20 (848)-445-8945 21 22 42 43 44 45 46 Abstract 47Some mood disorders, such as major depressive disorder, are more prevalent in women 48 than in men. However, historically preclinical studies in rodents have a lower inclusion rate of 49 females than males, possibly due to the fact that behavior can be affected by the estrous cycle. 50Several studies have demonstrated that chronic antidepressant treatment can decrease anxiety-51 like behaviors and increase adult hippocampal neurogenesis in male rodents. However, very few 52 studies have conclusively looked at the effects of antidepressants on behavior and neurogenesis 53 across the estrous cycle in naturally cycling female rodents. Here we analyze the effects of 54 chronic treatment with the selective serotonin reuptake inhibitor (SSRI) fluoxetine (Prozac) on 55 behavior and adult hippocampal neurogenesis in naturally cycling C57BL/6J females across all 56 four phases of the estrous cycle. Interestingly, we find that the effects of fluoxetine on both 57 behavior and adult hippocampal neurogenesis are driven by mice specifically in the estrus or 58 diestrus phases of the estrous cycle. Taken together our data is the first to illustrate the impact of 59 fluoxetine on brain and behavior across all four stages of the murine estrous cycle. 60 61 Highlights: 62• Chronic fluoxetine reduces anxiety-like behaviors in naturally cycling female mice 63• Chronic fluoxetine increases adult hippocampal neurogenesis in naturally cycling female 64 mice 65• The effects of chronic fluoxetine on behavior and adult hippocampal neurogenesis are 66 driven by the estrus and diestrus phases of the estrous cycle 67 68

Some mood disorders, such as major depressive disorder, are more prevalent in women than in men. However, historically preclinical studies in rodents have a lower inclusion rate of females than males, possibly due to the fact that behavior can be affected by the estrous cycle.Several studies have demonstrated that chronic antidepressant treatment can decrease anxietylike behaviors and increase adult hippocampal neurogenesis in male rodents. However, very few studies have conclusively looked at the effects of antidepressants on behavior and neurogenesis across the estrous cycle in naturally cycling female rodents. Here we analyze the effects of chronic treatment with the selective serotonin reuptake inhibitor (SSRI) fluoxetine (Prozac) on behavior and adult hippocampal neurogenesis in naturally cycling C57BL/6J females across all four phases of the estrous cycle. Interestingly, we find that the effects of fluoxetine on both behavior and adult hippocampal neurogenesis are driven by mice specifically in the estrus or diestrus phases of the estrous cycle. Taken together our data is the first to illustrate the impact of fluoxetine on brain and behavior across all four stages of the murine estrous cycle. Highlights:• Chronic fluoxetine reduces anxiety-like behaviors in naturally cycling female mice • Chronic fluoxetine increases adult hippocampal neurogenesis in naturally cycling female mice • The effects of chronic fluoxetine on behavior and adult hippocampal neurogenesis are driven by the estrus and diestrus phases of the estrous cycle