The startle response as a measure in mouse models of mood disorders

Ein großer Teil der Fragestellungen in den Neurowissenschaften beschäftigt sich mit dem Thema, wie das Säugerhirn Verhalten auslöst und steuert. Die Schreckreaktion ist ein relativ einfaches Verhalten, welches bei Säugetieren ohne großen Aufwand ausgelöst werden kann und variabel auf eine Vielfalt von experimentellen Behandlungen reagiert. Das Ziel der vorliegenden Arbeit war es, Schreckreaktions-Messungen am Max-Planck- Institut für Psychiatrie in München (MPI-P) zu etablieren. Vor dem Hintergrund aktueller Fragestellungen sollten die Experimente zu einsatzbereiten Messmethoden und Verhaltensparadigmen führen. In der vorliegenden Arbeit gelang es nicht, das Paradigma der furchtpotenzierten Schreckreaktion (FPS) zuverlässig in einem häufig am MPI-P eingesetzten Mausstamm anzuwenden. Das FPS maskierende Phänomen, daß die Präsentation eines unkonditionierten Tons bereits zu einer deutlich verstärkten Schreckreaktion in diesen Mäusen führt ("tone enhanced startle", TES) wurde dann charakterisiert und im Folgenden als ergänzendes Paradigma zur Messung und Abschätzung des Hörvermögens, der Stimulus Adaptation und der Aufmerksamkeit in Mäusen vorgeschlagen. Eine Literaturrecherche ergab, daß im Paradigma der Furchtkonditionierung ("fear conditioning", FC) und deren aktives Verlernen ("extinction of FC", ExFC) verwendete Stimulus-Parameter eine hohe Varianz zwischen verschiedenen Laboratorien aufweisen. Der im Verhalten ausgelesene Lernerfolg während einer FC wie auch einem ExFC hingen in den vorliegenden Experimenten wesentlich von der verwendeten Stimulusqualität ab (d.h. sinus-Ton oder weißes Rauschen). Im Umkehrschluß empfiehlt die vorliegende Arbeit einen überlegteren Umgang mit den eingetzten Stimulus-Parametern. Es zeigte sich, daß eine erhöhte Schreckreaktion (Übererregbarkeit) ohne weiteres in einem Tiermodell der Posttraumatischen Belastungsstörung ("posttraumatic stress disorder",PTSD) gemessen werden kann. Im Weiteren konnte gezeigt werden, daß verändertes Hippocampus-Volumen in diesen Tieren, gemessen über ultramikroskopische Aufnahmen und analog zu Hippocampusveränderungen in Patienten, unabhängig von anderen PTSD-ähnlichen Symptomen dieser Mäuse ist. In einem weiteren Abschnitt widmet sich die vorliegende Arbeit der laufenden Charakterisierung der Rolle von Dopaminrezeptoren (DR) in der Präpulsinhibition (PPI) und -Faszilitierung (PPF) der Schreckreaktion. Durch lokale injektion von DR-Antagonisten konnte gezeigt werden, daß die Blockade von DR1 wiederholbar PPI verstärkt, während die Rolle von DR2, getestet mit zwei verschiedenen Antagonisten, als ambivalent gedeutet werden muß. Basierend auf diesen Experimenten wurden optogenetische Methoden in die Schreckreaktionsmessung eingeführt. Transgenen Mäusen, die lichtsensitive Ionenkanäle in ihren neuronalen Zellmembranen bestimmter Zellpopulationen tragen, wurden Lichtblitze ins Gehirn appliziert. Auf diese Weise konnten PPI und PPF unabhängig voneinander manipuliert werden. Daraus folgend, und im Unterschied zur populären Summationshypothese der PPF, schlägt die vorliegende Arbeit einen eigenständigen, von der PPI unabhängigen PPF-Schaltkreis vor, der Pyramidenneuronen der präfrontalen Kortexschicht V beinhaltet. Die vorliegende Arbeit konnte erfolgreich verschiedene Protokolle und Verhaltensparadigmen der Schreckreaktionsmessung am MPI-P etablieren und zur sofortigen Nutzung zur Verfügung stellen. Es wurden nicht nur neue Techniken wie z.B. optogenetische Methoden in die Schreckreaktionsmessung eingeführt, die vorliegenden Experiemente leisten auch ihren Beitrag zur aktiven Forschung, in dem sie z.B. die große Bedeutung der Stimulus-Parameter für den Lernerfolg von Versuchstieren nachweisen.In neuroscience major efforts are focused on the question of how the mammalian brain generates and controls behaviour. The startle response is a relatively simple behaviour that can be easily elicited in mammals and is sensitive to a variety of experimental treatments. The aim of the present work was to establish startle response measures at the Max-Planck-Institute of Psychiatry (MPI-P), Munich, providing a set of readily applicable methods and paradigms, and contributing to questions in behavioural neuroscience. While the present thesis failed to robustly elicit fear potentiated startle (FPS) in a commonly used mouse strain at the MPI-P, strong unconditioned startle enhancement by acoustic stimulus presentation in that mouse strain was capitalised to propose tone enhanced startle (TES) as an additional paradigm to assess hearing capability, stimulus adaptation and attention in mice. A literature survey revealed considerably varying parameters used in fear conditioning (FC) and extinction of conditioned fear (ExFC). In the present work, FC, ExFC as well as FPS/TES highly depended on the stimulus quality (i.e. sine wave or white noise), demanding a more careful handling of stimulus parameters. Hyper-arousal was readily tested in a mouse model of posttraumatic stress disorder (PTSD). Additionally it was shown that altered hippocampal volume in these animals, assessed by ultramicroscopic measures and mimicking patient data, was independent of other symptoms present in this model. The present thesis contributes to the ongoing characterisation of the role of dopamine receptors (DR) in prepulse inhibition (PPI) and prepulse facilitation (PPF) of startle, manipulating PPI/F by injections of DR-antagonists into the prefrontal cortex of mice. It was found that blockade of DR1 reliably increases PPI, while the effect of DR2 was inconsistent, using to different DR2-antagonists. Based on this work, optogenetic methods were established. Applying intracerebral light flashes to transgenic mice carrying light sensitive ion channels on their neuronal cell membrane, PPI and PPF were manipulated independently, proposing the existence of a discrete PPF mediating pathway including prefrontal layer V pyramidal neurons, contrasting the popular summation hypothesis of PPF. The present work established and developed successfully different startle paradigms that are ready to use for animal characterisation and testing. Apart from combining startle measures with new techniques such as optogenetic methods, the present thesis points out the stimulus parameter dependence of animal learning, suggesting a fundamental discussion about fear conditioning and extinction learning protocols

Archival agility : some preliminary observations

History does not stand still. Historians in the 21st Century ask questions of the past—and reach at least preliminary answers—that had not even occurred to an earlier generation. To borrow the words of Harvard historian Akira Iriye, there has been, in recent decades, a “significant new development in the way in which historians conceptualize and seek to understand the past.”1 Among the few disciplinary constants is the primacy of the primary source, even if each individual historian’s choice of research materials is locked in a mutual embrace with the questions that they are asking

Emperor Hirohito's post-surrender reflections

This essay introduces readers to the recent discovery of the personal papers of Grand Steward Tajima Michiji. These documents capture the post-surrender reflections of Hirohito, Japan’s Shōwa Emperor, and record him speaking on such issues as his war responsibility, as well as the culpability of prewar politicians such as Konoe Fumimaro and General Tōjō Hideki. In August 2019, Nippon Hoso Kyokai (Japan Broadcasting Corporation) (nhk) announced that it had gained privileged access to the papers. Acting on advice from scholars, it then released extracts from Tajima’s audience records. Drawing not on the Tajima papers themselves, but on what the nhk has made available, the documents demonstrate that Hirohito, after Japan’s surrender, experienced anguish and over the war and its outcome. He continued as emperor because he accepted “moral responsibility” for the war that required him to help his nation and its people endure occupation and reconstruction. This article also describes Hirohito’s postwar reflections on several issues, such as Japanese field officers and subordinates in the 1930s initiating without authorization acts of aggression, the Rape of Nanjing, and Japan’s postwar rearmament. While the Tajima papers will not resolve the ongoing debate over the emperor’s responsibility for Japan’s path of aggression before 1945, they do provide valuable insights about his role in and reaction to events before, during, and after World War ii

Japanese primary sources relating to World War II : post-Cold War developments

This article introduces readers to World War ii-era Japanese primary sources that have become available, over the last three decades, at the major archives and libraries. It also illustrates how and why some of these hitherto unavailable archival materials have become publicly accessible. At first, political, diplomatic and military historians primarily conducted their research at Diplomatic Archives, Military Archives, and the Modern Japanese Political History Materials Room, until the Japanese Diet passed a law in 2011 stipulating that all government and agencies, except for the Foreign Ministry and Imperial Household Agency, must transfer archived documents to the National Archives of Japan (naj). Enhancing its importance for research, the naj played the lead role in creating and maintaining the Japan Center for Asian Historical Records that has sustained a major effort at digitization. Other important primary sources include documents related to Emperor Hirohito, the Documents on Japanese Foreign Policy series, holdings of the Military History Department, and materials non-governmental organizations have published. The amount of Japanese source materials and their digitization now has reached a level that meets the U.S. and European standards

‘Seoul Searching’: The History, Politics and Prejudice behind the Re-naming of Korea’s Capital in Chinese

On 19 January 2005, Seoul Mayor at the time and South Korea’s president at present, Lee Myung Bak, announced his desire to see the Chinese name for Seoul changed from the traditional rendition of Hancheng （漢城）, to Shouer (首爾). Lee made clear that he was motivated by a simple desire to remove a potential cause for Sino-Korean “confusion.” He further suggested that the principal beneficiary of the name change would be those Chinese in some way connected to Seoul. If Mayor Lee had hoped for an uncontroversial re-naming, he was proven right for the most part. Not only did the Chinese government grant Mayor Lee’s wish quickly and quietly, but regional media outlets also remained notably low-key on the naming issue. This article argues, nonetheless, that there is good reason to believe that Lee’s move was driven by overarching concerns about China’s growing regional clout, and that the significance of Seoul’s name change in Chinese extends well beyond semantics; it can in a sense be seen as a test-case for the PRC’s ability to leverage soft power in the region, and allay the concerns of its neighbours about the implications of its geo-strategic rise

Is my rival’s rival a friend? Popular third-party perceptions of territorial disputes in East Asia

This article examines how China's rise and increasing tensions with Japan are portrayed by South Korean bloggers. The deterioration in relations between China and Japan over the last two years generally projects onto the ways and means by which China's rise is portrayed in South Korea. Since Korea's relations with both its more populous neighbours have been historically fraught, and since it is also implicated in various territorial disputes with both countries, determining Korean sensibilities is an important way of gauging shifts in public opinion across the region. Although the conservative political establishments in both South Korea and Japan might see China as a constant threat, South Korean and Japanese netizens still popularly view each other with suspicion. By contrast, popular perceptions of the China threat in either country can be swayed by escalation of territorial disputes these two US allies still have with one anothe

Glassy timescale divergence and anomalous coarsening in a kinetically constrained spin chain

We analyse the out of equilibrium behavior of an Ising spin chain with an asymmetric kinetic constraint after a quench to a low temperature T. In the limit T\to 0, we provide an exact solution of the resulting coarsening process. The equilibration time exhibits a `glassy' divergence \teq=\exp(const/T^2) (popular as an alternative to the Vogel-Fulcher law), while the average domain length grows with a temperature dependent exponent, \dbar ~ t^{T\ln 2}. We show that the equilibration time \teq also sets the timescale for the linear response of the system at low temperatures.Comment: 4 pages, revtex, includes two eps figures. Proof of energy barrier hierarchy added. Version to be published in Phys Rev Let