bluuebunny/crossref_metadata_2025_split huggingface dataset:
Long-Lasting GABA-Mediated Depolarization Evoked by High-Frequency Stimulation in Pyramidal Neurons of Rat Hippocampal Slice Is Attributable to a Network-Driven, Bicarbonate-Dependent K+Transient
Authors: Kaila Kai , Lamsa Karri , Smirnov Sergei , Taira Tomi , Voipio Juha 
Published: April 2018

Biphasic GABAA-mediated postsynaptic responses can be readily evoked in CA1 pyramidal neurons of rat hippocampal slices by high-frequency stimulus (HFS) trains in the presence of ionotropic glutamate receptor antagonists. In the present experiments with sharp microelectrodes, whole-cell techniques, and K+-selective microelectrodes, an HFS train (40 pulses at 100 Hz) applied in stratum radiatum close to the recording site evoked a brief hyperpolarizing IPSP (hIPSP), which turned into a prolonged (2–3 sec) depolarization (GABA-mediateddepolarizingpostsynapticpotential; GDPSP). TheI–Vrelationships of the postsynaptic currents (hIPSC and GDPSC) had distinct characteristics: the hIPSC and the early GDPSC showed outward rectification, whereas the late GDPSC was reduced with positive voltage steps to zero or beyond (inward rectification), but often no clear reversal was seen. That two distinct currents contribute to the generation of the GDPSP was also evident from the finding that a second HFS train at peak or late GDPSP induced a prompt GABAA-mediated hyperpolarization. The GDPSP/C was dependent on the availability of bicarbonate, but not on interstitial or intrapyramidal carbonic anhydrase activity.The HFS train evoked a rapid GABAA-mediated bicarbonate-dependent increase in the extracellular K+concentration ([K+]o), and the GDPSP followed the K+transient in a sub-Nernstian manner. The spatial and pharmacological characteristics of the [K+]oshift indicated that it is generated by a local network of GABAergic interneurons. The brief ascending phase of the GDPSP is linked to a K+-dependent accumulation of intracellular Cl−. Thereafter, a nonsynaptic mechanism, a direct depolarizing effect of the [K+]oshift, is responsible for the most conspicuous characteristics of the GDPSP: its large amplitude and prolonged duration.
Specific C-Receptors for Itch in Human Skin
Authors: Schmelz Martin , Schmidt Roland , Bickel Andreas , Handwerker Hermann O. , Torebjörk H. Erik 
Published: April 2018

In microneurography experiments 56 unmyelinated nerve fibers were studied in the cutaneous branch of the peroneal nerve of healthy volunteers. Units were identified with the “marking” technique as mechanically and heat-responsive (CMH;n= 30), heat-responsive (CH;n= 13), or unresponsive to mechanical and heat stimulation (CMiHi;n= 13). None of the units showed spontaneous activity.These units were tested for responsiveness to iontophoresis of histamine (1 mA, 20 sec) from a small probe (diameter, 6 mm), which induced itch sensations lasting several minutes. Twenty-three units were unresponsive to histamine, and 25 units responded weakly with a few spike discharges after iontophoresis.Eight units, however, responded with sustained discharges to histamine, and their discharge patterns were matching the time course of the itch sensations. All C-units in this group were mechanically insensitive, and five of them were heat-responsive. They had very low conduction velocities of only 0.5 m/sec, on average, which is significantly lower than conduction velocities of the “polymodal” CMH units. This slow conduction velocities attributable to small axon diameters may be one reason why these units have not been encountered in previous studies. Histamine-sensitive C-units had very large innervation territories extending up to a diameter of 85 mm on the lower leg.We conclude that these C-fibers represent a new class of afferent nerve fibers with particularly thin axons but excessive terminal branching. This type of C-fiber probably represents the afferent units long searched for mediating itch sensations.
Responses to the Sensory Properties of Fat of Neurons in the Primate Orbitofrontal Cortex
Authors: Rolls Edmund T. , Critchley Hugo D. , Browning Andrew S. , Hernadi Istvan , Lenard Laszlo 
Published: April 2018

The primate orbitofrontal cortex is a site of convergence of information from primary taste, olfactory, and somatosensory cortical areas. We describe the responses of a population of single neurons in the orbitofrontal cortex that responds to fat in the mouth. The neurons respond, when fatty foods are being eaten, to pure fat such as glyceryl trioleate and also to substances with a similar texture but different chemical composition such as paraffin oil (hydrocarbon) and silicone oil [Si(CH3)2O)n]. This is evidence that the neurons respond to the oral texture of fat, sensed by the somatosensory system. Some of the population of neurons respond unimodally to the texture of fat. Other single neurons show convergence of taste inputs, and others of olfactory inputs, onto single neurons that respond to fat. For example, neurons were found that responded to the mouth feel of fat and the taste of monosodium glutamate (both found in milk), or to the mouth feel of fat and to odor. Feeding to satiety reduces the responses of these neurons to the fatty food eaten, but the neurons still respond to some other foods that have not been fed to satiety. Thus sensory-specific satiety for fat is represented in the responses of single neurons in the primate orbitofrontal cortex.Fat is an important constituent of food that affects its palatability and nutritional effects. The findings described provide evidence that the reward value (or pleasantness) of the mouth feel of fat is represented in the primate orbitofrontal cortex and that the representation is relevant to appetite.
Sex Steroid Regulation of the Inflammatory Response: Sympathoadrenal Dependence in the Female Rat
Authors: Green Paul G. , Dahlqvist Solbritt Rantapää , Isenberg William M. , Strausbaugh Holly J. , Miao Frederick J.-P. , Levine Jon D. 
Published: April 2018

To investigate the role of sex steroids in sex differences in the response of rats to the potent inflammatory mediator bradykinin (BK), we evaluated the effect of sex steroid manipulation on the magnitude of BK-induced synovial plasma extravasation (PE). The magnitude of BK-induced PE is markedly less in females. Ovariectomy of female rats increased BK-induced PE, and administration of 17β-estradiol to ovariectomized female rats reconstituted the female phenotype. Castration in male rats decreased BK-induced PE, and administration of testosterone or its nonmetabolizable analog dihydrotestosterone reconstituted the male phenotype. The results of these experiments strongly support the role of both male and female sex steroids in sex differences in the inflammatory response.Because the stress axes are sexually dimorphic and are important in the regulation of the inflammatory response, we evaluated the contribution of the hypothalamic–pituitary–adrenal and the sympathoadrenal axes to sex differences in BK-induced PE. Neither hypophysectomy nor inhibition of corticosteroid synthesis affected BK-induced PE in female or male rats. Adrenal denervation in females produced the same magnitude increase in BK-induced PE as adrenalectomy or ovariectomy, suggesting that the adrenal medullary factor(s) in females may account for the female sex steroid effect on BK-induced PE. Furthermore, we have demonstrated that in female but not male rats, estrogen receptor α immunoreactivity is present on medullary but not cortical cells in the adrenal gland. These data suggest that regulation of the inflammatory response by female sex steroids is strongly dependent on the sympathoadrenal axis, possibly by its action on estrogen receptors on adrenal medullary cells.
Presynaptically Located CB1 Cannabinoid Receptors Regulate GABA Release from Axon Terminals of Specific Hippocampal Interneurons
Authors: Katona István , Sperlágh Beáta , Sı́k Attila , Käfalvi Attila , Vizi E. Sylvester , Mackie Ken , Freund Tamás F. 
Published: April 2018

To understand the functional significance and mechanisms of action in the CNS of endogenous and exogenous cannabinoids, it is crucial to identify the neural elements that serve as the structural substrate of these actions. We used a recently developed antibody against the CB1 cannabinoid receptor to study this question in hippocampal networks. Interneurons with features typical of basket cells showed a selective, intense staining for CB1 in all hippocampal subfields and layers. Most of them (85.6%) contained cholecystokinin (CCK), which corresponded to 96.9% of all CCK-positive interneurons, whereas only 4.6% of the parvalbumin (PV)-containing basket cells expressed CB1. Accordingly, electron microscopy revealed that CB1-immunoreactive axon terminals of CCK-containing basket cells surrounded the somata and proximal dendrites of pyramidal neurons, whereas PV-positive basket cell terminals in similar locations were negative for CB1. The synthetic cannabinoid agonist WIN 55,212-2 (0.01–3 μm) reduced dose-dependently the electrical field stimulation-induced [3H]GABA release from superfused hippocampal slices, with an EC50value of 0.041 μm. Inhibition of GABA release by WIN 55,212-2 was not mediated by inhibition of glutamatergic transmission because the WIN 55,212-2 effect was not reduced by the glutamate blockers AP5 and CNQX. In contrast, the CB1 cannabinoid receptor antagonist SR 141716A (1 μm) prevented this effect, whereas by itself it did not change the outflow of [3H]GABA.These results suggest that cannabinoid-mediated modulation of hippocampal interneuron networks operate largely via presynaptic receptors on CCK-immunoreactive basket cell terminals. Reduction of GABA release from these terminals is the likely mechanism by which both endogenous and exogenous CB1 ligands interfere with hippocampal network oscillations and associated cognitive functions.
Interleukin-1β Immunoreactivity and Microglia Are Enhanced in the Rat Hippocampus by Focal Kainate Application: Functional Evidence for Enhancement of Electrographic Seizures
Authors: Vezzani Annamaria , Conti Mirko , De Luigi Ada , Ravizza Teresa , Moneta Daniela , Marchesi Francesco , De Simoni Maria Grazia 
Published: April 2018

Using immunocytochemistry and ELISA, we investigated the production of interleukin (IL)-1β in the rat hippocampus after focal application of kainic acid inducing electroencephalographic (EEG) seizures and CA3 neuronal cell loss. Next, we studied whether EEG seizures per se induced IL-1β and microglia changes in the hippocampus using bicuculline as a nonexcitotoxic convulsant agent. Finally, to address the functional role of this cytokine, we measured the effect of human recombinant (hr)IL-1β on seizure activity as one marker of the response to kainate.Three and 24 hr after unilateral intrahippocampal application of 0.19 nmol of kainate, IL-1β immunoreactivity was enhanced in glia in the injected and the contralateral hippocampi. At 24 hr, IL-1β concentration increased by 16-fold (p< 0.01) in the injected hippocampus. Reactive microglia was enhanced with a pattern similar to IL-1β immunoreactivity. Intrahippocampal application of 0.77 nmol of bicuculline methiodide, which induces EEG seizures but not cell loss, enhanced IL-1β immunoreactivity and microglia, although to a less extent and for a shorter time compared with kainate. One nanogram of (hr)IL-1β intrahippocampally injected 10 min before kainate enhanced by 226% the time spent in seizures (p< 0.01). This effect was blocked by coinjection of 1 μg (hr)IL-1β receptor antagonist or 0.1 ng of 3-((+)-2-carboxypiperazin-4-yl)-propyl-1-phosphonate, selective antagonists of IL-1β and NMDA receptors, respectively.Thus, convulsant and/or excitotoxic stimuli increase the production of IL-1β in microglia-like cells in the hippocampus. In addition, exogenous application of IL-1β prolongs kainate-induced hippocampal EEG seizures by enhancing glutamatergic neurotransmission.
Pharmacological Isolation of the Synaptic and Nonsynaptic Components of the GABA-Mediated Biphasic Response in Rat CA1 Hippocampal Pyramidal Cells
Authors: Smirnov Sergei , Paalasmaa Pekka , Uusisaari Marylka , Voipio Juha , Kaila Kai 
Published: April 2018

High-frequency stimulation (HFS) applied to stratum radiatum of a rat hippocampal slice in the presence of ionotropic glutamate receptor antagonists evokes a biphasic GABAAreceptor-dependent response in CA1 pyramidal neurons, with a brief hyperpolarizing IPSP (hIPSP) followed by a long-lasting depolarization. We show now that it is possible to pharmacologically separate the hIPSP and late depolarization from one another. In neurons intracellularly perfused for 1–2 hr with F−as the major anion and no ATP, the hIPSP (and the corresponding current, hIPSC) evoked by HFS was blocked, whereas neither the late depolarization nor its underlying current was attenuated. In contrast, internal perfusion with a high concentration (5 mm) of the impermeant lidocaine derivative QX-314 selectively abolished the depolarizing component of the biphasic response and also strongly reduced depolarizations evoked by extracellular microinjection of K+. Bath application of quinine (0.2–0.5 mm) or quinidine (0.1 mm) resulted in a pronounced inhibition of the HFS-induced extracellular K+concentration ([K+]o) transient but not of the bicarbonate-dependent alkaline shift in extracellular pH. The attenuation of the [K+]otransient was closely paralleled by a suppression of the HFS-evoked depolarization but not of the hIPSP. Quini(di)ne did not affect depolarizations induced by exogenous K+either.These data provide direct pharmacological evidence for the view that the HFS-induced biphasic response of the pyramidal neuron is composed of mechanistically distinct components: a direct GABAAreceptor-mediated phase, which is followed by a slow, nonsynaptic [K+]o-mediated depolarization. The bicarbonate-dependent, activity-induced [K+]otransient can be blocked by quini(di)ne, whereas its depolarizing action in the pyramidal neuron is inhibited by internal QX-314. The presence of fundamentally distinct components in GABAAreceptor-mediated actions evoked by HFS calls for further investigations of their functional role(s) in standard experimental maneuvers, such as those used in studies of synaptic plasticity and induction ofγoscillations.
The bHLH GeneHes1as a Repressor of the Neuronal Commitment of CNS Stem Cells
Authors: Nakamura Yuki , Sakakibara Shin-ichi , Miyata Takaki , Ogawa Masaharu , Shimazaki Takuya , Weiss Samuel , Kageyama Ryoichiro , Okano Hideyuki 
Published: April 2018

Hes1is one of the basic helix-loop-helix transcription factors that regulate mammalian CNS development, and its loss- and gain-of-function phenotypes indicate that it negatively regulates neuronal differentiation.Here we report thatHes1−/−mice expressed both early (TuJ1 and Hu) and late (MAP2 and Neurofilament) neuronal markers prematurely, and that there were approximately twice the normal number of neurons in theHes1−/−brain during early neural development. However, immunochemical analyses of sections and dissociated cells using neural progenitor markers, including nestin, failed to detect any changes inHes1−/−progenitor population. Therefore, further characterization of neural progenitor cells that discriminated between multipotent and monopotent cells was performed using two culture methods, low-density culture, and a neurosphere assay. We demonstrate that the self-renewal activity of multipotent progenitor cells was reduced in theHes1−/−brain, and that their subsequent commitment to the neuronal lineage was accelerated. TheHes1−/−neuronal progenitor cells were functionally abnormal, in that they divided, on average, only once, and then generated two neurons, (instead of one progenitor cell and one neuron), whereas wild-type progenitor cells divided more. In addition, someHes1−/−progenitors followed an apoptotic fate. The overproduction of neurons in the earlyHes1−/−brains may reflect this premature and immediate generation of neurons as well as a net increase in the number of neuronal progenitor cells.Taken together, we conclude thatHes1is important for maintaining the self-renewing ability of progenitors and for repressing the commitment of multipotent progenitor cells to a neuronal fate, which is critical for the correct number of neurons to be produced and for the establishment of normal neuronal function.
Reflex Excitability Regulates Prepulse Inhibition
Authors: Schicatano Edward J. , Peshori Kavita R. , Gopalaswamy Ramesh , Sahay Eva , Evinger Craig 
Published: April 2018

Presentation of a weak stimulus, a prepulse, before a reflex-evoking stimulus decreases the amplitude of the reflex response relative to reflex amplitude evoked without a preceding prepulse. For example, presenting a brief tone before a trigeminal blink-eliciting stimulus significantly reduces reflex blink amplitude. A common explanation of such data are that sensory processing of the prepulse modifies reflex circuit behavior. The current study investigates the converse hypothesis that the intrinsic characteristics of the reflex circuit rather than prepulse processing determine prepulse modification of trigeminal and acoustic reflex blinks.Unilateral lesions of substantia nigra pars compacta neurons created rats with hyperexcitable trigeminal reflex blinks but normally excitable acoustic reflex blinks. In control rats, presentation of a prepulse reduced the amplitude of both trigeminal and acoustic reflex blinks. In 6-OHDA-lesioned rats, however, the same acoustic prepulse facilitated trigeminal reflex blinks but inhibited acoustic reflex blinks. The magnitude of prepulse modification correlated with reflex excitability.Humans exhibited the same pattern of prepulse modification. An acoustic prepulse facilitated the trigeminal reflex blinks of subjects with hyperexcitable trigeminal reflex blinks caused by Parkinson's disease. The same prepulse inhibited trigeminal reflex blinks of age-matched control subjects. Prepulse modification also correlated with trigeminal reflex blink excitability. These data show that reflex modification by a prepulse reflects the intrinsic characteristics of the reflex circuit rather than an external adjustment of the reflex circuit by the prepulse.
Opioid Modulation of Recurrent Excitation in the Hippocampal Dentate Gyrus
Authors: Terman Gregory W. , Drake Carrie T. , Simmons Michele L. , Milner Teresa A. , Chavkin Charles 
Published: April 2018

κ opioid receptor activation inhibits granule cell-mediated excitatory neurotransmission in the hippocampal formation via a decrease in glutamate release from both perforant path and mossy fiber terminals. We now report a third, anatomically and pharmacologically distinct site of such κ opioid inhibition within the hippocampus. Granule cell population responses to selective stimulation of an excitatory hilar pathway were decreased by the κ1opioid receptor agonist U69,593, an effect blocked by the κ1antagonist norbinaltorphimine. U69,593 also inhibited hilar path induced long-term potentiation (LTP) of granule cell responses. LTP in this pathway was also blocked by the NMDA receptor antagonistd-2-amino-5-phosphonovalerate, unlike granule cell mossy fiber LTP in CA3.The κ opioid peptide dynorphin is present in hilar mossy fiber collaterals. Ultrastructural analysis of these collaterals demonstrated dynorphin-containing vesicles in asymmetric synapses formed between axon terminals and granule cell dendrites, suggesting direct granule cell–granule cell connections. Evoked release of endogenous dynorphin within the hilus was effective in reducing hilar excitation of granule cells, although this release, in contrast to the release of dynorphin in the dentate molecular layer, was not dependent on L-type calcium channels.No hilar path excitation was observed in the absence of bicuculline, suggesting a strong GABAA-mediated inhibition of this pathway. However, hilar path activity could be seen after LTP, with or without bicuculline. Thus, κ opioids can inhibit granule cell recurrent excitation, likely via effects on excitatory mossy fiber collaterals. Such collaterals are thought to be important in mediating temporal lobe epilepsy.
Adult Learning Deficits after Neonatal Exposure tod-Methamphetamine: Selective Effects on Spatial Navigation and Memory
Authors: Vorhees Charles V. , Inman-Wood Sandra L. , Morford LaRonda L. , Broening Harry W. , Fukumura Masao , Moran Mary S. 
Published: April 2018

The effects of neonatald-methamphetamine (MA) treatment on cued and spatial learning and memory were investigated. MA was administered to neonatal rats on postnatal days 11–20. All groups received four subcutaneous injections per day. Group MA40–4 received 40 mg · kg−1 · d−1of MA in four divided doses (10 mg/kg per injection). Group MA40–2 received 40 mg · kg−1 · d−1of MA in two divided (20 mg/kg/injection) and saline for the other two injections per day. Controls received saline for four injections per day. As adults, both MA groups showed no differences in swimming ability in a straight swimming channel. The MA40–4 group showed no differences in cued learning, but was impaired in hidden platform learning in the Morris water maze on acquisition. They also showed reduced memory performance on probe trials. Similar trends were seen on reversal learning and reversal probe trials. Reduced platform-size learning trials caused spatial learning impairments to re-emerge in the MA40–4 group. The MA40–2 group showed no differences in straight channel swimming, but was slower at finding the visible platform during cued learning. They were also impaired during acquisition and memory trials in the Morris hidden platform maze. They showed a similar trend on reversal learning and memory trials, but were not different during reduced platform-size learning trials. When the MA40–2 group's performance on hidden platform learning and memory trials was adjusted for cued trial performance, the spatial learning deficits remained. Deficits of spatial learning and memory are a selective effect of neonatal methamphetamine treatment irrespective of other learning and performance variables.
Bidirectional Modulation of Exocytosis by Angiotensin II Involves Multiple G-Protein-Regulated Transduction Pathways in Chromaffin Cells
Authors: Teschemacher Anja G. , Seward Elizabeth P. 
Published: April 2018

Angiotensin II (AngII) receptors couple to a multitude of different types of G-proteins resulting in activation of numerous signaling pathways. In this study we examined the consequences of this promiscuous G-protein coupling on secretion. Chromaffin cells were voltage-clamped at −80 mV in perforated-patch configuration, and Ca2+-dependent exocytosis was evoked with brief voltage steps to +20 mV. Vesicle fusion was monitored by changes in membrane capacitance (ΔCm), and released catecholamine was detected with single-cell amperometry. Ca2+signaling was studied by recording voltage-dependent Ca2+currents (ICa) and by measuring intracellular Ca2+([Ca2+]i) with fura-2 AM.AngII inhibitedICa(IC50= 0.3 nm) in a voltage-dependent, pertussis toxin (PTX)-sensitive manner consistent with Gi/o-protein coupling to Ca2+channels. ΔCmwas modulated bi-directionally; subnanomolar AngII inhibited depolarization-evoked exocytosis, whereas higher concentrations, in spite ofICainhibition, potentiated ΔCmfivefold (EC50= 3.4 nm). Potentiation of exocytosis by AngII involved activation of phospholipase C (PLC) and Ca2+mobilization from internal stores. PTX treatment did not affect AngII-dependent Ca2+mobilization or facilitation of exocytosis. However, protein kinase C (PKC) inhibitors decreased the facilitatory effects but not the inhibitory effects of AngII on stimulus-secretion coupling. The AngII type 1 receptor (AT1R) antagonist losartan blocked both inhibition and facilitation of secretion by AngII. The results of this study show that activation of multiple types of G-proteins and transduction pathways by a single neuromodulator acting through one receptor type can produce concentration-dependent, bi-directional regulation of exocytosis.