Sex Differences In Models Research Articles

Relationship between sex, APOE genotype, endocannabinoids and cognitive change in older adults with metabolic syndrome during a 3-year Mediterranean diet intervention

BackgroundThe Mediterranean diet (MedDiet) has demonstrated efficacy in preventing age-related cognitive decline and modulating plasma concentrations of endocannabinoids (eCBs) and N-acylethanolamines (NAEs, or eCB-like compounds), which are lipid mediators involved in multiple neurological disorders and metabolic processes. Hypothesizing that eCBs and NAEs will be biomarkers of a MedDiet intervention and will be related to the cognitive response, we investigated this relationship according to sex and apolipoprotein E (APOE) genotype, which may affect eCBs and cognitive performance.MethodsThis was a prospective cohort study of 102 participants (53.9% women, 18.8% APOE-ɛ4 carriers, aged 65.6 ± 4.5 years) from the PREDIMED-Plus-Cognition substudy, who were recruited at the Hospital del Mar Research Institute (Barcelona). All of them presented metabolic syndrome plus overweight/obesity (inclusion criteria of the PREDIMED-Plus) and normal cognitive performance at baseline (inclusion criteria of this substudy). A comprehensive battery of neuropsychological tests was administered at baseline and after 1 and 3 years. Plasma concentrations of eCBs and NAEs, including 2-arachidonoylglycerol (2-AG), anandamide (AEA), oleoylethanolamide (OEA), palmitoylethanolamide (PEA), and N-docosahexaenoylethanolamine (DHEA), were also monitored. Baseline cognition, cognitive changes, and the association between eCBs/NAEs and cognition were evaluated according to gender (crude models), sex (adjusted models), and APOE genotype.ResultsAt baseline, men had better executive function and global cognition than women (the effect size of gender differences was − 0.49, p = 0.015; and − 0.42, p = 0.036); however, these differences became nonsignificant in models of sex differences. After 3 years of MedDiet intervention, participants exhibited modest improvements in memory and global cognition. However, greater memory changes were observed in men than in women (Cohen’s d of 0.40 vs. 0.25; p = 0.017). In men and APOE-ε4 carriers, 2-AG concentrations were inversely associated with baseline cognition and cognitive changes, while in women, cognitive changes were positively linked to changes in DHEA and the DHEA/AEA ratio. In men, changes in the OEA/AEA and OEA/PEA ratios were positively associated with cognitive changes.ConclusionsThe MedDiet improved participants’ cognitive performance but the effect size was small and negatively influenced by female sex. Changes in 2-AG, DHEA, the OEA/AEA, the OEA/PEA and the DHEA/AEA ratios were associated with cognitive changes in a sex- and APOE-dependent fashion. These results support the modulation of the endocannabinoid system as a potential therapeutic approach to prevent cognitive decline in at-risk populations.Trial registrationISRCTN89898870.

Drug versus non-drug behaviors: A dual-reward model of sex differences and neurobiological mechanisms in rats.

Substance Use Disorders (SUDs) are an impactful problem characterized by chronic relapse and engagement in drug-related behaviors at the expense of non-drug behaviors. Brain regions implicated in drug and non-drug-related behaviors often overlap, complicating investigations of neurobiological mechanisms underlying SUDs. Here we presented a within-subject model for studying self-administration, reinforcer competition, extinction, and cued reinstatement of cocaine- and food-seeking in rats. Due to differences in cocaine- and food-reinforced behavior, we transformed data to proportions of baseline, revealing increased resistance to extinction and disproportionately greater cued reinstatement of cocaine seeking relative to food seeking. Consistent with previous reports, females showed greater preference for cocaine reinforcement than males, though these findings failed to reach statistical significance. To demonstrate the model's utility for investigating neurobiological mechanisms, we included proof-of-concept calcium imaging data demonstrating the utility of the behavioral model for detecting cellular activity patterns associated with cocaine- and food-seeking behaviors. Future studies utilizing this model should improve understanding of the development and expression of pathological behaviors characteristic of SUDs in humans, sex differences in these behaviors, and their neurobiological correlates. Thus, the model has utility for improving understanding of SUDs, leading to novel treatments to reduce the pathological behaviors associated with SUDs.

Reduction of lipid peroxidase levels in EFAD mouse model

AbstractBackgroundCerebral microbleeds (MBs) are more prevalent in APOE4 carriers and associated with Alzheimer Disease (AD). Loss of cerebrovascular integrity, blood‐brain barrier breakdown, and reduced Aβ clearance are also shown by APOE4 carrier mice. In AD, increased brain amyloid coupled with increased oxidative stress may synergistically contribute to MBs prevalence. EFAD mice carrying familial dominant AD genes in combination with human apoE alleles are a model for sex differences in AD, with greater amyloid accumulation and microbleeds in female E4FAD mice.Independently, Aβ and heme from microbleeds contribute to increased oxidative stress. New data suggest increased lipid peroxidation in E4 mice at baseline as measured by 4‐HNE. Peroxiredoxin 6 (Prdx6) and glutathione peroxidase 4 (GPx4) are the only known antioxidant enzymes capable of detoxifying oxidized phospholipids.MethodPrdx6 and GPx4 were studied by Western blot in cortical lysates of 6mo old EFAD mice. To evaluate Aβ contribution, we analyzed Prdx6 and GPx4 in 2mo old EFAD mice, which show 2 to 10‐fold lower Aβ compared to 6mo EFAD mice, and 6mo old EFAD non carrier siblings (no AD‐transgene).ResultPrdx6 was decreased in E4FAD mice (M: ‐30%; F: ‐50%) compared to E3FAD mice. GPx4 was decreased only n E4FAD females (M: no change; F: ‐50%). Younger mice did not show differences in either lipid peroxidases at 2mo. Interestingly, Prdx6 but not GPx4 was reduced in 6mo old female E4FAD non carrier siblings.ConclusionOur data suggest that the decreased levels of Prdx6 in 6mo old female E4 carrier mice in absence of Aβ might impair their ability to reduce oxidized lipids and predispose them to membrane alteration. Moreover, aging and increase of Aβ load together might contribute to the reduction of GPx4 levels in APOE4 carriers and the accumulation of MBs. Additional studies are required to clarify the underlying interaction sex‐apoE allele in MBs onset and its contribution to the pathogenesis of AD.

Acetazolamide Administration Restores the Blood Pressure Lowering Effect of Tempol in Female SHR

The mechanisms responsible for the sex differences in blood pressure (BP) in humans are not clear. Over the past several years, we have studied the spontaneously hypertensive rat (SHR) as a model of sex differences in BP control. Oxidative stress (OS) plays a major role in BP regulation in preclinical studies. There is a sex difference in the BP responses to pro‐oxidants and antioxidants in the SHR. In contrast to males, BP in female SHR does not decrease in response to Tempol or Apocynin. Acetazolamide (Aceta) inhibits proximal tubular sodium reabsorption, increasing sodium delivery to the distal tubule which increases distal tubule OS. We tested the hypothesis that an increase in sodium delivery in the distal tubule will restore the BP lowering effects of Tempol in female SHR.Materials and MethodsFemale SHR, aged twenty weeks, were implanted with radiotelemetry transmitters and following a two week recovery period, baseline mean arterial pressure (MAP) was measured 24 hrs per day. All rats were then given Aceta (100 mg/kg/day sc) for 14 days (n=14). After this period, a group of rats were randomized to receive Tempol (1mmol/L) in drinking water for an additional two weeks (Aceta + Tempol) (n=7/grp) and BP was compared to controls who received Aceta only (n=7/grp). MAP was measured continuously throughout the treatment periods.ResultsAt baseline, MAP was similar in both groups of female SHR (144 ± 1 vs. 145 ± 1 mmHg). Aceta administration for two weeks caused a 10 mmHg reduction in MAP, which was similar in both group of rats (132 ± 1 vs. 131 ± 1 mmHg, p=0.43). Tempol administration significantly lowered MAP in presence of Aceta (138 ± 1vs. 122 ± 1 mmHg, p<0.0001). Body weight was similar between Aceta and Aceta + Tempol groups (200.3 ± 2.0g vs. 192.2 ± 4.0 g).In conclusion, our data suggest that there are sex differences in proximal sodium reabsorption that may impact OS in SHR. By increasing sodium delivery to the distal nephron with acetazolamide, the BP lowering effect of Tempol is restored in female SHR. These data suggest that different mechanisms may control oxidative stress and blood pressure in male and female SHR.Support or Funding InformationThis project was funded by NIH R01 HL135089, P20 GM12334, & PO1HL51971This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Sex differences in smoking constructs and abstinence: The explanatory role of smoking outcome expectancies.

Scientific evidence suggests women experience more severe problems when attempting to quit smoking relative to men. Yet, little work has examined potential explanatory variables that maintain sex differences in clinically relevant smoking processes. Smoking outcome expectancies have demonstrated sex differences and associative relations with the smoking processes and behavior, including problems when attempting to quit, smoking-specific experiential avoidance, perceived barriers to quitting, and smoking abstinence. Thus, expectancies about the consequences of smoking may explain sex differences across these variables. Accordingly, the current study examined the explanatory role of smoking-outcome expectancies (e.g., long-term negative consequences, immediate negative consequences, sensory satisfaction, negative affect reduction, and appetite weight control) in models of sex differences across cessation-related problems, smoking-specific experiential avoidance, perceived barriers to quitting, and smoking abstinence. Participants included 450 (48.4% female; Mage = 37.45, SD = 13.50) treatment-seeking adult smokers. Results indicated that sex had an indirect effect on problems when attempting to quit smoking through immediate negative consequences and negative affect reduction expectancies; on smoking-specific experiential avoidance through long-term negative consequences, immediate negative consequences, and negative affect reduction expectancies; on barriers to quitting through negative affect reduction expectancies; and on abstinence through appetite weight control expectancies. The current findings suggest that sex differences in negative affect reduction expectancies and negative consequences expectancies may serve to maintain maladaptive smoking processes, whereas appetite weight control expectancies may promote short-term abstinence. These findings provide initial evidence for the conceptual role of smoking expectancies as potential "linking variables" for sex differences in smoking variables. (PsycINFO Database Record

Rapid Cortisol and Testosterone Responses to Sex-Linked Stressors: Implications for the Tend-and-Befriend Hypothesis

Current evolutionary theories regarding the nature of hormonal responses to a variety of salient social stimuli are incomplete in yielding evidentiary support for their assertions. This study offers more nuanced evidence for the Tend-and-Befriend model of sex differences in responses to social stimuli. Participants were randomly assigned to a mortality salience prime or a control condition prior to viewing a video of an out-group threat or a video of infants crying. Cortisol and testosterone responses were assessed. The results showed that in mortality salience conditions, females showed significantly higher cortisol responses to infants crying compared to males. Further, in both mortality salience and control conditions, females showed significantly higher testosterone responses to the crying infants than males. Males showed a greater testosterone response to viewing an out-group threat. Mortality salience prime did not impact testosterone responses in either sex. Results point to a more nuanced representation of hormonal responses to social stimuli and the need for multisystem measurement.

Using signals associated with safety in avoidance learning: computational model of sex differences

Avoidance behavior involves learning responses that prevent upcoming aversive events; these responses typically extinguish when the aversive events stop materializing. Stimuli that signal safety from aversive events can paradoxically inhibit extinction of avoidance behavior. In animals, males and females process safety signals differently. These differences help explain why women are more likely to be diagnosed with an anxiety disorder and exhibit differences in symptom presentation and course compared to men. In the current study, we extend an existing model of strain differences in avoidance behavior to simulate sex differences in rats. The model successfully replicates data showing that the omission of a signal associated with a period of safety can facilitate extinction in females, but not males, and makes novel predictions that this effect should depend on the duration of the period, the duration of the signal itself, and its occurrence within that period. Non-reinforced responses during the safe period were also found to be important in the expression of these patterns. The model also allowed us to explore underlying mechanisms for the observed sex effects, such as whether safety signals serve as occasion setters for aversive events, to determine why removing them can facilitate extinction of avoidance. The simulation results argue against this account, and instead suggest the signal may serve as a conditioned reinforcer of avoidance behavior.

Female-biased anorexia and anxiety in the Syrian hamster

Anorexia and anxiety cause significant mortality and disability with female biases and frequent comorbidity after puberty, but the scarcity of suitable animal models impedes understanding of their biological underpinnings. It is reported here that in adult or weanling Syrian hamsters, relative to social housing (SH), social separation (SS) induced anorexia characterized as hypophagia, weight loss, reduced adiposity, and hypermetabolism. Following anorexia, SS increased reluctance to feed, and thigmotaxis, in anxiogenic environments. Importantly, anorexia and anxiety were induced post-puberty with female biases. SS also reduced hypothalamic corticotrophin-releasing factor mRNA and serum corticosteroid levels assessed by RT-PCR and RIA, respectively. Consistent with the view that sex differences in adrenal suppression contributed to female biases in anorexia and anxiety by disinhibiting neuroimmune activity, SS elevated hypothalamic interleukin-6 and toll-like receptor 4 mRNA levels. Although corticosteroids were highest during SH, they were within the physiological range and associated with juvenile-like growth of white adipose, bone, and skeletal muscle. These results suggest that hamsters exhibit plasticity in bioenergetic and emotional phenotypes across puberty without an increase in stress responsiveness. Thus, social separation of hamsters provides a model of sex differences in anorexia and anxiety during adulthood and their pathogeneses during adolescence.

Sex differences in blood pressure control in SHR: lack of a role for EETs.

The mechanisms responsible for the gender difference in blood pressure (BP) in humans are not clear. Over the past several years we have studied the spontaneously hypertensive rat (SHR) as a model of sex differences in BP control. In the present study, we tested the hypothesis that renal vascular and microsomal epoxyeicosatrienoic acid (EET) levels are higher in females than males, and increasing vascular EETs by blocking epoxide hydrolase with AUDA will reduce BP more in males than females. Renal vascular and microsomal EETs were higher in female SHR than males. Mean arterial pressure (MAP by telemetry) was higher in males than females during the baseline period of 6 days, and although the epoxide hydrolase inhibitor, AUDA, given for 10 days increased renal microvascular EETs in both groups, AUDA did not affect MAP in either group. These data suggest that EETs do not contribute to the sex differences in hypertension in young SHR.

A Difficulty in the Concept of Affirmative Action: Evidence From Females in Legislatures

History’s societies vary on a number of dimensions, but appear more homogenous in distributing socioeconomic status across sexes. This appearance prompts the question of whether forces that are robust to laws and regulations might contribute to the persistence of sex-differences in hierarchical attainment. Given this motivation, we empirically evaluate Suzanne Scotchmer’s (2008) model of sex differences in risk aversion where (1) winner-take-all games (e.g., promotions in hierarchies) favor inherently risk-taking males, but (2) successful females maintain greater skill on average and (3) see this skill-advantage depreciate with repeated play. This model formally identifies an internal inconsistency in affirmative action law, an inconsistency for which we find empirical support in how the sex composition of national legislatures differs across electoral mechanisms (i.e., winner-take-all chambers employ a significantly greater proportion of males) and how re-election prospects for US Representatives differ by sex (i.e., females enjoy significantly longer durations, but only when evaluated early in their incumbencies). These results cannot easily be dismissed as statistical artifacts, and alternative models can (at best) rationalize our cross-sectional or time series results, but not both.

Sex differences in learning and inhibition in spontaneously hypertensive rats

Few studies have addressed potential differences in the nature of cognitive impairment observed in males and females with ADHD. In Experiment 1, we examined sex differences in conditioned inhibitory behaviour in spontaneously hypertensive rats (SHR strain), a purported animal model of ADHD. Rats were presented with two types of trials during each of the 15 conditioning sessions. On some trials an auditory stimulus (a tone) was presented and followed immediately by delivery of food reward. On the remaining trials the tone was preceded by presentation of a visual stimulus and on those trials food was not delivered after the tone was presented. As training progressed, conditioned responding during presentation of the tone increased on reinforced trials and decreased during the non-reinforced trials, indicative of successful discrimination and inhibition. Overall, female SHR rats exhibited less conditioned overall food cup behaviour compared to male rats. Female SHR rats also required more training sessions until they responded significantly more during presentation of the tone on reinforced trials versus non-reinforced trials. In addition, the magnitude of the discrimination was smaller in female SHR rats compared to males. In contrast, no sex differences were observed in WKY rats (commonly-used control strain) in Experiment 2. Importantly, there were no significant sex differences in baseline activity or motivation during either experiment, indicating that performance differences could not account for the observed results. These results suggest that male and female SHR rats differ in their ability to form conditioned associations and inhibit behavioural responses and may provide a useful model for sex differences in cognitive dysfunction specific to ADHD.

Age, Relationship, and Touch Initiation

Gender asymmetry in touch in U.S. populations is related to the age of the participants in some studies and to the relationships between the participants in others. In the present study, researchers observed dyads in public settings in the United States frequented by couples and recorded the occurrence of touch, the touch initiator, and the body areas touched. The researchers then approached the couples and asked them to complete questionnaires indicating their ages, their relationship, and their level of agreement on major issues. Age and relationship were predictive of the gender of touch initiators. Although levels of agreement were less predictive of touch initiation, the women indicated higher levels of agreement than the men did. The results were generally consistent with a model of sex differences in reproductive strategies.

Animal Models of Sex Differences in Pain and Analgesia

Animal Models of Sex Differences in Pain and Analgesia

On an evolutionary model of sex differences in mathematics: Do the data support the theory?

AbstractThe target article draws on evolutionary theory to formulate a biosocial model of sex differences in quantitative abilities. Unfortunately, the data do not support some of the crucial hypotheses. The male advantage in geometry is not appreciably greater than the male advantagi in algebra, and the greater male variability in mathematics cited by Gear is not cross-culturally invariant.

Sex-related differences in cognition: Development during early childhood

Fifty-five right-handed children from right-handed families between 2- and 5-years-of-age were individually administered two batteries of hand preference, verbal and spatial measures with a six month interval separating administrations. Early between-sex differences in production and comprehension abilities were revealed. Girls outscored boys on measures of verbal fluency and graphic reproduction of shapes. Boys outscored girls on a measure of verbal comprehension. Within-sex differences between comprehension and production abilities were also apparent. At both administrations, boys scored significantly higher on verbal tests of knowledge, comprehension and reasoning than on measures requiring oral or manual production. Girls showed the reverse pattern. By the second administration, however, the high production/low comprehension pattern was only significant for girls consistently demonstrating high degrees of right-hand preference across testing times. Significant between-sex differences in these comprehension versus production ability patterns ranged between 1/2 to 11/6 standard deviations in magnitude and accounted for 8–10% of the variance in children's ability difference scores. These results are interpreted as support for a biological basis of early sex-related cognitive differences and Kimura's (1983) model of sex differences in the organization of the left hemisphere.

Sex Differences Among Bank Employees in the Relationships of Commitment with Psychological Climate and Job Satisfaction

Chusmir's (1982) model of sex differences in organizational commitment was examined. Bank employees (N = 106) responded to two measures of organizational commitment (Hrebiniak & Alutto, 1972; Porte...

A Test of "Gender" and "Job" Models of Sex Differences in Job Involvement

The sources of gender differences in subjective job involvement are investigated utilizing cross-sectional and panel data from the 1972–73 and 1977 Quality of Employment Surveys. Analyses do not support previous arguments that differences in gender socialization and family responsibilities are the sources of females' lower involvement with a job. Instead, characteristics of the job setting, in particular work autonomy, are more important determinants of job involvement as men and women generally react similarly to their work conditions. Women are found to be more involved with their jobs than men after controlling differences in work autonomy. The findings also indicate women became more involved with their jobs over the period of study whereas men's subjective involvement decreased.

A Test of "Gender" and "Job" Models of Sex Differences in Job Involvement

The sources of gender differences in subjective job involvement are investigated utilizing cross-sectional and panel data from the 1972–73 and 1977 Quality of Employment Surveys. Analyses do not support previous arguments that differences in gender socialization and family responsibilities are the sources of females' lower involvement with a job. Instead, characteristics of the job setting, in particular work autonomy, are more important determinants of job involvement as men and women generally react similarly to their work conditions. Women are found to be more involved with their jobs than men after controlling differences in work autonomy. The findings also indicate women became more involved with their jobs over the period of study whereas men's subjective involvement decreased.