bluuebunny/crossref_metadata_2025 huggingface dataset:
Exposure to Acute Stress Induces Brain Interleukin-1β Protein in the Rat
Authors: Nguyen Kien T. , Deak Terrence , Owens Stephanie M. , Kohno Tadahiko , Fleshner Monika , Watkins Linda R. , Maier Steven F.
Published: April 2018

Peripheral immune stimulation such as that provided by lipopolysaccharide (LPS) has been reported to increase brain levels of IL-1β mRNA, immunoreactivity, and bioactivity. Stressors produce many of the same neural and endocrine responses as those that follow LPS, but the impact of stressors on brain interleukin-1β (IL-1β) has not been systematically explored. An ELISA designed to detect IL-1β was used to measure levels of IL-1β protein in rat brain. Brain IL-1β was explored after exposure to inescapable shock (IS; 100 1.6 mA tail shocks for 5 sec each) and LPS (1 mg/kg) as a positive control. Rats were killed either immediately or 2, 7, 24, or 48 hr after IS. Brains were dissected into hypothalamus, hippocampus, cerebellum, posterior cortex, and nucleus tractus solitarius regions. LPS produced widespread increases in brain IL-1β, but IS did not. Adrenal glucocorticoids are known to suppress IL-1β production in both the periphery and brain. Thus, it was possible that the stressor did provide stimulus input to the brain IL-1β system(s), but that the production of IL-1β protein was suppressed by the rapid and prolonged high levels of glucocorticoids produced by IS. To test this possibility rats were adrenalectomized or given sham surgery, with half of the adrenalectomized rats receiving corticosterone replacement to maintain basal corticosterone levels. IS produced large increases in brain IL-1β protein in the adrenalectomized subjects 2 hr after stress, whether basal corticosterone levels had been maintained. Thus elimination of the stress-induced rise in corticosterone unmasked a robust and widespread increase in brain IL-1β.
Perirhinal Cortex Ablation Impairs Visual Object Identification
Authors: Buckley Mark J. , Gaffan David
Published: April 2018

Impairments in both recognition memory and concurrent discrimination learning have been shown to follow perirhinal cortex ablation in the monkey. The pattern of these impairments is consistent with the hypothesis that the perirhinal cortex has a role in the visual identification of objects. In this study we compared the performance of a group of three cynomolgus monkeys with bilateral perirhinal cortex ablation with that of a group of three normal controls in two tasks designed to test this hypothesis more directly. In experiment 1 the subjects relearned a set of 40 familiar concurrent discrimination problems; the stimuli in each trial were digitized images of real objects presented in one of three different views. After attaining criterion they were tested on the same problems using similar, but previously unseen, views of the objects. In experiment 2 the subjects were tested on their ability to perform 10 of these familiar discriminations with each problem presented in the unfamiliar context of a digitized image of a unique complex scene. The subjects with ablations were significantly impaired on both tasks. These results demonstrate that the role of the perirhinal cortex is not restricted to memory, and they support the hypothesis that the perirhinal cortex is involved in visual object identification. We suggest that the perirhinal cortex is crucially involved in processing coherent concepts of individual objects. A deficit of this nature could underlie the pattern of impairments that follow perirhinal cortex damage in both visual object recognition memory and visual associative memory.
Feature Extraction by Burst-Like Spike Patterns in Multiple Sensory Maps
Authors: Metzner W. , Koch C. , Wessel R. , Gabbiani F.
Published: April 2018

In most sensory systems, higher order central neurons extract those stimulus features from the sensory periphery that are behaviorally relevant (e.g., Marr, 1982; Heiligenberg, 1991). Recent studies have quantified the time-varying information carried by spike trains of sensory neurons in various systems using stimulus estimation methods (Bialek et al., 1991; Wessel et al., 1996). Here, we address the question of how this information is transferred from the sensory neuron level to higher order neurons across multiple sensory maps by using the electrosensory system in weakly electric fish as a model. To determine how electric field amplitude modulations are temporally encoded and processed at two subsequent stages of the amplitude coding pathway, we recorded the responses of P-type afferents and E- and I-type pyramidal cells in the electrosensory lateral line lobe (ELL) to random distortions of a mimic of the fish’s own electric field. Cells in two of the three somatotopically organized ELL maps were studied (centromedial and lateral) (Maler, 1979; Carr and Maler, 1986). Linear and second order nonlinear stimulus estimation methods indicated that in contrast to P-receptor afferents, pyramidal cells did not reliably encode time-varying information about any function of the stimulus obtained by linear filtering and half-wave rectification. Two pattern classifiers were applied to discriminate stimulus waveforms preceding the occurrence or nonoccurrence of pyramidal cell spikes in response to the stimulus. These signal-detection methods revealed that pyramidal cells reliably encoded the presence of upstrokes and downstrokes in random amplitude modulations by short bursts of spikes. Furthermore, among the different cell types in the ELL, I-type pyramidal cells in the centromedial map performed a better pattern-recognition task than those in the lateral map and than E-type pyramidal cells in either map.
A Reluctant Gating Mode of Glycine Receptor Channels Determines the Time Course of Inhibitory Miniature Synaptic Events in Zebrafish Hindbrain Neurons
Authors: Legendre Pascal
Published: April 2018

Miniature IPSCs (mIPSCs) recorded in the Mauthner (M)-cell of zebrafish larvae have a broad amplitude distribution that is attributable only partly to the functional heterogeneity of postsynaptic glycine receptors (GlyRs). The role of the kinetic properties of GlyRs in amplitude fluctuation was investigated using fast-flow application techniques on outside-out patches. Short applications of a saturating glycine concentration evoked outside-out currents with a biphasic deactivation phase as observed for mIPSCs, and they were consistent with a rapid clearance of glycine from the synaptic cleft. Patch currents declined slowly during continuous applications of 3 mmglycine, but the biphasic deactivation phase of mIPSCs cannot reflect a desensitization process because paired-pulse desensitization was not observed. The maximum open probability (Po) of GlyRs was close to 0.9 with 3 mmglycine. Analyses of the onset of outside-out currents evoked by 0.1 mmglycine are consistent with the presence of two equivalent binding sites with aKdof O.3-O.4 mm. Activation and deactivation properties of GlyRs were better described with a kinetic model, including two binding states, a doubly liganded open state, and a reluctant gating mode leading to another open state. The 20–80% rise time of mIPSCs was independent of their amplitude and is identical to that of outside-out currents evoked by the applications of a saturating concentration of glycine (>1 mm). These results support the hypothesis that GlyR kinetics determines the time course of synaptic events at M-cell inhibitory synapses and that large mIPSC amplitude fluctuations are mainly of postsynaptic origin.
Evidence That Increased Hippocampal Expression of the Cytokine Interleukin-1β Is a Common Trigger for Age- and Stress-Induced Impairments in Long-Term Potentiation
Authors: Murray Ciara A. , Lynch Marina A.
Published: April 2018

Several cytokines and their receptors are identified in brain; one of these is the proinflammatory cytokine interleukin-1β that is synthesized and released from neurons and glia in response to stress or insult. Among the actions of interleukin-1β is its ability to inhibit long-term potentiation in the hippocampusin vitro, an action that mimics one of the consequences of stress and age. It has been shown that the concentration of interleukin-1β in brain tissue is increased in neurodegenerative conditions, and recent evidence from our laboratory has indicated an increase in the concentration of interleukin-1β in the hippocampus of aged rats. These observations led us to consider that the underlying common cause of impaired long-term potentiation in aged and stressed rats might be increased endogenous interleukin-1β concentration in hippocampus. The data presented here indicate that there was an inverse relationship between concentration of interleukin-1β in the dentate gyrus and long-term potentiation in perforant path→granule cell synapses in aged rats, stressed rats, and rats pretreated with interleukin-1β. The evidence suggested that the cytokine induces formation of reactive oxygen species that triggers lipid peroxidationin vivo, as well asin vitro, and that these changes lead to depletion of membrane arachidonic acid that correlates with impaired long-term potentiation. We propose that three theories of aging, the glucocorticoid theory, the membrane theory, and the free radical theory, constitute three facets of age with one underlying trigger: an increase in the endogenous concentration of interleukin-1β in hippocampus.
Attenuated Influx of Calcium Ions at Nerve Endings ofcspandshibireMutantDrosophila
Authors: Umbach Joy A. , Saitoe Minoru , Kidokoro Yoshi , Gundersen Cameron B.
Published: April 2018

Previous work has shown that cysteine-string proteins (csps) are synaptic vesicle proteins that are important for evoked neurotransmitter release atDrosophilaneuromuscular junctions. Indirect evidence has implicated csps in a regulatory link between synaptic vesicles and presynaptic calcium (Ca) channels. In this report, we use Ca Crimson to monitor stimulus-dependent changes of cytosolic Ca at motor nerve terminals ofcspmutantDrosophila. These mutants display temperature-sensitive (TS) paralysis and a presynaptic failure of evoked synaptic transmission. We show that this TS inhibition of neuromuscular transmission is correlated with a block of Ca ion entry at nerve endings ofcspmutants. These data support the hypothesis that csps mediate a regulatory interaction between synaptic vesicles and presynaptic Ca channels. Moreover, these results predict that if one depletes nerve endings of synaptic vesicles, one may see a reduction of presynaptic Ca ion entry. Defects of thedynamingene in TSshibiremutantDrosophilainterfere with synaptic vesicle recycling and lead to an activity-dependent depletion of these organelles. Our results show that Ca influx is blocked at nerve terminals ofshibiremutant larvae at the same time that synaptic transmission fails in these organisms. Thus, using two completely independentDrosophilamutants, we demonstrate that synaptic vesicles and csps are vital for the function of presynaptic Ca channels.
Massive Mitochondrial Degeneration in Motor Neurons Triggers the Onset of Amyotrophic Lateral Sclerosis in Mice Expressing a Mutant SOD1
Authors: Kong Jiming , Xu Zuoshang
Published: April 2018

Amyotrophic lateral sclerosis (ALS) involves motor neuron degeneration, skeletal muscle atrophy, paralysis, and death. Mutations in Cu,Zn superoxide dismutase (SOD1) are one cause of the disease. Mice transgenic for mutated SOD1 develop symptoms and pathology similar to those in human ALS. To understand the disease mechanism, we developed a simple behavioral assay for disease progression in mice. Using this assay, we defined four stages of the disease in mice expressing G93A mutant SOD1. By studying mice with defined disease stages, we tied several pathological features into a coherent sequence of events leading to motor neuron death. We show that onset of the disease involves a sharp decline of muscle strength and a transient explosive increase in vacuoles derived from degenerating mitochondria, but little motor neuron death. Most motor neurons do not die until the terminal stage, ∼9 weeks after disease onset. These results indicate that mutant SOD1 toxicity is mediated by damage to mitochondria in motor neurons, and this damage triggers the functional decline of motor neurons and the clinical onset of ALS. The absence of massive motor neuron death at the early stages of the disease indicates that the majority of motor neurons could be rescued after clinical diagnosis.
Competitive Signaling Between TrkA and p75 Nerve Growth Factor Receptors Determines Cell Survival
Authors: Yoon Sung Ok , Casaccia-Bonnefil Patrizia , Carter Bruce , Chao Moses V.
Published: April 2018

In addition to its role as a survival factor, nerve growth factor (NGF) has been implicated in initiating apoptosis in restricted cell types both during development and after terminal cell differentiation. NGF binds to the TrkA tyrosine kinase and the p75 neurotrophin receptor, a member of the tumor necrosis factor cytokine family. To understand the mechanisms underlying survival versus death decisions, the TrkA receptor was introduced into oligodendrocyte cell cultures that undergo apoptosis in a p75-dependent manner. Here we report that activation of the TrkA NGF receptor in oligodendrocytes negates cell death by the p75 receptor. TrkA-mediated rescue from apoptosis correlated with mitogen-activated protein kinase activation. Concurrently, activation of TrkA in oligodendrocytes resulted in suppression of c-jun kinase activity initiated by p75, whereas induction of NFκB activity by p75 was unaffected. These results indicate that TrkA-mediated rescue involves not only activation of survival signals but also simultaneous suppression of a death signal by p75. The selective interplay between tyrosine kinase and cytokine receptors provides a novel mechanism that achieves alternative cellular responses by merging signals from different ligand–receptor systems.
Regeneration of Cochlear Efferent Nerve Terminals after Gentamycin Damage
Authors: Hennig Anne K. , Cotanche Douglas A.
Published: April 2018

Chickens recover auditory function after hair cell loss caused by ototoxic drug damage or acoustic overstimulation, indicating that mechanisms exist to reestablish appropriate neuronal connections to regenerated hair cells. However, despite similar hair cell regeneration times, hearing recovery takes substantially longer after aminoglycoside than after sound damage. We have therefore begun examining damage and regeneration of efferent nerve terminals by immunolabeling whole-mount cochleae for differentially localized synaptic proteins and by visualizing the distribution of label with confocal microscopy. In undamaged cochleae, the synaptic proteins synapsin and syntaxin show similar distribution patterns corresponding to the large cup-like terminals on short hair cells. After gentamycin administration, these terminals are disrupted as hair cells are lost, leaving smaller, more numerous synapsin-reactive structures in the sensory epithelium. Syntaxin reactivity remains associated with the extruded hair cells, indicating that the presynaptic membrane is still attached to the postsynaptic site. In contrast, after sound damage, both synapsin and syntaxin reactivity are lost from the epithelium with extruded hair cells. As regenerated hair cells differentiate after gentamycin treatment, the synapsin labeling associated with cup-like efferent endings reappears but is not completely restored even after 60 d of recovery. Thus, efferent terminals are reestablished much more slowly than after sound damage (Wang and Raphael, 1996), consistent with the prolonged loss of hearing function. Thisin vivomodel system allows comparison of axonal reconnection after either complete loss (sound damage) or partial disruption (gentamycin treatment) of axon terminals. Elucidating the differences in recovery between these injuries can provide insights into reinnervation mechanisms.
Locomotor Activity in D2 Dopamine Receptor-Deficient Mice Is Determined by Gene Dosage, Genetic Background, and Developmental Adaptations
Authors: Kelly Michele A. , Rubinstein Marcelo , Phillips Tamara J. , Lessov Christina N. , Burkhart-Kasch Sue , Zhang Ge , Bunzow James R. , Fang Yuan , Gerhardt Gregory A. , Grandy David K. , Low Malcolm J.
Published: April 2018

Locomotor activity is a polygenic trait that varies widely among inbred strains of mice (Flint et al., 1995). To characterize the role of D2 dopamine receptors in locomotion, we generated F2hybrid (129/Sv × C57BL/6) D2 dopamine receptor (D2R)-deficient mice by gene targeting and investigated the contribution of genetic background to open-field activity and rotarod performance. Horizontal activity of D2R−/− mice was approximately half that of drug-naive, strain-matched controls but was significantly greater than haloperidol-treated controls, which were markedly hypokinetic. Wild-type 129/SvEv and C57BL/6 mice with functional D2 receptors had greater interstrain differences in spontaneous activity than those among the F2hybrid mutants. Incipient congenic strains of D2R-deficient mice demonstrated an orderly gene dosage reduction in locomotion superimposed on both extremes of parental background locomotor activity. In contrast, F2hybrid D2R−/− mice had impaired motor coordination on the rotarod that was corrected in the congenic C57BL/6 background. Wild-type 129/SvEv mice had the poorest rotarod ability of all groups tested, suggesting that linked substrain 129 alleles, not the absence of D2 receptors per se, were largely responsible for the reduced function of the F2hybrid D2R−/− and D2R+/− mice. Neurochemical and pharmacological studies revealed unexpectedly normal tissue striatal monoamine levels and no evidence for supersensitive D1, D3, or D4 dopamine receptors in the D2R−/− mice. However, after acute monoamine depletion, akinetic D2R+/− mice had a significantly greater synergistic restoration of locomotion in response to SKF38393 and quinpirole compared with any group of D2R+/+ controls. We conclude that D2R-deficient mice are not a model of Parkinson’s disease. Our studies highlight the interaction of multiple genetic factors in the analysis of complex behaviors in gene knock-out mice.
Dendritic Low-Threshold Calcium Currents in Thalamic Relay Cells
Authors: Destexhe Alain , Neubig Mike , Ulrich Daniel , Huguenard John
Published: April 2018

The low-threshold calcium current (IT) underlies burst generation in thalamocortical (TC) relay cells and plays a central role in the genesis of synchronized oscillations by thalamic circuits. Here we have combinedin vitrorecordings and computational modeling techniques to investigate the consequences of dendritically locatedITin TC cells. Simulations of a reconstructed TC cell were compared with the recordings obtained in the same cell to constrain the values of its passive parameters. T-current densities in soma and proximal dendrites were then estimated by matching the model to voltage-clamp recordings obtained in dissociated TC cells, which lack most of the dendrites. The distal dendritic T-current density was constrained by recordings in intact TC cells, which show 5–14 times larger peak T-current amplitudes compared with dissociated cells. Comparison of the model with the recordings of the same cell constrained further the T-current density in dendrites, which had to be 4.5–7.6 times higher than in the soma to reproduce all experimental results. Similar conclusions were reached using a simplified three-compartment model. Functionally, the model shows that the same amount of T-channels can lead to different bursting behaviors if they are exclusively somatic or distributed throughout the dendrites. In conclusion, this combination of models and experiments shows that dendritic T-currents are necessary to reproduce low-threshold calcium electrogenesis in TC cells. Dendritic T-current may also have significant functional consequences, such as an efficient modulation of thalamic burst discharges by corticothalamic feedback.
Multiple Routes to Astrocytic Differentiation in the CNS
Authors: Rajan Prithi , McKay Ronald D. G.
Published: April 2018

Ciliary neurotrophic factor (CNTF) acts instructively to switch multipotent stem cells of the CNS to an astrocytic fate. Here we show that CNTF causes activation of janus kinase–signal transducers and activators of transcription and mitogen-activated protein kinase (MAPK) pathways with differential kinetics in these cells. Inhibition studies indicate that activation of the MAPK pathway is required early in the differentiation process, whereas activation of signal transducer and activator of transcription (STAT) proteins is required for commitment to an astrocytic fate. Bone morphogenetic proteins have also been shown to cause astrocytic differentiation but do not cause STAT activation or astrocytic differentiation in fibroblast growth factor 2-expanded fetal stem cells used here. These results show that there are two distinct routes to initiate astrocytic commitment in multipotent CNS precursors.
Neurexophilins Form a Conserved Family of Neuropeptide-Like Glycoproteins
Authors: Missler Markus , Südhof Thomas C.
Published: April 2018

Neurexophilin was discovered as a neuronal glycoprotein that is copurified with neurexin Iα during affinity chromatography on immobilized α-latrotoxin (Petrenko et al., 1996). We have now investigated how neurexophilin interacts with neurexins, whether it is post-translationally processed by site-specific cleavage similar to neuropeptides, and whether related neuropeptide-like proteins are expressed in brain. Our data show that mammalian brains contain four genes for neurexophilins the products of which share a common structure composed of five domains: an N-terminal signal peptide, a variable N-terminal domain, a highly conserved central domain that is N-glycosylated, a short linker region, and a conserved C-terminal domain that is cysteine-rich. When expressed in pheochromocytoma (PC12) cells with a replication-deficient adenovirus, neurexophilin 1 was rapidly N-glycosylated and then slowly processed to a smaller mature form, probably by endoproteolytic cleavage. Similar expression experiments in other neuron-like cells and in fibroblastic cells revealed that N-glycosylation of neurexophilin 1 occurred in all cell types tested, whereas proteolytic processing was observed only in neuron-like cells. Finally, only recombinant neurexin Iα and IIIα but not neurexin Iβ interacted with neurexophilin 1 and were preferentially bound to the processed mature form of neurexophilin. Together our data demonstrate that neurexophilins form a family of related glycoproteins that are proteolytically processed after synthesis and bind to α-neurexins. The structure and characteristics of neurexophilins indicate that they function as neuropeptides that may signal via α-neurexins.
Defective Motor Behavior and Neural Gene Expression in RIIβ-Protein Kinase A Mutant Mice
Authors: Brandon Eugene P. , Logue Sheree F. , Adams Monique R. , Qi Ming , Sullivan Sean P. , Matsumoto Alvin M. , Dorsa Daniel M. , Wehner Jeanne M. , McKnight G. Stanley , Idzerda Rejean L.
Published: April 2018

Motor behavior is modulated by dopamine-responsive neurons in the striatum, where dopaminergic signaling uses G-protein-coupled pathways, including those that result in the activation of cAMP-dependent protein kinase (PKA). The RIIβ isoform of PKA is highly enriched in the striatum, and targeted disruption of the RIIβ gene in mice leads to a dramatic reduction in total PKA activity in this region. Although the mutant mice show typical locomotor responses after acute administration of dopaminergic drugs, they display abnormalities in two experience-dependent locomotor behaviors: training on the rotarod task and locomotor sensitization to amphetamine. In addition, amphetamine induction offosis absent, and the basal expression of dynorphin mRNA is reduced in the striatum. These results demonstrate that motor learning and the regulation of neuronal gene expression require RIIβ PKA, whereas the acute locomotor effects of dopaminergic drugs are relatively unaffected by this PKA deficiency.
A Novel Octopamine Receptor with Preferential Expression inDrosophilaMushroom Bodies
Authors: Han Kyung-An , Millar Neil S. , Davis Ronald L.
Published: April 2018

Octopamine is a neuromodulator that mediates diverse physiological processes in invertebrates. In some insects, such as honeybees and fruit flies, octopamine has been shown to be a major stimulator of adenylyl cyclase and to function in associative learning. To identify an octopamine receptor mediating this function inDrosophila, putative biogenic amine receptors were cloned by a novel procedure using PCR and single-strand conformation polymorphism. One new receptor, octopamine receptor in mushroom bodies (OAMB), was identified as an octopamine receptor because human andDrosophilacell lines expressing OAMB showed increased cAMP and intracellular Ca2+levels after octopamine application. Immunohistochemical analysis using an antibody made to the receptor revealed highly enriched expression in the mushroom body neuropil and the ellipsoid body of central complex, brain areas known to be crucial for olfactory learning and motor control, respectively. The preferential expression of OAMB in mushroom bodies and its capacity to produce cAMP accumulation suggest an important role in synaptic modulation underlying behavioral plasticity.
Upregulation of Pleiotrophin Gene Expression in Developing Microvasculature, Macrophages, and Astrocytes after Acute Ischemic Brain Injury
Authors: Yeh Hsiu-Jeng , He Yong Y. , Xu Jan , Hsu Chung Y. , Deuel Thomas F.
Published: April 2018

Pleiotrophin (PTN) is a heparin-binding, 18 kDa secretory protein that functions to induce mitogenesis, angiogenesis, differentiation, and transformationin vitro. PTN gene (Ptn) expression is highly regulated during development and is highest at sites in which mitogenesis, angiogenesis, and differentiation are active. In striking contrast, with the exception of the neuron, thePtngene is only minimally expressed in adults. We now demonstrate thatPtngene expression is strikingly upregulated within 3 d in OX42-positive macrophages, astrocytes, and endothelial cells in areas of developing neovasculature after focal cerebral ischemia in adult rat.Ptngene expression remains upregulated in these same cells and sites 7 and 14 d after ischemic injury. However, expression of thePtngene is significantly decreased in cortical neurons 6 and 24 hr after injury and is undetectable in degenerating neurons at day 3. Neurons in contralateral cortex continue to expressPtnin levels equal to control, uninjured brain. It is suggested that PTN may have a vital role in neovascular formation in postischemic brain and that postischemic brain is an important model in which to analyze sequential gene expression in developing neovasculature. In contrast,Ptngene expression in injured neurons destined not to recover is strikingly reduced, and potentially its absence may contribute to the failure of the neuron to survive.
Nitric Oxide-Dependent Production of cGMP Supports the Survival of Rat Embryonic Motor Neurons Cultured with Brain-Derived Neurotrophic Factor
Authors: Estévez Alvaro G. , Spear Nathan , Thompson J. Anthony , Cornwell Trudy L. , Radi Rafael , Barbeito Luis , Beckman Joseph S.
Published: April 2018

Trophic factor deprivation induces neuronal nitric oxide synthase (NOS) and apoptosis of rat embryonic motor neurons in culture. We report here that motor neurons constitutively express endothelial NOS that helps support the survival of motor neurons cultured with brain-derived neurotrophic factor (BDNF) by activating the nitric oxide-dependent soluble guanylate cyclase. Exposure of BDNF-treated motor neurons to nitro-l-arginine methyl ester (l-NAME) decreased cell survival 40–50% 24 hr after plating. Both low steady-state concentrations of exogenous nitric oxide (<0.1 μm) and cGMP analogs protected BDNF-treated motor neurons from death induced byl-NAME. Equivalent concentrations of cAMP analogs did not affect cell survival. Inhibition of nitric oxide-sensitive guanylate cyclase with 2 μm1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) reduced the survival of BDNF-treated motor neurons by 35%. cGMP analogs also protected from ODQ-induced motor neuron death, whereas exogenous nitric oxide did not. In all cases, cell death was prevented with caspase inhibitors. Our results suggest that nitric oxide-stimulated cGMP synthesis helps to prevent apoptosis in BDNF-treated motor neurons.
Calcium Currents and Calcium Signaling in Rod Bipolar Cells of Rat Retinal Slices
Authors: Protti Dario A. , Llano Isabel
Published: April 2018

Combined electrophysiological and imaging techniques were used to study calcium currents (ICa) and their sites of origin at rod bipolar cells in rat retinal slices. We report here for the first time the successful whole-cell patch-clamp recording from presynaptic boutons that were compared with somatic recordings. TTX-resistant inward currents were elicited in response to depolarization. The kinetic and pharmacological properties ofICawere very similar for recordings obtained from the soma and the presynaptic terminals.ICaactivated maximally between −30 and −20 mV was enhanced by Bay K 8644 and was blocked by isradipine and nifedipine. Peak amplitude and time to peak were −31.3 ± 1.2 pA and 3.2 ± 0.2 msec with somatic recordings (n= 54), whereas the corresponding values were −31.6 ± 6.1 pA and 3.2 ± 0.7 msec in recordings obtained directly from terminals (n= 6).ICashowed little inactivation during sustained depolarizations. No T-typeICawas observed with depolarizations from −90 mV. Concomitant with Ca2+entry, depolarization induced the appearance of transient outward currents that resembled IPSCs and were blocked by GABA and glycine receptor antagonists, suggesting that they arise from activation of amacrine feedback synapses. Upon depolarization, intracellular Ca2+([Ca2+]i) rises were restricted to the presynaptic terminals with no somatic or axonal changes and were linearly dependent on pulse duration when using a low-affinity Ca2+indicator. In cone bipolar cells,ICainactivated markedly, and [Ca2+]irises occurred in the axon, as well as in the presynaptic terminals.
A Neuronal Form of the Cell Adhesion Molecule L1 Contains a Tyrosine-Based Signal Required for Sorting to the Axonal Growth Cone
Authors: Kamiguchi Hiroyuki , Lemmon Vance
Published: April 2018

The neural cell adhesion molecule L1, which is present on axons and growth cones, plays a crucial role in the formation of major axonal tracts such as the corticospinal tract and corpus callosum. L1 is preferentially transported to axons and inserted in the growth cone membrane. However, how L1 is sorted to axons remains unclear. Tyr1176in the L1 cytoplasmic domain is adjacent to a neuron-specific alternatively spliced sequence, RSLE (Arg-Ser-Leu-Glu). The resulting sequence ofYRSLE conforms to a tyrosine-based consensus motif (YxxL) for sorting of integral membrane proteins into specific cellular compartments. To study a possible role of the YRSLE sequence in L1 sorting, chick DRG neurons were transfected with human L1 cDNA that codes for full-length L1 (L1FL), a non-neuronal form of L1 that lacks the RSLE sequence (L1ΔRSLE), mutant L1 with a Y1176A substitution (L1Y1176A), or L1 truncated immediately after the RSLE sequence (L1ΔC77). L1FLand L1ΔC77, both of which possess the YRSLE sequence, were expressed in the axonal growth cone and to a lesser degree in the cell body. In contrast, expression of both L1ΔRSLEand L1Y1176Awas restricted to the cell body and proximal axonal shaft. We also found that L1ΔRSLEand L1Y1176Awere integrated into the plasma membrane in the cell body after missorting. These data demonstrate that the neuronal form of L1 carries the tyrosine-based sorting signal YRSLE, which is critical for sorting L1 to the axonal growth cone.
Long-Term Effects of Sectioning the Olivocochlear Bundle in Neonatal Cats
Authors: Walsh Edward J. , McGee JoAnn , McFadden Sandra L. , Liberman M. Charles
Published: April 2018

The olivocochlear bundle (OCB) was cut in neonatal cats to evaluate its role in the development of normal cochlear function. Approximately 1 year after deefferentation, acute auditory nerve fiber (ANF) recordings were made from lesioned animals, lesion shams, and normal controls. The degree of deefferentation was quantified via light microscopic evaluation of the density of OCB fascicles in the tunnel of Corti, and selected cases were analyzed via electron microscopy. In the most successful cases, the deefferentation was virtually complete. ANFs from successfully lesioned animals exhibited significant pathophysiology compared with normals and with other animals in which the surgery failed to interrupt the OCB. Thresholds at the characteristic frequency (CF), the frequency at which ANFs are most sensitive, were elevated across the CF range, with maximal effects for CFs in the 10 kHz region. Frequency threshold or tuning curves displayed reduction of tip-to-tail ratios (the difference between CF and low-frequency “tail” thresholds) and decreased sharpness of tuning. These pathological changes are generally associated with outer hair cell (OHC) damage. However, light microscopic histological analysis showed minimal hair cell loss and no significant differences between normal and deefferented groups. Spontaneous discharge rates (SRs) were lower than normal; however, those fibers with the highest SRs remained more sensitive than those with lower SRs. Findings suggest that the interaction between OC efferents and OHCs early in development may be critical for full expression of active mechanical processes.
Reduced Activity of Hypothalamic Corticotropin-Releasing Hormone Neurons in Transgenic Mice with Impaired Glucocorticoid Receptor Function
Authors: Dijkstra Ivar , Tilders Fred J. H. , Aguilera Greti , Kiss Alexander , Rabadan-Diehl Cristina , Barden Nicholas , Karanth Sharada , Holsboer Florian , Reul Johannes M. H. M.
Published: April 2018

Loss of central glucocorticoid receptor (GR) function is thought to be involved in the development of neuroendocrine and psychiatric disorders associated with corticotropin-releasing hormone (CRH) hyperactivity. The possible causal relationship between defective GR function and altered activity of CRH neurons was studied in transgenic mice (TG) expressing antisense RNA against GR. Immunocytochemical studies showed significant reductions in CRH immunoreactive neurons in the paraventricular nucleus (PVN) and in CRH and vasopressin (AVP) stores in the external zone of the median eminence. Concomitantly, stimulus-evoked CRH secretion from mediobasal hypothalami of TG micein vitrowas reduced significantly. However, CRH mRNA levels in the PVN of TG mice were marginally lower than those in wild-type (WT) mice.125I-CRH binding autoradiography revealed no differences between WT and TG animals in any of the brain regions that were studied. Basal plasma corticosterone (cort) levels and125I-CRH binding, CRH-R1mRNA, POMC mRNA, and POMC hnRNA levels in the anterior pituitary gland were similar in WT and TG mice. Intraperitoneal injection of interleukin-1β (IL-1β) increased plasma cort levels, CRH mRNA in the PVN, and anterior pituitary POMC hnRNA similarly in WT and TG mice. The injection of saline significantly reduced anterior pituitary CRH-R1mRNA levels in WT mice, but not in TG mice, whereas IL-1β produced a decrease in these mRNA levels in both strains.

The data show that long-term GR dysfunction can be associated with reduced activity of CRH neurons in the PVN and decreased sensitivity of pituitary CRH-R1mRNA to stimulus-induced downregulation. Moreover, the hypothalamic changes observed in this model suggest that impaired GR function, at least if present since early embryonic life, does not necessarily result in CRH hyperexpression characteristics of disorders such as major depression.
Compartmentalization of Information Processing in anAplysiaFeeding Circuit Interneuron through Membrane Properties and Synaptic Interactions
Authors: Perrins Ray , Weiss Klaudiusz R.
Published: April 2018

We describe a pair of cerebral-to-buccal interneurons, CBI-5/6, which have outputs and inputs in two ganglia. The soma in the cerebral ganglion received synaptic inputs during buccal motor programs (BMPs) and after mechanical stimulation of the lips. During BMPs the soma received antidromic spikes generated in processes in the buccal ganglion. The soma was driven into a plateau potential by each of these inputs, during which it fired orthodromically at 0–5 Hz. The soma had outputs in the cerebral ganglion consisting of electrical coupling to the adjacent CBI-5/6 and to a cerebral-to-pedal neuron (CPN1). The buccal terminals of CBI-5/6 received inputs that generated rhythmic barrages (up to 25 Hz) of antidromic spikes during BMPs. The buccal terminals had chemical and electrical outputs to motor and premotor elements of feeding circuitry. This combination of synaptic interactions and endogenous properties mean that CBI-5/6 can process information in a number of ways. During the barrage of antidromic spikes, high-frequency firing will produce strong inputs to buccal followers and on their arrival at the soma will transfer excitation electrotonically to CPN1. Subthreshold input to the soma will be transferred electrotonically to cerebral followers but will not be relayed to postsynaptic buccal neurons. Plateau potentials after the antidromic spikes or local cerebral inputs will locally excite CPN1 via electrical coupling but will have little influence on buccal events because of the low orthodromic firing rate. Thus, CBI-5/6 may transmit information locally within the cerebral ganglion or more extensively in both buccal and cerebral ganglia simultaneously.
Mitogen-Activated Protein Kinases (Erk1,2) Phosphorylate Lys-Ser-Pro (KSP) Repeats in Neurofilament Proteins NF-H and NF-M
Authors: Veeranna  , Amin Niranjana D. , Ahn Natalie G. , Jaffe Howard , Winters Christine A. , Grant Philip , Pant Harish C.
Published: April 2018

Mammalian neurofilament proteins, particularly midsized (NF-M) and heavy (NF-H) molecular weight neurofilament proteins, are highly phosphorylated in axons. Neurofilament function depends on the state of phosphorylation of the numerous serine/threonine residues in these proteins. Most phosphorylation occurs in the lys-ser-pro (KSP) repeats in the C-terminal tail domains of NF-H and NF-M. In our previous study, cyclin-dependent kinase 5 (cdk5) was shown to phosphorylate specifically the KSPXK repeats in rat NF-H. Because 80% of the repeats are of the KSPXXXK type, it was of interest to determine which kinase phosphorylates these motifs. Using a synthetic KSPXXXK peptide to screen for a specific kinase, we fractionated rat brain extracts by column chromatography and identified extracellular signal-regulated kinase (Erk2) activated by an upstream activator, the mitogen-activated protein kinase kinase MAPKK (MEK), by Western blot analysis, sequence identification, and inhibition by a specific MEK inhibitor (PD 98059). The fraction containing Erk2, as well as bacterially expressed Erk1 and Erk2, phosphorylated all types of KSP motifs in peptides (KSPXK, KSPXXK, KSPXXXK, and KSPXXXXK) derived from NF-M and NF-H. They also phosphorylated an expressed 24 KSPXXXK repeat NF-H polypeptide, an expressed NF-H as well as dephosphorylated native rat NF-H, and NF-M proteins with accompanying decreases in their respective electrophoretic mobilities. A comparative kinetic study of Erk2 and cdk5 phosphorylation of KSPXK and KSPXXXK peptides revealed that, in contrast to cdk5, which phosphorylated only the KSPXK peptide, Erk2 could phosphorylate both. The preferred substrate for Erk2 was KSPXXXK peptide. The MEK inhibitor PD 98059 also inhibited phosphorylation of NF-H, NF-M, and microtubule-associated protein (MAP) in primary rat hippocampal cells and caused a decrease in neurite outgrowth, suggesting that Erk1,2 may play an important role in neurite growth and branching. These data suggest that neuronal Erk1 and Erk2 are capable of phosphorylating serine residues in diverse KSP repeat motifs in NF-M and NF-H.
Kir2.4: A Novel K+Inward Rectifier Channel Associated with Motoneurons of Cranial Nerve Nuclei
Authors: Töpert Christoph , Döring Frank , Wischmeyer Erhard , Karschin Christine , Brockhaus Johannes , Ballanyi Klaus , Derst Christian , Karschin Andreas
Published: April 2018

Members of the Kir2 subfamily of inwardly rectifying K+channels characterized by their strong current rectification are widely expressed both in the periphery and in the CNS in mammals. We have cloned from rat brain a fourth subfamily member, designated Kir2.4 (IRK4), which shares 53–63% similarity to Kir2.1, Kir2.2, or Kir2.3 on the amino acid level.In situhybridization analysis identifies Kir2.4 as the most restricted of all Kir subunits in the brain. Kir2.4 transcripts are expressed predominantly in motoneurons of cranial nerve motor nuclei within the general somatic and special visceral motor cell column and thus are uniquely related to a functional system. Heterologous expression of Kir2.4 inXenopusoocytes and mammalian cells gives rise to low-conductance channels (15 pS), with an affinity to the channel blockers Ba2+(Ki= 390 μm) and Cs+(Ki= 8.06 mm) 30–50-fold lower than in other Kir channels. Low Ba2+sensitivity allows dissection of Kir2.4 currents from other Kir conductances in hypoglossal motoneurons (HMs) in rat brainstem slices. The finding that Ba2+-mediated block of Kir2.4 in HMs evokes tonic activity and increases the frequency of induced spike discharge indicates that Kir2.4 channels are of major importance in controlling excitability of motoneuronsin situ.
Regulation of the Nigrostriatal Pathway by Metabotropic Glutamate Receptors during Development
Authors: Plenz Dietmar , Kitai Stephen T.
Published: April 2018

Dopamine neurons in the substantia nigra heavily innervate the striatum, making it the nucleus with the highest levels of dopamine in the adult brain. The present study analyzes the time course and the density of striatal innervation by nigral dopamine neurons and characterizes the role of the neurotransmitter glutamate during the development of the nigrostriatal pathway. For this purpose, organotypic cultures containing the cortex, the striatum, and the substantia nigra (triple cultures) were prepared from rat brains at postnatal day (PND) 0–2 and were cultured for up to 60 din vitro(DIV). Dopamine fibers and neurons were labeled using tyrosine hydroxylase (TH) immunohistochemistry. Striatal TH-ir fiber density was quantitatively analyzed using confocal laser scanning microscopy (CLSM). In long-term triple cultures (44 ± 3 DIV), the striatal dopamine fiber density was high and was weakly correlated with the number of nigral dopamine neurons. The high striatal dopamine fiber density mainly resulted from an enhanced ingrowth and ramification of dopamine fibers from nigral neurons during 8–17 DIV. The metabotropic glutamate receptor (mGluR) antagonistl(+)-2-amino-3-phosphonopropionic acid (l-AP-3) selectively inhibited this dopaminergic innervation of the striatum, whereas ionotropic GluR antagonists had no effect. Thel-AP-3-mediated inhibition was prevented by the mGluR agonist 1S,3R-aminocyclopentane-1,3-dicarboxylic acid (1S,3R-ACPD). The inhibition of the striatal dopaminergic innervation byl-AP-3 was further confirmed by anterograde tracing of the nigrostriatal projection withPhaseolus vulgarisleucoagglutinin. These results indicate that glutamate, by acting on group I mGluRs, plays an important “trophic” role for the development of the nigrostriatal dopamine pathway.
Pinna Movements of the Cat during Sound Localization
Authors: Populin Luis C. , Yin Tom C. T.
Published: April 2018

We measured the movements of the external ear, or pinna, using the magnetic search coil technique in cats trained to look at auditory and visual targets for a food reward. No behavioral contingencies were placed on pinna movements. Prominent pinna movements accompany eye movements when the animal orients to either auditory or visual stimuli. In visual trials the pinna movements are coordinated with eye movements, suggesting that they are part of the general orientation response of the animal. In auditory trials the pinna response was composed of two movements: short- and long-latency components. Whereas the long-latency component seemed to occur with the eye movement to the target, the short-latency component was coupled to the onset of the stimulus. The short-latency component (∼25 msec) was highly asymmetrical, being largest in the pinna ipsilateral to the stimuli. In one animal it persisted after >105trials.
Induced γ-Band Activity during the Delay of a Visual Short-Term Memory Task in Humans
Authors: Tallon-Baudry Catherine , Bertrand Olivier , Peronnet Franck , Pernier Jacques
Published: April 2018

It has been hypothesized that visual objects could be represented in the brain by a distributed cell assembly synchronized on an oscillatory mode in the γ-band (20–80 Hz). If this hypothesis is correct, then oscillatory γ-band activity should appear in any task requiring the activation of an object representation, and in particular when an object representation is held active in short-term memory: sustained γ-band activity is thus expected during the delay of a delayed-matching-to-sample task. EEG was recorded while subjects performed such a task. Induced (e.g., appearing with a jitter in latency from one trial to the next) γ-band activity was observed during the delay. In a control task, in which no memorization was required, this activity disappeared. Furthermore, this γ-band activity during the rehearsal of the first stimulus representation in short-term memory peaked at both occipitotemporal and frontal electrodes. This topography fits with the idea of a synchronized cortical network centered on prefrontal and ventral visual areas. Activities in the α band, in the 15–20 Hz band, and in the averaged evoked potential were also analyzed. The γ-band activity during the delay can be distinguished from all of these other components of the response, on the basis of either its variations or its topography. It thus seems to be a specific functional component of the response that could correspond to the rehearsal of an object representation in short-term memory.
Age-Related Changes in Neuronal Nicotinic Acetylcholine Receptor Subunit α4 Expression Are Modified by Long-Term Nicotine Administration
Authors: Rogers Scott W. , Gahring Lorise C. , Collins Allan C. , Marks Michael
Published: April 2018

The distribution of the neuronal nicotinic acetylcholine receptor subunit α4 (nAChRα4) in the brains of young (2–4 months) or aged (24–28 months) CBA/J mice was examined using immunohistochemical staining. Anti-nAChRα4 immunoreactivity corresponded with nAChRα4 RNA expression and high-affinity [3H]nicotine binding. Immunostaining in aged mice relative to that in young animals was diminished in the medial septum and diagonal band but was unchanged in the globus pallidus and substantia nigra. The staining of neurons was almost completely absent in the hippocampus of aged animals. The oral administration of nicotine to aged animals for 6 weeks did not alter nAChRα4 expression relative to that in aged controls. However, the long-term delivery of nicotine (11 months) to 14-month-old animals corresponded with the highly specific preservation of nAChRα4 expression in some neurons of the dentate gyrus region and in neurite processes of remaining neurons of the hippocampal CA1 region. These results support the conclusion that the loss of nAChRα4 expression occurs in key cholinergic regions during normal aging. Furthermore, sustained long-term nicotine delivery may promote highly region-specific retention of nAChR expression, but only if initiated before normal age-related receptor decline.