acase@tulane.edu / Women are at greater risk to develop the incurable psychiatric diseases posttraumatic stress disorder (PTSD) and major depressive disorder (MDD). In spite of the elevated risk associated with female biological sex, the vast majority of preclinical studies have exclusively used male rodents. Therefore, the neurobiology which underlies the increased susceptibility to stress-related mental illness associated with female sex is largely unknown. Currently, it is thought that regulation of the transcription factor cyclic-AMP response element binding protein (CREB) may act as a molecular locus capable of transducing aversive experiences into lasting changes in the structure and function of neurons in the hippocampus. However, the signal transduction cascades recruited by stress to modulate CREB activity are less well understood. Therefore, the goal of this thesis was to investigate stress-induced modulation of CREB phosphorylation and upstream signaling cascades in the hippocampus of male and female rodents exposed to severe stress. Exposure to either acute predator odor stress or chronic variable stress reduced phosphorylation of CREB in the male, but not the female hippocampus. Predator odor exposure rapidly reduced phosphorylation of extracellular signal-regulated kinase and increased nuclear expression of the synapto-nuclear messenger protein Jacob in the male hippocampus, consistent with the previously described CREB shut-off cascade. Chronic variable stress affected the activity of Sirtuin1, a metabolically-sensitive deacetylase known to interact with CREB, in the male, but not the female dentate gyrus sub-area of the hippocampus, possibly through recruitment of adenosine monophosphate activated protein kinase. Behaviorally, female rodents exposed to predator odor exhibited an impaired ability to discriminate between a context previously paired with the predator odor and a neutral context, possibly representing a fear over-generalizing phenotype. In contrast female rodents exposed to chronic variable stress did not exhibit the altered metabolic phenotypes observed in male rodents exposed to chronic variable stress, suggesting that females are more resilient to chronic stress. Collectively, these data suggest that the female hippocampus resists changes in CREB phosphorylation associated with severe stress which may contribute to sex differences observed in stress-related mental health disorders. / 1 / Damek Homiack
| Identifer | oai:union.ndltd.org:TULANE/oai:http://digitallibrary.tulane.edu/:tulane_75315 |
| Date | January 2017 |
| Contributors | Homiack, Damek (author), (author), Schrader, Laura (Thesis advisor), (Thesis advisor), School of Science & Engineering Neuroscience (Degree granting institution), NULL (Degree granting institution) |
| Publisher | Tulane University |
| Source Sets | Tulane University |
| Language | English |
| Detected Language | English |
| Type | Text |
| Format | electronic, 159 |
| Rights | 12 months, Copyright is in accordance with U.S. Copyright law. |
Page generated in 0.0017 seconds