Sex differences in salivary cortisol in response to acute stressors among healthy participants, in recreational or pathological gamblers, and in those with posttraumatic stress disorder

Sex differences in incidence and severity of some stress-related, neuropsychiatric disorders are often reported to favor men, suggesting that women may be more vulnerable to aberrant hypothalamic-pituitary-adrenal (HPA) axis responses to stress. In this review, we discuss several investigations that we, and others, have conducted assessing salivary cortisol as a measure of HPA function. We have examined basal cortisol among healthy men and women and also following acute exposure to stressors. Among healthy participants, men had higher basal cortisol levels than did women. In response to acute stressors, such as carbon dioxide or noise, respectively, cortisol levels were comparable between men and women or higher among women. We have also examined cortisol levels among those with problem eating, gambling, or posttraumatic stress disorder (PTSD). Women with restrained eating habits have higher basal cortisol levels than do women without restrained eating habits. Pathological gamblers have more aberrant stress response to gambling stimuli than do recreational gamblers, and these effects are more prominent among men than women. Men who have motor vehicle accident related PTSD, demonstrate more aberrant cortisol function, than do their female counterparts. Although these sex differences in cortisol seem to vary with type of stress exposure and/or pathophysiological status of the individual, other hormones may influence cortisol response. To address this, cortisol levels among boys and girls with different stress-related experiences, will be the subject of future investigation.     

Pre-experience of social exclusion suppresses cortisol response to psychosocial stress in women but not in men

Lack of social support and social exclusion is associated with adverse effects for mental and physical health. Additionally, women appear to be more vulnerable to social triggers of health disturbances. The hypothalamus–pituitary–adrenocortical-axis (HPA axis) might play a key role in this context as it has been shown both to relate to psychosocial conditions and health outcomes and to respond differentially depending on gender. In a previous experiment we found no effects of exclusion alone (operationalized via Cyberball) on cortisol secretion. Here we examine the effects of a social exclusion pre-experience on psychological and cortisol responses to a public speaking stressor. Subjects (33 m, 34 f) were randomly assigned to social exclusion (SE) or one of two control conditions (exclusion attributed to technical default (TD) and social inclusion (SI)). Afterwards salivary cortisol and psychological responses to a public speaking paradigm were assessed. Exclusion pre-treatment does not affect psychological responses to public speaking stress though with respect to cortisol significant. Cyberball by gender and Cyberball by gender by time interactions are found. SE-women show a blunted cortisol stress response to public speaking while cortisol responses of SE-men fall between SI-men and TD-men. Pre-experience of social exclusion leads to a blunted cortisol response to stress in women but not in men. This factor might contribute to the higher vulnerability to social triggers of health disturbances observed in women.     

Cannabinoid-hormone interactions in the regulation of motivational processes

There is a bi-directionality in hormone-cannabinoid interactions: cannabinoids affect prominent endocrine axes (such as the hypothalamic-pituitary-gonadal), and gonadal hormones modulate cannabinoid effects. This review will summarize recent research on these interactions, with a specific focus upon their implications for motivated behavior. Sexual behavior will serve as a “case study.” I will explore the hypothesis that ovarian hormones, in particular estradiol, may serve to release estrous behavior from endocannabinoid inhibition. Hormonal regulation of the endogenous cannabinoid system also affects processes that underlie drug abuse. This review will briefly discuss sex differences in behavioral responses to cannabinoids and explore potential mechanisms by which gonadal hormones alter cannabinoid reward. An examination of this research informs our perspective on how hormones and endocannabinoids may affect drug-seeking behavior as a whole and the development of addiction.     

Making heads from tails: Development of a reversed anterior-posterior axis during budding in an acoel

The anterior-posterior axis is a key feature of the bilaterian body plan. Although axis specification during embryogenesis has been studied extensively, virtually nothing is known about how this axis can be established post-embryonically, as occurs in budding animals. We investigated bud formation in the acoel Convolutriloba retrogemma, which reproduces by a remarkable process involving the formation of animals with linked but completely opposite body axes. Reverse axes are established anew during each round of budding and manifestations of the bud's new axis develop gradually, with regionalization of axial patterning genes (Hox and otx) and the establishment of organized musculature occurring secondarily, after bud initiation. A swath of tissue at the parent-bud boundary has no regenerative potential and appears devoid of inherent axial polarity. GSK-3 inhibitor trials suggest that Wnt/β-catenin or Hedgehog signalling may mediate the establishment of this unpolarized zone. Formation of unpolarized tissue may provide a buffer between opposing polarity cues and be a general mechanism by which budding animals establish and maintain linked body axes. In addition to elucidating the developmental basis of budding in a bilaterian, this study provides insight into convergence in animal budding mechanisms, redeployment of embryonic gene expression during budding, and Hox gene evolution.     

Additional sex combs-like 1 belongs to the enhancer of trithorax and polycomb group and genetically interacts with Cbx2 in mice

The Additional sex combs (Asx) gene of Drosophila behaves genetically as an enhancer of trithorax and polycomb (ETP) in displaying bidirectional homeotic phenotypes, suggesting that is required for maintenance of both activation and silencing of Hox genes. There are three murine homologs of Asx called Additional sex combs-like1, 2, and 3. Asxl1 is required for normal adult hematopoiesis; however, its embryonic function is unknown. We used a targeted mouse mutant line Asxl1^tm1Bc to determine if Asxl1 is required to silence and activate Hox genes in mice during axial patterning. The mutant embryos exhibit simultaneous anterior and posterior transformations of the axial skeleton, consistent with a role for Asxl1 in activation and silencing of Hox genes. Transformations of the axial skeleton are enhanced in compound mutant embryos for the polycomb group gene M33/Cbx2. Hoxa4, Hoxa7, and Hoxc8 are derepressed in Asxl1^tm1Bc mutants in the antero-posterior axis, but Hoxc8 expression is reduced in the brain of mutants, consistent with Asxl1 being required both for activation and repression of Hox genes. We discuss the genetic and molecular definition of ETPs, and suggest that the function of Asxl1 depends on its cellular context.     

Functional redundancy of EGF-CFC genes in epiblast and extraembryonic patterning during early mouse embryogenesis

During early mouse embryogenesis, multiple patterning and differentiation events require the activity of Nodal, a ligand of the transforming growth factor-beta (TGFβ) family. Although Nodal signaling is known to require activity of EGF-CFC co-receptors in many contexts, it has been unclear whether all Nodal signaling in the early mouse embryo is EGF-CFC dependent. We have investigated the double null mutant phenotypes for the EGF-CFC genes Cripto and Cryptic, which encode co-receptors for Nodal, and have found that they have partially redundant functions in early mouse development. Expression of Cripto and Cryptic is non-overlapping prior to gastrulation, since Cripto is expressed solely in the epiblast whereas Cryptic is expressed in the primitive endoderm of the late blastocyst and the visceral endoderm after implantation. Despite these non-overlapping expression patterns, Cripto; Cryptic double mutants display severe defects in epiblast, extraembryonic ectoderm, and anterior visceral endoderm (AVE), resulting in phenotypes that are highly similar to those of Nodal null mutants. Our results indicate that both Cripto and Cryptic function non-cell-autonomously during normal development, and that most if not all Nodal activity in early mouse embryogenesis is EGF-CFC-dependent.     

Polycomb group protein Ezh1 represses Nodal and maintains the left-right axis

The left-right (LR) axis is essential for the proper function of internal organs. In mammals and fish, left-sided Nodal expression governs LR patterning. Here, we show that the Polycomb group protein Ezh1, which is highly conserved from fish to human, participates in LR patterning. Knockdown of olezh1, a medaka homologue of Ezh1, led to LR reversal of internal organs. It was shown that OLEZH1 acts in silencing the expression of Spaw (a medaka homolog of Nodal) via a previously unknown pathway. Furthermore, coimmunoprecipitation showed physical interaction of Ezh1 with FoxH1, a Nodal regulator. This represents a novel mechanism for LR patterning and implies that Ezh1 has developmental importance.     

Contours of the hominoid lateral tibial condyle with implications for Australopithecus

Tibial condyle shape is alleged to vary among fossil tibiae attributed to Australopithecus, and has been argued to reflect functional differences of the knee. Convex anteroposterior curvature of the lateral tibial condyle in A. africanus has been interpreted to indicate a more chimpanzee-like locomotor repertoire than the flatter lateral tibial condyles of A. afarensis (Berger and Tobias, 1996, J. Hum. Evol. 30, 343). Alternatively, Latimer, Ohman, and Lovejoy (1987, Am. J. Phys. Anthropol. 74, 155) have suggested that in response to increased transarticular loads accompanied by larger body mass, joints should become flatter as size increases, both within and among species, so that the variation observed among hominin fossils reflects size alone rather than functional differences. In this study, three-dimensional surface areas of the lateral tibial condyle of humans, chimpanzees, and gorillas were computed using a Digibot II (Digibotics) laser scanner and the DataSculpt v.4.6 engineering software package to evaluate joint surface contours, and compared to two-dimensional surface area and arc and chord length measurements of the anteroposterior and mediolateral axes. Extant species measurements were then compared to those of A. afarensis (A.L. 129-1b, A.L. 288-1aq, A.L. 333x-26, A.L. 333-42) and A. africanus (Stw 514a). Results do not support the hypothesis that A. afarensis and A. africanus differ in condylar topology. They also do not support the hypothesis that joint surfaces become flatter with increased transarticular load accompanying increased body size, as curvature of the lateral tibial condyle in anteroposterior and mediolateral planes is not negatively allometric. However, femoral condylar shape is not included in this study, which may better reflect joint surface responses to increased body size. Finally, there is no basis from this study to reconstruct differences in locomotor behavior among fossil hominin taxa based on lateral tibial condyle morphology.     

Bivariate line-fitting methods for allometry

Fitting a line to a bivariate dataset can be a deceptively complex problem, and there has been much debate on this issue in the literature. In this review, we describe for the practitioner the essential features of line-fitting methods for estimating the relationship between two variables: what methods are commonly used, which method should be used when, and how to make inferences from these lines to answer common research questions. A particularly important point for line-fitting in allometry is that usually, two sources of error are present (which we call measurement and equation error), and these have quite different implications for choice of line-fitting method. As a consequence, the approach in this review and the methods presented have subtle but important differences from previous reviews in the biology literature. Linear regression, major axis and standardised major axis are alternative methods that can be appropriate when there is no measurement error. When there is measurement error, this often needs to be estimated and used to adjust the variance terms in formulae for line-fitting. We also review line-fitting methods for phylogenetic analyses. Methods of inference are described for the line-fitting techniques discussed in this paper. The types of inference considered here are testing if the slope or elevation equals a given value, constructing confidence intervals for the slope or elevation, comparing several slopes or elevations, and testing for shift along the axis amongst several groups. In some cases several methods have been proposed in the literature. These are discussed and compared. In other cases there is little or no previous guidance available in the literature. Simulations were conducted to check whether the methods of inference proposed have the intended coverage probability or Type I error. We identified the methods of inference that perform well and recommend the techniques that should be adopted in future work.     

Regulation of the glucocorticoid response to stress-related disorders by the Hsp90-binding immunophilin FKBP51

Immunophilin is the collective name given to a family of proteins that bind immunosuppressive drugs: Some immunophilins are Hsp90-binding cochaperones that affect steroid receptor function. Mood and anxiety disorders are stress-related diseases characterized by an impaired function of the mineralocorticoid and glucocorticoid receptors, two of the major regulatory elements of the hypothalamus-pituitary-adrenocortical axis. Genetic variations of the FK506-binding protein of 51-kDa, FKBP51, one of the immunophilins bound to those steroid receptor complexes, were associated with the effectiveness of treatments against depression and with a major risk-factor for the development of post-traumatic stress disorders. Interestingly, immunophilins show polymorphisms and some polymorphic isoforms of FKBP51 correlate with a greater impairment of steroid receptor functions. In this review, we discuss different aspects of the role of FKBP51 in such steroid receptor function and the impact of genetic variants of the immunophilin on the dysregulation of the stress response.