Non-Targeted Metabolomics Investigation of a Sub-Chronic Variable Stress Model Unveils Sex-Dependent Metabolic Differences Induced by Stress.

Depression is twice as prevalent in women as in men, however, most preclinical studies of depression have used male rodent models. This study aimed to examine how stress affects metabolic profiles depending on sex using a rodent depression model: sub-chronic variable stress (SCVS). The SCVS model of male and female mice was established in discovery and validation sets. The stress-induced behavioral phenotypic changes were similar in both sexes, however, the metabolic profiles of female plasma and brain became substantially different after stress, whereas those of males did not. Four stress-differential plasma metabolites-ß-hydroxybutyric acid (BHB), L-serine, glycerol, and myo-inositol-could yield biomarker panels with excellent performance to discern the stressed individuals only for females. Disturbances in BHB, glucose, 1,5-anhydrosorbitol, lactic acid, and several fatty acids in the plasma of stressed females implied a systemic metabolic shift to ß-oxidation in females. The plasma levels of BHB and corticosterone only in stressed females were observed not only in SCVS but also in an acute stress model. These results collectively suggest a sex difference in the metabolic responses by stress, possibly involving the energy metabolism shift to ß-oxidation and the HPA axis dysregulation in females.

Brain-wide cellular mapping of acute stress-induced activation in male and female mice.

Mood disorders are more prevalent and often reported to be more severe in women; however, little is known about the underlying mechanisms of this sexual prevalence. To gain insight into the functional differences in female brains in response to stress, we systemically compared brain activation in male and female C57BL/6N mice after acute stress exposure. We measured c-Fos expression levels in 18 brain areas related to stress responses after a 3-h long restraint stress and found that activation was sexually dimorphic in several brain areas, including the nucleus accumbens, ventral tegmental area, nucleus reuniens, and medial part of the lateral habenula. Moreover, stress-activated a substantial number of cells in the medial prefrontal cortex, amygdala, and lateral part of the lateral habenula; however, the levels of activation were comparable in males and females, suggesting that the core stress responding machineries are largely shared. Pearson correlation analysis revealed several interesting connections between the analyzed areas that are implicated in stress responses and depression. Overall, stress strengthened intra-circuitries in the hippocampus, amygdala, and prefrontal cortex in female mice, whereas more longer-range connections were highlighted in stressed male mice. Our study provides a highly valuable neuroanatomical framework for investigating the circuit mechanism underlying the higher vulnerability to depression in women.

Determining nicotine-related behavior changes in juvenile female rats through long-term maternal nicotine exposure.

Nicotine replacement therapy (NRT) has been developed as a drug therapy for smoking cessation and has been considered a safe alternative to smoking during pregnancy. However, the effects of long-term nicotine exposure via NRT on the fetus are still being debated. Here, we determined the effects of long-term maternal nicotine exposure in gestation and lactation on nicotine-related behavior and drug vulnerability in dams and offspring rats. To expose long-term nicotine, on gestation day 14, pregnant rats were implanted with osmotic minipumps releasing nicotine tartrate (6 mg/kg/day, subcutaneously, equivalent to 2 mg nicotine-freebase) for 28 days. The concentration of cotinine in blood was 373.0 ± 109.0 ng/ml in dams and 12.50 ± 1.19 ng/ml in offspring rats. In dams, we found no significant differences in anxiety-like behaviors and various maternal behaviors such as touching, sniffing, pup licking, laying on pups, and retrieval between saline- and nicotine-exposed groups. Adolescent offspring female rats showed no significant differences in anxiety-like behavior and forced alcohol consumption between saline- and nicotine-exposed groups. Nicotine-exposed offspring rats showed more increased nicotine aversion than saline-exposed groups, but the effect was disturbed in the forced alcohol consumption condition on the first day of the nicotine consumption test. Taken together, these results suggest that, in the last gestation and lactation period corresponding to the second and third trimester of human pregnancy, long-term maternal nicotine exposure has a minor effect on dam and female offspring health and does not involve serious pathological changes in rat offspring, despite the presence of nicotine in their blood.

The neural basis underlying female vulnerability to depressive disorders.

Depressive disorders are more prevalent and severe in women; however, our knowledge of the underlying factors contributing to female vulnerability to depression remains limited. Additionally, females are notably underrepresented in studies seeking to understand the mechanisms of depression. Various animal models of depression have been devised, but only recently have females been included in research. In this comprehensive review, we aim to describe the sex differences in the prevalence, pathophysiology, and responses to drug treatment in patients with depression. Subsequently, we highlight animal models of depression in which both sexes have been studied, in the pursuit of identifying models that accurately reflect female vulnerability to depression. We also introduce explanations for the neural basis of sex differences in depression. Notably, the medial prefrontal cortex and the nucleus accumbens have exhibited sex differences in previous studies. Furthermore, other brain circuits involving the dopaminergic center (ventral tegmental area) and the serotonergic center (dorsal raphe nucleus), along with their respective projections, have shown sex differences in relation to depression. In conclusion, our review covers the critical aspects of sex differences in depression, with a specific focus on female vulnerability in humans and its representation in animal models, including the potential underlying mechanisms. Employing suitable animal models that effectively represent female vulnerability would benefit our understanding of the sex-dependent pathophysiology of depression.

The link between social context-dependent anxious behavior and habenular mast cells in fear-conditioned rats.

Affiliative social behavior relieves the physiological reactivity to stressors, while social inequity, represented by unfairness in the social environment, causes emotional distress in animals. Mast cells are immune cells found in the brain that affect both the nervous system and emotional behavior. To determine the role of neuro-immunity in the programming of emotional behaviors, we observed brain mast cells and anxiety-like behaviors in female rats exposed to electrical foot shocks in different social environments. The following groups of rats were used in this study: control (unshocked) rats, solitarily shock-exposed rats, and shock-exposed rats in the presence of unshocked (unequal) or shocked (equal) conspecifics. An absence of significant difference in body weight or sucrose preference was seen among the different groups. Additionally, fear memory was augmented in rats shocked in the presence of either unshocked or shocked conspecifics than rats in the solitarily shocked group. Furthermore, rats shocked in the presence of unshocked conspecifics showed intensified anxiety-like behaviors after fear conditioning. Finally, we found an increase in the number of habenular mast cells in the intensified anxiogenic group, which had a significant correlation with the decreasing rate of anxiety-like behaviors. This provides evidence that habenular mast cells might be of importance in relieving the amplified biopsychological responses caused by social stress.

Alteration of adolescent aversive nicotine response and anxiety-like behavior in nicotine-exposed rats during late lactation period.

Early nicotine exposure is an important cause of further habitual tobacco smoking. Although nicotine has not only rewarding but also aversive properties, the effects of early nicotine exposure on the distinct properties of nicotine are not well known. To reveal the effects of early adolescent nicotine exposure on further persistent tobacco smoking, we demonstrated developmental changes in nicotine-related appetitive and aversive behaviors of rats exposed to nicotine during the late lactation period. Sprague-Dawley rats were injected with saline or nicotine (2, 6 and 12mg/kg). We performed a two bottle free-choice test using escalating doses of nicotine (25, 50 and 100µg/ml), saccharin and quinine and the open field test in both adolescent and adult rats. The rats' aversive response to nicotine was increased according to the increase in nicotine concentration. Adolescent rats showed higher nicotine preference and consumption behaviors than did adult rats at an aversive dose of nicotine. Nicotine-exposed rats increased adolescent nicotine consumption when the nicotine concentration was 12mg/kg. We observed significant increases in anxious behaviors in adolescent nicotine-injected rats compared to saline-injected rats, but there were no alterations in adult rats. In both adolescent and adult rats, saccharin and quinine intake were not significantly different between groups. Taken together, it suggests that repeated nicotine exposure in late lactation period affect changes in aversive nicotine responses and anxious behaviors during adolescence but there is no difference in adults.

Differential effects of pair housing on voluntary nicotine consumption: a comparison between male and female adolescent rats.

RATIONALE: Tobacco smoking occurs in a wide array of social circumstances. Social support for quitting is generally used to stop smoking, while peer interactions may be a crucial factor in triggering tobacco use among adolescents. OBJECTIVES: To determine the role of social factors on nicotine dependence, we compared single- and pair-housed rats subjected to voluntary oral nicotine consumption tests. METHODS: Six-week-old adolescent rats were subjected to experimental procedures and assigned to one of the following groups: a male single group, a male pair group with a sibling, a female single group, and a female pair group with a sibling. To measure voluntary nicotine intake, we adopted a two-bottle free-choice paradigm for each two days using 25 µg/ml and 100 µg/ml nicotine solution. RESULTS: There were no differences in change in body weight or food intake between the two groups of either sex. Pair-housed female rats showed a reduction in nicotine consumption and preference for both low- and high-dose nicotine solution, while pair-housed male rats showed only reduced consumption and preference for high-dose nicotine solution, but not low-dose solution, as compared to single-housed male rats. CONCLUSIONS: Nicotine consumption is sex-dependently controlled by the social circumstances of rats. This study broadens our perspectives on the role of social interactions as a therapeutic strategy to treat nicotine addiction-related behaviors depending on sex.