@phdthesis{Brembs2000,
  author    = {Brembs, Bj{\"o}rn},
  title     = {An Analysis of Associative Learning in Drosophila at the Flight Simulator},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-1039},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2000},
  abstract  = {Most natural learning situations are of a complex nature and consist of a tight conjunction of the animal's behavior (B) with the perceived stimuli. According to the behavior of the animal in response to these stimuli, they are classified as being either biologically neutral (conditioned stimuli, CS) or important (unconditioned stimuli, US or reinforcer). A typical learning situation is thus identified by a three term contingency of B, CS and US. A functional characterization of the single associations during conditioning in such a three term contingency has so far hardly been possible. Therefore, the operational distinction between classical conditioning as a behavior-independent learning process (CS-US associations) and operant conditioning as essentially behavior-dependent learning (B-US associations) has proven very valuable. However, most learning experiments described so far have not been successful in fully separating operant from classical conditioning into single-association tasks. The Drosophila flight simulator in which the relevant behavior is a single motor variable (yaw torque), allows for the first time to completely separate the operant (B-US, B-CS) and the classical (CS-US) components of a complex learning situation and to examine their interactions. In this thesis the contributions of the single associations (CS-US, B-US and B-CS) to memory formation are studied. Moreover, for the first time a particularly prominent single association (CS-US) is characterized extensively in a three term contingency. A yoked control shows that classical (CS-US) pattern learning requires more training than operant pattern learning. Additionally, it can be demonstrated that an operantly trained stimulus can be successfully transferred from the behavior used during training to a new behavior in a subsequent test phase. This result shows unambiguously that during operant conditioning classical (CS-US) associations can be formed. In an extension to this insight, it emerges that such a classical association blocks the formation of an operant association, which would have been formed without the operant control of the learned stimuli. Instead the operant component seems to develop less markedly and is probably merged into a complex three-way association. This three-way association could either be implemented as a sequential B-CS-US or as a hierarchical (B-CS)-US association. The comparison of a simple classical (CS-US) with a composite operant (B, CS and US) learning situation and of a simple operant (B-US) with another composite operant (B, CS and US) learning situation, suggests a hierarchy of predictors of reinforcement. Operant behavior occurring during composite operant conditioning is hardly conditioned at all. The associability of classical stimuli that bear no relation to the behavior of the animal is of an intermediate value, as is operant behavior alone. Stimuli that are controlled by operant behavior accrue associative strength most easily. If several stimuli are available as potential predictors, again the question arises which CS-US associations are formed? A number of different studies in vertebrates yielded amazingly congruent results. These results inspired to examine and compare the properties of the CS-US association in a complex learning situation at the flight simulator with these vertebrate results. It is shown for the first time that Drosophila can learn compound stimuli and recall the individual components independently and in similar proportions. The attempt to obtain second-order conditioning with these stimuli, yielded a relatively small effect. In comparison with vertebrate data, blocking and sensory preconditioning experiments produced conforming as well as dissenting results. While no blocking could be found, a sound sensory preconditioning effect was obtained. Possible reasons for the failure to find blocking are discussed and further experiments are suggested. The sensory preconditioning effect found in this study is revealed using simultaneous stimulus presentation and depends on the amount of preconditioning. It is argued that this effect is a case of 'incidental learning', where two stimuli are associated without the need of reinforcement. Finally, the implications of the results obtained in this study for the general understanding of memory formation in complex learning situations are discussed.},
  subject      = {Taufliege},
  language  = {en}
}
@phdthesis{Ewald2014,
  author    = {Ewald, Heike},
  title     = {Influence of context and contingency awareness on fear conditioning - an investigation in virtual reality},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-111226},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2014},
  abstract  = {Fear conditioning is an efficient model of associative learning, which has greatly improved our knowledge of processes underlying the development and maintenance of pathological fear and anxiety. In a differential fear conditioning paradigm, one initially neutral stimulus (NS) is paired with an aversive event (unconditioned stimulus, US), whereas another stimulus does not have any consequences. After a few pairings the NS is associated with the US and consequently becomes a conditioned stimulus (CS+), which elicits a conditioned response (CR). The formation of explicit knowledge of the CS/US association during conditioning is referred to as contingency awareness. Findings about its role in fear conditioning are ambiguous. The development of a CR without contingency awareness has been shown in delay fear conditioning studies. One speaks of delay conditioning, when the US coterminates with or follows directly on the CS+. In trace conditioning, a temporal gap or "trace interval" lies between CS+ and US. According to existing evidence, trace conditioning is not possible on an implicit level and requires more cognitive resources than delay conditioning. The associations formed during fear conditioning are not exclusively associations between specific cues and aversive events. Contextual cues form the background milieu of the learning process and play an important role in both acquisition and the extinction of conditioned fear and anxiety. A common limitation in human fear conditioning studies is the lack of ecological validity, especially regarding contextual information. The use of Virtual Reality (VR) is a promising approach for creating a more complex environment which is close to a real life situation. I conducted three studies to examine cue and contextual fear conditioning with regard to the role of contingency awareness. For this purpose a VR paradigm was created, which allowed for exact manipulation of cues and contexts as well as timing of events. In all three experiments, participants were guided through one or more virtual rooms serving as contexts, in which two different lights served as CS and an electric stimulus as US. Fear potentiated startle (FPS) responses were measured as an indicator of implicit fear conditioning. To test whether participants had developed explicit awareness of the CS-US contingencies, subjective ratings were collected. The first study was designed as a pilot study to test the VR paradigm as well as the conditioning protocol. Additionally, I was interested in the effect of contingency awareness. Results provided evidence, that eye blink conditioning is possible in the virtual environment and that it does not depend on contingency awareness. Evaluative conditioning, as measured by subjective ratings, was only present in the group of participants who explicitly learned the association between CS and US. To examine acquisition and extinction of both fear associated cues and contexts, a novel cue-context generalization paradigm was applied in the second study. Besides the interplay of cues and contexts I was again interested in the effect of contingency awareness. Two different virtual offices served as fear and safety context, respectively. During acquisition, the CS+ was always followed by the US in the fear context. In the safety context, none of the lights had any consequences. During extinction, a additional (novel) context was introduced, no US was delivered in any of the contexts. Participants showed enhanced startle responses to the CS+ compared to the CS- in the fear context. Thus, discriminative learning took place regarding both cues and contexts during acquisition. This was confirmed by subjective ratings, although only for participants with explicit contingency awareness. Generalization of fear to the novel context after conditioning did not depend on awareness and was observable only on trend level. In a third experiment I looked at neuronal correlates involved in extinction of fear memory by means of functional magnetic resonance imaging (fMRI). Of particular interest were differences between extinction of delay and trace fear conditioning. I applied the paradigm tested in the pilot study and additionally manipulated timing of the stimuli: In the delay conditioning group (DCG) the US was administered with offset of one light (CS+), in the trace conditioning group (TCG) the US was presented 4s after CS+ offset. Most importantly, prefrontal activation differed between the two groups. In line with existing evidence, the ventromedial prefrontal cortex (vmPFC) was activated in the DCG. In the TCG I found activation of the dorsolateral prefrontal cortex (dlPFC), which might be associated with modulation of working memory processes necessary for bridging the trace interval and holding information in short term memory. Taken together, virtual reality proved to be an elegant tool for examining human fear conditioning in complex environments, and especially for manipulating contextual information. Results indicate that explicit knowledge of contingencies is necessary for attitude formation in fear conditioning, but not for a CR on an implicit level as measured by FPS responses. They provide evidence for a two level account of fear conditioning. Discriminative learning was successful regarding both cues and contexts. Imaging results speak for different extinction processes in delay and trace conditioning, hinting that higher working memory contribution is required for trace than for delay conditioning.},
  subject      = {Klassische Konditionierung},
  language  = {en}
}
@phdthesis{Weissflog2011,
  author    = {Weißflog, Lena},
  title     = {Molecular Genetics of Emotional Dysregulation in Attention-Deficit/Hyperactivity Disorder},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-69345},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2011},
  abstract  = {Attention-deficit/hyperactivity disorder (ADHD) is a genetically complex childhood onset neurodevelopmental disorder which is highly persistent into adulthood. Several chromo-somal regions associated with this disorder were identified previously in genome-wide linkage scans, association (GWA) and copy number variation (CNV) studies. In this work the results of case-control and family-based association studies using a can-didate gene approach are presented. For this purpose, possible candidate genes for ADHD have been finemapped using mass array-based SNP genotyping. The genes KCNIP4, CDH13 and DIRAS2 have been found to be associated with ADHD and, in addition, with cluster B and cluster C personality disorders (PD) which are known to be related to ADHD. Most of the associations found in this work would not withstand correction for multiple testing. However, a replication in several independent populations has been achieved and in conjunction with previous evidence from linkage, GWA and CNV studies, it is assumed that there are true associations between those genes and ADHD. Further investigation of DIRAS2 by quantitative real-time PCR (qPCR) revealed expression in the hippocampus, cerebral cortex and cerebellum of the human brain and a significant increase in Diras2 expression in the mouse brain during early development. In situ hybrid-izations on murine brain slices confirmed the results gained by qPCR in the human brain. Moreover, Diras2 is expressed in the basolateral amygdala, structures of the olfactory system and several other brain regions which have been implicated in the psychopatholo-gy of ADHD. In conclusion, the results of this work provide further support to the existence of a strong genetic component in the pathophysiology of ADHD and related disorders. KCNIP4, CDH13 and DIRAS2 are promising candidates and need to be further examined to get more knowledge about the neurobiological basis of this common disease. This knowledge is essential for understanding the molecular mechanisms underlying the emergence of this disorder and for the development of new treatment strategies.},
  subject      = {Aufmerksamkeits-Defizit-Syndrom},
  language  = {en}
}
@phdthesis{Ziegler2004,
  author    = {Ziegler, Susanne},
  title     = {Die altersabh{\"a}ngige Makuladegeneration : Untersuchung zur genetischen Assoziation des Apolipoproteins E und des Alpha-2-Makroglobulins},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-15472},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2004},
  abstract  = {Die Arbeit dient der Aufkl{\"a}rung genetischer Ursachen der altersabh{\"a}ngigen Makuladegeneration (AMD) - einer komplexen Erkrankung mit bisher unklarer {\"A}tiologie. Ziel der Arbeit war die Untersuchung einer m{\"o}glichen Assoziation der AMD mit Polymorphismen in den Genen f{\"u}r Apolipoprotein E (ApoE) und Alpha-2-Makroglobulin. Voraussetzung f{\"u}r diese Arbeit waren Studien von Klaver et al. (1998) und Souied et al. (1998). Beide Studien belegen die Assoziation eines ApoE-Polymorphismus, dem ApoE-4-Allel, mit der AMD im Sinne eines protektiven Faktors: Bei den untersuchten AMD-Patienten war die H{\"a}ufigkeit des ApoE-4-Allels signifikant geringer als in den Kontrollgruppen. Diese Assoziation sollte in der vorliegenden Arbeit an einem neuen und gr{\"o}ßeren Patientenkollektiv untersucht werden. Das ApoE-4-Allel ist ein Risikofaktor f{\"u}r Morbus Alzheimer (Corder et al, 1993). Wie AMD ist die Alzheimer Erkrankung eine neurodegenerative Erkrankung des Alters mit komplexer {\"A}tiologie und Pathogenese. Deshalb wurde folgende Hypothese aufgestellt: Wenn das ApoE-4-Allel sowohl mit Morbus Alzheimer als auch mit der AMD assoziiert ist, sind m{\"o}glicherweise auch andere, mit Morbus Alzheimer assoziierte Polymorphismen an den pathogenetischen Vorg{\"a}ngen der AMD beteiligt. Ausgehend von dieser {\"U}berlegung wurden neben den ApoE-Polymorphismen zwei h{\"a}ufige Polymorphismen eines weiteren Risikofaktors f{\"u}r Alzheimer untersucht: das Alpha-2-Makroglobulin (A2M). Die in den Studien vorbeschriebene, signifikant geringere H{\"a}ufigkeit des ApoE-4-Allels bei AMD-Patienten konnte am vorliegenden Patientenkollektiv nicht nachvollzogen werden. Die ApoE-4-Allelfrequenz betrug in der Gruppe der AMD-Patienten 9,5\% und in der Gruppe der altersgem{\"a}ßen Kontrollpersonen ebenfalls 9,5\% (p=0,998). Ein signifikantes Ergebnis brachte der Vergleich der ApoE-4-Allelh{\"a}ufigkeit bei AMD-Patienten mit der H{\"a}ufigkeit in der Gruppe „Normalbev{\"o}lkerung", die sich durch ein geringeres Durchschnittsalter auszeichnet (p= 0,001; Altersdurchschnitt 82,3 vs. 39,8 Jahre). Hier liegt aber vermutlich ein „selection bias" zugrunde. Eine von Schachter et al. (1994) ver{\"o}ffentlichte Studie belegt die generelle Abnahme der H{\"a}ufigkeit des ApoE-4-Allels in h{\"o}heren Altersgruppen. Die Untersuchung der beiden A2M-Polymorphismen ergab keinen Hinweis auf eine m{\"o}gliche Assoziation mit der AMD. Weder die A2M-Allelverteilung (p=0,649) noch die Verteilung der Genotypen (p=0,1) zeigte signifikante Unterschiede. Der Vergleich der Ergebnisse mit den bisher publizierten Studien zur Assoziation des ApoE-4-Allels mit der AMD ergibt ein widerspr{\"u}chliches Bild. Obwohl die Studien von Klaver et al. (1998) und Souied et al. (1998) eine Assoziation des ApoE-4-Allels mit der AMD nachweisen, ist die H{\"a}ufigkeitsverteilung des Allels in vier nachfolgenden Assoziationsstudien (Schmidt et al., 2000; Pang et al., 2000; Simonelli et al., 2001; Schultz et al. 2003) sowie in der vorliegenden Arbeit nicht signifikant. Allerdings belegen auch neuere Studien eindeutig eine Assoziation des Allels mit der AMD (Baird et al., 2004; Zareparsi et al., 2004). M{\"o}glicherweise stellt das ApoE-4-Allel einen protektiven Faktor dar, der Effekt ist aber in verschiedenen Populationen unterschiedlich stark ausgepr{\"a}gt. F{\"u}r Populationen mit schw{\"a}cherer Auspr{\"a}gung sind vermutlich große Studien¬gruppen notwendig, um bei einer Assoziationsstudie signifikante Frequenzunterschiede zu erhalten. Weiterhin k{\"o}nnte die Heterogenit{\"a}t der AMD ein Problem bei Assoziationsstudien darstellen. Denkbar w{\"a}re, dass unterschiedliche Formen der AMD auch mit unterschiedlichen genetischen Risikokonstellationen assoziiert sind. Eine m{\"o}gliche Assoziation mit einem Polymorphismus w{\"u}rde in einem großen Patientenkollektiv, das unterschiedliche Formen der AMD enth{\"a}lt, statistisch nicht auffallen. Erst Untersuchungen an ausgew{\"a}hlten Patientengruppen, die nur einen streng definierten Ph{\"a}notyp enthalten, w{\"u}rden den Effekt sichtbar machen. Einen Beleg hierf{\"u}r bietet die Studie von Souied et al. (1998), die sich auf die exsudative Form der AMD beschr{\"a}nkt und eine deutlich signifikante Assoziation dieses Ph{\"a}notyps mit dem ApoE-4-Allel nachweist. Der Aussagewert der bisher durchgef{\"u}hrten Studien zur Assoziation des ApoE-4-Allels mit der AMD ist noch begrenzt. Dennoch k{\"o}nnen Assoziationsstudien dazu beitragen, die genetischen Ursachen der AMD zu entschl{\"u}sseln und damit die Grundlage f{\"u}r neue Therapieans{\"a}tze schaffen. Eine erfolgversprechende Strategie f{\"u}r zuk{\"u}nftige Assoziationsstudien ist sicherlich die Untersuchung an zahlenm{\"a}ßig ad{\"a}quaten und klinisch klar definierten Patientengruppen sowie einwandfreien, altersgem{\"a}ßen Kontrollpersonen.},
  language  = {de}
}