bluuebunny/crossref_metadata_2025 huggingface dataset:
Enriched Odor Exposure Increases the Number of Newborn Neurons in the Adult Olfactory Bulb and Improves Odor Memory
Authors: Rochefort Christelle , Gheusi Gilles , Vincent Jean-Didier , Lledo Pierre-Marie
Published: April 2018

In the mammalian forebrain, most neurons originate from proliferating cells in the ventricular zone lining the lateral ventricles, including a discrete area of the subventricular zone (SVZ). In this region, neurogenesis continues into adulthood. Most of the cells generated in the SVZ are neuronal precursors with progeny that migrate rostrally along a pathway known as the rostral migratory stream before they reach the main olfactory bulb (MOB) where they differentiate into local interneurons. The olfactory system thus provides an attractive model to investigate neuronal production and survival, processes involving interplay between genetic and epigenetic influences. The present study was conducted to investigate whether exposure to an odor-enriched environment affects neurogenesis and learning in adult mice. Animals housed in either a standard or an odor-enriched environment for 40 d were injected intraperitoneally with bromodeoxyuridine (BrdU) to detect proliferation among progenitor cells and to follow their survival in the MOB. The number of BrdU-labeled neurons was not altered 4 hr after a single BrdU injection. In contrast, the number of surviving progenitors 3 weeks after BrdU injection was markedly increased in animals housed in an enriched environment. This effect was specific because enriched odor exposure did not influence hippocampal neurogenesis. Finally, we showed that adult mice housed in odor-enriched cages display improved olfactory memory without a change in spatial learning performance. By maintaining a constitutive turnover of granule cells subjected to modulation by environmental cues, ongoing bulbar neurogenesis could be associated with improved olfactory memory.
The Neural Correlates of Moral Sensitivity: A Functional Magnetic Resonance Imaging Investigation of Basic and Moral Emotions
Authors: Moll Jorge , de Oliveira-Souza Ricardo , Eslinger Paul J. , Bramati Ivanei E. , Mourão-Miranda Janaı́na , Andreiuolo Pedro Angelo , Pessoa Luiz
Published: April 2018

Humans are endowed with a natural sense of fairness that permeates social perceptions and interactions. This moral stance is so ubiquitous that we may not notice it as a fundamental component of daily decision making and in the workings of many legal, political, and social systems. Emotion plays a pivotal role in moral experience by assigning human values to events, objects, and actions. Although the brain correlates of basic emotions have been explored, the neural organization of “moral emotions” in the human brain remains poorly understood. Using functional magnetic resonance imaging and a passive visual task, we show that both basic and moral emotions activate the amygdala, thalamus, and upper midbrain. The orbital and medial prefrontal cortex and the superior temporal sulcus are also recruited by viewing scenes evocative of moral emotions. Our results indicate that the orbital and medial sectors of the prefrontal cortex and the superior temporal sulcus region, which are critical regions for social behavior and perception, play a central role in moral appraisals. We suggest that the automatic tagging of ordinary social events with moral values may be an important mechanism for implicit social behaviors in humans.
Impaired Conditioned Fear and Enhanced Long-Term Potentiation inFmr2Knock-Out Mice
Authors: Gu Yanghong , McIlwain Kellie L. , Weeber Edwin J. , Yamagata Takanori , Xu Bisong , Antalffy Barbara A. , Reyes Christine , Yuva-Paylor Lisa , Armstrong Dawna , Zoghbi Huda , Sweatt J. David , Paylor Richard , Nelson David L.
Published: April 2018

FRAXE mental retardation results from expansion and methylation of a CCG trinucleotide repeat located in exon 1 of the X-linked FMR2 gene, which results in transcriptional silencing. The product of FMR2 is a member of a family of proteins rich in serine and proline, members of which have been associated with transcriptional activation. We have developed a murineFmr2gene knock-out model by replacing a fragment containing parts of exon 1 and intron 1 with theEscherichia coli lacZgene, placinglacZunder control of theFmr2promoter. Expression oflacZin the knock-out animals indicates thatFmr2is expressed in several tissues, including brain, bone, cartilage, hair follicles, lung, tongue, tendons, salivary glands, and major blood vessels. In the CNS,Fmr2expression begins at the time that cells in the neuroepithelium differentiate into neuroblasts. Mice lackingFmr2showed a delay-dependent conditioned fear impairment. Long-term potentiation (LTP) was found to be enhanced in hippocampal slices ofFmr2knock-out compared with wild-type littermates. To our knowledge, this mouse knock-out is the first example of an animal model of human mental retardation with impaired learning and memory performance and increased LTP. Thus, although a number of studies have suggested that diminished LTP is associated with memory impairment, our data suggest that increased LTP may be a mechanism that leads to impaired cognitive processing as well.
Time-Dependent Increases in Brain-Derived Neurotrophic Factor Protein Levels within the Mesolimbic Dopamine System after Withdrawal from Cocaine: Implications for Incubation of Cocaine Craving
Authors: Grimm Jeffrey W. , Lu Lin , Hayashi Teruo , Hope Bruce T. , Su Tsung-Ping , Shaham Yavin
Published: April 2018

Using a rat model of drug craving, we found that the responsiveness to cocaine cues progressively increases or incubates over the first 60 d of cocaine withdrawal. Here we studied whether alterations in brain-derived neurotrophic factor (BDNF) protein levels within the mesolimbic dopamine system are associated with this incubation phenomenon. BDNF is involved in synaptic plasticity and was found to enhance responding for cues associated with natural rewards. Rats were trained to press a lever to receive intravenous cocaine or oral sucrose for 6 hr/d for 10 d; each earned reward was paired with a tone–light cue. Resumption of lever-pressing behavior was then assessed on days 1, 30, or 90 of reward withdrawal. First, resistance to extinction was assessed during 6 hr in which lever presses were not reinforced and the cue was absent. Second, cue-induced reinstatement was assessed after extinction during 1 hr in which responding led to cue presentations. Other rats were killed without testing on days 1, 30, and 90 of reward withdrawal, and BDNF and nerve growth factor (NGF) protein levels were measured in the ventral tegmental area (VTA), accumbens, and amygdala. Lever pressing during extinction and cue-induced reinstatement tests of cocaine craving progressively increased after cocaine withdrawal. Time-dependent changes also were observed during the tests for sucrose craving, with maximal responding on day 30. BDNF, but not NGF, levels in the VTA, accumbens, and amygdala progressively increased after cocaine, but not sucrose, withdrawal. Time-dependent increases in BDNF levels may lead to synaptic modifications that underlie enhanced responsiveness to cocaine cues after prolonged withdrawal periods.
The RAS Effector RIN1 Modulates the Formation of Aversive Memories
Authors: Dhaka Ajay , Costa Rui M. , Hu Hailiang , Irvin Dwain K. , Patel Apoor , Kornblum Harley I. , Silva Alcino J. , O'Dell Thomas J. , Colicelli John
Published: April 2018

RAS proteins are critical regulators of mitosis and are mutationally activated in many human tumors. RAS signaling is also known to mediate long-term potentiation (LTP) and long-term memory formation in postmitotic neurons, in part through activation of the RAF–MEK–ERK pathway. The RAS effector RIN1 appears to function through competitive inhibition of RAS–RAF binding and also through diversion of RAS signaling to alternate pathways. We show that RIN1 is preferentially expressed in postnatal forebrain neurons in which it is localized in dendrites and physically associated with RAS, suggesting a role in RAS-mediated postsynaptic neuronal plasticity. Mice with anRin1gene disruption showed a striking enhancement in amygdala LTP. In addition, two independent behavioral tests demonstrated elevated amygdala-dependent aversive memory inRin1−/−mice. These results indicate that RIN1 serves as an inhibitory modulator of neuronal plasticity in aversive memory formation.
Interaction of Calcineurin and Type-A GABA Receptor γ2Subunits Produces Long-Term Depression at CA1 Inhibitory Synapses
Authors: Wang Jian , Liu ShuHong , Haditsch Ursula , Tu WeiHong , Cochrane Kimberley , Ahmadian Gholamreza , Tran Linda , Paw Jadine , Wang YuTian , Mansuy Isabelle , Salter Michael M. , Lu YouMing
Published: April 2018

Long-term depression (LTD) is an activity-dependent weakening of synaptic efficacy at individual inhibitory synapses, a possible cellular model of learning and memory. Here, we show that the induction of LTD of inhibitory transmission recruits activated calcineurin (CaN) to dephosphorylate type-A GABA receptor (GABAARs) via the direct binding of CaN catalytic domain to the second intracellular domain of the GABAAR-γ2subunits. Prevention of the CaN–GABAAreceptor complex formation by expression of an autoinhibitory domain of CaN in the hippocampus of transgenic mice blocks the induction of LTD. Conversely, genetic expression of the CaN catalytic domain in the hippocampus depresses inhibitory synaptic responses, occluding LTD. Thus, an activity-dependent physical and functional interaction between CaN and GABAAreceptors is both necessary and sufficient for inducing LTD at CA1 individual inhibitory synapses.
Spontaneous Calcium Transients in Developing Cortical Neurons Regulate Axon Outgrowth
Authors: Tang Fangjun , Dent Erik W. , Kalil Katherine
Published: April 2018

Growth cones of cortical axons pause for many hours in preparation for axon branching. They become large and complex compared with small advancing growth cones. We wanted to investigate whether calcium transients regulate the advance of mammalian CNS growth cones. We found that spontaneous calcium transients in developing cortical neurons have characteristic patterns, frequencies, and amplitudes. Importantly, neurons with large paused growth cones exhibit high-frequency spontaneous calcium transients, which are rare in those with small advancing growth cones. The incidence, frequencies, and amplitudes of calcium transients are inversely related to rates of axon outgrowth. The transients are mediated primarily by L-type voltage-gated calcium channels, and silencing them with channel blockers promotes axon outgrowth. Thus calcium transients regulate growth cone advance by direct effects on the growth cone.
The Functional Consequences of Changes in the Strength and Duration of Synaptic Inputs to Oscillatory Neurons
Authors: Prinz Astrid A. , Thirumalai Vatsala , Marder Eve
Published: April 2018

We studied the effect of synaptic inputs of different amplitude and duration on neural oscillators by simulating synaptic conductance pulses in a bursting conductance-based pacemaker model and by injecting artificial synaptic conductance pulses into pyloric pacemaker neurons of the lobster stomatogastric ganglion using the dynamic clamp. In the model and the biological neuron, the change in burst period caused by inhibitory and excitatory inputs of increasing strength saturated, such that synaptic inputs above a certain strength all had the same effect on the firing pattern of the oscillatory neuron. In contrast, increasing the duration of the synaptic conductance pulses always led to changes in the burst period, indicating that neural oscillators are sensitive to changes in the duration of synaptic input but are not sensitive to changes in the strength of synaptic inputs above a certain conductance. This saturation of the response to progressively stronger synaptic inputs occurs not only in bursting neurons but also in tonically spiking neurons. We identified inward currents at hyperpolarized potentials as the cause of the saturation in the model neuron. Our findings imply that activity-dependent or modulator-induced changes in synaptic strength are not necessarily accompanied by changes in the functional impact of a synapse on the timing of postsynaptic spikes or bursts.
Corticotropin Releasing Hormone Type 2 Receptors in the Dorsal Raphe Nucleus Mediate the Behavioral Consequences of Uncontrollable Stress
Authors: Hammack Sayamwong E. , Schmid Megan J. , LoPresti Matthew L. , Der-Avakian Andre , Pellymounter Mary Ann , Foster Alan C. , Watkins Linda R. , Maier Steven F.
Published: April 2018

Uncontrollable shock produces a constellation of behavioral changes that are not observed after equivalent escapable shock. These include interference with escape and potentiation of fear conditioning. The activation of corticotropin-releasing hormone (CRH) receptors within the caudal dorsal raphe nucleus (DRN) during inescapable tailshock (IS) has been shown to be critical for the development of these behavioral changes. CRH binds to two receptor subtypes, both of which are found in the DRN. The present set of studies examined which CRH receptor subtype mediates the effects of IS. Intra-DRN administration of the CRH2receptor antagonist anti-sauvagine-30 before IS dose-dependently blocked IS-induced behavioral changes; the CRH1receptor antagonist 2-methyl-4-(N-propyl-N-cycloproanemethylamino)-5-chloro-6-(2,4,6-trichloranilino)pyrimidine (NBI27914), administered in the same manner, did not. Moreover, the highly selective CRH2receptor agonist urocortin II (Ucn II) dose-dependently caused behavioral changes associated with IS in the absence of shock. Ucn II was effective at doses 100-fold lower than those previously required for CRH. The relationship between CRH2receptors and DRN 5-HT is discussed.
Apoptotic Death of β Cells after Optic Nerve Transection in Adult Cats
Authors: Kurimoto Takuji , Miyoshi Tomomitsu , Suzuki Akira , Yakura Toru , Watanabe Masami , Mimura Osamu , Fukuda Yutaka
Published: April 2018

We have revealed previously that the survival rate of β cells of cat retinal ganglion cells (RGCs) rapidly decreased to 29% on day 7 after optic nerve transection, whereas that of α cells slowly decreased to 64% on day 14 (Watanabe et al., 2001). The reason that β cells die more rapidly than α cells was not clear. In the present study, we tested the possibility that the rapid death of β cells is attributable to apoptosis, as shown for some axotomized RGCs in rats. The following results were obtained. First, the proportion of pyknotic cells in Nissl-stained cat retinas started to increase sharply starting on day 4 and reached a peak on day 6 after optic nerve transection. The time course of occurrence of pyknotic cells corresponded well with that of the rapid death of axotomized β cells. Secondly, the proportion of pyknotic cells was the highest in the area centralis (AC), in which β cells are densely distributed. The preferential death of axotomized RGCs in the AC was also confirmed by terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling staining in cross sections. Thirdly, after the intravitreal injection of caspase 3 inhibitor (z-DEVD-cmk) the survival of axotomized β cells on day 7 was significantly enhanced, whereas no such survival-promoting effect was obtained in axotomized α cells. Taken together, these results suggest that the rapid death of axotomized β cells is attributable mainly to apoptosis, which is mediated by caspase 3.
Frequency Modulation of Synchronized Ca2+Spikes in Cultured Hippocampal Networks through G-Protein-Coupled Receptors
Authors: Liu Zhijun , Geng Lin , Li Ruxin , He Xiangping , Zheng James Q. , Xie Zuoping
Published: April 2018

Synchronized spontaneous Ca2+spikes in networked neurons represent periodic burst firing of action potentials, which are believed to play a major role in the development and plasticity of neuronal circuitry. How these network activities are shaped and modulated by extrinsic factors during development, however, remains to be studied. Here we report that synchronized Ca2+spikes among cultured hippocampal neurons can be modulated by two small factors that act on G-protein-coupled receptors (GPCRs): the neuropeptide PACAP (pituitary adenylate cyclase-activating polypeptide) and the chemokine SDF-1 (stromal cell-derived factor-1). PACAP effectively increases the frequency of the synchronized Ca2+spikes when applied acutely; the PACAP potentiation of Ca2+spikes requires the activation of the PACAP-specific PAC1 GPCRs and is mediated by the activation of cAMP signaling pathway. SDF-1, on the other hand, significantly reduces the frequency of these Ca2+spikes through the activation of its specific GPCR CXCR4; the inhibitory action of SDF-1 is mediated by the inhibition of cAMP pathway through the Gicomponent of GPCRs. Taken together, these results demonstrate that synchronized neuronal network activity can be effectively modulated by physiologically and developmentally relevant small factors that act on GPCRs to target the cAMP pathway. Such modulation of neuronal activity through GPCRs may represent a significant mechanism that underlies the neuronal plasticity during neural development and functioning.
Conscious Expectation and Unconscious Conditioning in Analgesic, Motor, and Hormonal Placebo/Nocebo Responses
Authors: Benedetti Fabrizio , Pollo Antonella , Lopiano Leonardo , Lanotte Michele , Vighetti Sergio , Rainero Innocenzo
Published: April 2018

The placebo and nocebo effect is believed to be mediated by both cognitive and conditioning mechanisms, although little is known about their role in different circumstances. In this study, we first analyzed the effects of opposing verbal suggestions on experimental ischemic arm pain in healthy volunteers and on motor performance in Parkinsonian patients and found that verbally induced expectations of analgesia/hyperalgesia and motor improvement/worsening antagonized completely the effects of a conditioning procedure. We also measured the effects of opposing verbal suggestions on hormonal secretion and found that verbally induced expectations of increase/decrease of growth hormone (GH) and cortisol did not have any effect on the secretion of these hormones. However, if a preconditioning was performed with sumatriptan, a 5-HT1B/1Dagonist that stimulates GH and inhibits cortisol secretion, a significant increase of GH and decrease of cortisol plasma concentrations were found after placebo administration, although opposite verbal suggestions were given. These findings indicate that verbally induced expectations have no effect on hormonal secretion, whereas they affect pain and motor performance. This suggests that placebo responses are mediated by conditioning when unconscious physiological functions such as hormonal secretion are involved, whereas they are mediated by expectation when conscious physiological processes such as pain and motor performance come into play, even though a conditioning procedure is performed.
Step Response Analysis of Thermotaxis inCaenorhabditis elegans
Authors: Zariwala Hatim A. , Miller Adam C. , Faumont Serge , Lockery Shawn R.
Published: April 2018

The nematodeCaenorhabditis elegansmigrates toward a preferred temperature on a thermal gradient. A candidate neural network for thermotaxis inC. eleganshas been identified, but the behavioral strategy implemented by this network is poorly understood. In this study, we tested whether thermal migration is achieved by modulating the probability of turning behavior, as inC. eleganschemotaxis. This was done by subjecting unrestrained wild-type, cryophilic, or thermophilic worms to rapid spatially uniform temperature steps (3°C), up or down from the cultivation temperature. Each of the three types of worms we analyzed showed a different pair of responses to the two types of steps. Comparison of wild-type and mutant response patterns suggested a model in which thermal migration involves a unique response to the gradient depending on the orientation of the worm relative to its preferred temperature. Overall, however, turning probability was modulated in a manner consistent with a role for turning behavior in thermal migration. Our results suggest that sensory systems for thermotaxis and chemotaxis may converge on a common behavioral mechanism.
Mouse NG2+Oligodendrocyte Precursors Express mRNA for Proteolipid Protein But Not Its DM-20 Variant: A Study of Laser Microdissection-Captured NG2+Cells
Authors: Ye Ping , Bagnell Robert , D'Ercole A. Joseph
Published: April 2018

Despite recent advances in our understanding of lineage of oligodendrocytes, detailed molecular characterization of this lineagein vivois limited, primarily because of our inability to obtain a pure population of cellsin situ. To define the molecular characteristics of oligodendrocyte lineage cells during development and their response to injury, we developed a strategy that uses laser capture microdissection (LCM) to isolate cells from sections and reverse transcription-PCR to determine mRNA expression. As a first step, we examined the expression of myelin-specific protein genes in NG2+cells in cerebral cortex. We demonstrate that NG2+cells in both developing and adult mice express NG2 mRNA but not mRNA for proteins specific for astrocytes, neurons, or microglia, indicating that a highly pure population of antigen-specific cells of the oligodendrocyte lineage can be obtained using LCM. Furthermore, we show that NG2+cells express mRNAs for proteolipid protein (PLP), myelin basic protein, and 2′,3′-cyclic nucleotide 3′-phosphodiesterase, but they dot not express DM-20 mRNA, a PLP mRNA splicing variant. Our data demonstrate that antigen-specific cells of oligodendrocyte lineage differentially express mRNA for myelin-specific proteins and their variantsin vivo, partly define the gene expression in NG2+cells, and raise questions about the cellular sites of DM-20 expression. This work also shows that LCM is a valuable tool to define and analyze gene expression in the cells of the oligodendrocyte lineage.
Coexpression of Two Visual Pigments in a Photoreceptor Causes an Abnormally Broad Spectral Sensitivity in the Eye of the ButterflyPapilio xuthus
Authors: Arikawa Kentaro , Mizuno Shin , Kinoshita Michiyo , Stavenga Doekele G.
Published: April 2018

The compound eye of the butterflyPapilio xuthusconsists of three different types of ommatidia, each containing nine photoreceptor cells (R1–R9). We have found previously that the R5–R8 photoreceptors of type II ommatidia coexpress two different mRNAs, encoding opsins of green- and orange-red-absorbing visual pigments (Kitamoto et al., 1998). Do these cells contain two functionally distinct visual pigments? First, we identified the sensitivity spectrum of these photoreceptors by using combined intracellular recording and dye injection. We thus found that the R5–R8 of type II ommatidia have a characteristic sensitivity spectrum extending over an excessively broad spectral range, from the violet to the red region; the photoreceptors are therefore termed broadband photoreceptors. The spectral shape was interpreted with a computational model for type II ommatidia, containing a UV visual pigment in cells R1 and R2, two green visual pigments in cells R3 and R4, a far-UV-absorbing screening pigment (3-hydroxyretinol) in the distal part of the ommatidium, and a red-screening pigment that surrounds the rhabdom. The modeling suggests that both visual pigments in the R5–R8 photoreceptors participate in phototransduction. This work provides the first compelling evidence that multiple visual pigments participate in phototransduction in single invertebrate photoreceptors.
Deformation of Network Connectivity in the Inferior Olive of Connexin 36-Deficient Mice Is Compensated by Morphological and Electrophysiological Changes at the Single Neuron Level
Authors: De Zeeuw Chris I. , Chorev Edilzh , Devor Anna , Manor Yait , Van Der Giessen Ruben S. , De Jeu Marcel T. , Hoogenraad Casper C. , Bijman Jan , Ruigrok Tom J. H. , French Pim , Jaarsma Dick , Kistler Werner M. , Meier Carola , Petrasch-Parwez Elisabeth , Dermietzel Rolf , Sohl Goran , Gueldenagel Martin , Willecke Klaus , Yarom Yosi
Published: April 2018

Compensatory mechanisms after genetic manipulations have been documented extensively for the nervous system. In many cases, these mechanisms involve genetic regulation at the transcription or expression level of existing isoforms. We report a novel mechanism by which single neurons compensate for changes in network connectivity by retuning their intrinsic electrical properties. We demonstrate this mechanism in the inferior olive, in which widespread electrical coupling is mediated by abundant gap junctions formed by connexin 36 (Cx36). It has been shown in various mammals that this electrical coupling supports the generation of subthreshold oscillations, but recent work revealed that rhythmic activity is sustained in knock-outs of Cx36. Thus, these results raise the question of whether the olivary oscillations in Cx36 knock-outs simply reflect the status of wild-type neurons without gap junctions or the outcome of compensatory mechanisms. Here, we demonstrate that the absence of Cx36 results in thicker dendrites with gap-junction-like structures with an abnormally wide interneuronal gap that prevents electrotonic coupling. The mutant olivary neurons show unusual voltage-dependent oscillations and an increased excitability that is attributable to a combined decrease in leak conductance and an increase in voltage-dependent calcium conductance. Using dynamic-clamp techniques, we demonstrated that these changes are sufficient to transform a wild-type neuron into a knock-out-like neuron. We conclude that the absence of Cx36 in the inferior olive is not compensated by the formation of other gap-junction channels but instead by changes in the cytological and electroresponsive properties of its neurons, such that the capability to produce rhythmic activity is maintained.
Stoichiometry of Expressed KCNQ2/KCNQ3 Potassium Channels and Subunit Composition of Native Ganglionic M Channels Deduced from Block by Tetraethylammonium
Authors: Hadley Jennifer K. , Passmore Gayle M. , Tatulian Lucine , Al-Qatari Mona , Ye Fei , Wickenden Alan D. , Brown David A.
Published: April 2018

KCNQ2 and KCNQ3 potassium-channel subunits can form both homomeric and heteromeric channels; the latter are thought to constitute native ganglionic M channels. We have tried to deduce the stoichiometric contributions of KCNQ2 and KCNQ3 subunits to currents generated by the coexpression of KCNQ2 and KCNQ3 cDNA plasmids in Chinese hamster ovary (CHO) cells, and to native M currents in dissociated rat superior cervical ganglion (SCG) neurons, by comparing the block of these currents produced by tetraethylammonium (TEA) with the block of currents generated by a tandem KCNQ3/2 construct. TEA concentration–inhibition curves against coexpressed KCNQ2 plus KCNQ3 currents, and against native M currents in SCG neurons from 6-week-old [postnatal day 45 (P45)] rats, were indistinguishable from those for the expressed tandem construct, and fully accorded with a 1:1 stoichiometry. Inhibition curves in neurons from younger (P17) rats could be better fitted assuming an additional small proportion of current carried by KCNQ2 homomultimers. Single-cell PCR yielded signals for KCNQ2, KCNQ3, and KCNQ5 mRNAs in all SCG neurons tested from both P17 and P45 rats. Quantitative PCR of whole-ganglion mRNA revealed stable levels of KCNQ2 and KCNQ5 mRNA between P7 and P45, but excess and incrementing levels of KCNQ3 mRNA. Increasing levels of KCNQ3 protein between P17 and P45 were confirmed by immunocytochemistry. We conclude that coexpressed KCNQ2 plus KCNQ3 cDNAs generate channels with 1:1 (KCNQ2:KCNQ3) stoichiometry in CHO cells and that native M channels in SCG neurons adopt the same conformation during development, assisted by the increased expression of KCNQ3 mRNA and protein.
A Conditional Deletion of the NR1 Subunit of the NMDA Receptor in Adult Spinal Cord Dorsal Horn Reduces NMDA Currents and Injury-Induced Pain
Authors: South Samantha M. , Kohno Tatsuro , Kaspar Brian K. , Hegarty Deborah , Vissel Bryce , Drake Carrie T. , Ohata Megumi , Jenab Shirzad , Sailer Andreas W. , Malkmus Shelle , Masuyama Takashi , Horner Philip , Bogulavsky Johanna , Gage Fred H. , Yaksh Tony L. , Woolf Clifford J. , Heinemann Stephen F. , Inturrisi Charles E.
Published: April 2018

To determine the importance of the NMDA receptor (NMDAR) in pain hypersensitivity after injury, the NMDAR1 (NR1) subunit was selectively deleted in the lumbar spinal cord of adult mice by the localized injection of an adenoassociated virus expressing Cre recombinase into floxed NR1 mice. NR1 subunit mRNA and dendritic protein are reduced by 80% in the area of the virus injection, and NMDA currents, but not AMPA currents, are reduced 86–88% in lamina II neurons. The spatial NR1 knock-out does not alter heat or cold paw-withdrawal latencies, mechanical threshold, or motor function. However, injury-induced pain produced by intraplantar formalin is reduced by 70%. Our results demonstrate conclusively that the postsynaptic NR1 receptor subunit in the lumbar dorsal horn of the spinal cord is required for central sensitization, the central facilitation of pain transmission produced by peripheral injury.
Expression of the Activating Transcription Factor 3 Prevents c-Jun N-Terminal Kinase-Induced Neuronal Death by Promoting Heat Shock Protein 27 Expression and Akt Activation
Authors: Nakagomi Saya , Suzuki Yasuhiro , Namikawa Kazuhiko , Kiryu-Seo Sumiko , Kiyama Hiroshi
Published: April 2018

Activating transcription factor 3 (ATF3) is induced and functions both as a cellular response to stress and to stimulate proliferation in multiple tissues. However, in the nervous system ATF3 is expressed only in injured neurons. Here we reveal a function of ATF3 in neurons under death stress. Overexpression of ATF3 by adenovirus inhibits the mitogen-activated kinase kinase kinase 1 (MEKK1)–c-Jun N-Terminal Kinase (JNK)-induced apoptosis and induces neurite elongation via Akt activation in PC12 cells and superior nerve ganglion neurons. A DNA microarray study reveals that ATF3 expression and JNK activation induce expression of the heat shock protein 27 (Hsp27). Immunoprecipitation analysis and promoter assay for Hsp27 expression suggest that both ATF3 and c-Jun are necessary for transcriptional activation of Hsp27. Hsp27 expression significantly inhibits JNK-induced apoptosis as well as Akt activation in PC12 cells and superior cervical ganglion neurons. We conclude that the combination of ATF3 and c-Jun induces the anti-apoptotic factor Hsp27, which directly or indirectly activates Akt, and thereby possibly inhibits apoptosis and induces nerve elongation. Our results suggest that ATF3- and c-Jun-induced Hsp27 expression is a novel survival response in neurons under death stress such as nerve injury.
Short-Term Frequency-Dependent Plasticity at Recurrent Mossy Fiber Synapses of the Epileptic Brain
Authors: Feng Li , Molnár Peter , Nadler J. Victor
Published: April 2018

The recurrent mossy fiber pathway of the dentate gyrus expands dramatically in human temporal lobe epilepsy and in animal models of this disorder, creating monosynaptic connections among granule cells. This novel granule cell network can support reverberating excitation but is difficult to activate with low-frequency stimulation. This study used hippocampal slices from pilocarpine-treated rats to explore the dependence of synaptic transmission in this pathway on stimulus frequency. Minimal electrically evoked EPSCs exhibited a high failure rate (∼60%). Stimulus trains delivered at a frequency of <1 Hz depressed synaptic transmission, as evidenced by an increase in response failures. Conversely, stimulus trains delivered at higher frequencies reduced the percentage of response failures and increased the amplitude of compound EPSCs, including pharmacologically isolated NMDA receptor-mediated EPSCs. Short-term frequency-dependent facilitation was of modest size compared with mossy fiber synapses on other neuronal types. Facilitation depended on the activation of kainate receptors by released glutamate and was inhibited by feedback activation of type II metabotropic glutamate receptors. These results suggest that the recurrent mossy fiber pathway may be functionally silent during baseline asynchronous granule cell activityin vivoattributable, in part, to progressive transmission failure. The pathway may synchronize granule cell firing and may promote seizure propagation most effectively during the brief periods of high-frequency granule cell firing that occur during normal behavior, during the periods of hypersynchronous fast activity characteristic of epileptic brain and, most importantly, during the period of increasing granule cell activity that precedes a spontaneous seizure.
Effects of Gaze Shifts on Maintenance of Spatial Memory in Macaque Frontal Eye Field
Authors: Balan Puiu F. , Ferrera Vincent P.
Published: April 2018

The activity of 91 neurons in the frontal eye fields (FEFs) of two macaque monkeys was recorded while the animals performed a delayed spatial match-to-sample task. During the delay, the animals were required to shift their gaze to one of four eccentric locations. Neuronal activity during the delay was analyzed for sensitivity to cue location and eye position. One-third of the neurons showed significant delay activity selective for cue location, whereas slightly more than one-half of the neurons showed significant modulation of delay activity when the gaze was shifted to an eccentric location. Despite this modulation, the neurons continued to signal their preferred cue location during most of the delay. However, after recentering saccades, the memory signal was temporarily abolished and then reemerged over a period of few hundred milliseconds. This is consistent with the idea that spatial working memory is buffered outside of the FEF. For most neurons, delay activity tended to increase when the gaze was shifted away from the preferred location and to decrease when the gaze was shifted toward the preferred location. This pattern of modulation is consistent with a vector subtraction mechanism that allows for the superposition of multiple saccade plans.
Dissociation between Neurodegeneration and Caspase-11-Mediated Activation of Caspase-1 and Caspase-3 in a Mouse Model of Amyotrophic Lateral Sclerosis
Authors: Kang Shin Jung , Sanchez Ivelisse , Jing Naisen , Yuan Junying
Published: April 2018

Caspase-11 is a key regulator of caspase-1 and caspase-3 activation under pathological conditions. We show here that the expression ofcaspase-11is upregulated in the spinal cord of superoxide dismutase 1 (SOD1) G93A transgenic mice, a mouse model of amyotrophic lateral sclerosis (ALS), before the onset of motor dysfunction and remains at the high levels throughout the course of disease. The caspase-1- and caspase-3-like activities, as well as the level of interleukin-1β, were significantly reduced in the spinal cord of symptomaticcaspase-11–/–;SOD1 G93A mice compared with that ofcaspase-11+/–; SOD1 G93A mice. However, neurodegeneration, inflammatory responses, and the disease onset and progression in SOD1 G93A transgenic mice were not altered by the ablation ofcaspase-11gene. Thus, although caspases may contribute to certain aspects of pathology in this mouse model of ALS, their inhibition is not sufficient to prevent neurodegeneration. Our study urges caution when considering the inhibition of caspases as a direct therapeutic method for the treatment of chronic neurodegenerative diseases.
Short-Term Memory and Perceptual Decision for Three-Dimensional Visual Features in the Caudal Intraparietal Sulcus (Area CIP)
Authors: Tsutsui Ken-Ichiro , Jiang Min , Sakata Hideo , Taira Masato
Published: April 2018

The purpose of the present study was to examine whether neurons in the caudolateral part of the intraparietal sulcus (area CIP), a part of the posterior parietal cortex, contribute to short-term memory and perceptual decision of three-dimensional (3D) surface orientation, in addition to its purely visual nature of responding selectively to 3D surface orientation. Activities of CIP neurons were recorded while monkeys performed a modified delayed matching-to-sample (DMTS) task using stereoscopic stimuli. Seventy-seven neurons were examined with a routine of the DMTS task, and 94% (72 of 77) of them showed selectivity to surface orientation. Furthermore, 82% (63 of 77) of the examined neurons showed sustained activity during delay, and 60% (38 of 63) of them showed selective delay activity depending on the sample stimulus, suggesting that they contribute to short-term memory of 3D visual features. On the other hand, 53% (41 of 77) of the examined neurons showed modulation of visual response depending on whether a stimulus appeared as a sample, match, or nonmatch stimulus (contextual modulation). The majority (73%, 30 of 41) of these neurons with contextual modulation showed activity change depending on whether the test stimuli did or did not match the sample stimuli (match–nonmatch modulation), suggesting their involvement in matching, or perceptual decision, concerning 3D visual features. These findings suggest that CIP neurons play important roles not only in the perception of 3D visual features but also in cognitive functions such as short-term memory and perceptual decision of 3D visual information.
Action Potential Propagation in Dendrites of Rat Mitral CellsIn Vivo
Authors: Debarbieux F. , Audinat E. , Charpak S.
Published: April 2018

Odors evoke β-γ frequency field potential oscillations in the olfactory systems of awake and anesthetized vertebrates. In the rat olfactory bulb, these oscillations reflect the synchronous discharges of mitral cells that result from both their intrinsic membrane properties and their dendrodendritic interactions with local inhibitory interneurons. Activation of dendrodendritic synapses is purportedly involved in odor memory and odor contrast enhancement. Here we investigatein vivoto what extent action potentials propagate to remote dendrodendritic sites in the entire dendritic tree and if this propagation is changed during discharges at 40 Hz. By combining intracellular recording and two-photon microscopy imaging of intracellular calcium ([Ca2+]i), we show that in remote branches of the apical tuft and basal dendrites, transient Ca2+changes are triggered by single sodium action potentials. Neither the amplitude of these Ca2+transients nor that of action potentials obtained from intradendritic recordings showed a significant attenuation as a function of the distance from the soma. Calcium channel density seemed homogeneous; however, propagating action potentials occasionally failed to trigger a Ca2+transient at a site closer to the soma whereas it did farther. This suggests that measurements of calcium transients underestimate the occurrence of sodium action potentials. During 40 Hz bursts of action potentials, [Ca2+]iincreases with the number of action potentials in all dendritic compartments. These results suggest that the presence of release sites in dendrites is accompanied by an “axonal-like behavior” of the entire dendritic tree of mitral cells, including their most distal dendritic branches.
Thrombin-Induced Microglial Activation Produces Degeneration of Nigral Dopaminergic NeuronsIn Vivo
Authors: Choi Sang-H. , Joe Eun H. , Kim Seung U. , Jin Byung K.
Published: April 2018

The present study examined whether thrombin-induced microglial activation could contribute to death of dopaminergic neurons in the rat substantia nigra (SN)in vivo. Seven days after thrombin injection into the SN, tyrosine hydroxylase immunohistochemistry showed a significant loss of nigral dopaminergic neurons. In parallel, thrombin-activated microglia, visualized by immunohistochemical staining using antibodies against the complement receptor type 3 (OX-42) and the major histocompatibility complex class II antigens were also observed in the SN, where degeneration of nigral neurons was found. Reverse transcription PCR at various time points demonstrated that activated microgliain vivoexhibited an early and transient expression of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and several proinflammatory cytokines, including interleukin 1β (IL-1β), IL-6, and tumor necrosis factor α. Western blot analysis and double-label immunohistochemistry showed an increase in the expression of iNOS and COX-2 and the colocalization of these proteins within microglia. The thrombin-induced loss of SN dopaminergic neurons was partially inhibited byNG-nitro-l-arginine methyl ester hydrochloride, an NOS inhibitor, and by DuP-697, a COX-2 inhibitor. Additional studies demonstrated that extracellular signal-regulated kinase 1/2 (ERK1/2) and p38 mitogen-activated protein kinase (MAPK) were activated in the SN as early as 30 min after thrombin injection, and that these kinases were localized within microglia. Inhibition of ERK1/2 and p38 MAPK reduced iNOS and COX-2 mRNA expression and rescued dopaminergic neurons in the SN. The present results strongly suggest that microglial activation triggered by endogenous compound(s) such as thrombin may be involved in the neuropathological processes of dopaminergic neuronal cell death that occur in Parkinson's disease.
Controlled Movement Processing: Superior Colliculus Activity Associated with Countermanded Saccades
Authors: Paré Martin , Hanes Doug P.
Published: April 2018

We investigated whether the monkey superior colliculus (SC), an important midbrain structure for the regulation of saccadic eye movements, contains neurons with activity patterns sufficient to control both the cancellation and the production of saccades. We used a countermanding task to manipulate the probability that, after the presentation of a stop signal, the monkeys canceled a saccade that was planned in response to an eccentric visual stimulus. By modeling each animal's behavioral responses, with a race between GO and STOP processes leading up to either saccade initiation or cancellation, we estimated that saccade cancellation took on average 110 msec. Neurons recorded in the superior colliculus intermediate layers during this task exhibited the discharge properties expected from neurons closely involved in behavioral control. Both saccade- and fixation-related discharged differently when saccades were counter-manded instead of executed, and the time at which they changed their activity preceded the behavioral estimate of saccade cancellation obtained from the same trials by 10 and 13 msec, respectively. Furthermore, these intervals exceed the minimal amount of time needed for SC activity to influence eye movements. The additional observation that saccade-related neurons discharged significantly less when saccades were countermanded instead of executed suggests that saccades are triggered when these neurons reach a critical activation level. Altogether, these findings provide solid evidence that the superior colliculus contains the necessary neural signals to be directly involved in the decision process that regulates whether a saccade is to be produced.
Post-Training Intra-Basolateral Amygdala Infusions of Norepinephrine Enhance Consolidation of Memory for Contextual Fear Conditioning
Authors: LaLumiere Ryan T. , Buen Thea-Vanessa , McGaugh James L.
Published: April 2018

Post-training infusions of drugs, including noradrenergic agonists and antagonists, into the basolateral amygdala (BLA) influence the consolidation of memory for training in several tasks, including inhibitory avoidance. There is, however, conflicting evidence concerning whether post-training intra-BLA drug infusions modulate the consolidation of contextual fear conditioning (CFC). In the present study, norepinephrine (NE) was infused bilaterally into the BLA of male Sprague Dawley rats immediately after training on two CFC tasks: a Y-maze and a straight alley. Post-training intra-BLA infusions enhanced memory of CFC training in the Y-maze, as assessed by percentage of time spent freezing and shock arm entrance latencies. Post-training intra-BLA infusions of NE enhanced 48 hr retention of CFC training in the straight alley, as assessed by shock compartment entrance latencies and the number of shocks required to learn to avoid entering the shock compartment. These findings indicate that the consolidation of memory for CFC, like that for inhibitory avoidance training, is influenced by post-training neuromodulatory influences within the BLA. Thus, the findings provide additional evidence consistent with the hypothesis that the BLA has a general role in modulating memory consolidation.
Reversible Suppression of Glutamatergic Neurotransmission of Cerebellar Granule CellsIn Vivoby Genetically Manipulated Expression of Tetanus Neurotoxin Light Chain
Authors: Yamamoto Mutsuya , Wada Norio , Kitabatake Yasuji , Watanabe Dai , Anzai Masayuki , Yokoyama Minesuke , Teranishi Yutaka , Nakanishi Shigetada
Published: April 2018

We developed a novel technique that allowed reversible suppression of glutamatergic neurotransmission in the cerebellar network. We generated two lines of transgenic mice termed Tet and TeNT mice and crossed the two transgenic lines to produce the Tet/TeNT double transgenic mice. In the Tet mice, the tetracycline-controlled reverse activator (rtTA) was expressed selectively in cerebellar granule cells by the promoter function of the GABAAreceptor α6 subunit gene. In the TeNT mice, the fusion gene of tetanus neurotoxin light chain (TeNT) and enhanced green fluorescent protein (EGFP) was designed to be induced by the interaction of doxycycline (DOX)-activated rtTA with the tetracycline-responsive promoter. The Tet/TeNT mice grew normally even after DOX treatment and exhibited a restricted DOX-dependent expression of TeNT in cerebellar granule cells. Along with this expression, TeNT proteolytically cleaved the synaptic vesicle protein VAMP2 (also termed synaptobrevin2) and reduced glutamate release from granule cells. Both cleavage of VAMP2/synaptobrevin2 and reduction of glutamate release were reversed by removal of DOX. Among the four genotypes generated by heterozygous crossing of Tet and TeNT mice, only Tet/TeNT mice showed DOX-dependent reversible motor impairments as analyzed with fixed bar and rota-rod tests. Reversible suppression of glutamatergic neurotransmission thus can be manipulated with spatiotemporal accuracy by DOX treatment and removal. These transgenic mice will serve as an animal model to study the cerebellar function in motor coordination and learning.
Gap Junctional Coupling Underlies the Short-Latency Spike Synchrony of Retinal α Ganglion Cells
Authors: Hu Edward H. , Bloomfield Stewart A.
Published: April 2018

We examined whether coupling between neighboringα-type ganglion cells (α-GCs) in the rabbit retina underlies their synchronous spike activity. Simultaneous recordings were made from arrays of α-GCs to determine the synchrony of both spontaneous and light-evoked spike activity. One cell within each array was then injected with the biotinylated tracer Neurobiotin to determine which of the cells were coupled via gap junctions. Cross-correlation analyses indicated that neighboring off-center α-GCs maintain short-latency (∼2.5 msec) synchronous spiking, whereas the spontaneous spike activities of on-centerα-GC neighbors are not correlated. Without exception, those off-centerα-GCs showing synchronous spiking were found to be tracer coupled to both amacrine cells and neighboring off-centerα-GCs. In contrast, on-center α-GCs were never tracer coupled. Furthermore, whereas spikes initiated in an off-center α-GC with extrinsic current injection resulted in short-latency synchronized spiking in neighboring off-center α-GCs, this was never seen between on-center α-GCs. These results indicate that electrical coupling via gap junctions underlies the short-latency concerted spike activity of neighboring α-GCs.