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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

23 24 25 26 SOCIAL INSTABLITY ABSTRACT: 27Despite stress-associated disorders having a higher incidence rate in females, preclinical 28 research mainly focuses on males. Chronic stress paradigms, such as chronic social defeat and 29 chronic corticosterone administration, were mainly designed and validated in males and 30 subsequent attempts to use these paradigms in females has demonstrated sex differences in the 31 behavioral and HPA axis response to stress. Here, we developed a social stress paradigm, social 32 instability stress (SIS), which exposes adult mice to unstable social hierarchies for 7 weeks. SIS 33 effectively induces negative valence behaviors and hypothalamus-pituitary-adrenal (HPA) axis 34 activation in both males and females. Importantly, while there were effects of estrous cycle on 35 behavior, this variability did not impact the overall effects of SIS on behavior, suggesting estrous 36does not need to be tracked while utilizing SIS. Furthermore, the effects of SIS on negative 37 valence behaviors were also reversed following chronic antidepressant treatment with fluoxetine 38 (FLX) in both males and females. SIS also reduced adult hippocampal neurogenesis in female 39 mice, while chronic FLX treatment increased adult hippocampal neurogenesis in both males and 40 females. Overall, these data demonstrate that the SIS paradigm is an ethologically valid approach 41 that effectively induces chronic stress in both adult male and adult female mice. 42 SOCIAL INSTABLITYSamples were suctioned back into the pipette, placed on a microscope slide, and dried on a slide 131 warmer before imaged with an EVOS FL Auto 2.0 microscope (Thermofisher Scientific) at 10x 132 magnification (40, 41). Estrous phases were identified by the presence or absence of nucleated 133 epithelial cells, cornified epithelial cells, and leukocytes (41, 42 Figure 3B). 134 135 Behavioral Testing 136Open Field (OF). Motor activity was quantified via infrared photobeams in Plexiglass open field 137 boxes 43x43 cm 2 (Kinder Scientific). As previously described (13), activity chambers were 138