areas containing neurons capable of retrogradely transporting the adenovirus vector from the caudate. Control experiments established that this inflammation in distant brain areas was not a nonspecific consequence of degeneration.These experiments demonstrate that although adenovirus vectors can persist in the brain without causing chronic inflammation, they remain the potential target of a damaging cell-mediated immune response brought about by a subsequent peripheral exposure to vector. The finding of lymphocytes in brain areas that project to the caudate further shows that viral antigens that are retrogradely transported by neurons can also be the target of a T cell attack.
Conditioned and Unconditioned Stimuli Increase Frontal Cortical and Hippocampal Acetylcholine Release: Effects of Novelty, Habituation, and Fear
Authors: Acquas Elio , Wilson Catriona , Fibiger Hans C. 
Published: April 2018

Recent evidence showing that basal forebrain cholinergic neurons with projections to the frontal cortex and hippocampus are activated by behaviorally salient stimuli suggests that these neurons are involved in arousal and/or attentional processes. We sought in the present experiments to test this hypothesis by examining whether unconditioned stimuli (a tone and flashing light) that normally increase cortical and hippocampal acetylcholine (ACh) release would fail to do so after habituation (i.e., repeated presentation with no programmed consequences). In addition, the extent to which presentation of these stimuli would continue to increase ACh release when they had previously been paired with an aversive stimulus was investigated. Three experimental groups were used: habituation, novel stimuli, and conditioned fear. Subjects in each of these groups were placed in a training apparatus for twelve 200 min sessions. While the habituation group received extensive exposure to the tone and light during the training sessions, subjects in the novel stimuli group were placed in the apparatus but were never exposed to the tone or light during these sessions. The conditioned fear group was treated identically to the habituation group, with the addition that the tone and light were paired with footshock. On completion of these training schedules, all animals were implanted with microdialysis probes in the frontal cortex and hippocampus. Two days later, they were placed in the apparatus and the tone and light were presented to all subjects during microdialysis. In the novel stimuli group, the tone and light (unconditioned stimuli) produced significant increases in frontal cortical and hippocampal ACh release. Similarly, in the conditioned fear group, presentation of the tone and light (conditioned stimuli) also significantly increased ACh release in frontal cortex and hippocampus. In contrast, in the habituation group the tone and light failed to significantly enhance ACh release in either structure. During the test session, the tone and light elicited a variety of arousal- and fear-related behaviors in the novel stimuli and conditioned fear groups. In contrast, subjects in the habituation group generally failed to respond to these stimuli.These data indicate that cortically and hippocampally projecting basal forebrain cholinergic neurons are activated by conditioned and unconditioned stimuli that produce arousal in rats (novelty or conditioned fear). In contrast, presentation of these stimuli to habituated animals fails to enhance ACh release. These findings are consistent with a growing body of information indicating that ACh release in the cortex and hippocampus is reliably activated by behaviorally relevant stimuli. They also provide strong support for the hypothesis that cholinergic neurons in the basal forebrain are involved in arousal and/or attentional processes.
The Role of K+Currents in Frequency-Dependent Spike Broadening inAplysiaR20 Neurons: A Dynamic-Clamp Analysis
Authors: Ma Minghong , Koester John 
Published: April 2018

The R20 neurons ofAplysiaexhibit frequency-dependent spike broadening. Previously, we had used two-electrode voltage clamp to examine the mechanisms of this spike broadening (Ma and Koester, 1995). We identified three K+currents that mediate action-potential repolarization: a transient A-type K+current (IAdepol), a delayed rectifier current (IK-V), and a Ca2+-sensitive K+current (IK-Ca). A major constraint in that study was the lack of completely selective blockers forIAdepolandIK-V, resulting in an inability to assess directly the effects of their activation and inactivation on spike broadening. In the present study, the dynamic-clamp technique, which employs computer simulation to inject biologically realistic currents into a cell under current-clamp conditions (Sharp et al., 1993a,b), was used either to blockIAdepolorIK-Vor to modify their inactivation properties.The data in this paper, together with earlier results, lead to the following hypothesis for the mechanism of spike broadening in the R20 cells. As the spike train progresses, the primary responsibility for spike repolarization gradually shifts fromIAdepoltoIK-VtoIK-Ca. This sequence can be explained on the basis of the relative rates of activation and inactivation of each current with respect to the constantly changing spike durations, the cumulative inactivation ofIAdepolandIK-V, and the progressive potentiation ofIK-Ca. Positive feedback interactions between spike broadening and inactivation contribute to the cumulative inactivation of bothIAdepolandIK-V. The data also illustrate that when two or more currents have similar driving forces and partially overlapping activation characteristics, selectively blocking one current under current-clamp conditions can lead to a significant underestimate of its normal physiological importance.
Kinetics of NMDA Channel Opening
Authors: Dzubay Jeffrey A. , Jahr Craig E. 
Published: April 2018

The period required for NMDA channels to open for the first time after agonist binding (the first latency) was estimated in outside-out patch recordings from rat hippocampal neurons using fast-application techniques and the open channel blocker MK-801. In the presence of MK-801, brief applications ofl-glutamate or the low-affinity agonistl-cysteate resulted in a similar amount of block despite the much shorter period of channel activation byl-cysteate. A brief coapplication ofl-glutamate and MK-801 resulted in a block similar to that found with an application ofl-glutamate in a background of MK-801. These results, along with our findings that MK-801 does not block desensitized receptors, indicate that NMDA channels have a mean first latency of ∼10 msec, consistent with a peak open probability near 0.3. If NMDA channels at synapses behave similarly, relatively few channels would be required to produce the postsynaptic calcium transient associated with synaptic plasticity and developmental regulation.
Stimulus Specificity of Phase-Locked and Non-Phase-Locked 40 Hz Visual Responses in Human
Authors: Tallon-Baudry Catherine , Bertrand Olivier , Delpuech Claude , Pernier Jacques 
Published: April 2018

Considerable interest has been raised by non-phase-locked episodes of synchronization in the gamma-band (30–60 Hz). One of their putative roles in the visual modality is feature-binding. We tested the stimulus specificity of high-frequency oscillations in humans using three types of visual stimuli: two coherent stimuli (a Kanizsa and a real triangle) and a noncoherent stimulus (“no-triangle stimulus”). The task of the subject was to count the occurrences of a curved illusory triangle. A time–frequency analysis of single-trial EEG data recorded from eight human subjects was performed to characterize phase-locked as well as non-phase-locked high-frequency activities.We found an early phase-locked 40 Hz component, maximal at electrodes Cz–C4, which does not vary with stimulation type. We describe a second 40 Hz component, appearing around 280 msec, that is not phase-locked to stimulus onset. This component is stronger in response to a coherent triangle, whether real or illusory: it could reflect, therefore, a mechanism of feature binding based on high-frequency synchronization. Because both the illusory and the real triangle are more target-like, it could also correspond to an oscillatory mechanism for testing the match between stimulus and target. At the same latencies, the low-frequency evoked response components phase-locked to stimulus onset behave differently, suggesting that low- and high-frequency activities have different functional roles.
Apical Dendritic Location of Slow Afterhyperpolarization Current in Hippocampal Pyramidal Neurons: Implications for the Integration of Long-Term Potentiation
Authors: Sah Pankaj , Bekkers John M. 
Published: April 2018

Trains of action potentials in hippocampal pyramidal neurons are followed by a prolonged afterhyperpolarization (AHP) lasting several seconds, which is attributable to the activation of a slow calcium-activated potassium current (sIAHP). Here we examine the location of sIAHPon CA1 pyramidal neurons by comparing it with two GABAergic inhibitory postsynaptic currents (IPSCs) with known somatic and dendritic locations. Whole-cell patch-clamp recordings were made from CA1 pyramidal neurons in acute hippocampal slices. Stepping the membrane potential at the peak of sIAHPproduced a relaxation (“switchoff”) of the AHP current with a time constant of 7.4 ± 0.4 msec (mean ± SEM). The switchoff time constants for somatic and dendritic GABAAIPSCs were 3.5 ± 0.5 msec and 8.8 ± 0.3 msec, respectively. This data, together with cable modeling, indicates that active sIAHPchannels are distributed over the proximal dendrites within ∼200 μm of the soma. Excitatory postsynaptic potentials (EPSPs) evoked in stratum (s.) radiatum had their amplitudes shunted more by the AHP than did EPSPs evoked in s. oriens, suggesting that active AHP channels are restricted to the apical dendritic tree. Blockade of the AHP during a tetanus, which in control conditions elicited a decremental short-term potentiation (STP), converted STP to long-term potentiation (LTP). Thus, activation of the AHP increases the threshold for induction of LTP. These results suggest that in addition to its established role in spike frequency adaptation, the AHP works as an adjustable gain control, variably hyperpolarizing and shunting synaptic potentials arising in the apical dendrites.
The Fibroblast Growth Factor Receptor-1 Is Necessary for the Induction of Neurite Outgrowth in PC12 Cells by aFGF
Authors: Lin Hsien-Yi , Xu Jingsong , Ornitz David M. , Halegoua Simon , Hayman Michael J. 
Published: April 2018

The PC12 subclone, fnr-PC12 cells, is defective in neurite outgrowth in response to acidic fibroblast growth factor (aFGF); however, its response to nerve growth factor (NGF) is normal. Examination of the expression of FGF receptors (FGFRs) revealed that although PC12 cells express FGFR-1, -3, and -4, fnr-PC12 cells have a reduced level of expression of FGFR-1 but not FGFR-3 and -4. Transfection of FGFR-1 into fnr-PC12 cells efficiently restored aFGF-induced neurite outgrowth, whereas transfection of FGFR-3 was much less efficient. Transfection of a chimeric receptor consisting of the extracellular domain of FGFR-3 fused to the transmembrane and intracellular domain of FGFR-1, termed FR31b, efficiently restored aFGF-induced neurite outgrowth. This demonstrates that the difference between these two receptors in their ability to induce neurite outgrowth is attributable to differences in the signaling capacity of their cytoplasmic domains. Activation of the chimeric receptor by aFGF induced a stronger and more persistent increase in the tyrosine phosphorylation of cellular proteins than did activation of FGFR-3 alone. In particular, the activation of MAP kinase by FR31b was more persistent than when activated by FGFR-3. This difference in signaling potential of FGFR-1 and -3 in fnr-PC12 cells may account for the difference in the potential for induction of neurite outgrowth. These results demonstrate that FGF-induced neurite outgrowth in PC12 cells occurs mainly via FGFR-1 and not via the other FGFRs expressed in these cells.
Divergent Projections from the Anterior Inferotemporal Area TE to the Perirhinal and Entorhinal Cortices in the Macaque Monkey
Authors: Saleem K. S. , Tanaka K. 
Published: April 2018

Area TE is located at the latter part of the ventral visual cortical pathway, which is essential for visual recognition of objects. TE projects heavily to the perirhinal region, which is important for visual recognition memory of objects. To study the organization of projections from TE to the perirhinal (areas 35 and 36) and entorhinal (area 28) cortices, we made focal injections ofPhaseolus vulgarisleucoagglutinin (PHA-L) and large injections of biocytin or wheat germ agglutinin conjugated to horseradish peroxidase (WGA-HRP) into anterior levels of TE in macaque monkeys. Injections of PHA-L into the ventral part of anterior TE (TEav) resulted in labeling of terminals distributed widely in area 36 (approximately one-half of its total extent), although the injection sites were limited to 0.7 mm in width. The labeled terminals tended to be denser in the medial part of area 36. There was less dense but definite labeling in area 35 and the lateral part of area 28. After a single injection of PHA-L or WGA-HRP into the dorsal part of anterior TE (TEad), labeled terminals were confined to a small region at the lateral part of area 36 (less than one-tenth of its total extent). The projections to areas 35 and 28 from TEad were much sparser than those from TEav.The different patterns of projections to the perirhinal and entorhinal cortices, together with previously reported differences in their afferent and other efferent connections, suggest the functional differentiation between TEav and TEad. The divergent projection from TEav to the perirhinal cortex may facilitate the association of different visual features in the perirhinal cortex.
Protein Kinase and G-Protein Regulation of Ca2+Currents inHermissendaPhotoreceptors by 5-HT and GABA
Authors: Yamoah Ebenezer N. , Crow Terry 
Published: April 2018

The effects of serotonin (5-HT) and GABA on two Ca2+currents, a transient low-voltage-activated current (tLVA) and a sustained high-voltage-activated current (sHVA) were examined in isolated photoreceptors ofHermissenda. The sHVA current was blocked by 5-HT and reduced by activation of protein kinase C (PKC) with phorbol 12-myristate 13-acetate. The effects of 5-HT were transiently reversed by staurosporine and partially blocked by the PKC inhibitor peptide [PKC(19–36)]. GABA enhanced both the tLVA and sHVA currents at low concentrations (5 nmto 5 μm) and reduced the sHVA current at high concentrations (>10 μm). The GABA-mediated enhancement of the Ca2+current at low concentrations was sensitive to block by picrotoxin. The protein kinase A (PKA) inhibitor peptide [PKI(6–22)amide] blocked enhancement of both Ca2+currents produced by cAMP analogs and GABA, suggesting that the effects at low concentrations may be PKA mediated. Caged GTP-γ-S released by flash photolysis reduced the sHVA current, and pretreatment of the photoreceptors with pertussis toxin blocked the effects of higher concentrations of GABA, indicating that at higher concentrations, the effects may be G-protein mediated.
GABABReceptors, Monoamine Receptors, and Postsynaptic Inositol Trisphosphate-Induced Ca2+Release Are Involved in the Induction of Long-Term Potentiation at Visual Cortical Inhibitory Synapses
Authors: Komatsu Yukio 
Published: April 2018

γ-Aminobutyric acid (GABA)Areceptor-mediated inhibitory synaptic transmission in visual cortex undergoes long-term potentiation (LTP), which is input-specific and associative. The present study, conducted under a blockade of ionotropic glutamate receptors, demonstrates an induction mechanism of LTP considerably different from those of associative LTP at excitatory synapses. Inhibitory responses of layer V cells evoked by layer IV stimulation were studied in developing rat visual cortex slices by using intracellular and whole-cell recording methods. LTP induction was prevented by the application of an antagonist for GABABreceptors but not for GABAAor metabotropic glutamate receptors. Inhibition of postsynaptic G-proteins, phospholipase C, inositol trisphosphate (IP3) receptors, or Ca2+increase prevented the generation of LTP, as did the blockade of GABABreceptors.In rat cerebral cortex, GABABreceptor activation is not known to affect the IP3level by itself. However, it facilitates IP3formation induced by the activation of α1adrenoceptors, which are believed to be located postsynaptically. Accordingly, I examined the involvement of these and other amine receptors, including histamine H1, muscarinic acetylcholine, and serotonin 5-HT2receptors, all of which are coupled to IP3formation. Only the blockade of α1adrenoceptors or serotonin 5-HT2receptors prevented LTP induction in most, but not all, of the cells. These results suggest that LTP induction requires the activation of postsynaptic GABABreceptors and that its effect is mediated at least partly by facilitation of the monoamine-induced IP3formation, which then causes Ca2+release from the internal stores in postsynaptic cells.
Trans-Synaptic Stimulation of Cortical Acetylcholine Release after Partial 192 IgG-Saporin-Induced Loss of Cortical Cholinergic Afferents
Authors: Fadel Jim , Moore Holly , Sarter Martin , Bruno John P. 
Published: April 2018

Environmental and pharmacological stimulation of cortical acetylcholine (ACh) efflux was determined in rats sustaining partial deafferentation of cortical cholinergic inputs. Rats were bilaterally infused with the selective cholinotoxin 192 IgG-saporin (0.005 μg/0.5 μl/site) into the frontoparietal cortex. In the first experiment, animals were pretrained to associate the onset of darkness with presentation of a palatable fruit cereal reward. The ability of this stimulus to enhance frontoparietal ACh efflux alone, and with the benzodiazepine receptor (BZR) weak inverse agonist ZK 93,426 (1.0 or 5.0 mg/kg, i.p.), was determined in lesioned and sham-lesioned rats. Intracortical infusions of 192 IgG-saporin reduced basal cortical ACh efflux by 47% of sham-lesioned values, consistent with reductions in the density of AChE-positive fibers. In spite of this deafferentation, ZK 93,426 produced a transient potentiation of the cortical ACh efflux induced by the darkness/cereal stimulus similar to that observed in control animals. In the second experiment, the ability of the more efficacious BZR partial inverse agonist FG 7142 (8.0 mg/kg, i.p.) to enhance basal cortical ACh efflux was compared in lesioned and sham-lesioned rats. Again, lesioned rats exhibited an increase comparable to control animals after FG 7142. This drug-induced stimulation of cortical ACh efflux was comparably and completely blocked in both groups by co-perfusion with tetrodotoxin (1.0 μm). These results suggest similarities in the modulation of cortical ACh efflux in intact and partially deafferented rats and indicate the potential of BZR inverse agonists for restoring transmission in animals with partial loss of cortical cholinergic inputs.
Dynamics of Mismatch Correction in the Hippocampal Ensemble Code for Space: Interaction between Path Integration and Environmental Cues
Authors: Gothard Katalin M. , Skaggs William E. , McNaughton Bruce L. 
Published: April 2018

Populations of hippocampal neurons were recorded simultaneously in rats shuttling on a track between a fixed reward site at one end and a movable reward site, mounted in a sliding box, at the opposite end. While the rat ran toward the fixed site, the box was moved. The rat returned to the box in its new position. On the initial part of all journeys, cells fired at fixed distances from the origin, whereas on the final part, cells fired at fixed distances from the destination. Thus, on outward journeys from the box, with the box behind the rat, the position representation must have been updated by path integration. Farther along the journey, the place field map became aligned on the basis of external stimuli. The spatial representation was quantified in terms of population vectors. During shortened journeys, the vector shifted from an alignment with the origin to an alignment with the destination. The dynamics depended on the degree of mismatch with respect to the full-length journey. For small mismatches, the vector moved smoothly through intervening coordinates until the mismatch was corrected. For large mismatches, it jumped abruptly to the new coordinate. Thus, when mismatches occur, path integration and external cues interact competitively to control place-cell firing.When the same box was used in a different environment, it controlled the alignment of a different set of place cells. These data suggest that although map alignment can be controlled by landmarks, hippocampal neurons do not explicitly represent objects or events.
Proteolipid Protein Regulates the Survival and Differentiation of Oligodendrocytes
Authors: Yang Xiaoyi , Skoff Robert P. 
Published: April 2018

Proteolipid protein (PLP) has been postulated to play a critical role in the early differentiation of oligodendrocytes (OLs) in addition to its known role as a structural component of myelin. To identify this early function, we blocked the synthesis of PLP in glial cultures with antisense oligodeoxynucleotides that targeted the PLP initiation codon. Primary glial cultures were incubated with phosphorothioate-protected oligodeoxynucleotides (S-ODNs) for up to 11 d. PLP in OLs was reduced >90%. OLs treated with antisense S-ODNs appeared strikingly healthy as judged by (1) immunocytochemical staining for myelin glycolipids and myelin basic protein, (2) their prolonged survival compared with untreated cultures, and (3) their ability to re-establish membrane sheets after removal of the S-ODNs.Our studies show that PLP is required for elaboration and stability of the myelin membrane sheets made by most OLs, but it is not necessary for the network of processes established by OLs. More importantly, the number of OLs in the antisense-treated cultures was nearly sevenfold greater after a 10–11 d incubation with S-ODNs than in control cultures. The number of proliferating OL progenitors was not increased in the antisense-treated cultures, indicating that the increase in the number of OLs was attributable to prolonged OL survival. The tissue culture studies reveal that the absence of PLP/DM20 has the positive effect of promoting OL survival but the negative effect of preventing their full differentiation. This finding clarifies many of the paradoxical findings seen in the PLP mutants, the PLP overexpressers, and the PLP−animals.