bluuebunny/crossref_metadata_2025 huggingface dataset:
Assessment of Inhibition and Epileptiform Activity in the Septal Dentate Gyrus of Freely Behaving Rats During the First Week After Kainate Treatment
Authors: Hellier Jennifer L. , Patrylo Peter R. , Dou Ping , Nett Michelle , Rose Gregory M. , Dudek F. Edward
Published: April 2018

Mossy fiber reorganization has been hypothesized to restore inhibition months after kainate-induced status epilepticus. The time course of recovery of inhibition after kainate treatment, however, is not well established. We tested the hypothesis that if inhibition is decreased after kainate treatment, it is restored within the first week when little or no mossy fiber reorganization has occurred. Chronicin vivorecordings of the septal dentate gyrus were performed in rats before and 1, 4, and 7–8 d after kainate (multiple injections of 5 mg/kg, i.p.;n= 17) or saline (n= 11) treatment. Single and paired-pulse stimuli were used to assess synaptic inhibition. The first day after kainate treatment, only a fraction of rats showed multiple population spikes (35%), prolonged field postsynaptic potentials (76%), and loss of paired-pulse inhibition (29%) to perforant path stimulation. Thus, inhibition was reduced in only some of the kainate-treated rats. By 7–8 d after treatment, nearly all kainate-treated rats showed partial or full recovery in these response characteristics. Histological analysis indicated that kainate-treated rats had a significant decrease in the number of hilar neurons compared to controls, but Timm staining showed little to no mossy fiber reorganization. These results suggest that a decrease in synaptic inhibition in the septal dentate gyrus is not a prerequisite for epileptogenesis and that most of the recovery of inhibition occurs before robust Timm staining in the inner molecular layer.
Activity of Midbrain Reticular Formation and Neocortex during the Progression of Human Non-Rapid Eye Movement Sleep
Authors: Kajimura Naofumi , Uchiyama Makoto , Takayama Yutaka , Uchida Sunao , Uema Takeshi , Kato Masaaki , Sekimoto Masanori , Watanabe Tsuyoshi , Nakajima Toru , Horikoshi Satoru , Ogawa Kenichi , Nishikawa Masami , Hiroki Masahiko , Kudo Yoshihisa , Matsuda Hiroshi , Okawa Masako , Takahashi Kiyohisa
Published: April 2018

To clarify the neural correlates and brain activity during the progression of human non-rapid eye movement (NREM) sleep, we examined the absolute regional cerebral blood flow (rCBF) during light and deep NREM sleep and during wakefulness in normal humans using positron emission tomography with H215O. Relative changes in rCBF during light and deep NREM sleep in comparison to the rCBF during wakefulness were also analyzed. During light NREM sleep, the rCBF in the midbrain, in contrast to that in the pons and thalamic nuclei, did not decrease when compared to that during wakefulness, whereas rCBF decreased in the left medial frontal gyrus, left inferior frontal gyrus, and left inferior parietal gyrus of the neocortex. During deep NREM sleep, the rCBF in the midbrain tegmentum decreased, and there was a marked and bilateral decrease in the rCBF in all neocortical regions except for the perirolandic areas and the occipital lobe. There have been three groups of brain structures, each representing one type of deactivation during the progression of NREM sleep. The activity of the midbrain reticular formation is maintained during light NREM sleep and therefore represents a key distinguishing characteristic between light and deep NREM sleep. Selective deactivation of heteromodal association cortices, including those related to language, occurs with increasingly deep NREM sleep, which supports the recent theory that sleep is not a global, but it is a local process of the brain.
Neural Representation of a Rhythm Depends on Its Interval Ratio
Authors: Sakai Katsuyuki , Hikosaka Okihide , Miyauchi Satoru , Takino Ryousuke , Tamada Tomoe , Iwata Nobue Kobayashi , Nielsen Mathew
Published: April 2018

Rhythm is determined solely by the relationship between the time intervals of a series of events. Psychological studies have proposed two types of rhythm representation depending on the interval ratio of the rhythm: metrical and nonmetrical representation for rhythms formed with small integer ratios and noninteger ratios, respectively. We used functional magnetic resonance imaging to test whether there are two neural representations of rhythm depending on the interval ratio. The subjects performed a short-term memory task for a seven-tone rhythm sequence, which was formed with 1:2:4, 1:2:3, or 1:2.5:3.5 ratios. The brain activities during the memory delay period were measured and compared with those during the retention of a control tone sequence, which had constant intertone intervals. The results showed two patterns of brain activations; the left premotor and parietal areas and right cerebellar anterior lobe were active for 1:2:4 and 1:2:3 rhythms, whereas the right prefrontal, premotor, and parietal areas together with the bilateral cerebellar posterior lobe were active for 1:2.5:3.5 rhythm. Analysis on individual subjects revealed that these activation patterns depended on the ratio of the rhythms that were produced by the subjects rather than the ratio of the presented rhythms, suggesting that the observed activations reflected the internal representation of rhythm. These results suggested that there are two neural representations for rhythm depending on the interval ratio, which correspond to metrical and nonmetrical representations.
Expression of α1bAdrenoceptor mRNA in Corticotropin-Releasing Hormone-Containing Cells of the Rat Hypothalamus and Its Regulation by Corticosterone
Authors: Day Heidi E. W. , Campeau Serge , Watson Stanley J. , Akil Huda
Published: April 2018

Considerable evidence supports a role for brainstem adrenergic and noradrenergic inputs to corticotropin-releasing hormone (CRH) cells of the hypothalamic paraventricular nucleus (PVN), in the control of hypothalamic–pituitary–adrenocortical (HPA) axis function. However, little is known about specific adrenoceptor (ADR) subtypes in CRH-containing cells of the PVN. Here we demonstrate, using dualin situhybridization, that mRNA encoding α1bADR is colocalized with CRH in the rat PVN. Furthermore, we confirm that these α1bADR mRNA-containing cells are stress-responsive, by colocalization with c-fos mRNA after restraint, swim, or immune stress.

To determine whether expression of α1bADR mRNA is influenced by circulating glucocorticoids, male rats underwent bilateral adrenalectomy (ADX) or sham surgery, and were killed after 1, 3, 7, or 14 d.In situhybridization revealed levels of α1bADR mRNA were increased in the PVN 7 and 14 d after ADX, but were not altered in the hippocampus, amygdala, or dorsal raphe. Additional rats underwent ADX or sham surgery and received a corticosterone pellet (10 or 50 mg) or placebo for 7 d. Corticosterone replacement (10 mg) reduced the ADX-induced increase in PVN α1bADR mRNA to control levels, whereas 50 mg of corticosterone replacement resulted in a decrease in PVN α1bADR mRNA as compared with all other groups. Furthermore, levels of plasma corticosterone were significantly correlated (inverse relationship) with α1bADR mRNA in the PVN.

We conclude that α1bADR mRNA is expressed in CRH-containing, stress-responsive cells of the PVN and is highly sensitive to circulating levels of corticosterone. Because activation of the α1Badrenoceptor is predominantly excitatory within the brain, we predict that this receptor plays an important role in facilitation of the HPA axis response.
Cholinergic Septal Afferent Terminals Preferentially Contact Neuropeptide Y-Containing Interneurons Compared to Parvalbumin-Containing Interneurons in the Rat Dentate Gyrus
Authors: Dougherty Karen D. , Milner Teresa A.
Published: April 2018

Septal cholinergic neurons may affect hippocampal memory encoding and retrieval by differentially targeting parvalbumin (PARV)-containing basket cells and neuropeptide Y (NPY) interneurons. Thus, the cellular associations of cholinergic efferents, identified by the low-affinity, p75 neurotrophin receptor (p75NTR), with interneurons containing either PARV or NPY in the hilus of the rat dentate gyrus were examined in single sections using dual labeling immunoelectron microscopy. Most profiles immunoreactive (IR) for PARV and NPY were perikaryal and dendritic and found within the infragranular and central hilar regions, respectively, whereas most profiles with p75NTR-labeling were unmyelinated axons and axon terminals. Although PARV-labeled profiles were more numerous, p75NTR-labeled axons and terminals contacted few PARV-IR profiles compared to NPY-labeled profiles (2% of 561 for PARV vs 12% of 433 for NPY). Moreover, structures targeted by p75NTR-IR axon terminals varied depending on the presence of PARV or NPY immunoreactivity. p75NTR-IR terminals primarily contacted PARV-IR dendrites (87%) compared to somata (13%); however, they contacted more NPY-IR somata (57%) than dendrites (43%). p75NTR-labeled terminals formed exclusively symmetric (inhibitory-type) synapses with PARV-IR somata and dendrites; however, they formed mostly symmetric but also asymmetric (excitatory-type) synapses with NPY-IR somata and dendrites. These results suggest that septal cholinergic efferents in the dentate gyrus: (1) preferentially innervate NPY-containing interneurons compared to PARV-containing basket cells; and (2) may provide a more powerful (i.e., somatic contacts), yet functionally diverse (i.e., asymmetric and symmetric synapses), modulation of NPY-containing interneurons. Moreover, they provide evidence that neurochemical subsets of hippocampal interneurons can be distinguished by afferent input.
Functional Attributes Discriminating Mechano-Insensitive and Mechano-Responsive C Nociceptors in Human Skin
Authors: Weidner C. , Schmelz M. , Schmidt R. , Hansson B. , Handwerker H. O. , Torebjörk H. E.
Published: April 2018

Microneurography was used in healthy human subjects to record action potentials from unmyelinated nerve fibers (C units) in cutaneous fascicles of the peroneal nerve.

Activity-dependent slowing (n= 96) and transcutaneous electrical thresholds (n= 67) were determined. Eight units were sympathetic efferents according to their responses to sympathetic reflex provocations. Mechano-heat-responsive C units (CMH) (n= 56) had thresholds to von Frey hair stimulation ≤90 mN (6.5 bar). Mechano-insensitive C units (n= 32) were unresponsive to 750 mN (18 bar). Twenty-six mechano-insensitive units responded to heat (CH), and the remaining six units did not respond to physical stimuli but were proven to be afferent by their response to intracutaneous capsaicin (CMiHi).

Mechano-insensitive units had significantly slower conduction velocity (0.81 ± 0.03 m/sec), and CH units had higher heat thresholds (48.0 ± 0.6°C) compared with CMH units (1.01 ± 0.01 m/sec; 40.7 ± 0.4°C). Transcutaneous electrical thresholds were <9 mA for CMH units and >35 mA for CH and CMiHiunits. Activity-dependent slowing was much more pronounced in mechano-insensitive than in mechano-responsive units, without overlap. Sympathetic efferent C units showed intermediate slowing, significantly different from CMH, and completely separate from CH and CMiHiunits. The activity-dependent slowing of conduction provides evidence for different membrane attributes of different classes of C fibers in humans.
The Myristoylated Protein Rapsyn is Cotargeted with the Nicotinic Acetylcholine Receptor to the Postsynaptic Membrane via the Exocytic Pathway
Authors: Marchand Sophie , Bignami Fabrizia , Stetzkowski-Marden Françoise , Cartaud Jean
Published: April 2018

Rapsyn, a 43 kDa protein required to cluster nicotinic acetylcholine receptors (AChRs) at the neuromuscular junction, is tightly associated with the postsynaptic membrane via an N-terminal myristoylated site. Recent studies have shown that some acylated proteins associate with the exocytic pathway to become targeted to their correct destination. In this work, we usedTorpedoelectrocyte to investigate the intracellular routing of rapsyn compared to those of AChR and Na,K-ATPase, the respective components of the innervated and noninnervated membranes. We previously demonstrated that these latter two proteins are sorted and targeted to plasma membrane via distinct populations of post-Golgi vesicles (Camus et al., 1998). Biochemical and immunoelectron microscopy analyses of various populations of post-Golgi vesicles immunopurified with magnetic beads led us to identify post-Golgi transport vesicles containing both rapsyn and AChR. These data suggest that rapsyn, as for AChR, specifically follows the exocytic pathway. Furthermore, immunogold-labeling experiments providedin situevidence that AChR and rapsyn are cotransported in the same post-Golgi vesicles. Taken together, our observations suggest that rapsyn and AChR are cotargeted to the postsynaptic membrane.
Role of Tissue Plasminogen Activator Receptor LRP in Hippocampal Long-Term Potentiation
Authors: Zhuo Min , Holtzman David M. , Li Yonghe , Osaka Hiroshi , DeMaro Joe , Jacquin Mark , Bu Guojun
Published: April 2018

The low-density lipoprotein (LDL) receptor-related protein (LRP) is a multifunctional endocytic receptor that is expressed abundantly in neurons of the CNS. Both LRP and several of its ligands, including tissue plasminogen activator (tPA), apolipoprotein E/lipoproteins, α2-macroglobulin, and the β-amyloid precursor protein, have been implicated in various neuronal functions and in the pathogenesis of Alzheimer's disease. It has been reported that induction of tPA expression may contribute to activity-dependent synaptic plasticity in the hippocampus and cerebellum. In addition, long-term potentiation (LTP) is significantly decreased in mice lacking tPA. Here we demonstrate that tPA receptor LRP is abundantly expressed in hippocampal neurons and participates in hippocampal LTP. Perfusion of hippocampal slices with receptor-associated protein (RAP), an antagonist for ligand interactions with LRP, significantly reduced late-phase LTP (L-LTP). In addition, RAP also blocked the enhancing effect of synaptic potentiation by exogenous tPA in hippocampal slices prepared from tPA knock-out mice. Metabolic labeling and ligand binding analyses showed that both tPA and LRP are synthesized by hippocampal neurons and that LRP is the major cell surface receptor that binds tPA. Finally, we found that tPA binding to LRP in hippocampal neurons enhances the activity of cyclic AMP-dependent protein kinase, a key molecule that is known to be involved in L-LTP. Taken together, our results demonstrate that interactions between tPA and cell surface LRP are important for hippocampal L-LTP.
Arachidonic Acid Stimulates a Novel Cocaine-Sensitive Cation Conductance Associated with the Human Dopamine Transporter
Authors: Ingram Susan L. , Amara Susan G.
Published: April 2018

The dopamine transporter (DAT) exhibits several ionic currents that are either coupled to or uncoupled from the transport of substrate. Second messenger systems have been shown to modulate dopamine (DA) transport, however, the modulation of DAT-associated currents has not been studied in depth. Using the two-electrode voltage-clamp method to record fromXenopusoocytes expressing the human DAT, we examined the effects of arachidonic acid (AA) on membrane currents. AA (10–100 μm) stimulates a novel nonselective cation conductance seen only in oocytes expressing human DA transporter (hDAT). The AA-stimulated conductance is up to 50-fold greater than the current normally elicited by DA, but does not appear to arise from the modulation of previously described hDAT conductances, including the leak current and the current associated with electrogenic transport. In addition, DA dramatically potentiates and cocaine blocks the AA-stimulated DAT current. DA potentiates the AA-induced currents in the absence of sodium and chloride, indicating that these currents arise from processes distinct from those associated with substrate transport. The effects of AA were mimicked by other fatty acids with a rank order of potency correlated with their degree of unsaturation, suggesting that AA directly stimulates the novel cation current. Therefore, AA stimulation of this DAT-associated conductance may provide a novel mechanism for modulation of neuronal signaling.
Synaptic Depression and the Kinetics of Exocytosis in Retinal Bipolar Cells
Authors: Burrone Juan , Lagnado Leon
Published: April 2018

The capacitance technique was used to investigate exocytosis at the ribbon synapse of depolarizing bipolar cells from the goldfish retina. When the Ca2+current was activated strongly, the rapidly releasable pool of vesicles (RRP) was released with a single rate-constant of ∼300–500 sec−1. However, when the Ca2+current was activated weakly by depolarization in the physiological range (−45 to −25 mV), exocytosis from the RRP occurred in two phases. After the release of 20% or more of the RRP, the rate-constant of exocytosis fell by a factor of 4–10. Thus, synaptic depression was caused by a reduced sensitivity to Ca2+influx, as well as simple depletion of the RRP. In the resting state, the rate of exocytosis varied with the amplitude of the Ca2+current raised to the power of 2. In the depressed state, the sensitivity to Ca2+influx was reduced approximately fourfold. The initial phase of exocytosis accelerated e-fold for every 2.1 mV depolarization over the physiological range and averaged 120 sec−1at −25 mV.

The synapse of depolarizing bipolar cells therefore responds to a step depolarization in a manner similar to a high-pass filter. This transformation appears to be determined by the presence of rapidly releasable vesicles with differing sensitivities to Ca2+influx. This might occur if vesicles were docked to the plasma membrane at different distances from Ca2+channels. These results suggest that the ribbon synapse of depolarizing bipolar cells may be a site of adaptation in the retina.
Proteasome Involvement and Accumulation of Ubiquitinated Proteins in Cerebellar Granule Neurons Undergoing Apoptosis
Authors: Canu Nadia , Barbato Christian , Ciotti Maria Teresa , Serafino Annalucia , Dus Laura , Calissano Pietro
Published: April 2018

We investigated the potential role of the ubiquitin proteolytic system in the death of cerebellar granule neurons induced by reduction of extracellular potassium. Inhibitors of proteasomal function block apoptosis if administered at onset of this process, but they do not exert such effect when added 2–3 hr later. The same inhibitors also prevent caspase-3 activity and calpain-caspase-3-mediated processing of tau protein, suggesting that proteasomes are involved upstream of the caspase activation. Although the proteasomes seem to play an early primary role in programmed cell death, we found that with progression of apoptosis, during the execution phase, a perturbation in normal ubiquitin-proteasome function occurs, and high levels of ubiquitinated proteins accumulate in the cytoplasm of dying cells. Such accumulation correlates with a progressive decline of proteasome chymotrypsin and trypsin-like activities and, to a lower extent, of postacidic-like activity. Both intracytoplasmic accumulation of ubiquitinated proteins and decline of proteasome function are reversed by the pan-caspase inhibitor Z-VAD-fmk. The decline in proteasome function is accompanied by, and likely attributable to, a marked and progressive decline of deubiquitinating activities. The finding that the proteasomes are early involved in apoptosis and that ubiquitinated proteins accumulate during this process prospect granule neurons as a model system aimed at correlating these events with neurodegenerative diseases.
The Transcription Factor DBP Affects Circadian Sleep Consolidation and Rhythmic EEG Activity
Authors: Franken Paul , Lopez-Molina Luis , Marcacci Lysiane , Schibler Ueli , Tafti Mehdi
Published: April 2018

Albumin D-binding protein (DBP) is a PAR leucine zipper transcription factor that is expressed according to a robust circadian rhythm in the suprachiasmatic nuclei, harboring the circadian master clock, and in most peripheral tissues. Mice lacking DBP display a shorter circadian period in locomotor activity and are less active. Thus, although DBP is not essential for circadian rhythm generation, it does modulate important clock outputs. We studied the role of DBP in the circadian and homeostatic aspects of sleep regulation by comparing DBP deficient mice (dbp−/−) with their isogenic controls (dbp+/+) under light–dark (LD) and constant-dark (DD) baseline conditions, as well as after sleep loss. Whereas total sleep duration was similar in both genotypes, the amplitude of the circadian modulation of sleep time, as well as the consolidation of sleep episodes, was reduced indbp−/− under both LD and DD conditions. Quantitative EEG analysis demonstrated a marked reduction in the amplitude of the sleep–wake-dependent changes in slow-wave sleep delta power and an increase in hippocampal theta peak frequency indbp−/− mice. The sleep deprivation-induced compensatory rebound of EEG delta power was similar in both genotypes. In contrast, the rebound in paradoxical sleep was significant indbp+/+ mice only. It is concluded that the transcriptional regulatory protein DBP modulates circadian and homeostatic aspects of sleep regulation.
SNARE Protein-Dependent Glutamate Release from Astrocytes
Authors: Araque Alfonso , Li Nianzhen , Doyle Robert T. , Haydon Philip G.
Published: April 2018

We investigated the cellular mechanisms underlying the Ca2+-dependent release of glutamate from cultured astrocytes isolated from rat hippocampus. Using Ca2+imaging and electrophysiological techniques, we analyzed the effects of disrupting astrocytic vesicle proteins on the ability of astrocytes to release glutamate and to cause neuronal electrophysiological responses, i.e., a slow inward current (SIC) and/or an increase in the frequency of miniature synaptic currents. We found that the Ca2+-dependent glutamate release from astrocytes is not caused by the reverse operation of glutamate transporters, because the astrocyte-induced glutamate-mediated responses in neurons were affected neither by inhibitors of glutamate transporters (β-threo-hydroxyaspartate, dihydrokainate, andl-trans-pyrrolidine-2,4-dicarboxylate) nor by replacement of extracellular sodium with lithium. We show that Ca2+-dependent glutamate release from astrocytes requires an electrochemical gradient necessary for glutamate uptake in vesicles, because bafilomycin A1, a vacuolar-type H+-ATPase inhibitor, reduced glutamate release from astrocytes. Injection of astrocytes with the light chain of the neurotoxin Botulinum B that selectively cleaves the vesicle-associated SNARE protein synaptobrevin inhibited the astrocyte-induced glutamate response in neurons. Therefore, the Ca2+-dependent glutamate release from astrocytes is a SNARE protein-dependent process that requires the presence of functional vesicle-associated proteins, suggesting that astrocytes store glutamate in vesicles and that it is released through an exocytotic pathway.
Nerve Injury Induces Gap Junctional Coupling among Axotomized Adult Motor Neurons
Authors: Chang Qiang , Pereda Alberto , Pinter Martin J. , Balice-Gordon Rita J.
Published: April 2018

Neonatal spinal motor neurons are electrically and dye-coupled by gap junctions, but coupling is transient and disappears rapidly after birth. Here we report that adult motor neurons become recoupled by gap junctions after peripheral nerve injury. One and 4–6 weeks after nerve cut, clusters of dye-coupled motor neurons were observed among axotomized, but not control, lumbar spinal motor neurons in adult cats. Electrical coupling was not apparent, probably because of the electrotonic distance between dendrodendritic gap junctions and the somatic recording location. Analyses of gap junction protein expression in cat and rat showed that the repertoire of connexins expressed by normal adult motor neurons, Cx36, Cx37, Cx40, Cx43, and Cx45, was unchanged after axotomy. Our results suggest that the reestablishment of gap junctional coupling among axotomized adult motor neurons may occur by modulation of existing gap junction proteins that are constitutively expressed by motor neurons. After injury, interneuronal gap junctional coupling may mediate signaling that maintains the viability of axotomized motor neurons until synaptic connections are reestablished within their targets.
A Highly Conserved Enhancer in theDlx5/Dlx6Intergenic Region is the Site of Cross-Regulatory Interactions betweenDlxGenes in the Embryonic Forebrain
Authors: Zerucha Ted , Stühmer Thorsten , Hatch Gary , Park Byung K. , Long Qiaoming , Yu Guoying , Gambarotta Adrianna , Schultz Joshua R. , Rubenstein John L. R. , Ekker Marc
Published: April 2018

FourDlxhomeobox genes,Dlx1,Dlx2,Dlx5, andDlx6are expressed in the same primordia of the mouse forebrain with temporally overlapping patterns. The four genes are organized as two tail-to-tail pairs,Dlx1/Dlx2andDlx5/Dlx6, a genomic arrangement conserved in distantly related vertebrates like zebrafish. TheDlx5/Dlx6intergenic region contains two sequences of a few hundred base pairs, remarkably well conserved between mouse and zebrafish. Reporter transgenes containing these two sequences are expressed in the forebrain of transgenic mice and zebrafish with patterns highly similar to endogenousDlx5andDlx6expression. The activity of the transgene is drastically reduced in mouse mutants lacking bothDlx1andDlx2,consistent with the decrease in endogenousDlx5andDlx6expression. These results suggest that cross-regulation by Dlx proteins, mediated by the intergenic sequences, is essential forDlx5andDlx6expression in the forebrain. This hypothesis is supported by cotransfection and DNA-protein binding experiments. We propose that theDlxgenes are part of a highly conserved developmental pathway that regulates forebrain development.
Immune Deficiency in Mouse Models for Inherited Peripheral Neuropathies Leads to Improved Myelin Maintenance
Authors: Schmid Christoph D. , Stienekemeier Martina , Oehen Stephan , Bootz Frank , Zielasek Jürgen , Gold Ralf , Toyka Klaus V. , Schachner Melitta , Martini Rudolf
Published: April 2018

The adhesive cell surface molecule P0is the most abundant glycoprotein in peripheral nerve myelin and fulfills pivotal functions during myelin formation and maintenance. Mutations in the corresponding gene cause hereditary demyelinating neuropathies. In mice heterozygously deficient in P0(P0+/−mice), an established animal model for a subtype of hereditary neuropathies, T-lymphocytes are present in the demyelinating nerves. To monitor the possible involvement of the immune system in myelin pathology, we cross-bred P0+/−mice with null mutants for the recombination activating gene 1 (RAG-1) or with mice deficient in the T-cell receptor α-subunit. We found that in P0+/−mice myelin degeneration and impairment of nerve conduction properties is less severe when the immune system is deficient. Moreover, isolated T-lymphocytes from P0+/−mice show enhanced reactivity to myelin components of the peripheral nerve, such as P0, P2, and myelin basic protein. We hypothesize that autoreactive immune cells can significantly foster the demyelinating phenotype of mice with a primarily genetically based peripheral neuropathy.
Cyclooxygenase-2 Contributes to Functional Hyperemia in Whisker-Barrel Cortex
Authors: Niwa Kiyoshi , Araki Eiichi , Morham Scott G. , Ross M. Elizabeth , Iadecola Costantino
Published: April 2018

The prostanoid-synthesizing enzyme cyclooxygenase-2 (COX-2) is expressed in selected cerebral cortical neurons and is involved in synaptic signaling. We sought to determine whether COX-2 participates in the increase in cerebral blood flow produced by synaptic activity in the somatosensory cortex. In anesthetized mice, the vibrissae were stimulated mechanically, and cerebral blood flow was recorded in the contralateral somatosensory cortex by a laser–Doppler probe. We found that the COX-2 inhibitor NS-398 attenuates the increase in somatosensory cortex blood flow produced by vibrissal stimulation. Furthermore, the flow response was impaired in mice lacking the COX-2 gene, whereas the associated increase in whisker-barrel cortex glucose use was not affected. The increases in cerebral blood flow produced by hypercapnia, acetylcholine, or bradykinin were not attenuated by NS-398, nor did they differ between wild-type and COX-2 null mice. The findings provide evidence for a previously unrecognized role of COX-2 in the mechanisms coupling synaptic activity to neocortical blood flow and provide an insight into one of the functions of constitutive COX-2 in the CNS.
Mechanisms of Calcium Decay Kinetics in Hippocampal Spines: Role of Spine Calcium Pumps and Calcium Diffusion through the Spine Neck in Biochemical Compartmentalization
Authors: Majewska Ania , Brown Edward , Ross Jonathan , Yuste Rafael
Published: April 2018

Dendritic spines receive most excitatory inputs in the CNS and compartmentalize calcium. Although the mechanisms of calcium influx into spines have been explored, it is unknown what determines the calcium decay kinetics in spines. With two-photon microscopy we investigate action potential-induced calcium dynamics in spines from rat CA1 pyramidal neurons in slices. The [Ca2+]iin most spines shows two decay kinetics: an initial fast component, during which [Ca2+]iin spines decays to dendritic levels, followed by a slower decay phase in which the spine follows dendritic kinetics. The correlation between [Ca2+]iin spine and dendrite at the breakpoint of the decay kinetics demonstrates diffusional equilibration between spine and dendrite during the slower component. To explain the faster initial decay, we rule out saturation or kinetic effects of endogenous or exogenous buffers and focus instead on (1) active calcium extrusion and (2) buffered diffusion of calcium from spine to dendrite. The presence of an undershoot in most spines indicates that extrusion mechanisms can be intrinsic to the spine. Supporting the two mechanisms, pharmacological blockade of smooth endoplasmic reticulum calcium (SERCA) pumps and the length of the spine neck affect spine decay kinetics. Using a mathematical model, we find that the contribution of calcium pumps and diffusion varies from spine to spine. We conclude that dendritic spines have calcium pumps and that their density and kinetics, together with the morphology of the spine neck, determine the time during which the spine compartmentalizes calcium.
Activity and Calcium-Dependent Mechanisms Maintain Reliable Interneuron Synaptic Transmission in a Rhythmic Neural Network
Authors: Parker David
Published: April 2018

Inputs from glutamatergic excitatory interneurons (EIN) to motor neurons in the lamprey spinal cord locomotor network exhibit activity-dependent depression during spike trains. The mechanism underlying this depression has been examined here, and its relevance to transmitter release during rhythmic activity has been investigated.

The depression of EIN inputs was greater after larger initial EPSPs and reduced in low-calcium Ringer's solution, effects that are consistent with depression caused by depletion of releasable transmitter stores. However, the depression was greater at lower stimulation frequencies and could be reversed by increasing the stimulation frequency. In addition, high-calcium Ringer's solution and the slow intracellular calcium chelator EGTA-AM, which both failed to affect the amplitude of low frequency-evoked EPSPs, reduced and increased the depression, respectively. These results are inconsistent with a simple depletion mechanism but suggest that ongoing activity and calcium-dependent mechanisms oppose depletion.

The network relevance of this mechanism was examined using physiologically relevant bursts to simulate EIN spiking during rhythmic activity. Although considerably more EPSPs were evoked than during spike trains, burst-evoked EPSPs did not depress. However, single EPSPs evoked at the interburst interval depressed, and burst transmission was disrupted by EGTA-AM, again suggesting the involvement of activity and calcium-dependent mechanisms. By responding to the calcium changes evoked by increased interneuron activity, this mechanism can monitor transmitter requirements caused by EIN spiking, allowing reliable transmission across different patterns of network activity. However, not all types of spinal interneurons exhibit reliable burst transmission, suggesting specificity of this mechanism to a subset of neurons.
Serotonin-Driven Long-Range Inhibitory Connections in the Cerebellar Cortex
Authors: Dieudonné Stéphane , Dumoulin Andréa
Published: April 2018

Disturbances of the serotoninergic neuromodulation in the cerebellar cortex have been involved in several types of ataxia, but the physiological action of serotonin in this structure remains poorly understood. We report that in slices of the rat cerebellar vermis, serotonin triggers the firing of an inhibitory interneuron presynaptic to Golgi cells. The Lugaro cell, a neglected interneuronal type, satisfies the expected criteria for this input, whereas basket cells, stellate cells, or Golgi cells do not. Lugaro cells are selectively excited by serotonin, and their firing behavior (sustained steady frequency in the 5–15 Hz range) resembles the pattern of occurrence of serotonin-evoked IPSCs in Golgi cells. Immunohistochemical stainings and single cell reconstructions show that Lugaro cell axons form a parasagittal plexus but also extend long transverse branches that run parallel to the parallel fibers and are partly myelinated. Electrophysiological data suggest that these transverse axons participate in synaptic contacts of the Lugaro cells with Golgi cells, and we calculated that in the intact cerebellum a given Lugaro cell contacts >100 Golgi cells. Serotonin modulation of Lugaro cells may constitute an intracortical switch involved in information patterning at the level of Golgi cells and granule cells populations, and particularly in synchronizations recorded along the transverse axisin vivo.
Cortical Cell Orientation Selectivity Fails to Develop in the Absence of ON-Center Retinal Ganglion Cell Activity
Authors: Chapman Barbara , Gödecke Imke
Published: April 2018

Neuronal activity is necessary for the normal development of visual cortical cell receptive fields. When neuronal activity is blocked, cortical cells fail to develop normal ocular dominance and orientation selectivity. Patterned activity has been shown to play an instructive, rather than merely permissive, role in the segregation of geniculocortical afferents into ocular dominance columns. To test whether normal patterns of activity are necessary to instruct the development of cortical orientation selectivity, we studied ferrets raised without ON-center retinal ganglion cell activity. The ON-center blockade was produced by daily intravitreal injections ofdl-2-amino-4-phosphonobutyric acid (APB). Effects of this treatment on the development of orientation selectivity in primary visual cortex were assessed using extracellular electrode recordings and optical imaging. In animals raised with an ON-center blockade starting after visual cortical cells are visually driven but still poorly tuned for orientation, cortical cell responsivity was maintained, but no maturation of orientation selectivity was seen. No recovery of orientation tuning was seen in animals treated with APB during the normal period of orientation development and then allowed several months of development without treatment. These results suggest that patterns of neuronal activity carried in the separate ON- and OFF-center visual pathways are necessary for the development of orientation selectivity in visual cortical neurons of the ferret and that there is a critical period for this development.
Dual Serotonin (5-HT) Projections to the Nucleus Accumbens Core and Shell: Relation of the 5-HT Transporter to Amphetamine-Induced Neurotoxicity
Authors: Brown Pierre , Molliver Mark E.
Published: April 2018

Dopamine release in the nucleus accumbens (NAc) has been implicated as mediating the rewarding effects of stimulant drugs; however, recent studies suggest that 5-HT release may also contribute. In an effort to assess the role of 5-HT in drug-mediated reward, this study analyzed the serotonergic innervation of NAc using immunocytochemistry for 5-HT and the 5-HT transporter (SERT). We report that in control rats the NAc receives two distinct types of 5-HT axons that differ in regional distribution, morphology, and SERT expression. Most regions of the NAc are innervated by thin 5-HT axons that express SERT, but in the caudal NAc shell nearly all 5-HT axons lack SERT and have large spherical varicosities. Two weeks after methamphetamine orp-chloroamphetamine (PCA) treatment, most 5-HT axons in dorsal striatum and NAc have degenerated; however, the varicose axons in the shell appear intact. These drug-resistant 5-HT axons that lack SERT densely innervate the caudal one-third of the accumbens shell, the same location where dopamine axons are spared after methamphetamine. Moreover, 4 hr after PCA, the varicose axons in the caudal shell retain prominent stores of 5-HT, whereas 5-HT axons in the rest of the NAc are depleted of neurotransmitter. The results demonstrate that two functionally different 5-HT projections innervate separate regions of the NAc and that selective vulnerability to amphetamines may result from differential expression of SERT. We postulate that action potentials conducted from the raphe nuclei can release 5-HT throughout the NAc, whereas transporter-mediated release induced by stimulant drugs is more restricted and unlikely to occur in the caudal NAc shell.
Neuroactive Steroid 3α-Hydroxy-5α-Pregnan-20-One Modulates Electrophysiological and Behavioral Actions of Ethanol
Authors: VanDoren Margaret J. , Matthews Douglas B. , Janis Gregory C. , Grobin A. Chistina , Devaud Leslie L. , Morrow A. Leslie
Published: April 2018

Neuroactive steroids are synthesizedde novoin brain, yet their physiological significance remains elusive. We provide biochemical, electrophysiological, and behavioral evidence that several specific actions of alcohol (ethanol) are mediated by the neurosteroid 3α-hydroxy-5α-pregnan-20-one (3α,5α-THP; allopregnanolone). Systemic alcohol administration elevates 3α,5α-THP levels in the cerebral cortex to pharmacologically relevant concentrations. The elevation of 3α,5α-THP is dose- and time-dependent. Furthermore, there is a significant correlation between 3α,5α-THP levels in cerebral cortex and the hypnotic effect of ethanol. Blockade ofde novobiosynthesis of 5α-reduced steroids using the 5α-reductase inhibitor finasteride prevents several effects of ethanol. Pretreatment with finasteride causes no changes in baseline bicuculline-induced seizure threshold but reverses the anticonvulsant effect of ethanol. Finasteride pretreatment also reverses ethanol inhibition of spontaneous neural activity in medial septal/diagonal band of Broca neurons while having no direct effect on spontaneous firing rates. Thus, elevation of 3α,5α-THP levels by acute ethanol administration represents a novel mechanism of ethanol action as well as an important modulatory role for neurosteroids in the CNS.
Control of Synaptic Depression by Glutamate Transporters
Authors: Tureček Rostislav , Trussell Laurence O.
Published: April 2018

The role of glutamate transporters in the regulation of synaptic depression was examined in the avian nucleus magnocellularis. Repetitive stimulation of presynaptic auditory nerve fibers resulted in acute depression of EPSCs. Pharmacological blockade of glutamate transport in glial cells enhanced residual glutamate in the synaptic cleft and markedly increased the extent of depression at stimulus frequencies above 20 Hz via a postsynaptic mechanism. Glutamate pyruvate transaminase, a glutamate scavenger, accelerated the decay of the EPSC and reduced synaptic depression, indicating that transporters are not completely effective in rapid removal of glutamate. Regulation of residual transmitter by glia may thus serve to control synaptic strength in a frequency-dependent manner.
Synaptic Activity Modulates the Induction of Bidirectional Synaptic Changes in Adult Mouse Hippocampus
Authors: Ngezahayo Anaclet , Schachner Melitta , Artola Alain
Published: April 2018

Activity-dependent synaptic plasticity is critical for learning and memory. Considerable attention has been paid to mechanisms that increase or decrease synaptic efficacy, referred to as long-term potentiation (LTP) and long-term depression (LTD), respectively. It is becoming apparent that synaptic activity also modulates the ability to elicit subsequent synaptic changes. We provide direct experimental evidence that this modulation is attributable, at least in part, to variations in the level of postsynaptic depolarization required for inducing plasticity. In slices from adult hippocampal CA1, a brief pairing protocol known to produce LTP can also induce LTD. The voltage–response function for the induction of LTD and LTP in naive synapses exhibits three parts: at a postsynaptic membrane potential during pairing (Vm) ≤ −40 mV, no synaptic modification is obtained; atVmbetween −40 and −20 mV, LTD is induced; and, finally, atVm> −20 mV, LTP is generated. This function varies with initial synaptic efficacy. In depressed synapses, Θ−, theVmabove which LTD is generated, is shifted toward more depolarizedVmsand Θ+, the LTD–LTP crossover point or, equivalently, theVmabove which LTP is induced, toward more polarizedVms. Conversely in potentiated synapses, Θ−is shifted toward more polarizedVms. Therefore synaptic activity changes synaptic efficacy and accordingly adjusts the voltages for eliciting subsequent synaptic modifications. The concomitant shifts in the voltages for inducing LTD and LTP in opposite directions promote synaptic potentiation and inhibit synaptic depression in depressed synapses and vice versa in potentiated synapses.
Mechanisms of Cannabinoid Inhibition of GABAASynaptic Transmission in the Hippocampus
Authors: Hoffman Alexander F. , Lupica Carl R.
Published: April 2018

The localization of cannabinoid (CB) receptors to GABAergic interneurons in the hippocampus indicates that CBs may modulate GABAergic function and thereby mediate some of the disruptive effects of marijuana on spatial memory and sensory processing. To investigate the possible mechanisms through which CB receptors may modulate GABAergic neurotransmission in the hippocampus, whole-cell voltage-clamp recordings were performed on CA1 pyramidal neurons in rat brain slices. Stimulus-evoked GABAAreceptor-mediated IPSCs were reduced in a concentration-dependent manner by the CB receptor agonist WIN 55,212–2 (EC50of 138 nm). This effect was blocked by the CB1 receptor antagonist SR141716A (1 μm) but not by the opioid antagonist naloxone. In contrast, evoked GABAB-mediated IPSCs were insensitive to the CB agonist. WIN 55,212–2 also reduced the frequency of spontaneous, action potential-dependent IPSCs (sIPSCs), without altering action potential-independent miniature IPSCs (mIPSCs), measured while sodium channels were blocked by tetrodotoxin (TTX). Blockade of voltage-dependent calcium channels (VDCCs) by cadmium also eliminated the effect of WIN 55,212–2 on sIPSCs. Depolarization of inhibitory terminals with elevated extracellular potassium caused a large increase in the frequency of mIPSCs that was inhibited by both cadmium and WIN 55,212–2. The presynaptic effect of WIN 55,212–2 was also investigated using the potassium channel blockers barium and 4-aminopyridine. Neither of these agents significantly altered the effect of WIN 55,212–2 on evoked IPSCs. Together, these data suggest that presynaptic CB1 receptors reduce GABAA- but not GABAB-mediated synaptic inhibition of CA1 pyramidal neurons by inhibiting VDCCs located on inhibitory nerve terminals.
Highly Localized Ca2+Accumulation Revealed by Multiphoton Microscopy in an Identified Motoneuron and Its Modulation by Dopamine
Authors: Kloppenburg Peter , Zipfel Warren R. , Webb Watt W. , Harris-Warrick Ronald M.
Published: April 2018

Calcium is essential for synaptic transmission and the control of the intrinsic firing properties of neurons; this makes Ca2+channels a prime target for neuromodulators. A combination of multiphoton microscopy and voltage-clamp recording was used to determine the localization of voltage-dependent Ca2+accumulation in the two pyloric dilator (PD) neurons of the pyloric network in the spiny lobster,Panulirus interruptus,and its modulation by dopamine. We monitored [Ca2+]iin fine distal branches in the neuropil >350 μm below the surface of the ganglion during controlled voltage steps in voltage clamp. Ca2+accumulation originated mostly from small, fairly rare, spatially restricted varicosities on distal neuritic arborizations. Ca2+diffused from these point sources into adjacent regions. Varicosities with similar morphology in the PD neuron have been shown previously to be sites of synaptic contacts. We have demonstrated in earlier studies that dopamine inhibits activity and greatly reduces synaptic transmission from the PD neuron. In ∼60% of the varicosities, the voltage-activated Ca2+accumulation was reduced by exogenous dopamine (DA) (10−4m). DA decreased the peak amplitude of Ca2+accumulation but had no effect on the rise and decay time. We conclude that DA reduces chemical synaptic transmission from the PD neurons at least in part by decreasing Ca2+entry at neurotransmitter release sites.
Early and Selective Loss of Neuromuscular Synapse Subtypes with Low Sprouting Competence in Motoneuron Diseases
Authors: Frey Dunja , Schneider Corinna , Xu Lan , Borg Jacques , Spooren Will , Caroni Pico
Published: April 2018

The addition or loss of synapses in response to changes in activity, disease, or aging is a major aspect of nervous system plasticity in the adult. The mechanisms that affect the turnover and maintenance of synapses in the adult are poorly understood and are difficult to investigate in the brain. Here, we exploited a unique anatomical arrangement in the neuromuscular system to determine whether subtypes of synapses can differ in anatomical plasticity and vulnerability. In three genetic mouse models of motoneuron disease of diverse origin and severity, we observed a gradual and selective loss of synaptic connections that begun long before the onset of clinical deficits and correlated with the timing of disease progression. A subgroup of fast-type (fast-fatiguable) neuromuscular synapses was highly vulnerable and was lost very early on. In contrast, slow-type synapses resisted up to the terminal phase of the disease. Muscle-specific differences were also evident. Similar selective losses were detected in aged mice. These selective vulnerability properties of synapses coincided with hitherto unrecognized major differences in stimulus-induced anatomical plasticity that could also be revealed in healthy mice. Using paralysis and/or growth-associated protein 43 overexpression to induce synaptic sprouting, we found that slow-type, disease-resistant synapses were particularly plastic. In contrast, fast-type synapses with the highest vulnerability failed to exhibit any stimulus-induced change. The results reveal pronounced subtype specificity in the anatomical plasticity and susceptibility to loss of neuromuscular synapses and suggest that degenerative motoneuron diseases involve a common early pathway of selective and progressive synaptic weakening also associated with aging.