bluuebunny/crossref_metadata_2025 huggingface dataset:
Efficient Routing Strategies of N × N RM-OXC Using C Band Based on T-FBG and OC
Authors: Singh Manpreet , Rani Aruna , Dewra Sanjeev
Published: April 2018

A novel architecture of N×N reconfigurable multiwavelength optical cross-connect based on tunable fiber Bragg grating (FBG) and optical circulator is proposed. The effect of cross talk in dense wavelength division multiplexing system with 0.8-nm channel spacing at 9×10 Gbps is also evaluated. Optical signal to noise ratio achieved is 40.95 dB at input transmission power of −10 dBm with acceptable bit error rate, i.e. 1.16×10−10at −30 dB FBG cross talk in the presence of fiber nonlinearities. It is found that signal is transmitted to a distance of 50 km without optical amplifier.
Chronic pelvic pain – pain catastrophizing, pelvic pain and quality of life
Authors: Sewell Megan , Churilov Leonid , Mooney Samantha , Ma Tony , Maher Peter , Grover Sonia R.
Published: April 2018

Background and aims

Chronic pelvic pain (CPP) impacts significantly on the lives of women. Negative coping responses such as pain catastrophizing are thought to be significant in predicting both pain severity and outcome. The combined effect of the individual’s response to pain and its severity on their quality of life (QoL) has not been well studied in women with CPP. Aims were to determine the prevalence of pain catastrophizing in women with CPP and to examine the associations between pain catastrophizing and levels of dysmenorrhea, non-cyclical pelvic pain, dyspareunia, dysuria, dyschezia and QoL.

Methods

A cross-sectional study including women aged 18–50 years, referred to a tertiary gynecology outpatients department at an Australian women’s hospital in 2015. Participants completed questionnaires including: pain catastrophizing scale (PCS); pelvic pain levels in the prior 3 months; and the World Health Organisation Quality of life – Bref Questionnaire (WHOQoL-Bref). Statistical analysis was performed using STATA (StataCorp, USA Version13).

Results

Participants (n = 115) had a median age of 29.0 [interquartile range (IQR): 23.0–38.0] years. The Pain catastrophizing score revealed that 60/113 [95% confidence interval (CI): 48.6, 71.2] of participants had a clinically relevant total score ≥30. There were statistically significant positive correlations between pain catastrophizing scores and pelvic pain levels in all five pain categories studied, dysmenorrhea (ρ = 0.37, p = 0.0001), non-cyclical pelvic pain (ρ = 0.46, p<0.0001), dyspareunia (ρ = 0.32, p = 0.0008), dysuria (ρ = 0.32, p = 0.0005) and dyschezia (ρ = 0.38, p = 0.0012). Participants who reported maximal pain levels (5/5) had significantly higher median pain catastrophizing scores when compared to those who reported no pain (0/5) in all categories. Overall QoL was considered as “good” in 71/113 (95% CI: 60.1, 81.0) participants and “poor” in 42/113 (95% CI: 32.0, 53.0) participants. Comparison to Australian female norms revealed significantly lower QoL scores in the physical domain, across all ages, and in psychological domain for those aged <30 and 30–40 years. There was a significant association between increased catastrophizing scores and reduced odds of good QoL. An increase in PCS by one point is associated with a 6.3% decrease in the odds of good QoL [odds ratio (OR) per one-point increase: 0.94 (95% CI: 0.89, 0.98), p = 0.008].

Conclusions

Pain catastrophizing is prevalent at clinically relevant levels in women with CPP across all domains. It is associated with higher pain levels and decreased QoL.

Implications

There is potential for further studies to investigate the predictive nature of pain catastrophizing and management targeting catastrophizing to improve outcomes in women with CPP.
Synthesis, crystal structure and photoluminescence of Re(I)2(μ-4,4′-bipyridine)(8-quinolinolato)2(CO)6
Authors: Vogler Arnd , Bodensteiner Michael
Published: April 2018

The binuclear complex Re(I)2(μ-4,4′-bipyridine)(8-quinolinolato)2(CO)6 has been prepared and characterized including the crystal structure. This complex shows, dependent on the conditions, three emissions, which originate from the quinolinolate IL excited state (fluorescence and phosphorescence) and from a Re(I) to 4,4′-bipyridine MLCT state (phosphorescence).
Three GABA Receptor-Mediated Postsynaptic Potentials in Interneurons in the Rat Lateral Geniculate Nucleus
Authors: Zhu J. Julius , Lo Fu-Sun
Published: April 2018

Inhibition is crucial for the thalamus to relay sensory information from the periphery to the cortex and to participate in thalamocortical oscillations. However, the properties of inhibitory synaptic events in interneurons are poorly defined because in part of the technical difficulty of obtaining stable recording from these small cells. With the whole-cell recording technique, we obtained stable recordings from local interneurons in the lateral geniculate nucleus and studied their inhibitory synaptic properties. We found that interneurons expressed three different types of GABA receptors: bicuculline-sensitive GABAAreceptors, bicuculline-insensitive GABAAreceptors, and GABABreceptors. The reversal potentials of GABA responses were estimated by polarizing the membrane potential. The GABAAreceptor-mediated responses had a reversal potential of approximately −82 mV, consistent with mediation via Cl−channels. The reversal potential for the GABABresponse was −97 mV, consistent with it being a K+conductance. The roles of these GABA receptors in postsynaptic responses were also examined in interneurons. Optic tract stimulation evoked a disynaptic IPSP that was mediated by all three types of GABA receptors and depended on activation of geniculate interneurons. Stimulation of the thalamic reticular nucleus evoked an IPSP, which appeared to be mediated exclusively by bicuculline-sensitive GABAAreceptors and depended on the activation of reticular cells. The results indicate that geniculate interneurons form a complex neuronal circuitry with thalamocortical and reticular cells via feed-forward and feedback circuits, suggesting that they play a more important role in thalamic function than thought previously.
Vascular Endothelial Growth Factor Has Neurotrophic Activity and Stimulates Axonal Outgrowth, Enhancing Cell Survival and Schwann Cell Proliferation in the Peripheral Nervous System
Authors: Sondell Mariann , Lundborg Göran , Kanje Martin
Published: April 2018

Vascular endothelial growth factor (VEGF) is a mitogen for endothelial cells, and it promotes angiogenesisin vivo. Here we report that VEGF165has neurotrophic actions on cultured adult mouse superior cervical ganglia (SCG) and dorsal root ganglia (DRG), measured as axonal outgrowth. Maximal effect was observed at 10–50 ng/ml for SCG and 100 ng/ml for DRG. VEGF-induced axonal outgrowth was inhibited by the mitogen-activated protein kinase kinase inhibitor PD 98059 but not by the protein kinase inhibitor K252a. VEGF also increased survival of both neurons and satellite cells and the number of proliferating Schwann cells. Immunocytochemistry and immunoblotting revealed that VEGF was expressed in virtually all nerve cells in the SCG but only in a population of small-diameter (<35 μm) neurons representing ∼30% of the neurons in DRG. Immunostaining showed that the VEGF receptor fetal liver kinase receptor (flk-1) was found on nerve cell bodies in DRG and to a lesser extent on neurons in SCG. Growth cones of regenerating axons from both types of ganglia exhibited flk-1 immunoreactivity, as did Schwann cells. We conclude that VEGF has both neurotrophic and mitogenic activity on cells in the peripheral nervous system.
κ-Opioid Tolerance and Dependence in Cultures of Dopaminergic Midbrain Neurons
Authors: Dalman Friedrich C. , O’Malley Karen L.
Published: April 2018

Repeated cocaine exposure upregulates κ opioids and their receptors in the mesocorticolimbic system; the ensuing κ-mediated dysphoria appears to contribute to addiction and withdrawal. As a potential rehabilitation strategy to reverse cocaine-induced κ sensitization, the present study used tritiated dopamine release assays to examine the induction of κ-opioid tolerance in cultured mesencephalic neurons. Administration of the κ agonist U69,593 inhibited tetrodotoxin-sensitive, spontaneous (EC50= 1.5 nm), and potassium-stimulated (EC50= 10 nm) release. These effects were blocked by pertussis toxin and by the κ antagonist nor-binaltorphimine. The 2 d agonist exposure (1 μm) caused a shift in the U69,593 dose–response curve that was greater in the potassium-stimulated paradigm (140-fold) than in the spontaneous release assay (sixfold). These results were attributable to the attenuation of κ-receptor signaling mechanisms and to dependence. In the stimulated release assay, attenuation of κ signaling caused by 4 hr of U69,593 exposure recovered with a half-life of 1.1 hr, whereas attenuation after 144 hr of exposure recovered slowly (t½= 20 hr). In the spontaneous release assay, attenuation of κ-opioid signaling occurred slowly (t½= 22 hr), and resensitization after a 144 hr exposure was rapid (t½< 1 hr). κ-Opioid dependence was observed after 144 hr of U69,593 exposure. Thus multiple mechanisms of adaptation to κ-opioid exposure occur in mesocorticolimbic neurons. These data support the idea that the administration of κ opioids might facilitate drug rehabilitation.
α-Synuclein Shares Physical and Functional Homology with 14-3-3 Proteins
Authors: Ostrerova Natalie , Petrucelli Leonard , Farrer Matthew , Mehta Nitinkumar , Choi Peter , Hardy John , Wolozin Benjamin
Published: April 2018

α-Synuclein has been implicated in the pathophysiology of many neurodegenerative diseases, including Parkinson’s disease (PD) and Alzheimer’s disease. Mutations in α-synuclein cause some cases of familial PD (Polymeropoulos et al., 1997; Kruger et al., 1998). In addition, many neurodegenerative diseases show accumulation of α-synuclein in dystrophic neurites and in Lewy bodies (Spillantini et al., 1998). Here, we show that α-synuclein shares physical and functional homology with 14-3-3 proteins, which are a family of ubiquitous cytoplasmic chaperones. Regions of α-synuclein and 14-3-3 proteins share over 40% homology. In addition, α-synuclein binds to 14-3-3 proteins, as well as some proteins known to associate with 14-3-3, including protein kinase C, BAD, and extracellular regulated kinase, but not Raf-1. We also show that overexpression of α-synuclein inhibits protein kinase C activity. The association of α-synuclein with BAD and inhibition of protein kinase C suggests that increased expression of α-synuclein could be harmful. Consistent with this hypothesis, we observed that overexpression of wild-type α-synuclein is toxic, and overexpression of α-synuclein containing the A53T or A30P mutations exhibits even greater toxicity. The activity and binding profile of α-synuclein suggests that it might act as a protein chaperone and that accumulation of α-synuclein could contribute to cell death in neurodegenerative diseases.
Estrogen Stimulates a Transient Increase in the Number of New Neurons in the Dentate Gyrus of the Adult Female Rat
Authors: Tanapat Patima , Hastings Nicholas B. , Reeves Alison J. , Gould Elizabeth
Published: April 2018

To determine whether a sex difference exists in the production of hippocampal cells during adulthood, we examined proliferating cells and their progeny in adult rats using the thymidine analog bromodeoxyuridine (BrdU) combined with immunohistochemistry for markers of neurons and glia. Additionally, to determine whether ovarian hormones affect cell proliferation, we examined the numbers of BrdU-labeled cells at different estrous cycle stages and after ovarian steroid manipulation. Stereological analyses of the numbers of BrdU-labeled cells revealed that females produced more cells than males in the dentate gyrus but not in the subventricular zone. The production of new hippocampal cells in females appears to be affected by ovarian hormone levels; ovariectomy diminished the number of BrdU-labeled cells, an effect reversed by estrogen replacement. A natural fluctuation in cell proliferation was also noted; females produced more cells during proestrus (when estrogen levels are highest) compared with estrus and diestrus. Many of these cells acquired neuronal characteristics, including the formation of dendrites and expression of Turned-On-After-Division 64 kDa, a marker of immature granule neurons, and the calcium-binding protein calbindin, a marker of mature granule neurons. However, examination of the numbers of pyknotic cells and the numbers of BrdU-labeled cells at longer survival times revealed that many new cells in the dentate gyrus eventually degenerate. Consistently the number of labeled cells in females is no longer higher than that observed in males by 2 weeks after the last BrdU injection. These findings suggest that estrogen-enhanced cell proliferation during proestrus results in more immature neurons in the hippocampal formation of females compared with males and present the possibility that these new cells exert an important influence on hippocampal function.
Directing Gene Expression to Gustducin-Positive Taste Receptor Cells
Authors: Wong Gwendolyn T. , Ruiz-Avila Luis , Margolskee Robert F.
Published: April 2018

We have demonstrated that an 8.4 kb segment (GUS8.4) from the upstream region of the mouse α-gustducin gene acts as a fully functional promoter to targetlacZtransgene expression to the gustducin-positive subset of taste receptor cells (TRCs). The GUS8.4promoter drove TRC expression of the β-galactosidase marker at high levels and in a developmentally appropriate pattern. The gustducin minimal 1.4 kb promoter (GUS1.4) by itself was insufficient to specify TRC expression. We also identified an upstream enhancer from the distal portion of the murine gustducin gene that, in combination with the minimal promoter, specified TRC expression of transgenes. Expression of thelacZtransgene from the GUS8.4promoter and of endogenous gustducin was coordinately lost after nerve section and simultaneously recovered after reinnervation, confirming the functionality of this promoter. Transgenic expression of rat α-gustducin restored responsiveness of gustducin null mice to both bitter and sweet compounds, demonstrating the utility of the gustducin promoter.
Intracellular Ca2+Oscillations in Luteinizing Hormone-Releasing Hormone Neurons Derived from the Embryonic Olfactory Placode of the Rhesus Monkey
Authors: Terasawa Ei , Schanhofer Willard K. , Keen Kim L. , Luchansky Laurelee
Published: April 2018

To understand the mechanism of pulsatile luteinizing hormone-releasing hormone (LHRH) release, we examined whether cultured LHRH neurons exhibit spontaneous intracellular Ca2+([Ca2+]i) signaling. The olfactory placode and the ventral migratory pathway of LHRH neurons from rhesus monkey embryos at embryonic ages 35–37 were dissected out and cultured on glass coverslips. Two to five weeks later, cultured cells were labeled with fura-2 and examined for [Ca2+]isignaling by recording changes in [Ca2+]ievery 10 sec for 30–175 min. Cells were fixed and immunostained for LHRH and neuron-specific enolase. In 20 cultures, 572 LHRH-positive cells exhibited [Ca2+]ioscillations at an interpulse interval (IPI) of 8.2 ± 0.7 min and a duration of 88.8 ± 2.9 sec. LHRH-negative neurons in culture exhibited only occasional [Ca2+]ioscillations. In 17 of 20 cultures with LHRH-positive cells, [Ca2+]ioscillations occurred synchronously in 50–100% of the individual cells, whereas [Ca2+]ioscillations in cells in the remaining three cultures did not synchronize. Strikingly, in 12 of 17 cultures the synchronization of [Ca2+]ioscillations repeatedly occurred in complete unison at 52.8 ± 3.0 min intervals, which is similar to the period observed for LHRH release, whereas in 5 of 17 cultures the less tight synchronization of [Ca2+]ioscillations repeatedly occurred at 23.4 ± 4.6 min intervals. IPI of [Ca2+]ioscillations in cells with tight synchronization and less tight synchronization did not differ from IPI in cells without synchronization. The results indicate that LHRH neurons derived from the monkey olfactory placode possess an endogenous mechanism for synchronization of [Ca2+]ioscillations. Whether synchronization of [Ca2+]ioscillations relates to neurosecretion remains to be investigated.
Molecular Evidence for the Early Specification of Presumptive Functional Domains in the Embryonic Primate Cerebral Cortex
Authors: Donoghue Maria J. , Rakic Pasko
Published: April 2018

To identify molecules that may play a role in the initiation of cerebral cortical area formation, we examined the expression of the Eph receptors and their ligands, the ephrins, during primate corticogenesis. We selected the macaque monkey neocortex because of its clear areal subdivisions, large surface area, protracted development (gestation = 165 d), and similarity to the human brain.In situhybridizations, performed at early [embryonic day 65 (E65)], middle (E80), and late (E95) stages of cortical development, revealed that EphA system family members are expressed in distinct gradients and laminar and areal domains in the embryonic neocortex. Indeed, several regionally restricted molecular patterns are already apparent within the cortical plate at E65, before the formation of thalamocortical connections, suggesting that the initial expression of some EphA system members is regulated by programs intrinsic to cortical cells. For example, EphA3, EphA6, and EphA7 are all selectively expressed within the presumptive visual cortex. However, although EphA6 and EphA7 are present throughout this region, EphA3 is only expressed in the prospective extrastriate cortex, suggesting that cortical cells harbor functional biases that may influence the formation of appropriate synaptic connections. Although several patterns of early gene expression are stable (e.g., EphA3, EphA4, and EphA6), others change as development proceeds (e.g., EphA5, EphA7, ephrin-A2, ephrin-A3, and ephrin-A5), perhaps responding to extrinsic cues. Thus, at E95, after connections between the cortical plate and thalamus have formed, receptor subtypes EphA3, EphA5, EphA6, and EphA7 and the ligand ephrin-A5 are expressed in posterior regions, whereas EphA4 and ephrin-A2 and ephrin-A3 are either uniformly distributed or anteriorly biased. Taken together, our results demonstrate molecular distinctions among cells of the embryonic primate neocortex, revealing hitherto unrecognized compartmentalization early in corticogenesis.
Targeted Mutagenesis of the POU-Domain GeneBrn4/Pou3f4Causes Developmental Defects in the Inner Ear
Authors: Phippard Deborah , Lu Lihui , Lee Daniel , Saunders James C. , Crenshaw E. Bryan
Published: April 2018

Targeted mutagenesis in mice demonstrates that the POU-domain geneBrn4/Pou3f4plays a crucial role in the patterning of the mesenchymal compartment of the inner ear.Brn4is expressed extensively throughout the condensing mesenchyme of the developing inner ear. Mutant animals displayed behavioral anomalies that resulted from functional deficits in both the auditory and vestibular systems, including vertical head bobbing, changes in gait, and hearing loss. Anatomical analyses of the temporal bone, which is derived in part from the otic mesenchyme, demonstrated several dysplastic features in the mutant animals, including enlargement of the internal auditory meatus. Many phenotypic features of the mutant animals resulted from the reduction or thinning of the bony compartment of the inner ear. Histological analyses demonstrated a hypoplasia of those regions of the cochlea derived from otic mesenchyme, including the spiral limbus, the scala tympani, and strial fibrocytes. Interestingly, we observed a reduction in the coiling of the cochlea, which suggests that Brn-4 plays a role in the epithelial–mesenchymal communication necessary for the cochlear anlage to develop correctly. Finally, the stapes demonstrated several malformations, including changes in the size and morphology of its footplate. Because the stapes anlage does not express theBrn4gene, stapes malformations suggest that theBrn4gene also plays a role in mesenchymal–mesenchymal signaling. On the basis of these data, we suggest that Brn-4 enhances the survival of mesodermal cells during the mesenchymal remodeling that forms the mature bony labyrinth and regulates inductive signaling mechanisms in the otic mesenchyme.
Site-Specific Migration and Neuronal Differentiation of Human Neural Progenitor Cells after Transplantation in the Adult Rat Brain
Authors: Fricker Rosemary A. , Carpenter Melissa K. , Winkler Christian , Greco Corinne , Gates Monte A. , Björklund Anders
Published: April 2018

Neural progenitor cells obtained from the embryonic human forebrain were expanded up to 107-fold in culture in the presence of epidermal growth factor, basic fibroblast growth factor, and leukemia inhibitory growth factor. When transplanted into neurogenic regions in the adult rat brain, the subventricular zone, and hippocampus, thein vitropropagated cells migrated specifically along the routes normally taken by the endogenous neuronal precursors: along the rostral migratory stream to the olfactory bulb and within the subgranular zone in the dentate gyrus, and exhibited site-specific neuronal differentiation in the granular and periglomerular layers of the bulb and in the dentate granular cell layer. The cells exhibited substantial migration also within the non-neurogenic region, the striatum, in a seemingly nondirected manner up to ∼1–1.5 mm from the graft core, and showed differentiation into both neuronal and glial phenotypes. Only cells with glial-like features migrated over longer distances within the mature striatum, whereas the cells expressing neuronal phenotypes remained close to the implantation site. The ability of the human neural progenitors to respondin vivoto guidance cues and signals that can direct their differentiation along multiple phenotypic pathways suggests that they can provide a powerful and virtually unlimited source of cells for experimental and clinical transplantation.
Impairment of AMPA Receptor Function in Cerebellar Granule Cells of Ataxic Mutant MouseStargazer
Authors: Hashimoto Kouichi , Fukaya Masahiro , Qiao Xiaoxi , Sakimura Kenji , Watanabe Masahiko , Kano Masanobu
Published: April 2018

The spontaneous recessive mutant mousestargazer(stg) begins to show ataxia around postnatal day 14 and display a severe impairment in the acquisition of classical eyeblink conditioning in adulthood. These abnormalities have been attributed to the specific reduction in brain-derived neurotrophic factor (BDNF) and the subsequent defect in TrkB receptor signaling in cerebellar granule cells (GCs). In thestgmutant cerebellum, we found that EPSCs at mossy fiber (MF) to GC synapses are devoid of the fast component mediated by AMPA-type glutamate receptors despite the normal slow component mediated by NMDA receptors. The sensitivity ofstgmutant GCs to exogenously applied AMPA was greatly reduced, whereas that to NMDA was unchanged. Glutamate release from MF terminals during synaptic transmission to GCs appeared normal. By contrast, AMPA receptor-mediated EPSCs were normal in CA1 pyramidal cells of thestgmutant hippocampus. Thus, postsynaptic AMPA receptor function was selectively impaired instgmutant GCs, although the transcription of four AMPA receptor subunit genes in thestgGC was comparable to the wild-type GC. We also examined the cerebellum of BDNF knockout mice and found that their MF–GC synapses had a normal AMPA receptor-mediated EPSC component. Thus, the impaired AMPA receptor function in thestgmutant GC is not likely to result from the reduced BDNF–TrkB signaling. These results suggest that the defect in MF to GC synaptic transmission is a major factor that causes the cerebellar dysfunction in thestgmutant mouse.
Development of Topography within Song Control Circuitry of Zebra Finches during the Sensitive Period for Song Learning
Authors: Iyengar Soumya , Viswanathan Sandya S. , Bottjer Sarah W.
Published: April 2018

Refinement of topographic maps during sensitive periods of development is a characteristic feature of diverse sensory and motor circuits in the nervous system. Within the neural system that controls vocal learning and behavior in zebra finches, axonal connections of the cortical nucleus lMAN demonstrate striking functional and morphological changes during vocal development in juvenile males. These circuits are uniquely important for song production during the sensitive period for vocal learning, and the overall size of these brain regions and their patterns of axonal connectivity undergo dramatic growth and regression during this time. Axonal connections to and from lMAN are topographically organized in adult males that have already learned song. We wondered whether the large-scale changes seen in lMAN circuitry during the time that vocal behavior is being learned and refined could be accompanied by the emergence of topographic mapping. However, results presented herein demonstrate that most of these song-control circuits show the same broad patterns of axonal connectivity between subregions of individual nuclei at the onset of song learning as seen in adult birds. Thus, coarse topographic organization is not dependent on the types of experience that are crucial for vocal learning. Furthermore, this maintenance of topographic organization throughout the period of song learning is clearly not achieved by maintenance of static axonal arbors. In fact, because the volumes of song-control nuclei are growing (or regressing), topography must be maintained by active remodeling of axonal arbors to adapt to the changes in overall size of postsynaptic targets. A salient exception to this pattern of conserved topography is the projection from lMAN to the motor cortical region RA: this pathway is diffusely organized at the onset of song learning but undergoes substantial refinement during early stages of song learning, suggesting that remodeling of axonal connections within this projection during the period of vocal learning may signify the production of increasingly refined vocal utterances.
Synaptic Control of Spiking in Cerebellar Purkinje Cells: Dynamic Current Clamp Based on Model Conductances
Authors: Jaeger Dieter , Bower James M.
Published: April 2018

Previous simulations using a realistic model of a cerebellar Purkinje cell suggested that synaptic control of somatic spiking in this cell type is mediated by voltage-gated intrinsic conductances and that inhibitory rather than excitatory synaptic inputs are more influential in controlling spike timing. In this paper, we have tested these predictions physiologically using dynamic current clamping to apply model-derived synaptic conductances to Purkinje cellsin vitro. As predicted by the model, this input transformed thein vitropattern of spiking into a different spike pattern typically observedin vivo. A net inhibitory synaptic current was required to achieve such spiking, indicating the presence of strong intrinsic depolarizing currents. Spike-triggered averaging confirmed that the length of individual intervals between spikes was correlated to the amplitude of the inhibitory conductance but was not influenced by excitatory inputs. Through repeated presentation of identical stimuli, we determined that the output spike rate was very sensitive to the relative balance of excitation and inhibition in the input conductances. In contrast, the accuracy of spike timing was dependent on input amplitude and was independent of spike rate. Thus, information could be encoded in Purkinje cell spiking in a precise spike time code and a rate code at the same time. We conclude that Purkinje cell responses to synaptic input are strongly dependent on active somatic and dendritic properties and that theories of cerebellar function likely need to incorporate single-cell dynamics to a greater degree than is customary.
5-HT1B Receptor Knock-Out Mice Exhibit Increased Exploratory Activity and Enhanced Spatial Memory Performance in the Morris Water Maze
Authors: Malleret Gaël , Hen René , Guillou Jean-Louis , Segu Louis , Buhot Marie-Christine
Published: April 2018

In an attempt to characterize the contribution of the 5-HT1B receptor to behavior, 5-HT1B knock-out (KO) mice were subjected to a battery of behavioral paradigms aimed at differentiating various components of cognitive and emotional behaviors. In an object exploration task, wild-type (WT) and 5-HT1B KO mice did not differ in locomotor activity. 5-HT1B KO mice, however, displayed lower thigmotaxis (an index of anxiety) associated with a higher level of object exploratory activity, but no genotype differences were observed in the elevated plus maze. 5-HT1B KO mice also displayed a lack of exploratory habituation. In the spatial version of the Morris water maze, 5-HT1B KO mice showed higher performances in acquisition and transfer test, which was not observed in the visual version of the task. No genotype differences were found in contextual fear conditioning, because both WT and 5-HT1B KO mice were able to remember the context where they had received the aversive stimulus. The deletion of the 5-HT1B receptor, associated with appropriate behavioral paradigms, thus allowed us to dissociate anxiety from response to novelty, and perseverative behavior (lack of habituation) from adaptive behavioral inhibition underlying cognitive flexibility (transfer stage in the water maze). The deletion of the 5-HT1B receptor did not result in significant developmental plasticities for other major 5-HT receptor types but may have influenced other neurotransmission systems. The 5-HT1B receptor may be a key target for serotonin in the modulation of cognitive behavior, particularly in situations involving a high cognitive demand.
Differential Activation of Adenylyl Cyclases by Spatial and Procedural Learning
Authors: Guillou Jean-Louis , Rose Gregory M. , Cooper Dermot M. F.
Published: April 2018

Adenylyl cyclases (ACs) are involved in a variety of advanced CNS functions, including some types of learning and memory. At least nine AC isoforms are expressed in the brain, which are divisible into three broad classes based on the ability of Ca2+to modulate their activity. This study examined the hypothesis that different learning tasks would differentially activate ACs in selected brain regions. The ability of forskolin or Ca2+to enhance AC activity in the hippocampus, parietal cortex, striatum, and cerebellum was examined after mice had been trained in either a spatial or procedural learning task using a Morris water maze. Sensitivity of ACs to forskolin was enhanced to a greater degree in most brain regions after procedural learning, but Ca2+-sensitive ACs in the hippocampus were more sensitive to spatial learning. Because nonspecific behavioral elements, such as stress or motor activity, were similar in both experimental tasks, these results provide the first evidence that acquisition of different kinds of learning is associated with selective changes in particular AC species in a mammalian brain and support the idea that different biochemical processing, involving particular isoforms of ACs, subserves different memory systems.
Direct Agonists for Serotonin Receptors Enhance Locomotor Function in Rats that Received Neural Transplants after Neonatal Spinal Transection
Authors: Kim Duckhyun , Adipudi V. , Shibayama M. , Giszter Simon , Tessler Alan , Murray Marion , Simansky Kenny J.
Published: April 2018

We analyzed whether acute treatment with serotonergic agonists would improve motor function in rats with transected spinal cords (spinal rats) and in rats that received transplants of fetal spinal cord into the transection site (transplant rats). Neonates received midthoracic spinal transections within 48 hr of birth; transplant rats received fetal (embryonic day 14) spinal cord grafts at the time of transection. At 3 weeks, rats began 1–2 months of training in treadmill locomotion. Rats in the transplant group developed better weight-supported stepping than spinal rats. Systemic administration of two directly acting agonists for serotonergic 5-HT2receptor subtypes, quipazine and (+/−)-1-[2,5]-dimethoxy-4-iodophenyl-2-aminopropane), further increased weight-supported stepping in transplant rats. The improvement was dose-dependent and greatest in rats with poor to moderate baseline weight support. In contrast, indirectly acting serotonergic agonists, which block reuptake of 5-HT (sertraline) or release 5-HT and block its reuptake (d-fenfluramine), failed to enhance motor function. Neither direct nor indirect agonists significantly improved locomotion in spinal rats as a group, despite equivalent upregulation of 5-HT2receptors in the lumbar ventral horn of lesioned rats with and without transplants. The distribution of immunoreactive serotonergic fibers within and caudal to the transplant did not appear to correspond to restoration of motor function. Our results confirm our previous demonstration that transplants improve motor performance in spinal rats. Additional stimulation with agonists at subtypes of 5-HT receptors produces a beneficial interaction with transplants that further improves motor competence.
Arachidonic Acid Reciprocally Alters the Availability of Transient and Sustained Dendritic K+Channels in Hippocampal CA1 Pyramidal Neurons
Authors: Colbert Costa M. , Pan Enhui
Published: April 2018

The dendrites of hippocampal CA1 pyramidal cell dendrites express a high density of transient A-type K+channels, which play a critical role in the back-propagation of action potentials and in the determination of dendritic excitability. Recently, arachidonic acid and its nonmetabolizable analogue 5,8,11,14-eicosatetraynoic acid (ETYA) were shown to block transient K+channels in the somata of these cells (Keros and McBain, 1997), but to have little effect on the somatic action potential. In the present study we have investigated the effects of arachidonic acid and ETYA on the gating of channels and the excitability of the apical dendrites of CA1 pyramidal neurons. We found not only a block of transient K+channels, but also an enhancement of sustained outward currents. The sustained currents consisted of at least two distinct channel types. The larger conductance channel (>50 pS) was identified as a K+channel. Arachidonic acid greatly enhanced the amplitude of back-propagating dendritic action potentials (>200 μm from the soma) but did not result in sustained depolarizations of the dendrites similar to those seen with 4-aminopyridine (4-AP) application. In fact, arachidonic acid reduced dendritic excitability when applied after 4-AP. Thus, arachidonic acid appears to cause a shift of available channels from the fast, transient type to the slower, sustained types. The net effect appears to be an enhancement of dendritic action potential amplitude that occurs without compromising the electrical stability of the dendrites.
Signal Transfer in Passive Dendrites with Nonuniform Membrane Conductance
Authors: London Michael , Meunier Claude , Segev Idan
Published: April 2018

In recent years it became clear that dendrites possess a host of ion channels that may be distributed nonuniformly over their membrane surface. In cortical pyramids, for example, it was demonstrated that the resting membrane conductance Gm(x) is higher (the membrane is “leakier”) at distal dendritic regions than at more proximal sites. How does this spatial nonuniformity in Gm(x) affect the input–output function of the neuron? The present study aims at providing basic insights into this question. To this end, we have analytically studied the fundamental effects of membrane non-uniformity in passive cable structures.

Keeping the total membrane conductance over a given modeled structure fixed (i.e., a constant number of passive ion channels), the classical case of cables with uniform membrane conductance is contrasted with various nonuniform cases with the following general conclusions. (1) For cylindrical cables with “sealed ends,” monotonic increase in Gm(x) improves voltage transfer from the input location to the soma. The steeper the Gm(x), the larger the improvement. (2) This effect is further enhanced when the stimulation is distal and consists of a synaptic input rather than a current source. (3) Any nonuniformity in Gm(x) decreases the electrotonic length, L, of the cylinder. (4) The system time constant τ0is larger in the nonuniform case than in the corresponding uniform case. (5) When voltage transients relax with τ0, the dendritic tree is not isopotential in the nonuniform case, at variance with the uniform case. The effect of membrane nonuniformity on signal transfer in reconstructed dendritic trees and on the I/f relation of the neuron is also considered, and experimental methods for assessing membrane nonuniformity in dendrites are discussed.
Persistent Increased DNA-Binding and Expression of Serum Response Factor Occur with Epilepsy-Associated Long-Term Plasticity Changes
Authors: Morris T. Allen , Jafari Neda , Rice Ann C. , Vasconcelos Olavo , DeLorenzo Robert J.
Published: April 2018

We have previously shown that NMDA receptor activation during status epilepticus (SE) is required to produce epilepsy inin vitroandin vivomodels. As in human symptomatic epilepsy, the epilepsy in these models is permanent, suggesting that the pathological activation of NMDA receptors causes permanent plasticity changes in the brain. Ca2+influx through NMDA receptors is known to transiently activate a key transcription factor, serum response factor (SRF). Thus, we investigated whether this factor, in terms of its expression and ability to bind to the consensus serum response element, was altered long term in the pilocarpine model of epilepsy. In hippocampal nuclear extracts, SRF binding to DNA was significantly increased over saline-injected control rats at 24 hr and at 8 weeks after the onset of SE. This increase was shown to be the result of significantly elevated levels of SRF. DNA binding was also persistently increased in the cortical, but not in the cerebellar, extracts. Hippocampal expression of SRF was localized to neurons using immunohistochemistry. NMDA receptor activation during SE was required for these changes to take place, and the spontaneous seizures seen in epileptic rats did not appear to be responsible for the increase in SRF. The results demonstrate that SRF is persistently elevated after SE in the pilocarpine model of epilepsy and support the theory that long-term gene changes in this model occur and are associated with the long-lasting plasticity changes that are initiated during epileptogenesis.
Knock-Out of the Neural Death Effector Domain Protein PEA-15 Demonstrates That Its Expression Protects Astrocytes from TNFα-Induced Apoptosis
Authors: Kitsberg Daniel , Formstecher Etienne , Fauquet Mireille , Kubes Miroslav , Cordier Jocelyne , Canton Brigitte , Pan GuoHua , Rolli Malvyne , Glowinski Jacques , Chneiweiss Hervé
Published: April 2018

Apoptosis is a very general phenomenon, but only a few reports concern astrocytes. Indeed, astrocytes express receptors for tumor necrosis factor (TNF) α, a cytokine demonstrated on many cells and tissues to mediate apoptosis after recruitment of adaptor proteins containing a death effector domain (DED). PEA-15 is a DED-containing protein prominently expressed in the CNS and particularly abundant in astrocytes. This led us to investigate if PEA-15 expression could be involved in astrocytic protection against deleterious effects of TNF.In vitroassays evidence that PEA-15 may bind to DED-containing protein FADD and caspase-8 known to be apical adaptors of the TNF apoptotic signaling. After generation of PEA-15 null mutant mice, our results demonstrate that PEA-15 expression increases astrocyte survival after exposure to TNF.
Differential Roles of Ca2+/Calmodulin-Dependent Protein Kinase II and Mitogen-Activated Protein Kinase Activation in Hippocampal Long-Term Potentiation
Authors: Liu Jie , Fukunaga Kohji , Yamamoto Hideyuki , Nishi Katsuhide , Miyamoto Eishichi
Published: April 2018

The roles of Ca2+/calmodulin-dependent protein kinase II (CaM kinase II) and mitogen-activated protein kinase (MAPK) in long-term potentiation (LTP) were investigated in the CA1 area of hippocampal slices, using electrophysiological and biochemical approaches. A brief high-frequency stimulation, but not low-frequency stimulation, delivered to Schaffer collateral/commissural afferents produced a stable LTP and activated both CaM kinase II and 42 kDa MAPK. Different from the activity of CaM kinase II, the increase in MAPK activity was transient. At a concentration of 50 μm,but not of 30 μm,PD098059, a potent inhibitor of MAPK kinase, markedly inhibited the induction of LTP. Although the two concentrations had similar inhibitory effects on MAPK activity, only 50 μmPD098059 suppressed the activation of CaM kinase II. Application of calmidazolium, an antagonist of calmodulin, blocked both CaM kinase II activation and the LTP induction without affecting the increase in 42 kDa MAPK activity. Application of neurotrophin brain-derived neurotrophic factor (BDNF) promoted the induction of LTP, with concomitant activation of CaM kinase II. Under the same conditions, BDNF failed to activate MAPK in hippocampal slices. These results indicate that, although the LTP induction is accompanied by increases in two kinase activities, only CaM kinase II activation is required for this event.
Dendritic Ca2+-Activated K+Conductances Regulate Electrical Signal Propagation in an Invertebrate Neuron
Authors: Wessel Ralf , Kristan William B. , Kleinfeld David
Published: April 2018

Activity-dependent changes in the short-term electrical properties of neurites were investigated in the anterior pagoda (AP) cell of leech. Imaging studies revealed that backpropagating Na+spikes and synaptically evoked EPSPs caused Ca2+entry through low-voltage-activated Ca2+channels that are distributed throughout the neurites. Voltage-clamp recordings from the soma revealed a TEA-sensitive outward current that was reduced when Ca2+entry was blocked with Co2+or when the intracellular concentration of free Ca2+was reduced by a high-affinity Ca2+buffer. Ca2+released in the neurite from a caged Ca2+compound caused a hyperpolarization of the membrane potential. These data imply that the AP cell expresses Ca2+-activated K+conductances, and that these conductances are present in the neurites. When the Ca2+-activated K+current was reduced through the block of Ca2+entry, backpropagating Na+spikes and synaptically evoked EPSPs increased in amplitude. Hence, the activity-dependent changes in the intracellular [Ca2+] together with the Ca2+-activated K+conductances participate in the regulation of dendritic signal propagation.
Drosophila presenilinIs Required for Neuronal Differentiation and Affects Notch Subcellular Localization and Signaling
Authors: Guo Yiquan , Livne-Bar Izhar , Zhou Lily , Boulianne Gabrielle L.
Published: April 2018

Presenilins are a highly conserved family of proteins first identified as causative genes in early onset familial Alzheimer’s disease. Recent studies have suggested a role for presenilins in the Notch-signaling pathway, but their specific function within this pathway remains unclear. Here, we have characterized theDrosophila presenilingene and protein and studied their interaction with Notch in both mutants and transgenics. We find that theDrosophilapresenilin protein is proteolytically cleaved and broadly expressed during development with the highest levels in neurons within the larval CNS. We also show that mutations inDrosophila presenilin(Dps) genetically interact with Notch and result in an early pupal-lethal phenotype characterized by defects in eye and wing development and incomplete neuronal differentiation within the larval CNS. Moreover, we find that processing of Notch in the Golgi by the furin protease is unaffected in Dps mutants and that Notch is present and may even accumulate on the plasma membrane of neuroblasts in the larval CNS of Dps mutants. In contrast, overexpression ofDpsin transgenics causes Notch to accumulate in the cytoplasm. Taken together, these results indicate thatDrosophilapresenilin is required for proper neuronal differentiation and may regulate the subcellular localization of Notch proteins within cells, necessary for their accumulation and subsequent signaling capabilities.
Multiple Actions of Neurturin Correlate with Spatiotemporal Patterns of Ret Expression in Developing Chick Cranial Ganglion Neurons
Authors: Hashino Eri , Johnson Eugene M. , Milbrandt Jeffrey , Shero Marlene , Salvi Richard J. , Cohan Christopher S.
Published: April 2018

The neurotrophic effects of neurturin (NRTN) on chick cranial ganglia were evaluated at various embryonic stagesin vitroand related to its receptor expression. NRTN promoted the outgrowth and survival of ciliary ganglion neurons at early embryonic (E) stages (E6–E12), trigeminal ganglion neurons at midstages (E9–E16), and vestibular ganglion neurons at late stages (E12–E16). NRTN had no positive effects on cochlear ganglion neurons throughout development. In accordance with the time and order of onset in NRTN responsiveness, Ret protein was first detected in ciliary ganglia at E6, subsequently in trigeminal ganglia at E9, and in vestibular ganglia at E12. Ret was absent in E16 ciliary ganglia as well as in cochlear ganglia at all developmental stages that were tested. Exogenous application of retinoic acid induced NRTN responsiveness and Ret protein expression from E9 vestibular ganglion neurons, suggesting that retinoic acid can regulate Ret protein expression in peripheral sensory neuronsin vitro. Ret was confined to the neuron cell body, whereas GFRα was localized predominantly in peripheral and central neurite processes. No noticeable change in GFRα expression was seen in any cranial ganglia throughout the developmental stages that were tested (E6–E16). These results demonstrate that NRTN exerts neurotrophic effects on different cranial ganglia at different developmental stages and that the onset and offset of NRTN responsiveness are regulated mainly by the spatiotemporal patterns of Ret, but not of GFRα receptors. The results also substantiate the recently emerging view that NRTN may be an essential target-derived neurotrophic factor for parasympathetic neurons during development.
Overexpression of Nerve Growth Factor in Skin Selectively Affects the Survival and Functional Properties of Nociceptors
Authors: Stucky C. L. , Koltzenburg M. , Schneider M. , Engle M. G. , Albers K. M. , Davis B. M.
Published: April 2018

Mice that overexpress nerve growth factor (NGF-OE) in the skin have double the normal number of cutaneous sensory neurons, have increased innervation of the skin and spinal cord, and are hyperalgesic. Here, we have asked whether the increased cutaneous NGF level results in a selective survival of only certain functional types of neurons and whether it changes the properties of cutaneous neurons. Using electron microscopy, we show that the number of both myelinated and unmyelinated nociceptors increases substantially in NGF-OE mice by a factor of 3.3 and 1.5, respectively. Using extracellular recordings from single units, we demonstrate that large myelinated (Aβ) fibers are unchanged in prevalence and receptive properties. In contrast, among thin myelinated (Aδ) fibers, the percentage of nociceptors increased from a normal 65 to 97%, consistent with a selective survival of nociceptors during embryogenesis. These afferents showed a twofold increase in their mechanical responsiveness, but their heat responsiveness remained normal. Among unmyelinated (C) fibers, there was a profound increase in the percentage of heat responsive neurons from a normal 42 to 96%. This change cannot be accounted for by a selective survival of heat-sensitive neurons. Unmyelinated nociceptors increased fourfold in their thermal responsiveness but decreased in mechanical responsiveness. Therefore, target-derived NGF selectively rescues nociceptors during the period of programmed cell death with different efficacy for thin myelinated or unmyelinated fibers. NGF also affects the response to noxious heat or mechanical stimuli in each group differently, implying specific regulations of transduction processes rather than general changes of excitability.