| dc.contributor.advisor | Bringmann, Henrik Prof. Dr. | |
| dc.contributor.author | Hu, Yang | |
| dc.date.accessioned | 2023-01-31T14:02:26Z | |
| dc.date.available | 2023-02-08T00:50:09Z | |
| dc.date.issued | 2023-01-31 | |
| dc.identifier.uri | http://resolver.sub.uni-goettingen.de/purl?ediss-11858/14481 | |
| dc.identifier.uri | http://dx.doi.org/10.53846/goediss-9689 | |
| dc.format.extent | XXX Seiten | de |
| dc.language.iso | eng | de |
| dc.rights.uri | http://creativecommons.org/licenses/by/4.0/ | |
| dc.subject.ddc | 570 | de |
| dc.title | Sleep control by TFAP2a and TFAP2b transcription factors in mice | de |
| dc.type | doctoralThesis | de |
| dc.contributor.referee | Bayer, Thomas A. Prof. Dr. | |
| dc.date.examination | 2022-02-14 | de |
| dc.description.abstracteng | Sleep is a universal behavior that exists across species. We previously found that deletion of transcription factor APTF-1 induces sleep loss in C. elegans and Drosophila. In mammals, sleep has two states: rapid eye movement sleep (REMS) and non-REM sleep (NREMS), which can be distinguished by EEG spectral power. There are five homologs of APTF-1 in mammals, from Tfap2a to e. However, little is known about whether these homologs, Tfap2a and b, have a conserved role of regulating sleep in animals with a more complex brain. Therefore, I characterized the sleep and wakefulness of Tfap2a and b mutants in mice. Consistent with our previous finding, paralogs of Tfap2a and b control sleep in mice. However, Tfap2a and b control sleep in a bidirectional manner. EEG results showed that Tfap2a+/- mice exhibited higher sleep drive, whereas Tfap2b+/- mice showed a reduced sleep quality with shortened NREMS amount during baseline recording. As expected, sleep deprivation induced a stronger delta and theta power rebound in Tfap2a mutants, but a weaker response in Tfap2b mutants. This functional divergence was also observed in behaviors beyond sleep. Tfap2b+/- mice displayed depression-like behavior while Tfap2a+/- mice were hyperactive and showed more resistance to the stressful environment. With the decreased sleep quality, learning and memory were impaired in Tfap2b mutants. In addition, Tfap2b mutants exhibited a slightly shortened circadian period. In summary, Tfap2a and b control sleep in mice as well, but in a bidirectional way. It might support the hypothesis that, as nervous system evolved, the function of Tfap2a and b genes also diverged.
GABAergic neurons play a key role promoting sleep. The development of GABAergic neurons is regulated by various transcription factors. However, it is not clear whether or how Tfap2a and b are involved in the expression and function of GABAergic neurons. Here I measured the expression of the genes that control GABA synthesis and transportation in Tfap2a+/- and Tfap2b+/- mice. Results from qPCR has confirmed a role of Tfap2b, but not TFap2a, in regulating the GABAergic gene expression. However, the role of Tfap2b was complex. The expression of GAD65, GAD67, Vgat was decreased in cortex, brainstem, cerebellum, but increased in striatum. Further, using ISH, a decrease number of the GAD67 expressing GABAergic cells was detected in the parafacial zone, a sleep-promoting center located in the lower brainstem. Since the expression of Tfap2b in brain starts early at developmental stages, E14.5 brains were extracted and analyzed using RNA-seq. Results have revealed various differentially regulated genes from homeobox, Slc family and those related to neurotransmission function. Together with qPCR and ISH results, they provided molecular evidences implying a functional role of GABAergic neurons expressing Tfap2b gene. Next, I characterized the function of GABAergic neurons expressing Tfap2b in sleep in Vgat-Tfap2b-/- mice. EEG analysis showed that sleep quantity and intensity were reduced in female Vgat-Tfap2b-/- mice during baseline recording. Consistent with this observation, the homeostatic sleep response was also weakened in these mutants. These results together suggest that Tfap2b plays a role in the GABAergic system at molecular and behavioral functional level.
In conclusion, my study has revealed a conserved role of Tfap2b and its paralog Tfap2a in sleep control. It is very likely that Tfap2b exerts its conserved function in sleep through GABAergic system. | de |
| dc.contributor.coReferee | Ehrenreich, Hannelore Prof. Dr. Dr. | |
| dc.contributor.thirdReferee | Eichele, Gregor Prof. Dr. | |
| dc.contributor.thirdReferee | Nave, Klaus-Armin Prof. Dr. | |
| dc.contributor.thirdReferee | Pooresmaeili, Arezoo Dr. | |
| dc.subject.eng | sleep | de |
| dc.subject.eng | mouse | de |
| dc.subject.eng | transcription factor | de |
| dc.subject.eng | GABA | de |
| dc.subject.eng | genetic modified | de |
| dc.identifier.urn | urn:nbn:de:gbv:7-ediss-14481-8 | |
| dc.affiliation.institute | Göttinger Graduiertenschule für Neurowissenschaften, Biophysik und molekulare Biowissenschaften (GGNB) | de |
| dc.subject.gokfull | Biologie (PPN619462639) | de |
| dc.description.embargoed | 2023-02-08 | de |
| dc.identifier.ppn | 1832867420 | |
| dc.notes.confirmationsent | Confirmation sent 2023-01-31T14:15:01 | de |