The neurotoxin 6-hydroxydopamine (6-OHDA), following pretreatment with the norepinephrine transport inhibitor desipramine, selectively destroys dopaminergic neurons. When given to rats, neonatal 6-OHDA (n6-OHDA) crosses the blood-brain barrier to destroy 90-99% of dopaminergic nerves in pars compacta substantia nigra (SNpc). The n6-OHDA-lesioned rat is posed as a reasonable animal model for PD: (a) the magnitude of dopaminergic neuronal destruction is expansive, (b) mapping of dopaminergic denervation has been defined, (c) effects on dopamine (DA) receptor alterations have been elucidated (d) as well as changes in receptor sensitivity status, (e) reactive sprouting of serotoninergic innervation (i.e. hyperinnervation) has been mapped, and (f) interplay between serotoninergic and dopaminergic systems is characterized. (g) A broad range of locomotor and stereotyped behaviors has been assessed and (h) large numbers of neurochemical assessments have been attained. (i) n6-OHDA-lesioned rats survive 6-OHDA lesioning and (j) the rat is behaviorally indistinguishable from controls. Dopaminergic destruction in early ontogeny rather in adulthood is a 'treatment liability' of this model, yet other animal models have liability issues of a serious nature-the initial one being use of a neurotoxin to produce the animal model of PD. The n6-OHDA-lesioned rat is proposed as a PD model for its value in associating the SNpc dopaminergic lesion with behavioral outcomes, also for replicability of dopaminergic destruction, and the accompanying neuronal adaptations and interplay between neuronal phenotypes in brain-which provide a means to better define and understand the range of deficits and neuronal adaptations that are likely to occur in human PD.

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The purpose of this study was to determine the effects of an atypical pattern of early acoustic stimulation on auditory development. Previous human research suggests that the acoustic environment of pre-term human infants in the Neonatal Intensive Care Unit (NICU) negatively affects some aspects of auditory development. Animal research suggests that premature auditory stimulation interrupts auditory development. Because mice are born before their auditory systems are developed, they make an excellent model for research on fetal and postnatal plasticity of the auditory system. The premature auditory state of newborn mice is similar to that of the NICU pre-term infant, albeit, natural for mice C57 mouse pups were exposed to an augmented acoustic environment (AAE) of a nightly 12-hour regiment of 70 dB SPL noise burst, beginning before age 12 days (onset of hearing) and lasting for one month. The prepulse inhibition (PPI) of mice exposed to the AAE was compared to that of non-exposed mice to observe short-term and long-term effects. Results showed that the prepulse inhibition of the AAE exposed mice did not differ significantly from that of the non-exposed mice. However, it is possible that the measurement used, PPI, may not have been appropriate or that the AAE may not have been an appropriate simulation of the NICU environment.

Professional research project (Au.D.)--University of South Florida, 2003. / Title from PDF of title page. / Document formatted into pages; contains 20 pages. / Includes bibliographical references. / Text (Electronic thesis) in PDF format. / ABSTRACT: The purpose of this study was to determine the effects of an atypical pattern of early acoustic stimulation on auditory development. Previous human research suggests that the acoustic environment of pre-term human infants in the Neonatal Intensive Care Unit (NICU) negatively affects some aspects of auditory development. Animal research suggests that premature auditory stimulation interrupts auditory development. Because mice are born before their auditory systems are developed, they make an excellent model for research on fetal and postnatal plasticity of the auditory system. The premature auditory state of newborn mice is similar to that of the NICU pre-term infant, albeit, natural for mice C57 mouse pups were exposed to an augmented acoustic environment (AAE) of a nightly 12-hour regiment of 70 dB SPL noise burst, beginning before age 12 days (onset of hearing) and lasting for one month. / ABSTRACT: The prepulse inhibition (PPI) of mice exposed to the AAE was compared to that of non-exposed mice to observe short-term and long-term effects. Results showed that the prepulse inhibition of the AAE exposed mice did not differ significantly from that of the non-exposed mice. However, it is possible that the measurement used, PPI, may not have been appropriate or that the AAE may not have been an appropriate simulation of the NICU environment. / System requirements: World Wide Web browser and PDF reader. / Mode of access: World Wide Web.

La tumeur des cellules de la granulosa (GCT) représente 5% des cas de cancers ovariens chez la femme. Bien que considérées comme peu malignes, la mort survient dans 80% des cas suite à une recrudescence de la maladie. En dépit de ces statistiques sinistres, peu d’études ont été portées sur ce type de cancer. Le premier objectif de cette étude consistait à élucider les mécanismes moléculaires causant les GCT en démontrant l’implication de la voie de signalisation PI3K/AKT dans leur étiologie. Pour ce faire, nous avons employé la technologie Cre-Lox afin de cibler le gène Pten (antagoniste de cette voie) spécifiquement dans les cellules de la granulosa chez la souris. Ces souris (Ptenflox/flox;Amhr2cre/+) ont occasionnellement développé des GCT, soutenant notre hypothèse de l’importance de la voie PI3K/AKT dans leur étiologie. La voie WNT/CTNNB1 est une autre voie de signalisation qui a récemment été impliquée dans le développement des GCT. Dans le cadre de ce projet, nous avons également testé l’existence possible d’une synergie fonctionnelle entre les voies WNT/CTNNB1 et PI3K/AKT dans le développement de la maladie. Pour ce faire, nous avons créé le modèle transgénique Ptenflox/flox;Ctnnb1flox(ex3)/+;Amhr2cre/+, chez lequel les cellules de la granulosa présentant non seulement une désinhibition de la voie PI3K/AKT, mais aussi une suractivation de la voie WNT/CTNNB1. Tel que prédit, les souris Ptenflox/flox;Ctnnb1flox(ex3)/+;Amhr2cre/+ ont développé une forme de GCT beaucoup plus agressive que celle observée chez les femelles Ptenflox/flox;Amhr2cre/+. Spécifiquement, le développement des tumeurs se déclenchait plus tôt, leur croissance était beaucoup plus rapide, nous avons pu observer des métastases pulmonaires et la dissémination des cellules tumorales dans la cavité péritonéale, et la maladie était invariablement fatale avant l’âge de 8 semaines. Le modèle Ptenflox/flox;Ctnnb1flox (ex3)/+;Amhr2cre/+ a donc servi à démontrer l'existence d'une synergie entre les voies WNT/CTNNB1 et PI3K/AKT dans le développement de la GCT. De façon inattendue, les souris Ptenflox/flox;Amhr2cre/+ ont aussi présenté un phénotype de sous-fertilité qui n’était pas d’origine ovarienne. Il a récemment été démontré que la souche Amhr2cre dirige l’expression de Cre non seulement aux cellules de la granulosa, mais aussi au stroma utérin et au myomètre. Le second objectif de ce travail était donc de démontrer si et comment le phénotype d’infertilité chez les souris Ptenflox/flox;Amhr2cre/+ pouvait découler d’un défaut utérin. Lors de l'implantation, les cellules du stroma utérin se différencient en cellules déciduelles pour former la décidua maternelle (DM), qui se régresse ensuite par apoptose afin de faciliter l’invasion des cellules trophoblastiques. De plus, la DM, en collaboration avec le tissu foetal, recrute des uNKs dont le rôle est de remodeler les artères spiralées pour augmenter l’apport sanguin maternel vers le foetus en développement. Nous avons pu démontrer que l'utérus des femelles gestantes Ptenflox/flox;Amhr2cre/+ présentait une DM anormalement résistante à l'apoptose, moins de uNKs et des artères spiralées non-remodelées. Par conséquent, l’invasion des cellules du trophoblaste était restreinte, compromettant le développement et la survie de l'embryon. Nous avons donc établi pour la première fois l’importance de Pten lors de la décidualisation et de l’invasion du trophoblaste. / The granulosa cell tumor (GCT) represents up to 5% of all ovarian cancer cases in women. Although GCT is characterized as a low-grade malignancy, death occurs in approximately 80% of cases following to the disease’s recurrence. Despite these statistics, very few studies have been dedicated to increasing our understanding of the molecular mechanisms responsible for the development of GCT. The first objective of this work was to elucidate some of these molecular mechanisms by proving the involvement of the PI3K/AKT signaling pathway in the etiology of GCT. To this end, we used Cre-LoxP technology to conditionally target Pten (a PI3K/AKT signaling antagonist) in granulosa cells. These transgenic mice (Ptenflox/flox;Amhr2cre/+) occasionally developed GCT, supporting our hypothesis on the importance of the PI3K/AKT pathway in the etiology of this disease. The WNT/CTNNB1 signaling pathway has also recently been implicated in GCT development. We therefore postulated that a functional synergy may exist between the WNT/CTNNB1 and PI3K/AKT pathways in development of GCT. To test this, we created a second transgenic model (Ptenflox/flox;Ctnnb1flox(ex3)/+;Amhr2cre/+), in which the granulosa cells featured not only a disinhibition of the PI3K/AKT pathway but also a constitutive activation of the WNT/CTNNB1 pathway. As predicted, the Ptenflox/flox;Ctnnb1flox(ex3)/+;Amhr2cre/+ mice developed a form of GCT that was much more aggressive than the one observed in the Ptenflox/flox;Amhr2cre/+ model. Specifically, the tumors developed sooner, their growth was faster, pulmonary metastases and the seeding of tumor cells in the abdominal cavity were observed, and the disease was invariably fatal by 8 weeks of age. The Ptenflox/flox;Ctnnb1flox(ex3)/+;Amhr2cre/+ model therefore served to demonstrate a synergy between the WNT/CTNNB1 and PI3K/AKT pathways in GCT development. Unexpectedly, the majority of the Ptenflox/flox;Amhr2cre/+ females presented an infertility phenotype that was not caused by an ovarian defect. Recently, it has been shown that the Amhr2cre strain can direct the Cre activity not only to the granulosa cells but also to the uterine stroma and myometrium. The second objective of this work was therefore to determine if and how the infertility observed in Ptenflox/flox;Amhr2cre/+ mice could be caused by a uterine defect. During implantation, uterine stromal cells differentiate into decidual cells and form the maternal decidua (MD), which subsequently regresses by apoptosis to facilitate trophoblast invasion. In collaboration with the fetal tissue, the MD also recruits uNKs, which are responsible for spiral artery remodeling that increases maternal blood flow to the developing fetus. We were able to demonstrate that the uteri of pregnant Ptenflox/flox;Amhr2cre/+ females had a MD that was resistant to apoptosis, less uNKs, and spiral arteries that were not properly remodeled. Consequently, the trophoblast cell invasion was restricted, thereby compromising the development and survival of the embryo. We have therefore established for the first time the importance of Pten during the decidualization of the uterine stroma and trophoblast invasion.

La tumeur des cellules de la granulosa (GCT) représente 5% des cas de cancers ovariens chez la femme. Bien que considérées comme peu malignes, la mort survient dans 80% des cas suite à une recrudescence de la maladie. En dépit de ces statistiques sinistres, peu d’études ont été portées sur ce type de cancer. Le premier objectif de cette étude consistait à élucider les mécanismes moléculaires causant les GCT en démontrant l’implication de la voie de signalisation PI3K/AKT dans leur étiologie. Pour ce faire, nous avons employé la technologie Cre-Lox afin de cibler le gène Pten (antagoniste de cette voie) spécifiquement dans les cellules de la granulosa chez la souris. Ces souris (Ptenflox/flox;Amhr2cre/+) ont occasionnellement développé des GCT, soutenant notre hypothèse de l’importance de la voie PI3K/AKT dans leur étiologie. La voie WNT/CTNNB1 est une autre voie de signalisation qui a récemment été impliquée dans le développement des GCT. Dans le cadre de ce projet, nous avons également testé l’existence possible d’une synergie fonctionnelle entre les voies WNT/CTNNB1 et PI3K/AKT dans le développement de la maladie. Pour ce faire, nous avons créé le modèle transgénique Ptenflox/flox;Ctnnb1flox(ex3)/+;Amhr2cre/+, chez lequel les cellules de la granulosa présentant non seulement une désinhibition de la voie PI3K/AKT, mais aussi une suractivation de la voie WNT/CTNNB1. Tel que prédit, les souris Ptenflox/flox;Ctnnb1flox(ex3)/+;Amhr2cre/+ ont développé une forme de GCT beaucoup plus agressive que celle observée chez les femelles Ptenflox/flox;Amhr2cre/+. Spécifiquement, le développement des tumeurs se déclenchait plus tôt, leur croissance était beaucoup plus rapide, nous avons pu observer des métastases pulmonaires et la dissémination des cellules tumorales dans la cavité péritonéale, et la maladie était invariablement fatale avant l’âge de 8 semaines. Le modèle Ptenflox/flox;Ctnnb1flox (ex3)/+;Amhr2cre/+ a donc servi à démontrer l'existence d'une synergie entre les voies WNT/CTNNB1 et PI3K/AKT dans le développement de la GCT. De façon inattendue, les souris Ptenflox/flox;Amhr2cre/+ ont aussi présenté un phénotype de sous-fertilité qui n’était pas d’origine ovarienne. Il a récemment été démontré que la souche Amhr2cre dirige l’expression de Cre non seulement aux cellules de la granulosa, mais aussi au stroma utérin et au myomètre. Le second objectif de ce travail était donc de démontrer si et comment le phénotype d’infertilité chez les souris Ptenflox/flox;Amhr2cre/+ pouvait découler d’un défaut utérin. Lors de l'implantation, les cellules du stroma utérin se différencient en cellules déciduelles pour former la décidua maternelle (DM), qui se régresse ensuite par apoptose afin de faciliter l’invasion des cellules trophoblastiques. De plus, la DM, en collaboration avec le tissu foetal, recrute des uNKs dont le rôle est de remodeler les artères spiralées pour augmenter l’apport sanguin maternel vers le foetus en développement. Nous avons pu démontrer que l'utérus des femelles gestantes Ptenflox/flox;Amhr2cre/+ présentait une DM anormalement résistante à l'apoptose, moins de uNKs et des artères spiralées non-remodelées. Par conséquent, l’invasion des cellules du trophoblaste était restreinte, compromettant le développement et la survie de l'embryon. Nous avons donc établi pour la première fois l’importance de Pten lors de la décidualisation et de l’invasion du trophoblaste. / The granulosa cell tumor (GCT) represents up to 5% of all ovarian cancer cases in women. Although GCT is characterized as a low-grade malignancy, death occurs in approximately 80% of cases following to the disease’s recurrence. Despite these statistics, very few studies have been dedicated to increasing our understanding of the molecular mechanisms responsible for the development of GCT. The first objective of this work was to elucidate some of these molecular mechanisms by proving the involvement of the PI3K/AKT signaling pathway in the etiology of GCT. To this end, we used Cre-LoxP technology to conditionally target Pten (a PI3K/AKT signaling antagonist) in granulosa cells. These transgenic mice (Ptenflox/flox;Amhr2cre/+) occasionally developed GCT, supporting our hypothesis on the importance of the PI3K/AKT pathway in the etiology of this disease. The WNT/CTNNB1 signaling pathway has also recently been implicated in GCT development. We therefore postulated that a functional synergy may exist between the WNT/CTNNB1 and PI3K/AKT pathways in development of GCT. To test this, we created a second transgenic model (Ptenflox/flox;Ctnnb1flox(ex3)/+;Amhr2cre/+), in which the granulosa cells featured not only a disinhibition of the PI3K/AKT pathway but also a constitutive activation of the WNT/CTNNB1 pathway. As predicted, the Ptenflox/flox;Ctnnb1flox(ex3)/+;Amhr2cre/+ mice developed a form of GCT that was much more aggressive than the one observed in the Ptenflox/flox;Amhr2cre/+ model. Specifically, the tumors developed sooner, their growth was faster, pulmonary metastases and the seeding of tumor cells in the abdominal cavity were observed, and the disease was invariably fatal by 8 weeks of age. The Ptenflox/flox;Ctnnb1flox(ex3)/+;Amhr2cre/+ model therefore served to demonstrate a synergy between the WNT/CTNNB1 and PI3K/AKT pathways in GCT development. Unexpectedly, the majority of the Ptenflox/flox;Amhr2cre/+ females presented an infertility phenotype that was not caused by an ovarian defect. Recently, it has been shown that the Amhr2cre strain can direct the Cre activity not only to the granulosa cells but also to the uterine stroma and myometrium. The second objective of this work was therefore to determine if and how the infertility observed in Ptenflox/flox;Amhr2cre/+ mice could be caused by a uterine defect. During implantation, uterine stromal cells differentiate into decidual cells and form the maternal decidua (MD), which subsequently regresses by apoptosis to facilitate trophoblast invasion. In collaboration with the fetal tissue, the MD also recruits uNKs, which are responsible for spiral artery remodeling that increases maternal blood flow to the developing fetus. We were able to demonstrate that the uteri of pregnant Ptenflox/flox;Amhr2cre/+ females had a MD that was resistant to apoptosis, less uNKs, and spiral arteries that were not properly remodeled. Consequently, the trophoblast cell invasion was restricted, thereby compromising the development and survival of the embryo. We have therefore established for the first time the importance of Pten during the decidualization of the uterine stroma and trophoblast invasion.