@article{cao_meitzen_2021, title={Perinatal activation of ER alpha and ER beta but not GPER-1 masculinizes female rat caudate-putamen medium spiny neuron electrophysiological properties}, volume={125}, ISSN={["1522-1598"]}, DOI={10.1152/jn.00063.2021}, abstractNote={ This study is the first to demonstrate that estradiol and estrogen receptor α and β stimulation during early development sexually differentiates the electrophysiological properties of caudate-putamen medium spiny neurons, the primary output neuron of the striatal regions. Overall, this evidence provides new insight into the neuroendocrine mechanism by which caudate-putamen neuron electrophysiology is sexually differentiated and demonstrates the powerful action of early hormone exposure upon individual neuron electrophysiology. }, number={6}, journal={JOURNAL OF NEUROPHYSIOLOGY}, author={Cao, Jinyan and Meitzen, John}, year={2021}, month={Jun}, pages={2322–2338} }
 @article{willett_cao_dorris_johnson_ginnari_meitzen_2019, title={Electrophysiological Properties of Medium Spiny Neuron Subtypes in the Caudate-Putamen of Prepubertal Male and Female Drd1a-tdTomato Line 6 BAC Transgenic Mice}, volume={6}, ISSN={["2373-2822"]}, DOI={10.1523/ENEURO.0016-19.2019}, abstractNote={AbstractThe caudate-putamen is a striatal brain region essential for sensorimotor behaviors, habit learning, and other cognitive and premotor functions. The output and predominant neuron of the caudate-putamen is the medium spiny neuron (MSN). MSNs present discrete cellular subtypes that show differences in neurochemistry, dopamine receptor expression, efferent targets, gene expression, functional roles, and most importantly for this study, electrophysiological properties. MSN subtypes include the striatonigral and the striatopallidal groups. Most studies identify the striatopallidal MSN subtype as being more excitable than the striatonigral MSN subtype. However, there is some divergence between studies regarding the exact differences in electrophysiological properties. Furthermore, MSN subtype electrophysiological properties have not been reported disaggregated by biological sex. We addressed these questions using prepubertal male and female Drd1a-tdTomato line 6 BAC transgenic mice, an important transgenic line that has not yet received extensive electrophysiological analysis. We made acute caudate-putamen brain slices and assessed a robust battery of 16 relevant electrophysiological properties using whole-cell patch-clamp recording, including intrinsic membrane, action potential, and miniature EPSC (mEPSC) properties. We found that: (1) MSN subtypes exhibited multiple differential electrophysiological properties in both sexes, including rheobase, action potential threshold and width, input resistance in both the linear and rectified ranges, and mEPSC amplitude; (2) select electrophysiological properties showed interactions between MSN subtype and sex. These findings provide a comprehensive evaluation of mouse caudate-putamen MSN subtype electrophysiological properties across females and males, both confirming and extending previous studies.}, number={2}, journal={ENEURO}, author={Willett, Jaime A. and Cao, Jinyan and Dorris, David M. and Johnson, Ashlyn G. and Ginnari, Laura A. and Meitzen, John}, year={2019} }
 @article{willett_cao_johnson_patel_dorris_meitzen_2020, title={The estrous cycle modulates rat caudate-putamen medium spiny neuron physiology}, volume={52}, ISSN={["1460-9568"]}, DOI={10.1111/ejn.14506}, abstractNote={AbstractThe neuroendocrine environment in which the brain operates is both dynamic and differs by sex. How differences in neuroendocrine state affect neuron properties has been significantly neglected in neuroscience research. Behavioral data across humans and rodents indicate that natural cyclical changes in steroid sex hormone production affect sensorimotor and cognitive behaviors in both normal and pathological contexts. These behaviors are critically mediated by the caudate–putamen. In the caudate–putamen, medium spiny neurons (MSNs) are the predominant and primary output neurons. MSNs express membrane‐associated estrogen receptors and demonstrate estrogen sensitivity. However, how the cyclical hormone changes across the estrous cycle may modulate caudate–putamen MSN electrophysiological properties remains unknown. Here, we performed whole‐cell patch‐clamp recordings on male, diestrus female, proestrus female, and estrus female caudate–putamen MSNs. Action potential, passive membrane, and miniature excitatory post‐synaptic current properties were assessed. Numerous MSN electrical properties robustly differed by cycle state, including resting membrane potential, rheobase, action potential threshold, maximum evoked action potential firing rate, and inward rectification. Strikingly, when considered independent of estrous cycle phase, all but one of these properties do not significantly differ from male MSNs. These data indicate that female caudate–putamen MSNs are sensitive to the estrous cycle, and more broadly, the importance of considering neuroendocrine state in studies of neuron physiology.}, number={1}, journal={EUROPEAN JOURNAL OF NEUROSCIENCE}, author={Willett, Jaime A. and Cao, Jinyan and Johnson, Ashlyn and Patel, Opal H. and Dorris, David M. and Meitzen, John}, year={2020}, month={Jul}, pages={2737–2755} }
 @article{cao_dorris_meitzen_2018, title={Electrophysiological properties of medium spiny neurons in the nucleus accumbens core of prepubertal male and female Drd1a-tdTomato line 6 BAC transgenic mice}, volume={120}, ISSN={["1522-1598"]}, DOI={10.1152/jn.00257.2018}, abstractNote={ The nucleus accumbens core (AcbC) is a striatal brain region essential for integrating motivated behavior and reward processing with premotor function. In humans and rodents, research has identified sex differences and sex steroid hormone sensitivity in AcbC-mediated behaviors, in disorders, and in rats in the electrophysiological properties of the AcbC output neuron type, the medium spiny neuron (MSN). It is unknown whether the sex differences detected in MSN electrophysiological properties extend to mice. Furthermore, MSNs come in distinct subtypes with subtle differences in electrophysiological properties, and it is unknown whether MSN subtype-specific electrophysiology varies by sex. To address these questions, we used male and female Drd1a-tdTomato line 6 bacterial artificial chromosome transgenic mice. We made acute brain slices of the AcbC, and performed whole cell patch-clamp recordings across MSN subtypes to comprehensively assess AcbC MSN subtype electrophysiological properties. We found that ( 1 mice MSNs did not exhibit the sex differences detected in rat MSNs, and 2) electrophysiological properties differed between MSN subtypes in both sexes, including rheobase, resting membrane potential, action potential properties, intrinsic excitability, input resistance in both the linear and rectified ranges, and miniature excitatory postsynaptic current properties. These findings significantly extend previous studies of MSN subtypes performed in males or animals of undetermined sex and indicate that the influence of sex upon AcbC MSN properties varies between rodent species.  NEW & NOTEWORTHY This research provides the most comprehensive assessment of medium spiny neuron subtype electrophysiological properties to date in a critical brain region, the nucleus accumbens core. It additionally represents the first evaluation of whether mouse medium spiny neuron subtype electrophysiological properties differ by sex. }, number={4}, journal={JOURNAL OF NEUROPHYSIOLOGY}, author={Cao, Jinyan and Dorris, David M. and Meitzen, John}, year={2018}, month={Oct}, pages={1712–1727} }
 @misc{cao_willett_dorris_meitzen_2018, title={Sex Differences in Medium Spiny neuron excitability and Glutamatergic Synaptic input: Heterogeneity Across Striatal Regions and evidence for Estradiol-Dependent Sexual Differentiation}, volume={9}, ISSN={["1664-2392"]}, DOI={10.3389/fendo.2018.00173}, abstractNote={Steroid sex hormones and biological sex influence how the brain regulates motivated behavior, reward, and sensorimotor function in both normal and pathological contexts. Investigations into the underlying neural mechanisms have targeted the striatal brain regions, including the caudate–putamen, nucleus accumbens core (AcbC), and shell. These brain regions are of particular interest to neuroendocrinologists given that they express membrane-associated but not nuclear estrogen receptors, and also the well-established role of the sex steroid hormone 17β-estradiol (estradiol) in modulating striatal dopamine systems. Indeed, output neurons of the striatum, the medium spiny neurons (MSNs), exhibit estradiol sensitivity and sex differences in electrophysiological properties. Here, we review sex differences in rat MSN glutamatergic synaptic input and intrinsic excitability across striatal regions, including evidence for estradiol-mediated sexual differentiation in the nucleus AcbC. In prepubertal animals, female MSNs in the caudate–putamen exhibit a greater intrinsic excitability relative to male MSNs, but no sex differences are detected in excitatory synaptic input. Alternatively, female MSNs in the nucleus AcbC exhibit increased excitatory synaptic input relative to male MSNs, but no sex differences in intrinsic excitability were detected. Increased excitatory synaptic input onto female MSNs in the nucleus AcbC is abolished after masculinizing estradiol or testosterone exposure during the neonatal critical period. No sex differences are detected in MSNs in prepubertal nucleus accumbens shell. Thus, despite possessing the same neuron type, striatal regions exhibit heterogeneity in sex differences in MSN electrophysiological properties, which likely contribute to the sex differences observed in striatal function.}, journal={FRONTIERS IN ENDOCRINOLOGY}, author={Cao, Jinyan and Willett, Jaime A. and Dorris, David M. and Meitzen, John}, year={2018}, month={Apr} }
 @article{arambula_fuchs_cao_patisaul_2017, title={Effects of perinatal bisphenol A exposure on the volume of sexually-dimorphic nuclei of juvenile rats: A CLARITY-SPA consortium study}, volume={63}, ISSN={["1872-9711"]}, DOI={10.1016/j.neuro.2017.09.002}, abstractNote={Bisphenol A (BPA) is a high volume endocrine disrupting chemical found in a wide variety of products including plastics and epoxy resins. Human exposure is nearly ubiquitous, and higher in children than adults. Because BPA has been reported to interfere with sex steroid hormone signaling, there is concern that developmental exposure, even at levels below the current FDA No Observed Adverse Effect Level (NOAEL) of 5mg/kg body weight (bw)/day, can disrupt brain sexual differentiation. The current studies were conducted as part of the CLARITY-BPA (Consortium Linking Academic and Regulatory Insights on BPA Toxicity) program and tested the hypothesis that perinatal BPA exposure would induce morphological changes in hormone sensitive, sexually dimorphic brain regions. Sprague-Dawley rats were randomly assigned to 5 groups: BPA (2.5, 25, or 2500μg/kgbw/day), a reference estrogen (0.5μg ethinylestradiol (EE2)/kgbw/day), or vehicle. Exposure occurred by gavage to the dam from gestational day 6 until parturition, and then to the offspring from birth through weaning. Unbiased stereology was used to quantify the volume of the sexually dimorphic nucleus (SDN), the anteroventral periventricular nucleus (AVPV), the posterodorsal portion of the medial amygdala (MePD), and the locus coeruleus (LC) at postnatal day 28. No appreciable effects of BPA were observed on the volume of the SDN or LC. However, AVPV volume was enlarged in both sexes, even at levels below the FDA NOAEL. Collectively, these data suggest the developing brain is vulnerable to endocrine disruption by BPA at exposure levels below previous estimates by regulatory agencies.}, journal={NEUROTOXICOLOGY}, author={Arambula, Sheryl E. and Fuchs, Joelle and Cao, Jinyan and Patisaul, Heather B.}, year={2017}, month={Dec}, pages={33–42} }
 @article{hicks_sullivan_cao_sluzas_rebuli_patisaul_2016, title={Interaction of bisphenol A (BPA) and soy phytoestrogens on sexually dimorphic sociosexual behaviors in male and female rats}, volume={84}, ISSN={["1095-6867"]}, DOI={10.1016/j.yhbeh.2016.06.010}, abstractNote={Concerns have been raised regarding the potential for endocrine disrupting compounds (EDCs) to alter brain development and behavior. Developmental exposure to bisphenol A (BPA), a ubiquitous EDC, has been linked to altered sociosexual and mood-related behaviors in various animal models and children but effects are inconsistent across laboratories and animal models creating confusion about potential risk in humans. Exposure to endocrine active diets, such as soy, which is rich in phytoestrogens, may contribute to this variability. Here, we tested the individual and combined effects of low dose oral BPA and soy diet or the individual isoflavone genistein (GEN; administered as the aglycone genistin (GIN)) on rat sociosexual behaviors with the hypothesis that soy would obfuscate any BPA-related effects. Social and activity levels were unchanged by developmental exposure to BPA but soy diet had sex specific effects including suppressed novelty preference, and open field exploration in females. The data presented here reinforce that environmental factors, including anthropogenic chemical exposure and hormone active diets, can shape complex behaviors and even reverse expected sex differences.}, journal={HORMONES AND BEHAVIOR}, author={Hicks, Kimani D. and Sullivan, Alana W. and Cao, Jinyan and Sluzas, Emily and Rebuli, Meghan and Patisaul, Heather B.}, year={2016}, month={Aug}, pages={121–126} }
 @article{cao_dorris_meitzen_2016, title={Neonatal Masculinization Blocks Increased Excitatory Synaptic Input in Female Rat Nucleus Accumbens Core}, volume={157}, ISSN={["1945-7170"]}, DOI={10.1210/en.2016-1160}, abstractNote={Steroid sex hormones and genetic sex regulate the phenotypes of motivated behaviors and relevant disorders. Most studies seeking to elucidate the underlying neuroendocrine mechanisms have focused on how 17β-estradiol modulates the role of dopamine in striatal brain regions, which express membrane-associated estrogen receptors. Dopamine action is an important component of striatal function, but excitatory synaptic neurotransmission has also emerged as a key striatal substrate and target of estradiol action. Here, we focus on excitatory synaptic input onto medium spiny neurons (MSNs) in the striatal region nucleus accumbens core (AcbC). In adult AcbC, miniature excitatory postsynaptic current (mEPSC) frequency is increased in female compared with male MSNs. We tested whether increased mEPSC frequency in female MSNs exists before puberty, whether this increased excitability is due to the absence of estradiol or testosterone during the early developmental critical period, and whether it is accompanied by stable neuron intrinsic membrane properties. We found that mEPSC frequency is increased in female compared with male MSNs before puberty. Increased mEPSC frequency in female MSNs is abolished after neonatal estradiol or testosterone exposure. MSN intrinsic membrane properties did not differ by sex. These data indicate that neonatal masculinization via estradiol and/or testosterone action is sufficient for down-regulating excitatory synaptic input onto MSNs. We conclude that excitatory synaptic input onto AcbC MSNs is organized long before adulthood via steroid sex hormone action, providing new insight into a mechanism by which sex differences in motivated behavior and other AbcC functions may be generated or compromised.}, number={8}, journal={ENDOCRINOLOGY}, author={Cao, Jinyan and Dorris, David M. and Meitzen, John}, year={2016}, month={Aug}, pages={3181–3196} }
 @article{willett_will_hauser_dorris_cao_meitzen_2016, title={No Evidence for Sex Differences in the Electrophysiological Properties and Excitatory Synaptic Input onto Nucleus Accumbens Shell Medium Spiny Neurons}, volume={3}, ISSN={["2373-2822"]}, DOI={10.1523/eneuro.0147-15.2016}, abstractNote={Visual Overview Sex differences exist in how the brain regulates motivated behavior and reward, both in normal and pathological contexts. Investigations into the underlying neural mechanisms have targeted the striatal brain regions, including the dorsal striatum and nucleus accumbens core and shell. Sex differences exist in how the brain regulates motivated behavior and reward, both in normal and pathological contexts. Investigations into the underlying neural mechanisms have targeted the striatal brain regions, including the dorsal striatum and nucleus accumbens core and shell. These investigations yield accumulating evidence of sexually different electrophysiological properties, excitatory synaptic input, and sensitivity to neuromodulator/hormone action in select striatal regions both before and after puberty. It is unknown whether the electrical properties of neurons in the nucleus accumbens shell differ by sex, and whether sex differences in excitatory synaptic input are present before puberty. To test the hypothesis that these properties differ by sex, we performed whole-cell patch-clamp recordings on male and female medium spiny neurons (MSNs) in acute brain slices obtained from prepubertal rat nucleus accumbens shell. We analyzed passive and active electrophysiological properties, and miniature EPSCs (mEPSCs). No sex differences were detected; this includes those properties, such as intrinsic excitability, action potential afterhyperpolarization, threshold, and mEPSC frequency, that have been found to differ by sex in other striatal regions and/or developmental periods. These findings indicate that, unlike other striatal brain regions, the electrophysiological properties of nucleus accumbens shell MSNs do not differ by sex. Overall, it appears that sex differences in striatal function, including motivated behavior and reward, are likely mediated by other factors and striatal regions.}, number={1}, journal={ENEURO}, author={Willett, Jaime A. and Will, Tyler and Hauser, Caitlin A. and Dorris, David M. and Cao, Jinyan and Meitzen, John}, year={2016} }
 @article{wong_cao_dorris_meitzen_2016, title={Genetic sex and the volumes of the caudate-putamen, nucleus accumbens core and shell: original data and a review}, volume={221}, ISSN={["1863-2661"]}, DOI={10.1007/s00429-015-1158-9}, abstractNote={Sex differences are widespread across vertebrate nervous systems. Such differences are sometimes reflected in the neural substrate via neuroanatomical differences in brain region volume. One brain region that displays sex differences in its associated functions and pathologies is the striatum, including the caudate-putamen (dorsal striatum), nucleus accumbens core and shell (ventral striatum). The extent to which these differences can be attributed to alterations in volume is unclear. We thus tested whether the volumes of the caudate-putamen, nucleus accumbens core, and nucleus accumbens shell differed by region, sex, and hemisphere in adult Sprague-Dawley rats. As a positive control for detecting sex differences in brain region volume, we measured the sexually dimorphic nucleus of the medial preoptic area (SDN-POA). As expected, SDN-POA volume was larger in males than in females. No sex differences were detected in the volumes of the caudate-putamen, nucleus accumbens core or shell. Nucleus accumbens core volume was larger in the right than left hemisphere across males and females. These findings complement previous reports of lateralized nucleus accumbens volume in humans, and suggest that this may possibly be driven via hemispheric differences in nucleus accumbens core volume. In contrast, striatal sex differences seem to be mediated by factors other than striatal region volume. This conclusion is presented within the context of a detailed review of studies addressing sex differences and similarities in striatal neuroanatomy.}, number={8}, journal={BRAIN STRUCTURE & FUNCTION}, author={Wong, Jordan E. and Cao, Jinyan and Dorris, David M. and Meitzen, John}, year={2016}, month={Nov}, pages={4257–4267} }
 @article{cao_echelberger_liu_sluzas_mccaffrey_buckley_patisaul_2015, title={Soy but not bisphenol A (BPA) or the phytoestrogen genistin alters developmental weight gain and food intake in pregnant rats and their offspring}, volume={58}, ISSN={["0890-6238"]}, DOI={10.1016/j.reprotox.2015.07.077}, abstractNote={Endocrine disrupting compounds (EDCs) are hypothesized to promote obesity and early puberty but their interactive effects with hormonally active diets are poorly understood. Here we assessed individual and combinatorial effects of soy diet or the isoflavone genistein (GEN; administered as the aglycone genistin GIN) with bisphenol A (BPA) on body weight, ingestive behavior and female puberal onset in Wistar rats. Soy-fed dams gained less weight during pregnancy and, although they consumed more than dams on a soy-free diet during lactation, did not become heavier. Their offspring (both sexes), however, became significantly heavier (more pronounced in males) pre-weaning. Soy also enhanced food intake and accelerated female pubertal onset in the offspring. Notably, pubertal onset was also advanced in females placed on soy diet at weaning. Males exposed to BPA plus soy diet, but not BPA alone, had lighter testes. BPA had no independent effects.}, journal={REPRODUCTIVE TOXICOLOGY}, author={Cao, Jinyan and Echelberger, Roger and Liu, Min and Sluzas, Emily and McCaffrey, Katherine and Buckley, Brian and Patisaul, Heather B.}, year={2015}, month={Dec}, pages={282–294} }
 @article{dorris_cao_willett_hauser_meitzen_2015, title={Intrinsic excitability varies by sex in prepubertal striatal medium spiny neurons}, volume={113}, ISSN={["1522-1598"]}, DOI={10.1152/jn.00687.2014}, abstractNote={ Sex differences in neuron electrophysiological properties were traditionally associated with brain regions directly involved in reproduction in adult, postpubertal animals. There is growing acknowledgement that sex differences can exist in other developmental periods and brain regions as well. This includes the dorsal striatum (caudate/putamen), which shows robust sex differences in gene expression, neuromodulator action (including dopamine and 17β-estradiol), and relevant sensorimotor behaviors and pathologies such as the responsiveness to drugs of abuse. Here we examine whether these sex differences extend to striatal neuron electrophysiology. We test the hypothesis that passive and active medium spiny neuron (MSN) electrophysiological properties in prepubertal rat dorsal striatum differ by sex. We made whole cell recordings from male and females MSNs from acute brain slices. The slope of the evoked firing rate to current injection curve was increased in MSNs recorded from females compared with males. The initial action potential firing rate was increased in MSNs recorded from females compared with males. Action potential after-hyperpolarization peak was decreased, and threshold was hyperpolarized in MSNs recorded from females compared with males. No sex differences in passive electrophysiological properties or miniature excitatory synaptic currents were detected. These findings indicate that MSN excitability is increased in prepubertal females compared with males, providing a new mechanism that potentially contributes to generating sex differences in striatal-mediated processes. Broadly, these findings demonstrate that sex differences in neuron electrophysiological properties can exist prepuberty in brain regions not directly related to reproduction. }, number={3}, journal={JOURNAL OF NEUROPHYSIOLOGY}, author={Dorris, David M. and Cao, Jinyan and Willett, Jaime A. and Hauser, Caitlin A. and Meitzen, John}, year={2015}, month={Feb}, pages={720–729} }
 @article{rebuli_cao_sluzas_delclos_camacho_lewis_vanlandingham_patisaul_2014, title={Investigation of the Effects of Subchronic Low Dose Oral Exposure to Bisphenol A (BPA) and Ethinyl Estradiol (EE) on Estrogen Receptor Expression in the Juvenile and Adult Female Rat Hypothalamus}, volume={140}, ISSN={["1096-0929"]}, DOI={10.1093/toxsci/kfu074}, abstractNote={Concerns have been raised regarding the long-term impacts of early life exposure to the ubiquitous environmental contaminant bisphenol A (BPA) on brain organization. Because BPA has been reported to affect estrogen signaling, and steroid hormones play a critical role in brain sexual differentiation, there is also concern that BPA exposure could alter neural sex differences. Here, we examine the impact of subchronic exposure from gestation to adulthood to oral doses of BPA below the current no-observed-adverse-effect level (NOAEL) of 5 mg/kg body weight (bw)/day on estrogen receptor (ESR) expression in sexually dimorphic brain regions of prepubertal and adult female rats. The dams were gavaged daily with vehicle (0.3% carboxymethylcellulose), 2.5, 25, 260, or 2700 μg BPA/kg bw/day, or 0.5 or 5.0 μg ethinyl estradiol (EE)/kg bw/day from gestational day 6 until labor began. Offspring were then gavaged directly from the day after birth until the day before scheduled sacrifice on postnatal days 21 or 90. Using in situ hybridization, one or more BPA doses produced significant decreases in Esr1 expression in the juvenile female rat anteroventral periventricular nucleus (AVPV) of the hypothalamus and significant decreases in Esr2 expression in the adult female rat AVPV and medial preoptic area (MPOA), relative to vehicle controls. BPA did not simply reproduce EE effects, indicating that BPA is not acting solely as an estrogen mimic. The possible consequences of long-term changes in hypothalamic ESR expression resulting from subchronic low dose BPA exposure on neuroendocrine effects are discussed and being addressed in ongoing, related work.}, number={1}, journal={TOXICOLOGICAL SCIENCES}, author={Rebuli, Meghan E. and Cao, Jinyan and Sluzas, Emily and Delclos, K. Barry and Camacho, Luisa and Lewis, Sherry M. and Vanlandingham, Michelle M. and Patisaul, Heather B.}, year={2014}, month={Jul}, pages={190–203} }
 @article{cao_rebuli_rogers_todd_leyrer_ferguson_patisaul_2013, title={Prenatal Bisphenol A Exposure Alters Sex-Specific Estrogen Receptor Expression in the Neonatal Rat Hypothalamus and Amygdala}, volume={133}, ISSN={["1096-0929"]}, DOI={10.1093/toxsci/kft035}, abstractNote={Bisphenol A (BPA) exposure is ubiquitous, and in laboratory animals, early-life BPA exposure has been shown to alter sex-specific neural organization, neuroendocrine physiology, and behavior. The specific mechanisms underlying these brain-related outcomes, however, remain largely unknown, constraining the capacity to ascertain the potential human relevance of neural effects observed in animal models. In the perinatal rat brain, estrogen is masculinizing, suggesting that BPA-induced perturbation of estrogen receptor (ESR) expression may underpin later in-life neuroendocrine effects. We hypothesized that prenatal BPA exposure alters sex-specific ESR1 (ERα) and ESR2 (ERβ) expression in postnatal limbic nuclei. Sprague Dawley rats were mated and gavaged on gestational days (GDs) 6-21 with vehicle, 2.5 or 25 μg/kg bw/day BPA, or 5 or 10 μg/kg bw/day ethinyl estradiol. An additional group was restrained but not gavaged (naïve control). Offspring were sacrificed the day after birth to quantify ESR gene expression throughout the hypothalamus and amygdala by in situ hybridization. Relative to the vehicle group, significant effects of BPA were observed on ESR1 and ESR2 expression throughout the mediobasal hypothalamus and amygdala in both sexes. Significant differences in ESR expression were also observed in the mediobasal hypothalamus and amygdala of the naïve control group compared with the vehicle group, highlighting the potential for gavage to influence gene expression in the developing brain. These results indicate that ESR expression in the neonatal brain of both sexes can be altered by low-dose prenatal BPA exposure.}, number={1}, journal={TOXICOLOGICAL SCIENCES}, author={Cao, Jinyan and Rebuli, Meghan E. and Rogers, James and Todd, Karina L. and Leyrer, Stephanie M. and Ferguson, Sherry A. and Patisaul, Heather B.}, year={2013}, month={May}, pages={157–173} }
 @article{cao_joyner_mickens_leyrer_patisaul_2014, title={Sex-specific Esr2 mRNA expression in the rat hypothalamus and amygdala is altered by neonatal bisphenol A exposure}, volume={147}, ISSN={["1470-1626"]}, DOI={10.1530/rep-13-0501}, abstractNote={Perinatal life is a critical window for sexually dimorphic brain organization, and profoundly influenced by steroid hormones. Exposure to endocrine-disrupting compounds may disrupt this process, resulting in compromised reproductive physiology and behavior. To test the hypothesis that neonatal bisphenol A (BPA) exposure can alter sex-specific postnatalEsr2(Erβ) expression in brain regions fundamental to sociosexual behavior, we mappedEsr2mRNA levels in the principal nucleus of the bed nucleus of the stria terminalis (BNSTp), paraventricular nucleus (PVN), anterior portion of the medial amygdaloid nucleus (MeA), super optic nucleus, suprachiasmatic nucleus, and lateral habenula across postnatal days (PNDs) 0–19. Next, rat pups of both sexes were subcutaneously injected with 10 μg estradiol benzoate (EB), 50 μg/kg BPA (LBPA), or 50 mg/kg BPA (HBPA) over the first 3 days of life andEsr2levels were quantified in each region of interest (ROI) on PNDs 4 and 10. EB exposure decreasedEsr2signal in most female ROIs and in the male PVN. In the BNSTp,Esr2expression decreased in LBPA males and HBPA females on PND 10, thereby reversing the sex difference in expression. In the PVN,Esr2mRNA levels were elevated in LBPA females, also resulting in a reversal of sexually dimorphic expression. In the MeA, BPA decreasedEsr2expression on PND 4. Collectively, these data demonstrate that region- and sex-specificEsr2expression is vulnerable to neonatal BPA exposure in regions of the developing brain critical to sociosexual behavior in rat.}, number={4}, journal={REPRODUCTION}, author={Cao, Jinyan and Joyner, Linwood and Mickens, Jillian A. and Leyrer, Stephanie M. and Patisaul, Heather B.}, year={2014}, month={Apr}, pages={537–554} }
 @article{cao_patisaul_2012, title={Sex-specific expression of estrogen receptors α and β and Kiss1 in the postnatal rat amygdala}, volume={521}, ISSN={0021-9967}, url={http://dx.doi.org/10.1002/cne.23185}, DOI={10.1002/cne.23185}, abstractNote={AbstractThe rodent amygdaloid complex is composed of numerous subnuclei important for the sex‐specific regulation of sociosexual behavior. Although estrogen receptors (ERs) are critical for organizing functional and cytoarchitectural sex differences in these subnuclei, a detailed developmental profile of ER expression in the amygdaloid complex is not available. Moreover, the kisspeptin gene (Kiss1) was recently identified in the adult amygdala, but it remains unknown if it is expressed during development. To fill these data gaps, rat brains (5–7/group) were assessed on postnatal days (PNDs) 0, 2, 4, 7, and 19 for ER alpha (ERα; Esr1), beta (ERβ; Esr2), and Kiss1 expression using in situ hybridization. Expression was quantified in the posterodorsal portion of the medial amygdala posterodorsal (MePD), lateral (PLCo), and medial (PMCo) components of the posterior cortical nucleus, and the amygdalohippocampal area (AHi). ERα expression was high throughout the amygdala at birth, but sexually dimorphic only in the AHi. ERα expression in the MePD and the PLCo showed a U‐shaped expression pattern over time. In the PMCo, ERα expression decreased from PND 2 and remained low through PND 19. Sexually dimorphic expression of ERβ in the MePD was observed on PND 0, with higher levels in females, but reversed by PND 4 due to declining levels in females. No Kiss1 signal was observed in the postnatal amygdala, suggesting that expression arises after puberty. These data reveal that ER expression is region‐specific within the neonatal amygdala. These differences likely contribute to sex differences in sociosexual behavior across the lifespan. J. Comp. Neurol. 521:465–478, 2013. © 2012 Wiley Periodicals, Inc.}, number={2}, journal={Journal of Comparative Neurology}, publisher={Wiley}, author={Cao, Jinyan and Patisaul, Heather B.}, year={2012}, month={Dec}, pages={465–478} }
 @article{cao_patisaul_2011, title={Sexually dimorphic expression of hypothalamic estrogen receptors α and β and kiss1 in neonatal male and female rats}, volume={519}, ISSN={0021-9967}, url={http://dx.doi.org/10.1002/cne.22648}, DOI={10.1002/cne.22648}, abstractNote={AbstractRelease of gonadotropins in adult rodents is sex specific and dependent upon kisspeptin (Kiss1) neurons. This crucial pathway within the hypothalamic‐pituitary‐gonadal (HPG) axis is profoundly influenced by neonatal estrogens, which induce a male‐like phenotype. Classically, estrogen activity is mediated via the estrogen receptors α and β (ERα and ERβ), but the relative roles each plays in organizing the sex‐specific ontogeny of kisspeptin signaling pathways remain unresolved. Thus, the present study used in situ hybridization histochemistry (ISHH) to map the temporal and sexually dimorphic neonatal mRNA expression profiles of ERα, ERβ, and Kiss1 in the anterioventral periventricular nucleus (AVPV), medial preoptic area (MPOA), ventromedial nucleus (VMN), and arcuate nucleus (ARC), all regions critical for kisspeptin regulation of gonadotropin secretion. In general, females had higher levels of ERα, in all regions examined, a sex difference that persisted until postnatal day (PND) 19 except in the ARC. Males had significantly more ERβ expression in the AVPV at birth, but this sex difference was lost and then re‐emerged on PND 19, with females having more than males. VMN ERβ levels were higher in females until PND 19. Kiss1 was not detectable until PND 11 in the anterior hypothalamus, but expression levels were equivalent at birth in the ARC. By PND 2, ARC ERα and Kiss1 levels were abundant, sexually dimorphic (higher in females), and, respectively, showed a U‐ and a bell‐shaped pattern with age. Sex differences in ARC Kiss1 expression provide evidence that Kiss1 may play a role in the sexual dimorphic organization of the neonatal brain. These detailed profiles of neonatal Kiss1 and ERs mRNA levels will help elucidate the relative roles each plays in the sex‐specific, estrogen‐dependent organization of gonadotropin signaling pathways. J. Comp. Neurol. 519:2954–2977, 2011. © 2011 Wiley‐Liss, Inc.}, number={15}, journal={The Journal of Comparative Neurology}, publisher={Wiley}, author={Cao, Jinyan and Patisaul, Heather B.}, year={2011}, month={Aug}, pages={2954–2977} }
 @article{cao_patisaul_petersen_2011, title={Aryl hydrocarbon receptor activation in lactotropes and gonadotropes interferes with estradiol-dependent and -independent preprolactin, glycoprotein alpha and luteinizing hormone beta gene expression}, volume={333}, ISSN={["0303-7207"]}, DOI={10.1016/j.mce.2010.12.027}, abstractNote={Arylhydrocarbon receptor (Ahr) activation by 2,3,7,8-tetrachlordibenzo-p-dioxin (TCDD) interferes with female reproductive functions, but there is little information on the specific targets of TCDD in the hypothalamic–pituitary–gonadal (HPG) axis. In these studies, we found that TCDD upregulated known AhR target genes, cytochrome p450 1a1 (Cyp1a1), Cyp1a2 and Cyp1b1 in the rat pituitary gland. Moreover, 75% of pituitary lactotropes and 45% of gonadotropes contained Ahr mRNA, and most Ahr-containing cells were estrogen receptor 1 (Esr1)-positive. TCDD abrogated estradiol (E2)-induced prolactin (Prl) expression in vivo and in vitro; conversely, E2 blocked TCDD upregulation of luteinizing hormone beta (Lhb) and glycoprotein hormone alpha polypeptide (Cga) expression. TCDD had no effect on levels of Ahr mRNA, but upregulated Esr1 mRNA. E2 independently repressed Ahr and Esr1 expression and blocked TCDD upregulation of Esr1. Thus, complex interactions between Ahr and Esr alter Prl and luteinizing hormone (LH) synthesis by direct actions in lactotropes and gonadotropes. These findings provide important insights into how TCDD disrupts female reproductive functions.}, number={2}, journal={MOLECULAR AND CELLULAR ENDOCRINOLOGY}, author={Cao, Jinyan and Patisaul, Heather B. and Petersen, Sandra L.}, year={2011}, month={Feb}, pages={151–159} }
 @article{losa_todd_sullivan_cao_mickens_patisaul_2011, title={Neonatal exposure to genistein adversely impacts the ontogeny of hypothalamic kisspeptin signaling pathways and ovarian development in the peripubertal female rat}, volume={31}, ISSN={["0890-6238"]}, DOI={10.1016/j.reprotox.2010.10.002}, abstractNote={Neonatal exposure to estrogenic endocrine disrupting compounds (EDCs) can advance pubertal onset and induce premature anestrous in female rats. It was recently discovered that hypothalamic kisspeptin (KISS) signaling pathways are sexually dimorphic and regulate both the timing of pubertal onset and estrous cyclicity. Thus we hypothesized that disrupted sex specific ontogeny of KISS signaling pathways might be a mechanism underlying these EDC effects. We first established the sex specific development of KISS gene expression, cell number and neural fiber density across peripuberty in the anteroventral periventricular nucleus (AVPV) and arcuate nucleus (ARC), hypothesizing that the sexually dimorphic aspects of KISS signaling would be most vulnerable to EDCs. We next exposed female rats to the phytoestrogen genistein (GEN, 1 or 10 mg/kg bw), estradiol benzoate (EB, 10 μg), or vehicle from post natal day (P) 0–3 via subcutaneous (sc) injection. Animals were sacrificed on either P21, 24, 28, or 33 (n = 5–14 per group at each age). Vaginal opening was significantly advanced by EB and the higher dose of GEN compared to control animals and was accompanied by lower numbers of KISS immunoreactive fibers in the AVPV and ARC. Ovarian morphology was also assessed in all age groups for the presence of multiple oocyte follicles (MOFs). The number of MOFs decreased over time in each group, and none were observed in control animals by P24. MOFs were still present, however, in the EB and 10 mg/kg GEN groups beyond P24 indicating a disruption in the timing of ovarian development.}, number={3}, journal={REPRODUCTIVE TOXICOLOGY}, author={Losa, Sandra M. and Todd, Karina L. and Sullivan, Alana W. and Cao, Jinyan and Mickens, Jillian A. and Patisaul, Heather B.}, year={2011}, month={Apr}, pages={280–289} }
 @article{qiao_cao_xie_shi_2009, title={Cell Growth Inhibition and Gene Expression Regulation by (-)-Epigallocatechin-3-Gallate in Human Cervical Cancer Cells}, volume={32}, ISSN={["1976-3786"]}, DOI={10.1007/s12272-009-1917-3}, abstractNote={EGCG [(-)-epigallocatechin-3-gallate] has shown its antitumor ability and perhaps a potential regimen for cancer patients. The goal of this study was to investigate the effect of EGCG on human papilloma virus (HPV) positive cervical cancer cell lines. EGCG inhibited the growth of CaSki (HPV16 positive) and HeLa (HPV18 positive) cells in a time- and concentration-dependent manner. Cell cycle arrest and apoptosis were observed in two cell lines after EGCG exposure. More importantly, we focused on EGCG regulation ability on pivotal genes involved in cervical cancer: viral oncogenes E6/E7, estrogen receptor (ER) and aromatase. Our results suggested that EGCG may be suitable for prevention and treatment of cervical cancer.}, number={9}, journal={ARCHIVES OF PHARMACAL RESEARCH}, author={Qiao, Yanyan and Cao, Jinyan and Xie, Liangqun and Shi, Xiaolin}, year={2009}, month={Sep}, pages={1309–1315} }