Anne T. M. Konkle

When is a sex difference not a sex difference

Brain sexual differentiation in mammals requires activity of gonadal hormones; organizational effects of these steroids on brain development occur early in life while activational ones in adulthood ensure appropriate and timely sex-specific behaviors. This traditional view has long served as a reliable model for sexual differentiation of reproductively relevant brain structures. Here, we take a fresh look at this model but refocused in the context of sexual differentiation of non-reproductive parameters and with an emphasis on the hippocampus, a telencephalic brain structure predominantly involved in cognition and stress regulation. We explore sex differences in morphology, neurochemistry, and hippocampal-dependent behaviors to propose a new prototype that can be used to explain and further investigate the effects of steroid hormones, those synthesized gonadally or intracerebrally, on hippocampal development and function. We also propose that a new vernacular be employed, one that distinguishes hormonally modulated responses from sex differences, and argue these are mechanistically and functionally distinct. Understanding when and how the sexes are different is as important as understanding when and how they are the same, at the biological, social, and cultural level.

Evaluation of the effects of chronic mild stressors on hedonic and physiological responses: sex and strain compared

The chronic mild stress (CMS) paradigm was developed in order to simulate in animals the symptom of anhedonia, a major feature of depression. Typically, changes in hedonic status are interpreted from a decrease in either intake or preference for a mild sucrose solution. Although the incidence of clinical depression is significantly higher in women than in men, the study of this disorder in most animal models of depression has been based on the responses of male rodents. The purpose of this study was to compare the effects of 6 weeks of CMS administration among male and female rats of two rat strains, Sprague-Dawley (SD) and Long Evans (LE), with respect to physiological (body, adrenal gland, and spleen weight) and biochemical (plasma corticosterone levels) indices of stress as well as evaluations of 1 and 24 h sucrose intake and preference. Estrous cycle was tracked throughout the study. Overall, our results indicate a slower rate of weight gain in animals, greater in males, exposed to the chronic stressor regime. Furthermore, CMS is shown to disrupt estrous cycling, predominantly in the Long Evans strain of rats. The main behavioral finding was a significant reduction in 24 h sucrose intake in female treated groups, which was not accompanied by alterations in preference. Corticosterone levels were elevated in CMS-treated animals relative to the singly housed control groups, but exposure to a subsequent stressor was not influenced by the stress history. Taken together, the effects of chronic stressor exposure are evident, based on physiological and biochemical indices, although none of the measures distinguished any striking gender specific reactions. The usefulness of sucrose intake or preference as behavioral indices of CMS-induced anhedonia in males and females is modest at best.

Impact of sex and hormones on new cells in the developing rat hippocampus: a novel source of sex dimorphism?

The hippocampus is a key brain region regulating complex cognitive and emotional responses, and is implicated in the etiology of depressive and anxiety disorders, many of which exhibit some degree of sex difference. The male rat hippocampus is consistently reported to be slightly but significantly larger than the female. The majority of studies on the development of volumetric sex differences have focused on the effects of estradiol (E2), with relatively few focusing on androgens. We examined the impact of both E2 and androgens on newly born cells in the developing rat hippocampus, and report that neonatal males have significantly more 5‐bromo‐2′‐deoxyuridine‐5′‐monophosphate (BrdU)+ cells than females. Both testosterone (T) and dihydrotestosterone treatment of females significantly increased the number of BrdU+ cells, an effect blocked by the androgen receptor antagonist, flutamide. However, only T significantly increased the number of neuronal nuclear antigen+ neurons in the female rat hippocampus. Interestingly, E2 treatment also increased BrdU+ cells in females, but had no effect on neuron number. Instead, E2 and T significantly increased the number of newly born glial fibrillary acidic protein or glutamine synthetase+ glial cells in females, indicating that androgens and E2 may act independently to achieve distinct endpoints. Quantification of pyknotic cells at two different developmental time points indicates no sex difference in the number of cells dying, suggesting, but not proving, that gonadal steroids are promoting cell genesis.

The effects of chronic mild stress on male Sprague-Dawley and Long Evans rats: I. Biochemical and physiological analyses.

The chronic unpredictable mild stress (CMS) is a paradigm developed in animals to model the relatively minor and unanticipated irritants that lead to a state of anhedonia in some individuals. However, the effectiveness of CMS is sometimes difficult to establish, for which unique strain sensitivities has been attributed as one contributing factor. These considerations led us to design the present study, which was an investigation of the corticosterone response to CMS in two outbred rat strains--Sprague-Dawley and Long Evans. Animals were exposed to one of two conditions--control or CMS--for 3 weeks during which body weight and fecal count were regularly monitored. At the end of this period, blood was sampled at a variety of time intervals following induction of a brief restraint stressor. First, a significant effect of CMS on corticosterone levels was evident at time 0 (prior to the application of the acute restraint stressor) in both strains. Second, the typical quadratic pattern of stressor-elicited fluctuations in this measure was similar in both Sprague-Dawley and Long Evans rats, with consistently elevated levels for the first hour following exposure to the acute stressor; near baseline values were observed at 2 h. However, only in the Long Evans strain were CMS related values much less than that observed in the control group after restraint stress. Third, both strains showed a reduced weight gain in the CMS groups relative to control groups. Fourth, spleen and adrenal weights were similar across all groups. Fifth, fecal counts remained stable across weeks of treatment in all groups with the exception of the Long Evans rats exposed to CMS; in this group, average counts were systematically reduced over the treatment period. We conclude that a history of chronic stress significantly blunts corticosterone levels in Long Evans but not Sprague-Dawley rats following exposure to an acute stressor. Physiological indices however are less influenced by this experience, at least when the exposure is limited to 3 weeks.

Strain and gender specific effects in the forced swim test: Effects of previous stress exposure

The chronic mild stress (CMS) procedure was developed in rodents to target anhedonia, the core symptom of depressive melancholia. Stress exposure has been shown to induce a variety of physiological, biochemical and behavioral alterations associated with depression, although its anhedonic consequences as indexed by either sucrose intake and preference or thresholds for brain stimulation reward are less reliably observed. In the present study, we assessed the effects of six weeks of CMS on the latter measure in two strains of male and female rats subsequently challenged with an acute psychophysical stressor, forced swimming; their behavior in the swimming cylinder was evaluated on two consecutive days. While brain stimulation reward thresholds and response rates were unchanged by CMS exposure, significant differences in forced swim behaviors were observed between male control and CMS groups. In particular, male Long Evans rats with a history of CMS showed the largest decrease in the duration of active behaviors on the second test day, a pattern less evident in the Sprague-Dawley strain of rats, or in any of the female groups. The results suggest that the effects of depressogenic manipulations are strain and gender dependent, with male Long Evans rats most susceptible, as demonstrated by the selective reduction of struggling behaviors. Inclusion of multiple measures, including the forced swim test, would provide a better understanding of the psychopathological profile engendered by chronic exposure to mild stressors and its genetic specificity.

Bisphenol-A: Epigenetic Reprogramming and Effects on Reproduction and Behavior

Bisphenol A (BPA) is a synthetic compound used in the production of many polycarbonate plastics and epoxy resins. It is one of the most widely produced chemicals in the world today and is found in most canned goods, plastics, and even household dust. Exposure to BPA is almost universal: most people have measurable amounts of BPA in both urine and serum. BPA is similar in structure to estradiol and can bind to multiple targets both inside and outside the nucleus, in effect acting as an endocrine disruptor. Research on BPA exposure has accelerated in the past decade with findings suggesting that perinatal exposure to BPA can negatively impact both male and female reproduction, create alterations in behavior, and act as a carcinogen. BPA can have both short term and long term effects with the latter typically occurring through epigenetic mechanisms such as DNA methylation. This review will draw on both human and animal studies in an attempt to synthesize the literature and examine the effects of BPA exposure on reproduction, behavior, and carcinogenesis with a focus on the potential epigenetic mechanisms by which it acts.

Behavioral and physiological effects of chronic mild stress in female rats

Anhedonia, a core symptom of clinical depression, refers to the loss of interest in normally rewarding stimuli; the chronic mild stress paradigm, an animal model of depression, was designed with this as an underlying feature. The procedure consists of the administration of a variety of ecologically relevant stressors over long durations. Its effects have been thoroughly investigated in male but not female rats. This study examines the appropriateness of stressors designed to evaluate the development and progression of depression in two strains of female rats, the effectiveness of two measures of anhedonia, and the relationship between stress reactivity and the estrous cycle. Changes in hedonic status were indexed for three weeks following a three week baseline period using two standard behavioral measures of anhedonia: sucrose intake and preference and thresholds for brain stimulation reward. Decreases in 24 h sucrose intake were observed in both strains during the first week of stress manipulations, and continued to decline thereafter for the remainder of the stress phase; in contrast, sucrose preference was unaffected by the stressors, indicating an overall reduction in fluid intake. No changes in the thresholds for brain stimulation reward were observed. The cyclical pattern of estrous was altered in both strains with a significant reduction in the number of regular cycles as a consequence of both the stressors and brain stimulation reward. Furthermore, cyclicity was not reinstated in many animals even six weeks after stress manipulations and behavioral tests had ceased. While the physiological measures suggest that the mild stressors are disruptive to female rats, the results of the behavioral tests are not consistent with the notion that the stressors induce an anhedonic state.

Doublecortin as a marker of adult neuroplasticity in the canary song control nucleus HVC

It is established that in songbirds the size of several brain song control nuclei varies seasonally, based on changes in cell size, dendritic branching and, in nucleus HVC, the incorporation of newborn neurons. In the developing and adult mammalian brain, the protein doublecortin (DCX) is expressed in postmitotic neurons and, as a part of the microtubule machinery, required for neuronal migration. We recently showed that in adult canaries, DCX‐immunoreactive (ir) cells are present throughout the telencephalon, but the link between DCX and the active neurogenesis observed in songbirds remained uncertain. We demonstrate here that DCX labels recently born cells in the canary telencephalon and that, in parallel with changes in HVC volume, the number of DCX‐ir cells is increased specifically in the HVC of testosterone‐treated males compared with castrates, and in castrated testosterone‐treated males paired with a female as compared with males paired with another male. The numbers of elongated DCX‐ir cells (presumptive migrating neurons) and round multipolar DCX‐ir cells (differentiating neurons) were also affected by the sex of the subjects and their photoperiodic condition (photosensitive vs photostimulated vs photorefractory). Thus, in canaries the endocrine state, as well as the social or photoperiodic condition independently of variation in steroid hormone action, affects the number of cells expressing a protein involved in neuronal migration specifically in brain areas that incorporate new neurons in the telencephalon. The DCX gene may be one of the targets by which testosterone and social stimuli induce seasonal changes in the volume of song nuclei.

MP3 player listening habits of 17 to 23 year old university studentsa)

This study evaluated the potential risk to hearing associated with the use of portable digital audio players. Twenty-eight university students (12 males, 16 females; aged 17-23) completed a 49-item questionnaire assessing user listening habits and subjective measures of hearing health. Sound level measurements of participants self-identified typical and worst case volume levels were taken in different classrooms with background sound levels between 43 and 52 dBA. The median frequency and duration of use was 2 h per day, 6.5 days a week. The median sound levels and interquartile ranges (IQR) at typical and worst case volume settings were 71 dBA (IQR=12) and 79 dBA (IQR=9), respectively. When typical sound levels were considered with self-reported duration of daily use, none of the participants surpassed Leq(8) 85 dBA. On the questionnaire, 19 students reported experiencing at least one symptom of possible noise-induced hearing loss. Significant differences in MP3 user listening patterns were found between respondents who had experienced tinnitus and those who had not. The findings add to a growing body of literature that collectively supports a need for further research investigating MP3 player user listening habits in order to assess their potential risk to hearing health.

Tracing the neuroanatomical profiles of reward pathways with markers of neuronal activation.

Functional neuroanatomical tools have played an important role in proposing which structures underlie brain stimulation reward circuitry. This review focuses on studies employing metabolic markers of neuronal and glial activation, including 2-deoxyglucose, cytochrome oxidase, and glycogen phosphorylase, and a marker of cellular activation, the immediate early gene c-fos. The principles underlying each method, their application to the study of brain stimulation reward, and their strengths and limitations are described. The usefulness of this strategy in identifying candidate structures, and the degree of overlap in the patterns of activation arising from different markers is addressed in detail. How these data have contributed to an understanding of the organization of reward circuitry and directed our thinking towards an alternative framework of neuronal arrangement is discussed in the final section.