L'objectif de cette thèse a été d'investiguer la question de la généralité et de l'automatisation des processus de contrôle inhibiteur au fil du développement cognitif. Cette question a été approchée par différentes études expérimentales menées chez l'enfant, chez l'adolescent et chez l'adulte. Trois études ont porté sur la généralité des processus de contrôle inhibiteur agissant dans des tâches appartenant à des domaines cognitifs différents. Dans la première, nous avons voulu répondre à deux problématiques liées aux divergences présentes dans la littérature sur le développement du contrôle inhibiteur dans des contextes émotionnels. Le but de cette étude était de déterminer (a) si le contrôle inhibiteur froid (dans des contextes affectivement neutres) et le contrôle inhibiteur chaud (dans des contextes émotionnellement chargés) suivent un pattern développemental identique, particulièrement à l'adolescence et (b) le degré de spécificité de ces deux types de contrôle inhibiteur au fil du développement. Pour cela, nous avons comparé les performances d'enfants de 10 ans, d'adolescents de 13 ans et de jeunes adultes de 21 ans à une tâche de Stroop couleur-mot affectivement neutre et une tâche de Stroop émotionnel. Dans une deuxième étude, nous avons testé auprès d'un groupe d'enfants de 9 ans si les processus inhibiteurs impliqués dans une tâche classique piagétienne de conservation du nombre (i.e., domaine logico-mathématique) étaient identiques ou partiellement identiques à ceux impliqués dans la résolution de la tâche neuropsychologique classique de Stroop couleur-mot (i.e., domaine verbal). Dans une troisième étude, nous avons testé auprès d'un groupe d'enfants de 10 ans et d'un groupe de jeunes adultes de 20 ans la transférabilité des processus inhibiteurs entre une tâche de discrimination de lettres en miroir (dont il a récemment été démontré qu'elle nécessite l'inhibition) et une tâche classique de Stroop couleur-mot, afin de déterminer (a) si la mise en place de mécanismes inhibiteurs impliqués dans la résolution d'un conflit à un niveau perceptif très précoce (la reconnaissance visuelle de symboles) peut faciliter la résolution d'un conflit à un niveau de traitement beaucoup plus tardif (niveau sémantique et moteur), et (b) si l'âge affecte cette transférabilité. Ensuite nous nous sommes intéressés à l'automaticité des processus de contrôle inhibiteur, testant si le contrôle inhibiteur peut fonctionner de manière totalement inconsciente sur des conflits provoqués par deux stimuli subliminaux interférents. Pour cela, nous avons conçu un paradigme d'amorçage composé d'essais dans lesquels un item de Stroop inversé subliminal précédait un item de Stroop visible. Le but de ce paradigme était de vérifier la présence d'un effet d'adaptation de conflit et d'un effet d'amorçage négatif du stimulus subliminal sur le stimulus visible, deux effets rapportés dans les études utilisant des stimuli visibles et suggérant un transfert des processus de contrôle de l'amorce à la cible. Enfin dans une cinquième étude nous avons cherché à savoir si les différences interindividuelles en termes de contrôle inhibiteur découlent en partie des processus prénataux, sur base de l'analyse de la forme sulcale du cortex, considérée comme une caractéristique qualitative de l'anatomie cérébrale déterminée pendant la vie fœtale et stable au cours du développement. En utilisant l'imagerie par résonance magnétique anatomique, nous avons analysé les corrélations entre les performances à une tâche de Stroop couleur-mot et la forme sulcale de deux régions clefs du réseau neuronal du contrôle inhibiteur, le cortex cingulaire antérieur dorsal et le sillon frontal inférieur (qui limite le gyrus frontal inférieur), chez un groupe d'enfants de 10 ans et un groupe d'adultes de 22 ans. En conclusion, cette thèse apporte un nouvel éclairage à la question de la généralité et de l'automatisation des processus d'inhibition exécutive dans une perspective développementale / The objective of this thesis was to investigate the question of the domain-generality of inhibitory control and its automatization throughout development. This question has been approached by various experimental studies in children, adolescents and adults. Three studies have focused on the generality of control processes operating in tasks belonging to different cognitive domains. In the first study, we wanted to answer two questions related to the discrepancies found in the literature on the development of inhibitory control in affectively charged contexts. The aim of this study was to determine (a) whether cool inhibition (control processes in emotionally neutral contexts) and hot inhibition (control processes in emotionally charged contexts) follow the same developmental pattern, and (b) the degree of specificity of these two types of inhibitory control throughout development. We thus compared the performance of 10-year-olds, 13-year-olds and 21-year-olds to an emotionally neutral color-word Stroop task and an emotional Stroop task. In a second study on 9-year-old children, we tested whether the inhibitory processes involved in a classical Piagetian conservation task (i.e., logico-mathematical domain) were identical or partially identical to those involved in the resolution of the classical neuropsychological color-word Stroop task (i.e., verbal domain). In a third study, we tested on a group of 10-year-old children and a group of 20-year-old young adults the transferability of inhibitory processes between a mirror letters discrimination task (that has recently been shown to require inhibition) and a color-word Stroop task, to determine (a) whether the resolution of a conflict at an early perceptual stage of the processing stream (recognition of visual symbols) can facilitate the resolution of a conflict arising at a much later stage (semantic and motor levels), and (b) if age affects this transferability. Then we looked at the automaticity of the inhibition processes by testing whether inhibitory control can operate completely unconsciously on conflicts arising between two subliminal interfering stimuli. To this end, we designed a priming paradigm consisting of trials in which a subliminal reverse Stroop item preceded a visible Stroop item. The aim of this paradigm was to verify the presence of a conflict adaptation effect and a negative priming effect produced by the subliminal items on the visible items. These two effects are commonly reported in studies using visible stimuli and suggest a transfer of control processes from the prime to the probe. Finally, in a fifth study, we investigated whether inter-individual differences in inhibitory control are in part due to prenatal processes, based on the analysis of the sulcal pattern, considered as a qualitative feature of the cerebral anatomy that is determined during fetal life and is stable during development. Using anatomical magnetic resonance imaging, we analyzed the correlations between the performance on a color-word Stroop task and the sulcal pattern of two key regions of the inhibitory control neural network, the dorsal anterior cingulate cortex and the inferior frontal sulcus (which limits the lower frontal gyrus) in a group of 10-year-old children and in a group of 22-year-old adults. In conclusion, this thesis sheds new light on the question of the generality and the automatization of the inhibitory control processes from a developmental perspective.

In the adult mammalian brain, neural stem cells (NSCs) in the dentate gyrus (DG) of hippocampus continuously give rise to new neurons that provide structural plasticity and playing a role in learning and memory. Alterations in this process of adult neurogenesis have been linked to the pathology of various neurodegenerative diseases. Nevertheless, our knowledge regarding adult neurogenesis in the spectrum disorder of amyotrophic lateral sclerosis (ALS)/ frontotemporal dementia (FTD) remains incomplete. Therefore, I aimed to characterize how the ALS/FTD-associated mutation within the FUS protein affects adult NSCs during aging and how this may contribute to hippocampal function. For this purpose, a heterozygous knock-in ALS/FTD mouse model was used in which one copy of FUS harbors a deletion of its nuclear localization signal and their wild-type littermates were used as a control. The obtained results suggest a strong impact of the developing FUS-associated pathology on the hippocampal NSCs in the adult brain. For the first time, an age-dependent increase in NSCs proliferation and in the production of early postmitotic neurons was observed. In addition, the hippocampal network function and the response of adult neurogenesis to external stimulations seem to be altered by FUS mutation. The expected boost of NSC activity upon external stimulation appears to be blocked at particular developmental stages, however, the effect of the used strategies on the function of the hippocampal-cortical circuitry could still be detected. For further investigation, the in vitro analyses of adult NSCs were performed. Their proliferation activity was markedly increased, in comparison to wild-type cells, confirming the in vivo results. It appears that cells harboring mutated FUS are more likely to exit the quiescence state and enter the cell cycle. Furthermore, the combined cultivation of cells of both genotypes revealed that wild-type cells accelerate their proliferation to a similar level as mutant cells. Interestingly, the proliferation behavior of mutant cells remained unchanged regardless of the presence of wild-type cells. This suggests a spreading or transfer of the pathological mechanisms between the NSCs. Additionally, a commonly known hallmark of ALS/FTD pathology, the generation and accumulation of stress granules, was examined. Understanding the pathomechanisms of ALS/FTD-FUS in relation to adult hippocampal neurogenesis clearly requires further investigation. This appears to be crucial to provide the fundamental basis for new NSC-based preventative and therapeutic strategies.:1. Introduction 8 1.1. Adult hippocampal neurogenesis 9 1.1.1. The process of generating new granule neurons within the adult dentate gyrus 9 1.1.2. Regulation and function of AHN 12 1.2. Amyotrophic lateral sclerosis/ frontotemporal dementia 17 1.2.1. Amyotrophic lateral sclerosis/ frontotemporal dementia – spectrum disorder 17 1.2.2. FUS protein characterization and its contribution to ALS/FTD pathology 20 1.2.3. Knock-in mouse model of ALS/FTD-FUS 24 2. Aims 27 3. Materials and methods 28 3.1. In vivo 28 3.1.1. Animals 28 3.1.2. Physical activity 28 3.1.3. Enrichment environment 28 3.1.4. Thymidine labeling and tissue preparation 29 3.1.5. Immunohistochemistry - DAB staining 29 3.1.6. Quantification 30 3.1.7. Electrophysiology 30 3.1.8. Statistical analysis 30 3.2. In vitro 31 3.2.1. Generation of cell line 31 3.2.2. Culturing cell lines 31 3.2.3. Western Blotting 32 3.2.3.1. Collecting protein lysates 32 3.2.3.2. Bradford method 32 3.2.3.3. Electrophoresis and transfer 32 3.2.3.4. Fluorescent immunostaining 33 3.2.4. CFSE labeling and FACS analysis 33 3.2.5. Stress treatment 34 3.2.6. Fluorescent immunostaining (without BrdU) 34 3.2.7. BrdU labeling 35 3.2.8. Fluorescent immunostaining with BrdU 35 3.2.9. Cell cycle analysis 35 3.2.10. Statistical analysis 36 4. Results 37 4.1. In vivo 37 4.1.1. General characterization of the knock-in mouse model of ALS/FTD-FUS 37 4.1.2. Proliferation of hippocampal NSCs in FusDNLS/wt mice is unchanged at young age but strongly increased at old age 38 4.1.3. Response of AHN to external stimulus, such as physical activity, is altered in aged FusDNLS/wt mice 41 4.1.4. FUS mutation causes an increased generation of DCX-positive immature neurons in the DG and an altered response to the stimulatory effects of ENR in mice at 12 months of age 45 4.2. In vitro 52 4.2.1. Partial cytoplasmic mislocalization of mutant FUS protein in FusDNLS/wt cells 52 4.2.2. General level of FUS protein remains stable regardless of genotype 54 4.2.3. FusDNLS/wt cells generated from young animals exhibit distinct proliferation pattern 56 4.2.4. Fuswt/wt cells, cultured together with FusDNLS/wt ones, exhibit FusDNLS/wt-like acceleration of proliferation activity 57 4.2.5. Stress granules dynamics in cells in vitro 59 4.2.6. FusDNLS/wt cells are more likely-activated 65 5. Discussion 67 6. Bibliography 79

Die Verarbeitung unbekannter und visuell vertrauter Gesichter wurde mittels simultaner Messung von Elektroenzephalogramm (EEG), Magnetoenzephalogramm (MEG) und Verhaltensreaktionen untersucht. Dipollokalisationen zeigten, dass MEG und EEG bei 170 ms und 400 bis 500 ms nach Beginn von Gesichterdarbietungen Aktivierung der posterioren Gyri fusiformes (GF) abbilden. Damit konnten beide Zeitbereiche als Aktivität des fusiformen Gesichterareals interpretiert werden. In einem Primingparadigma wurde bei viermaliger Wiederholung unbekannter Gesichter ein Reaktionszeitpriming gezeigt, das für Wiederholungen mit einem Zeitabstand (Lag) von Sekunden stärker als für mehrere Minuten war. Im EEG bewirkten nur Wiederholungen mit kurzem Lag einen Wiederholungseffekt von 300 ms bis 600 ms an posterioren und zentralen Elektroden. Dieser wurde als Korrelat impliziter Gedächtnisverarbeitung von Gesichtern im GF interpretiert. Ein frontaler Wiederholungseffekt ab 700 ms wurde als Ausdruck inzidentellen Erkennens der Gesichterwiederholungen angesehen. Das MEG zeigte posterior einen Wiederholungseffekt ab 800 ms für das kurze Lag. Für das lange Lag wurden keine MEG- oder EEG-Effekte gefunden. Die Wiederholung des Primingexperimentes mit den in einem Lerntraining vertraut gewordenen Gesichtern erzeugte eine generelle Verkürzung der Reaktionszeiten, aber eine Abschwächung des Primingeffektes für das kurze Lag und einen Verlust der Abhängigkeit der Primingstärke vom Zeitabstand. Diese Veränderungen gingen im EEG mit dem Trend zur Verstärkung des posterioren Wiederholungseffektes ab 500 ms einher. Im MEG konnte für die vertrauten Gesichter ein dem EEG in Zeit und Entstehungsort analoger Wiederholungseffekt gezeigt werden. Die Ergebnisse der Untersuchung von Priming bringen Evidenz für die Existenz von Primingeffekten für unbekannte Gesichter. Sie zeigen die Abhängigkeit der Primingeffekte vom Wiederholungsabstand und die Veränderung von Primingeffekten beim Erwerb visueller Vertrautheit. / The processing of unfamiliar and visually familiar faces was examined in a simultaneous measurement of Electroencephalogram (EEG), Magnetoencephalogram (MEG) and behavioural reactions during the presentation of a priming task. Dipole modelling on the EEG and MEG data localized activity in posterior fusiform gyri around 170 ms and between 400 and 500 ms post stimulus onset. Both time ranges were interpreted as activity correlates of the fusiform face area. In the priming paradigm unfamiliar faces were repeated four times. A reaction time priming effect could be shown. This effect was stronger for a short lag (seconds) between repetitions than for minutes. In EEG, only repetitions with short lag evoked a repetition effect at posterior and central electrodes between 300 and 600 ms. This effect was interpreted as a correlate of implicit memory processes presumably generated in the fusiform gyrus. A frontal repetition effect starting around 700 ms was considered a reflection of the incidental recognition of the face repetitions. The MEG data showed a repetition effect for the short lag starting at 800 ms. No electrophysiological effects of face repetition were found for the long lag. Some months later, the same subjects were visually familiarized with the faces in three learning sessions and the priming experiment was repeated. An overall shortening of reaction times was found together with a weakening of the priming effect for the short lag and an absence of the lag’s influence on the strength of the priming effects. In the EEG data a trend for a strengthening of the posterior repetition effect from 500 ms onward emerged. The MEG data yielded a repetition effect for the familiar faces that was analogous to the EEG effect. The results of the priming task give evidence for the existence of priming effects for unfamiliar and familiar faces. They furthermore demonstrate the dependency of priming effects on the lag between repetitions and the visual familiarity of the faces.

Der Hippocampus ist eine von zwei Gehirnregionen, in der zeitlebens kontinuierlich neue Nervenzellen gebildet werden. Er spielt eine wichtige Rolle bei der Gedächtniskonsolidierung und wird mit der funktionellen Entstehung neurodegenerativer Erkrankungen in Verbindung gebracht. Strukturveränderungen im erwachsenen Gehirn, die mit einer Depression einhergehen, sind laut Literatur auf einen geringen Serotoninspiegel und reduzierte hippocampale Neurogenese zurückzuführen. Selektive Serotonin-Wiederaufnahmehemmer (SSRI) erhöhen die Serotoninkonzentration im synaptischen Spalt und üben einen positiven Effekt auf die adulte Neurogenese aus. In der vorliegenden Arbeit wird untersucht, wie Veränderungen in der Serotonin (5-HT)-Neurotransmission durch einmalige oder chronische Gaben von Fluoxetin und speziellen Agonisten und Antagonisten für die Serotoninrezeptoren 5-HT1a und 5-HT2 in der erwachsenen Maus die Proliferation und Differenzierung von neugebildeten Nervenzellen im Gyrus dentatus beeinflussen. Die Ergebnisse zeigen, dass ein konträres Agieren beider Rezeptoren zu einem ausgewogenen Serotoninspiegel führt. 5-HT1a- und 5-HT2c-Rezeptoren haben einen Einfluss auf das Überleben neugebildeter Nervenzellen, wobei sie unterschiedliche Entwicklungsstadien innerhalb der adulten Neurogenese kontrollieren. Die vorliegende Arbeit bekräftigt außerdem, dass die chronische Gabe von Fluoxetin die adulte Neurogenese steigert. / The hippocampus as one region with ongoing neurogenesis throughout life contributes to the formation of long-term memory and has also been implicated in the pathology of major depression. Studies suggest that depression might be due to decreased levels of serotonin and reduced neurogenesis in the adult brain and that the beneficial effects of selective serotonin reuptake inhibitors would require adult hippocampal neurogenesis. Here, I investigated how modulation of serotonergic neurotransmission by acute and chronic treatment with the antidepressant fluoxetine, and selective serotonin receptor agonists and antagonists in adult mice influences precursor cell activity during development. I focused on 5-HT1a and 5-HT2 receptors as major mediators of serotonin action. The present findings suggest that an opposed action of 5-HT1a and 5-HT2c receptor subtypes result in a balanced regulation of serotonin levels in the dentate gyrus. Both receptors differentially affect intermediate cell stages in adult hippocampal neurogenesis and play an important role in the survival of newly generated neurons. Furthermore, this study confirms that chronic fluoxetine treatment increases adult neurogenesis. In conclusion, the latency of onset of fluoxetine action can be explained by a balanced interplay of 5-HT1a and 5-HT2c receptor subtypes.

In der Folge eines Status epilepticus entwickelt sich häufig eine chronische Epilepsie. In der vorliegenden Dissertation wurde die Fragestellung bearbeitet, ob ein Inhibitionsverlust im Gyrus dentatus Grundlage der Epileptogenese nach Status epilepticus ist. Ein selbst-erhaltender Status epilepticus (SSSE) wurde an erwachsenen Ratten durch elektrische Stimulation ausgelöst. Das Auftreten spontaner epileptischer Anfälle wurde im Verlauf von acht Wochen nach Status epilepticus zu drei Zeitpunkten (1, 4 und 8 Wochen) mittels Videoüberwachung erfasst. Zu denselben Zeitpunkten und vor Status epilepticus wurden elektrophysiologische Messungen im Gyrus dentatus durchgeführt. Die Aktivität der Prinzipalzellen des Gyrus dentatus unterliegt unter physiologischen Bedingungen einer ausgeprägten inhibitorischen Kontrolle. Durch Analyse von Doppelreizantworten wurden Veränderungen der Inhibition in dieser für die Epileptogenese relevanten Hirnstruktur beurteilt. Im Verlauf von acht Wochen nach SSSE entwickelte sich bei einem Großteil der Versuchstiere eine chronische Epilepsie. Zum spätesten Beobachtungszeitpunkt traten rekurrente spontane epileptische Anfälle bei 80 Prozent der Tiere auf. Die Inhibition im Gyrus dentatus war eine Woche nach Status epilepticus signifikant reduziert. Vier und acht Wochen nach SSSE zeigte sich eine zunehmende Wiederannäherung an die vor dem Status epilepticus erhobenen Messwerte, so dass von einem transienten Inhibitionsverlust im Gyrus dentatus nach Status epilepticus gesprochen werden kann. Zusammenfassend konnte in der Dissertation gezeigt werden, dass sich in der Folge eines Status epilepticus bei der Mehrzahl der Tiere eine chronische Epilepsie entwickelt. Der Inhibitionsverlust im Gyrus dentatus war zu einem Zeitpunkt am größten, da noch keine spontanen epileptischen Anfälle auftraten. Als sich bei den meisten Tieren eine chronische Epilepsie entwickelt hatte, war die Inhibition komplett wiederhergestellt. Daher ist ein Inhibitionsverlust im Gyrus dentatus nach einem Status epilepticus nicht der führende pathophysiologische Mechanismus für die Entwicklung einer chronischen Epilepsie. / Development of chronic epilepsy as a consequence of status epilepticus is a frequent clinical observation. The aim of this work was to test the hypothesis that epileptogenesis after status epilepticus depends on a loss of inhibitory function in the dentate gyrus. A self-sustaining status epilepticus (SSSE) was induced in rats by continuous electrical stimulation of the perforant path. The occurrence of spontaneous epileptic seizures was assessed by video monitoring 1, 4 and 8 weeks after SSSE. At the same time points and directly before SSSE, inhibition in the dentate gyrus was measured using a paired pulse paradigm. In this region, excitability of principal cells is under physiological conditions effectively controlled by the activity of inhibitory interneurons. In addition, the dentate gyrus is relevant for the process of epileptogenesis due to anatomical properties. In the time course after SSSE, the fraction of animals showing spontaneous epileptic seizures increased steadily reaching 80 % after eight weeks. One week after SSSE, inhibition in the dentate gyrus was significantly reduced. This loss proved to be transient, as inhibition recovered after 4 weeks and reached pre-status values after 8 weeks. In conclusion, the majority of animals developed chronic epilepsy as a consequence of status epilepticus. Loss of inhibition in the dentate gyrus was maximal while spontaneous seizures had not yet developed. Inhibition was normalized when most animals had become epileptic. Thus, loss of inhibition in the dentate gyrus following status epilepticus is not a decisive mechanism in the emergence of spontaneous seizures.

Basierend auf der aktuellen Studienlage wurde versucht, Modellannahmen zum auditi- ven Sprachverständnisses weiter zu ergründen. Im Mittelpunkt stand dabei die Rolle des Gyrus angularis der sprachdominanten Hemisphäre bei der semantischen Integration von Worten in einen gegebenen Satzkontext. Zu diesem Zweck wurden 15 gesunde Proban- den mithilfe von repetitiver transkranieller Magnetstimulation (rTMS) in einem Sprach- verständnisexperiment untersucht. So konnte die funktionelle Relevanz der genannten Hirnregion in Abhängigkeit der Signalqualität des gehörten Satzes und des semanti- schen Kontextes untersucht werden. Zielparameter waren dabei der Anteil der korrekt wiederholten Wörter und Schlüsselwörter des Satzes sowie die Reaktionsgeschwindigkeit.

The dorsal dentate gyrus (DDG) of the hippocampus plays a role in the expression of different forms of flexible behaviour mainly due to its ability to sustain neurogenesis throughout life. In the present thesis, we examined the role that the DDG and its adjacent areas, both collectively referred to as dorsal medial hippocampus (DMH), play in flexible, adaptive behaviour and cognitive processing. We used the neurotoxin, colchicine, to induce lesions of the DDG, which were found to affect neighbouring areas. Thus these lesions will be referred to as lesions of the DMH. In the first experiment, rats were tested for (1) perseverative behaviour before and after receiving chronic methamphetamine (METH) treatment, (2) METH-induced locomotor activity and stereotypy in an open field, and (3) working memory in a T-maze. The results showed that rats with lesions of the DMH exhibited perseveration and supersensitivity to the locomotor- and stereotypy-inducing effects of METH (0, 0.1, 0.3, 1 mg/kg i.p.) as well as increased long-term METH sensitization. Rats with DMH lesions also showed significant working memory deficits. Taken together, these results reveal specific forms of behavioural inflexibility in rats with lesions of the DMH that are mainly associated with perseveration, drug-related behaviours, including stimulant motor supersensitivity and drug sensitization, and impaired working memory functions.

Hintergrund und Ziel der Untersuchung: Patienten mit schizophrenen Erkrankungen zeigen in einer Vielzahl von Untersuchungssituationen eine verminderte Funktion frontaler Hirnregionen (Hypofrontalität), die insbesondere auch den anterioren cingulären Cortex (ACC) betrifft. Verschiedene Arten antipsychotischer Medikation unterscheiden sich hinsichtlich ihrer Wirkung auf Metabolismus und Funktion des Frontalcortex, wobei es Hinweise darauf gibt, dass atypische Antipsychotika diesen Bereich des Gehirns positiv beeinflussen, während konventionelle Antipsychotika (Typika) hier nur geringe oder sogar negative Effekte zeigen. Hinsichtlich der Auswahl eines Antipsychotikums zu Beginn einer medikamentösen Behandlung gibt es bislang keine etablierten neurophysiologischen/biologischen Marker, die eine Vorhersage der Therapie-Response unter verschiedenen Arten antipsychotischer Medikation erlauben. Ziel der Studie war es daher, die Eignung der NoGo-Anteriorisierung (NGA) als Prädiktor der Therapie-Response schizophrener Patienten unter typischer bzw. atypischer Medikation zu untersuchen. Die NGA ist ein neurophysiologischer Marker, der die Funktion präfrontaler Areale einschließlich des ACC widerspiegeln soll. Unter Zuhilfenahme dieses Parameters wurde an einer Gruppe schizophrener Patienten überprüft, ob das Ausmaß der initialen Hypofrontalität eine Vorhersage der individuellen Therapie-Response erlaubt. Methoden: Es wurden 76 Patienten mit Erkrankungen aus dem schizophrenen Formenkreis zu jeweils drei Messzeitpunkten neurophysiologisch, neuropsychologisch und psychometrisch getestet. Die Baseline-Messung (t1) fand innerhalb der ersten drei Tage eines stationär-psychiatrischen Aufenthalts, die beiden Folgemessungen (t2, t3) drei bzw. sechs Wochen nach Beginn einer Therapie mit typischen (n=36) oder atypischen Antipsychotika (n=40) statt. Im Rahmen der neurophysiologischen Untersuchung führten die Patienten eine Go-NoGo-Aufgabe durch, wobei anhand der durch Go- und NoGo-Stimuli evozierten ereigniskorrelierten Potentiale individuell die NGA ermittelt wurde. Beide Behandlungsgruppen wurden aufgrund der NGA-Werte zu t1 in Patienten mit initial starker vs. schwacher Frontalhirnfunktion unterteilt (Mediansplit). Ergebnisse: Alle Patientengruppen zeigten eine signifikante Besserung der psychotischen Symptomatik im Verlauf des 6-wöchigen Untersuchungszeitraums. Außerdem hatten Atypika hypothesengemäß einen signifikant positiven Einfluss auf die Entwicklung der neuropsychologischen Testleistungen, während Typika oftmals mit einer Verschlechterung entsprechender Maße einhergingen. Atypika hatten zudem eine günstigere Wirkung auf die subjektiv erlebte Lebensqualität der Patienten. Darüber hinaus war die zu t1 erhobene NGA ein signifikanter Prädiktor der Therapie-Response. Niedrige Werte der NGA zu Beginn der Behandlung sagten dabei ein besonders gutes Ansprechen auf atypische Antipsychotika voraus, während hohe Werte der NGA zu t1 mit einer besonders deutlichen klinischen Besserung unter typischer Medikation einhergingen. Die NGA korrelierte zudem signifikant mit den neuropsychologischen Testleistungen, unterlag selbst aber keinen systematischen Veränderungen unter typischer vs. atypischer Medikation. Schlussfolgerung: Der auf der Basis früherer Untersuchungen vermutete Zusammenhang zwischen der NGA und präfrontalen Hirnfunktionen konnte anhand der vorliegenden Befunde bestätigt werden. Außerdem war aufgrund der zu Beginn einer stationär-psychiatrischen Behandlung gemessenen NGA eine signifikante Vorhersage der Therapie-Response unter typischen und atypischen Antipsychotika möglich. Die NGA könnte somit im klinischen Alltag zu einer individualisierten Entscheidungsfindung bei der Auswahl eines antipsychotischen Präparats, unter Berücksichtigung pathophysiologischer Aspekte der Erkrankung, beitragen. / Background and objective: Schizophrenic patients often exhibit functional deficits in frontal cortical areas (hypofrontality), particularly within the anterior cingulate cortex (ACC). Different classes of antipsychotic medication differ with respect to their influence on function and metabolism of the frontal cortex, with a more positive effect of atypical as compared to typical compounds. Regarding the therapeutic choice of a particular antipsychotic substance, previous research efforts have not yet been able to establish neurobiological markers that are able to predict the patients’ clinical response to different kinds of antipsychotic medication. The present study, therefore, aimed at examining the NoGo-Anteriorization (NGA) as a possible predictor of the clinical response to typical and atypical antipsychotic treatment. The NGA is a neurophysiological marker that presumably reflects activation of prefrontal cortical structures, including the ACC. For the present study, a group of schizophrenic patients was examined three times in the course of a psychiatric in-patient treatment, to confirm that prefrontal cortical function is positively influenced by atypical antipsychotics, and to explore whether the amount of hypofrontality at the beginning of treatment (quantified by means of the NGA) allows for a prediction of the clinical response to both kinds of antipsychotic medication. Methods: 76 patients with schizophrenic illnesses were examined three times each, by means of neurophysiological, neuropsychological and psychometric measures. Baseline measurements (t1) were conducted within the first three days of a psychiatric in-patient treatment, follow-up measurements (t2, t3) three and six weeks after the start of a therapy with typical (n=36) or atypical antipsychotics (n=40). For the neurophysiological examination, patients performed a Go-NoGo-task, and the individual NGA was calculated on the basis of the corresponding Go- and NoGo-ERPs (event-related potentials). Moreover, the NGA at baseline was used to subdivide both treatment groups into patients with initially strong vs. weak frontal cortical function (NGA above and below group-median, respectively). Results: On a clinical level, patients in each of the four study groups improved significantly over the course of the study period. In line with previous findings, atypical antipsychotics furthermore positively influenced neuropsychological test performance, whereas typical medication often caused a decline in test scores. Similarly, atypical compounds had a more favourable impact on the patients’ self-reported quality of life. Moreover, baseline values of the NGA significantly predicted the patients’ clinical response: Low values at t1 were associated with a particularly strong improvement under atypical medication, whereas high initial values of the NGA predicted a particularly good response to typical antipsychotics. The NGA furthermore significantly correlated with neuropsychological test scores, but did not systematically change over the course of a treatment with typical vs. atypical antipsychotics. Conclusion: The present findings confirm the putative association between the NGA and prefrontal brain functions. Furthermore, the NGA at the beginning of a psychiatric in-patient treatment significantly predicted the clinical response to typical and atypical antipsychotic treatment. Since the NGA can be easily determined in clinical routine settings, it might be a useful parameter for the development of individualised treatment strategies based on pathophysiological aspects of schizophrenic illnesses.

Foi realizada a comparação entre os achados de espectroscopia de prótons por ressonância magnética utilizando a sequência PRESS (point resolved spectroscopy), com TE curto (35ms) no cíngulo posterior e hipocampos de 29 pacientes com doença de Alzheimer (leve e moderada) e 15 controles. As relações de metabólitos com melhor sensibilidade e especificidade na diferenciação entre os grupos foram em ordem decrescente: Naa/Cr do cíngulo, mI/Naa do cíngulo, mI/Naa dos hipocampos e mI/Cr dos hipocampos. Não houve vantagens, nesta casuística, na realização da espectroscopia de prótons nos hipocampos, um local tecnicamente mais difícil e demorado em relação ao cíngulo posterior. Observou-se correlação positiva da relação Naa/Cr e negativa da relação mI/Naa do cíngulo posterior com o MMSE / The objective of this study is to compare the findings on Magnetic Resonance Spectroscopy using PRESS (point resolved spectroscopy) technique with short TE (35ms) in the posterior cingulate and hippocampi of 29 patients with Alzheimer's disease (mild and moderate) and 15 controls. The metabolic ratios with highest sensitivity and specificity were (in a decreasing order): posterior cingulate Naa/Cr, posterior cingulate mI/Naa, hippocampi mI/Naa and hippocampi mI/Cr. In the group analised it seems there is no advantage in performing MRS in the hippocampi instead of posterior cingulate, a technically challenging location, usually leading to a longer examination time. In the posterior cingulate we observed a positive correlation with Naa/Cr ratio and a negative correlation with mI/Naa ratio and the MMSE

Adult hippocampal neurogenesis—a unique form of plasticity in the dentate gyrus (DG)—is regulated by experience, and when manipulated can have specific effects on behavior. Different methods have been used over the years to study new neurons’ functional role in the hippocampus, many of which focus on ablating neurogenesis. While ablation methods can test the necessity of adult-born granule cells (abGCs) for behavior, these techniques remove all abGCs from the circuit and thus do not allow one to determine which properties of abGCs are required for behavior. Such information is required to understand the mechanism of their action. Thus, new strategies are needed to determine what properties of young abGCs allow them to distinguish themselves from their mature counterparts and uniquely impact behavior. Recent hypotheses have suggested that the enhanced synaptic plasticity exhibited by 4–6-week-old abGCs allows them to uniquely contribute to hippocampal circuit function, and thus behavior. The primary goal of this thesis was to explore the contribution young abGCs’ heightened synaptic plasticity makes to hippocampal function. This was achieved using a transgenic mouse approach that allowed for the conditional deletion of NR2B from abGCs. Overall, iNR2BNes mice generated the same number of new neurons in adulthood as control mice at baseline. These neurons survived and matured with only a slight reduction in dendritic complexity. However, a potentially important electrophysiological property of these neurons—their enhanced synaptic plasticity—had been eliminated. From an electrophysiological standpoint, iNR2BNes mice resemble mice with ablated neurogenesis, while from all other neurogenic standpoints examined they most closely resemble wild-type mice. Consequently, these mice provided a novel model to test the extent to which young abGCs’ enhanced plasticity contributes to hippocampal-dependent behaviors. The results reveal that eliminating NR2B-containing NMDA receptors from abGCs does not alter baseline anxiety or antidepressant (AD)-like behavior. However, iNR2BNes mice differed from controls in measures of cognitive function. These mice were able to learn in the contextual fear conditioning test, but were impaired in the more difficult contextual fear discrimination test. Mice also exhibited a decreased novelty exploration phenotype that impaired their performance in the novel object recognition test. Together, these results indicate that the NR2B-dependent heightened plasticity exhibited by 4–6-week-old abGCs is necessary for responses to novelty and fine contextual discrimination, but does not contribute to baseline anxiety or emotionality. AD treatment increases levels of adult neurogenesis in the hippocampus, and these newborn neurons have been shown to be necessary for some of the behavioral effects of ADs seen in rodents. In addition, the maturation timeline of adult neurogenesis correlates with the onset of behavioral responses to ADs. ADs also enhance a neurogenesis-dependent form of long-term potentiation (LTP) in the DG evoked by medial perforant path stimulation under intact GABAergic tone called ACSF-LTP. Thus, a potential mechanism by which abGCs may contribute to AD behavioral efficacy is by providing extra plastic units to the DG circuit. This theory was tested by once again using the mouse line in which NR2B can be conditionally deleted from abGCs in the DG. Here, we found that deletion of the NR2B subunit significantly attenuated a neurogenesis-dependent behavioral response to fluoxetine in the novelty suppressed feeding test, and additionally blocked fluoxetine’s ability to enhance young abGCs’ maturation and subsequent integration into the hippocampal network. This suggests that eliminating abGCs’ enhanced plasticity decreases their ability to influence DG output resulting in an AD response that is less robust than seen in control mice. Control experiments revealed the specificity of this effect, as NR2B deletion did not impact the effect of fluoxetine in a neurogenesis-independent behavioral assay (tail suspension test) or in an assay that was insensitive to fluoxetine in this strain of mice (elevated plus maze). Our efforts to isolate the contribution of abGCs’ unique physiology from the neurogenic effects of fluoxetine were not entirely successful as the results presented here also revealed slight group differences in neurogenesis between control mice and mice lacking NR2B in young neurons. Yet, this data still supports the idea that fluoxetine increases the ability of abGCs to participate in DG output by increasing the chance that new neurons will be activated during DG stimulation. This may be achieved either by increasing their overall number, increasing their potential to make synaptic connections, or increasing their ability to strengthen their connections. However, due to the close link between activity and maturation that appears to be enhanced with fluoxetine treatment, a different approach with greater temporal resolution is needed to separate the neurogenic effects of fluoxetine from the physiological contribution abGCs make to hippocampal output. With this in mind, a mouse line in which abGCs could be temporally inhibited was also generated. Cellular and behavioral characterization of mice conditionally expressing hM4Di—a mutated muscarinic acetylcholine receptor that is insensitive to endogenous acetylcholine, but can be activated by the biologically inert, highly bioavailable compound, clozapine N-oxide (CNO)—has begun. Results show that acute CNO treatment in mice expressing this designer receptor exclusively activated by a designer drug (DREADD) in DG granule cells can impair encoding of contextual fear memory. Chronically treating these mice had an anxiogenic effect in the open field test, but otherwise anxiety and emotionality in these mice were comparable to controls. Chronic CNO treatment in mice expressing hM4Di in young abGCs effectively decreased these cells’ dendritic complexity, but did not alter proliferation or early survival. Thus, hM4Di DREADDs represent a novel tool that can be used to modulate activity of neurons in a temporally restricted manner, allowing for both acute and chronic manipulations of hippocampal granule cells. The experiments put forth in this thesis will highlight the importance of abGCs enhanced plasticity. The utility as well as potential pitfalls of the mouse models used here to test theories of abGC function will also be explored. Hopefully this analysis will provide an improved framework in which future experiments can be developed with the aim of uncovering novel insights into the hippocampal circuitry that underlies learning and memory and discovering new strategies for the treatment of neurological and psychiatric disorders.