Sex differences in cognition following variations in endocrine status.

Spatial memory, mediated primarily by the hippocampus, is responsible for orientation in space and retrieval of information regarding location of objects and places in an animal's environment. Since the hippocampus is dense with steroid hormone receptors and is capable of robust neuroplasticity, it is not surprising that changes in spatial memory performance occur following a variety of endocrine alterations. Here, we review cognitive changes in both spatial and nonspatial memory tasks following manipulations of the hypothalamic-pituitary-adrenal and gonadal axes and after exposure to endocrine disruptors in rodents. Chronic stress impairs male performance on numerous behavioral cognitive tasks and enhances or does not impact female cognitive function. Sex-dependent changes in cognition following stress are influenced by both organizational and activational effects of estrogen and vary depending on the developmental age of the stress exposure, but responses to gonadal hormones in adulthood are more similar than different in the sexes. Also discussed are possible underlying neural mechanisms for these steroid hormone-dependent, cognitive effects. Bisphenol A (BPA), an endocrine disruptor, given at low levels during adolescent development, impairs spatial memory in adolescent male and female rats and object recognition memory in adulthood. BPA's negative effects on memory may be mediated through alterations in dendritic spine density in areas that mediate these cognitive tasks. In summary, this review discusses the evidence that endocrine status of an animal (presence or absence of stress hormones, gonadal hormones, or endocrine disruptors) impacts cognitive function and, at times, in a sex-specific manner.

A Case Report of the Ongoing Management and Comorbidities of Loin Pain Hematuria Syndrome with an Unusual Presentation.

Loin pain hematuria syndrome (LPHS) is a rare chronic pain disorder that is poorly understood. LPHS presents as unilateral or bilateral flank pain with hematuria of unknown cause. The lack of knowledge surrounding pathogenesis and effective treatment has resulted in missed diagnoses as well as narcotic addiction in some patients. In this case, we describe the presentation and management of a 30-year-old female with a history of anxiety, depression, chronic pelvic bleeding, and pain recently diagnosed with LPHS after a total hysterectomy. She presented with ongoing pelvic pain symptoms with recent tachycardia, recurrent urinary tract infections, and nephrolithiasis. Loin pain hematuria presents as a particularly rare and difficult diagnosis to manage with multiple, sometimes unpredictable, comorbidities. This case serves as an example of a unique presentation with additional uncommon symptoms.

E-cigarette sharing behavior among college students: An exploratory study.

INTRODUCTION: The purpose of this study was to explore sharing behavior among college students who use e-cigarettes. METHODS: A convenience sample of current e-cigarette users answered questionnaire items regarding sharing behavior (e.g., the number of people that have shared e-cigarettes, the settings that sharing takes place, reasons for sharing). RESULTS: Of the 121 participants, 24% shared e-cigarettes every day and 76% shared some days. The most common setting (91%) for sharing was at social gatherings, and participants shared most often (52%) with one or two people, which happened most often (99%) with friends. The top reason (80%) for sharing e-cigarettes was to feel the effects of nicotine. CONCLUSIONS: The finds support the need to address sharing behavior in youth e-cigarette use and the need for more stringent e-cigarette policies and cessation resources.

Rapid Golgi Stain for Dendritic Spine Visualization in Hippocampus and Prefrontal Cortex.

Golgi impregnation, using the Golgi staining kit with minor adaptations, is used to impregnate dendritic spines in the rat hippocampus and medial prefrontal cortex. This technique is a marked improvement over previous methods of Golgi impregnation because the premixed chemicals are safer to use, neurons are consistently well impregnated, there is far less background debris, and for a given region, there are extremely small deviations in spine density between experiments. Moreover, brains can be accumulated after a certain point and kept frozen until further processing. Using this method any brain region of interest can be studied. Once stained and cover slipped, dendritic spine density is determined by counting the number of spines for a length of dendrite and expressed as spine density per 10 µm dendrite.

A potential role for dendritic spines in bisphenol-A induced memory impairments during adolescence and adulthood.

Developmental exposure to Bisphenol A (BPA), an endocrine disrupting chemical, alters many behaviors and neural parameters in rodents and non-human-primates. The effects of BPA are mediated via gonadal hormone, primarily, estrogen receptors, and are not limited to the perinatal period since recent studies show impairments further into development. The studies described in this chapter address the effects of BPA administration during early adolescence on memory and dendritic spine density in intact male and female rats as well as ovariectomized (OVX) rats in late adolescence and show that some of these adolescent induced changes endure into adulthood. In general, BPA impairs spatial memory and induces decreases in dendritic spine density in the hippocampus and the medial prefrontal cortex, two areas important for memory. The effects of adolescent BPA in intact females are compared to OVX females in an attempt to address the importance of estrogens in the mechanism(s) underlying the profound neuronal alterations occurring during adolescent development. In addition, potential mechanisms by which acute and chronic BPA induce structural alterations are discussed. These studies suggest a complex interaction between low doses of BPA, gonadal state and neural development.

Effects of adolescent Bisphenol-A exposure on memory and spine density in ovariectomized female rats: Adolescence vs adulthood.

The endocrine disruptor, Bisphenol-A (BPA), alters many behavioral and neural parameters in rodents. BPA administration to gonadally intact adolescent rats increases anxiety, impairs spatial memory, and decreases dendritic spine density when measured in adulthood. Since BPA's action seems to be mediated through gonadal steroid receptors, the current experiments were done in ovariectomized (OVX) female rats to examine the effects on behavior and spine density of adolescent BPA exposure under controlled hormone conditions. OVX (postnatal day, PND, 21) female Sprague-Dawley rats (n = 66) received subcutaneous injections of BPA (40 µg/kg/bodyweight), 17ß-Estradiol (E2, 50 µg/kg/bodyweight), or saline during adolescence (PND 38-49). Following the last injection brains were processed for Golgi impregnation (Exp1), behavioral and spine density in adolescence (Exp2), or in adulthood (Exp3). In Exp1, E2 increased spine density in CA1 pyramidal cells and BPA decreased spine density in granule cells of the dentate gyrus (DG). In Exp2, BPA impaired spatial memory on the object placement (OP) task, E2 increased spine density in CA1, BPA decreased spine density in the DG and the medial prefrontal cortex (mPFC). When measured in adulthood (Exp3), BPA impaired OP and object recognition (OR) performance, E2 increased spine density in CA1, and BPA decreased spine density in CA1, the mPFC and the DG. Results provide novel data on the effects of adolescent BPA in an OVX model and are compared to data in intact animals and within the context of understanding the importance of the profound neuronal alterations occurring during adolescent development.

Sex differences in chronic stress effects on cognition in rodents.

Chronic stress causes deleterious changes in physiological function in systems ranging from neural cells in culture to laboratory rodents, sub-human primates and humans. It is notable, however, that the vast majority of research in this area has been conducted in males. In this review, we provide information about chronic stress effects on cognition in female rodents and contrast it with responses in male rodents. In general, females show cognitive resilience to chronic stressors which impair male cognitive function using spatial tasks including the radial arm maze, radial arm water maze, Morris water maze, Y-maze and object placement. Moreover, stress often enhances female performance in some of these cognitive tasks. Memory in females is not affected by stress in non-spatial memory tasks like recognition memory and temporal order recognition memory while males show impaired memory following stress. We discuss possible bases for these sex-dependent differences including the use of different strategies by the sexes to solve cognitive tasks. Whether the sex differences result from changes in non-mnemonic factors is also considered. Sex-dependent differences in alcohol and drug influences on stress responses are also described. Finally, the role of neurally derived estradiol in driving sex differences and providing resilience to stress in females is shown. The importance of determining the nature and extent of sex differences in stress responses is that such differences may provide vital information for understanding why some stress related diseases have different incidence rates between the sexes and for developing novel therapeutic treatments.

Bisphenol-A exposure during adolescence leads to enduring alterations in cognition and dendritic spine density in adult male and female rats.

We have previously demonstrated that adolescent exposure of rats to bisphenol-A (BPA), an environmental endocrine disrupter, increases anxiety, impairs spatial memory, and decreases dendritic spine density in the CA1 region of the hippocampus (CA1) and medial prefrontal cortex (mPFC) when measured in adolescents in both sexes. The present study examined whether the behavioral and morphological alterations following BPA exposure during adolescent development are maintained into adulthood. Male and female, adolescent rats received BPA, 40µg/kg/bodyweight, or control treatments for one week. In adulthood, subjects were tested for anxiety and locomotor activity, spatial memory, non-spatial visual memory, and sucrose preference. Additionally, stress-induced serum corticosterone levels and dendritic spine density in the mPFC and CA1 were measured. BPA-treated males, but not females, had decreased arm visits on the elevated plus maze, but there was no effect on anxiety. Non-spatial memory, object recognition, was also decreased in BPA treated males, but not in females. BPA exposure did not alter spatial memory, object placement, but decreased exploration during the tasks in both sexes. No significant group differences in sucrose preference or serum corticosterone levels in response to a stress challenge were found. However, BPA exposure, regardless of sex, significantly decreased spine density of both apical and basal dendrites on pyramidal cells in CA1 but had no effect in the mPFC. Current data are discussed in relation to BPA dependent changes, which were present during adolescence and did, or did not, endure into adulthood. Overall, adolescent BPA exposure, below the current reference safe daily limit set by the U.S.E.P.A., leads to alterations in some behaviors and neuronal morphology that endure into adulthood.

Adolescent bisphenol-A exposure decreases dendritic spine density: role of sex and age.

Bisphenol-A (BPA), a common environmental endocrine disruptor, modulates estrogenic, androgenic, and antiandrogenic effects throughout the lifespan. We recently showed that low dose BPA exposure during adolescence increases anxiety and impairs spatial memory independent of sex. In this study, six week old Sprague Dawley rats (n=24 males, n=24 females) received daily subcutaneous injections (40 µg/kg bodyweight) of BPA or vehicle for one week. Serum corticosterone levels in response to a 1 h restraint stress and spine density were examined at age 7 (cohort 1) and 11 (cohort 2) weeks. Adolescent BPA exposure did not alter stress dependent corticosterone responses but decreased spine density on apical and basal dendrites of pyramidal cells in the medial prefrontal cortex (mPFC) and hippocampal CA1 region (CA1). Sex differences in spine density were observed on basal dendrites of the mPFC and CA1 with females having greater spine density than males. This sex difference was further augmented by both age and treatment, with results indicating that BPA-dependent decreases in spine density were more pronounced in males than females on mPFC basal dendrites. Importantly, the robust neuronal alterations were observed in animals exposed to BPA levels below the current U.S.E.P.A. recommended safe daily limit. These results are the first demonstrating that BPA given during adolescence leads to enduring effects on neural morphology at adulthood. Given that humans are routinely exposed to low levels of BPA through a variety of sources, the decreased spine density reported in both male and female rats after BPA exposure warrants further investigation.

Epigenetic dysregulation of SHANK3 in brain tissues from individuals with autism spectrum disorders.

The molecular basis for the majority of cases of autism spectrum disorders (ASD) remains unknown. We tested the hypothesis that ASD have an epigenetic cause by performing DNA methylation profiling of five CpG islands (CGI-1 to CGI-5) in the SHANK3 gene in postmortem brain tissues from 54 ASD patients and 43 controls. We found significantly increased overall DNA methylation (epimutation) in three intragenic CGIs (CGI-2, CGI-3 and CGI-4). The increased methylation was clustered in the CGI-2 and CGI-4 in ∼15% of ASD brain tissues. SHANK3 has an extensive array of mRNA splice variants resulting from combinations of five intragenic promoters and alternative splicing of coding exons. Altered expression and alternative splicing of SHANK3 isoforms were observed in brain tissues with increased methylation of SHANK3 CGIs in ASD brain tissues. A DNA methylation inhibitor modified the methylation of CGIs and altered the isoform-specific expression of SHANK3 in cultured cells. This study is the first to find altered methylation patterns in SHANK3 in ASD brain samples. Our finding provides evidence to support an alternative approach to investigating the molecular basis of ASD. The ability to alter the epigenetic modification and expression of SHANK3 by environmental factors suggests that SHANK3 may be a valuable biomarker for dissecting the role of gene and environment interaction in the etiology of ASD.

Adolescent exposure to Bisphenol-A increases anxiety and sucrose preference but impairs spatial memory in rats independent of sex.

The endocrine disruptor Bisphenol-A (BPA) has been shown to modulate estrogenic, androgenic, and anti-androgenic effects. The effects of BPA exposure during early organizational periods of development have been well documented. The current study focuses on the effects of short term, low-dose BPA exposure on anxiety, spatial memory and sucrose preference in adolescent rats. Seven week old Sprague Dawley rats (n=18 male, n=18 female) received daily subcutaneous injections (40 µg/kg body weight) of BPA or vehicle for 12 days. Starting on day 6 of injections, subjects were tested on the elevated plus maze which provides a measure of anxiety, the open field test which provides a measure of anxiety and locomotor activity, and object placement, a measure of spatial memory. On the twelfth day of BPA administration, sucrose preference was tested using a standard two-bottle choice (tap versus sucrose solution). All rats gained weight during the study; there was a main effect of sex, but not BPA treatment on body weight. The results indicate that BPA exposure, regardless of sex, increased anxiety on both the elevated plus maze and open field. Spatial memory was impaired on the object recognition task with BPA animals spending significant less time with the object in the novel location than controls. Finally, a significant increase in sucrose consumption for both male and female subjects exposed to BPA was observed. The current data shows that short term BPA exposure, below the current reference safe daily limit of 50 µg/kg day set by the United States Environmental Protection Agency, during adolescent development increases anxiety, impairs spatial memory, and increases sucrose consumption independent of sex.

Sexual abuse prevention: a training program for developmental disabilities service providers.

Persons with developmental disabilities are at an increased risk for becoming victims of sexual abuse. Research has revealed that the largest group of identified perpetrators of sexual abuse is developmental disability service providers. The purpose of the present study was to develop, implement, and evaluate the effectiveness of a sexual abuse prevention training program. Participants were administered a survey assessing knowledge and attitudes before and after the training workshop. Small improvements in knowledge and attitudes about sexual abuse and the sexuality of persons with developmental disabilities were found; however, ge-neral attitudes about individuals with developmental disabilities did not change. Suggestions for future directions in this area are provided.

Aged rats: sex differences and responses to chronic stress.

Cognitive, as well as physiological, sex differences exist in young adult rats under both basal conditions and following chronic stress; however, few studies have examined whether sex differences remain in aged subjects and whether responses to stress are altered. We compared aged male and female Fischer 344 rats (21.5 months at testing) without stress and when given 21 days of restraint for 6 h/day on locomotion, anxiety-related behaviors, object recognition (non-spatial memory), object placement (spatial memory), body weight and serum steroid hormone levels. Control (unstressed) females had lower levels of estradiol and testosterone and higher corticosterone than males, and stress had no lasting effect on hormone concentrations. Females weighed less than males and showed less weight loss with stress. Locomotion measures on an open field were similar in the sexes and unaffected by stress. Anxiety-related behavior measures on the field showed that males were generally more anxious and that stress increased male, but decreased, female anxiety-related behaviors. In memory testing, exploration of objects was not different between the sexes, with or without stress, while stress increased exploration in both sexes during object recognition trials. Both males and females, regardless of treatment, discriminated between old and new objects at short, but not long, inter-trial delays. The typical advantage of young males for spatial memory performance was not observed in aged subjects on the object placement tasks. Stress-dependent enhancements in females and impairments in males for object placement are reported for young rats, but in aged rats, neither sex was altered by stress. Current data suggest that aging is associated with changes in the pattern of sex differences present in young adult rats in some behaviors and in the behavioral responses to stress.

Sexually dimorphic effects of prenatal stress on cognition, hormonal responses, and central neurotransmitters.

Exposure to stress during gestation results in physiological and behavioral alterations that persist into adulthood. This study examined the effects of prenatal stress on the postnatal expression of sexually differentiated cognitive, hormonal, and neurochemical profiles in male and female rats. Pregnant dams were subjected to restraint stress three times daily for 45 min during d 14-21 of pregnancy. The offspring of control and prenatally stressed dams were tested for anxiety-related and cognitive behaviors, stress and gonadal steroid hormone levels, as well as monoamines and metabolite levels in selected brain regions. Postnatal testosterone levels (measured at 1 and 5 d) did not differ between controls and prenatally stressed animals. In adulthood, the serum corticosterone response to stress was attenuated in prenatally stressed females, eliminating the sex difference normally observed in this parameter. Prenatally stressed females exhibited higher anxiety levels, evidenced by longer open field entry latencies. Prenatal stress had no effect on object recognition memory, but eliminated the advantage normally seen in the male performance of a spatial memory task. Neurochemical profiles of prenatally stressed females were altered toward the masculine phenotype in the prefrontal cortex, amygdala, and hippocampus. Thus, prenatal stress altered subsequent cognitive, endocrine, and neurochemical responses in a sex-specific manner. These data reinforce the view that prenatal stress affects multiple aspects of brain development, interfering with the expression of normal behavioral, neuroendocrine, and neurochemical sex differences. These data have implications for the effects of prenatal stress on the development of sexually dimorphic endocrine and neurological disorders.

Functional aspects of estrogen neuroprotection.

Evidence that estrogen protects neurons against toxic/ ischemic insults or degenerative/aging processes is evident in a variety of in vitro and in vivo systems. However, a critical remaining question is: Does the demonstrated morphologic and neurochemical protection by estrogen lead to a preservation of brain function or an enhanced ability to recover? To date, little basic research is available on this issue. Cognition is a critical function that might provide a sensitive way to examine this question. As a first step, we present results showing that two chronic environmental insults, psychoactive drugs and stress, produce gender-specific responses in cognitive abilities. Specifically, females appear less sensitive than males to cognitive impairments following chronic exposure to these factors. Results are presented in male and female rats utilizing cognitive tests that assess visual (object recognition) and spatial memory (object placement and radial arm maze) following chronic amphetamine, methamphetamine, or daily restraint stress. Following regimes of chronic stress or amphetamine, males were impaired on these tasks while females were either unaffected, less affected, or enhanced in performance. These observations suggest that differences in circulating gonadal hormone levels between the sexes may contribute to the differential sensitivity of the sexes and provide endogenous neuroprotection for females. Surprisingly, ovariectomized females were still not impaired following a stress regimen that impaired males (21 d of daily restraint). These data taken together with neurochemical data on estrogen neuroprotective effects indicate that it is possible that neuroprotection by estrogen may result from hormone action both during sexual differentiation (organizational effect) and in adulthood (activational effect). These considerations and possible unwanted/untoward effects of chronic estrogen use are discussed in relation to the use of selective estrogen receptor modulators for chronic treatment of both males and females. In conclusion, although compelling evidence for neuroprotection by estrogen has been presented in anatomic and neurochemical studies, it is clear that the functional/ behavioral aspects need further investigation.

Chronic stress effects on memory: sex differences in performance and monoaminergic activity.

Increasing evidence suggests that the time course of advantageous versus deleterious effects of stress on physiologic function is also apparent in some brain functions, including learning and memory. This article reviews the effects of chronic stress on behavioral performance and, more importantly, shows that sex of the subject, as well as duration and intensity of stress, is an important determinant of the functional/behavioral, neurochemical, and anatomical consequences of the stress. Following chronic stress (7-28 days of restraint, 6 h/day), male and female rats were tested on a visual memory task (object recognition) and two spatial memory tasks (object placement and radial arm maze). At 21 days, stress impaired males on all tasks while females were either enhanced (spatial memory tasks) or not impaired (nonspatial memory tasks). Additionally, the influence of the hypothalamic-pituitary-adrenocortical axis in mediating the sex-specific responses to stress is considered. Behavioral and neurochemical assessments following chronic stress in ovariectomized females, with and without estradiol, suggest that estrogen exerts both organizational and activational influences on the observed sex differences in response to stress. Furthermore, stress differentially affected central transmitter levels in the frontal cortex, hippocampus, and amygdala depending on sex. The possible role of these sex-specific changes in neurotransmitter levels in mediating behavioral differences in response to stress is discussed. While these results are thus far limited to a few studies and require both further investigation and verification, chronic stress appears to be associated with distinct, sex-differentiated behavioral/cognitive and neurochemical responses. We conclude that sex differences must be taken into account when investigating or describing stress and associated sequalae.