All ETDs from UAB

Advisory Committee Chair

Yogesh Dwivedi

Advisory Committee Members

Franklin Amthor

Richard Shelton

Robert Sorge

Christianne Strang

Document Type

Dissertation

Date of Award

2019

Degree Name by School

Doctor of Philosophy (PhD) College of Arts and Sciences

Abstract

Depression is the leading cause of disability worldwide and impacts nearly 350 million people with a disproportionate representation in women with a 1:1.7 ratio of occurrence compared to men. This disorder is characterized by shifts in mood to include feelings of hopelessness, sadness, and lethargy as well as changes in diet, motivation, and sleep patterns. Further, over 50% of patients who struggle with depression also have suicidal ideation and as many as 10% of those commit suicide. At present, treatment plans include behavioral therapy (often) in conjunction with antidepressant medications which act on monoamines and their circuits in the central nervous system. However, whilst research has shed light on many aspects of the underlying pathophysiology, it is not fully understood. Psychological stressors are known to have a significant impact on the initiation and development of depressive episodes. It is not fully understood how psychological stress is translated into physiological duress and symptomology which results in changes in behavior. However, the work of this dissertation proposes that activity related to the activation of the cellular stress response, the unfolded protein response, may shed light on some of the unknown connection between psychological stress and resulting physiology. The unfolded protein response (UPR) is an evolutionarily conserved cascade of responses that occurs at the cellular level in the endoplasmic reticulum in response to stressful environments which result in a diminished quality of protein folded. Upon activation, the UPR initiates cascades which act to repair and remove misfolded proteins from the endoplasmic reticulum. If the cell is overwhelmed and is unable to correct the misfolded proteins, then under prolonged stress, the UPR will initiate the apoptotic sequences thus leading to cell death. During activation, the UPR also initiates inflammation cascades which result in a pro-inflammatory environment. In previous studies, both inflammation and apoptosis have been shown to play an important role in the physiology of depression. Here we show that the UPR is intimately involved in the underlying pathophysiology of depression and is sufficient to, downstream of activation in the hippocampus, elicit depressive behaviors.

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