@article{lynch_towers_rissman_2023, title={Editorial: Women in psychiatry 2022: Addictive disorders}, volume={14}, ISSN={["1664-0640"]}, DOI={10.3389/fpsyt.2023.1157677}, abstractNote={COPYRIGHT © 2023 Lynch, Towers and Rissman. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. Editorial: Women in psychiatry 2022: Addictive disorders}, journal={FRONTIERS IN PSYCHIATRY}, author={Lynch, Wendy J. and Towers, E. Blair and Rissman, Emilie F.}, year={2023}, month={Apr} }
 @article{rissman_lynch_2023, title={Role of hormones in substance use disorders}, ISSN={["1423-0194"]}, DOI={10.1159/000533291}, abstractNote={Addictive drugs, such as cocaine and heroin, have well-documented actions on behavior. The mechanisms that these drugs employ have been under investigation for decades although the investigation of how gonadal and pituitary hormones impact these mechanisms is a relatively new focus. Here, we have assembled a group of primary-literature papers solicited from many of the leading addiction laboratories in the world. The papers in this compellation highlight different drug classes, hormones, levels of analysis, and animal models. Our hope is that this “ wide angle ” approach provides us some overarching conclusions on common mechanisms. In this editorial, we present an overview of each paper and then speculate about general principles. The fi rst}, journal={NEUROENDOCRINOLOGY}, author={Rissman, Emilie F. and Lynch, Wendy J.}, year={2023}, month={Aug} }
 @article{le_lynch_rissman_2023, title={Sex chromosome complement and estradiol modify cocaine self-administration behaviors in male mice}, ISSN={["1423-0194"]}, DOI={10.1159/000531648}, abstractNote={Introduction: Women are more vulnerable to cocaine’s reinforcing effects and have a more rapid course to addiction after initial cocaine use as compared to men. Studies in rodents similarly indicate an enhanced sensitivity to the reinforcing effects of cocaine in females versus males. Levels of estradiol (E2) are correlated with vulnerability to the rewarding actions of cocaine. Here, we asked if sex chromosome complement (SCC) influences vulnerability to cocaine use. Methods: We used the four-core genotype mouse that produces gonadal males and females with either XX or XY SCC. Mice were gonadectomized and implanted with either an estradiol (E2) or cholesterol-filled pellet. This allowed us to determine the effects of SCC in the absence (cholesterol-treated) and presence of tonic high physiological hormone levels (estradiol). Acquisition of cocaine self-administration was determined over a 12-day period using an escalated dose procedure (0.3 mg/kg/infusion, sessions 1–6; 0.6 mg/kg/infusion, sessions 6–12). Results: Without estradiol treatment, a greater percentage of castrated XY mice acquired cocaine self-administration and did so at a faster rate than XX castrates and ovariectomized XY females. These same XY males acquired sooner, infused more cocaine, and directed more nose pokes to the rewarded nose-poke hole than XX castrates and XY males receiving E2. Conclusion: Our results suggest that in gonadal male mice, SCC and estradiol can modulate the reinforcing effects of cocaine which may influence the likelihood of cocaine use.}, journal={NEUROENDOCRINOLOGY}, author={Le, Aaron L. and Lynch, Wendy J. and Rissman, Emilie}, year={2023}, month={Jun} }
 @article{harp_martini_rosenow_mesner_johnson_farber_rissman_2022, title={Fentanyl-induced acute and conditioned behaviors in two inbred mouse lines: Potential role for Glyoxalase}, volume={243}, ISSN={["1873-507X"]}, DOI={10.1016/j.physbeh.2021.113630}, abstractNote={An increase in opioid-overdose deaths was evident before the COVID-19 pandemic, and has escalated since its onset. Fentanyl, a highly potent synthetic opioid, is the primary driver of these recent trends. The current study used two inbred mouse strains, C57BL/6 J and A/J, to investigate the genetics of behavioral responses to fentanyl. Mice were tested for conditioned place preference and fentanyl-induced locomotor activity. C57BL/6J mice formed a conditioned place preference to fentanyl injections and fentanyl increased their activity. Neither effect was noted in A/J mice. We conducted RNA-sequencing on the nucleus accumbens of mice used for fentanyl-induced locomotor activity. Surprisingly, we noted few differentially expressed genes using treatment as the main factor. However many genes differed between strains. We validated differences in two genes: suppressor APC domain containing 1 (Sapcd1) and Glyoxalase 1 (Glo1), with quantitative PCR on RNA from the nucleus accumbens and prefrontal cortex (). In both regions A/J mice had significantly higher expression of both genes than did C57BL/6 J. In prefrontal cortex, fentanyl treatment decreased Glo1 mRNA. Glyoxalase 1 catalyzes the detoxification of reactive alpha-oxoaldehydes such as glyoxal and methylglyoxal, is associated with anxiety and activity levels, and its inhibition reduces alcohol intake. We suggest that future studies assess the ability of Glo1 and related metabolites to modify opioid intake.}, journal={PHYSIOLOGY & BEHAVIOR}, author={Harp, Samuel J. and Martini, Mariangela and Rosenow, Will and Mesner, Larry D. and Johnson, Hugh and Farber, Charles R. and Rissman, Emilie F.}, year={2022}, month={Jan} }
 @article{henriksen_andrade_harris_rissman_wolstenholme_2020, title={Bisphenol A Exposure in utero Disrupts Hypothalamic Gene Expression Particularly Genes Suspected in Autism Spectrum Disorders and Neuron and Hormone Signaling}, volume={21}, ISSN={["1422-0067"]}, DOI={10.3390/ijms21093129}, abstractNote={Bisphenol A (BPA) is an endocrine-disrupting compound detected in the urine of more than 92% of humans, easily crosses the placental barrier, and has been shown to influence gene expression during fetal brain development. The purpose of this study was to investigate the effect of in utero BPA exposure on gene expression in the anterior hypothalamus, the basal nucleus of the stria terminalis (BNST), and hippocampus in C57BL/6 mice. Mice were exposed in utero to human-relevant doses of BPA, and then RNA sequencing was performed on male PND 28 tissue from whole hypothalamus (n = 3/group) that included the medial preoptic area (mPOA) and BNST to determine whether any genes were differentially expressed between BPA-exposed and control mice. A subset of genes was selected for further study using RT-qPCR on adult tissue from hippocampus to determine whether any differentially expressed genes (DEGs) persisted into adulthood. Two different RNA-Seq workflows indicated a total of 259 genes that were differentially expressed between BPA-exposed and control mice. Gene ontology analysis indicated that those DEGs were overrepresented in categories relating to mating, cell–cell signaling, behavior, neurodevelopment, neurogenesis, synapse formation, cognition, learning behaviors, hormone activity, and signaling receptor activity, among others. Ingenuity Pathway Analysis was used to interrogate novel gene networks and upstream regulators, indicating the top five upstream regulators as huntingtin, beta-estradiol, alpha-synuclein, Creb1, and estrogen receptor (ER)-alpha. In addition, 15 DE genes were identified that are suspected in autism spectrum disorders.}, number={9}, journal={INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES}, author={Henriksen, Anne D. and Andrade, Alejandro and Harris, Erin P. and Rissman, Emilie F. and Wolstenholme, Jennifer T.}, year={2020}, month={May} }
 @misc{martini_corces_rissman_2020, title={Mini-review: Epigenetic mechanisms that promote transgenerational actions of endocrine disrupting chemicals: Applications to behavioral neuroendocrinology}, volume={119}, ISSN={["1095-6867"]}, DOI={10.1016/j.yhbeh.2020.104677}, abstractNote={It is our hope this mini-review will stimulate discussion and new research. Here we briefly examine the literature on transgenerational actions of endocrine disrupting chemicals (EDCs) on brain and behavior and their underlying epigenetic mechanisms including: DNA methylation, histone modifications, and non-coding RNAs. We stress that epigenetic modifications need to be examined in a synergistic manner, as they act together in situ on chromatin to change transcription. Next we highlight recent work from one of our laboratories (VGC). The data provide new evidence that the sperm genome is poised for transcription. In developing sperm, gene enhancers and promoters are accessible for transcription and these activating motifs are also found in preimplantation embryos. Thus, DNA modifications associated with transcription factors during fertilization, in primordial germ cells (PGCs), and/or during germ cell maturation may be passed to offspring. We discuss the implications of this model to EDC exposures and speculate on whether natural variation in hormone levels during fertilization and PGC migration may impart transgenerational effects on brain and behavior. Lastly we discuss how this mechanism could apply to neural sexual differentiation.}, journal={HORMONES AND BEHAVIOR}, author={Martini, Mariangela and Corces, Victor G. and Rissman, Emilie F.}, year={2020}, month={Mar} }
 @article{martini_irvin_lee_lynch_rissman_2020, title={Sex chromosome complement influences vulnerability to cocaine in mice}, volume={125}, ISSN={["1095-6867"]}, DOI={10.1016/j.yhbeh.2020.104821}, abstractNote={Women acquire cocaine habits faster and are more motivated to obtain drug than men. In general, female rodents acquire intravenous cocaine self-administration (SA) faster and show greater locomotor responses to cocaine than males. Sex differences are attributed to differences in circulating estradiol. We used the four core genotype (FCG) mouse to ask whether sex chromosome complement influences vulnerability to cocaine's reinforcing and/or locomotor-activating effects. The FCG cross produces ovary-bearing mice with XX or XY genotypes (XXF, XYF) and testes-bearing mice with XX or XY genotypes (XXM, XYM). A greater percentage of gonadal females acquired cocaine SA via infusions into jugular catheters as compared with XYM mice, but XXM mice were not significantly different than any other group. Discrimination of the active versus inactive nose poke holes and cocaine intake were in general greater in gonadal females than in gonadal males. Progressive ratio tests for motivation revealed an interaction between sex chromosomes and gonads: XYM mice were more motivated to self-administer cocaine taking more infusions than mice in any other group. Locomotor responses to cocaine exposure revealed effects of sex chromosomes. After acute exposure, activity was greater in XX than in XY mice and the reverse was true for behavioral sensitization. Mice with XY genotypes displayed more activity than XX mice when given cocaine after a 10-day drug-free period. Our data demonstrate that sex chromosome complement alone and/or interacting with gonadal status can modify cocaine's reinforcing and locomotor-activating effects. These data should inform current studies of sex differences in drug use.}, journal={HORMONES AND BEHAVIOR}, author={Martini, Mariangela and Irvin, Joshua W. and Lee, Christina G. and Lynch, Wendy J. and Rissman, Emilie F.}, year={2020}, month={Sep} }
 @misc{harp_martini_lynch_rissman_2020, title={Sexual Differentiation and Substance Use: A Mini-Review}, volume={161}, ISSN={["1945-7170"]}, DOI={10.1210/endocr/bqaa129}, abstractNote={The organizational/activational hypothesis suggests that gonadal steroid hormones like testosterone and estradiol are important at two different times during the lifespan when they perform two different functions. First steroids "organize" brain structures early in life and during puberty, and in adults these same hormones "activate" sexually dimorphic behaviors. This hypothesis has been tested and proven valid for a large number of behaviors (learning, memory, social and sexual behaviors). Sex differences in drug addiction are well established for both humans and animal models. Previous research in this field has focused primarily on cocaine self-administration by rats. Traditionally, observed sex differences have been explained by the sex-specific concentrations of gonadal hormones present at the time of the drug-related behavior. Studies with gonadectomized rodents establishes an activational role for estradiol which facilitates vulnerability in females, and when estradiol is combined with progesterone, addiction is attenuated. Literature on organizational actions of steroids is sparse but predicts that testosterone, after it is aromatized to estradiol, changes aspects of the neural reward system. Here we summarize these data and propose that sex chromosome complement also plays a role in determining sex-specific drug-taking behavior. Future research is needed to disentangle the effects of hormones and sex chromosome complement, and we propose the four core genotypes mouse model as an effective tool for answering these questions.}, number={9}, journal={ENDOCRINOLOGY}, author={Harp, Samuel J. and Martini, Mariangela and Lynch, Wendy J. and Rissman, Emilie F.}, year={2020}, month={Sep} }
 @article{drobna_talarovicova_schrader_fennell_snyder_rissman_2019, title={Bisphenol F has different effects on preadipocytes differentiation and weight gain in adult mice as compared with Bisphenol A and S}, volume={420}, ISSN={["0300-483X"]}, DOI={10.1016/j.tox.2019.03.016}, abstractNote={Bisphenol S (2,2-bisulfone, BPS) and Bisphenol F (2,2-bis [4-hydroxyphenol]methane, BPF) are analogs of Bisphenol A (2,2-bis[4-hydroxyphenyl]propane, BPA), a widely used endocrine disrupting compound present in polycarbonate plastics, thermal receipts and epoxy resins that line food cans. Here we examined effects of BPA, BPS, and BPF in low concentrations on differentiation in murine 3T3-L1 preadipocytes. We also fed adult male mice chow with one of three doses of BPF (0, 0.5, 5, 50 mg/kg chow, or approximately 0.044, 0.44 and 4.4 mg/kg body weight per day) for 12 weeks, collected body weights, food intake, and tested for glucose tolerance. The doses of BPF used produced mean concentrations of 0, 6.2, 43.6, and 561 ng/mL in plasma. In 3T3-L1 cells BPS had the greatest effects, along with BPA, both increased expression of several genes required for preadipocyte differentiation over 12 days in culture. In contrast, BPF decreased expression of several genes late in differentiation. This dichotomy was also reflected in lipid accumulation as BPA and BPS treated cells had elevated lipid concentrations compared to controls or cells treated with BPF. Male mice fed either the highest or lowest concentrations of BPF gained less weight than controls with no effects on glucose levels or glucose tolerance. Plasma levels of BPF reflected doses in food with no overlap between doses. In summary, our results suggest that BPS has a strong potential to be obesogenic while effects of BPF are subtler and potentially in the opposite direction.}, journal={TOXICOLOGY}, author={Drobna, Zuzana and Talarovicova, Alzbeta and Schrader, Hannah E. and Fennell, Timothy R. and Snyder, Rodney W. and Rissman, Emilie F.}, year={2019}, month={May}, pages={66–72} }
 @article{wolstenholme_drobna_henriksen_goldsby_stevenson_irvin_flaws_rissman_2019, title={Transgenerational Bisphenol A Causes Deficits in Social Recognition and Alters Postsynaptic Density Genes in Mice}, volume={160}, ISSN={["1945-7170"]}, DOI={10.1210/en.2019-00196}, abstractNote={Bisphenol A (BPA) is a ubiquitous endocrine-disrupting chemical (EDC). Developmental exposure produces changes in behavior and gene expression in brain. Here we examined social recognition behaviors in mice, three generations (F3) after exposure to gestational BPA. Second generation mice were bred in one of four mating combinations to reveal whether characteristics in F3 were acquired via maternal or paternal exposures. After repeated habituation to the same mouse, offspring of dams from the BPA-lineage failed to display increased investigation of a novel mouse. Genes involved in excitatory post-synaptic densities (PSD) were examined in F3 brains using qPCR. Differential expression of genes important for function and stability of PSDs were assessed at three developmental ages. Several related PSD genes - SH3 and multiple ankyrin repeat domains 1 (Shank1), Homer scaffolding protein 1c (Homer1c), DLG associated protein 1 (Gkap), and discs large MAGUK scaffold protein 4 (PSD95) - were differentially expressed in control- versus BPA-lineage brains. Using a second strain of F3 inbred mice exposed to BPA, we noted the same differences in Shank1 and PSD95 expression found in C57BL/6J mice. In sum, transgenerational BPA exposure disrupted social interactions in mice and dysregulated normal expression of PSD genes during neural development. The fact that the same genetic effects were found in two different mouse strains and in several brain regions, increased potential for translation. The genetic and functional relationship between PSD and abnormal neurobehavioral disorders is well established and our data suggest that BPA may contribute, in a transgenerational manner, to neurodevelopmental diseases.}, number={8}, journal={ENDOCRINOLOGY}, author={Wolstenholme, Jennifer T. and Drobna, Zuzana and Henriksen, Anne D. and Goldsby, Jessica A. and Stevenson, Rachel and Irvin, Joshua W. and Flaws, Jodi A. and Rissman, Emilie F.}, year={2019}, month={Aug}, pages={1854–1867} }
 @article{harris_allardice_schenk_rissman_2018, title={Effects of maternal or paternal bisphenol A exposure on offspring behavior}, volume={101}, ISSN={["1095-6867"]}, DOI={10.1016/j.yhbeh.2017.09.017}, abstractNote={Bisphenol A (BPA) is an endocrine disrupting chemical used in the production of polycarbonate plastics and resins. Exposure to BPA during gestation has been proposed as a risk factor for the development of neurobehavioral disorders, such as autism spectrum disorder. To address the behavioral impact of developmental exposure to BPA, we tested offspring of mice exposed to a daily low dose of BPA during pregnancy. We also asked if preconception exposure of the sire affected behaviors in offspring. Sires that consumed BPA for 50 days prior to mating weighed less than controls, but no effects on any reproductive measures were noted. Juvenile offspring exposed to BPA maternally, but not paternally, spent less time in the open arms of the elevated plus maze than controls, indicating increased anxiety-like behavior. However, neither parental exposure group differed significantly from controls in the social recognition task. We also assessed the behaviors of maternally exposed offspring in two novel tasks: ultrasonic vocalizations (USVs) in pups and operant reversal learning in adults. Maternal BPA exposure increased the duration and median frequency of USVs emitted by pups during maternal separation. In the reversal learning task, females responded more accurately and earned more rewards than males. Additionally, control females received more rewards than BPA females during the acquisition phase of the task. These are among the first studies conducted to ask if BPA exposure via the sire affects offspring behavior and the first study to report effects of gestational BPA exposure on pup USVs and adult operant responding.}, journal={HORMONES AND BEHAVIOR}, author={Harris, Erin P. and Allardice, Heather A. and Schenk, A. Katrin and Rissman, Emilie F.}, year={2018}, month={May}, pages={68–76} }
 @article{drobna_henriksen_wolstenholme_montiel_lambeth_shang_harris_zhou_flaws_adli_et al._2018, title={Transgenerational Effects of Bisphenol A on Gene Expression and DNA Methylation of Imprinted Genes in Brain}, volume={159}, ISSN={["1945-7170"]}, DOI={10.1210/en.2017-00730}, abstractNote={Bisphenol A (BPA) is a ubiquitous man-made endocrine disrupting compound (EDC). Developmental exposure to BPA changes behavioral and reproductive phenotypes, and these effects can last for generations. We exposed embryos to BPA, producing two lineages: controls and BPA exposed. In the third filial generation (F3), brain tissues containing the preoptic area, the bed nucleus of the stria terminalis, and the anterior hypothalamus were collected. RNA sequencing (RNA-seq) and subsequent data analyses revealed 50 differentially regulated genes in the brains of F3 juveniles from BPA vs control lineages. BPA exposure can lead to loss of imprinting, and one of the two imprinted genes in our data set, maternally expressed gene 3 (Meg3), has been associated with EDCs and neurobehavioral phenotypes. We used quantitative polymerase chain reaction to examine the two imprinted genes in our data set, Meg3 and microRNA-containing gene Mirg (residing in the same loci). Confirming the RNA-seq, Meg3 messenger RNA was higher in F3 brains from the BPA lineage than in control brains. This was true in brains from mice produced with two different BPA paradigms. Next, we used pyrosequencing to probe differentially methylated regions of Meg3. We found transgenerational effects of BPA on imprinted genes in brain. Given these results, and data on Meg3 methylation in humans, we suggest this gene may be a biomarker indicative of early life environmental perturbation.}, number={1}, journal={ENDOCRINOLOGY}, author={Drobna, Zuzana and Henriksen, Anne D. and Wolstenholme, Jennifer T. and Montiel, Catalina and Lambeth, Philip S. and Shang, Stephen and Harris, Erin P. and Zhou, Changqing and Flaws, Jodi A. and Adli, Mazhar and et al.}, year={2018}, month={Jan}, pages={132–144} }
 @article{quinnies_harris_snyder_sumner_rissman_2017, title={Direct and transgenerational effects of low doses of perinatal di-(2-ethylhexyl) phthalate (DEHP) on social behaviors in mice}, volume={12}, ISSN={["1932-6203"]}, DOI={10.1371/journal.pone.0171977}, abstractNote={Di-(2-ethylhexyl) phthalate (DEHP) is an endocrine disrupting chemical commonly used as a plasticizer in medical equipment, food packaging, flooring, and children’s toys. DEHP exposure during early development has been associated with adverse neurobehavioral outcomes in children. In animal models, early exposure to DEHP results in abnormal development of the reproductive system as well as altered behavior and neurodevelopment. Based on these data, we hypothesized that developmental exposure to DEHP would decrease social interactions and increase anxiety-like behaviors in mice in a dose-dependent manner, and that the effects would persist over generations. C57BL/6J mice consumed one of three DEHP doses (0, 5, 40, and 400 μg/kg body weight) throughout pregnancy and during the first ten days of lactation. The two higher doses yielded detectable levels of DEHP metabolites in serum. Pairs of mice from control, low, and high DEHP doses were bred to create three dose lineages in the third generation (F3). Average anogenital index (AGI: anogenital distance/body weight) was decreased in F1 males exposed to the low dose of DEHP and in F1 females exposed to the highest dose. In F1 mice, juvenile pairs from the two highest DEHP dose groups displayed fewer socially investigative behaviors and more exploratory behaviors as compared with control mice. The effect of DEHP on these behaviors was reversed in F3 mice as compared with F1 mice. F1 mice exposed to low and medium DEHP doses spent more time in the closed arms of the elevated plus maze than controls, indicating increased anxiety-like behavior. The generation-dependent effects on behavior and AGI suggest complex mechanisms by which DEHP directly impacts reproductive and neurobehavioral development and influences germline-inherited traits.}, number={2}, journal={PLOS ONE}, author={Quinnies, Kayla M. and Harris, Erin P. and Snyder, Rodney W. and Sumner, Susan S. and Rissman, Emilie F.}, year={2017}, month={Feb} }
 @article{goldsby_wolstenholme_rissman_2017, title={Multi- and transgenerational consequences of Bisphenol A on sexually dimorphic cell populations in mouse brain}, volume={158}, number={1}, journal={Endocrinology}, author={Goldsby, J. A. and Wolstenholme, J. T. and Rissman, E. F.}, year={2017}, pages={21–30} }
 @article{mcinnis_bonthuis_rissman_park_2016, title={Inheritance of steroid-independent male sexual behavior in male offspring of B6D2F1 mice}, volume={80}, ISSN={["1095-6867"]}, DOI={10.1016/j.yhbeh.2016.02.003}, abstractNote={The importance of gonadal steroids in modulating male sexual behavior is well established. Individual differences in male sexual behavior, independent of gonadal steroids, are prevalent across a wide range of species, including man. However, the genetic mechanisms underlying steroid-independent male sexual behavior are poorly understood. A high proportion of B6D2F1 hybrid male mice demonstrates steroid-independent male sexual behavior (identified as “maters”), providing a mouse model that opens up avenues of investigation into the mechanisms regulating male sexual behavior in the absence of gonadal hormones. Recent studies have revealed several proteins that play a significant factor in regulating steroid-independent male sexual behavior in B6D2F1 male mice, including amyloid precursor protein (APP), tau, and synaptophysin. The specific goals of our study were to determine whether steroid-independent male sexual behavior was a heritable trait by determining if it was dependent upon the behavioral phenotype of the B6D2F1 sire, and whether the differential expression of APP, tau, and synaptophysin in the medial preoptic area found in the B6D2F1 sires that did and did not mate after gonadectomy was similar to those found in their male offspring. After adult B6D2F1 male mice were bred with C57BL/6J female mice, they and their male offspring (BXB1) were orchidectomized and identified as either maters or “non-maters”. A significant proportion of the BXB1 maters was sired only from B6D2F1 maters, indicating that the steroid-independent male sexual behavior behavioral phenotype of the B6D2F1 hybrid males, when crossed with C57BL/6J female mice, is inherited by their male offspring. Additionally, APP, tau, and synaptophysin were elevated in in the medial preoptic area in both the B6D2F1 and BXB1 maters relative to the B6D2F1 and BXB1 non-maters, respectively, suggesting a potential genetic mechanism for the inheritance of steroid-independent male sexual behavior.}, journal={HORMONES AND BEHAVIOR}, author={McInnis, Christine M. and Bonthuis, Paul J. and Rissman, Emilie F. and Park, Jin Ho}, year={2016}, month={Apr}, pages={132–138} }
 @article{rissman_2016, title={The Endocrine Society Centennial: No Longer a Surprise: Estrogenic Chemicals in a Multitude of Places}, volume={157}, ISSN={["1945-7170"]}, DOI={10.1210/en.2016-1445}, abstractNote={Nowadays, we are bombarded with information on a large number of endocrine-disrupting chemicals. We hear and read about endocrine-disrupting chemicals on blogs, the web, news stories, television specials, advertisements, and of course scientific articles. Reports claim these ubiquitous compounds are responsible for increased rates of cancer, autism, obesity, hypospadias, and infertility, just to name a few. But it was not always this way. In fact, the scientific study of endocrine-disrupting chemicals is relatively new: a recent PubMed search found a total of 6184 hits for the term, 739 articles in 2015 as compared with 4, 20 years ago in 1995.}, number={8}, journal={ENDOCRINOLOGY}, author={Rissman, Emilie F.}, year={2016}, month={Aug}, pages={2969–2971} }
 @article{quinnies_cox_rissman_2015, title={Immune Deficiency Influences Juvenile Social Behavior and Maternal Behavior}, volume={129}, ISSN={["1939-0084"]}, DOI={10.1037/bne0000053}, abstractNote={Mice with severe combined immunodeficiency (SCID) lack functional T and B lymphocytes, and have impaired cognitive abilities. We assessed social behaviors in male SCID and C57BL/6 (B6) juvenile mice. In a social preference task, SCID mice spent more time than B6 mice investigating a novel adult male mouse. In a social recognition task, SCID mice habituated to a novel ovariectomized mouse, but failed to show dishabituation when presented with an unfamiliar individual. We hypothesized that partial immune restoration could normalize behaviors. SCID pups (postnatal Day 7) received either saline or splenocytes from normal donors. Splenocyte-replaced SCID mice spent less time interacting with a novel mouse than saline-injected SCID or B6 control mice. Again, control SCID mice failed to dishabituate to a novel mouse, but splenocyte-replaced SCID mice showed dishabituation. In both of these studies, B6 and SCID pairs were used to produce offspring that remained with their dams until weaning. There are no studies of maternal behavior in SCID dams; therefore to investigate the potential role for this factor, we quantified maternal behavior in SCID and B6 dams; several significant differences were found. To control for differences in maternal care, we mated heterozygous SCIDs to produce offspring. These homozygous SCID and wild-type offspring reared by dams of the same genotypes displayed similar responses to a novel mouse; however, in the social recognition task, SCID males did not display dishabituation to a novel mouse. Taken together, our data indicate that Gene × Environment interactions influence social interactions in immune deficient mice.}, number={3}, journal={BEHAVIORAL NEUROSCIENCE}, author={Quinnies, Kayla M. and Cox, Kimberly H. and Rissman, Emilie F.}, year={2015}, month={Jun}, pages={331–338} }
 @article{quinnies_bonthuis_harris_shetty_rissman_2015, title={Neural growth hormone: regional regulation by estradiol and/or sex chromosome complement in male and female mice}, volume={6}, ISSN={["2042-6410"]}, DOI={10.1186/s13293-015-0026-x}, abstractNote={Sex differences in pituitary growth hormone (GH) are well documented and coordinate maturation and growth. GH and its receptor are also produced in the brain where they may impact cognitive function and synaptic plasticity, and estradiol produces Gh sex differences in rat hippocampus. In mice, circulating estradiol increases Gh mRNA in female but not in male medial preoptic area (mPOA); therefore, additional factors regulate sexually dimorphic Gh expression in the brain. Thus, we hypothesized that sex chromosomes interact with estradiol to promote sex differences in GH. Here, we assessed the contributions of both estradiol and sex chromosome complement on Gh mRNA levels in three large brain regions: the hippocampus, hypothalamus, and cerebellum.We used the four core genotypes (FCG) mice, which uncouple effects of sex chromosomes and gonadal sex. The FCG model has a deletion of the sex-determining region on the Y chromosome (Sry) and transgenic insertion of Sry on an autosome. Adult FCG mice were gonadectomized and given either a blank Silastic implant or an implant containing 17β-estradiol. Significant differences in GH protein and mRNA were attributed to estradiol replacement, gonadal sex, sex chromosome complement, and their interactions, which were assessed by ANOVA and planned comparisons.Estradiol increased Gh mRNA in the cerebellum and hippocampus, regardless of sex chromosome complement or gonadal sex. In contrast, in the hypothalamus, females had higher Gh mRNA than males, and XY females had more Gh mRNA than XY males and XX females. This same pattern was observed for GH protein. Because the differences in Gh mRNA in the hypothalamus did not replicate prior studies using other mouse models and tissue from mPOA or arcuate nucleus, we examined GH protein in the arcuate, a subdivision of the hypothalamus. Like the previous reports, and in contrast to the entire hypothalamus, a sex chromosome complement effect showed that XX mice had more GH than XY in the arcuate.Sex chromosome complement regulates GH in some but not all brain areas, and within the hypothalamus, sex chromosomes have cell-specific actions on GH. Thus, sex chromosome complement and estradiol both contribute to GH sex differences in the brain.}, journal={BIOLOGY OF SEX DIFFERENCES}, author={Quinnies, Kayla M. and Bonthuis, Paul J. and Harris, Erin P. and Shetty, Savera R. J. and Rissman, Emilie F.}, year={2015}, month={Apr} }
 @article{cox_quinnies_eschendroeder_didrick_eugster_rissman_2015, title={Number of X-chromosome genes influences social behavior and vasopressin gene expression in mice}, volume={51}, ISSN={0306-4530}, url={http://dx.doi.org/10.1016/J.PSYNEUEN.2014.10.010}, DOI={10.1016/J.PSYNEUEN.2014.10.010}, abstractNote={Sex differences in behavior are widespread and often caused by hormonal differences between the sexes. In addition to hormones, the composition and numbers of the sex chromosomes also affect a variety of sex differences. In humans, X-chromosome genes are implicated in neurobehavioral disorders (i.e. fragile-X, autism). To investigate the role of X-chromosome genes in social behavior, we used a mouse model that has atypical sex chromosome configurations resembling Turner (45, XO) and Klinefelter syndromes (47, XXY). We examined a number of behaviors in juvenile mice. Mice with only one copy of most X-chromosome genes, regardless of gonadal sex, were less social in dyadic interaction and social preference tasks. In the elevated plus maze, mice with one X-chromosome spent less time in the distal ends of the open arms as compared to mice with two copies of X-chromosome genes. Using qRTPCR, we noted that amygdala from female mice with one X-chromosome had higher expression levels of vasopressin (Avp) as compared to mice in the other groups. Finally, in plasma from girls with Turner syndrome we detected reduced vasopressin (AVP) concentrations as compared to control patients. These novel findings link sex chromosome genes with social behavior via concentrations of AVP in brain, adding to our understanding of sex differences in neurobehavioral disorders.}, journal={Psychoneuroendocrinology}, publisher={Elsevier BV}, author={Cox, Kimberly H. and Quinnies, Kayla M. and Eschendroeder, Alex and Didrick, Paula M. and Eugster, Erica A. and Rissman, Emilie F.}, year={2015}, month={Jan}, pages={271–281} }
 @article{lu_su_zhao_johnston_sherman_rissman_lau_ailawadi_upchurch_2014, title={Dietary phytoestrogens inhibit experimental aneurysm formation in male mice}, volume={188}, ISSN={0022-4804}, url={http://dx.doi.org/10.1016/J.JSS.2013.11.1108}, DOI={10.1016/J.JSS.2013.11.1108}, abstractNote={The purpose of these experiments was to test the hypothesis that dietary phytoestrogens would diminish experimental aortic aneurysm formation.Six-wk-old C57BL/6 mice were divided into groups, fed either a diet with minimal phytoestrogen content or a regular commercial rodent diet with high phytoestrogen content for 2 wk. At the age of 8 wk, aortic aneurysms were induced by infusing the isolated infrarenal abdominal aorta with 0.4% elastase for 5 min. Mice were recovered and the diameter of the infused aorta was measured at postoperative days 3, 7, and 14. Abdominal aorta samples were collected for histology, cytokine array, and gelatin zymography after aortic diameter measurement. Blood samples were also collected to determine serum phytoestrogens and estradiol levels. Multiple-group comparisons were done using an analysis of variance with post hoc Tukey tests.Compared with mice on a minimal phytoestrogen diet, mice on a regular rodent diet had higher levels of serum phytoestrogens (male, 1138 ± 846 ng/dL; female, 310 ± 295 ng/dL). These serum phytoestrogen levels were also much higher than their own endogenous estradiol levels (109-fold higher for males and 35.5-fold higher for females). Although aortic diameters of female mice were unaffected by the phytoestrogen concentration in the diets, male mice on the regular rodent diet (M+ group) developed smaller aortic aneurysms than male mice on the minimal phytoestrogen diet (M- group) on postoperative day 14 (M+ 54.8 ± 8.8% versus M- 109.3 ± 37.6%; P < 0.001). During aneurysm development (postoperative days 3 and 7), there were fewer neutrophils, macrophages, and lymphocytes in the aorta from the M+ group than from the M- group. Concentrations of multiple proinflammatory cytokines (matrix metalloproteinases [MMPs]; interleukin 1β [IL-1β]; IL-6; IL-17; IL-23; monocyte chemoattractant protein-1; regulated on activation, normal T cell expressed and secreted; interferon γ; and tumor necrosis factor α) from aortas of the M+ group were also lower than those from the aortas of the M- group. Zymography also demonstrated that the M+ group had lower levels of aortic MMP-9s than the M- group on postoperative day 14 (P < 0.001 for pro-MMP-9, P < 0.001 for active MMP-9).These results suggest that dietary phytoestrogens inhibit experimental aortic aneurysm formation in male mice via a reduction of the inflammatory response in the aorta wall. The protective effect of dietary phytoestrogens on aneurysm formation warrants further investigation.}, number={1}, journal={Journal of Surgical Research}, publisher={Elsevier BV}, author={Lu, Guanyi and Su, Gang and Zhao, Yunge and Johnston, William F. and Sherman, Nicholas E. and Rissman, Emilie F. and Lau, Christine and Ailawadi, Gorav and Upchurch, Gilbert R., Jr.}, year={2014}, month={May}, pages={326–338} }
 @article{goodman_garg_reuter_mattioli_rissman_pizarro_2014, title={Loss of estrogen-mediated immunoprotection underlies female gender bias in experimental Crohn’s-like ileitis}, volume={7}, ISSN={1933-0219 1935-3456}, url={http://dx.doi.org/10.1038/MI.2014.15}, DOI={10.1038/MI.2014.15}, abstractNote={The incidence and severity of Crohn's disease (CD) are increased in female patients. Using SAMP1/YitFc (SAMP) mice, a spontaneous model of chronic intestinal inflammation that displays histologic and pathogenic similarities to human CD, we investigated the potential mechanism(s) contributing to sex differences observed in CD. Similar to gender differences observed in CD patients, SAMP female (SAMP-F) mice displayed an earlier onset and more severe ileitis compared with SAMP male (SAMP-M) mice. Furthermore, T-regulatory cells (Tregs) from gut-associated lymphoid tissue (GALT) of SAMP-F mice were reduced in frequency and impaired in their in vitro and in vivo suppressive functions compared with that of SAMP-M mice. Given the interaction between sex hormones and Treg function, we investigated the possible role of estrogen (E2) in SAMP ileitis. SAMP-M mice responded to exogenous E2 administration by expanding Treg frequency and reducing ileal inflammation, whereas SAMP-F mice were resistant. Conventional T cells and Tregs responded differentially to estrogen signaling, leading to distinct immunoprotective effects mediated by distinct estrogen receptor (ER) isoforms. These mechanisms were impaired in T cells from SAMP-F mice. Thus, hormone signaling influences the expansion and function of GALT Tregs in an ER-dependent manner and contributes to gender-based differences in experimental CD.}, number={5}, journal={Mucosal Immunology}, publisher={Springer Science and Business Media LLC}, author={Goodman, W A and Garg, R R and Reuter, B K and Mattioli, B and Rissman, E F and Pizarro, T T}, year={2014}, month={Mar}, pages={1255–1265} }
 @article{cox_bonthuis_rissman_2014, title={Mouse model systems to study sex chromosome genes and behavior: Relevance to humans}, volume={35}, ISSN={0091-3022}, url={http://dx.doi.org/10.1016/J.YFRNE.2013.12.004}, DOI={10.1016/J.YFRNE.2013.12.004}, abstractNote={Sex chromosome genes directly influence sex differences in behavior. The discovery of the Sry gene on the Y chromosome (Gubbay et al., 1990; Koopman et al., 1990) substantiated the sex chromosome mechanistic link to sex differences. Moreover, the pronounced connection between X chromosome gene mutations and mental illness produces a strong sex bias in these diseases. Yet, the dominant explanation for sex differences continues to be the gonadal hormones. Here we review progress made on behavioral differences in mouse models that uncouple sex chromosome complement from gonadal sex. We conclude that many social and cognitive behaviors are modified by sex chromosome complement, and discuss the implications for human research. Future directions need to include identification of the genes involved and interactions with these genes and gonadal hormones.}, number={4}, journal={Frontiers in Neuroendocrinology}, publisher={Elsevier BV}, author={Cox, Kimberly H. and Bonthuis, Paul J. and Rissman, Emilie F.}, year={2014}, month={Oct}, pages={405–419} }
 @article{gore_balthazart_bikle_carpenter_crews_czernichow_diamanti-kandarakis_dores_grattan_hof_et al._2014, title={Reprint of: Policy decisions on endocrine disruptors should be based on science across disciplines: A response to Dietrich et al.}, volume={65}, ISSN={0018-506X}, url={http://dx.doi.org/10.1016/J.YHBEH.2013.09.001}, DOI={10.1016/J.YHBEH.2013.09.001}, abstractNote={This article is part of a Special Issue “Energy Balance”.The prevalence of adult obesity has risen markedly in the last quarter of the 20th century and has not been reversed in this century. Less well known is the fact that obesity prevalence has risen in domestic, laboratory, and feral animals, suggesting that all of these species have been exposed to obesogenic factors present in the environment. This review emphasizes interactions among three biological processes known to influence energy balance: Sexual differentiation, endocrine disruption, and maternal programming. Sexual dimorphisms include differences between males and females in body weight, adiposity, adipose tissue distribution, ingestive behavior, and the underlying neural circuits. These sexual dimorphisms are controlled by sex chromosomes, hormones that masculinize or feminize adult body weight during perinatal development, and hormones that act during later periods of development, such as puberty. Endocrine disruptors are natural and synthetic molecules that attenuate or block normal hormonal action during these same developmental periods. A growing body of research documents effects of endocrine disruptors on the differentiation of adipocytes and the central nervous system circuits that control food intake, energy expenditure, and adipose tissue storage. In parallel, interest has grown in epigenetic influences, including maternal programming, the process by which the mother's experience has permanent effects on energy-balancing traits in the offspring. This review highlights the points at which maternal programming, sexual differentiation, and endocrine disruption might dovetail to influence global changes in energy balancing traits.}, number={2}, journal={Hormones and Behavior}, publisher={Elsevier BV}, author={Gore, A.C. and Balthazart, J. and Bikle, D. and Carpenter, D.O. and Crews, D. and Czernichow, P. and Diamanti-Kandarakis, E. and Dores, R.M. and Grattan, D. and Hof, P.R. and et al.}, year={2014}, month={Feb}, pages={190–193} }
 @article{gore_balthazart_bikle_carpenter_crews_czernichow_diamanti-kandarakis_dores_grattan_hof_et al._2014, title={Reprint of: Policy decisions on endocrine disruptors should be based on science across disciplines: A response to Dietrich, et al.}, volume={35}, ISSN={0091-3022}, url={http://dx.doi.org/10.1016/J.YFRNE.2013.09.003}, DOI={10.1016/J.YFRNE.2013.09.003}, number={1}, journal={Frontiers in Neuroendocrinology}, publisher={Elsevier BV}, author={Gore, A.C. and Balthazart, J. and Bikle, D. and Carpenter, D.O. and Crews, D. and Czernichow, P. and Diamanti-Kandarakis, E. and Dores, R.M. and Grattan, D. and Hof, P.R. and et al.}, year={2014}, month={Jan}, pages={2–5} }
 @article{johnston_su_salmon_lu_rissman_ailawadi_upchurch_2013, title={Aromatase Deletion Accelerates Female Experimental Abdominal Aortic Aneurysm Formation}, volume={58}, ISSN={0741-5214}, url={http://dx.doi.org/10.1016/J.JVS.2013.07.042}, DOI={10.1016/J.JVS.2013.07.042}, abstractNote={The protective effects of female sex on the development of abdominal aortic aneurysms (AAAs) have been attributed to the anti-inflammatory effects of estrogen. All estrogen synthesis depends on the enzyme aromatase, which is located centrally in the ovaries, as well as peripherally in adipose tissue, bone, and vascular smooth muscle cells. We hypothesized that aromatase genetic deletion would diminish the protective effect of female sex and would be associated with increased aortic diameter in female mice. Female 8- to 10-week-old mice with aromatase (wild type: WT) and without aromatase (ArKO) underwent elastase aortic perfusion. WT male mice underwent elastase perfusion as a positive control. To evaluate the contribution of peripheral estrogen conversion, female WT and ArKO mice that had undergone ovariectomy (ovx) at 6 weeks were perfused with elastase. Thus, four groups of female mice were compared: WT, ArKO, WT ovx, and ArKO ovx. At aortic harvest, maximal aortic dilations, aortic inflammatory cytokines, and serum estradiol concentrations were compared with analysis of variance. Female WT mice had significant reduction in aortic dilation compared with male WT mice (F WT: 51.15.9% vs M WT: 79.3 1.6%; P < .005). The protective effects of female sex were mostly overcome with ovariectomy (WT ovx: 70.64.1%; P < .05 vs F WT) and completely eliminated with deletion of aromatase (ArKO: 78.57.8%; P < .05 vs F WT). Peripheral estrogen conversion accounted for 30% of the protective effect of female sex. Female mice with both aromatase deletion and ovariectomy had the largest aortic dilation (87.35.6%; P < .001 vs F WT and P < .05 vs WT ovx). Concordantly, female ArKO ovx mice had significantly higher levels of proinflammatory cytokines Monocyte chemotactic protein-1 and interleukin-1. As expected, deletion of aromatase or ovariectomy was associated with decreased serum estradiol levels with a direct correlation between decreasing estradiol levels and increasing aortic dilation (R = −0.465; P < .05). The protective effects of estrogen on AAAs can be divided into central and peripheral estrogen effects depending on the site of estrogen synthesis. Central estrogen synthesis from the ovaries accounted for the majority of the protective effects of estrogen, while peripheral estrogen conversion accounted for only one-third of the effect. These findings may explain the increased incidence of AAAs in postmenopausal women lacking central estrogen synthesis.}, number={4}, journal={Journal of Vascular Surgery}, publisher={Elsevier BV}, author={Johnston, William Forrest and Su, Gang and Salmon, Morgan and Lu, Guanyi and Rissman, Emilie F. and Ailawadi, Gorav and Upchurch, Gilbert Rivers, Jr.}, year={2013}, month={Oct}, pages={1146–1147} }
 @article{wolstenholme_goldsby_rissman_2013, title={Transgenerational effects of prenatal bisphenol A on social recognition}, volume={64}, ISSN={0018-506X}, url={http://dx.doi.org/10.1016/J.YHBEH.2013.09.007}, DOI={10.1016/J.YHBEH.2013.09.007}, abstractNote={Bisphenol A (BPA) is a man-made endocrine disrupting compound used to manufacture polycarbonate plastics. It is found in plastic bottles, canned food linings, thermal receipts and other commonly used items. Over 93% of people have detectable BPA levels in their urine. Epidemiological studies report correlations between BPA levels during pregnancy and activity, anxiety, and depression in children. We fed female mice control or BPA-containing diets that produced plasma BPA concentrations similar to concentrations in humans. Females were mated and at birth, pups were fostered to control dams to limit BPA exposure to gestation in the first generation. Sibling pairs were bred to the third generation with no further BPA exposure. First (F1) and third (F3) generation juveniles were tested for social recognition and in the open field. Adult F3 mice were tested for olfactory discrimination. In both generations, BPA exposed juvenile mice displayed higher levels of investigation than controls in a social recognition task. In F3 BPA exposed mice, dishabituation to a novel female was impaired. In the open field, no differences were noted in F1 mice, while in F3, BPA lineage mice were more active than controls. No impairments were detected in F3 mice, all were able to discriminate different male urine pools and urine from water. No sex differences were found in any task. These results demonstrate that BPA exposure during gestation has long lasting, transgenerational effects on social recognition and activity in mice. These findings show that BPA exposure has transgenerational actions on behavior and have implications for human neurodevelopmental behavioral disorders.}, number={5}, journal={Hormones and Behavior}, publisher={Elsevier BV}, author={Wolstenholme, Jennifer T. and Goldsby, Jessica A. and Rissman, Emilie F.}, year={2013}, month={Nov}, pages={833–839} }
 @article{stolzenberg_stevens_rissman_2012, title={Experience-facilitated improvements in pup retrieval; evidence for an epigenetic effect}, volume={62}, ISSN={0018-506X}, url={http://dx.doi.org/10.1016/j.yhbeh.2012.05.012}, DOI={10.1016/j.yhbeh.2012.05.012}, abstractNote={The quality and quantity of maternal care received during infancy are highly predictive of successful infant development. It has been well established, primarily in rats, that the combination of hormonal and infant stimuli at birth modifies neural circuits that regulate maternal responsiveness. During subsequent interactions, infant stimuli are more likely to elicit rapid maternal responsiveness. Some species, such as humans, can display maternal care in the absence of the endocrine events of pregnancy and birth. Similarly, virgin C57BL/6J female mice, display maternal care toward infants, and experience with infants elicits long-lasting increases in maternal care. We hypothesized that these experience-induced changes in behavior may be mediated by chromatin modifications, which in turn change expression of genes that promote maternal care. One site of action is the medial preoptic area (MPOA). To test our hypothesis we treated virgin female mice with sodium butyrate, a histone deacetylase inhibitor. This treatment potentiated maternal responsiveness as well as the expression of several genes: estrogen receptor β (Esr2), oxytocin (Oxt), and cyclicAMP response element binding protein (CREB) binding protein (Crebbp; a histone acetyltransferase) in the MPOA. These data suggest that experience induces high levels of maternal care via epigenetic modifications.}, number={2}, journal={Hormones and Behavior}, publisher={Elsevier BV}, author={Stolzenberg, Danielle S. and Stevens, Jacqueline S. and Rissman, Emilie F.}, year={2012}, month={Jul}, pages={128–135} }
 @article{abel_rissman_2012, title={Location, location, location: Genetic regulation of neural sex differences}, volume={13}, ISSN={1389-9155 1573-2606}, url={http://dx.doi.org/10.1007/S11154-011-9186-0}, DOI={10.1007/S11154-011-9186-0}, abstractNote={Sex differences in many behaviors such as cognition, mood, and motor skills are well-documented in animals and humans and are regulated by many neural circuits. Sexual dimorphisms within cell populations in these circuits play critical roles in the production of these behavioral dichotomies. Here we focus on three proteins that have well described sexual dimorphisms; calbindin-D28k, a calcium binding protein, tyrosine hydroxylase, the rate limiting enzyme involved in dopamine synthesis and vasopressin, a neuropeptide with central and peripheral sites of action. We describe the sex differences in subpopulations of these proteins, with particular emphasis on laboratory mice. Our thrust is to examine genetic bases of sex differences and how the use of genetically modified models has advanced our understanding of this topic. Regional sex differences in the expression of these three proteins are driven by sex chromosome complement, steroid receptors or in some instances both. While studies of sex differences attributable to sex chromosome genes are still few in number it is exciting to note that this variable factors into expression differences for all three of these proteins. Different genetic mechanisms, which elaborate sex differences, may be employed stochastically in different cell populations. Alternately, general patterns involving the timing of differentiation of the sex differences, relative to the "critical period" in hormonal differences between males and female neonates may emerge. In conclusion, future directions in this area should include examination of the importance of location, timing, steroidal receptor/sex chromosome gene synergy and epigenetics in molding neural sex differences.}, number={3}, journal={Reviews in Endocrine and Metabolic Disorders}, publisher={Springer Science and Business Media LLC}, author={Abel, Jean LeBeau and Rissman, Emilie F.}, year={2012}, pages={151–161} }
 @article{abel_rissman_2012, title={Running-induced epigenetic and gene expression changes in the adolescent brain}, volume={31}, ISSN={0736-5748 1873-474X}, url={http://dx.doi.org/10.1016/j.ijdevneu.2012.11.002}, DOI={10.1016/j.ijdevneu.2012.11.002}, abstractNote={Abstract Physical exercise is associated with positive neural functioning. Here we examined the gene expression consequences of 1 week of voluntary wheel running in adolescent male mice. We assayed expression levels of genes associated with synaptic plasticity, signaling pathways, and epigenetic modifying enzymes. Two regions were examined: the hippocampus, which is typically examined in exercise studies, and the cerebellum, an area directly involved in motor control and learning. After 1 week of exercise, global acetylation of histone 3 was increased in both brain regions. Interestingly this was correlated with increased brain derived neural growth factor in the hippocampus, as noted in many other studies, but only a trend was found in cerebellum. Differences and similarities between the two areas were noted for genes encoding functional proteins. In contrast, the expression pattern of DNA methyltransferases ( Dnmts ) and histone deacetylases ( Hdacs ), genes that influence DNA methylation and histone modifications in general, decreased in both regions with exercise. We hypothesize that epigenetic mechanisms, involving many of the genes assessed here, are essential for the positive affects of exercise on behavior and suspect these data have relevance for adolescent boys.}, number={6}, journal={International Journal of Developmental Neuroscience}, publisher={Wiley}, author={Abel, Jean LeBeau and Rissman, Emilie F.}, year={2012}, month={Nov}, pages={382–390} }
 @article{bonthuis_cox_rissman_2012, title={X-chromosome dosage affects male sexual behavior}, volume={61}, ISSN={0018-506X}, url={http://dx.doi.org/10.1016/j.yhbeh.2012.02.003}, DOI={10.1016/j.yhbeh.2012.02.003}, abstractNote={Sex differences in the brain and behavior are primarily attributed to dichotomous androgen exposure between males and females during neonatal development, as well as adult responses to gonadal hormones. Here we tested an alternative hypothesis and asked if sex chromosome complement influences male copulatory behavior, a standard behavior for studies of sexual differentiation. We used two mouse models with non-canonical associations between chromosomal and gonadal sex. In both models, we found evidence for sex chromosome complement as an important factor regulating sex differences in the expression of masculine sexual behavior. Counter intuitively, males with two X-chromosomes were faster to ejaculate and display more ejaculations than males with a single X. Moreover, mice of both sexes with two X-chromosomes displayed increased frequencies of mounts and thrusts. We speculate that expression levels of a yet to be discovered gene(s) on the X-chromosome may affect sexual behavior in mice and perhaps in other mammals.}, number={4}, journal={Hormones and Behavior}, publisher={Elsevier BV}, author={Bonthuis, Paul J. and Cox, Kimberly H. and Rissman, Emilie F.}, year={2012}, month={Apr}, pages={565–572} }
 @article{champagne_rissman_2011, title={Behavioral epigenetics: A new frontier in the study of hormones and behavior}, volume={59}, ISSN={0018-506X}, url={http://dx.doi.org/10.1016/j.yhbeh.2011.02.011}, DOI={10.1016/j.yhbeh.2011.02.011}, number={3}, journal={Hormones and Behavior}, publisher={Elsevier BV}, author={Champagne, Frances A. and Rissman, Emilie F.}, year={2011}, month={Mar}, pages={277–278} }
 @article{mccarver_bhatia_chambers_clarke_etzel_foster_hoyer_leeder_peters_rissman_et al._2011, title={NTP-CERHR expert panel report on the developmental toxicity of soy infant formula}, volume={92}, ISSN={1542-9733}, url={http://dx.doi.org/10.1002/bdrb.20314}, DOI={10.1002/bdrb.20314}, abstractNote={Soy infant formula contains soy protein isolates and is fed to infants as a supplement to or replacement for human milk or cow milk. Soy protein isolates contains estrogenic isoflavones (phytoestrogens) that occur naturally in some legumes, especially soybeans. Phytoestrogens are nonsteroidal, estrogenic compounds. In plants, nearly all phytoestrogens are bound to sugar molecules and these phytoestrogen-sugar complexes are not generally considered hormonally active. Phytoestrogens are found in many food products in addition to soy infant formula, especially soy-based foods such as tofu, soy milk, and in some over-the-counter dietary supplements. Soy infant formula was selected for National Toxicology Program (NTP) evaluation because of (1) the availability of large number of developmental toxicity studies in laboratory animals exposed to the isoflavones found in soy infant formula (namely, genistein) or other soy products, as well as few studies on human infants fed soy infant formula, (2) the availability of information on exposures in infants fed soy infant formula, and (3) public concern for effects on infant or child development. On October 2, 2008 (73 FR 57360), the NTP Center for the Evaluation of Risks to Human Reproduction (CERHR) announced its intention to conduct an updated review of soy infant formula to complete a previous evaluation that was initiated in 2005. Both the current and previous evaluations relied on expert panels to assist the NTP in developing its conclusions on the potential developmental effects associated with the use of soy infant formula, presented in the NTP Brief on Soy Infant Formula. The initial expert panel met on March 15 to 17, 2006, to reach conclusions on the potential developmental and reproductive toxicities of soy infant formula and its predominant isoflavone constituent genistein. The expert panel reports were released for public comment on May 5, 2006 (71 FR 28368). On November 8, 2006 (71 FR 65537), CERHR staff released draft NTP Briefs on Genistein and Soy Formula that provided the NTP's interpretation of the potential for genistein and soy infant formula to cause adverse reproductive and/or developmental effects in exposed humans. However, CERHR did not complete these evaluations, finalize the briefs, or issue NTP Monographs on these substances based on this initial evaluation. Between 2006 and 2009, a substantial number of new publications related to human exposure or reproductive and/or developmental toxicity were published for these substances. Thus, CERHR determined that updated evaluations of genistein and soy infant formula were needed. However, the current evaluation focuses only on soy infant formula and the potential developmental toxicity of its major isoflavone components, e.g. genistein, daidzein (and estrogenic metabolite, equol), and glycitein. This updated evaluation does not include an assessment on the potential reproductive toxicity of genistein following exposures during adulthood as was carried out in the 2006 evaluation. CERHR narrowed the scope of the evaluation because the assessment of reproductive effects of genistein following exposure to adults was not considered relevant to the consideration of soy infant formula use in infants during the 2006 evaluation. To obtain updated information about soy infant formula for the CERHR evaluation, the PubMed (Medline) database was searched from February 2006 to August 2009 with genistein/genistin, daidzein/daidzin, glycitein/glycitin, equol, soy, and other relevant keywords. References were also identified from the bibliographies of published literature. The updated expert panel report represents the efforts of a 14-member panel of government and nongovernment scientists, and was prepared with assistance from NTP staff. The finalized report, released on January 15, 2010 (75 FR 2545), reflects consideration of public comments received on a draft report that was released on October 19, 2009, for public comment and discussions that occurred at a public meeting of the expert panel held December 16 to 18, 2009 (74 FR 53509). The finalized report presents conclusions on (1) the strength of scientific evidence that soy infant formula or its isoflavone constituents are developmental toxicants based on data from in vitro, animal, or human studies; (2) the extent of exposures in infants fed soy infant formula; (3) the assessment of the scientific evidence that adverse developmental health effects may be associated with such exposures; and (4) knowledge gaps that will help establish research and testing priorities to reduce uncertainties and increase confidence in future evaluations. The Expert Panel expressed minimal concern for adverse developmental effects in infants fed soy infant formula. This level of concern represents a "2" on the five-level scale of concern used by the NTP that ranges from negligible concern ("1") to serious concern ("5"). The Expert Panel Report on Soy Infant Formula was considered extensively by NTP staff in preparing the 2010 NTP Brief on Soy Infant Formula, which represents the NTP's opinion on the potential for exposure to soy infant formula to cause adverse developmental effects in humans. The NTP concurred with the expert panel that there is minimal concern for adverse effects on development in infants who consume soy infant formula. This conclusion was based on information about soy infant formula provided in the expert panel report, public comments received during the course of the expert panel evaluation, additional scientific information made available since the expert panel meeting, and peer reviewer critiques of the draft NTP Brief by the NTP Board of Scientific Counselors (BSC) on May 10, 2010 (Meeting materials are available at http://ntp.niehs.nih.gov/go/9741.). The BSC voted in favor of the minimal concern conclusion with 7 yes votes, 3 no votes, and 0 abstentions. One member thought that the conclusion should be negligible concern and two members thought that the level of concern should be higher than minimal concern. The NTP's response to the May 10, 2010 review ("peer-review report") is available on the NTP website at http://ntp.niehs.nih.gov/go/9741. The monograph includes the NTP Brief on Soy Infant Formula as well as the entire final Expert Panel Report on Soy Infant Formula. Public comments received as part of the NTP's evaluation of soy infant formula and other background materials are available at http://cerhr.niehs.nih.gov/evals/index.html.}, number={5}, journal={Birth Defects Research Part B: Developmental and Reproductive Toxicology}, publisher={Wiley}, author={McCarver, Gail and Bhatia, Jatinder and Chambers, Christina and Clarke, Robert and Etzel, Ruth and Foster, Warren and Hoyer, Patricia and Leeder, J. Steven and Peters, Jeffrey M. and Rissman, Emilie and et al.}, year={2011}, month={Sep}, pages={421–468} }
 @article{wolstenholme_rissman_connelly_2011, title={The role of Bisphenol A in shaping the brain, epigenome and behavior}, volume={59}, ISSN={0018-506X}, url={http://dx.doi.org/10.1016/j.yhbeh.2010.10.001}, DOI={10.1016/j.yhbeh.2010.10.001}, abstractNote={Bisphenol A (BPA) is a xenoestrogen that was first synthesized in 1891. Its estrogenic properties were discovered in 1930, and shortly after that chemists identified its usefulness in the production of epoxy resins. Since the 1950s BPA has been used as a synthetic monomer in the manufacturing of polycarbonate plastic, polystyrene resins, and dental sealants. Roughly 6.5 billion pounds of BPA are produced each year and it is the major estrogenic compound that leaches into nearby water and food supplies (vom Saal et al., 2007). BPA has been detected in 95% of human urine samples, which indicates that environmental exposure is widespread (Calafat et al., 2005). Moreover, BPA affects reproductive tissues and the brain. Thus many studies have focused on the effects of BPA during embryonic development. The most recent FDA update (Administration January 2010) points to "some concern about the potential effects of Bisphenol A on the brain, behavior, and prostate gland in fetuses, infants, and young children." In light of this concern, we present an updated review of BPA's action on the brain and behavior. We begin with a discussion of BPA's role as both an endocrine active compound and an agent that alters DNA methylation. Next, we review publications that have reported effects of BPA on brain and behavior. We end with our interpretation of these data and suggestions for future research directions.}, number={3}, journal={Hormones and Behavior}, publisher={Elsevier BV}, author={Wolstenholme, Jennifer T. and Rissman, Emilie F. and Connelly, Jessica J.}, year={2011}, month={Mar}, pages={296–305} }
 @article{kauffman_bojkowska_rissman_2010, title={Critical periods of susceptibility to short-term energy challenge during pregnancy: Impact on fertility and offspring development}, volume={99}, ISSN={0031-9384}, url={http://dx.doi.org/10.1016/j.physbeh.2009.10.017}, DOI={10.1016/j.physbeh.2009.10.017}, abstractNote={In female mammals, reproduction is tightly regulated by energy status and food availability. Although acute energetic challenges inhibit female reproductive behavior and gonadotropin secretion, less attention has been given to the effects of short-term energetic challenge on pregnancy and gestation. Furthermore, species differences in pregnancy physiology necessitate more detailed analyses of specific pregnancy models. Here, we studied musk shrews, which display induced ovulation and obligate delayed implantation, and whose reproductive physiology is tightly linked to metabolic status. We tested whether acute energetic challenges of varied degrees given at specific pregnancy stages (including before and after delayed implantation) have different effects on gestational outcome and offspring postnatal development. We found that 48 h of either 40% or 50% food restriction, which reduced body weight and strongly inhibited sexual behavior, had minimal effects on pregnancy success and litter dynamics when administered early in gestation (pre-implantation). However, < 30% of females experiencing short-term food restriction later in gestation successfully gave birth (versus ≥ 70% of ad-libitum fed controls), and the pups of these food-restricted females exhibited a 30% slower postnatal growth trajectory. Interestingly, although pregnancy success and litter dynamics were unaffected by food restriction before implantation, gestation length was increased by metabolic challenges experienced at this time, indicating that energy status may regulate the timing of implantation. We conclude that 1) there are critical periods of pregnancy, particularly after implantation, when short-term, mild energetic challenges have significant impacts on fertility and offspring postnatal development, and 2) delayed implantation may have evolved, in part, as a buffering mechanism to prevent pregnancy failure during impaired energy balance in early gestation.}, number={1}, journal={Physiology & Behavior}, publisher={Elsevier BV}, author={Kauffman, Alexander S. and Bojkowska, Karolina and Rissman, Emilie F.}, year={2010}, month={Jan}, pages={100–108} }
 @article{cox_gatewood_howeth_rissman_2010, title={Gestational exposure to bisphenol A and cross-fostering affect behaviors in juvenile mice}, volume={58}, ISSN={0018-506X}, url={http://dx.doi.org/10.1016/j.yhbeh.2010.07.008}, DOI={10.1016/j.yhbeh.2010.07.008}, abstractNote={Bisphenol-A (BPA) is a component of polycarbonate resins, and, lately, concern has been raised about its potential negative effects on human health. BPA is an estrogen analog and, in addition, it can act as a DNA hypomethylator. We examined the effects of gestational exposure to BPA on several behaviors in C57BL/6J mice. Because BPA affects maternal care, which, may have long-lasting effects on offspring behavior, we tested mice raised by either biological or fostered dams. Both diet and dam affected behavior in juvenile mice in a social novelty task and the elevated plus maze (EPM). In a social novelty task, the amount of time spent interacting with an adult male was affected by sex and gestational diet, but only in juveniles raised by a foster dam. Control females spent less time sniffing a novel adult than did control males or females exposed to BPA during gestation. In the EPM, juveniles reared by foster dams and exposed to BPA during gestation spent less time in the distal half of the open arm as compared with juveniles gestated on a control diet. Adult offspring raised by their biological dams showed the same response pattern; gestational BPA increased anxiety as compared with control diet. Our results show that prenatal BPA exposure affects social behavior and anxiety in the EPM. Moreover, some facet(s) of the infant-maternal interaction may modify these effects.}, number={5}, journal={Hormones and Behavior}, publisher={Elsevier BV}, author={Cox, Kimberly H. and Gatewood, Jessica D. and Howeth, Chelsea and Rissman, Emilie F.}, year={2010}, month={Nov}, pages={754–761} }
 @article{bonthuis_cox_searcy_kumar_tobet_rissman_2010, title={Of mice and rats: Key species variations in the sexual differentiation of brain and behavior}, volume={31}, ISSN={0091-3022}, url={http://dx.doi.org/10.1016/j.yfrne.2010.05.001}, DOI={10.1016/j.yfrne.2010.05.001}, abstractNote={Mice and rats are important mammalian models in biomedical research. In contrast to other biomedical fields, work on sexual differentiation of brain and behavior has traditionally utilized comparative animal models. As mice are gaining in popularity, it is essential to acknowledge the differences between these two rodents. Here we review neural and behavioral sexual dimorphisms in rats and mice, which highlight species differences and experimental gaps in the literature, that are needed for direct species comparisons. Moving forward, investigators must answer fundamental questions about their chosen organism, and attend to both species and strain differences as they select the optimal animal models for their research questions.}, number={3}, journal={Frontiers in Neuroendocrinology}, publisher={Elsevier BV}, author={Bonthuis, P.J. and Cox, K.H. and Searcy, B.T. and Kumar, P. and Tobet, S. and Rissman, E.F.}, year={2010}, month={Jul}, pages={341–358} }
 @article{park_bonthuis_ding_rais_rissman_2009, title={Androgen- and estrogen-independent regulation of copulatory behavior following castration in male B6D2F1 mice}, volume={56}, ISSN={0018-506X}, url={http://dx.doi.org/10.1016/j.yhbeh.2009.05.007}, DOI={10.1016/j.yhbeh.2009.05.007}, abstractNote={Male reproductive behavior is highly dependent upon gonadal steroids. However, between individuals and across species, the role of gonadal steroids in male reproductive behavior is highly variable. In male B6D2F1 hybrid mice, a large proportion (about 30%) of animals demonstrate the persistence of the ejaculatory reflex long after castration. This provides a model to investigate the basis of gonadal steroid-independent male sexual behavior. Here we assessed whether non-gonadal steroids promote mating behavior in castrated mice. Castrated B6D2F1 hybrids that persisted in copulating (persistent copulators) were treated with the androgen receptor blocker, flutamide, and the aromatase enzyme inhibitor, letrozole, for 8 weeks. Other animals were treated with the estrogen receptor blocker, ICI 182,780, via continual intraventricular infusion for 2 weeks. None of these treatments eliminated persistent copulation. A motivational aspect of male sexual behavior, the preference for a receptive female over another male, was also assessed. This preference persisted after long-term castration in persistent copulators, and administration of ICI 182,780 did not influence partner preference. To assess the possibility of elevated sensitivity to sex steroids in brains of persistent copulators, we measured mRNA levels for genes that code for the estrogen receptor-alpha, androgen receptor, and aromatase enzyme in the medial preoptic area and bed nucleus of the stria terminalis. No differences in mRNA of these genes were noted in brains of persistent versus non-persistent copulators. Taken together our results suggest that non-gonadal androgens and estrogens do not maintain copulatory behavior in B6D2F1 mice which display copulatory behavior after castration.}, number={2}, journal={Hormones and Behavior}, publisher={Elsevier BV}, author={Park, Jin Ho and Bonthuis, Paul and Ding, Alice and Rais, Salehin and Rissman, Emilie F.}, year={2009}, month={Aug}, pages={254–263} }
 @article{kudwa_harada_honda_rissman_2009, title={Regulation of progestin receptors in medial amygdala: Estradiol, phytoestrogens and sex}, volume={97}, ISSN={0031-9384}, url={http://dx.doi.org/10.1016/j.physbeh.2009.02.023}, DOI={10.1016/j.physbeh.2009.02.023}, abstractNote={Exposure to estrogens during critical developmental periods and in adulthood affects sex differences in the brain. We examined the roles of estradiol (E2) and phytoestrogens, and their interactions, on potential sex differences in brain. We used aromatase knockout (ArKO) mice, which cannot produce endogenous estrogens, along with wild type (WT) littermates. Mice were gestated, raised and maintained on a diet either rich in phytoestrogens or a diet virtually void of soy-derived phytoestrogens. Adult males and females were gonadectomized and received implants filled with 17-β-estradiol to induce progestin receptors (PR), while controls received empty implants. Mice were sacrificed five days later and brain sections containing the posterodorsal medial amygdala (MePD) were processed for PR immunoreactivity. Activation of sex differences in PR required adult E2 treatment. A diet high in phytoestrogens was required for expression of sex differences in PR after E2 treatment. Our data underscore the important contribution of dietary phytoestrogens for the development of sex differences in PR-ir in the adult mouse medial amygdala. We hypothesize that both aromatization of androgens to estrogens and dietary sources of additional estrogens are part of the normal requirement for sex differences in the rodent brain.}, number={2}, journal={Physiology & Behavior}, publisher={Elsevier BV}, author={Kudwa, A.E. and Harada, N. and Honda, S.-I. and Rissman, E.F.}, year={2009}, month={May}, pages={146–150} }
 @article{grgurevic_büdefeld_rissman_tobet_majdic_2008, title={Aggressive behaviors in adult SF-1 knockout mice that are not exposed to gonadal steroids during development.}, volume={122}, ISSN={1939-0084 0735-7044}, url={http://dx.doi.org/10.1037/0735-7044.122.4.876}, DOI={10.1037/0735-7044.122.4.876}, abstractNote={Sex hormones are a major factor responsible for the development of sex differences. Steroidogenic factor 1 (SF-1) is a key regulator of gonadal and adrenal development, and SF-1 knockout mice (SF-1 KO) are born without gonads and adrenal glands. Consequently, these mice are not exposed to gonadal sex steroids. SF-1 KO pups die shortly after birth due to adrenal deficiency. In the present study, SF-1 KO mice were rescued by neonatal corticosteroid injections followed by adrenal transplantations on day 7-8 postnatally. Control mice received corticosteroid injections and were gonadectomized prior to puberty. Mice were observed interacting with ovariectomized hormone primed females and gonad-intact males. In the absence of sex steroid replacement, adult SF-1 KO mice were significantly more aggressive than control mice in tests with stimulus females. After testosterone treatment, control males displayed significantly more aggression towards male intruders than control female mice, or male and female SF-1 KO mice, suggesting a developmental role of gonadal hormones in the expression of aggressive behavior and affirming SF-1 KO mice as a behavioral model to investigate affects of fetal gonad deficiency.}, number={4}, journal={Behavioral Neuroscience}, publisher={American Psychological Association (APA)}, author={Grgurevic, Neza and Büdefeld, Tomaz and Rissman, Emilie F. and Tobet, Stuart A. and Majdic, Gregor}, year={2008}, pages={876–884} }
 @article{millar_pawson_morgan_rissman_lu_2008, title={Diversity of actions of GnRHs mediated by ligand-induced selective signaling}, volume={29}, ISSN={0091-3022}, url={http://dx.doi.org/10.1016/j.yfrne.2007.06.002}, DOI={10.1016/j.yfrne.2007.06.002}, abstractNote={Geoffrey Wingfield Harris’ demonstration of hypothalamic hormones regulating pituitary function led to their structural identification and therapeutic utilization in a wide spectrum of diseases. Amongst these, Gonadotropin Releasing Hormone (GnRH) and its analogs are widely employed in modulating gonadotropin and sex steroid secretion to treat infertility, precocious puberty and many hormone-dependent diseases including endometriosis, uterine fibroids and prostatic cancer. While these effects are all mediated via modulation of the pituitary gonadotrope GnRH receptor and the Gq signaling pathway, it has become increasingly apparent that GnRH regulates many extrapituitary cells in the nervous system and periphery. This review focuses on two such examples, namely GnRH analog effects on reproductive behaviors and GnRH analog effects on the inhibition of cancer cell growth. For both effects the relative activities of a range of GnRH analogs is distinctly different from their effects on the pituitary gonadotrope and different signaling pathways are utilized. As there is only a single functional GnRH receptor type in man we have proposed that the GnRH receptor can assume different conformations which have different selectivity for GnRH analogs and intracellular signaling proteins complexes. This ligand-induced selective-signaling recruits certain pathways while by-passing others and has implications in developing more selective GnRH analogs for highly specific therapeutic intervention.}, number={1}, journal={Frontiers in Neuroendocrinology}, publisher={Elsevier BV}, author={Millar, Robert P. and Pawson, Adam J. and Morgan, Kevin and Rissman, Emilie F. and Lu, Zhi-Liang}, year={2008}, month={Jan}, pages={17–35} }
 @article{bojkowska_hamczyk_tsai_riggan_rissman_2008, title={Neuropeptide Y influences acute food intake and energy status affects NPY immunoreactivity in the female musk shrew (Suncus murinus)}, volume={53}, ISSN={0018-506X}, url={http://dx.doi.org/10.1016/j.yhbeh.2007.10.013}, DOI={10.1016/j.yhbeh.2007.10.013}, abstractNote={Neuropeptide Y (NPY) stimulates feeding, depresses sexual behavior, and its expression in the brain is modulated by energetic status. We examined the role of NPY in female musk shrews, a species with high energetic and reproductive demands; they store little fat, and small changes in energy can rapidly diminish or enhance sexual receptivity. Intracerebroventricular infusion of NPY enhanced acute food intake in shrews; however, NPY had little affect on sexual receptivity. The distribution of NPY immunoreactivity in the female musk shrew brain was unremarkable, but energy status differentially affected NPY immunoreactivity in several regions. Similar to what has been noted in other species, NPY immunoreactivity was less dense in brains of ad libitum shrews and greater in shrews subjected to food restriction. In two midbrain regions, both of which contain high levels of gonadotropin releasing hormone II (GnRH II), which has anorexigenic actions in shrews, NPY immunoreactivity was more sensitive to changes in food intake. In these regions, acute re-feeding (90-180 min) after food restriction reduced NPY immunoreactivity to levels noted in ad libitum shrews. We hypothesize that interactions between NPY and GnRH II maintain energy homeostasis and reproduction in the musk shrew.}, number={2}, journal={Hormones and Behavior}, publisher={Elsevier BV}, author={Bojkowska, Karolina and Hamczyk, Magdalena M. and Tsai, Houng-Wei and Riggan, Anna and Rissman, Emilie F.}, year={2008}, month={Feb}, pages={342–350} }
 @article{schneider_rissman_2008, title={Regulation of food intake by gonadotropin releasing hormone II in an animal model of binge eating disorder}, volume={51}, ISSN={0195-6663}, url={http://dx.doi.org/10.1016/j.appet.2008.04.215}, DOI={10.1016/j.appet.2008.04.215}, number={2}, journal={Appetite}, publisher={Elsevier BV}, author={Schneider, J.S. and Rissman, E.}, year={2008}, month={Sep}, pages={398} }
 @article{mcphielalmansingh_tejada_weaver_rissman_2008, title={Sex chromosome complement affects social interactions in mice}, volume={54}, ISSN={0018-506X}, url={http://dx.doi.org/10.1016/j.yhbeh.2008.05.016}, DOI={10.1016/j.yhbeh.2008.05.016}, abstractNote={Sex differences in behavior can be attributed to differences in steroid hormones. Sex chromosome complement can also influence behavior, independent of gonadal differentiation. The mice used for this work combined a spontaneous mutation of the Sry gene with a transgene for Sry that is incorporated into an autosome thus disassociating gonad differentiation from sex chromosome complement. The resulting genotypes are XX and XY(-) females (ovary-bearing) along with XXSry and XY(-)Sry males (testes-bearing). Here we report results of basic behavioral phenotyping conducted with these mice. Motor coordination, use of olfactory cues to find a food item, general activity, foot shock threshold, and behavior in an elevated plus maze were not affected by gonadal sex or sex chromosome complement. In a one-way active avoidance learning task females were faster to escape an electric shock than males. In addition, sex chromosome complement differences were noted during social interactions with submissive intruders. Female XY(-) mice were faster to follow an intruder than XX female mice. All XY(-) mice spent more time sniffing and grooming the intruder than the XX mice, with XY(-) females spending the most amount of time in this activity. Finally, XX females were faster to display an asocial behavior, digging, and engaged in more digging than XXSry male mice. All of these behaviors were tested in gonadectomized adults, thus, differences in circulating levels of gonadal steroids cannot account for these effects. Taken together, these data show that sex chromosome complement affects social interaction style in mice.}, number={4}, journal={Hormones and Behavior}, publisher={Elsevier BV}, author={Mcphielalmansingh, A and Tejada, L and Weaver, J and Rissman, E}, year={2008}, month={Sep}, pages={565–570} }
 @article{kudwa_boon_simpson_handa_rissman_2007, title={Dietary phytoestrogens dampen female sexual behavior in mice with a disrupted aromatase enzyme gene.}, volume={121}, ISSN={1939-0084 0735-7044}, url={http://dx.doi.org/10.1037/0735-7044.121.2.356}, DOI={10.1037/0735-7044.121.2.356}, abstractNote={Aromatization of testosterone (T) to estradiol (E2) during perinatal development in male rodents plays a significant role in sexual differentiation of the brain and adult behaviors. Exposure to estrogens during development can enhance masculine behaviors in adult females and reduce expression of female-typical behaviors in adult males. Previous studies have shown that, in addition to naturally occurring estrogens, dietary phytoestrogens can affect sexual differentiation. To distinguish between the effects of endogenous T-derived E2 and exogenous phytoestrogens, the authors used an aromatase knockout (ArKO) mouse that cannot produce E2 but is responsive to E2 via estrogen receptors alpha and beta. Dams and their litters were maintained either on a standard mouse chow that was rich in phytoestrogens or on a chow nearly devoid of phytoestrogens. Mice were maintained on their perinatal diets after weaning. Adults of both sexes were gonadectomized and tested for lordosis behavior. In the ArKO females raised on a diet high in phytoestrogens, lordosis was reduced in comparison with females of both genotypes on the low phytoestrogen diet. The authors' findings suggest that dietary phytoestrogen consumption may partially defeminize adult female sexual behavior in the mouse.}, number={2}, journal={Behavioral Neuroscience}, publisher={American Psychological Association (APA)}, author={Kudwa, Andrea E. and Boon, Wah C. and Simpson, Evan R. and Handa, Robert J. and Rissman, Emilie F.}, year={2007}, pages={356–361} }
 @article{edelmann_wolfe_scordalakes_rissman_tobet_2007, title={Neuronal nitric oxide synthase and calbindin delineate sex differences in the developing hypothalamus and preoptic area}, volume={67}, ISSN={1932-8451 1932-846X}, url={http://dx.doi.org/10.1002/dneu.20507}, DOI={10.1002/dneu.20507}, abstractNote={Throughout the hypothalamus there are several regions known to contain sex differences in specific cellular, neurochemical, or cell grouping characteristics. The current study examined the potential origin of sex differences in calbindin expression in the preoptic area and hypothalamus as related to sources of nitric oxide. Specific cell populations were defined by immunoreactive (ir) calbindin and neuronal nitric oxide synthase (nNOS) in the preoptic area/anterior hypothalamus (POA/AH), anteroventral periventricular nucleus (AVPv), and ventromedial nucleus of the hypothalamus (VMN). The POA/AH of adult mice was characterized by a striking sex difference in the distribution of cells with ir‐calbindin. Examination of the POA/AH of androgen receptor deficient Tfm mice suggests that this pattern was in part androgen receptor dependent, since Tfm males had reduced ir‐calbindin compared with wild‐type males and more similar to wild‐type females. At P0 ir‐calbindin was more prevalent than in adulthood, with males having significantly more ir‐calbindin and nNOS than have females. Cells that contained either ir‐calbindin or ir‐nNOS in the POA/AH were in adjacent cell groups, suggesting that NO derived from the enzymatic activity of nNOS may influence the development of ir‐calbindin cells. In the region of AVPv, at P0, there was a sex difference with males having more ir‐nNOS fibers than have females while ir‐calbindin was not detected. In the VMN, at P0, ir‐nNOS was greater in females than in males, with no significant difference in ir‐calbindin. We suggest that NO as an effector molecule and calbindin as a molecular biomarker illuminate key aspects of sexual differentiation in the developing mouse brain. © 2007 Wiley Periodicals, Inc. Develop Neurobiol, 2007.}, number={10}, journal={Developmental Neurobiology}, publisher={Wiley}, author={Edelmann, Michelle and Wolfe, Cory and Scordalakes, Elka M. and Rissman, Emilie F. and Tobet, Stuart}, year={2007}, pages={1371–1381} }
 @article{majdic_budefeld_grgurevic_rissman_tobet_2006, title={A model for hormone independent development of sex differences in brain and behavior}, volume={27}, ISSN={0091-3022}, url={http://dx.doi.org/10.1016/j.yfrne.2006.03.221}, DOI={10.1016/j.yfrne.2006.03.221}, abstractNote={This article is part of a Special Issue "Estradiol and cognition".This review discusses the unique contribution of nonhuman primate research to our understanding of the neurocognitive effects of estrogens throughout the adult lifespan in females. Mounting evidence indicates that estrogens affect many aspects of hippocampal, prefrontal and cholinergic function in the primate brain and the underlying mechanisms are beginning to be elucidated. In addition, estrogens may also influence cognitive function indirectly, via the modulation of other systems that impact cognition. We will focus on the effects of estrogens on sleep and emphasize the need for primate models to better understand these complex interactions. Continued research with nonhuman primates is essential for the development of therapies that are optimal for the maintenance of women's cognitive health throughout the lifespan.}, number={1}, journal={Frontiers in Neuroendocrinology}, publisher={Elsevier BV}, author={Majdic, Gregor and Budefeld, Tomaz and Grgurevic, Neza and Rissman, Emilie and Tobet, Stuart}, year={2006}, month={May}, pages={96–97} }
 @article{imwalle_bateman_wills_honda_harada_rissman_2006, title={Impairment of spatial learning by estradiol treatment in female mice is attenuated by estradiol exposure during development}, volume={50}, ISSN={0018-506X}, url={http://dx.doi.org/10.1016/j.yhbeh.2006.06.005}, DOI={10.1016/j.yhbeh.2006.06.005}, abstractNote={High doses of estradiol (E(2)) can impair spatial learning in the Morris water maze, in ovariectomized mice, but the same dose has no effect on adult castrated males. Here, we test the hypothesis that this sex difference is caused by neonatal actions of E(2). In Experiment 1, C57BL/6J pups were given daily estradiol benzoate (EB) or oil injections from the day of birth until postnatal Day 3. Adults were gonadectomized and received EB (s.c.) or oil 28 h before the first day of training, and 4 h before each of four daily training sessions on the Morris water maze. Females given oil as neonates, and EB prior to training displayed the poorest performance. Females that received EB as neonates and EB prior to training were insensitive to the deleterious effects of adult EB and performed better than males given the same hormone treatments. We conducted a second experiment using aromatase enzyme knockout (ArKO) mice. Adult male and female ArKO and wild-type (WT) littermates were gonadectomized and received either injections of oil or EB prior to and during water maze training (as described above). Hormone treatment failed to affect performance, yet, female but not male ArKO mice showed impaired learning compared to WT littermates. Thus, exposure to estradiol during neonatal development can counteract the deleterious effects of EB on adult spatial learning.}, number={5}, journal={Hormones and Behavior}, publisher={Elsevier BV}, author={Imwalle, D. Bradley and Bateman, Heather L. and Wills, Aileen and Honda, Shin-Ichiro and Harada, Nobuhiro and Rissman, Emilie F.}, year={2006}, month={Dec}, pages={693–698} }
 @article{bodo_rissman_2006, title={New roles for estrogen receptor β in behavior and neuroendocrinology☆}, volume={27}, ISSN={0091-3022}, url={http://dx.doi.org/10.1016/j.yfrne.2006.02.004}, DOI={10.1016/j.yfrne.2006.02.004}, abstractNote={In this review we critically examine the data on functions of the estrogen receptor beta (ERbeta) in both behavior and neuroendocrinology. The influence of estradiol via the ERbeta has been assessed using several methods: estrogen receptor knockout mice, specific ERbeta selective agonists, and phytoestrogens which preferentially bind to ERbeta rather than ERalpha. The behavior for which a solid database and consensus is forming is anxiety; activation of ERbeta reduces anxiety on a number of tasks and in several species. Moreover, the relationship between ERbeta and serotonin may be critical for the regulation of this behavior by estradiol. There have been very few studies on learning and memory but the little we know suggests that ERbeta is involved in visuospatial learning; in its absence learning is inhibited. Recent work has suggested a unique function for ERbeta in sexual differentiation; its activation in male neonates may promote defeminization of sexual behavior. Several neurotransmitter-containing neurons in the rat paraventricular nucleus coexpress ERbeta including; vasopressin, oxytocin, prolactin, and to a lesser extent corticotrophin releasing hormone. Given the potential for ERbeta to interact with these important neurotransmitters and its co-expression in gonadotropin releasing hormone neurons it is surprising how normal the hypothalamic-pituitary-adrenal and -gonadal axes appear to be in ERbeta knockout mice. Either this represents a species difference (the neuroanatomy has been conducted in the rat) or compensatory actions of ERalpha or other mechanisms. Exciting avenues for future research include; in vivo interactions between ERalpha and ERbeta, actions of non-estrogenic ligands with ERbeta, and the role of ERbeta in sexual differentiation.}, number={2}, journal={Frontiers in Neuroendocrinology}, publisher={Elsevier BV}, author={Bodo, C and Rissman, E}, year={2006}, month={Jul}, pages={217–232} }
 @article{kudwa_michopoulos_gatewood_rissman_2006, title={Roles of estrogen receptors α and β in differentiation of mouse sexual behavior}, volume={138}, ISSN={0306-4522}, url={http://dx.doi.org/10.1016/j.neuroscience.2005.10.018}, DOI={10.1016/j.neuroscience.2005.10.018}, abstractNote={Sex differences in brain and behavior are ubiquitous in sexually reproducing species. Developmental differences in circulating concentrations of gonadal steroids underlie many sexual dimorphisms. During the late embryonic and early perinatal periods, the testes produce androgens, thus, male brains are exposed to testosterone, and in situ testosterone is aromatized to estradiol. In contrast, females are not exposed to high concentrations of testosterone or estradiol until puberty. In many species, neural sex differences and sexually dimorphic behaviors in adults are initiated primarily by estradiol exposure during early development. In brain, estradiol activates two independent processes: masculinization of neural circuits and networks that are essential for expression of male-typical adult behaviors, and defeminization, the loss of the ability to display adult female-typical behaviors. Here, data for the roles of each of the known estrogen receptors (estrogen receptor alpha and estrogen receptor beta) in these two processes are reviewed. Based on work done primarily in knockout mouse models, separate roles for the two estrogen receptors are suggested. Estrogen receptor alpha is primarily involved in masculinization, while estrogen receptor beta has a major role in defeminization of sexual behaviors. In sum, estradiol can have selective effects on distinct behavioral processes via selective interactions with its two receptors, estrogen receptor alpha and estrogen receptor beta.}, number={3}, journal={Neuroscience}, publisher={Elsevier BV}, author={Kudwa, A.E. and Michopoulos, V. and Gatewood, J.D. and Rissman, E.F.}, year={2006}, month={Mar}, pages={921–928} }
 @article{kudwa_bodo_gustafsson_rissman_2005, title={A previously uncharacterized role for estrogen receptor  : Defeminization of male brain and behavior}, volume={102}, ISSN={0027-8424 1091-6490}, url={http://dx.doi.org/10.1073/pnas.0500752102}, DOI={10.1073/pnas.0500752102}, abstractNote={Sex differences in brain and behavior are ubiquitous in sexually reproducing species. One cause of sexual dimorphisms is developmental differences in circulating concentrations of gonadal steroids. Neonatal testes produce androgens; thus, males are exposed to both testosterone and estradiol, whereas females are not exposed to high concentrations of either hormone until puberty. Classically, the development of neural sex differences is initiated by estradiol, which activates two processes in male neonates; masculinization, the development of male-type behaviors, and defeminization, the loss of the ability to display female-type behaviors. Here, we test the hypothesis that defeminization is regulated by estrogen receptor beta (ERbeta). Adult male ERbeta knockout and WT mice were gonadectomized, treated with female priming hormones, and tested for receptive behavior. Indicative of incomplete defeminization, male ERbeta knockout mice showed significantly higher levels of female receptivity as compared with WT littermates. Testes-intact males did not differ in any aspects of their male sexual behavior, regardless of genotype. In olfactory preference tests, males of both genotypes showed equivalent preferences for female-soiled bedding. Based on these results, we hypothesize that ERbeta is involved in defeminization of brain and behavior. This aspect of ERbeta function may lead to developments in our understanding of neural-based sexually dimorphic human behaviors.}, number={12}, journal={Proceedings of the National Academy of Sciences}, publisher={Proceedings of the National Academy of Sciences}, author={Kudwa, A. E. and Bodo, C. and Gustafsson, J.-A. and Rissman, E. F.}, year={2005}, month={Mar}, pages={4608–4612} }
 @article{kudwa_dominguez-salazar_cabrera_sibley_rissman_2005, title={Dopamine D5 receptor modulates male and female sexual behavior in mice}, volume={180}, ISSN={0033-3158 1432-2072}, url={http://dx.doi.org/10.1007/s00213-005-2150-5}, DOI={10.1007/s00213-005-2150-5}, abstractNote={[[{:Label=>"RATIONALE", :NlmCategory=>"BACKGROUND"}, "Dopamine exerts its actions through at least five receptor (DAR) isoforms. In female rats, D5 DAR may be involved in expression of sexual behavior. We used a D5 knockout (D5KO) mouse to assess the role of D5 DAR in mouse sexual behavior. Both sexes of D5KO mice are fertile and exhibit only minor disruptions in exploratory locomotion, startle, and prepulse inhibition responses."], [{:Label=>"OBJECTIVE", :NlmCategory=>"OBJECTIVE"}, "This study was conducted to characterize the sexual behavior of male and female D5KO mice relative to their WT littermates."], [{:Label=>"METHODS", :NlmCategory=>"METHODS"}, "Female WT and D5KO littermates were ovariectomized and given a series of sexual behavior tests after treatment with estradiol benzoate (EB) and progesterone (P). Once sexual performance was optimal the dopamine agonist, apomorphine (APO), was substituted for P. Male mice were observed in pair- and trio- sexual behavior tests. To assess whether the D5 DAR is involved in rewarding aspects of sexual behavior, WT and D5KO male mice were tested for conditioned place preference."], [{:Label=>"RESULTS", :NlmCategory=>"RESULTS"}, "Both WT and D5KO females can display receptivity after treatment with EB and P, but APO was only able to facilitate receptivity in EB-primed WT, not in D5KO, mice. Male D5KO mice display normal masculine sexual behavior in mating tests. In conditioned preference tests, WT males formed a conditioned preference for context associated with either intromissions alone or ejaculation as the unconditioned stimulus. In contrast, D5KO males only showed a place preference when ejaculation was paired with the context."], [{:Label=>"CONCLUSIONS", :NlmCategory=>"CONCLUSIONS"}, "In females, the D5 DAR is essential for the actions of dopamine on receptivity. In males, D5 DAR influences rewarding aspects of intromissions. Taken together, the work suggests that the D5 receptor mediates dopamine's action on sexual behavior in both sexes, perhaps via a reward pathway."]]}, number={2}, journal={Psychopharmacology}, publisher={Springer Science and Business Media LLC}, author={Kudwa, A. E. and Dominguez-Salazar, E. and Cabrera, D. M. and Sibley, D. R. and Rissman, E. F.}, year={2005}, month={Feb}, pages={206–214} }
 @article{kauffman_buenzle_fraley_rissman_2005, title={Effects of galanin-like peptide (GALP) on locomotion, reproduction, and body weight in female and male mice}, volume={48}, ISSN={0018-506X}, url={http://dx.doi.org/10.1016/j.yhbeh.2005.01.010}, DOI={10.1016/j.yhbeh.2005.01.010}, abstractNote={Galanin-like peptide (GALP) has been implicated in the neuroendocrine regulation of both feeding and reproduction. In male rodents and primates, intracerebroventricular (icv) infusions of GALP stimulate luteinizing hormone (LH) release, induce Fos expression in brain areas implicated in feeding and reproduction, and affect food intake and body weight in rodents. In gonad-intact and castrated male rats, icv administration of GALP also stimulates male sexual behavior. While the effects of GALP on male physiology and behavior are well documented, no studies have addressed such a role of GALP in females. We tested the effects of icv GALP infusions on LH release, locomotor activity, motor control, and body weight regulation in adult ovariectomized female mice hormonally primed with estradiol benzoate and progesterone. In addition, sexually-experienced male and female mice were treated with GALP and tested for sexual behavior. In females, GALP reduced open-field locomotor activity, the ability to maintain grip on an accelerating rotarod, and 24-h body weight in a dose-dependent manner. GALP also increased LH secretion in female mice, an effect that was blocked by pre-treatment with Antide, a gonadotropin-releasing hormone (GnRH) type-1 receptor antagonist. GALP infusions slightly decreased the occurrence of lordosis behavior in female mice and significantly increased the latencies with which females displayed receptivity. Unlike previous reports in male rats, GALP inhibited male sexual behavior in mice. Our data indicate that in female mice, GALP stimulates LH release via GnRH, and decreases body weight, motor control, and locomotor activity via GnRH-independent pathways. Furthermore, our sexual behavior and locomotor findings suggest species-specific differences in the mechanism and/or location of GALP action in the brains of rats and mice.}, number={2}, journal={Hormones and Behavior}, publisher={Elsevier BV}, author={Kauffman, Alexander S. and Buenzle, Jennifer and Fraley, Gregory S. and Rissman, Emilie F.}, year={2005}, month={Aug}, pages={141–151} }
 @article{imwalle_gustafsson_rissman_2005, title={Lack of functional estrogen receptor β influences anxiety behavior and serotonin content in female mice}, volume={84}, ISSN={0031-9384}, url={http://dx.doi.org/10.1016/j.physbeh.2004.11.002}, DOI={10.1016/j.physbeh.2004.11.002}, abstractNote={Estrogen has been linked to the modulation of anxiety in females. Here we report results of anxiety tests conducted in female estrogen receptor β (ERβ) knockout (ERβKO) and wild-type (WT) mice. Ovariectomized (OVX) mice treated with chronic estradiol (E2) replacement did not behave differently on the elevated plus-maze when compared with OVX mice that did not experience hormone replacement. However, a genotype difference was noted; WT females were more likely to explore the distal portion of the open arm of the maze than ERβKO littermates. In addition, ERβKO female mice had significantly lower serotonin (5-HT) content than WT littermates in several brain regions including: the bed nucleus of the stria terminalis, preoptic area, and hippocampus. A similar trend was noted in the dorsal raphe nucleus. Dopamine content was reduced within the caudate putamen in ERβKO mice as compared to brains from WT animals. Thus, in the absence of functional ERβ, regardless of the presence or absence of circulating E2 in plasma, female mice exhibited enhanced anxiety and decreased concentrations of 5-HT or dopamine in several brain regions. We hypothesize that ERβ is required during development to modulate the effects of estrogen on anxiety and catecholamine concentrations in female mouse brains.}, number={1}, journal={Physiology & Behavior}, publisher={Elsevier BV}, author={Imwalle, D. Bradley and Gustafsson, Jan-Åke and Rissman, Emilie F.}, year={2005}, month={Jan}, pages={157–163} }
 @article{dominguez-salazar_bateman_rissman_2004, title={Background matters: the effects of estrogen receptor α gene disruption on male sexual behavior are modified by background strain}, volume={46}, ISSN={0018-506X}, url={http://dx.doi.org/10.1016/j.yhbeh.2004.05.006}, DOI={10.1016/j.yhbeh.2004.05.006}, abstractNote={One approach to study interactions between behavior and genetics is to use inbred mice with different genetic backgrounds. To examine the effect of background on a specific gene, we conducted a series of experiments with a well-characterized knockout (KO) mouse, the estrogen receptor alpha KO (ERalphaKO). The ERalphaKO mouse has so far been examined in one inbred line, C57BL/6J. Here, we examined the behavior of ERalphaKO mice within three different backgrounds mixed with C57BL/6J; DBA/2J, BALB/c, and A/J. First, we assessed masculine sexual behavior in both intact male and testosterone-treated female offspring. More ERalphaKO males in the DBA/2J (5/12) and BALB/c (5/13) backcrosses displayed intromissions and many ejaculated as compared with males in a C57BL/6J and A/J mixed background. Many fewer ERalphaKO females than males displayed masculine sexual behavior in any of the three hybrid crosses. We assessed fertility in males from the C57BL/6J by DBA/2J cross and found that one of 12 ERalphaKO males sired a litter. Several other characteristics of sexual behavior and physiology were unaffected by genetic background in ERalphaKO mice. Our data suggest that genetic background has dramatic effects on male sexual behavior and its dependence on the ERalpha gene.}, number={4}, journal={Hormones and Behavior}, publisher={Elsevier BV}, author={Dominguez-Salazar, Emilio and Bateman, Heather L. and Rissman, Emilie F.}, year={2004}, month={Nov}, pages={482–490} }
 @article{burns-cusato_scordalakes_rissman_2004, title={Of mice and missing data: what we know (and need to learn) about male sexual behavior}, volume={83}, ISSN={0031-9384}, url={http://dx.doi.org/10.1016/j.physbeh.2004.08.015}, DOI={10.1016/j.physbeh.2004.08.015}, abstractNote={With recent advances in molecular genetics, the popularity of mice as subjects for behavioral neuroscience is increasing at an exponential rate. Unfortunately, the existing body of knowledge on sexual behavior in male mice is not large and many basic gaps exist. The assumption that what is true of rats is also true of mice is a dangerous one that can misdirect and, in the worst case, impede progress. We summarize the current knowledge about the sexual behavior of male mice, with an emphasis on hormonal bases of these behaviors. Behavioral differences between strains, developmental actions of steroids, activational actions of steroids given peripherally and in the brain, and data generated in various receptor knockout and related mice are discussed. In addition, suggestions are made for the standardization of experimental protocols used in investigations of the sexual physiology and behavior of male mice in order to facilitate between-experiment and between-laboratory comparisons and to expedite the growth of knowledge in this area.}, number={2}, journal={Physiology & Behavior}, publisher={Elsevier BV}, author={Burns-Cusato, Melissa and Scordalakes, Elka M. and Rissman, Emilie F.}, year={2004}, month={Nov}, pages={217–232} }
 @article{burnscusato_scordalakes_rissman_2004, title={Of mice and missing data: what we know (and need to learn) about male sexual behavior}, volume={83}, ISSN={0031-9384}, url={http://dx.doi.org/10.1016/S0031-9384(04)00353-1}, DOI={10.1016/S0031-9384(04)00353-1}, abstractNote={With recent advances in molecular genetics, the popularity of mice as subjects for behavioral neuroscience is increasing at an exponential rate. Unfortunately, the existing body of knowledge on sexual behavior in male mice is not large and many basic gaps exist. The assumption that what is true of rats is also true of mice is a dangerous one that can misdirect and, in the worst case, impede progress. We summarize the current knowledge about the sexual behavior of male mice, with an emphasis on hormonal bases of these behaviors. Behavioral differences between strains, developmental actions of steroids, activational actions of steroids given peripherally and in the brain, and data generated in various receptor knockout and related mice are discussed. In addition, suggestions are made for the standardization of experimental protocols used in investigations of the sexual physiology and behavior of male mice in order to facilitate between-experiment and between-laboratory comparisons and to expedite the growth of knowledge in this area.}, number={2}, journal={Physiology & Behavior}, publisher={Elsevier BV}, author={Burnscusato, M and Scordalakes, E and Rissman, E}, year={2004}, month={Nov}, pages={217–232} }