In the present study 5-hydroxytryptamine (5-HT) 1A receptor knockout mice (KO), mice overexpressing the 5-HT1A receptor (OE), and wild-type (WT) mice were used to investigate the influence of 5-HT1A receptor on the development of the serotonergic system in the brain, from the embryonic day 12.5 to the postnatal day 15.5. Neither the absence nor the overexpression of 5-HT1A receptor influenced the development and differentiation of serotonergic neurons in the raphe area of the mouse brain. However, a delay in the initial development of the serotonergic projections to the mesencephalic tegmentum, cerebral cortex and hypothalamus was observed in both transgenic mice lines. The brain levels of 5-HT and 5-hydroxyindoleacetic acid were significantly higher in both transgenic mice lines during the late embryonic and early postnatal periods as compared to WT mice. An increase in the turnover of 5-HT was not observed before the early postnatal period. Both the absence and the overexpression of 5-HT1A receptor delayed the development of the dopaminergic system of the mesencephalic tegmentum in the early embryonic period. In OE mice the postnatal development of the noradrenergic system appeared to be exaggerated. The immunoreactivity for the neurotrophic protein S100ß was higher in the cerebral cortex, striatum and hippocampus of OE mice as compare to WT and KO mice. The expression of synaptic proteins, such as synapatobrevin and synaptotagmin was reduced in KO and OE mice during the early embryonic period. This reduction may be linked to the delayed development of the serotonergic projections and the dopaminergic system. In addition, no influence of 5-HT1A receptor mutations on the myelination of the brain was observed. Zusammenfassung In der vorliegenden Arbeit wurden die 5-Hydroxytryptamin (5-HT)1A Rezeptor Knockout (KO), überexprimierenden (ÜE) Mäuse und die Wild-Typ (WT) Mäuse, in den Entwicklungsperioden vom embryonalen Tag 12,5 bis postnatalen Tag 15,5 untersucht, um weitere Informationen über den Einfluss vom 5-HT1A Rezeptor auf die Entwicklung des serotonergen Systems im Gehirn zu erhalten. Sowohl das Fehlen des 5-HT1A Rezeptors als auch dessen Überexpression hatten zwar keinen Einfluss auf die Entwicklung und Differenzierung der serotonergen Neurone in den Raphe Regionen, verzögerte aber die erste Entwicklung der serotonergen Innervierungen im mesencephalen Tegmentum, Hypothalamus und cerebralen Cortex. In den späten embryonalen und insbesondere frühpostnatalen Perioden waren die 5-HT- und 5-HIAA-Spiegel bei KO und ÜE Mäusen im Vergleich zu WT Mäusen signifikant erhöht. Eine Erhöhung des 5-HT Turnovers wurde erst in der frühpostnatalen Periode beobachtet. Auch die Entwicklung des dopaminergen Systems im Mesencephalon war in der frühen embryonalen Periode sowohl bei KO als auch bei ÜE Mäusen verlangsamt. Die Überexpression des 5-HT1A Rezeptors begünstigte möglicherweise die postnatale Entwicklung des noradrenergen Systems. Bei ÜE Mäusen war die Immunreaktivität des neurotrophen Proteins S100? im cerebralen Cortex, Hippocampus und Striatum stärker als bei WT und KO Mäusen. Die Expression der synaptischen Proteine wie Synaptobrevin und Synaptotagmin war sowohl bei KO als auch bei ÜE Mäusen in der frühen embryonalen Periode verzögert. Dies könnte mit der verzögerten Entwicklung der serotonergen Projektionen und des dopaminergen Systems in Zusammenhang stehen. Darüber hinaus hatten transgene Veränderungen am 5-HT1A Rezeptor keinen Einfluss auf die Myelinisierung im Gehirn der Maus. Schlagwörter: serotonerges System, Entwicklung des Gehirns, 5-HT1A Rezeptor, transgene Mäuse, dopaminerges System, noradrenerges System, S100ß, Synaptisches Protein, Myelinisierung / In the present study 5-hydroxytryptamine (5-HT) 1A receptor knockout mice (KO), mice overexpressing the 5-HT1A receptor (OE), and wild-type (WT) mice were used to investigate the influence of 5-HT1A receptor on the development of the serotonergic system in the brain, from the embryonic day 12.5 to the postnatal day 15.5. Neither the absence nor the overexpression of 5-HT1A receptor influenced the development and differentiation of serotonergic neurons in the raphe area of the mouse brain. However, a delay in the initial development of the serotonergic projections to the mesencephalic tegmentum, cerebral cortex and hypothalamus was observed in both transgenic mice lines. The brain levels of 5-HT and 5-hydroxyindoleacetic acid were significantly higher in both transgenic mice lines during the late embryonic and early postnatal periods as compared to WT mice. An increase in the turnover of 5-HT was not observed before the early postnatal period. Both the absence and the overexpression of 5-HT1A receptor delayed the development of the dopaminergic system of the mesencephalic tegmentum in the early embryonic period. In OE mice the postnatal development of the noradrenergic system appeared to be exaggerated. The immunoreactivity for the neurotrophic protein S100ß was higher in the cerebral cortex, striatum and hippocampus of OE mice as compare to WT and KO mice. The expression of synaptic proteins, such as synapatobrevin and synaptotagmin was reduced in KO and OE mice during the early embryonic period. This reduction may be linked to the delayed development of the serotonergic projections and the dopaminergic system. In addition, no influence of 5-HT1A receptor mutations on the myelination of the brain was observed.

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Celiac ganglia are important sites of signal integration and transduction. Their complex neurochemical anatomy has been studied extensively in guinea pigs but not in mice. The goal of this study was to provide detailed neurochemical characterization of mouse celiac ganglia and noradrenergic nerves in two target tissues, spleen and stomach. A vast majority of mouse celiac neurons express a noradrenergic phenotype, which includes tyrosine hydroxylase (TH), vesicular monoamine transporter 2, and the norepinephrine transporter. Over 80% of these neuron also express neuropeptide Y (NPY), and this coexpression is maintained by dissociated neurons in culture. Likewise, TH and NPY were colocalized in noradrenergic nerves throughout the spleen and in stomach blood vessels. Somatostatin was not detected in principal neurons but did occur in small, TH-negative cells presumed to be interneurons and in a few varicose nerve fibers. Cholinergic nerves provided the most abundant input to the ganglia, and small percentages of these also contained nitric oxide synthase or vasoactive intestinal polypeptide. A low-to-moderate density of nerves also stained separately for the latter markers. Additionally, nerve bundles and varicose nerve fibers containing the sensory neuropeptides, calcitonin gene-related polypeptide, and substance P, occurred at variable density throughout the ganglia. Collectively, these findings demonstrate that principal neurons of mouse celiac ganglia have less neurochemical diversity than reported for guinea pig and other species but receive input from nerves expressing an array of neurochemical markers. This profile suggests celiac neurons integrate input from many sources to influence target tissues by releasing primarily norepinephrine and NPY.

Despite a high proportion of the population experiencing traumatic events within their lifetime, the number of individuals who go on to develop posttraumatic stress disorder (PTSD) is comparatively small; herein highlighting the importance of individual differences in imparting risk and resilience towards the development and maintenance of PTSD. Existing literature illustrates that biological and ecological factors are important in predicting PTSD development, with pathological vulnerabilities excepting their effects at pre- peri- and post trauma stages. Whilst cognitive and emotion based models of PTSD account for the role of a minority of known pre-trauma risk factors, individual differences in peri- and post trauma processes are held as critical to the development of PTSD. The broad range of risk factors implicated in the empirical literature, and necessity of traumatic exposure to PTSD, implicates the utility of a diathesis-stress conceptualisation of PTSD development. The current thesis employed an analogue VR-trauma paradigm to investigate the respective importance of vulnerability factors at each stage, in the prediction of analogue PTSD symptoms (memory problems, startle responses, re-exposure fear habituation), whilst measuring affective and electrophysiological concomitance. Findings supported the importance of peri-traumatic responses in the prediction of PTSD, where present, showing increased predictive capacities over pre- and post-trauma factors. Biological and ecological factors also illustrated important predictive associations, with genetic SNPs implicated in reflex startle and cardiac responses towards intrusive memories. Moreover, peri-traumatic HR decelerations and accelerations mediated the association between pre-trauma factors and cued recall inaccuracy and intrusion severity respectively. Results support existing cognitive and emotional models in their emphasis on peri-traumatic processes but suggest the added utility of a diathesis stress conceptualisation of the development of PTSD, in highlighting the importance of pre-trauma biological and ecological risk and resilience factors.