Genetic and environmental interventions altering the course of brain aging: evidence from the zebrafish (Danio Rerio) model

buir.advisorAdams, Michelle Marie
dc.contributor.authorEravşar, Elif Tuğce Karoğlu
dc.date.accessioned2021-05-25T06:23:20Z
dc.date.available2021-05-25T06:23:20Z
dc.date.copyright2021-04
dc.date.issued2021-04
dc.date.submitted2021-05-18
dc.descriptionCataloged from PDF version of article.en_US
dc.descriptionThesis (Ph.D.): Bilkent University, Department of Neuroscience, İhsan Doğramacı Bilkent University, 2021.en_US
dc.descriptionIncludes bibliographical references (leaves 181-202).en_US
dc.description.abstractAge-related cognitive decline occurs during normal aging, although there is no prominent neural loss in the brain. Subtle molecular alterations in synaptic and cellular dynamics are likely underlying these cognitive alterations. One challenge is the widely heterogeneous profile regarding age-related behavioral changes and neurobiological underpinnings. Therefore, it is crucial to characterize how individual factors can contribute to successful or unsuccessful aging and whether these factors can induce shared patterns of alterations in the cellular and synaptic dynamics. Three different intervention approaches were utilized in the current study. The first intervention was a genetic manipulation in the cholinergic system component acetylcholinesterase (AChE), which results in reduced levels of this enzyme in the achesb55/+ mutants. Previous studies have characterized this model as a delayed aging model because of its preserved cognitive abilities at an older age. The current study was the first study analyzing the neurobiological changes in this mutant model within the context of aging. It was shown that reduced brain AChE activity levels persist in different age groups, including old age in the mutant animals. This reduction was accompanied by subtle decreases in the other elements of the cholinergic system, including acetylcholine and nicotinic acetylcholine receptor subunit alpha-7. Genotype significantly altered key glutamatergic receptor subunits such as N-methyl D-aspartate-type receptor subunit 2B (NR2B) and glutamate receptor subunits 2 and 3 (GluR2/3), with these markers significantly reduced in the achesb55/+ mutants and likely maintaining homeostatic synaptic scaling. At old age, a significant age-related elevation was observed in the synaptophysin levels (SYP) of the old achesb55/+ mutants, and this mutation prevented an age-related decline in the gephyrin (GEP) levels which was evident in the wild-type controls. This mutation also altered the cellular dynamics; an immature neuronal marker, embryonic lethal abnormal-vision (ELAV Drosophila) like-3 (HuC) was significantly upregulated in the achesb55/+ mutants at all ages. In contrast, the levels of inflammation-related markers, glial fibrillary acidic protein (GFAP) and reactive oxygen species (ROS), were downregulated subtly in the mutants. It can be concluded that reduced levels of brain AChE can be associated with altered excitatory homeostasis and preserved levels of GEP and SYP through aging. At the same time, the neuronal marker was upregulated, and inflammation-related markers were downregulated. The second intervention was applying short-term environmental enrichment using the sensory cues to young and old zebrafish to induce successful aging. It was shown that environmental enrichment increases the brain weight in old zebrafish, prevents age-related decrements in the levels of synaptic proteins, including SYP and NR2B, and doublecortin-like kinase (DCAMKL1). Additionally, environmentally enriched old zebrafish had elevated levels of GEP while applying this environmental intervention did not modulate the age-related increases in oxidative stress indicators. The third intervention was also a non-genetic approach. Two short-term opposing dietary treatments, such as caloric restriction (CR) and over-feeding (OF), were applied to young and old zebrafish and an ad-libitum diet. It was demonstrated that a short-term CR regimen upregulated the glutamatergic components of neurotransmission such as GluR2/3 and post-synaptic density 95 (PSD95). Significant age-related decline in GEP levels was observed in old zebrafish in the OF dietary condition. Expression levels of synaptic and regulatory genes were relatively stable, while inflammation-related gene tnfa was altered in an age-dependent manner. Additionally, in the young zebrafish, a significant elevation of trunk cortisol was demonstrated in the OF group compared to CR-fed young zebrafish. Taken together, evaluating different components such as the cholinergic system, diet, and environment can provide us insights into the neurobiological underpinning of successful aging and possible determinants of unhealthy aging.en_US
dc.description.provenanceSubmitted by Betül Özen (ozen@bilkent.edu.tr) on 2021-05-25T06:23:20Z No. of bitstreams: 1 10394936.pdf: 5862309 bytes, checksum: e58b16814f6615947a60256bdc135292 (MD5)en
dc.description.provenanceMade available in DSpace on 2021-05-25T06:23:20Z (GMT). No. of bitstreams: 1 10394936.pdf: 5862309 bytes, checksum: e58b16814f6615947a60256bdc135292 (MD5) Previous issue date: 2021-05en
dc.description.statementofresponsibilityby Elif Tuğce Karoğlu Eravşaren_US
dc.format.extentxvii, 202 leaves : illustrations (color) ; 30 cm.en_US
dc.identifier.itemidB126172
dc.identifier.urihttp://hdl.handle.net/11693/76358
dc.language.isoEnglishen_US
dc.rightsinfo:eu-repo/semantics/openAccessen_US
dc.subjectCholinergic systemen_US
dc.subjectAging brainen_US
dc.subjectEnvironmental enrichmenten_US
dc.subjectSynaptic proteinsen_US
dc.subjectCalorie intakeen_US
dc.subjectZebrafishen_US
dc.titleGenetic and environmental interventions altering the course of brain aging: evidence from the zebrafish (Danio Rerio) modelen_US
dc.title.alternativeBeyin yaşlanmasını değiştiren genetik ve çevresel müdahaleler: zebrabaliği (Danio Rerio) modelinden bulgularen_US
dc.typeThesisen_US
thesis.degree.disciplineNeuroscience
thesis.degree.grantorBilkent University
thesis.degree.levelDoctoral
thesis.degree.namePh.D. (Doctor of Philosophy)

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