bluuebunny/crossref_metadata_2025 huggingface dataset:
Increased Neuromuscular Activity Reduces Sprouting in Partially Denervated Muscles
Authors: Tam Siu Lin , Archibald Vey , Jassar Balvinder , Tyreman Neil , Gordon Tessa
Published: April 2018

The effects of increasing neural activity on sprouting remain unclear and controversial. In a rat model of partial denervation of skeletal muscles, we investigated the effect of neuromuscular activity on sprouting. Rat hindlimb muscles were partially denervated by avulsion of either L4 or L5 spinal root. Immediately after partial denervation, the rats were divided into three groups: (1) normal caged activity, (2) running exercise on wheels, 8 hr daily, and (3) functional electrical stimulation (FES) of sciatic nerves, 20 Hz for 8 hr daily. At 1 month, muscle unit (MU) enlargement was quantitated electrophysiologically and histochemically. MU twitch force was increased by four- to fivefold by partial denervation in extensively denervated tibialis anterior (TA) and medial gastrocnemius (MG) and by approximately twofold in moderately denervated plantaris (PL) and soleus (SOL). For the extensively denervated TA and MG muscles, MU enlargement, measured electrophysiologically, declined significantly after an average of 1757 ± 310 m/d running exercise and daily FES for 1 month. The detrimental effects on MU enlargement were much less but significant in the moderately denervated PL and did not reach statistical significance in the moderately denervated SOL muscle. Histochemical evaluation of sprouting showed a reduction in the number of sprouts in the extensively denervated TA muscle, but not the moderately denervated PL and SOL muscles, by increased neuromuscular activity. Thus, increased neuromuscular activity is detrimental primarily in muscles that are extensively denervated, and the MUs are smaller than under conditions in which the muscles experience normal physiological levels of activation.
Intensity-Dependent, Rapid Activation of Presynaptic Metabotropic Glutamate Receptors at a Central Synapse
Authors: Awatramani Gautam B. , Slaughter Malcolm M.
Published: April 2018

Synaptic signals from retinal bipolar cells were monitored by measuring EPSCs in ganglion cells voltage-clamped at −70 mV. Spontaneous EPSCs were strongly suppressed byl-2-amino-4-phosphonobutyrate (AP-4), an agonist at group III metabotropic glutamate receptors (mGluRs). Agonists of group I or II mGluRs were ineffective. AP-4 also suppressed ganglion cell EPSCs evoked by bipolar cell stimulation using potassium puffs, sucrose puffs, or zaps of current (0.5–1 μA). In addition, AP-4 suppressed Off EPSCs evoked by dim-light stimuli. This indicates that group III mGluRs mediate a direct suppression of bipolar cell transmitter release. An mGluR antagonist, (RS)-α-cyclopropyl-4-phosphonophenylyglycine (CPPG), blocked the action of AP-4. When bipolar cells were weakly stimulated, AP-4 produced a large suppression of the EPSC, but CPPG alone had little effect. Conversely, when bipolar cells were strongly stimulated, CPPG produced an enhancement of the EPSC, but AP-4 alone had little effect. This indicates that endogenous feedback regulates bipolar cell transmitter release and that the dynamic range of the presynaptic metabotropic autoreceptor is similar to that of the postsynaptic ionotropic receptor. Furthermore, the feedback is rapid and intensity-dependent. Hence, concomitant activation of presynaptic and postsynaptic glutamate receptors shapes the responses of ganglion cells.
G-Protein Inhibition of N- and P/Q-Type Calcium Channels: Distinctive Elementary Mechanisms and Their Functional Impact
Authors: Colecraft Henry M. , Brody David L. , Yue David T.
Published: April 2018

Voltage-dependent G-protein inhibition of presynaptic Ca2+channels is a key mechanism for regulating synaptic efficacy. G-protein βγ subunits produce such inhibition by binding to and shifting channel opening patterns from high to low open probability regimes, known respectively as “willing” and “reluctant” modes of gating. Recent macroscopic electrophysiological data hint that only N-type, but not P/Q-type channels can open in the reluctant mode, a distinction that could enrich the dimensions of synaptic modulation arising from channel inhibition. Here, using high-resolution single-channel recording of recombinant channels, we directly distinguished this core contrast in the prevalence of reluctant openings. Single, inhibited N-type channels manifested relatively infrequent openings of submillisecond duration (reluctant openings), which differed sharply from the high-frequency, millisecond gating events characteristic of uninhibited channels. By contrast, inhibited P/Q-type channels were electrically silent at the single-channel level. The functional impact of the differing inhibitory mechanisms was revealed in macroscopic Ca2+currents evoked with neuronal action potential waveforms (APWs). Fitting with a change in the manner of opening, inhibition of such N-type currents produced both decreased current amplitude and temporally advanced waveform, effects that would not only reduce synaptic efficacy, but also influence the timing of synaptic transmission. On the other hand, inhibition of P/Q-type currents evoked by APWs showed diminished amplitude without shape alteration, as expected from a simple reduction in the number of functional channels. Variable expression of N- and P/Q-type channels at spatially distinct synapses therefore offers the potential for custom regulation of both synaptic efficacy and synchrony, by G-protein inhibition.
Interaction of Stoned and Synaptotagmin in Synaptic Vesicle Endocytosis
Authors: Fergestad Tim , Broadie Kendal
Published: April 2018

TheDrosophiladicistronicstonedlocus encodes two distinctive presynaptic proteins, Stoned A (STNA) and Stoned B (STNB); STNA is a novel protein without homology to known synaptic proteins, and STNB contains a domain with homology to the endocytotic protein AP50. Both Stoned proteins colocalize precisely with endocytotic proteins including the AP2 complex and Dynamin in the “lattice network” characteristic of endocytotic domains inDrosophilapresynaptic terminals. FM1–43 dye uptake studies instonedmutants demonstrate a striking decrease in the size of the endo–exo-cycling synaptic vesicle pool and loss of spatial regulation of the vesicular recycling intermediates. Mutant synapses display a significant delay in vesicular membrane retrieval after depolarization and neurotransmitter release. These studies suggest that the Stoned proteins play a role in mediating synaptic vesicle endocytosis. We have documented previously a highly specific synaptic mislocalization and degradation of Synaptotagmin I instonedmutants. Here we show that transgenic overexpression of Synaptotagmin I rescuesstonedembryonic lethality and restores endocytotic recycling to normal levels. Furthermore, overexpression of Synaptotagmin I in otherwise wild-type animals results in increased synaptic dye uptake, indicating that Synaptotagmin I directly regulates the endo–exo-cycling synaptic vesicle pool size. In parallel with recent biochemical studies, this genetic analysis strongly suggests that Stoned proteins regulate the AP2–Synaptotagmin I interaction during synaptic vesicle endocytosis. We conclude that Stoned proteins control synaptic transmission strength by mediating the retrieval of Synaptotagmin I from the plasma membrane.
Ca2+-Independent Protein Kinase C Apl II Mediates the Serotonin-Induced Facilitation at DepressedAplysiaSensorimotor Synapses
Authors: Manseau Frédéric , Fan Xiaotang , Hueftlein Tina , Sossin Wayne S. , Castellucci Vincent F.
Published: April 2018

At nondepressedAplysiasensory to motor synapses, serotonin (5-HT) facilitates transmitter release primarily through a protein kinase A pathway. In contrast, at depressedAplysiasensory to motor synapses, 5-HT facilitates transmitter release primarily through a protein kinase C (PKC)-dependent pathway. It is known that only two phorbol ester-activated PKC isoforms, the Ca2+-dependent PKC Apl I and the Ca2+-independent PKC Apl II, exist in theAplysianervous system. For the first time, we have now been able to functionally determine which isoform of PKC is involved in a particular form of plasticity. We microinjected cultured sensorimotor pairs of neurons with various PKC constructs tagged with the enhanced green fluorescent protein as a reporter for successful plasmid expression. Our results demonstrate that short-term facilitation of depressed synapses is mediated by PKC Apl II. Dominant-negative PKC Apl II, but not dominant-negative PKC Apl I, disrupted the normal kinetics of 5-HT-induced facilitation by completely blocking its rapid onset. This effect was specific to depressed synapses, because dominant-negative PKC Apl II did not inhibit 5-HT-mediated facilitation of nondepressed synapses. Our results suggest that not only different signal transduction pathways but also different isoforms of a specific cascade may mediate physiological responses according to the state of a synapse.
Noticing Familiar Objects in Real World Scenes: The Role of Temporal Cortical Neurons in Natural Vision
Authors: Sheinberg David L. , Logothetis Nikos K.
Published: April 2018

During natural vision, the brain efficiently processes views of the external world as the eyes actively scan the environment. To better understand the neural mechanisms underlying this process, we recorded the activity of individual temporal cortical neurons while monkeys looked for and identified familiar targets embedded in natural scenes. We found a group of visual neurons that exhibited stimulus-selective neuronal bursts just before the monkey's response. Most of these cells showed similar selectivity whether effective targets were viewed in isolation or encountered in the course of exploring complex scenes. In addition, by embedding target stimuli in natural scenes, we could examine the activity of these stimulus-selective cells during visual search and at the time targets were fixated and identified. We found that, during exploration, neuronal activation sometimes began shortly before effective targets were fixated, but only if the target was the goal of the next fixation. Furthermore, we found that the magnitude of this early activation varied inversely with reaction time, indicating that perceptual information was integrated across fixations to facilitate recognition. The behavior of these visually selective cells suggests that they contribute to the process of noticing familiar objects in the real world.
Tuning and Topography in an Odor Map on the Rat Olfactory Bulb
Authors: Meister Markus , Bonhoeffer Tobias
Published: April 2018

The sense of smell originates in a diverse array of receptor neurons, comprising up to 1000 different types. To understand how these parallel channels encode chemical stimuli, we recorded the responses of glomeruli in the olfactory bulbs of the anesthetized rat, by optical imaging of intrinsic signals. Odor stimulation produced two kinds of optical responses at the surface of the bulb: a broad diffuse component superposed by discrete small spots. Histology showed that the spots correspond to individual glomeruli, and that ∼400 of them can be monitored in this way. Based on its wavelength-dependence, this optical signal appears to derive from changes in light scattering during neural activity. Pure odorants generally activated several glomeruli in a bilaterally symmetric pattern, whose extent varied greatly with concentration. A simple formalism for ligand binding accounts quantitatively for this concentration dependence and yields the effective affinity with which a glomerulus responds to an odorant. When tested with aliphatic molecules of increasing carbon chain length, many glomeruli were sharply tuned for one or two adjacent chain lengths. Glomeruli with similar tuning properties were located near each other, producing a systematic map of molecular chain length on the surface of the olfactory bulb. Given local inhibitory circuits within the olfactory bulb, this can account for the observed functional inhibition between related odors. We explore several parallels to the function and architecture of the visual system that help interpret the neural representation of odors.
Methamphetamine-Induced Rapid and Reversible Changes in Dopamine Transporter Function: AnIn VitroModel
Authors: Sandoval Verónica , Riddle Evan L. , Ugarte Yvette V. , Hanson Glen R. , Fleckenstein Annette E.
Published: April 2018

This laboratory has demonstrated that a single methamphetamine (METH) injection rapidly and reversibly decreases the activity of the dopamine transporter (DAT), as assessedex vivoin synaptosomes prepared from treated rats. This decrease does not occur because of residual drug introduced by the original injection or nor is it associated with a change in binding of the DAT ligand WIN35428. The purpose of this study was to elucidate the mechanism or mechanisms of this METH effect by determining whether direct application of this stimulant to synaptosomes causes changes in DAT similar to those observedex vivo. Similar to theex vivoeffect, incubation of striatal synaptosomes with METH decreased DAT activity, but not WIN35428 binding: the effect on activity was not eliminated by repeated washing of synaptosomes. Also, as observedex vivo, incubation with 3,4-methylenedioxymethamphetamine, but not cocaine or methylphenidate, caused a METH-like reduction in DAT function. The rapid and reversible METH-induced diminution in DAT activity did not occur because of a change in membrane potential, as assessedin vitroandex vivoby [3H]tetraphenylphosphonium accumulation. However, the METH-related decline in DAT function may be attributed to phosphorylation because NPC15437, a protein kinase C inhibitor, attenuated the METH-induced decline in DAT function. Similarities between previously reported effectsex vivoof a single METH injection on serotonin and norepinephrine transporter function and effects of direct METH applicationin vitrowere also found. Together, these data demonstrate that thein vitroincubation model mimics the rapid and reversible effects observed after a single METH injection.
Action Potential Bursting in Subicular Pyramidal Neurons Is Driven by a Calcium Tail Current
Authors: Jung Hae-yoon , Staff Nathan P. , Spruston Nelson
Published: April 2018

Subiculum is the primary output area of the hippocampus and serves as a key relay center in the process of memory formation and retrieval. A majority of subicular pyramidal neurons communicate via bursts of action potentials, a mode of signaling that may enhance the fidelity of information transfer and synaptic plasticity or contribute to epilepsy when unchecked. In the present study, we show that a Ca2+tail current drives bursting in subicular pyramidal neurons. An action potential activates voltage-activated Ca2+channels, which deactivate slowly enough during action potential repolarization to produce an afterdepolarization that triggers subsequent action potentials in the burst. The Ca2+channels underlying bursting are located primarily near the soma, and the amplitude of Ca2+tail currents correlates with the strength of bursting across cells. Multiple channel subtypes contribute to Ca2+tail current, but the need for an action potential to produce the slow depolarization suggests a central role for high-voltage-activated Ca2+channels in subicular neuron bursting.
Increased Histone Acetyltransferase and Lysine Acetyltransferase Activity and Biphasic Activation of the ERK/RSK Cascade in Insular Cortex During Novel Taste Learning
Authors: Swank Michael W. , Sweatt J. David
Published: April 2018

Changes in gene expression are thought to be involved in neuronal plasticity associated with learning and memory. Although acetylation of lysine residues on histones by histone acetyltransferases (HAT) is an obligatory component of transcription, HAT activity has been largely ignored in studies of the nervous system. We developed a new model for studying novel taste learning using novel solid food presentation to nondeprived animals. Using this behavioral paradigm, we investigated short- and long-term regulation of lysine acetyltransferase activity and the ERK/mitogen-activated protein kinase (MAPK)/RSK cascade in insular cortex, a CNS region known to be crucial for the formation of novel taste memories. We observed that novel taste learning elicited biphasic (acute and long-lasting) activation of two distinct lysine acetyltransferase activities along with the ERK/MAPK cascade in insular cortex.In vitrostudies revealed that the ERK cascade could regulate the lysine acetylation of a 42 kDa lysine acetyltransferase substrate, suggesting a causal relationship between ERK activation and lysine acetyltransferase activity in insular cortex. Overall, our studies reveal an unanticipated long-lasting activation of insular cortex signal transduction cascades in novel taste learning. Furthermore, our studies suggest the hypothesis that acute and long-term ERK activation and lysine–histone acetyltransferase activation may play a role in regulating gene expression in single-trial learning and long-term memory formation.
Retrograde Carbon Monoxide Is Required for Induction of Long-Term Potentiation in Rat Superior Cervical Ganglion
Authors: Alkadhi Karim A. , Al-Hijailan Reem S. , Malik Kahkashan , Hogan Yvonne H.
Published: April 2018

Carbon monoxide (CO), produced in the body by the enzyme heme oxygenase (HO), has been suggested as a retrograde synaptic messenger with a prominent role in the long-term potentiation (LTP) of certain areas of the brain. LTP of sympathetic ganglia is 5-HT3receptor-dependent and has been shown to require nitric oxide for the maintenance, but not for the induction, phase. We investigated the possibility of CO being required for the induction of ganglionic LTP. Pretreatment of rat isolated superior cervical ganglia with oxyhemoglobin (25–100 μm) completely blocked LTP. In the same ganglia, prolonged washout of oxyhemoglobin did not uncover any potentiation of the compound action potential. Oxyhemoglobin had no significant effect on the maintenance phase in ganglia with established LTP. Pretreatment of ganglia with the HO inhibitor zinc protoporphyrin-IX (ZnPP) (10 μm) completely and irreversibly prevented the expression of tetanus-evoked LTP. However, in the same ganglia, after superfusion of CO in the presence of ZnPP, tetanic stimulation readily evoked LTP. No effect was seen on the maintenance phase when ZnPP was superfused on ganglia with established LTP. Pretreatment of ganglia with the 5-HT3receptor antagonist ondansetron (0.4 μm) alone completely and irreversibly blocked LTP. However, in the presence of CO, ondansetron did not block LTP. These results suggest that activation of 5-HT3receptors may be involved in the production of CO. The results also suggest that CO, probably originating outside the presynaptic nerve terminal, is involved in the induction of LTP.
Tactile Responses in the Granule Cell Layer of Cerebellar Folium Crus IIa of Freely Behaving Rats
Authors: Hartmann Mitra J. , Bower James M.
Published: April 2018

We recorded activity from the granule cell layer (GCL) of cerebellar folium Crus IIa as freely moving rats engaged in a variety of natural behaviors, including grooming, eating, and free tactile exploration. Multiunit responses in the 1000–4500 Hz range were found to be strongly correlated with tactile stimulation of lip and whisker (perioral) regions. These responses occurred regardless of whether the stimulus was externally or self-generated and during both active and passive touch. In contrast, perioral movements that did not tactually stimulate this region of the face (e.g., chewing) produced no detectable increases in GCL activity. In addition, GCL responses were not correlated with movement extremes. When rats used their lips actively for palpation and exploration, the tactile responses in the GCL were not detectably modulated by ongoing jaw movements. However, active palpation and exploratory behaviors did result in the largest and most continuous bursts of GCL activity: responses were on average 10% larger and 50% longer during palpation and exploration than during grooming or passive stimulation. Although activity levels differed between behaviors, the position and spatial extent of the peripheral receptive field was similar over all behaviors that resulted in tactile input. Overall, our data suggest that the 1000–4500 Hz multiunit responses in the Crus IIa GCL of awake rats are correlated with tactile input rather than with movement or any movement parameter and that these responses are likely to be of particular importance during the acquisition of sensory information by perioral structures.
Status Epilepticus Causes Necrotic Damage in the Mediodorsal Nucleus of the Thalamus in Immature Rats
Authors: Kubová Hana , Druga Rastislav , Lukasiuk Katarzyna , Suchomelová Lucie , Haugvicová Renata , Jirmanová Iza , Pitkänen Asla
Published: April 2018

Status epilepticus (StE) in immature rats causes long-term functional impairment. Whether this is associated with structural alterations remains controversial. The present study was designed to test the hypothesis that StE at an early age results in neuronal loss. StE was induced with lithium–pilocarpine in 12-d-old rats, and the presence of neuronal damage was investigated in the brain from 12 hr up to 1 week later using silver and Fluoro-Jade B staining techniques. Analysis of the sections indicated consistent neuronal damage in the central and lateral segments of the mediodorsal nucleus of the thalamus, which was confirmed using adjacent cresyl violet-stained preparations. The mechanism of thalamic damage (necrosis vs apoptosis) was investigated further using TUNEL, immunohistochemistry for caspase-3 and cytochrome c, and electron microscopy. Activated microglia were detected using OX-42 immunohistochemistry. The presence of silver and Fluoro-Jade B-positive degenerating neurons in the mediodorsal thalamic nucleus was associated with the appearance of OX-42-immunopositive activated microglia but not with the expression of markers of programmed cell death, caspase-3, or cytochrome c. Electron microscopy revealed necrosis of the ultrastructure of damaged neurons, providing further evidence that the mechanism of StE-induced damage in the mediodorsal thalamic nucleus at postnatal day 12 is necrosis rather than apoptosis. Finally, these data together with previously described functions of the medial and lateral segments of the mediodorsal thalamic nucleus suggest that some functions, such as adaptation to novelty, might become compromised after StE early in development.
Locomotor Recovery in Spinal Cord-Injured Rats Treated with an Antibody Neutralizing the Myelin-Associated Neurite Growth Inhibitor Nogo-A
Authors: Merkler Doron , Metz Gerlinde A. S. , Raineteau Olivier , Dietz Volker , Schwab Martin E. , Fouad Karim
Published: April 2018

The limited plastic and regenerative capabilities of axons in the adult mammalian CNS can be enhanced by the application of a monoclonal antibody (mAb), IN-1, raised against the myelin-associated neurite growth inhibitor Nogo-A. The aim of the present study was to investigate the effects of this treatment on the functional recovery of adult rats with a dorsal over-hemisection of the spinal cord. Directly after injury, half of the animals were implanted with mAb IN-1-secreting hybridoma cells, whereas the others received cells secreting a control antibody (anti-HRP). A broad spectrum of locomotor tests (open field locomotor) score, grid walk, misstep withdrawal response, narrow-beam crossing) was used to characterize locomotor recovery during the 5 weeks after the injury. In all behavioral tests, the recovery in the mAb IN-1-treated group was significantly augmented compared with the control antibody-treated rats. EMG recordings of flexor and extensor muscles during treadmill walking confirmed the improvement of the locomotor pattern in the mAb IN-1-treated rats; step-cycle duration, rhythmicity, and coupling of the hindlimbs were significantly improved. No differences between the two groups with regard to nociception were observed in the tail flick test 5 weeks after the operation. These results indicating improved functional recovery suggest that the increased plastic and regenerative capabilities of the CNS after Nogo-A neutralization result in a functionally meaningful rewiring of the motor systems.
Reinforcement of Early Long-Term Potentiation (Early-LTP) in Dentate Gyrus by Stimulation of the Basolateral Amygdala: Heterosynaptic Induction Mechanisms of Late-LTP
Authors: Frey Sabine , Bergado-Rosado Jorge , Seidenbecher Thomas , Pape Hans-Christian , Frey J. Uwe
Published: April 2018

The basolateral amygdala (BLA) can influence distinct learning and memory formation. Hippocampal long-term potentiation (LTP), the most prominent cellular model of memory formation, can be modulated by stimulation of the BLA in its induction and early maintenance. However, it is not known how the late maintenance of LTP beyond its initial phases might be affected. Behavioral stimuli have been shown to result in a reinforcement of a transient early-LTP into a lasting potentiation. Here we show that BLA stimulation mimics the behavioral effects on early-LTP in freely moving rats when the BLA is activated within a time window of 30 min before or after tetanization of the perforant path. The reinforcement of LTP was blocked by inhibitors of muscarinergic and β-adrenergic but not dopaminergic receptors and was dependent on translation. Through these heterosynaptic associative interactions, hippocampal sensory information can be stabilized by amygdaloidal influences.
Presynaptic Ca2+Channels and Neurotransmitter Release at the Terminal of a Mouse Cortical Neuron
Authors: Qian Jing , Noebels Jeffrey L.
Published: April 2018

Regional variation in synaptic efficacy is an important determinant of associative processing as information flows through major circuits of the brain. The perforant path is the principal route of entry from cortex to the hippocampus and contains the first synapse in the cortical–hippocampal projection pathway. We used optical imaging techniques to analyze presynaptic Ca2+entry and neurotransmitter release at synapses in the medial perforant path linking stellate neurons located in layer II of the entorhinal cortex to granule cells in the dentate gyrus. Similar to other excitatory central synapses, the relationship between neurotransmitter release and the amount of Ca2+influx can be best described by a Hill equation with a Hill coefficient of 3.5. Our Ca2+channel toxin studies indicate that P/Q-type channels are the predominant Ca2+source triggering neurotransmitter release in this pathway, as shown by a potent inhibition of Ca2+entry and synaptic transmission by the P/Q-type channel blocker ω-agatoxin IVA. However, compared with the downstream hippocampal pyramidal neuron CA3–CA1 synapse, neurotransmitter release was less sensitive to the N-type Ca2+channel blocker ω-conotoxin GVIA, although the amount of N-type Ca2+current is comparable. The contribution of N-type channels to neurotransmitter release approximates that found at the CA3–CA1 synapse when tested under lower [Ca2+]o, which effectively reduces the size of the Ca2+microdomain surrounding each channel. These results suggest that P/Q-type channels are more closely associated with release machinery then N-type channels at this synapse and that cooperativity differences for each channel subtype may characterize variations in signaling at central synapses.
Sparks and Puffs in Oligodendrocyte Progenitors: Cross Talk between Ryanodine Receptors and Inositol Trisphosphate Receptors
Authors: Haak Laurel L. , Song Long-Sheng , Molinski Tadeusz F. , Pessah Isaac N. , Cheng Heping , Russell James T.
Published: April 2018

Investigating how calcium release from the endoplasmic reticulum (ER) is triggered and coordinated is crucial to our understanding of how oligodendrocyte progenitor cells (OPs) develop into myelinating cells. Sparks and puffs represent highly localized Ca2+release from the ER through ryanodine receptors (RyRs) and inositol trisphosphate receptors (IP3Rs), respectively. To study whether sparks or puffs trigger Ca2+waves in OPs, we performed rapid high-resolution line scan recordings in fluo-4-loaded OP processes. We found spontaneous and evoked sparks and puffs, and we have identified functional cross talk between IP3Rs and RyRs. Local events evoked using the IP3-linked agonist methacholine (MeCh) showed significantly different morphology compared with events evoked using the caffeine analog 3,7-dimethyl-1-propargylxanthine (DMPX). Pretreatment with MeCh potentiated DMPX-evoked events, whereas inhibition of RyRs potentiated events evoked by low concentrations of MeCh. Furthermore, activation of IP3Rs but not RyRs was critical for Ca2+wave initiation. Using immunocytochemistry, we show OPs express the specific Ca2+release channel subtypes RyR3 and IP3R2 in patches along OP processes. RyRs are coexpressed with IP3Rs in some patches, but IP3Rs are also found alone. This differential distribution pattern may underlie the differences in local and global Ca2+signals mediated by these two receptors. Thus, in OPs, interactions between IP3Rs and RyRs determine the spatial and temporal characteristics of calcium signaling, from microdomains to intracellular waves.
A Role of Netrin-1 in the Formation of the Subcortical Structure Striatum: Repulsive Action on the Migration of Late-Born Striatal Neurons
Authors: Hamasaki Tadashi , Goto Satoshi , Nishikawa Shigeyuki , Ushio Yukitaka
Published: April 2018

The mammalian striatum arises in the basal telencephalon and contains morphologically homogenous neurons that can be divided into two distinct compartments, patches and the matrix. During development, patch neurons are generated first to form a striatal primordium. After a large influx of later-born matrix neurons into this region, the unique mosaic arrangement of these two neuronal phenotypes is established. The massive migration of matrix neurons continues during the embryonic period, and they eventually comprise 80–85% of the mature striatum. To elucidate the cellular mechanism or mechanisms underlying this critical event in striatal histogenesis, we examined the migration characteristics of striatal subventricular zone (SVZ) cells at embryonic day 18 when neurogenesis peaks for matrix neurons. Using gel cultures, we show that netrin-1, one of the diffusible guidance cues expressed in the striatal ventricular zone (VZ), exerts a repulsive action on migrating SVZ cells. This effect is blocked in the presence of antibodies against Deleted in colorectal cancer (DCC), a putative receptor for netrin-1. The expression patterns ofnetrin-1and DCC strongly suggest the involvement of this effect in the outward migration of SVZ cells into the striatal postmitotic region. Our cell tracing study using living brain slices demonstrates that striatal SVZ cells migrate toward and disperse throughout the striatum, in which they differentiate into phenotypes of striatal projection neurons. We suggest that netrin-1 expressed in the striatal VZ serves to guide the large influx of striatal matrix neurons into the striatal primordium and is thereby involved in the initial formation of fundamental striatal structures.
GαolfLevels Are Regulated by Receptor Usage and Control Dopamine and Adenosine Action in the Striatum
Authors: Hervé Denis , Le Moine Catherine , Corvol Jean-Christophe , Belluscio Leonardo , Ledent Catherine , Fienberg Allen A. , Jaber Mohamed , Studler Jeanne-Marie , Girault Jean-Antoine
Published: April 2018

In the striatum, dopamine D1and adenosine A2Areceptors stimulate the production of cAMP, which is involved in neuromodulation and long-lasting changes in gene expression and synaptic function. Positive coupling of receptors to adenylyl cyclase can be mediated through the ubiquitous GTP-binding protein GαSsubunit or through the olfactory isoform, Gαolf, which predominates in the striatum. In this study, using doublein situhybridization, we show that virtually all striatal efferent neurons, identified by the expression of preproenkephalin A, substance P, or D1receptor mRNA, contained high amounts of GαolfmRNA and undetectable levels of GαsmRNA. In contrast, the large cholinergic interneurons contained both Gαolfand Gαstranscripts. To assess the functional relationship between dopamine or adenosine receptors and G-proteins, we examined G-protein levels in the striatum of D1and A2Areceptor knock-out mice. A selective increase in Gαolfprotein was observed in these animals, without change in mRNA levels. Conversely, Gαolflevels were decreased in animals lacking a functional dopamine transporter. These results indicate that Gαolfprotein levels are regulated through D1and A2Areceptor usage. To determine the functional consequences of changes in Gαolflevels, we used heterozygous Gαolfknock-out mice, which possess half of the normal Gαolflevels. In these animals, the locomotor effects of amphetamine and caffeine, two psychostimulant drugs that affect dopamine and adenosine signaling, respectively, were markedly reduced. Together, these results identify Gαolfas a critical and regulated component of both dopamine and adenosine signaling.
Dorsal Hippocampal Kindling Produces a Selective and Enduring Disruption of Hippocampally Mediated Behavior
Authors: Hannesson Darren K. , Howland John , Pollock Michael , Mohapel Paul , Wallace Amy E. , Corcoran Michael E.
Published: April 2018

Kindling produces enduring neural changes that are subsequently manifest in enhanced susceptibility to seizure-evoking stimuli and alterations in some types of behavior. The present study investigated the effects of dorsal hippocampal (dHPC) kindling on a variety of behaviors to clarify the nature of previously reported effects on spatial task performance. Rats were kindled twice daily with dHPC stimulation until three fully generalized seizures were evoked. Beginning 7 d later and on successive days, rats were tested in an elevated plus maze, a large circular open field, an open field object exploration task, and a delayed-match-to-place (DMTP) task in a water maze to assess anxiety-related and activity-related behavior (tasks 1 and 2), object recognition memory (task 3), and spatial cognition (task 4). Kindling disrupted performance on the DMTP task in a manner that was not delay dependent and produced a mild enhancement of activity-related behaviors in the open field task but not the elevated plus maze. All other aspects of testing were spared. These findings indicate that dHPC kindling produces enduring and selective effects on behavior that are consistent with a restricted disruption of hippocampally mediated functions. Possible bases for these effects are changes in local NMDA receptor function and/or changes in local inhibition, which might alter the optimal conditions for experience-dependent induction of intrahippocampal plasticity. This preparation may be useful for studying the mechanisms of mnemonic dysfunction associated with temporal lobe epilepsy and may offer unique insights into the mechanisms underlying normal hippocampal function.
Hierarchical Processing of Horizontal Disparity Information in the Visual Forebrain of Behaving Owls
Authors: Nieder Andreas , Wagner Hermann
Published: April 2018

According to their restricted receptive fields and input-filter characteristics, disparity-sensitive neurons at early processing levels of the visual system perform rather ambiguous computations; they respond vigorously to disparity in false-matched images and show multiple response peaks in their disparity-tuning profiles. On the other hand, the perception of depth from binocular disparity is reliable, thus raising the question as to where and how in the brain additional processing is accomplished leading toward behaviorally relevant disparity detection. To address this issue, tuning data during stimulation with correlated and anticorrelated random-dot stereograms (a-RDS) were obtained from 52 disparity-sensitive visual Wulst neurons in three behaving owls. From the disparity-tuning curves, several quantitative measures were derived that allowed to determine the response ambiguity of a cell. A systematic decline of response ambiguities with increasing response latencies was observed. An increase in response latencies of neurons was correlated with a decrease of the strength of responses to a-RDS. Declining responses to a-RDS are expected for global detectors, because an owl was not able to discriminate depth in psychophysical tests with a-RDS. In addition, suppression of response side peaks was increased and disparity tuning was enhanced with growing response latencies. These results suggest a functional hierarchy of disparity processing in the owl's forebrain, leading from spatial filters to more global disparity detectors that may be able to solve the correspondence problem. Nonlinear threshold operations and inhibition are proposed as candidate mechanisms to resolve coding ambiguities.
Neuronal Survival after CNS Insult Is Determined by a Genetically Encoded Autoimmune Response
Authors: Kipnis Jonathan , Yoles Eti , Schori Hadas , Hauben Ehud , Shaked Iftach , Schwartz Michal
Published: April 2018

Injury to the CNS is often followed by a spread of damage (secondary degeneration), resulting in neuronal losses that are substantially greater than might have been predicted from the severity of the primary insult. Studies in our laboratory have shown that injured CNS neurons can benefit from active or passive immunization with CNS myelin-associated antigens. The fact that autoimmune T-cells can be both beneficial and destructive, taken together with the established phenomenon of genetic predisposition to autoimmune diseases, raises the question: will genetic predisposition to autoimmune diseases affect the outcome of traumatic insult to the CNS? Here we show that the survival rate of retinal ganglion cells in adult mice or rats after crush injury of the optic nerve or intravitreal injection of a toxic dosage of glutamate is up to twofold higher in strains that are resistant to the CNS autoimmune disease experimental autoimmune encephalomyelitis (EAE) than in susceptible strains. The difference was found to be attributed, at least in part, to a beneficial T-cell response that was spontaneously evoked after CNS insult in the resistant but not in the susceptible strains. In animals of EAE-resistant but not of EAE-susceptible strains devoid of mature T-cells (as a result of having undergone thymectomy at birth), the numbers of surviving neurons after optic nerve injury were significantly lower (by 60%) than in the corresponding normal animals. Moreover, the rate of retinal ganglion cell survival was higher when the optic nerve injury was preceded by an unrelated CNS (spinal cord) injury in the resistant strains but not in the susceptible strains. It thus seems that, in normal animals of EAE-resistant strains (but not of susceptible strains), the injury evokes an endogenous protective response that is T-cell dependent. These findings imply that a protective T-cell-dependent response and resistance to autoimmune disease are regulated by a common mechanism. The results of this study compel us to modify our understanding of autoimmunity and autoimmune diseases, as well as the role of autoimmunity in non-autoimmune CNS disorders. They also obviously have far-reaching clinical implications in terms of prognosis and individual therapy.
TheOMP–lacZTransgene Mimics the Unusual Expression Pattern ofOR-Z6, a New Odorant Receptor Gene on Mouse Chromosome 6: Implication for Locus-Dependent Gene Expression
Authors: Pyrski Martina , Xu Zheng , Walters Eric , Gilbert Debra J. , Jenkins Nancy A. , Copeland Neal G. , Margolis Frank L.
Published: April 2018

Reporter gene expression in the olfactory epithelium of H-lacZ6 transgenic mice mimics the cell-selective expression pattern known for some odorant receptor genes. The transgene construct in these mice consists of thelacZcoding region, driven by the proximal olfactory marker protein (OMP) gene promoter, and shows expression in a zonally confined subpopulation of olfactory neurons. To address mechanisms underlying the odorant receptor-like expression pattern of thelacZconstruct, we analyzed the transgene-flanking region and identifiedOR-Z6, the first cloned odorant receptor gene that maps to mouse chromosome 6.OR-Z6bears the highest sequence similarity (85%) to a human odorant receptor gene at the syntenic location on human chromosome 7. We analyzed the expression pattern ofOR-Z6in olfactory tissues of H-lacZ6 mice and show that it bears strong similarities to that mapped for β-galactosidase. Expression of both genes in olfactory neurons is primarily restricted to the same medial subregion of the olfactory epithelium. Axons from both neuronal subpopulations project to the same ventromedial aspect of the anterior olfactory bulbs. Furthermore, colocalization analyses in H-lacZ6 mice demonstrate thatOR-Z6-reactive glomeruli receive axonal input fromlacZ-positive neurons as well. These results suggest that the expression of both genes is coordinated and that transgene expression in H-lacZ6 mice is regulated by locus-dependent mechanisms.
MIP-1α, MCP-1, GM-CSF, and TNF-α Control the Immune Cell Response That Mediates Rapid Phagocytosis of Myelin from the Adult Mouse Spinal Cord
Authors: Ousman Shalina S. , David Samuel
Published: April 2018

The slow immune response in the adult mammalian CNS results in slow myelin phagocytosis along degenerating white matter after injury. This has important consequences for axon regeneration because of the presence of axon growth inhibitors in myelin. In addition, abnormal immune cell responses in the CNS lead to demyelinating disease. Lysophosphatidylcholine (LPC) can induce an inflammatory response in the CNS, producing rapid demyelination without much damage to adjacent cells. In this study, we searched for the molecular switches that turn on this immune cell response. Using reverse transcription PCR analysis, we show that mRNA expression of macrophage inflammatory protein-1α (MIP-1α), macrophage chemotactic protein-1 (MCP-1), granulocyte macrophage-colony stimulating factor (GM-CSF), and tumor necrosis factor-α (TNF-α) in the spinal cord is rapidly and transiently upregulated after intraspinal injection of LPC. Neutralizing these signaling molecules with function-blocking antibodies suppresses recruitment of T-cells, neutrophils, and monocytes into the spinal cord, as well as significantly reduces the number of phagocytic macrophages and the demyelination induced by LPC. These findings will have important implications for CNS regeneration and demyelinating disease.
Taxol Induces Apoptosis in Cortical Neurons by a Mechanism Independent of Bcl-2 Phosphorylation
Authors: Figueroa-Masot Xavier A. , Hetman Michal , Higgins Matthew J. , Kokot Niels , Xia Zhengui
Published: April 2018

Bcl-2, an antiapoptotic protein, protects cells against many but not all forms of apoptosis. For example, Bcl-2 does not protect non-neuronal cells against taxol, a microtubule-stabilizing agent. The underlying mechanism for the ineffectiveness of Bcl-2 against taxol has been the subject of intense interest. Data from non-neuronal cells indicate that taxol-induced apoptosis requires activation of N-terminal c-Jun protein kinase (JNK) that phosphorylates and inactivates Bcl-2. This suggests the interesting possibility that the apoptotic activity of JNK may be caused by phosphorylation of Bcl-2 and inhibition of the antiapoptotic activity of Bcl-2. Here we report that taxol induces apoptosis in cortical neurons but by a mechanism significantly different from that in non-neuronal cells. In contrast to human embryonic kidney 293 cells, expression of wild-type Bcl-2 in cortical neurons protected against taxol-induced apoptosis, and taxol did not induce Bcl-2 phosphorylation. Furthermore, cortical neurons express high basal JNK activity, and taxol did not stimulate total JNK activity. However, taxol activated a subpool of JNK in the nucleus and stimulated c-Jun phosphorylation. JNK inhibition or expression of a dominant-negative c-Jun abrogated taxol-induced apoptosis in cortical neurons, suggesting a role for JNK and JNK-mediated transcription in taxol-stimulated apoptosis. Furthermore, taxol-induced apoptosis in cortical neurons required inhibition of phosphatidylinositol 3-kinase signaling. These data suggest that taxol induces apoptosis in neurons by a mechanism quite distinct from that of non-neuronal cell lines and emphasize the importance of elucidating apoptotic mechanisms specific for neurons in the CNS.
Hes1andHes5Activities Are Required for the Normal Development of the Hair Cells in the Mammalian Inner Ear
Authors: Zine Azel , Aubert Alexandre , Qiu Jiping , Therianos Stavros , Guillemot Francois , Kageyama Ryoichiro , de Ribaupierre Francois
Published: April 2018

The mammalian inner ear contains two sensory organs, the cochlea and vestibule. Their sensory neuroepithelia are characterized by a mosaic of hair cells and supporting cells. Cochlear hair cells differentiate in four rows: a single row of inner hair cells (IHCs) and three rows of outer hair cells (OHCs). Recent studies have shown that Math1, a mammalian homolog ofDrosophila atonalis a positive regulator of hair cell differentiation. The basic helix–loop–helix (bHLH) genesHes1andHes5(mammalianhairyandEnhancer-of-splithomologs) can influence cell fate determination by acting as negative regulators to inhibit the action of bHLH-positive regulators. We show by using reverse transcription-PCR analysis thatHes1,Hes5, andMath1are expressed in the developing mouse cochleae.In situhybridization revealed a widespread expression ofHes1in the greater epithelial ridge (GER) and in lesser epithelial ridge (LER) regions.Hes5is predominantly expressed in the LER, in supporting cells, and in a narrow band of cells within the GER.

Examination of cochleae fromHes1−/−mice showed a significant increase in the number of IHCs, whereas cochleae fromHes5−/−mice showed a significant increase in the number of OHCs. In the vestibular system, targeted deletion ofHes1and to a lesser extentHes5lead to formation of supernumerary hair cells in the saccule and utricle.

The supernumerary hair cells in the mutant mice showed an upregulation of Math1. These data indicate thatHes1andHes5participate together for the control of inner ear hair cell production, likely through the negative regulation of Math1.
Neuronal Cyclic AMP Controls the Developmental Loss in Ability of Axons to Regenerate
Authors: Cai Dongming , Qiu Jin , Cao Zixuan , McAtee Marietta , Bregman Barbara S. , Filbin Marie T.
Published: April 2018

Unlike neonatal axons, mammalian adult axons do not regenerate after injury. Likewise, myelin, a major factor in preventing regeneration in the adult, inhibits regeneration from older but not younger neurons. Identification of the molecular events responsible for this developmental loss of regenerative capacity is believed key to devising strategies to encourage regeneration in adults after injury. Here, we report that the endogenous levels of the cyclic nucleotide, cAMP, are dramatically higher in young neurons in which axonal growth is promoted both by myelin in general and by a specific myelin component, myelin-associated glycoprotein (MAG), than in the same types of neurons that, when older, are inhibited by myelin–MAG. Inhibiting a downstream effector of cAMP [protein kinase A (PKA)] prevents myelin–MAG promotion from young neurons, and elevating cAMP blocks myelin–MAG inhibition of neurite outgrowth in older neurons. Importantly, developmental plasticity of spinal tract axons in neonatal rat pupsin vivois dramatically reduced by inhibition of PKA. Thus, the switch from promotion to inhibition by myelin–MAG, which marks the developmental loss of regenerative capacity, is mediated by a developmentally regulated decrease in endogenous neuronal cAMP levels.