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dc.contributor.advisorStachowiak, Ewa
dc.contributor.authorPowell, Hanna
dc.date.accessioned2019-04-04T20:33:13Z
dc.date.available2019-04-04T20:33:13Z
dc.date.issued2019
dc.date.submitted2019-01-24 12:51:17
dc.identifier.urihttp://hdl.handle.net/10477/79442
dc.descriptionM.S.
dc.description.abstractSchizophrenia (SZ) is a psychiatric disease, which affects approximately one percent of the global population. Schizophrenia is a neurodevelopmental disorder, which affects in utero brain development within the first trimester well before its clinical manifestation during adolescence. The symptoms that characterize SZ and lead to its diagnosis are typically divided into positive symptoms (dilutions, paranoia, etc.) and negative symptoms (decreases in cognitive functioning, social skills, executive functioning, etc.)(Millan, Fone, Steckler, & Horan, 2014) Over 300 genes were found to be altered in SZ affecting diverse developmental pathways which when dysregulated may increase the likelihood of disease manifestation. Recent studies indicate that the affected signaling pathways converge on and dysregulate the pan-ontogenetic INFS pathway (E. K. Stachowiak et al., 2017) However, genetics isn’t the only factor causing SZ, a number of environmental factors exist, which in combination with genetics has been proposed to influence the expression of the disease (Schmitt, Hasan, Gruber, & Falkai, 2011).One of the major environmental risk factors is thought to be maternal immune activation (MIA), which occurs when a pregnant mother experiences a severe immune insult that activates immune cytokines for a sustained amount of time. Tumor necrosis factor-alpha (TNFα), is of particular interest because it has been found to be present in maternal serum and embryotic fluid. It also tops the cytokine cascade, and thus is responsible for the activation of a great number of immune factors (Brown & Derkits, 2010). This study focuses on the effect of immune factor, TNFα, on neurodevelopment during early pregnancy using the in vitro model of cerebral organoids (“mini brains”) to discover if there is a significant difference between neurodevelopment that occurs with and without maternal immune activation. In order to recapitulate this the organoids were treated with 50pg TNFα at two weeks of growth, the treatment lasted nine days and then the organoids were allowed two weeks to recover and then harvested at 37 days. The following four experimental groups were used: nontreated control (C), control treated with TNFα (C+TNFα), schizophrenia (SZ) and schizophrenia treated with TNFα (SZ+TNFα). The two untreated groups received only nutritional supplements during the nine-day treatment period.Results indicate significant differences of SZ as compared to C organoids, both quantitative and qualitative: Ki67(decreased number of rosettes), Pan-Neu (decreased Pan-Neu+ cells in superficial cortex), and Calretinin (increased Calretinin+ cells in cortex), Olig4 (increased number of Olig4+ cells in cortex) and FGFR1 (more cells expressing nuclear FGFR1) and SEM (morphology, increased amount fibers, decreased amount cells and empty space) microscopy. Both the disease, SZ, and the application of immune cytokine, TNFα, alter the experimental organoids in significant ways from nontreated organoids. TNFα applied to C organoids (C+TNF) induced developmental changes which were similar to the SZ organoids. When TNF was applied to SZ organoids (SZ+TNF) the changes seen were generally similar to those seen in nontreated SZ, except in some cases such as Calretinin where in TNF exacerbated the SZ induced neurodevelopmental effects. In conclusion, a developmental insult, such as MIA, may itself significantly affect human brain development and lead to SZ-like malformations, and thus potentially the disease. In combination with SZ-genetic background MIA induced changes may further exacerbated and influence the severity of the disorder
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dc.language.isoen
dc.publisherState University of New York at Buffalo
dc.rightsUsers of works found in University at Buffalo Institutional Repository (UBIR) are responsible for identifying and contacting the copyright owner for permission to reuse. University at Buffalo Libraries do not manage rights for copyright-protected works and cannot assist with permissions.
dc.subjectNeurosciences
dc.subjectImmunology
dc.subjectGenetics
dc.titleThe effects of immune factor, TNFα, on human fetal neural development and schizophrenia in a cerebral organoid model
dc.typeThesis
dc.rights.holderCopyright retained by author.


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