Vasilakis, Georgia
(2018)
The effect of sex-specific factors and stress exposure on expression of GABA-related genes in the basolateral amygdala of mice.
Undergraduate Thesis, University of Pittsburgh.
(Unpublished)
Abstract
Major depressive disorder (MDD) is a common, often severe illness of mood regulation that affects approximately 350 million people worldwide. Women are twice as likely to be diagnosed with depression compared to men, but the molecular mechanisms underlying this sex difference are unclear. Previous human postmortem studies suggest that there is a dysfunction of inhibitory gamma-aminobutyric acid (GABA) function and brain-derived neurotropic factor (BDNF) function across corticolimbic brain regions, including the basolateral amygdala (BLA). Interestingly, post-mortem brain tissue from depressed patients suggests that there might be a sex difference in the way GABA is affected in depression, with more robust deficits in women with depression. Proper GABA function is also crucial during adolescence, as disruption could lead to susceptibility to mood disorders in adulthood. In our translational approach, we used the Four Core Genotypes (FCG) mouse model, in which genetic and gonadal sex are decoupled, to examine how sex-related factors influence GABA- and BDNF-related gene expression in the BLA in both adulthood and development. In a cohort of chronically-stressed adult mice (N=12- 20/group) as well as in a cohort of gonadally-intact mice at three developmental time-points (N=19-26/group), we quantified the gene expression of five genes: Sst, a marker a marker of a GABA-interneuron subtype that preferentially targets distal dendrites of pyramidal cells; Gad67 and Gad65, genes that code for rate-limiting enzymes of GABA synthesis; TrkB, a gene that codes for the BDNF receptor, and Bdnf, a gene that codes for BDNF protein. We found an opposing effect of testosterone (similar to a typical male level) and male genetic sex (XY) on expression of Sst, with testosterone increasing Sst expression (p<0.04), but lower Sst expression in XY mice (p<0.04). This result also mirrored the behavioral results, with lower anxiety-like behavior in testosterone-treated mice, but higher anxiety-like behavior in XY mice. We also found genetic sex effects suggesting a differing developmental trajectory of the GABA and BDNF systems, where XY mice develop later than XX mice. Together, my findings highlight the complex relationship of sex-related factors on GABA- and BDNF-related gene expression through development that, if altered, could lead to adult psychopathology.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
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| ETD Committee: |
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| Date: |
23 April 2018 |
| Date Type: |
Publication |
| Defense Date: |
12 March 2018 |
| Approval Date: |
23 April 2018 |
| Submission Date: |
5 April 2018 |
| Access Restriction: |
2 year -- Restrict access to University of Pittsburgh for a period of 2 years. |
| Number of Pages: |
73 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
David C. Frederick Honors College
Dietrich School of Arts and Sciences > Neuroscience |
| Degree: |
BPhil - Bachelor of Philosophy |
| Thesis Type: |
Undergraduate Thesis |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
Major depressive disorder, depression, GABA-related gene expression, FCG mice, MDD, SST, developmental trajectory |
| Date Deposited: |
23 Apr 2018 19:08 |
| Last Modified: |
23 Apr 2020 05:15 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/33984 |
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