bluuebunny/crossref_metadata_2025 huggingface dataset:
Diadenosine Tetraphosphate Protects against Injuries Induced by Ischemia and 6-Hydroxydopamine in Rat Brain
Authors: Wang Yun , Chang Chen-Fu , Morales Marisela , Chiang Yung-Hsiao , Harvey Brandon K. , Su Tsung-Ping , Tsao Li-I , Chen Suyu , Thiemermann Christoph
Published: April 2018

Diadenosine tetraphosphate (AP4A), an endogenous diadenosine polyphosphate, reduces ischemic injury in the heart. In this study, we report the potent and protective effects of AP4A in rodent models of stroke and Parkinson's disease. AP4A, given intracerebroventricularly before middle cerebral artery (MCA) ligation, reduced cerebral infarction size and enhanced locomotor activity in adult rats. The intravenous administration of AP4A also induced protection when given early after MCA ligation. AP4A suppressed terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling (TUNEL) induced by hypoxia/reperfusion in primary cortical cultures, and reduced both ischemia-induced translocation of mitochondrial cytochromecand the increase in cytoplasmic caspase-3 activityin vivo. The purinergic P2/P4antagonist di-inosine pentaphosphate or P1-receptor antagonist sulfonylphenyl theophylline, but not the P2-receptor antagonist suramin, antagonized the effect of AP4A, suggesting that the observed protection is mediated through an anti-apoptotic mechanism and the activation of P1- and P4-purinergic receptors.

AP4A also afforded protection from toxicity induced by unilateral medial forebrain bundle injection of 6-hydroxydopamine (6-OHDA). One month after lesioning, vehicle-treated rats exhibited amphetamine-induced rotation. Minimal tyrosine hydroxylase immunoreactivity was detected in the lesioned nigra or striatum. No KCl-induced dopamine release was found in the lesioned striatum. All of these indices of dopaminergic degeneration were attenuated by pretreatment with AP4A. In addition, AP4A reduced TUNEL in the lesioned nigra 2 d after 6-OHDA administration. Collectively, our data suggest that AP4A is protective against neuronal injuries induced by ischemia or 6-OHDA through the inhibition of apoptosis. We propose that AP4A may be a potentially useful target molecule in the therapy of stroke and Parkinson's disease.
Ketamine-Xylazine-Induced Slow (< 1.5 Hz) Oscillations in the Rat Piriform (Olfactory) Cortex Are Functionally Correlated with Respiration
Authors: Fontanini Alfredo , Spano PierFranco , Bower James M.
Published: April 2018

The occurrence of low frequency (<1.5 Hz) cerebral cortical oscillations during slow-wave sleep has recently lead to the suggestion that this pattern of activity is specifically associated with conditions in which the brain is mostly closed to external inputs and running on its own. In the current experiments, we used a combination ofin vivointracellular and extracellular field potential recordings obtained under conditions of ketamine-xylazine anesthesia to examine slow-wave behavior in the olfactory system. We demonstrate the occurrence of low-frequency oscillations in field potentials of both the olfactory bulb and cortex and in the membrane potentials of cortical pyramidal cells. By monitoring ongoing breathing, we also show that these oscillations are all correlated with the natural breathing cycle. Using a tracheotomized preparation, we demonstrate that slow oscillatory patterns could occasionally be produced even when air is no longer entering the nose, supporting the view that the olfactory system has an intrinsic propensity to oscillate. However, in the case of tracheotomized rats, the amplitude and regularity of the oscillations as well as their patterns of correlation are disrupted. All temporal relationships were restored when air was pulsed into the nostrils. We conclude that, in the olfactory system of freely breathing rats, there is a strong relationship between the occurrence and timing of slow oscillations and the ongoing periodic sensory input resulting from respiration. This coupling between olfactory cortex slow oscillations and respiration may result from the interaction between respiratory-related rhythmic input and the tendency for olfactory structures to oscillate intrinsically. We believe this finding has important functional as well as evolutionary implications.
MinK-Related Peptide 2 Modulates Kv2.1 and Kv3.1 Potassium Channels in Mammalian Brain
Authors: McCrossan Zoe A. , Lewis Anthony , Panaghie Gianina , Jordan Peter N. , Christini David J. , Lerner Daniel J. , Abbott Geoffrey W.
Published: April 2018

Delayed rectifier potassium current diversity and regulation are essential for signal processing and integration in neuronal circuits. Here, we investigated a neuronal role for MinK-related peptides (MiRPs), membrane-spanning modulatory subunits that generate phenotypic diversity in cardiac potassium channels. Native coimmunoprecipitation from rat brain membranes identified two novel potassium channel complexes, MiRP2-Kv2.1 and MiRP2-Kv3.1b. MiRP2 reduces the current density of both channels, slows Kv3.1b activation, and slows both activation and deactivation of Kv2.1. Altering native MiRP2 expression levels byRNAigene silencing or cDNA transfection toggles the magnitude and kinetics of endogenous delayed rectifier currents in PC12 cells and hippocampal neurons. Computer simulations predict that the slower gating of Kv3.1b in complexes with MiRP2 will broaden action potentials and lower sustainable firing frequency. Thus, MiRP2, unlike other known neuronal β subunits, provides a mechanism for influence over multiple delayed rectifier potassium currents in mammalian CNS via modulation of α subunits from structurally and kinetically distinct subfamilies.
Oscillations in Endogenous Inputs to Neurons Affect Excitability and Signal Processing
Authors: Parkis Marjorie A. , Feldman Jack L. , Robinson Dean M. , Funk Gregory D.
Published: April 2018

Synchrony and oscillations in neuronal firing play important roles in information processing in the mammalian brain. Here, we evaluate their role in controlling neuronal output in a well defined motor behavior, breathing, using anin vitropreparation from neonatal rat that generates respiratory-related motor output. In this preparation, phrenic motoneurons (PMNs) receive endogenous rhythmic inspiratory currents with prominent oscillations in the 20-50 Hz range. We recorded these inspiratory currents in individual PMNs and used them as test inputs for the same motoneuron (MN) during the normally silent expiratory periods. The impact of the oscillations on MN output was evaluated by filtering the currents before injection. Responses to unfiltered inspiratory currents were indistinguishable from voltage changes during spontaneous inspiratory periods. More than 90% of action potentials occurred within milliseconds [-2 to +4] of the oscillation peaks. The timing of action potentials was highly reproducible in response to unfiltered currents. Attenuation of the oscillations by low-pass filtering (<50 Hz) decreased the precision in action potential timing and significantly reduced the number of action potentials by ∼35%. The adrenergic agonist phenylephrine increased instantaneous firing frequency in responses evoked by square-wave or low-pass filtered inspiratory currents but had no effect on firing frequency evoked by unfiltered currents. We conclude that oscillations control the precise timing of action potentials, help to maximize synaptic drive efficiency, and constrain MN firing frequencies to those optimal for muscle contraction.
Mutations indeadly seven/notch1aReveal Developmental Plasticity in the Escape Response Circuit
Authors: Liu Katharine S. , Gray Michelle , Otto Stefanie J. , Fetcho Joseph R. , Beattie Christine E.
Published: April 2018

The relatively simple neural circuit driving the escape response in zebrafish offers an excellent opportunity to study properties of neural circuit formation. The hindbrain Mauthner cell is an essential component of this circuit. Mutations in the zebrafishdeadly seven/notch1a(des) gene result in supernumerary Mauthner cells. We addressed whether and how these extra cells are incorporated into the escape-response circuit. Calcium imaging revealed that all Mauthner cells indesb420mutants were active during an elicited escape response. However, the kinematic performance of the escape response in mutant larvae was very similar to wild-type fish. Analysis of the relationship between Mauthner axon collaterals and spinal neurons revealed that there was a decrease in the number of axon collaterals per Mauthner axon in mutant larvae compared with wild-type larvae, indicative of a decrease in the number of synapses formed with target spinal neurons. Moreover, we show that Mauthner axons projecting on the same side of the nervous system have primarily nonoverlapping collaterals. These data support the hypothesis that excess Mauthner cells are incorporated into the escape-response circuit, but they divide their target territory to maintain a normal response, thus demonstrating plasticity in the formation of the escape-response circuit. Such plasticity may be key to the evolution of the startle responses in mammals, which use larger populations of neurons in circuits similar to those in the fish escape response.
Disruption of an Intersubunit Interaction Underlies Ca2+-Calmodulin Modulation of Cyclic Nucleotide-Gated Channels
Authors: Zheng Jie , Varnum Michael D. , Zagotta William N.
Published: April 2018

Cyclic nucleotide-gated channels are key molecular elements for olfactory transduction. Olfactory adaptation caused by repeated exposure to an odorant has been proposed to be mediated by the binding of Ca2+-calmodulin to the NH2-terminal domain of the channel, breaking its interaction with the COOH-terminal domain and downregulating the channel. We used a fluorescence resonance energy transfer (FRET) approach to study the structural aspects of this domain-domain interaction under physiological conditions in real time. Fluorescent proteins enhanced cyan fluorescent protein and enhanced yellow fluorescent protein were genetically attached at sites adjacent to the NH2- and COOH-terminal interacting domains, respectively, allowing direct observation of molecular rearrangements in intact channels. FRET signals caused by the specific interdomain interaction were observed in both intact cells and excised patches. Comparison of the effective FRET efficiencies demonstrated that the interaction occurs specifically between subunits but not within the same subunit. Binding of Ca2+-calmodulin caused a reversible decrease in FRET with the same time course as channel downregulation. These results suggest that a separation or reorientation of the interacting domains between subunits by Ca2+-calmodulin leads to channel downregulation. The quaternary arrangement presents a structural framework for understanding the molecular mechanism of olfactory adaptation.
α-Conotoxin PIA Is Selective for α6 Subunit-Containing Nicotinic Acetylcholine Receptors
Authors: Dowell Cheryl , Olivera Baldomero M. , Garrett James E. , Staheli Sarah T. , Watkins Maren , Kuryatov Alexander , Yoshikami Doju , Lindstrom Jon M. , McIntosh J. Michael
Published: April 2018

Until now, there have been no antagonists to discriminate between heteromeric nicotinic acetylcholine receptors (nAChRs) containing the very closely related α6 and α3 subunits. nAChRs containing α3, α4, or α6 subunits in combination with β2, occasionally β4, and sometimes β3 or α5 subunits, are thought to play important roles in cognitive function, pain perception, and the reinforcing properties of nicotine. We cloned a novel gene from the predatory marine snailConus purpurascens. The predicted peptide, α-conotoxin PIA, potently blocks the chimeric α6/α3β2β3 subunit combination as expressed in oocytes but neither the muscle nor the major neuronal nAChR α4β2. Additionally, this toxin is the first described ligand to discriminate between nAChRs containing α6 and α3 subunits. Exploiting the unusual intron conservation of conotoxin genes may represent a more general approach for defining conotoxin ligand scaffolds to discriminate among closely related receptor populations.
Metabotropic Modulation of Motoneurons by Scratch-Like Spinal Network Activity
Authors: Alaburda Aidas , Hounsgaard Jørn
Published: April 2018

Glutamate is the main excitatory transmitter in the spinal motor network. The excitation is to a large extent mediated by ionotropic receptors, but glutamate also activates metabotropic receptors. In motoneurons in spinal cord slices the activation of group I metabotropic glutamate (mGlu1) receptors leads to facilitation of CaV1.3 L-type calcium channels. Here we investigate whether this pathway is activated by motor network activity induced by natural sensory stimuli. The lumbar carapace and spinal cord were isolated from adult turtles. In this preparation, mechanical stimulation in the receptive field for the scratch reflex induced episodes of rhythmic motor network activity. During an episode the excitability of coactivated motoneurons increased. This increase was associated with an increased persistent inward current and was abolished by local blockade of either mGlu1 receptors or CaV1.3 L-type calcium channels near the recording site. We conclude that glutamate released during spinal motor network activity excites motoneurons by parallel activation of ionotropic and mGlu1 receptors. The metabotropic facilitation of L-type calcium channels contributes significantly to this excitation. Our findings establish intrinsic modulation as an active component in the spinal motor network for limb movements.
Central Amygdala Lesions Block Ultrasonic Vocalization and Freezing as Conditional But Not Unconditional Responses
Authors: Choi June-Seek , Brown Thomas H.
Published: April 2018

Bilateral amygdala (AM) lesions prevent the acquisition of fear-related conditional responses (CRs) in rats, a result that is most commonly concluded to reflect a learning or memory deficit. An alternative hypothesis is that AM-lesioned animals fail to acquire certain fear CRs simply because they cannot perform these behaviors. This performance-deficit hypothesis is usually invoked in regard to studies in which the CR is freezing, the most commonly measured behavior. Here we explore this interpretation by measuring two different behaviors [freezing and 22 kHz ultrasonic vocalization (USV)] elicited under three conditions (during context conditioning, during subsequent retention testing, and after ejaculation) in experimental rats [that received electrolytic lesions of the central nucleus of the amygdala (ACe)] and control animals (that received a sham operation). If ACe damage produces a discrete motor deficit that specifically renders the animal unable to remain immobile, then freezing should be blocked or impaired when elicited under all three conditions, whereas USV should be spared. Alternatively, if ACe damage selectively interferes with CR formation, maintenance, or expression, then both freezing and USV should be blocked or impaired when elicited as CRs during acquisition and retention testing but spared when evoked as unconditional responses (URs) to ejaculation. ACe damage blocked or severely impaired both freezing and USV elicited as CRs but had no effect on either behavior elicited as URs. We reject the motor-deficit hypothesis and discuss some viable alternatives.
Brain-Derived Neurotrophic Factor Modulation of GABAergic Synapses by Postsynaptic Regulation of Chloride Transport
Authors: Wardle Rinda A. , Poo Mu-ming
Published: April 2018

Brain-derived neurotrophic factor (BDNF) potentiates excitatory synapses in a variety of systems by promoting presynaptic transmitter release. The existing evidence indicates that BDNF attenuates inhibitory transmission, but reports differ considerably in their characterization of the effect and proposed mechanisms. We examined the effects of exogenously applied BDNF on EPSCs and IPSCs recorded from functionally identified neurons in dissociated rat hippocampal cultures. When recording from glutamatergic neurons, we found that BDNF exerted differential effects at excitatory versus inhibitory synapses: increasing amplitude of EPSCs but slightly decreasing that of IPSCs. Furthermore, when recording from GABAergic neurons, we found that BDNF increased the IPSC amplitude. That these differential BDNF effects reflect distinct presynaptic and postsynaptic mechanisms was suggested by the BDNF-induced changes in miniature EPSCs and IPSCs. An increased mini-frequency was found at all synapses, indicating elevated presynaptic transmitter secretion; a change in the amplitude of mini-IPSCs was found at GABAergic cells, suggesting postsynaptic modulation of GABA responses. Selective postsynaptic mechanisms were further examined by comparing the effect of BDNF on GABA-induced currents recorded from glutamatergic versus GABAergic cells. For GABAergic but not glutamatergic postsynaptic cells, BDNF induced a shift in the reversal potential (EIPSC) toward more positive levels, hence reducing the inhibitory action of IPSCs. This BDNF-induced effect correlates with the existing level of furosemide-sensitive K+-Cl-transport activity in the postsynaptic cell. Thus, BDNF may decrease the efficacy of inhibitory transmission by acute postsynaptic downregulation of Cl-transport, in addition to its well known presynaptic effect.
Heterogeneous Modulation of Place Cell Firing by Changes in Context
Authors: Anderson Michael I. , Jeffery Kathryn J.
Published: April 2018

Hippocampal place cells show spatially localized activity that can be modulated by both geometric information (e.g., the distances and directions of features in the environment) and nongeometric information (e.g., colors, odors, and possibly behaviors). Nongeometric information may allow the discrimination of different spatial contexts. Understanding how nongeometric (or contextual) information affects hippocampal activity is important in light of proposals that the hippocampus may play a role in constructing a representation of spatial context. We investigated the contextual modulation of place cell activity by recording hippocampal place cells while rats foraged in compound contexts comprising black or white color paired with lemon or vanilla odor. Some cells responded to the color or odor changes alone, but most responded to varying combinations of both. Thus, we demonstrate, for the first time, that there is a heterogeneous input by contextual inputs into the hippocampus. We propose a model of contextual remapping of place cells in which the geometric inputs are selectively activated by subsets of contextual stimuli. Because it appears that different place cells are affected by different subsets of contextual stimuli, the representation of the entire context would require activity at the population level, supporting a role for the hippocampus in constructing a representation of spatial context.
Lobster (Panulirus interruptus) Pyloric Muscles Express the Motor Patterns of Three Neural Networks, Only One of Which Innervates the Muscles
Authors: Thuma Jeff B. , Morris Lee G. , Weaver Adam L. , Hooper Scott L.
Published: April 2018

In several systems, including some well studied invertebrate “model” preparations, rapid, rhythmic inputs drive slow muscles. In this situation muscle contractions can summate temporally between motor neuron bursts, tonically contract, and low-pass filter broad-band input. We have investigated how the muscles innervated by each motor neuron type of the rapid, rhythmic (cycle period, ∼1 sec) lobster pyloric network respond when driven by previously recordedin vitropyloric network activity from intact stomatogastric nervous systems. Under these conditions the much slower gastric mill and cardiac sac networks of the stomatogastric nervous system are also active and modify pyloric activity. All of the muscles show pyloric timed phasic contractions that ride on a sustained tonic contraction; muscle activity can range from being almost completely phasic to almost completely tonic. The modifications of pyloric neuron activity induced by gastric mill (cycle period, ∼10 sec) activity result in some pyloric muscles showing prominent, gastric mill-timed, changes in either phasic or tonic contraction amplitude. The strong modification of pyloric neuron activity induced by cardiac sac (cycle period, ∼60 sec) activity alters the contractions of all pyloric muscles. These changes are sufficient that for some muscles, in some preparations, the primary muscle output is cardiac sac-timed. This is the first work to examine the motor responses of all pyloric muscle classes to spontaneous stomatogastric activity and shows that the pyloric motor pattern is a complex combination of the activities of three neural networks, although only one (the pyloric) innervates the muscles.
Convergence and Interaction of Hippocampal and Amygdalar Projections within the Prefrontal Cortex in the Rat
Authors: Ishikawa Akinori , Nakamura Shoji
Published: April 2018

The orbital and medial prefrontal cortex (OMPFC) receives inputs from the CA1/subicular (CA1/S) region of the ventral hippocampus and the basolateral nucleus of the amygdala (BLA). Despite many studies about these projections, little is known as to how CA1/S and BLA inputs converge and interact within the OMPFC. Extracellular recordings of single-unit activity in the OMPFC were performed in sodium pentobarbitone-anesthetized rats. OMPFC neurons driven by CA1/S or BLA stimulation were more frequently encountered in the ventral portion of the prelimbic (v-PrL) and infralimbic cortex (IL). OMPFC neurons showing excitatory convergence of both inputs from the CA1/S and BLA were also located predominantly in the v-PrL and IL. The excitatory latencies of these neurons from both the CA1/S and BLA revealed almost identical values. Excitatory responses of OMPFC neurons to CA1/S (or BLA) stimulation were markedly augmented by simultaneous BLA (or CA1/S) stimulation, whereas the inhibitory influence of the BLA (or CA1/S) on CA1/S-induced (or BLA-induced) excitation was apparent when BLA (or CA1/S) stimulation was given 20-40 msec before CA1/S (or BLA) stimulation. Similar results were also observed when reciprocal connections between the CA1/S and BLA were severed to exclude the influences of these connections on one another. From these studies, we concluded that excitatory and inhibitory inputs from the hippocampus and amygdala converge and interact in the v-PrL and IL. Furthermore, the results indicate that simultaneous activation of hippocampal and amygdalar neurons may be important for amplification of OMPFC neuronal activity.
Matrix Metalloproteinase Inhibition Alters Functional and Structural Correlates of Deafferentation-Induced Sprouting in the Dentate Gyrus
Authors: Reeves Thomas M. , Prins Mayumi L. , Zhu JiePei , Povlishock John T. , Phillips Linda L.
Published: April 2018

Molecules comprising the extracellular matrix (ECM), and the family of matrix metalloproteinases (MMPs) that regulate them, perform essential functions during neuroplasticity in both developing and adult nervous systems, including substrate guidance during neuritogenesis and the establishment of boundaries for axonal terminal fields. MMP proteolysis of ECM molecules may perform a permissive or inductive role in fiber remodeling and synaptogenesis initiated by deafferentation. This study examined functional and structural effects of MMP inhibition during the early phases of deafferentation-induced sprouting, characterizing components of the degeneration/proliferation cycle that may be dependent on MMP activity. Adult rats received unilateral lesions of the entorhinal cortex to induce collateral sprouting of the crossed temporodentate fiber pathway. This was followed by intraventricular infusion of the MMP inhibitor FN-439 (2.9 mg/kg) or saline vehicle. After 7 d postlesion, rats underwentin vivoelectrophysiological recording or histological processing for electron microscopic analysis. Lesioned rats receiving vehicle exhibited normal sprouting and synaptogenesis, with the emergence of the capacity for long-term potentiation (LTP) within the sprouting pathway, and the successful clearance of degenerating terminals with subsequent synaptic proliferation. In contrast, lesioned rats receiving the MMP inhibitor failed to develop the capacity for LTP and showed persistent cellular debris. Current source density analysis also revealed an FN-439-induced disruption of the current sink, normally localized to the middle region of the granule cell dendrites, corresponding to the terminal field of the crossed temporodentate fibers. These results establish a role for MMP-dependent processes in the deafferentation/sprouting cycle.
NMDA Currents and Receptor Protein Are Downregulated in the Amygdala during Maintenance of Fear Memory
Authors: Zinebi Fatiha , Xie Jiangang , Liu Jie , Russell Rex T. , Gallagher Joel P. , McKernan Margaret G. , Shinnick-Gallagher Patricia
Published: April 2018

The amygdala plays a critical role in fear conditioning, a model of emotional learning and cue-induced anxiety. In the lateral amygdala, fear conditioning is associated with an enduring increase in synaptic strength mediated through AMPA receptors and with a reduction in paired-pulse facilitation, reflecting an increased probability of neurotransmitter release. Here we show that NMDA-mediated transmission in the thalamic-to-lateral amygdala pathway is not facilitated after fear conditioning, although probability of transmitter release is enhanced. Rather, the EC50for NMDA receptor (NR)-mediated current is shifted threefold to fourfold to the right in fear-conditioned animals, suggesting a postsynaptic alteration in NMDA receptors in the maintenance phase of fear memory. Furthermore, the ability of nonselective and subunit-selective antagonists of NMDA receptors to block NMDA receptor-mediated EPSCs is reduced in lateral amygdala neurons from fear-conditioned animals, suggesting a reduction in NMDA receptors at thalamolateral amygdala synapses. In addition, Western blots show a reduction in phosphorylated-NR1, NR2A, and NR2B subunit protein expression in amygdalas from fear-conditioned animals. These data indicate that postsynaptic mechanisms are involved in synaptic plasticity in the thalamoamygdala pathway in fear conditioning and raise the possibility that: (1) downregulation of the NMDA receptor may protect against excitotoxicity of unchecked NMDA receptor recruitment during induction and consolidation of fear memories, (2) reduced NMDA current and protein may allow persistence of the “capacity to reactivate” amygdala pathways in NMDA receptor-dependent fear memories, or (3) a persistent long-term depression of NMDA transmission may occur after fear learning.
Experience-Dependent Activation Patterns in Human Brain during Visual-Motor Associative Learning
Authors: Eliassen James C. , Souza Timothy , Sanes Jerome N.
Published: April 2018

Multiple brain regions, including parietal and frontal cortical areas, seem to participate in learning and rehearsing associations between spatially defined visual cues and appropriate motor responses. However, because most previous studies have related learning to changes in brain activation according to elapsed time or number of trials but not categories based on performance, it remains unclear how and when areas implicated in learning sensory-motor associations actually participate in the process. The current experiment used functional magnetic resonance imaging to examine changes in brain activation when participants learned to associate an arbitrarily located visual cue with a finger movement. Associative trials were categorized as incorrect, first correct, or subsequent correct. Participants also performed a spatially compatible visual-motor control task. A group analysis revealed four major findings addressing the behavioral processes occurring during forming and rehearsing visual-motor rules. First, brain networks related to processing associative information, through initial learning to rehearsal, yielded more activation in a myriad of neocortical structures than did a simple motor task. Second, we revealed frontal and parietal areas that differentially processed errors and correct responses. Third, we found frontal-parietal networks that seemed to mediate the transition of learning to rehearsing arbitrary visual-motor associations and that this activation exhibited dynamic characteristics. Last, we found a frontal-parietal network that appeared to have a key role in expressing the learned sensory-motor association. The current results provide a foundation for understanding how neocortical structures participate in the various behavioral processes that combine to form and consolidate novel and arbitrary sensory-motor associations.
Spike Timing-Dependent Serotonergic Neuromodulation of Synaptic Strength Intrinsic to a Central Pattern Generator Circuit
Authors: Sakurai Akira , Katz Paul S.
Published: April 2018

Neuromodulation is often thought to have a static, gain-setting function in neural circuits. Here we report a counter example: the neuromodulatory effect of a serotonergic neuron is dependent on the interval between its spikes and those of the neuron being modulated. The serotonergic dorsal swim interneurons (DSIs) are members of the escape swim central pattern generator (CPG) in the molluskTritonia diomedea. DSI spike trains heterosynaptically enhanced synaptic potentials evoked by another CPG neuron, ventral swim interneuron B (VSI-B), when VSI-B action potentials occurred within 10 sec of a DSI spike train; however, if VSI-B was stimulated 20-120 sec after DSI, then the amplitude of VSI-B synaptic potentials decreased. Consistent with this, VSI-B-evoked synaptic currents exhibited a temporally biphasic and bidirectional change in amplitude after DSI stimulation. Both the DSI-evoked enhancement and decrement were occluded by serotonin and blocked by the serotonin receptor antagonist methysergide, suggesting that both phases are mediated by serotonin. In most preparations, however, bath-applied serotonin caused only a sustained enhancement of VSI-B synaptic strength. The heterosynaptic modulation interacted with short-term homosynaptic plasticity: DSI-evoked depression was offset by VSI-B homosynaptic facilitation. This caused a complicated temporal pattern of neuromodulation when DSI and VSI-B were stimulated to fire in alternating bursts to mimic the natural motor pattern: DSI strongly enhanced summated VSI-B synaptic potentials and suppressed single synaptic potentials after the cessation of the artificial motor pattern. Thus, spike timing-dependent serotonergic neuromodulatory actions can impart temporal information that may be relevant to the operation of the CPG.
The Sleep-Modulating Peptide Cortistatin Augments the h-Current in Hippocampal Neurons
Authors: Schweitzer Paul , Madamba Samuel G. , Siggins George R.
Published: April 2018

Cortistatin (CST) is a sleep-modulating peptide found exclusively in the brain. Although CST is closely related to somatostatin (SST) and binds to SST receptors, CST has effects on sleep and neuronal activity in cortex and hippocampus that differ from SST. To uncover the cellular mechanisms affected by CST, we studied the electrophysiological postsynaptic effects of CST and assessed its interaction with SST on hippocampal CA1 pyramidal neurons. CST altered intrinsic membrane properties and occluded SST effects, indicating that both peptides similarly augment the sustained K+M- and leak-currents (IMandIK(L)). In the presence of SST, however, CST elicited an additional inwardly rectifying component in the hyperpolarized range. This effect was unaffected by barium, used to block K+currents, but was completely prevented by the selective h-current (Ih) blocker ZD7288. CST, but not SST, selectively increasedIhin a concentration-dependent manner by augmenting its maximum conductance. CST did not shift theIhactivation curve, and the peptide effect was unaffected by a membrane-permeable analog of cAMP. We conclude that CST and SST similarly increase K+conductances in hippocampal neurons, most likely by activating SST receptors. However, CST additionally augmentsIh, a voltage-dependent current that plays a key role in the modulation of synaptic integration and regulates oscillatory activity. Our results indicate that CST targets a specific conductance unaffected by SST to modulate cellular mechanisms implicated in sleep regulation.
Ca2+Dependency of N-Cadherin Function Probed by Laser Tweezer and Atomic Force Microscopy
Authors: Baumgartner Werner , Golenhofen Nikola , Grundhöfer Niko , Wiegand Johannes , Drenckhahn Detlev
Published: April 2018

This study was undertaken to provide a biophysical basis for the hypothesis that activity-dependent modulation of cadherin-mediated adhesion by transient changes of extracellular calcium ([Ca2+]e) is causally involved in coordination of synaptic plasticity. Characterization of homophilic N-cadherin binding by atomic force microscopy and laser tweezer trapping of N-cadherin-coated microbeads attached to the cell surface of cultured neuronal cells showed that adhesive activity of N-cadherin is effectively regulated between 0.3 and 0.8 mm[Ca2+]e. Furthermore, we show that an increase of [Ca2+]i, which is known to be essential for induction of synaptic plasticity, causes significant reduction of cadherin-mediated bead adhesion that could be completely suppressed by inhibition of actin depolymerization. The results of this study show that N-cadherin has ideal biophysical properties to serve as a Ca2+-dependent sensor for synaptic activity and, at the same time, is strategically located to control synaptic adhesion. A drop of [Ca2+]eand a concomitant increase of [Ca2+]imay act in concert to modulate N-cadherin-based adhesive contacts at synaptic sites.
A Role of Rnd1 GTPase in Dendritic Spine Formation in Hippocampal Neurons
Authors: Ishikawa Yukio , Katoh Hironori , Negishi Manabu
Published: April 2018

Rho family of small GTPases are key regulators for morphological changes of neurons on the basis of reorganization of the actin cytoskeleton. Rnd1, a novel member of this family, is predominantly expressed in neurons in brain; however, the neuronal functions of Rnd1 are not known. Here we investigated the effect of Rnd1 on neuronal morphology. Northern blot analysis of Rnd1 expression in rat brain showed that Rnd1 mRNA was highly expressed during early postnatal period, the synaptogenic stage.In situhybridization analysis at this period revealed that Rnd1 mRNA was strongly expressed in neurons, including the hippocampal pyramidal neurons. Furthermore, immunoblot analysis showed that Rnd1 protein was localized in synaptosomal membrane fraction. Ectopical overexpression of Rnd1 in cultured rat hippocampal neurons promoted the elongation of dendritic spines. On the other hand, suppression of endogenous Rnd1 level by antisense oligonucleotide of Rnd1 caused the increase in the percentage of headless protrusions accompanied by the reduction in the spine number and spine width and shortened the length of the headless protrusions. These results indicate that Rnd1 plays a role in spine formation in the developmental synaptogenic stage.
Different Roles for Orbitofrontal Cortex and Basolateral Amygdala in a Reinforcer Devaluation Task
Authors: Pickens Charles L. , Saddoris Michael P. , Setlow Barry , Gallagher Michela , Holland Peter C. , Schoenbaum Geoffrey
Published: April 2018

The orbitofrontal cortex (OFC) and basolateral amygdala (BLA) are critical for using learned representations of outcomes to guide behavior. Neurophysiological findings suggest complementary roles in which the BLA acquires associations between cues and outcomes and the OFC subsequently uses them to guide behavior. Here, we have used a reinforcer devaluation paradigm to test this hypothesis. In this paradigm, rats are first trained to associate a light conditioned stimulus (CS) with a food outcome, and then the food is devalued by pairing it with illness. After this devaluation procedure, responding to the CS is assessed in a single probe session. Previously, we have shown that BLA and OFC lesions made before training do not affect the acquisition of conditioned responding but do impair the sensitivity of that responding to reinforcer devaluation. Rats with such lesions fail to exhibit the spontaneous decrease in conditioned responding to the light cue observed in controls in the probe test. Here, we have extended those findings by showing that performance in the probe test is impaired by OFC lesions made after light-food conditioning but not by BLA lesions made after that training. These findings indicate that the OFC and BLA play different roles in mediating normal goal-directed performance in this, and likely other, settings. The BLA seems critical to forming representations linking cues to the incentive properties of outcomes but not for maintaining these representations in memory, updating them with new information, or for expressing them in behavior. In contrast, the OFC seems essential for one or more of these latter processes.
Analgesia Induced by Dietary Restriction Is Mediated by the κ-Opioid System
Authors: de los Santos-Arteaga Mercedes , Sierra-Domínguez Sergio A. , Fontanella German H. , Delgado-García José M. , Carrión Ángel M.
Published: April 2018

Progress in the control and treatment of pain may be facilitated by a better understanding of mechanisms underlying nociceptive processing. Here we show that mice subjected to an intermittent fasting diet (IFD) display markedly reduced responses in models of thermal and visceral pain compared with mice fedad libitum(AL). Pharmacological analyses suggest that a change in the endogenous κ-opioid system underlies IFD-induced analgesia. The levels of prodynorphin mRNA and κ-opioid receptors in the spinal cord are higher in IFD than in AL mice. Furthermore, in spinal cord nuclear protein extracts, the activity of the transcriptional repressor DREAM (downstream regulatory element antagonist modulator), the main regulator of prodynorphin expression, is lower in IFD than in AL mice. Finally, c-Fos expression in dorsal spinal cord after noxious stimulation is significantly lower in IFD than in AL animals, indicating that dynorphin could block nociceptive information at the spinal cord. These results suggest that dietary restriction together with administration of κ-opioid agonists could be useful as a new therapeutic approach for pain relief.
Early Skill Learning Is Expressed through Selection and Tuning of Cortically Represented Muscle Synergies
Authors: Kargo William J. , Nitz Douglas A.
Published: April 2018

Skill learning may be based on integrating and adapting movement building blocks organized in the CNS. We examined at what level integration and adaptation occur during early skill learning, the level of individual muscles, muscle synergies or combinations of synergies through time, and whether these operations are expressed through the primary motor cortex (M1). Forelimb muscle and M1 cell activity were recorded over the first day of training on a reach-to-grasp task in rodents. Independent components analysis was used to assess how well muscle activation patterns could be described as time-varying combinations of synergies. In 3 of 11 animals, prereach M1 activity predicted the activation of different combinations of independent components (ICs) to perform the task. With training, animals increasingly adopted postures and prereach patterns of M1 activity that supported activation of the more successful combination. With training, animals also adjusted the activation magnitude (6 of 11 animals) and weights (11 of 11) of specific ICs that constituted the selected combination. Weights represent how IC activation patterns were distributed to forelimb muscles; this distribution pattern was adapted with training. M1 cells (37 of 100) had task-related firing rates that were significantly correlated with IC activation patterns. Changes in M1 firing rates were associated with corresponding changes in either the activation magnitude or weights of the correlated IC. Our data suggest that early skill learning is expressed through selection and tuning of M1 firing rates, which specify time-varying patterns of synergistic muscle contractions in the limb.
Cell-Type-Specific Contributions of Medial Prefrontal Neurons to Flexible Behaviors
Authors: Nakayama Hirofumi , Ibañez-Tallon Ines , Heintz Nathaniel
Published: April 2018

Behavioral flexibility and impulse control are necessary for successful execution of adaptive behavior. They are impaired in patients with damage to the prefrontal cortex (PFC) and in some clinically important conditions, such as obsessive-compulsive disorder. Although the medial prefrontal cortex (mPFC) has been investigated as a critical structure for behavioral flexibility and impulse control, the contribution of the underlying pyramidal neuron cell types in the mPFC remained to be understood. Here we show that interneuron-mediated local inactivation of pyramidal neurons in the mPFC of male and female mice induces both premature responses and choice bias, and establish that these impulsive and compulsive responses are modulated independently. Cell-type-specific photoinhibition of pyramidal deep layer corticostriatal or corticothalamic neurons reduces behavioral flexibility without inducing premature responses. Together, our data confirm the role of corticostriatal neurons in behavioral flexibility and demonstrate that flexible behaviors are also modulated by direct projections from deep layer corticothalamic neurons in the mPFC to midline thalamic nuclei.

SIGNIFICANCE STATEMENTBehavioral flexibility and impulse control are indispensable for animals to adapt to changes in the environment and often affected in patients with PFC damage and obsessive-compulsive disorder. We used a probabilistic reversal task to dissect the underlying neural circuitry in the mPFC. Through characterization of the three major pyramidal cell types in the mPFC with optogenetic silencing, we demonstrated that corticostriatal and corticothalamic but not corticocortical pyramidal neurons are temporally recruited for behavioral flexibility. Together, our findings confirm the role of corticostriatal projections in cognitive flexibility and identify corticothalamic neurons as equally important for behavioral flexibility.
Mineralogical and geochemical variation in stream sediments impacted by acid mine drainage is related to hydro-geomorphic setting
Authors: Singer David M. , Jefferson Anne J. , Traub Eric L. , Perdrial Nicolas
Published: April 2018

Acid mine drainage (AMD) discharge has severe, long lasting impacts on water quality and stream ecology in affected watersheds due in part to the dynamic relationship between toxic metals (e.g. Al, Mn, and Cu) and Fe(III) oxy-hydroxides. Localized areas of biogeochemical activity that can mediate mineralogical transformation changes and cause metal release are potentially linked to stream geomorphology. This relationship has not been previously considered with respect to potential longitudinal variation within an impacted stream. The current work aims to determine how Fe(III) (oxy)-hydroxide speciation and distribution, and pore water chemistry in an AMD-impacted streambed, are affected by the presence of two geomorphic structures (a debris dam and step-pool sequence) in an Ohio watershed impacted by historical coal mining. In terms of solid phase mineralogy and geochemistry, in both the tributary and main stem, goethite was the dominant Fe-bearing phase throughout the AMD deposit depth in cores taken upstream of the geomorphic structures, whereas poorly-crystalline phases dominated downstream of the structures, despite the presence of Fe in the reducible fraction. The concentrations and distribution of extractable Al, Mn, and Cu were also different upstream versus downstream of each structure. Pore water Fe and Mn concentrations were higher downstream of the structures than upstream. Strong downward hydraulic gradients were present above the debris dam and in step-pool 1, whereas weaker upward hydraulic gradients were present below the debris dam and in step-pool 2. This work highlights that AMD deposit speciation and distribution, and pore water chemistry, are not spatially uniform within stream reaches, potentially as a result of groundwater-stream exchange-facilitated interactions in the presence of AMD-derived materials.
Growth trajectory and pubertal tempo from birth till final height in a girl with Wolf-Hirschhorn syndrome
Authors: Siew Jia Xuan , Yap Fabian
Published: April 2018

Growth anomaly is a prominent feature in Wolf-Hirschhorn syndrome (WHS), a rare congenital disorder caused by variable deletion of chromosome 4p. While growth charts have been developed for WHS patients 0–4 years of age and growth data available for Japanese WHS patients 0–17 years, information on pubertal growth and final height among WHS children remain lacking. Growth hormone (GH) therapy has been reported in two GH-sufficient children with WHS, allowing for pre-puberty catch up growth; however, pubertal growth and final height information was also unavailable. We describe the complete growth journey of a GH-sufficient girl with WHS from birth until final height (FH), in relation to her mid parental height (MPH) and target range (TR). Her growth trajectory and pubertal changes during childhood, when she was treated with growth hormone (GH) from 3 years 8 months old till 6 months post-menarche at age 11 years was fully detailed.

Learning points:

Pubertal growth characteristics and FH information in WHS is lacking.

While pre-pubertal growth may be improved by GH, GH therapy may not translate to improvement in FH in WHS patients.

Longitudinal growth, puberty and FH data of more WHS patients may improve the understanding of growth in its various phases (infancy/childhood/puberty).
AŞAMALI ÇÜRÜK TEDAVİSİ
Authors: OZ Fatma Dilsad , GÖKALP Saadet
Published: April 2018

Günümüzde diş dokusunun
sağlıklı olarak kalmasında pulpanın önemi daha iyi anlaşıldıkça, diş hekimleri
çürük temizlenmesi sırasında pulpa ekspoz olsa bile pulpanın canlılığının
korunması için daha çok çaba sarf etmeye başlamışlardır. Çünkü pulpasız dişlerde
dişin kırılması gibi kritik komplikasyonlar ortaya çıkabilmektedir. Diş
hekimliği uygulamalarında diş hekimleri, eğer çürük tamamen uzaklaştırılacaksa
pulpa ekspozu ile sonuçlanabilecek derin çürüklerle çok sık karşılaşırlar.
Pulpanın doğal rejenerasyon yeteneğinin çok yüksek olduğu araştırmacılar
tarafından gözlenmektedir. Direk pulpa kaplaması tipik olarak pulpanın
korunması için uygulanır. Bununla birlikte çürük kaldırılmasına bağlı olarak
ekspoz olan pulpaya direk pulpa kaplaması uygulamasına alternatif olarak çürük
dokunun tamamı kaldırılmadan ilk randevude yumuşak dentinin sadece bir kısmı
kaldırılarak kavite  geçici restore
edilir ve bir süre sonra tekrar açılır. İleri ekskavasyon bu randevuda yapılır
ve kavite kalıcı olarak restore edilir. Bu uygulamanın amacı lezyonun
ilerlemesini durdurmaktır ve pulpal ekspoz olmadan tersiyer dentin oluşumuna
izin vermektir. Bu tedavi yöntemi ile ilgili literatürde bulunan pek çok
çalışma incelenerek tedavinin prognozu hakkında bilgi edinilmiştir.
Das grundlegend reformierte Wertpapierhandelsgesetz – Umsetzung von MiFID II (Conduct of Business im Kundenverhältnis)
Authors: Grundmann Stefan
Published: April 2018

Das Wertpapierhandelsgesetz (WpHG) erlebt mit dem 2. Finanzmarktnovellierungsgesetz zum Jahresbeginn 2018 die wohl grundlegendste Reform seiner gut zwanzigjährigen Geschichte – insbesondere, wenn man die noch während des Umsetzungszeitraums stattgefundene Auslagerung des gesamten Rechts der Marktintegrität und Ad-hoc-Publizität hinzudenkt. Deutlicher Ausdruck von alldem ist die umfassende neue Nummerierung des Gesetzes, von der auch im Folgenden ausgegangen wird. Inhaltlich zielt die Novelle vor allem auf ein noch tieferes Eingehen auf die individuellen Verhältnisse des jeweiligen Anlegers (mit dem sog. Zielmarktkonzept) und auf eine noch intensivere Ausräumung von bzw. Warnung vor Interessenkonflikten (im Vergütungsregime, in Alternativmodellen der Beratung, in Warnung durch Aufklärung). Das prägende Umfeld bleibt europäisch, mit MiFID II und MiFIR als den Rechtsakten nochmals vertieft und noch stärker primäre Richtschnur bei der Anwendung.