Sex differences in animal models of depression

Accumulated data demonstrate that the A/T single-nucleotide polymorphism (SNP) rs324981 in the human neuropeptide S receptor 1 (NPSR1) gene, resulting in an amino acid change from asparagine (N) to isoleucine (I) at position 107, is associated with susceptibility to psychiatric disorders. Neuropeptide S (NPS) has also been implicated in modulating these disorders in rodent experiments. However, the effect of this SNP on NPSR1 activity remains unclear. To elucidate the pathophysiological and pharmacological implications of this SNP, we generated a mouse model carrying the human-specific AA variant in NPSR1...

Depression affects 20% of the general population and is a leading cause of disability worldwide, with a strong female prevalence. Current pharmacotherapies have significant limitations, and one third of patients are unresponsive. Male Wistar-Kyoto rats exposed to chronic mild stress (CMS) were recently proposed as a model to study antidepressant resistance. However, sex differences and interindividual vulnerability to stress are yet unexplored in this model. We aimed to investigate these in the context of the behavioural impact of CMS in the sucrose preference test, elevated plus maze (EPM), forced swim test (FST), open field test and daily locomotor activity rhythms, in male and female WKY rats exposed or not to a 4-week CMS protocol...

Trauma and chronic stress exposure are the strongest predictors of lifetime neuropsychiatric disease presentation. These disorders often have significant sex biases, with females having higher incidences of affective disorders such as major depression, anxiety, and PTSD. Understanding the mechanisms by which stress exposure heightens disease vulnerability is essential for developing novel interventions. Current rodent stress models consist of a battery of sensory, homeostatic, and psychological stressors that are ultimately integrated by corticotropin-releasing factor (CRF) neurons to trigger corticosteroid release...

Animal models have been used extensively in in vivo studies, especially within the biomedical field. Traditionally, single-sex studies, mostly males, are used to avoid any potential confounding variation caused by sex difference and the female estrous cycle. Historically, female animal subjects are believed to exhibit higher variability, and this could increase the statistical power needed to test a hypothesis. This study sets out to evaluate whether a sex difference does exist in mouse behavior, and whether female mice featured higher variability...

The underlying biological mechanisms that contribute to the heterogeneity of major depressive disorder (MDD) presentation remain poorly understood, highlighting the need for a conceptual framework that can explain this variability and bridge the gap between animal models and clinical endpoints. Here, we hypothesize that comparative analysis of molecular data from different experimental systems of chronic stress, and MDD has the potential to provide insight into these mechanisms and address this gap. Thus, we compared transcriptomic profiles of brain tissue from postmortem MDD subjects and from mice exposed to chronic variable stress (CVS) to identify orthologous genes...

BACKGROUND: Hypersomnolence is a common and disruptive side effect of cranial radiotherapy and is associated with fatigue and disturbances in mood and cognition in primary brain tumor (PBT) patients. The biological underpinnings of this effect are not understood. Our laboratory has previously found that the presence of a single nucleotide polymorphism (rs934945, G-E mutation) in the PERIOD2 (PER2) clock gene was associated with a decreased likelihood of fatigue in PBT patients. Here, we aim to understand the effects of PER2 polymorphism on radiation susceptibility within a murine model of cranial-irradiation-induced hypersomnolence (C-RIH)...

Opioids are well-known to cause respiratory depression, but despite clinical evidence of dysphagia, the effects of opioids on swallow excitability and motor pattern are unknown. We sought to test the effects of the clinically-relevant opioid buprenorphine on pharyngeal swallow and respiratory drive in male and female rats. We also evaluated utility of serotonin 5-HT1A agonists (8-OH-DPAT and buspirone) to improve swallowing and breathing outcomes following buprenorphine administration. Experiments were performed on 44 freely breathing Sprague Dawley rats anesthetized with sodium pentobarbital...

Mesolimbic dopamine (DA) regulates vigor in motivated behavior. While previous results have mainly been performed in male rodents, the present studies compared CD1 male and female mice in effort-based decision-making tests of motivation. These tests offered choices between several reinforcers that require different levels of effort (progressive ratio/choice task and 3-choice-T-maze task). Sweet reinforcers were used in both tasks. In the operant tasks, females worked harder as the task required more effort to access a 10% sucrose solution...

Dysregulation of the mesolimbic reward circuitry is implicated in the pathophysiology of stress-related illnesses such as depression and anxiety. These disorders are more frequently diagnosed in females, and sex differences in the response to stress are likely to be one factor that leads to enhanced vulnerability of females. In this study, we use subchronic variable stress (SCVS), a model in which females are uniquely vulnerable to behavioral disturbances, to investigate sexually divergent mechanisms of regulation of the ventral tegmental area by stress...

The monoamine hypothesis has significantly improved our understanding of mood disorders and their treatment by linking monoaminergic abnormalities to the pathophysiology of mood disorders. Even 50 years after the monoamine hypothesis was established, some patients do not respond to treatments for depression, including selective serotonin reuptake drugs. Accumulating evidence shows that patients with treatment-resistant depression (TRD) have severe abnormalities in the neuroplasticity and neurotrophic factor pathways, indicating that different treatment approaches may be necessary...

Lysergic acid diethylamide (LSD), psilocybin, and psilocin are being intensively evaluated as potential therapeutics to treat depression, anxiety, substance use disorder, and a host of other psychiatric illnesses. Pre-clinical investigation of these compounds in rodent models forms a key component of their drug development process. In this review, we will summarize the evidence gathered to date surrounding LSD, psilocybin, and psilocin in rodent models of the psychedelic experience, behavioural organization, substance use, alcohol consumption, drug discrimination, anxiety, depression-like behaviour, stress response, and pharmacokinetics...

Anxiety and depressive disorders are closely associated; however, the pathophysiology of these disorders remains poorly understood. Further exploration of the mechanisms involved in anxiety and depression such as the stress response may provide new knowledge that will contribute to our understanding of these disorders. Fifty-eight 8-12-week-old C57BL6 mice were separated into experimental groups by sex as follows: male controls ( n = 14), male restraint stress ( n = 14), female controls ( n = 15) and female restraint stress ( n = 15)...

Schizophrenia is a psychiatric disorder with a global prevalence of approximately 0.45%. It is considered a mental illness, with negative symptoms, positive symptoms, and cognitive dysfunction. The outcomes of studies on the role of microglia and neuroinflammation have been conflicting. In addition, there is a poor understanding of the sex differences in microglial expression and neuroinflammation markers in the prefrontal cortex, hippocampus, and nucleus accumbens. Understanding the exact roles of neuroinflammation may guide the development of efficient therapeutic drugs that can address the negative, positive, and cognitive symptoms of the disease...

Major depressive disorder (MDD) is underlined by neurochemical changes in the brain. Proton magnetic resonance spectroscopy (1 H MRS) is a useful tool for their examination as it provides information about the levels of metabolites. This review summarises the current knowledge of 1 H MRS findings from rodent models of MDD, assesses the results from both a biological and a technical perspective, and identifies the main sources of bias. From a technical point of view, bias-introducing factors are the diversity of the measured volumes and their positioning in the brain, the data processing, and the metabolite concentration expression...

The early postnatal period represents an exceptionally vulnerable phase for the development of neurobiological alterations, aberrant behavior, and psychiatric disorders. Altered GABAergic activity in the hippocampus and the amygdala have been identified in humans diagnosed with depression or anxiety disorders, as well as in respective animal models. Changes in GABAergic activity can be visualized by immunohistochemical staining of parvalbumin (PV) protein. Therewith, alterations in PV intensity as well as in the integrity of the perineural net surrounding PV positive (PV+) interneurons have been reported as consequences of early stress...

Investigation of the neurobiology of depression in humans depends on animal models that attempt to mimic specific features of the human disorder. However, frequently-used paradigms based on social stress cannot be easily applied to female mice which has led to a large sex bias in preclinical studies of depression. Furthermore, most studies focus on one or only a few behavioral assessments, with time and practical considerations prohibiting a comprehensive evaluation. In this study, we demonstrate that predator stress effectively induced depression-like behaviors in both male and female mice...

Sex differences in the prevalence, symptomatology, severity, and other aspects of various neuropsychiatric diseases have been consistently reported. Stress and fear-related psychopathologies, such as anxiety disorders, depression, and post-traumatic stress disorder, are more prevalent in women. Investigations of the mechanisms underlying this sex disparity have described the influence of gonadal hormones in both humans and animal models. However, gut microbial communities are also likely to play a role, as these communities differ between the sexes, are involved in a bidirectional cycling of sex hormones and their metabolites, and are associated with changes in fear-related psychopathologies when gut microbiota are altered or removed...

BACKGROUND: Puberty-driven increases in the secretion of testosterone may be a biological factor that protects males against the development of depression. Although all males produce testosterone, there are substantial between-person differences that could contribute to differential vulnerability to depression among pre-adolescent and adolescent boys, particularly after pubertal onset. Indeed, experimental animal and human data have shown that low testosterone increases risk for depressive-like symptoms in males, whereas higher levels of testosterone may be protective; however, prior studies have primarily investigated these effects in adulthood...

Parental care is essential for proper development of stress response and emotion-related behaviours. Epidemiological studies show that parental loss in childhood represents a major risk factor for the development of mental disorders throughout the lifespan, including schizophrenia, depression, and anxiety. In most mammalian species, the mother is the main source of care and maternal behaviours regulate several physiological systems. Maternal deprivation (DEP) for 24 h is a paradigm widely used to disinhibit the hypothalamic-pituitary-adrenal axis response to stress during the stress hyporesponsive period...

BACKGROUND: Recent preclinical and clinical studies have shed light on the possible impact of sex and oestrous/menstrual cycle on ketamine's antidepressant action but with incongruous results. The preclinical studies that have shown the effects of ovarian sex hormones have not done so in animal models of depression. Thus, the aim of the present study is to scrutinize the acute behavioural responses to a subanaesthetic dose of S-ketamine in males vs females and in different oestrous phases in free-cycling females in a well-powered translational approach...