Sex Differences In Animal Models Research Articles

Sex-specific variations in spatial reference memory acquisition: Insights from a comprehensive behavioral test battery in C57BL/6JRj mice

Sex differences in declarative memory are described in humans, revealing a female or a male advantage depending on the task. Specifically, spatial memory (i.e., spatial navigation) is typically most efficient in men. This sexual dimorphism has been replicated in male rats but not clearly in mice. In this study, sex differences in spatial memory were assessed in thirty-six C57BL/6 J mice (Janvier Labs; i.e., C57BL/6JRj mice), a widely used mouse substrain. Both male and female mice (12 weeks-old) were subjected to standard behavioral paradigms: the elevated plus maze, the open field test, the novel object and place tests, the forced swimming test, and the water maze test for spatial navigation. Across assessment, no sex differences were found in measures of locomotor activity, emotional and behavioral responses, and object and place recognition memories. In the water maze, male mice were faster in learning the platform location in the reference memory training and used more spatial strategies during the first training days. However, both sexes reached a similar asymptotic performance and performed similarly in the probe trial for long-term memory consolidation. No sex differences were found in the cued training, platform inversion sessions, or spatial working memory sessions. Hippocampal expression of the brain-derived neurotrophic factor was similar in both sexes, either in basal conditions or after performing the behavioral training battery. Importantly, female mice were not more variable than males in any measure analyzed. This outcome encourages the investigation of sex differences in animal models and the usefulness of including female mice in behavioral research.

Sex differences in animal models: A case of diabetes mellitus herbal treatment

Herbal extracts have been used for control of type 2 diabetes mellitus for many centuries and the use of animal models to test the potency of these remedies is imperative. Given that preclinical studies may eventually inform clinical research and therapeutic developments, the impact of sex should be taken into consideration as an important biological variable in order to produce precise and reproducible results applicable to both men and women. This paper sought to find out whether there is sex differentiated outcomes on aherbal treatment for type 2 diabetes mellitus. Alloxan induced diabetic wistar rats were the experimental subjects used in the study. Twenty-eight albino Wistar rats, fourteen males and fourteen females, aged 6-7 weeks and weighing 100-140 grams were subjected to this test. The response of interest was the change in blood glucose level 2 hours after the administration of the herbal treatment. A sharper rise in blood glucose level among the female rats was recorded compared to the males upon ingestion of glucose. On the other hand, the average change in blood glucose level was higher among the male rats compared to the females. This suggested that the course of the diabetes disease and the treatment effect was different in male and female rats. This study recommends the use of both male and female subjects in animal studies at both the experimental and analysis stages for completing the understanding about disease mechanisms and in driving the course of advanced diagnostic and therapeutic approaches.

Gender and Sex-Related Differences in Normal Tissue Effects Induced by Platinum Compounds.

Gender medicine in the field of oncology is an under-researched area, despite the existing evidence towards gender-dependent response to therapy and treatment-induced adverse effects. Oncological treatment aims to fulfil its main goal of achieving high tumour control by also protecting normal tissue from acute or chronic damage. Chemotherapy is an important component of cancer treatment, with a large number of drugs being currently in clinical use. Cisplatin is one of the most commonly employed chemotherapeutic agents, used either as a sole drug or in combination with other agents. Cisplatin-induced toxicities are well documented, and they include nephrotoxicity, neurotoxicity, gastrointestinal toxicity, ototoxicity, just to name the most frequent ones. Some of these toxicities have short-term sequelae, while others are irreversible. Furthermore, research showed that there is a strong gender-dependent aspect of side effects caused by the administration of cisplatin. While evidence towards sex differences in animal models is substantial, clinical studies considering sex/gender as a variable factor are limited. This work summarises the current knowledge on sex/gender-related side effects induced by platinum compounds and highlights the gaps in research that require more attention to open new therapeutic possibilities and preventative measures to alleviate normal tissue toxicity and increase patients’ quality of life in both males and females.

Sex Differences in Animal Models of Sodium-Valproate-Induced Autism in Postnatal BALB/c Mice: Whole-Brain Histoarchitecture and 5-HT2A Receptor Biomarker Evidence.

Simple SummaryValproic acid (VPA) is a well-known antiepileptic medication and mood stabiliser that is frequently prescribed for the treatment of epilepsy, particularly in children, and has proven human teratogenic activity. VPA inhibits histone deacetylase, which causes teratogenicity and cell toxicity. VPA-induced autism in rodents during the pre- and postnatal periods has shown the development of an autism-like phenotype. In mice, the 14th postnatal day is thought to correspond to the third trimester of human development; it is an important period in which neuronal migration, differentiation, myelination, synaptogenesis and gliogenesis occur in the cerebellum, striatum and hippocampus. Therefore, we exposed postnatal day 14 (PND 14) mice to VPA, which resulted in autistic-like behaviours manifested as reduced social interaction, increased repetitive stereotyped behaviour and anxiety, cognitive dysfunction, lowered sensitivity to pain and neurodevelopmental delay. BALB/c mice were used in this work because they are less reactive to social contact in VPA-induced autism than many other inbred mouse strains, such as C57/129 mice. In humans, two to three times more men are affected by autism spectrum disorder (ASD) than women, and, for this reason, the current study compares the histopathological changes and 5-hydroxy-tryptamine 2A (5-HT2A) receptor protein expression in the brain tissue of male and female animals with VPA-induced autism.Autism spectrum disorder (ASD) is characterised by problems with social interaction, verbal and nonverbal communication and repetitive behaviour. In mice, the 14th postnatal day is believed to correspond to the third trimester of human embryonic development and is considered a vital period for central nervous system development. It has been shown that ASD affects 2 to 3 times more male than female individuals. In the present study, ASD was induced in 14 postnatal day (PND) BALB/c mice using valproic acid (VPA). VPA administration brought about substantial differences in the histoarchitecture of the brain in both male and female mice, linked to behavioural deficits. We observed that both male and female mice showed similar morphological changes in the prefrontal cortex, hippocampus and Purkinje cells. We also observed hair loss from PND 17 to 25, which was again similar between male and female mice. However, there were higher rates of change in the cerebral cortex, frontal cortex and temporal lobe and hippocampus in VPA-treated male animals. With respect to the cerebellum, we did not observe any alterations by haematoxylin and eosin (H&E) staining, but detailed morphological observation using scanning electron microscopy (SEM) showed a higher rate of phenotype changes in VPA-treated male animals. Moreover, 5-HT2A receptor protein levels were upregulated in the cerebral cortex, hippocampus and Purkinje cells in VPA-treated male mice compared with control animals and VPA-treated female mice, as shown by immunohistochemical analysis. Based on all these findings, we conclude that male animals are more susceptible to VPA-induced ASD than females.

Biological Sex As a Critical Variable in CD4+ Effector T Cell Function in Preclinical Models of Multiple Sclerosis.

Significance:T cells play a pivotal role in maintaining adaptive immune responses against pathogens. However, misdirected T cell responses against self-tissues may lead to autoimmune disease. Biological sex has profound effects on T cell function and is an important determinant of disease incidence and severity in autoimmune diseases such as multiple sclerosis (MS).Recent Advances:Many autoimmune diseases skew toward higher female incidence, including MS; however, it is has become increasingly more accepted that men living with MS are more prone to developing a progressive disease course and to having worsened disease outcomes.Critical Issues:In this review, we discuss what is known about the role of biological sex on T cell development and differentiation, examining evidence that male sex can augment T helper 17 (Th17) responses. Next, we outline what is known about sex differences in animal models of MS, and about the distinct roles played by sex hormones versus sex chromosomes in pathogenesis in these models. Finally, we discuss recent advances that examine the molecular basis for worsened disease outcomes in males, with a particular focus on the role played by Th17 cells in these models.Future Directions:Better understanding the role of biological sex in T cell function may pave the way to effective personalized treatment strategies in MS and other autoimmune diseases. Antioxid. Redox Signal. 37, 135–149.

Animal Models of Anxiety and Depression: Incorporating the Underlying Mechanisms of Sex Differences in Macroglia Biology.

Animal models have been utilized to explore the mechanisms by which mood disorders develop. Ethologically based stress paradigms are used to induce behavioral responses consistent with those observed in humans suffering from anxiety and depression. While mood disorders are more often diagnosed in women, animal studies are more likely to be carried out in male rodents. However, understanding the mechanisms behind anxiety- and depressive-like behaviors in both sexes is necessary to increase the predictive and construct validity of the models and identify therapeutic targets. To understand sex differences following stress, we must consider how all cell types within the central nervous system are influenced by the neuroendocrine system. This review article discusses the effects of stress and sex steroids on the macroglia: astrocytes and oligodendrocytes. Glia are involved in shaping the synapse through the regulation of neurotransmitter levels and energy resources, making them essential contributors to neural dynamics following stress. As the role of glia in neuromodulation has become more apparent, studies exploring the mechanisms by which glia are altered by stress and steroids will provide insight into sex differences in animal models. These insights will facilitate the optimization of animal models of psychiatric disorders and development of future therapeutic targets.

The importance of examining sex differences in animal models validated to induce an addiction-like phenotype

The importance of examining sex differences in animal models validated to induce an addiction-like phenotype

Sex differences in the elevated plus-maze test and large open field test in adult Wistar rats

There is a growing need for a better understanding of sex differences in animal models of psychiatric disorders. The elevated plus-maze (EPM) test and large open field (LOF) test are widely used to study anxiety-like behavior in rodents. Our studies explored sex differences in anxiety and activity parameters in the LOF and EPM and determined whether these parameters correlate within and between tests. Drug naïve adult male and female Wistar rats (n = 47/sex) were used for the studies, and the rats were tested for 5 min in the EPM and 10 min in the LOF. The females spent more time on the open arms of the EPM and made more open arms entries than the males. The females also spent more time in the center zone of the LOF and made more center zone entries. The females traveled a greater distance in the LOF and EPM. There was a moderate positive correlation between time on the open arms of the EPM and time in the center zone of the LOF. There was also a moderate positive correlation between open arms entries in the EPM and center zone entries in the LOF. A hierarchical cluster analysis revealed one cluster with LOF parameters, one cluster with EPM parameters, and one cluster with parameters related to the avoidance of open spaces. In conclusion, these findings indicate that female rats display less anxiety-like behavior in the EPM and LOF. Furthermore, there are sex differences for almost all behavioral parameters in these anxiety tests.

Sex Differences in Animal Models of Opioid Reward.

This review aims to discuss sex differences observed in preclinical rodent models of opioid reward. Utilizing a variety of methodological approaches and drug regimens, no clear consensus has emerged regarding the effects of opiates between males and females. This is quite dissimilar to work examining psychostimulants, where female animals reliably exhibit stronger behavioral responses. With opioid research quickly expanding to determine the neural underpinnings of opioid addiction, further research is essential to determine the conditions wherein sex differences may occur and how they may relate to the human condition.

Sex Differences in Animal Models of Traumatic Brain Injury.

Traumatic brain injury (TBI) is highly prevalent and there is currently no adequate treatment. Understanding the underlying mechanisms governing TBI and recovery remains an elusive goal. The heterogeneous nature of injury and individual’s response to injury have made understanding risk and susceptibility to TBI of great importance. Epidemiologic studies have provided evidence of sex-dependent differences following TBI. However, preclinical models of injury have largely focused on adult male animals. Here, we review 50 studies that have investigated TBI in both sexes using animal models. Results from these studies are highly variable and model dependent, but largely show females to have a protective advantage in behavioral outcomes and pathology following TBI. Further research of both sexes using newer models that better recapitulate mild and repetitive TBI is needed to characterize the nature of sex-dependent injury and recovery, and ultimately identifies targets for enhanced recovery.

Studying Sex Differences in Animal Models of Addiction: An Emphasis on Alcohol-Related Behaviors.

Animal models are essential for understanding the biological factors that contribute to drug and alcohol addiction and discovering new pharmacotherapies to treat these disorders. Alcohol (ethanol) is the most commonly abused drug in the world, and as the prevalence of alcohol use disorder (AUD) increases, so does the need for effective pharmacotherapies. In particular, treatments with high efficacy in the growing number of female AUD sufferers are needed. Female animals remain underrepresented in biomedical research and sex differences in the brain's response to alcohol are poorly understood. To help bridge the gender gap in addiction research, this Review discusses strategies that researchers can use to examine sex differences in the context of several common animal models of AUD. Self-administration, two-bottle choice, drinking in the dark, and conditioned place preference are discussed, with a focus on the role of estrogen as a mediator of sex differences in alcohol-related behaviors.

Sex differences in animal models: Focus on stress and addiction

Sex differences in animal models: Focus on stress and addiction

Sex differences in animal models of decision making.

The ability to weigh the costs and benefits of various options to make an adaptive decision is critical to an organism's survival and wellbeing. Many psychiatric diseases are characterized by maladaptive decision making, indicating a need for better understanding of the mechanisms underlying this process and the ways in which it is altered under pathological conditions. Great strides have been made in uncovering these mechanisms, but the majority of what is known comes from studies conducted solely in male subjects. In recent years, decision-making research has begun to include female subjects to determine whether sex differences exist and to identify the mechanisms that contribute to such differences. This Mini-Review begins by describing studies that have examined sex differences in animal (largely rodent) models of decision making. Possible explanations, both theoretical and biological, for such differences in decision making are then considered. The Mini-Review concludes with a discussion of the implications of sex differences in decision making for understanding psychiatric conditions. © 2016 Wiley Periodicals, Inc.

Sex Differences in Animal Models: Focus on Addiction.

The purpose of this review is to discuss ways to think about and study sex differences in preclinical animal models. We use the framework of addiction, in which animal models have excellent face and construct validity, to illustrate the importance of considering sex differences. There are four types of sex differences: qualitative, quantitative, population, and mechanistic. A better understanding of the ways males and females can differ will help scientists design experiments to characterize better the presence or absence of sex differences in new phenomena that they are investigating. We have outlined major quantitative, population, and mechanistic sex differences in the addiction domain using a heuristic framework of the three established stages of the addiction cycle: binge/intoxication, withdrawal/negative affect, and preoccupation/anticipation. Female rats, in general, acquire the self-administration of drugs and alcohol more rapidly, escalate their drug taking with extended access more rapidly, show more motivational withdrawal, and (where tested in animal models of "craving") show greater reinstatement. The one exception is that female rats show less motivational withdrawal to alcohol. The bases for these quantitative sex differences appear to be both organizational, in that estradiol-treated neonatal animals show the male phenotype, and activational, in that the female phenotype depends on the effects of gonadal hormones. In animals, differences within the estrous cycle can be observed but are relatively minor. Such hormonal effects seem to be most prevalent during the acquisition of drug taking and less influential once compulsive drug taking is established and are linked largely to progesterone and estradiol. This review emphasizes not only significant differences in the phenotypes of females and males in the domain of addiction but emphasizes the paucity of data to date in our understanding of those differences.

Alcohol preferring (P) rats as a model for examining sex differences in alcohol use disorder and its treatment

RationaleDespite epidemiological and clinical data indicating marked gender differences in alcohol use disorders (AUDs), few preclinical studies have examined sex differences in animal models of AUDs. ObjectiveThe purpose of this study was to first characterize sex differences in ethanol consumption and reinforcement in an alcohol preferring (P) rat model of alcoholism, then use this model to screen pharmacological treatments for sex-specific effects. MethodsEthanol consumption was first assessed in male and female P rats under a three-bottle free-choice procedure. Next, ethanol's reinforcing effects were assessed under a fixed-ratio 1 (FR1) schedule followed by a progressive-ratio (PR) schedule. Finally, the effects of two pharmacological treatments for AUDs, naltrexone (1mg/kg) and topiramate (10 or 20mg/kg), alone and in combination, were tested for sex-specific differences in their efficacy at reducing ethanol's reinforcing effects. ResultsAlthough females initially had higher consumption of and preference for ethanol, male rats increased their consumption and preference over time and rapidly became equal to females. Following prolonged 24-hour/day access, males and females self-administered similar levels of ethanol under FR1 and PR schedules. In response to pharmacological treatment, we observed some sex differences and similarities, most notably, a more robust effect of the combination of naltrexone and topiramate in males as compared to females. ConclusionsThis model of selectively bred P rats may be useful for understanding sex differences in AUDs and related behavior and their underlying neurobiological mechanisms and treatment.

Sex differences in animal models of psychiatric disorders

Psychiatric disorders are characterized by sex differences in their prevalence, symptomatology and treatment response. Animal models have been widely employed for the investigation of the neurobiology of such disorders and the discovery of new treatments. However, mostly male animals have been used in preclinical pharmacological studies. In this review, we highlight the need for the inclusion of both male and female animals in experimental studies aiming at gender-oriented prevention, diagnosis and treatment of psychiatric disorders. We present behavioural findings on sex differences from animal models of depression, anxiety, post-traumatic stress disorder, substance-related disorders, obsessive-compulsive disorder, schizophrenia, bipolar disorder and autism. Moreover, when available, we include studies conducted across different stages of the oestrous cycle. By inspection of the relevant literature, it is obvious that robust sex differences exist in models of all psychiatric disorders. However, many times results are conflicting, and no clear conclusion regarding the direction of sex differences and the effect of the oestrous cycle is drawn. Moreover, there is a lack of considerable amount of studies using psychiatric drugs in both male and female animals, in order to evaluate the differential response between the two sexes. Notably, while in most cases animal models successfully mimic drug response in both sexes, test parameters and treatment-sensitive behavioural indices are not always the same for male and female rodents. Thus, there is an increasing need to validate animal models for both sexes and use standard procedures across different laboratories.

Sex Differences in Animal Models of Depression and Antidepressant Response

Many stress-related mental disorders, including depression and post-traumatic stress disorder occur more often in women than in men. While social and cultural factors certainly contribute to these differences, neurobiological sex differences seem to also play an important role. A rapidly burgeoning literature from basic and clinical research documents sex differences in brain anatomy, chemistry and function, as well as in stress and drug responses. For example, some clinical studies have reported that women may have a better outcome when treated with selective serotonin re-uptake inhibitors, in comparison to tricyclic antidepressants. Furthermore, relatively limited basic research has been devoted to developing animal models and consequently describing drug treatments which are sensitive to sex differences. In this MiniReview, we discuss sex differences in behavioural aspects, as well as neurochemical, neurobiological and pharmacological findings that we have collected from several different animal models and tests of depression. These are the forced swim test, the chronic mild stress and the learned helplessness models, the Flinders sensitive line rats, which is a genetic model of depression and the lipopolysaccharide-induced sickness behaviour, a putative inflammatory model of depression. Collectively, our data have shown that in all animal models assayed, serotonergic neurochemical responses were differently affected in males and females, ultimately producing sex-dependent behavioural effects. In addition, Flinders sensitive line rats exhibited a sexually dimorphic response to chronic antidepressant treatment. These sex-differentiated neurochemical and behavioural alterations lend support to a major role of serotonin in the mediation of sexually dimorphic responses.

Sex differences in depressed substance abusers.

The main goal of this article is to highlight gender-specific differences in the epidemiology, clinical nature, and treatment responses of comorbid depression and substance abuse. The second goal is to make recommendations for future research in the area of gender-specific aspects of comorbid depression and substance abuse. A literature review was conducted using the keywords sex, gender, depression, and substance use disorders for the time period 1980 to the present. We first outline the well-known sex differences in the epidemiology of depressed substance abusers and discuss the clinical significance of substance abuse in depression. Two distinct ways of understanding the role of substance abuse in depression are presented. The first is the role that depression may play in escalation of substance use, and the second is depression as a common sequela of chronic substance abuse. These 2 manifestations that are not mutually exclusive, often co-occurring in female substance abusers, have important treatment implications. Research on treatment response for the above clinical presentations is discussed followed by a summary of the factors that may influence sex differences in the association between depression and substance abuse. Recommendations for future research examining sex differences in animal models of depression, substance abuse, and therapeutic response to medications were made. The need for gender-specific clinical research on the association between depression, stress, and substance abuse is also highlighted.

Sex differences in open-field behavior in response to the β-carboline FG 7142 in rats

Sex differences in animal models of anxiety and depression that employ external stimuli have been previously reported. This study examined the effect of gender on pharmacologically induced anxiety in rats coupled with novel handling, injection, and activity in an open-field test. The anxiogenic compound FG 7142 significantly decreased male open-field exploratory at 5, 10, and 20 mg/kg, while rearing behavior was decreased only at the 20 mg/kg dose. Female rats were more resistant to the effects of FG 7142 on open-field exploratory behavior, decreasing open-field activity, and rearing behavior only after the administration of a dose of 40 mg/kg. In addition, a significant sex difference was observed in the open-field activity of rats injected with the vehicle control. Male rats were less active but showed a similar level of rearing behavior when compared to female rats. The greater sensitivity of male rats to the activity-suppressant effects of FG 7142 could explain the sex differences observed in several other animal models of anxiety and depression.