Adult hippocampal neurogenesis has been implicated in the pathophysiology of depression and in the therapeutic effects of antidepressant drugs. Current methods that study neurogenesis measure the incorporation of 5-bromo-2-deoxyuridine (BrdU) by immunohistochemistry, which is time consuming and labor intensive. Therefore, a significantly more rapid flow cytometric method was characterized to measure BrdU incorporation in the adult mouse brain. The sensitivity of mice to the effects of antidepressant treatments is dependent on genetic background. Thus, studies were conducted comparing the responsiveness of two inbred mouse strains, MRL/MpJ, which displays enhanced regenerative capacity, and C57BL/6J, the control strain in the regeneration studies, to the acute and chronic effects of antidepressants on neurochemistry and behavior. Acutely, MRL/MpJ mice displayed more robust responses to citalopram, a selective serotonin reuptake inhibitor (SSRI) and desipramine, a tricyclic, in the tail suspension test. Moreover, as compared to C57BL/6J mice, MRL/MpJ mice had higher brain tissue levels of serotonin and dopamine, as well as a greater release of hippocampal serotonin following citalopram treatment. Chronic administration of fluoxetine (SSRI) or desipramine elevated hippocampal cell proliferation only in MRL/MpJ mice, but did not alter the survival of hippocampal progenitors in either strain. In MRL/MpJ mice, chronic treatment with fluoxetine or desipramine elevated brain derived neurotrophic factor (BDNF) protein levels in several brain regions. The pattern of antidepressant effects differed in C57/BL/6J mice. Animals were tested in the novelty-induced hypophagia (NIH) paradigm, to examine a behavior associated with chronic antidepressant treatment. MRL/MpJ mice chronically administered fluoxetine or desipramine had shorter latencies to consume food in the novel environment than untreated mice, while the same treatments did not affect the behavior of C57BL/6J mice. The positive effects of chronic antidepressants on hippocampal cell proliferation and BDNF paralleled the ability of these drugs to produce changes in NIH behavior. This dissertation highlights the advantages of utilizing flow cytometry to study hippocampal neurogenesis and its applicability to the discovery of novel therapeutics with pro-neurogenic properties. It also identifies the MRL/MpJ mouse as a strain with superior sensitivity to antidepressants that may lead to a better understanding of the genetics behind antidepressant efficacy.
