Species-specific differences in sensorimotor adaptation are correlated with differences in social structure

Here, we report a species difference in the strength and duration of long-term sensorimotor adaptation in the electromotor output of weakly electric fish. The adaptation is produced by changes in intrinsic excitability in the electromotor pacemaker nucleus; this change is a form of memory that correlates with social structure. A weakly electric fish may be jammed by a similar electric organ discharge (EOD) frequency of another fish and prevents jamming by transiently raising its own emission frequency, a behavior called the jamming avoidance response (JAR). The JAR requires activation of NMDA receptors, and prolonged JAR performance results in long-term frequency elevation (LTFE) of a fish’s EOD frequency for many hours after the jamming stimulus. We find that LTFE is stronger in a shoaling species (Eigenmannia virescens) with a higher probability of encountering jamming conspecifics, when compared to a solitary species (Apteronotus leptorhynchus). Additionally, LTFE persists in Eigenmannia, whereas, it decays over 5–9 h in Apteronotus.     

Sex differences in endothelial STAT3 mediate sex differences in myocardial inflammation

Recent studies have shown that females have improved myocardial functional recovery, TNF receptor 1 (TNFR1) signaling resistance, and increased STAT3 phosphorylation following acute ischemia/reperfusion (I/R) compared with males. We hypothesized that 1) STAT3 deficiency in endothelial cells (EC) impairs myocardial functional recovery in both sexes, 2) EC STAT3 deficiency equalizes sex differences in functional recovery, and 3) knockout of EC STAT3 decreases activation of myocardial STAT3 and increases p38 MAPK activation following acute I/R. Isolated male and female mouse hearts from WT and EC STAT3 knockout (STAT3KO) were subjected to 20-min ischemia/60-min reperfusion, and +/- dP/dt were continuously recorded. Heart tissue was analyzed for the active forms of STAT3 and p38 MAPK as well as expression of caspase-8 (Western blot) following I/R. EC STATKO had significantly decreased myocardial functional recovery in both sexes (%recovered +dP/dt: male 51.6 +/- 3.1 vs. 32.1 +/- 13.1%, female 79.1 +/- 3.6 vs. 43.6 +/- 9.1%; -dP/dt: male 52.2 +/- 3.3 vs. 28.9 +/- 12%, female 75.2 +/- 4.1 vs. 38.6 +/- 10%). In addition, EC STAT3KO neutralized sex differences in myocardial function, which existed in WT mice. Interestingly, EC STAT3 deficiency decreased myocardial STAT3 activation but increased myocardial p38 MAPK activation in both sexes; however, this was seen to a greater degree in females. We conclude that EC STAT3 deficiency resulted in decreased recovery of myocardial function in both sexes and neutralized sex differences in myocardial functional recovery following I/R. This observation was associated with decreased activation of myocardial STAT3 and increased activation of p38 MAPK in EC STAT3KO heart after I/R.     

Sex differences in recombination

One of the stronger empirical generalizations to emerge from the study of genetic systems is that achiasmate meiosis, which has evolved 25–30 times, is always restricted to the heterogametic sex in dioecious species, usually the male. Here we collate data on quantitative sex differences in chiasma frequency from 54 species (4 hermaphroditic flatworms, 18 dioecious insects and vertebrates and 32 hermaphroditic plants) to test whether similar trends hold. Though significant sex differences have been observed within many species, only the Liliaceae show a significant sexual dimorphism in chiasma frequency across species, with more crossing over in embryo mother cells than in pollen mother cells; chiasma frequencies are unrelated to sex and gamety in all other higher taxa studied. Further, the magnitude of sexual dimorphism, independent of sign, does not differ among the three main ecological groups (dioecious animals, plants, and hermaphroditic animals), contrary to what would be expected if it reflected sex-specific selection on recombination. These results indicate that the strong trends for achiasmate meiosis do not apply to quantitative sex differences in recombination, and contradict theories of sex-specific costs and benefits. An alternative hypothesis suggests that sex differences may be more-or-less neutral, selection determining only the mean rate of recombination. While male and female chiasma frequencies are more similar than would be expected under complete neutrality, a less absolute form of the hypothesis is more difficult to falsify. In female mice the sex bivalent has more chiasmata for its length than the autosomes, perhaps compensating for the absence of recombination in males. Finally, we observe that chiasma frequencies in males and females are positively correlated across species, validating the use of only one sex in comparative studies of recombination.     

Gender differences in depression

Depression is twice as common in women as in men, although some concern has been raised in terms of misdiagnosing depression in men. The incidence of depression in women varies during the life span. The peak incidence during childbearing years appears to be associated with cyclic hormonal changes. Women also present with reproductive -specific mood disorders: pre-menstrual dysphoric disorder (PMDD), depression in pregnancy, postpartal mood disorder (PDD) and perimenopausal depressive disorder. Gender differences were repeatedly observed in response to antidepressant medication. Premenopausal women appear to respond poorly and to show low tolerability to TCAs, but they tend to show greater responsiveness to the SSRIs. In contrast, men and postmenopausal women can respond equally to the TCAs and SSRIs. These differences are contributed to gender differences in pharmacokinetics of antidepressants and to the influence of menstrual cycle. These findings suggest the need for a gender-specific approach to the evaluation and management of depression.     

Regional differences in arrhythmogenesis

JGP study shows that the subendocardium is more susceptible to spontaneous Ca²⁺ release events that can initiate arrhythmias, and this may be reduced by local CaMKII inhibition.

Calcium release and uptake must be carefully controlled in cardiomyocytes to ensure that the heart maintains a regular beat, and spontaneous Ca²⁺ release (SCR) from the sarcoplasmic reticulum—due to leaky ryanodine receptors, for example—can trigger lethal ventricular arrhythmias. In this issue of JGP, Dries et al. demonstrate that the subendocardial layer of the ventricular wall is particularly susceptible to arrhythmogenic SCR, and that this could potentially be treated by local inhibition of calcium/calmodulin-dependent kinase II (CaMKII; 1).Using living myocardial slices, Eef Dries (left), Cesare Terracciano (center), and colleagues show that, following injury, the subendocardial layer of the rat ventricular wall is more susceptible than the subepicardial layer to arrhythmogenic SCR events. High-resolution Ca²⁺ imaging of the subendocardium shows the increased number of SCRs (green dots) in the region bordering the injured tissue. The frequency of SCRs and ectopic contractions can be reduced by CaMKII inhibition.SCRs have been extensively studied in isolated cardiomyocytes, but arrhythmias are multicellular events (2) in which the behavior of individual cells is influenced by their interactions with neighboring cells and the extracellular matrix. “In addition, myocardial electrophysiology changes at different depths of the ventricular wall, and the vast majority of studies do not account for this transmurality,” explains Cesare Terracciano, a professor at the National Heart and Lung Institute, Imperial College London.Terracciano’s group has pioneered the use of living myocardial slices prepared from different layers of the ventricular wall to study regional differences in the electrical and mechanical properties of healthy hearts (3,4). However, it is unclear how these differences are impacted by injury or disease and whether this leaves some layers of the heart wall more susceptible to SCRs and arrhythmogenesis.Terracciano and colleagues, including first author Eef Dries, therefore prepared myocardial slices from different layers of the rat ventricular wall and subjected them to cryoinjury (1). Structural remodeling—in the form of reduced T-tubule density—was similar in both subendocardial and subepicardial slices after injury, but only subendocardial slices showed an increase in spontaneous, arrhythmic contractions.Dries et al. used a fluorescent Ca²⁺ indicator and high-resolution imaging to examine Ca²⁺ signaling in the “border zone” surrounding the cryoinjury, as this region has been implicated in triggering arrhythmias following myocardial infarction. “Intriguingly, and only in subendocardial slices after injury, we observed a reduction in the amplitude of calcium transients that also became slower to decline, changes that are hallmarks of heart failure,” Terracciano says. “SCR events were more frequent and more closely distributed when we cryoinjured the slices but, again, only in the subendocardium.”The clustering of multiple SCRs in both space and time makes them more likely to trigger an ectopic contraction. One possibility is that the open probability of ryanodine receptors is increased in subendocardial slices. This could be caused by enhanced CaMKII-mediated phosphorylation of ryanodine receptors and, indeed, Dries et al. found that, after cryoinjury, receptor phosphorylation is increased in subendocardial, but not subepicardial, slices (1).Accordingly, Terracciano and colleagues found that the CaMKII inhibitor AIP reduced the frequency of SCRs and spontaneous contractions in cryoinjured subendocardial slices. In contrast, AIP had no effect on injured subepicardial slices or on normal, healthy cardiac tissue. CaMKII inhibitors have been proposed as potential therapies for cardiac arrhythmias, but their use has so far been limited by off-target effects. Dries et al.’s results suggest that targeting CaMKII inhibitors to specific regions of the ventricular wall (using localized gene therapy, for example) could greatly improve their efficacy.“A picture is emerging that subendocardial slices are more susceptible to arrhythmogenic stimuli, and this can be important for understanding and treating arrhythmias,” Terracciano says. He now plans to study injured myocardial slices over longer time periods and investigate the molecular changes underlying the enhanced arrhythmogenic susceptibility of the subendocardium, as well as testing localized gene therapy approaches in animal models of disease.     

Individual differences in odor imaging ability reflect differences in olfactory and emotional perception

We asked whether the large variability in odor imaging ability is underlain by interindividual differences in the processing of smells and emotion. Olfactory imaging ability, anhedonia level, and odor perception were measured in 40 subjects, using the Vividness of Olfactory Imagery Questionnaire (VOIQ), the Physical Anhedonia Scale, and the European Test of Olfactory Capabilities. "Good" olfactory imagers, defined primarily on the basis of the VOIQ, rated pleasant smells as more familiar and had lower anhedonia scores than "bad" olfactory imagers. Based on self-reported measures, these results suggest that, like olfactory perception, the mental imagery of smells is related to emotion and that, beyond their differences in vividness, good and bad olfactory imagers differ in their experience of emotion and long-term memory of smells.     

Gender differences in Parkinson's disease

Because estrogen has numerous effects on dopamine neurotransmission, many researchers are interested in its possible use to either slow the progression or reduce the risk of Parkinson's disease (PD). The incidence of PD is greater in men than in women. Gender differences in neurotoxicity have been observed, and basic research in experimental animals indicates that estrogen protects neurons from various forms of injury. However, the results of retrospective surveys of the neuroprotective effects of estrogen replacement in PD have been mixed, with some showing no effect on risk and others showing a reduction in risk. A mildly significant gender difference in disability and quality-of-life reporting has been noted, with women citing greater disability and reduced quality of life. Gender differences have been shown in response to treatment of PD, for example, in how levodopa is metabolized-women have greater levodopa bioavailability. In the Parkinson's Disease on Estrogen Therapy Replacement in the Menopause Years (POETRY) study, participants were found to have improved scores on the Unified Parkinson Disease Rating Scale. Based on the POETRY results, it is hypothesized that estrogen replacement therapy (ERT) may lead to improvement in PD symptoms and provide an opportunity to reduce the dosage of antiparkinsonian medication in women.     

Inter-species differences in drug properties

There has been a clear trend towards decreased reliance upon animal studies and increased emphasis upon experiments with human-derived tissues. Nonetheless, we continue to need investigations of interspecies differences for two principal reasons: (1) to prospectively design experiments so that the animal species most similar to humans can be chosen, on a case-by-case basis, for each drug; (2) to properly evaluate and interpret data obtained from the experiments ("risk assessment"). Four core examples derived from the work in our FDA laboratory are used to illustrate these points. For paclitaxel, different metabolites were formed in humans and rats, which makes metabolic drug-drug interaction studies in rats irrelevant. For zidovudine (AZT), rapid glucuronidation in humans produced a much shorter half-life than expected from studies in animals, which have negligible glucuronidation. The toxicology and efficacy of both parent drug and metabolite need to be assessed in cases such as iododeoxydoxorubicin, in which the parent molecule is the dominant circulating species in mice, but patients have more than 10-fold greater exposure to the metabolite compared with the parent. While rats have highly-active arylamine N-acetyltransferases, dogs totally lack this enzyme family, and humans have intermediate amounts. For some situations, we've suggested that it can be desirable to inhibit NAT to make the human exposure more similar to dogs. In conclusion, although the ratio of animal:human data is decreasing, our ability to use animal data effectively for drug development has actually increased. Continued focus should be placed upon the application of comparative interspecies data for prospective design of animal experiments and retrospective interpretation of animal findings in terms of the potential for human risk and benefit.     

Sex differences in autoimmune diseases

Women are more susceptible to a variety of autoimmune diseases including systemic lupus erythematosus (SLE), multiple sclerosis (MS), primary biliary cirrhosis, rheumatoid arthritis and Hashimoto's thyroiditis. This increased susceptibility in females compared to males is also present in animal models of autoimmune diseases such as spontaneous SLE in (NZBxNZW)F1 and NZM.2328 mice, experimental autoimmune encephalomyelitis (EAE) in SJL mice, thyroiditis, Sjogren's syndrome in MRL/Mp-lpr/lpr mice and diabetes in non-obese diabetic mice. Indeed, being female confers a greater risk of developing these diseases than any single genetic or environmental risk factor discovered to date. Understanding how the state of being female so profoundly affects autoimmune disease susceptibility would accomplish two major goals. First, it would lead to an insight into the major pathways of disease pathogenesis and, secondly, it would likely lead to novel treatments which would disrupt such pathways.     

Rat sex differences in anesthesia

Studies involving substantially lengthy rat surgeries require extended anesthesia periods and often involve use of sodium pentobarbital (PENT). Results of previous experiments from our laboratory and elsewhere suggest that the duration of anesthesia and the need for anesthetic supplementation may differ between male and female rats. In the study reported here, we induced anesthesia in male and female Sprague Dawley rats (n = 10 for each sex), using a three-step procedure: brief induction with 5% isoflurane inhalation, PENT (50 mg/kg of body weight, i.p.), combined with 50 mg of PENT/kg given intragastrically. Adequate anesthesia depth was confirmed by absence of a response to a toe pinch. Plasma PENT concentration was measured at sequential 20-min periods and was found, on average, to be lower (P = 0.03) in male (13.28 +/- 1.13 microg/ml) than in female (20.27 +/- 0.66 microg/ml) rats, and decreased more rapidly (P = 0.003) in male rats. Distribution to a fractionally greater lean body mass and more rapid metabolism in males may account for these differences and explain the need for anesthetic supplementation in male, but not female rats.     

Sex differences in primary hypertension

Men have higher blood pressure than women through much of life regardless of race and ethnicity. This is a robust and highly conserved sex difference that it is also observed across species including dogs, rats, mice and chickens and it is found in induced, genetic and transgenic animal models of hypertension. Not only do the differences between the ovarian and testicular hormonal milieu contribute to this sexual dimorphism in blood pressure, the sex chromosomes also play a role in and of themselves. This review primarily focuses on epidemiological studies of blood pressure in men and women and experimental models of hypertension in both sexes. Gaps in current knowledge regarding what underlie male-female differences in blood pressure control are discussed. Elucidating the mechanisms underlying sex differences in hypertension may lead to the development of anti-hypertensives tailored to one's sex and ultimately to improved therapeutic strategies for treating this disease and preventing its devastating consequences.