Examining an Animal Model of Depression with Recurrent Depression-like Episodes
Lebedeva, Katherina A 1988-
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Depression is a complex psychiatric disorder. It is recognized as a cyclical disease with multiple episode relapses. Many preclinical animal models have been utilized to study the behavioral and neurobiological characteristics of depression, however, almost without exception, these models do not recapitulate the recurrent nature of this disorder. It is suggested that the relationship between major depression and stress, which is the important risk factor for depression, changes over time: the depressive episodes either become increasingly autonomous of stress and occur spontaneously, or the depressed individual becomes increasingly sensitized to stress so that smaller stressors can trigger subsequent episode relapses. Therefore, a close examination of potential mechanisms evoking recurrent depressive episodes is needed. The primary goals of this dissertation were to develop an animal model of recurrent depression using repeated and cyclic corticosterone (CORT) administration and to gain a better understanding of the consequences of such treatment on behavioral and neurobiological alterations in rodents. To begin, in Chapter 2, I examined the effect of two cycles of repeated CORT injections on rat behavior measured via repeated forced swim testing. I found that CORT produced increasingly greater effects on the depression-like behavior of rats during the second cycle of CORT exposure. These data suggested the development of a sensitized behavioral vulnerability in rats following CORT re-exposure. In Chapter 3, non-repeated behavioral testing of naïve rats was employed to examine the influence of cyclic CORT treatment on several measures of depression-like behavior, the number and maturation rate of immature dentate granule cells, as well as changes in hippocampal REST protein expression. Consistent with the results of the first experiment, CORT produced larger increases in depression-like and anhedonia-like behaviors in second and third cycles, without changes in general locomotor behavior. Aggravation of depression-like behavior was accompanied by an accumulated decline in neurogenesis and dendritic complexity of newborn neurons in the dentate gyrus. Additionally, I discovered that glucocorticoid treatment also exerted its adverse effects on transcriptional regulation in the hippocampus, characterized by hippocampal REST protein levels. Finally, Chapter 4 included a preliminary examination of the effects of cyclic CORT exposure on changes in hippocampal microglia. CORT produced cumulative decreases in hippocampal microglia area fraction and cell morphology, which are closely coupled with microglial activation and neuroinflammatory processes. These changes were strongly correlated with decreases in dentate granule neuron maturation and increases in depression-like behavior, suggesting that the activation of hippocampal microglia may be associated with exacerbation of depressive symptoms and paralleled decreases in the number and complexity of hippocampal immature neuron population. The overall findings of this dissertation provide evidence that repeated and cyclic glucocorticoid treatment can be used as an animal model of recurrent depression, as it provides a means to investigate the neurobiological changes governing depressive symptom relapse. Data presented in this dissertation further advance our understanding of the effects of CORT on brain and behavior, and provide support for a relationship between increasingly severe depression-like symptoms, decreases in neurogenesis and newborn cell maturation rate, as well as alterations in hippocampal REST levels and microglial cell activation.
DegreeDoctor of Philosophy (Ph.D.)
CommitteeKalynchuk, Lisa; Caruncho, Hector; Cummings, Jorden; Paterson, Phyllis; Campbell, Jamie
Copyright DateMay 2017