bluuebunny/crossref_metadata_2025 huggingface dataset:
Stimulation of β-Amyloid Precursor Protein Trafficking by Insulin Reduces Intraneuronal β-Amyloid and Requires Mitogen-Activated Protein Kinase Signaling
Authors: Gasparini Laura , Gouras Gunnar K. , Wang Rong , Gross Rachel S. , Beal M. Flint , Greengard Paul , Xu Huaxi
Published: April 2018

Alzheimer's Disease (AD) is characterized by cerebral accumulation of β-amyloid peptides (Aβ), which are proteolytically derived from β-amyloid precursor protein (βAPP). βAPP metabolism is highly regulated via various signal transduction systems, e.g., several serine/threonine kinases and phosphatases. Several growth factors known to act via receptor tyrosine kinases also have been demonstrated to regulate sβAPP secretion. Among these receptors, insulin and insulin-like growth factor-1 receptors are highly expressed in brain, especially in hippocampus and cortex. Emerging evidence indicates that insulin has important functions in brain regions involved in learning and memory. Here we present evidence that insulin significantly reduces intracellular accumulation of Aβ and that it does so by accelerating βAPP/Aβ trafficking from thetrans-Golgi network, a major cellular site for Aβ generation, to the plasma membrane. Furthermore, insulin increases the extracellular level of Aβ both by promoting its secretion and by inhibiting its degradation via insulin-degrading enzyme. The action of insulin on βAPP metabolism is mediated via a receptor tyrosine kinase/mitogen-activated protein (MAP) kinase kinase pathway. The results suggest cell biological and signal transduction mechanisms by which insulin modulates βAPP and Aβ trafficking in neuronal cultures.
The Homeostatic Regulation of Sleep Need Is under Genetic Control
Authors: Franken Paul , Chollet Didier , Tafti Mehdi
Published: April 2018

Delta power, a measure of EEG activity in the 1–4 Hz range, in slow-wave sleep (SWS) is in a quantitative and predictive relationship with prior wakefulness. Thus, sleep loss evokes a proportional increase in delta power, and excess sleep a decrease. Therefore, delta power is thought to reflect SWS need and its underlying homeostatically regulated recovery process. The neurophysiological substrate of this process is unknown and forward genetics might help elucidate the nature of what is depleted during wakefulness and recovered during SWS. We applied a mathematical method that quantifies the relationship between the sleep–wake distribution and delta power to sleep data of six inbred mouse strains. The results demonstrated that the rate at which SWS need accumulated varied greatly with genotype. This conclusion was confirmed in a “dose–response” study of sleep loss and changes in delta power; delta power strongly depended on both the duration of prior wakefulness and genotype. We followed the segregation of the rebound of delta power after sleep deprivation in 25 BXD recombinant inbred strains by quantitative trait loci (QTL) analysis. One “significant” QTL was identified on chromosome 13 that accounted for 49% of the genetic variance in this trait. Interestingly, the rate at which SWS need decreases did not vary with genotype in any of the 31 inbred strains studied. These results demonstrate, for the first time, that the increase of SWS need is under a strong genetic control, and they provide a basis for identifying genes underlying SWS homeostasis.
Coexpression of Microsomal-Type Prostaglandin E Synthase with Cyclooxygenase-2 in Brain Endothelial Cells of Rats during Endotoxin-Induced Fever
Authors: Yamagata Kanato , Matsumura Kiyoshi , Inoue Wataru , Shiraki Takuma , Suzuki Kyoko , Yasuda Shin , Sugiura Hiroko , Cao Chunyu , Watanabe Yasuyoshi , Kobayashi Shigeo
Published: April 2018

Fever is triggered by an elevation of prostaglandin E2(PGE2) in the brain. However, the mechanism of its elevation remains unanswered. We herein cloned the rat glutathione-dependent microsomal prostaglandin E synthase (mPGES), the terminal enzyme for PGE2biosynthesis, and examined its induction in the rat brain after intraperitoneal injection of pyrogen lipopolysaccharide (LPS). In Northern blot analysis,mPGESmRNA was weakly expressed in the brain under the normal conditions but was markedly induced between 2 and 4 hr after the LPS injection.In situhybridization study revealed that LPS-inducedmPGESmRNA signals were mainly associated with brain blood vessels, especially vein or venular-type ones, in the whole brain area. Immunohistochemical study demonstrated that mPGES-like immunoreactivity was expressed in the perinuclear region of brain endothelial cells, which were identified as von Willebrand factor-positive cells. Furthermore, in the perinuclear region of the endothelial cells, mPGES was colocalized with cyclooxygenase-2 (COX-2), which is the enzyme essential for the production of the mPGES substrate PGH2. Inhibition of cyclooxygenase-2 activity resulted in suppression of both PGE2level in the CSF and fever (Cao et al., 1997), suggesting that the two enzymes were functionally linked and that this link is essential for fever. These results demonstrate that brain endothelial cells play an essential role in the PGE2production during fever by expressing COX-2 and mPGES.
Intrathecal HIV-1 Envelope Glycoprotein gp120 Induces Enhanced Pain States Mediated by Spinal Cord Proinflammatory Cytokines
Authors: Milligan Erin D. , O'Connor Kevin A. , Nguyen Kien T. , Armstrong Charles B. , Twining Carin , Gaykema Ron P. A. , Holguin Adelina , Martin David , Maier Steven F. , Watkins Linda R.
Published: April 2018

Perispinal (intrathecal) injection of the human immunodeficiency virus-1 (HIV-1) envelope glycoprotein gp120 creates exaggerated pain states. Decreases in response thresholds to both heat stimuli (thermal hyperalgesia) and light tactile stimuli (mechanical allodynia) are rapidly induced after gp120 administration. gp120 is the portion of HIV-1 that binds to and activates microglia and astrocytes. These glial cells have been proposed to be key mediators of gp120-induced hyperalgesia and allodynia because these pain changes are blocked by drugs thought to affect glial function preferentially. The aim of the present series of studies was to determine whether gp120-induced pain changes involve proinflammatory cytokines [interleukin-1β (IL-1) and tumor necrosis factor-α (TNF-α)], substances released from activated glia. IL-1 and TNF antagonists each prevented gp120-induced pain changes. Intrathecal gp120 produced time-dependent, site-specific increases in TNF and IL-1 protein release into lumbosacral CSF; parallel cytokine increases in lumbar dorsal spinal cord were also observed. Intrathecal administration of fluorocitrate (a glial metabolic inhibitor), TNF antagonist, and IL-1 antagonist each blocked gp120-induced increases in spinal IL-1 protein. These results support the concept that activated glia in dorsal spinal cord can create exaggerated pain states via the release of proinflammatory cytokines.
Circadian Clock Regulation of pH in the Rabbit Retina
Authors: Dmitriev Andrey V. , Mangel Stuart C.
Published: April 2018

Although it is generally accepted that the acid–base ratio of tissue, as represented by the pH, is strictly regulated to maintain normal function, recent studies in the mammalian nervous system have shown that neuronal activity can result in significant shifts in pH. In the mammalian retina, many cellular phenomena, including neuronal activity, are regulated by a circadian clock. We thus investigated whether a clock regulates retinal pH, using pH-sensitive microelectrodes to measure the extracellular pH (pHo) of thein vitrorabbit retina in the subjective day and night, that is, under conditions of constant darkness. These measurements demonstrated that a circadian clock regulates the pHoof the rabbit retina so that the pHois lower at night than in the day. This day/night difference in retinal pHowas observed when the rabbits were maintained on a normal light/dark cycle and after they were maintained on a light/dark cycle that was phase-delayed by 9 hr. Continuous recordings of retinal pHoaround subjective dusk indicated that the change from daytime to nighttime pHois relatively fast and suggested that the clock that regulates pHois located in the retina. The lowest pHorecorded in the retina in both the day and night was in the vicinity of the inner segments of photoreceptor cells, supporting the idea that photoreceptors serve as the primary source of protons. The circadian-induced shift in pHowas several times greater than light-induced pHochanges. These findings suggest that a circadian clock in the mammalian retina regulates retinal pH.
Neuroprotection Mediated by Glial Cell Line-Derived Neurotrophic Factor: Involvement of a Reduction of NMDA-Induced Calcium Influx by the Mitogen-Activated Protein Kinase Pathway
Authors: Nicole Olivier , Ali Carine , Docagne Fabian , Plawinski Laurent , MacKenzie Eric T. , Vivien Denis , Buisson Alain
Published: April 2018

The glial cell line-derived neurotrophic factor (GDNF) is first characterized for its trophic activity on dopaminergic neurons. Recent data suggested that GDNF could modulate the neuronal death induced by ischemia. The purpose of this study was to characterize the influence of GDNF on cultured cortical neurons subjected to two paradigms of injury (necrosis and apoptosis) that have been identified during cerebral ischemia and to determine the molecular mechanisms involved. First, we demonstrated that both neurons and astrocytes express the mRNA and the protein for GDNF and its receptor complex (GFRα-1 and c-Ret). Next, we showed that the application of recombinant human GDNF to cortical neurons and astrocytes induces the activation of the MAP kinase (MAPK) pathway, as visualized by an increase in the phosphorylated forms of extracellular signal-regulated kinases (ERKs). Thereafter, we demonstrated that GDNF fails to prevent apoptotic neuronal death but selectively attenuates slowly triggered NMDA-induced excitotoxic neuronal death via a direct effect on cortical neurons. To further characterize the neuroprotective mechanisms of GDNF against NMDA-mediated neuronal death, we showed that a pretreatment with GDNF reduces NMDA-induced calcium influx. This effect likely results from a reduction of NMDA receptor activity rather than an enhanced buffering or extrusion capacity for calcium. Finally, we also demonstrated that an ERKs activation pathway is necessary for GDNF-mediated reduction of the NMDA-induced calcium response. Together, these results describe a novel mechanism by which the activation of MAPK induced by GDNF modulates NMDA receptor activity, a mechanism that could be responsible for the neuroprotective effect of GDNF in acute brain injury.
A Novel Role of Vasopressin in the Brain: Modulation of Activity-Dependent Water Flux in the Neocortex
Authors: Niermann Heike , Amiry-Moghaddam Mahmood , Holthoff Knut , Witte Otto W. , Ottersen Ole Petter
Published: April 2018

The brain contains an intrinsic vasopressin fiber system the function of which is unknown. It has been demonstrated recently that astrocytes express high levels of a water channel, aquaporin-4 (AQP4). Because vasopressin is known to regulate aquaporin expression and translocation in kidney collecting ducts and thereby control water reabsorption, we hypothesized that vasopressin might serve a similar function in the brain. By recording intrinsic optical signals in an acute cortical slice preparation we showed that evoked neuronal activity generates a radial water flux in the neocortex. The rapid onset and high capacity of this flux suggest that it is mediated through the AQP4-containing astrocytic syncytium that spans the entire thickness of the neocortical mantle. Vasopressin and vasopressin receptor V1a agonists were found to facilitate this flux. V1a antagonists blocked the facilitatory effect of vasopressin and reduced the water flux even in the absence of any exogenous agonist. V2 agonists or antagonists had no effect. These data suggest that vasopressin and V1a receptors play a crucial role in the regulation of brain water and ion homeostasis, most probably by modulating aquaporin-mediated water flux through astrocyte plasma membranes.
Lack of Neurotrophin-4 Causes Selective Structural and Chemical Deficits in Sympathetic Ganglia and Their Preganglionic Innervation
Authors: Roosen Alexander , Schober Andreas , Strelau Jens , Böttner Martina , Faulhaber Jörg , Bendner Gerald , McIlwrath Sabrina L. , Seller Horst , Ehmke Heimo , Lewin Gary R. , Unsicker Klaus
Published: April 2018

Neurotrophin-4 (NT-4) is perhaps the still most enigmatic member of the neurotrophin family. We show here thatNT-4is expressed in neurons of paravertebral and prevertebral sympathetic ganglia, i.e., the superior cervical (SCG), stellate (SG), and celiac (CG) ganglion. Mice deficient forNT-4showed a significant reduction (20–30%) of preganglionic sympathetic neurons in the intermediolateral column (IML) of the thoracic spinal cord. In contrast, neuron numbers in the SCG, SG, and CG were unchanged. Numbers of axons in the thoracic sympathetic trunk (TST) connecting the SG with lower paravertebral ganglia were also reduced, whereas axon numbers in the cervical sympathetic trunk (CST) were unaltered. Axon losses in the TST were paralleled by losses of synaptic terminals on SG neurons visualized by electron microscopy. Furthermore, immunoreactivity for the synaptic vesicle antigen SV2 was clearly reduced in the SG and CG. Levels of catecholamines and tyrosine hydroxylase immunoreactivity were dramatically reduced in the SG and the CG but not in the SCG. Despite this severe phenotype in the sympathetic system, blood pressure levels were not reduced and displayed a pattern more typical of deficits in baroreceptor afferents. Numbers of IML neurons were unaltered at postnatal day 4, suggesting a postnatal requirement for their maintenance. In light of these and previous data, we hypothesize that NT-4 provided by postganglionic sympathetic neurons is required for establishing and/or maintaining synapses of IML neurons on postganglionic cells. Impairment of synaptic connectivity may consequently reduce impulse flow, causing a reduction in transmitter synthesis in postganglionic neurons.
The Expression Pattern of the Cell Cycle Inhibitor p19INK4dby Progenitor Cells of the Rat Embryonic Telencephalon and Neonatal Anterior Subventricular Zone
Authors: Coskun Volkan , Luskin Marla B.
Published: April 2018

In this study we investigated whether the pattern of expression of the cyclin-dependent kinase inhibitor p19INK4dby the unique progenitor cells of the neonatal anterior subventricular zone (SVZa) can account for their ability to divide even though they express phenotypic characteristics of differentiated neurons. p19INK4dwas chosen for analysis because it usually acts to block permanently the cell cycle at the G1phase. p19INK4dimmunoreactivity and the incorporation of bromodeoxyuridine (BrdU) by SVZa cells were compared with that of the more typical progenitor cells of the prenatal telencephalic ventricular zone. In the developing telencephalon, p19INK4dis expressed by postmitotic cells and has a characteristic perinuclear distribution depending on the laminar position and state of differentiation of a cell. Moreover, the laminar-specific staining of the developing cerebral cortex revealed that the ventricular zone (VZ) is divided into p19INK4d(+) and p19INK4d(−) sublaminae, indicating that the VZ has a previously unrecognized level of functional organization. Furthermore, the rostral migratory stream, traversed by the SVZa-derived cells, exhibits an anteriorhigh–posteriorlowgradient of p19INK4dexpression. On the basis of the p19INK4dimmunoreactivity and BrdU incorporation, SVZa-derived cells appear to exit and reenter the cell cycle successively. Thus, in contrast to telencephalic VZ cells, SVZa cells continue to undergo multiple rounds of division and differentiation before becoming postmitotic.
Mobilization of Calcium from Intracellular Stores, Potentiation of Neurotransmitter-Induced Calcium Transients, and Capacitative Calcium Entry by 4-Aminopyridine
Authors: Grimaldi Maurizio , Atzori Marco , Ray Pulak , Alkon Daniel L.
Published: April 2018

In this study we analyzed the effect of 4-aminopyridine (4-AP) on free cytosolic calcium concentration ([Ca2+]i) in basal conditions, after stimulation with neurotransmitters, and during capacitative calcium entry.

Using fura-2 ratiometric calcium imaging, we found that 4-AP increased [Ca2+]iin type I astrocytes, neurons, and in skeletal muscle cells. The [Ca2+]ielevation induced by 4-AP was concentration-dependent and consisted of two phases: the first was dependent on intracellular calcium mobilization, and the second was dependent on extracellular calcium influx. 4-AP also increased the second messenger inositol trisphosphate in both neurons and astrocytes.

In astrocytes, 4-AP treatment potentiated the sustained phase of the [Ca2+]ielevation induced by ATP and bradykinin. In addition, capacitative calcium entry was potentiated severalfold by 4-AP, in astrocytes and muscle cells but not in neurons. These effects of 4-AP were completely and promptly reversible. 4-AP blocked voltage-sensitive K+currents in astrocytes. However, voltage-sensitive K+channel blockers inhibiting these currents did not affect agonist-induced calcium transients or capacitative calcium entry, indicating that 4-AP effects on [Ca2+]iwere not caused by the blockade of voltage-gated K+channels.

We conclude that 4-AP is able to affect calcium homeostasis at multiple levels, from increasing basal [Ca2+]ito potentiating capacitative calcium entry. The potentiation of capacitative calcium entry in astrocytes or muscle cells may explain some of the therapeutic activities of 4-AP as a neurotransmission enhancer.
Long-Lasting Reconfiguration of Two Interacting Networks by a Cooperation of Presynaptic and Postsynaptic Plasticity
Authors: Nargeot Romuald
Published: April 2018

The functional reconfiguration of central neuronal networks, a phenomenon by which neurons change their participation in network operation, is important for organizing adaptive behaviors. Such reconfiguration can be expressed in a long-lasting manner (hours, days) after a training paradigm. The present study shows that such a long-lasting network reconfiguration requires a cooperation of both presynaptic and postsynaptic modifications in a neuronal interaction between two functionally distinct networks. In isolated preparations of the lobster stomatogastric nervous system, the single ventral dilator (VD) neuron can switch its functional participation from one discrete network (the pyloric network) to another (the cardiac sac network). This switching capability can be long-lasting and can be induced by a sensitizing procedure. A persistent change that was associated with this neuronal switching was found in each of the two networks. First, the intrinsic membrane properties of the VD neuron that allow it to participate spontaneously in the pyloric network are altered. Second, bursting activity is strengthened in the inferior ventricular neurons that both drive cardiac sac network activity and monosynaptically excite the VD neuron in phase with this network activity. Importantly, these changes in intrinsic properties of both presynaptic and postsynaptic neurons are required to allow the VD neuron switching, because expression of either the presynaptic or the postsynaptic change alone did not permit VD neuron switching to occur. These results suggest that a cooperative modification of a discrete network interaction is able to persistently switch the output pattern of a motor neuron as a result of a sensitizing paradigm.
Negative Cross Talk between Anionic GABAAand Cationic P2X Ionotropic Receptors of Rat Dorsal Root Ganglion Neurons
Authors: Sokolova Elena , Nistri Andrea , Giniatullin Rashid
Published: April 2018

Using whole-cell patch-clamp recording and intracellular Ca2+imaging of rat cultured DRG neurons, we studied the cross talk between GABAAand P2X receptors. A rapidly fading current was the main response to ATP, whereas GABA elicited slowly desensitizing inward currents. Coapplication of these agonists produced a total current much smaller than the linear summation of individual responses (68 ± 5% with 10 μmATP plus 100 μmGABA). Occlusion was observed regardless of ATP response type. Neurons without functional P2X receptors manifested no effect of ATP on GABA currents (and vice versa). Occlusion was also absent in the presence of the P2X blocker trinitrophenyl-ATP (TNP-ATP) or of the GABA blocker picrotoxin, indicating a lack of involvement by metabotropic ATP or GABA receptors. Less occlusion was obtained when ATP was applied 2 sec after GABA than when GABA was applied after ATP. Changing the polarity of GABA currents by using intracellular SO42−instead of Cl−significantly reduced the occlusion of ATP currents by GABA, suggesting an important role for Cl−efflux in this phenomenon. Occlusion was enhanced whenever intracellular Ca2+([Ca2+]i) was not buffered, indicating the cross talk-facilitating role of this divalent cation. Ca2+imaging showed that ATP (but not GABA) increased [Ca2+]iin voltage-clamped or intact neurons. Our data demonstrated a novel Cl−and Ca2+-dependent interaction between cationic P2X and anionic GABAAreceptors of DRG neurons. Such negative cross talk might represent a model for a new mechanism to inhibit afferent excitation to the spinal cord as GABA and ATP are coreleased within the dorsal horn.
Chemokines and Glycoprotein120 Produce Pain Hypersensitivity by Directly Exciting Primary Nociceptive Neurons
Authors: Oh Seog Bae , Tran Phuong B. , Gillard Samantha E. , Hurley Robert W. , Hammond Donna L. , Miller Richard J.
Published: April 2018

Human immunodeficiency virus-1 (HIV-1) infection is associated with numerous effects on the nervous system, including pain and peripheral neuropathies. We now demonstrate that cultured rat dorsal root ganglion (DRG) neurons express a wide variety of chemokine receptors, including those that are thought to act as receptors for the HIV-1 coat protein glycoprotein120 (gp120). Chemokines that activate all of the known chemokine receptors increased [Ca2+]iin subsets of cultured DRG cells. Many neurons responded to multiple chemokines and also to bradykinin, ATP, and capsaicin. Immunohistochemical studies demonstrated the expression of the CXCR4 and CCR4 chemokine receptors on populations of DRG neurons that also expressed substance P and the VR1 vanilloid receptor. RT-PCR analysis confirmed the expression of CXCR4, CX3CR1, CCR4, and CCR5 mRNAs in DRG neurons. Chemokines and gp120 produced excitatory effects on DRG neurons and also stimulated the release of substance P. Chemokines and gp120 also produced allodynia after injection into the rat paw. Thus these results provide evidence that chemokines and gp120 may produce painful effects via direct actions on chemokine receptors expressed by nociceptive neurons. Chemokine receptor antagonists may be important therapeutic interventions in the pain that is associated with HIV-1 infection and inflammation.
α2-Chimaerin, a Cdc42/Rac1 Regulator, Is Selectively Expressed in the Rat Embryonic Nervous System and Is Involved in Neuritogenesis in N1E-115 Neuroblastoma Cells
Authors: Hall Christine , Michael Gregory J. , Cann Nansi , Ferrari Giovanna , Teo Mabel , Jacobs Tom , Monfries Clinton , Lim Louis
Published: April 2018

Neuronal differentiation involves Rac and Cdc42 GTPases. α-Chimaerin, a Rac/Cdc42 regulator, occurs as α1- and alternatively spliced Src homology 2 (SH2) domain-containing α2-isoforms. α2-chimaerin mRNA was highly expressed in the rat embryonic nervous system, especially in early postmitotic neurons. α1-chimaerin mRNA was undetectable before embryonic day 16.5. Adult α2-chimaerin mRNA was restricted to neurons within specific brain regions, with highest expression in the entorhinal cortex. α2-chimaerin protein localized to neuronal perikarya, dendrites, and axons. The overall pattern of α2-chimaerin mRNA expression resembles that of cyclin-dependent kinase regulator p35 (CDK5/p35) which participates in neuronal differentiation and with which chimaerin interacts. To determine whether α2-chimaerin may have a role in neuronal differentiation and the relevance of the SH2 domain, the morphological effects of both chimaerin isoforms were investigated in N1E-115 neuroblastoma cells. When plated on poly-lysine, transient α2-chimaerin but not α1-chimaerin transfectants formed neurites. Permanent α2-chimaerin transfectants generated neurites whether or not they were stimulated by serum starvation, and many cells were enlarged. Permanent α1-chimaerin transfectants displayed numerous microspikes and contained F-actin clusters, a Cdc42-phenotype, but generated few neurites. In neuroblastoma cells, α2-chimaerin was predominantly soluble with some being membrane-associated, whereas α1-chimaerin was absent from the cytosol, being membrane- and cytoskeleton-associated, paralleling their subcellular distribution in brain. Transient transfection with α2-chimaerin mutated in the SH2 domain (N94H) generated an α1-chimaerin-like phenotype, protein partitioned in the particulate fraction, and in NGF-stimulated pheochromocytoma cell line 12 (PC12) cells, neurite formation was inhibited. These results indicate a role for α2-chimaerin in morphological differentiation for which its SH2 domain is vital.
Hyperactivity and Intact Hippocampus-Dependent Learning in Mice Lacking the M1Muscarinic Acetylcholine Receptor
Authors: Miyakawa Tsuyoshi , Yamada Masahisa , Duttaroy Alokesh , Wess Jürgen
Published: April 2018

Members of the muscarinic acetylcholine receptor family are thought to play key roles in the regulation of a large number of important functions of the CNS. However, the precise roles of the individual muscarinic receptor subtypes in modulating these processes are not well understood at present, primarily because of the lack of ligands with sufficient receptor subtype selectivity. To investigate the behavioral significance of the M1muscarinic receptor (M1R), which is abundantly expressed in the forebrain, we subjected M1receptor-deficient mice (M1R−/−mice) to a battery of behavioral tests.M1R−/−mice showed no significant impairments in neurological reflexes, motor coordination, pain sensitivity, and prepulse inhibition. Strikingly, however,M1R−/−mice consistently exhibited a pronounced increase in locomotor activity in various tests, including open field, elevated plus maze, and light/dark transition tests. Moreover,M1R−/−mice showed reduced immobilization in the Porsolt forced swim test and reduced levels of freezing after inescapable footshocks, suggesting thatM1R−/−mice are hyperactive under stressful conditions as well. An increased number of social contacts was observed in a social interaction test. Surprisingly,M1R−/−mice displayed no significant cognitive impairments in the Morris water maze and in contextual fear conditioning.M1R−/−mice showed slight performance deficits in auditory-cued fear conditioning and in an eight-arm radial maze, most likely because of the hyperactivity phenotype displayed by theM1R−/−mice. Our results indicate that M1muscarinic receptors play an important role in the regulation of locomotor activity but appear to be less critical for cognitive processes, as generally assumed.
Attention Systems and the Organization of the Human Parietal Cortex
Authors: Rushworth M. F. S. , Paus T. , Sipila P. K.
Published: April 2018

Event-related functional magnetic resonance imaging was used to compare activity in the human parietal cortex in two attention-switching paradigms. On each trial of the visual switching (VS) paradigm, subjects attended to one of two visual stimuli on the basis of either their color or shape. Trials were presented in blocks interleaved with cues instructing subjects to either continue attending to the currently relevant dimension or to switch to the other stimulus dimension. In the response switching (RS) paradigm, subjects made one of two manual responses to the single stimulus presented on each trial. The rules for stimulus–response mapping were reversed on different trials. Trials were presented in blocks interleaved with cues that instructed subjects to either switch stimulus–response mapping rules or to continue with the current rule. Brain activity at “switch” and “stay” events was compared. The results revealed distinct parietal areas concerned with visual attentional set shifts (VS) and visuomotor intentional set shifts (RS). In VS, activity was recorded in the lateral part of the intraparietal region. In RS, activity was recorded in the posterior medial intraparietal region and adjacent posterior superior and dorsomedial parietal cortex. The results also suggest that the basic functional organization of the intraparietal sulcus and surrounding regions is similar in both macaque and human species.
Whisker Deafferentation and Rodent Whisking Patterns: Behavioral Evidence for a Central Pattern Generator
Authors: Gao Puhong , Bermejo Roberto , Zeigler H. Philip
Published: April 2018

Even in the absence of explicit stimulation, rats emit patterns of rhythmic whisking movements. Because of their stereotyped nature and their persistence after sensory denervation and cortical ablation, whisking movements have been assumed to reflect the output of a central pattern generator (CPG). However, identification of a movement pattern as the product of a CPG requires evidence that its generation, patterning, and coordination are independent of sensory input. To provide such evidence, we used optoelectronic instrumentation to obtain high-resolution records of the movement trajectories of individual whiskers in rats whose heads were fixed to isolate their exploratory whisking from exafferent inputs. Unconditioned whisking patterns were quantitatively characterized by a biometric analysis of the kinematics, rhythmicity, and coordination of bilaterally homologous vibrissa movements. Unilateral and bilateral sectioning of the infraorbital nerve, which innervates the whiskers, was then performed to block reafferent inputs generated by the animal's own whisking movements. Unilateral sectioning of the nerve has no effect on whisking kinematics but is followed by a significant but relatively transient bilateral increase in whisking frequency. However, bilateral deafferentation, when performed in a single-stage procedure, does not disrupt the generation, patterning, or bilateral coordination of whisking patterns in the rat. These findings provide strong behavioral evidence for a whisking CPG and are discussed in relation to its possible location and properties.
Presynaptic Ca2+-Activated K+Channels in Glutamatergic Hippocampal Terminals and Their Role in Spike Repolarization and Regulation of Transmitter Release
Authors: Hu Hua , Shao Li-Rong , Chavoshy Sorush , Gu Ning , Trieb Maria , Behrens Ralf , Laake Petter , Pongs Olaf , Knaus Hans Günther , Ottersen Ole Petter , Storm Johan F.
Published: April 2018

Large-conductance Ca2+-activated K+channels (BK, also called Maxi-K orSlochannels) are widespread in the vertebrate nervous system, but their functional roles in synaptic transmission in the mammalian brain are largely unknown. By combining electrophysiology and immunogold cytochemistry, we demonstrate the existence of functional BK channels in presynaptic terminals in the hippocampus and compare their functional roles in somata and terminals of CA3 pyramidal cells. Double-labeling immunogold analysis with BK channel and glutamate receptor antibodies indicated that BK channels are targeted to the presynaptic membrane facing the synaptic cleft in terminals of Schaffer collaterals in stratum radiatum. Whole-cell, intracellular, and field-potential recordings from CA1 pyramidal cells showed that the presynaptic BK channels are activated by calcium influx and can contribute to repolarization of the presynaptic action potential (AP) and negative feedback control of Ca2+influx and transmitter release. This was observed in the presence of 4-aminopyridine (4-AP, 40–100 μm), which broadened the presynaptic compound action potential. In contrast, the presynaptic BK channels did not contribute significantly to regulation of action potentials or transmitter release under basal experimental conditions, i.e., without 4-AP, even at high stimulation frequencies. This is unlike the situation in the parent cell bodies (CA3 pyramidal cells), where BK channels contribute strongly to action potential repolarization. These results indicate that the functional role of BK channels depends on their subcellular localization.
Roles of Glutamate Receptor δ2 Subunit (GluRδ2) and Metabotropic Glutamate Receptor Subtype 1 (mGluR1) in Climbing Fiber Synapse Elimination during Postnatal Cerebellar Development
Authors: Hashimoto Kouichi , Ichikawa Ryoichi , Takechi Hajime , Inoue Yoshiro , Aiba Atsu , Sakimura Kenji , Mishina Masayoshi , Hashikawa Tsutomu , Konnerth Arthur , Watanabe Masahiko , Kano Masanobu
Published: April 2018

Climbing fiber (CF) synapse formation onto cerebellar Purkinje cells (PCs) is critically dependent on the synaptogenesis from parallel fibers (PFs), the other input to PCs. Previous studies revealed that deletion of the glutamate receptor δ2 subunit (GluRδ2) gene results in persistent multiple CF innervation of PCs with impaired PF synaptogenesis, whereas mutation of the metabotropic glutamate receptor subtype 1 (mGluR1) gene causes multiple CF innervation with normal PF synaptogenesis. We demonstrate that atypical CF-mediated EPSCs (CF-EPSCs) with slow rise times and small amplitudes coexisted with typical CF-EPSCs with fast rise times and large amplitudes in PCs from GluRδ2 mutant cerebellar slices. CF-EPSCs in mGluR1 mutant and wild-type PCs had fast rise times. Atypical slow CF responses of GluRδ2 mutant PCs were associated with voltage-dependent Ca2+signals that were confined to PC distal dendrites. In the wild-type and mGluR1 mutant PCs, CF-induced Ca2+signals involved both proximal and distal dendrites. Morphologically, CFs of GluRδ2 mutant mice extended to the superficial regions of the molecular layer, whereas those of wild-type and mGluR1 mutant mice did not innervate the superficial one-fifth of the molecular layer. It is therefore likely that surplus CFs of GluRδ2 mutant mice form ectopic synapses onto distal dendrites, whereas those of wild-type and mGluR1 mutant mice innervate proximal dendrites. These findings suggest that GluRδ2 is required for consolidating PF synapses and restricting CF synapses to the proximal dendrites, whereas the mGluR1-signaling pathway does not affect PF synaptogenesis but is involved in eliminating surplus CF synapses at the proximal dendrites.
Experience-Dependent Plasticity of Mouse Visual Cortex in the Absence of the Neuronal Activity-Dependent Markeregr1/zif268
Authors: Mataga Nobuko , Fujishima Sayaka , Condie Brian G. , Hensch Takao K.
Published: April 2018

Neuronal activity elicits a rapid increase in the expression of several immediate early genes (IEGs). To clarify a role for IEG response in activity-dependent development, we examined the contribution of theegr1/zif268gene during visual cortical processing and plasticity in mice. We first analyzed the expression ofegr1mRNA in wild-type (WT) mice using Northern blot hybridization. In the visual cortex, expression ofegr1mRNA increased dramatically after eye opening, systemic injection of kainate, or 30 min of photostimulation after a brief (5 d) period of dark adaptation. Thus, the expression ofegr1is regulated by synaptic activity in the mouse visual cortex, as it is in other species (e.g., monkeys, cats, and rats).

To evaluate whether this transcription factor is directly involved in activity-dependent plasticity, mice lacking Egr1 were deprived of the use of one eye during the developmental critical period [postnatal day 24 (P24)–P34]. Extracellularin vivosingle-unit recordings from the binocular zone of the visual cortex revealed that visual responses developed normally inegr1knock-out (KO) mice. Moreover, a similarly significant shift of responsiveness in favor of the open eye was produced in both KO and WT mice by either brief (4 d) or long-term (>2 weeks) occlusion of one eye. There was no apparent compensation amongegr2,egr3, orc-fosmRNA and protein expression in the visual cortex ofegr1KO mice.

Taken together, these results indicate thategr1is a useful marker of sensory input in mice but is not intrinsically necessary for the experience-dependent plasticity of the visual cortex. Our findings underscore a mechanistic distinction between sensory plasticity and long-lasting forms of synaptic potentiation in the hippocampus, for whichegr1/zif268was recently found to be essential.
Perceptual Correlates of Neural Representations Evoked by Odorant Enantiomers
Authors: Linster Christiane , Johnson Brett A. , Yue Esther , Morse Alix , Xu Zhe , Hingco Edna E. , Choi Yoojin , Choi Mark , Messiha Ahdy , Leon Michael
Published: April 2018

Spatial activation patterns within the olfactory bulb are believed to contribute to the neural representation of odorants. In this study, we attempted to predict the perceptions of odorants from their evoked patterns of neural activity in the olfactory bulb. We first describe the glomerular activation patterns evoked by pairs of odorant enantiomers based on the uptake of [14C]2-deoxyglucose in the olfactory bulb glomerular layer. Using a standardized data matrix enabling the systematic comparison of these spatial odorant representations, we hypothesized that the degree of similarity among these representations would predict their perceptual similarity. The two enantiomers of carvone evoked overlapping but significantly distinct regions of glomerular activity; however, the activity patterns evoked by the enantiomers of limonene and of terpinen-4-ol were not statistically different from one another. Commensurate with these data, rats spontaneously discriminated between the enantiomers of carvone, but not between the enantiomers of limonene or terpinen-4-ol, in an olfactory habituation task designed to probe differences in olfactory perception.
Prevention of Cannabinoid Withdrawal Syndrome by Lithium: Involvement of Oxytocinergic Neuronal Activation
Authors: Cui Shu-Sen , Bowen Rudy C. , Gu Gui-Bao , Hannesson Darren K. , Yu Peter H. , Zhang Xia
Published: April 2018

Cannabis (i.e., marijuana and cannabinoids) is the most commonly used illicit drug in developed countries, and the lifetime prevalence of marijuana dependence is the highest of all illicit drugs in the United States. To provide clues for finding effective pharmacological treatment for cannabis-dependent patients, we examined the effects and possible mechanism of lithium administration on the cannabinoid withdrawal syndrome in rats.

A systemic injection of the mood stabilizer lithium, at serum levels that were clinically relevant, prevented the cannabinoid withdrawal syndrome. The effects of lithium were accompanied by expression of the cellular activation marker Fos proteins within most oxytocin-immunoreactive neurons and a significant increase in oxytocin mRNA expression in the hypothalamic paraventricular and supraoptic nuclei. Lithium also produced a significant elevation of oxytocin levels in the peripheral blood. We suggest that the effects of lithium against the cannabinoid withdrawal syndrome are mediated by oxytocinergic neuronal activation and subsequent release and action of oxytocin within the CNS. In support of our hypothesis, we found that the effects of lithium against the cannabinoid withdrawal syndrome were antagonized by systemic preapplication of an oxytocin antagonist and mimicked by systemic or intracerebroventricular injection of oxytocin.

These results demonstrate that oxytocinergic neuronal activation plays a critical role in the action of lithium against the cannabinoid withdrawal syndrome in rats, thus providing a potentially novel strategy for the treatment of cannabis dependence in humans.
Role of Calcium, Glutamate Neurotransmission, and Nitric Oxide in Spreading Acidification and Depression in the Cerebellar Cortex
Authors: Chen Gang , Dunbar Robert L. , Gao Wangcai , Ebner Timothy J.
Published: April 2018

This study investigated the mechanisms underlying the recently reported fast spreading acidification and transient depression in the cerebellar cortexin vivo. Spreading acidification was evoked by surface stimulation in the rat and mouse cerebellar cortex stained with the pH-sensitive dye neutral red and monitored using epifluorescent imaging. The probability of evoking spreading acidification was dependent on stimulation parameters; greater frequency and/or greater amplitude were more effective. Although activation of the parallel fibers defined the geometry of the spread, their activation alone was not sufficient, because blocking synaptic transmission with low Ca2+prevented spreading acidification. Increased postsynaptic excitability was also a major factor. Application of either AMPA or metabotropic glutamate receptor antagonists reduced the likelihood of evoking spreading acidification, but stronger stimulation intensities were still effective. Conversely, superfusion with GABA receptor antagonists decreased the threshold for evoking spreading acidification. Blocking nitric oxide synthase (NOS) increased the threshold for spreading acidification, and nitric oxide donors lowered the threshold. However, spreading acidification could be evoked in neuronal NOS-deficient mice (B6;129S-Nos1tm1plh). The depression in cortical excitability that accompanies spreading acidification occurred in the presence of AMPA and metabotropic glutamate receptor antagonists and NOS inhibitors. These findings suggest that spreading acidification is dependent on extracellular Ca2+and glutamate neurotransmission with a contribution from both AMPA and metabotropic glutamate receptors and is modulated by nitric oxide. Therefore, spreading acidification involves both presynaptic and postsynaptic mechanisms. We hypothesize that a regenerative process, i.e., a nonpassive process, is operative that uses the cortical architecture to account for the high speed of propagation.
Comparing the Functional Representations of Central and Border Whiskers in Rat Primary Somatosensory Cortex
Authors: Brett-Green Barbara A. , Chen-Bee Cynthia H. , Frostig Ron D.
Published: April 2018

The anatomical representations of the large facial whiskers, termed barrels, are topographically organized and highly segregated in the posteromedial barrel subfield (PMBSF) of rat layer IV primary somatosensory cortex. Although the functional representations of single whiskers are aligned with their appropriate barrels, their areal extents are rather large, spreading outward from the appropriate barrel along the tangential plane and thereby spanning multiple neighboring and non-neighboring barrels and septal regions. To date, single-whisker functional representations have been characterized primarily for whiskers whose corresponding barrels are located centrally within the PMBSF (central whiskers). Using intrinsic signal imaging verified with post-imaging single-unit recording, we demonstrate that border whiskers, whose barrels are located at the borders of the PMBSF, also evoke large activity areas that are similar in size to those of central whiskers but spread beyond the PMBSF and sometimes beyond primary somatosensory cortex into the neighboring dysgranular zones. This study indicates that the large functional representation of a single whisker is a basic functional feature of the rat whisker-to-barrel system and, combined with results from other studies, suggest that a large functional representation of a small, point-like area on the sensory epithelium may be a functional feature of primary sensory cortex in general.
Microtubule-Associated Protein 1A (MAP1A) and MAP1B: Light Chains Determine Distinct Functional Properties
Authors: Noiges Rainer , Eichinger René , Kutschera Waltraud , Fischer Irmgard , Németh Zsuzsanna , Wiche Gerhard , Propst Friedrich
Published: April 2018

The microtubule-associated proteins 1A (MAP1A) and 1B (MAP1B) are distantly related protein complexes consisting of heavy and light chains and are thought to play a role in regulating the neuronal cytoskeleton, MAP1B during neuritogenesis and MAP1A in mature neurons. To elucidate functional differences between MAP1B and MAP1A and to determine the role of the light chain in the MAP1A protein complex, we chose to investigate the functional properties of the light chain of MAP1A (LC2) and compare them with the light chain of MAP1B (LC1). We found that LC2 binds to microtubulesin vivoandin vitroand induces rapid polymerization of tubulin. A microtubule-binding domain in its NH2terminus was found to be necessary and sufficient for these activities. The analysis of LC1 revealed that it too bound to microtubules and induced tubulin polymerization via a crucial but structurally unrelated NH2-terminal domain. The two light chains differed, however, in their effects on microtubule bundling and stabilityin vivo. Furthermore, we identified actin filament binding domains located at the COOH terminus of LC2 and LC1 and obtained evidence that binding to actin filaments is attributable to direct interaction with actin. Our findings establish LC2 as a crucial determinant of MAP1A function, reveal LC2 as a potential linker of neuronal microtubules and microfilaments, and suggest that the postnatal substitution of MAP1B by MAP1A leads to expression of a protein with an overlapping but distinct set of functions.
Versican Is Upregulated in CNS Injury and Is a Product of Oligodendrocyte Lineage Cells
Authors: Asher Richard A. , Morgenstern Daniel A. , Shearer Morven C. , Adcock Kathryn H. , Pesheva Penka , Fawcett James W.
Published: April 2018

Chondroitin sulfate proteoglycan (CS-PG) expression is increased in response to CNS injury and limits the capacity for axonal regeneration. Previously we have shown that neurocan is one of the CS-PGs that is upregulated (Asher et al., 2000). Here we show that another member of the aggrecan family, versican, is also upregulated in response to CNS injury. Labeling of frozen sections 7 d after a unilateral knife lesion to the cerebral cortex revealed a clear increase in versican immunoreactivity around the lesion. Western blot analysis of extracts prepared from injured and uninjured tissue also revealed considerably more versican in the injured tissue extract.In vitrostudies revealed versican to be a product of oligodendrocyte lineage cells (OLCs). Labeling was seen between the late A2B5-positive stage and the O1-positive pre-oligodendrocyte stage. Neither immature, bipolar A2B5-positive cells, nor differentiated, myelin-forming oligodendrocytes were labeled. The amount of versican in conditioned medium increased as these cells differentiated. Versican and tenascin-R colocalized in OLCs, and coimmunoprecipitation indicated that the two exist as a complex in oligodendrocyte-conditioned medium. Treatment of pre-oligodendrocytes with hyaluronidase led to the release of versican, indicating that its retention at the cell surface is dependent on hyaluronate (HA). In rat brain, approximately half of the versican is bound to hyaluronate. We also provide evidence of a role for CS-PGs in the axon growth-inhibitory properties of oligodendrocytes. Because large numbers of OLCs are recruited to CNS lesions, these results suggest that OLC-derived versican contributes to the inhospitable environment of the injured CNS.