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Androgens Enhance Adult Hippocampal Neurogenesis in Males but Not Females in an Age

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Androgens Enhance Adult Hippocampal Neurogenesis in Males but Not Females in an Age bioRxiv preprint doi: https://doi.org/10.1101/539296; this version posted February 3, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 1 Androgens enhance adult hippocampal neurogenesis in males but not females in an age- 2 dependent manner 3 4 Paula Duarte-Guterman1, Dwayne K. Hamson1, Steven R. Wainwright1, Carmen Chow1, Jessica 5 Chaiton1, Stephanie Lieblich1, Neil V. Watson2, Liisa A.M. Galea1 6 7 1. Djavad Mowafaghian Centre for Brain Health and Department of Psychology, University of 8 British Columbia, Vancouver, BC, Canada 9 2. Department of Psychology, Simon Fraser University, Burnaby, BC, Canada 10 11 12 Address all correspondence and requests for reprints to: 13 L. A. M. Galea, PhD, 14 Djavad Mowafaghian Centre for Brain Health 15 2215 Wesbrook Mall 16 Vancouver, British Columbia 17 V6T 1Z3, Canada 18 2136 West Mall, Vancouver, 19 British Columbia, V6T 1Z4, Canada. 20 E-mail: [email protected]. 1 bioRxiv preprint doi: https://doi.org/10.1101/539296; this version posted February 3, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 21 Abstract 22 Androgens (testosterone and dihydrotestosterone) increase adult hippocampal 23 neurogenesis by increasing new neuron survival in male rats and mice via an androgen receptor 24 pathway, but it is not known whether androgens regulate neurogenesis in females and whether 25 the effect is age-dependent. We investigated the effects of dihydrotestosterone, a potent 26 androgen, on neurogenesis in adult and middle-aged males and females. Rats were 27 gonadectomized and injected with the DNA synthesis marker, bromodeoxyuridine (BrdU). The 28 following day rats began receiving daily injections of oil or DHT for 30 days. We evaluated cell 29 proliferation (Ki67) and new neuron survival (BrdU and BrdU/NeuN) in the hippocampus of 30 male and female rats using immunohistochemistry. As expected, DHT increased new neuron 31 survival in young males but surprisingly not in middle-aged male rats. In females, DHT did not 32 significantly affect adult neurogenesis in young or middle age. Our results indicate that DHT 33 regulates adult hippocampal neurogenesis in a sex- and age-dependent manner. 2 bioRxiv preprint doi: https://doi.org/10.1101/539296; this version posted February 3, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 34 Main text 35 Neurogenesis, the production of new neurons, in the hippocampus continues through the 36 life span of most mammals studied to date (Kempermann et al., 2018). Sex hormones (estrogens 37 and androgens) regulate different aspects of hippocampal neurogenesis: e.g. proliferation and/or 38 survival of these new neurons in rodents (reviewed in Duarte-Guterman et al., 2015b; Mahmoud 39 et al., 2016). There is also evidence of sex differences in how hormones regulate neurogenesis. 40 For example, estradiol regulates new neuron survival and cell proliferation in female but not 41 male rodents (Barker and Galea, 2008). We have previously shown that androgens (testosterone 42 and dihydrotestosterone) increase the survival of new neurons but not cell proliferation in the 43 hippocampus of male rats via an androgen receptor (AR) pathway (Spritzer and Galea, 2007; 44 Hamson et al., 2013) and mice (Swift-Gallant et al., 2018). However it is not known whether 45 androgens regulate any aspects of adult neurogenesis in females. In addition to sex, age can also 46 modulate the effects of hormones on hippocampal neurogenesis. In middle age, the hippocampus 47 loses its ability to respond to estrogens in female rats. For instance, estradiol increases cell 48 proliferation in the hippocampus in young but not middle-aged nulliparous female rats (Chiba et 49 al., 2007; Barha and Galea, 2011). The objective of this study was to investigate the effects of 50 dihydrotestosterone (DHT) on hippocampal neurogenesis (proliferation and new neuron 51 survival) in young and middle-aged male and female rats. 52 At 2 months (~70 days old, young) and 11-12 months of age (middle-aged), 53 gonadectomized male and female Sprague–Dawley rats received a single intraperitoneal 54 injection of bromodeoxyuridine (BrdU; 200mg/kg) to label dividing cells and their progeny 55 (Hamson et al., 2013). The following day, males and females were injected subcutaneously with 56 either 0.25mg dihydrotestosterone (DHT in 0.1ml of sesame oil) or an equivalent volume of 3 bioRxiv preprint doi: https://doi.org/10.1101/539296; this version posted February 3, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 57 sesame oil for 30 days. Twenty-four hours after the final injection, animals were overdosed with 58 sodium pentobartitol and brains perfused and collected for BrdU (survival of 30 day old cells), 59 Ki67 (cell proliferation marker), androgen receptor (AR), and BrdU/NeuN (new neurons using 60 NeuN, marker for mature neurons) immunohistochemistry (Hamson et al., 2013; Swift-Gallant et 61 al., 2018). Thus, in this experiment, BrdU+ cells were 30 day-old daughter cells from progenitor 62 cells that had been synthesizing DNA for a 2-hour period 31 days before euthanasia. All 63 protocols were approved by the Animal Care Committee at the University of British Columbia 64 and conformed to the guidelines set out by the Canadian Council for Animal Care. 65 A researcher blind to experimental conditions counted BrdU+ and Ki67-immunoreactive 66 (ir) cells in the entire rostrocaudal extent of the granule cell layer (GCL) including the sub 67 granular zone, defined as the 50 µm band between the GCL and the hilus. An estimate of the 68 total number of cells in the GCL and hilus was calculated by multiplying the number of cells 69 counted by 10 to account for the fact that we used 1/10 series of sections (Tanapat et al., 2005; 70 Spritzer and Galea, 2007; Swift-Gallant et al., 2018). GCL and hilus volumes were quantified 71 from digitized images using Cavelier’s principle, multiplying the sum of the area of each section 72 by the section thickness (40 µm Gundersen et al., 1988). Androgen receptor immunoreactivity 73 was characterized using a relative scale: robust (+++), intermediate (++), light (+), or absent (0) 74 in the GCL, CA1, and CA3 regions in DHT and oil treated groups as we have done before 75 (Hamson et al., 2013). To determine whether BrdU+ cells were of a neuronal phenotype, in a 76 subset of brains, all BrdU+ cells within a section were examined for co-labeling with NeuN 77 (neuronal marker) for 50 cells (young adult group) or all cells (middle-aged group) were 78 phenotyped. All analyses were performed using Statistica v.8.0 (StatSoft Inc, Tulsa, OK). 79 Volume of the dentate gyrus (GCL and hilus) and density of BrdU+ cells (total cells per unit 4 bioRxiv preprint doi: https://doi.org/10.1101/539296; this version posted February 3, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 80 volume) were analyzed using repeated measures analysis of variance (ANOVA) with age 81 (young, middle-aged), sex (male, female), and treatment (DHT, oil) as between subjects factors, 82 and region (GCL, hilus) as a within subjects factor. Density of Ki67-ir cells and proportion of 83 BrdU/NeuN co-labeled cells were analyzed using ANOVA with age (young, middle-aged), sex 84 (male, female), and treatment (DHT, oil) as between subjects factors. When appropriate, post- 85 hoc analysis used the Neuman-Keul’s procedure. Test statistics were considered significant if p ≤ 86 0.05. 87 Regardless of age and treatment, the GCL and hilus were larger in males compared to 88 females (main effect of sex; F(1,42)=4.42; P<0.05; Table 1). The volume of the GCL and hilus 89 increased with age irrespective of sex and treatment (main effect of age; F(1,42)=47.37; 90 P<0.0001). In the case of the hilus, the volume increased with aging more so in males than in 91 females (interaction between region, age, and sex; F(1,42)=20.20; P<0.0001). As expected, the 92 volume of the hilus was larger than the volume of the GCL (main effect of region; 93 F(1,44)=1450.14; P<0.0001). Treatment with DHT did not significantly affect GCL or hilus 94 volumes (all P’s>0.08). To account for the sex differences in GCL and hilus volumes, we present 95 BrdU and Ki67 counts as densities (total cells per unit volume). 96 DHT treatment increased the density of BrdU+ cells in the GCL in young males 97 (P<0.001) but not in young females or middle-aged animals of both sexes (all P’s>0.9; 98 interaction between age, sex, treatment and region; F(1,42)=4.03; P=0.05; Figure 1).
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