1,721,008 research outputs found
Selective mitochondrial Ca2+ uptake deficit in disease endstage vulnerable motoneurons of the SOD1G93A mouse model of amyotrophic lateral sclerosis
No full textKey points center dot So far, increased excitability and calcium handling problems have been discussed as causes for motoneuron death in amyotrophic lateral sclerosis (ALS) mainly on the basis of studies in juvenile presymptomatic mice. center dot We developed a brainstem preparation to analyse excitability and calcium handling during disease progression up to disease endstage of motoneurons in an ALS mouse model. center dot Increased excitability of motoneurons is not seen at disease endstage, challenging this factor as a direct cause for motoneuron death in ALS. center dot We show that calcium handling is remodelled during disease progression from mitochondrial uptake to mitochondrial uptake failure and increased plasma membrane extrusion, providing a compensatory mechanism that fails at disease endstage and might lead to a toxic calcium overload of the cells. center dot Supporting this newly described compensatory endeavour of the motoneurons might be a promising therapeutic strategy. Abstract Amyotrophic lateral sclerosis is a progressive neurodegenerative disease that targets some somatic motoneuron populations, while others, e.g. those of the oculomotor system, are spared. The pathophysiological basis of this pattern of differential vulnerability, which is preserved in a transgenic mouse model of amyotrophic lateral sclerosis (SOD1G93A), and the mechanism of neurodegeneration in general are unknown. Hyperexcitability and calcium dysregulation have been proposed by others on the basis of data from juvenile mice that are, however, asymptomatic. No studies have been done with symptomatic mice following disease progression to the disease endstage. Here, we developed a new brainstem slice preparation for whole-cell patch-clamp recordings and single cell fura-2 calcium imaging to study motoneurons in adult wild-type and SOD1G93A mice up to disease endstage. We analysed disease-stage-dependent electrophysiological properties and intracellular Ca2+ handling of vulnerable hypoglossal motoneurons in comparison to resistant oculomotor neurons. Thereby, we identified a transient hyperexcitability in presymptomatic but not in endstage vulnerable motoneurons. Additionally, we revealed a remodelling of intracellular Ca2+ clearance within vulnerable but not resistant motoneurons at disease endstage characterised by a reduction of uniporter-dependent mitochondrial Ca2+ uptake and enhanced Ca2+ extrusion across the plasma membrane. Our study challenged the notion that hyperexcitability is a direct cause of neurodegeneration in SOD1G93A mice, but molecularly identified a Ca2+ clearance deficit in motoneurons and an adaptive Ca2+ handling strategy that might be targeted by future therapeutic strategies.Ulm University; BMBF/EU ProgramEranet Goettingen [01EW0912]; [SFB 815
Die Neurobiologie der Unsicherheit : Unvorhergesehenes regt das Gehirn zum Lernen an
No full textUnsicherheit gehört zum Leben. Sie weckt unsere Bereitschaft zum Lernen, fördert Flexibilität und wirkt sich produktiv auf unser Verhalten aus. Sie kann uns Glücksmomente bescheren, aber auch das Gefühl von Bedrohung und Angst. Neurophysiologen entdecken gerade erst, wie das Gehirn mit Unsicherheit umgeht
Identification of a dual mesocorticolimbic dopamine system with selective axonal projections in adult mouse (Mus musculus L.)
No full textDopaminerge (DA) Neurone sind im Mittelhirn hauptsächlich in zwei Nuklei lokalisiert: in der Substantia nigra (SN, A9) und Area tegmentalis ventralis (VTA, A10). Währene DA SN Neurone das dorsale Striatum innervieren, projizieren die DA VTA Neurone in kortikolimbische Hirnareale (u.a. präfrontaler Kortex (PFC), basolaterale Amygdala (BLA), Nukleus Accumbens (NAc) core/shell). Die eingehend charakterisierten klassischen mesostriatalen DA Neurone sind essentiell für die Ausführung von Willkürbewegungen und für die Vermittlung prädiktiver Belohnungssignale. Dagegen sind die elektrophysiologischen Eigenschaften der DA Neurone, die durch eine vornehmlich tonische Dopaminfreisetzung in kortikolimbischen Hirnarealen beispielsweise die Salienz appetitiver und aversiver Stimuli, sowie kognitive (working memory) und emotionale Funktionen vermitteln, weitgehend unbekannt.
Im Rahmen der vorliegenden Arbeit wurde daher selektives retrogrades Tracing in Kombination mit elektrophysiologischen und immunhistochemischen Methoden durchgeführt, um die anatomischen, morphologischen und funktionellen Eigenschaften mesokortikolimbischer DA Neurone im Vergleich zu den klassischen mesostriatalen DA Neuronen in adulten C57Bl/6 Mäusen zu analysieren.
In der vorliegenden Arbeit wurde herausgefunden, dass das mesokortikolimbische DA System anatomisch, molekular und funktionell von zwei unterschiedlichen Phänotypen DA Neurone gebildet wird. Dabei konnte neben dem klassischen Typ, erstmals die Existenz eines weiteren DA Phänotyps mit unkonventionellen elektrophysiologischen Eigenschaften beschrieben werden.
Es konnte gezeigt werden, dass DA Neurone, die den PFC, die BLA und die core Subregion des NAc innervieren vor allem in der medialen VTA des intermediären Mittelhirn lokalisiert waren. Dagegen waren die DA Nervenzellen, die in den lateralen shell des NAc sowie in das dorsolaterale Striatum projizieren und präferentiell in der lateralen VTA in der SN und in der Area retrorubralis (A8) lokalisiert. Die topographische Dualität des mesokortikolimbischen DA Systems konnte auch in einer differentiellen Proteinexpression wiedergefunden werden. Mesokortikale, mesoamygdaläre und mesolimbische core DA Neurone waren im Vergleich zu mesolimbischen shell und mesostriatalen DA Neuronen durch eine geringe Expression des Dopamintransporters (DAT) gekennzeichnet. Ferner konnte gezeigt werden, dass das Markerprotein Calbindin nur bedingt für die Differenzierung des DA Mittelhirnsystems geeignet ist.
Die maximale Feuerungsrate der mesostriatalen und mesolimbischen shell DA Neurone lag stets unterhalb von 10 Hz und war ebenso wie weitere elektophysiologische Parameter (Aktionspotentialdauer, Nachhyperpolarisation) konsistent mit den in der Literatur beschriebenen klassischen DA SN Neuronen in vivo und in vitro. Im unterschwelligen Bereich eines Aktionspotentials war eine schnelle Inaktivierung eines spannungabhängigen Kaliumauswärtsstroms (A-Strom) charakteristisch. Bei Injektion hyperpolarisierender Ströme wiesen diese Zellen eine für DA Neurone typische zeitabhängige Verringerung des korrespondierenden Membranpotentials auf (sag Amplitude, vermittelt über HCN Kanälen). Die Applikation von 100 µM Dopamin führte zu einer über somatodendritische D2 Autorezeptoren vermittelten kompletten und persistierenden Inhibition der Spontanaktivität.
Im Gegensatz hierzu waren mesokortikale, mesoamygdaläre und mesolimbische core DA Neurone durch unkonventionelle elektrophysiologische Eigenschaften gekennzeichnet. Diese Zellen konnten ungewöhnlich hohe maximale Feuerungsraten von etwa 20-30 Hz erreichen. Die Aktionspotentialdauer war signifikant länger und die Amplitude der Nachhyperpolarisation signifkant niedriger. Weiterhin gab es keine Hinweise auf das Vorhandensein von HCN Kanälen und die Inaktivierung des A-Typ Kanals war signifikant langsamer. Die Applikation von Dopamin führte entweder zu keiner (mesokortikale DA Neurone) oder nur zu einer transienten (mesoamygdaläre, mesolimbische core DA Neurone) Inhibition der Spontanaktivität. Ferner konnte gezeigt werden, dass GIRK2 Kanäle, die durch somatodendritische D2 Autorezeptoren aktiviert werden, signifikant niedriger in den unkonventionellen DA Neuronen exprimiert sind. Der funktionelle Dualismus des mesokortikolimbischen DA System konnte anhand einer hierarchischen Clusteranalyse statistisch bestätigt werden.
Die unkonventionellen elektrophysiologischen Eigenschaften machen die mesokortikalen, mesoamygdalären und mesolimbischen core DA Neuronen zu geeigneten Kandidaten für die Vermittlung tonischer Dopaminfreisetzung in vivo und haben somit eine wichtige Funktion bei der Vermittlung kognitiver, motivationaler und emotionaler Fähigkeiten.
Der in der vorliegenden Arbeit vorgestellte anatomische, morphologische, funktionelle und molekulare Dualismus des mesokortikolimbischen DA Systems liefert die zelluläre Basis für die selektive Modulation DA Subpopulationen und ist somit von besonderer Bedeutung für die Entwicklung neuer spezifischer, nebenwirkungsarmer Arzneimittel in der Therapie neurologischer Erkrankungen wie beispielsweise Schizophrenie, Morbus Parkinson und ADHS.The mesocorticolimbic dopamine system is essential for cognitive and emotive brain functions and thus an important target in major brain diseases like schizophrenia, drug addiction and attention-deficit-hyperactivity-disorder. However, the cellular basis for the diversity in behavioral functions and associated dopamine-release pattern within the mesocorticolimbic system has remained unclear. Here I report the identification of a novel type of dopaminergic neuron within the mesocorticolimbic dopamine system with unconventional fast-firing properties and low dopamine transporter (DAT) expression that selectively projects to prefrontal cortex, nucleus accumbens core and to basolateral amygdala. In contrast, well-described conventional slow-firing dopamine midbrain neurons only project to the lateral shell of the nucleus accumbens and the dorsolateral striatum. Among this dual dopamine midbrain system defined in this study by converging anatomical, electrophysiological and molecular properties, mesoprefrontal dopaminergic neurons are unique as only they do not possess functional somatodendritic GIRK2 (G-protein coupled inward rectifying potassium channel 2)-coupled dopamine D2 autoreceptors
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Distinct Subthreshold Signatures of Midbrain Dopamine Neurons Drive Firing Patterns During Noxious Events
No full textThe author has granted permission for their work to be available to the general public.Midbrain dopamine neurons are strongly implicated in reward and aversion. Aversive stimuli are encoded by the firing pattern of dopamine neurons, which governs when dopamine is released at target regions. A response to an aversive stimulus is generated by integrating activity from multiple afferents, and changes in dopamine neuron firing activity are the result of dynamic changes in synaptic input. Using intracellular in vivo recordings, I was able to characterize the subthreshold signatures that elicit either an increase or decrease in dopamine firing activity. A spontaneous increase in dopamine neuron firing activity occurred via two distinct subthreshold mechanisms: 1) A large hyperpolarization followed by a rebound burst; and 2) a transient depolarization and plateau burst. Subthreshold responses evoked by a noxious foot shock were then characterized as either: 1) a large hyperpolarization during a pause in firing, 2) a depolarization during a phasic increase in firing, and 3) a large hyperpolarization followed by a rebound increase in firing activity. Determining the underlying biophysical mechanisms mediating changes in firing pattern provides insight into the afferents that elicit a response during a foot shock.Neuroscience, Developmental and Regenerative Biolog
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Dispelling the Myths Behind First-author Citation Counts
Full text linkWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
- …
