Is There an Inflammatory Profile of Perinatal Depression?

PURPOSE OF REVIEW: To synthesize and critically examine recent evidence regarding associations between immune system activity and perinatal depression. RECENT FINDINGS: Despite a significant number of studies assessing potential immunological markers of perinatal depression, it does not appear that levels of any individual pro- or anti-inflammatory marker is a useful predictor of perinatal depression. Some recent studies have observed differences in overall immune system functioning and adaptation across this period, taking into account multiple pro- and anti- inflammatory markers. Furthermore, there is evidence for interactions between depression and maternal psychosocial factors. Immune system functioning may be a mechanism through which social determinants of health contribute to risk for perinatal depression. There is substantial evidence implicating dysregulated immune activity in perinatal depression, yet little clarity regarding a consistent immune profile, especially based on analysis of circulating peripheral cytokines.

Sex-specific maternal programming of corticosteroid-binding globulin by predator odour.

Predation is a key organizing force in ecosystems. The threat of predation may act to programme the endocrine hypothalamic-pituitary-adrenal axis during development to prepare offspring for the environment they are likely to encounter. Such effects are typically investigated through the measurement of corticosteroids (Cort). Corticosteroid-binding globulin (CBG) plays a key role in regulating the bioavailability of Cort, with only free unbound Cort being biologically active. We investigated the effects of prenatal predator odour exposure (POE) in mice on offspring CBG and its impact on Cort dynamics before, during and after restraint stress in adulthood. POE males, but not females, had significantly higher serum CBG at baseline and during restraint and lower circulating levels of Free Cort. Restraint stress was associated with reduced liver transcript abundance of SerpinA6 (CBG-encoding gene) only in control males. POE did not affect SerpinA6 promoter DNA methylation. Our results indicate that prenatal exposure to a natural stressor led to increased CBG levels, decreased per cent of Free Cort relative to total and inhibited restraint stress-induced downregulation of CBG transcription. These changes suggest an adaptive response to a high predator risk environment in males but not females that could buffer male offspring from chronic Cort exposure.

The role of sex-differentiated variations in stress hormones, antioxidants, and neuroimmune responses in relation to social interaction impairment in a rodent model of autism.

Males are more likely to develop autism as a neurodevelopmental disorder than females, but the mechanisms underlying male susceptibility are not fully understood. In this paper, we used a well-characterized propionic acid (PPA) rodent model of autism to study sex differences in stress hormones, antioxidants' status, and the neuroimmune response that may contribute to the preponderance of autism in males. Sprague Dawley rats of both sexes were divided into a saline-treated group as controls and PPA-treated groups, receiving 250 mg/kg of PPA per day for three days. Animals' social behavior was examined using the three-chamber social test. Hormones (ACTH, corticosterone, melatonin, and oxytocin), oxidative stress biomarkers (glutathione, glutathione-S-transferase, and ascorbic acid), and cytokines (IL-6, IL-1α, IL-10, and IFNγ) were measured in the brain tissue of all the animals. The results showed a sex dimorphic social response to PPA treatment, where males were more susceptible to the PPA treatment and exhibited a significant reduction in social behavior with no effects observed in females. Also, sex differences were observed in the levels of hormones, antioxidants, and cytokines. Female rats showed significantly higher corticosterone and lower oxytocin, antioxidants, and cytokine levels than males. The PPA treatment later modulated these baseline differences. Our study indicates that the behavioral manifestation of autism in PPA-treated males and not females could be linked to neural biochemical differences between the sexes at baseline, which might play a protective role in females. Our results can contribute to early intervention strategies and treatments used to control autism, an increasingly prevalent disorder.

Perinatal high-fat diet impairs pup retrieval and induces sex-specific changes in ultrasonic vocalization characteristics of rat pups.

Rodent pups emit ultrasonic vocalizations (USVs) to solicit maternal behavior, promoting their survival. Conversely, maternal behaviors affect the expression of pup USVs. We previously demonstrated that a maternal diet high in saturated fat (HFD) alters maternal behavior and is associated with early maturation of pups and their stress physiology. Here, we assessed the developmental profiles of pup USVs using quantitative and qualitative measures on postnatal days (PND)7 and 13. Quantitative measures included call counts, duration, and frequency, while qualitative measures examined calls' sonographic structures. HFD offspring lacked the typical decrease in USV numbers with age observed among control offspring. They also had shorter calls at PND7 compared to control and HFD offspring at PND13. HFD female offspring showed a greater number of one-frequency-sweep calls, while male pups showed a greater number of two-frequency-sweep calls compared to control offspring. Concomitantly, HFD dams showed impaired pup retrieval on PND7. The data suggest that fewer USVs of shorter duration in HFD offspring may alter dam solicitation and thus impair maternal pup retrieval. This study highlights the impacts of perinatal HFD exposure on the dyadic reciprocal interaction between dam and pups, which may set the stage for long-lasting effects on offspring physiology and behavior.

LRRK2(I2020T) functional genetic interactors that modify eye degeneration and dopaminergic cell loss in Drosophila.

Progressive degeneration of dopaminergic neurons in the substantia nigra pars compacta is the primary cause for motor symptoms observed in Parkinson's disease (PD). Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most commonly linked contributor to familial PD. LRRK2 is suggested to be involved in a wide variety of cellular processes, but deciphering its role in the pathogenesis of PD has been difficult. Modelling PD in rodents has been a persistent challenge for the field. However, the fruit fly has been exploited to recapitulate PD gene related dopaminergic cell loss. Using the GAL4-UAS system and established models of hLRRK2 induced eye degeneration in Drosophila, we conducted an unbiased suppressor/enhancer screen to uncover genetic modifiers of LRRK2. We have identified 36 candidate interactors that modify LRRK2 induced toxicity in the Drosophila eye. Importantly, we determined that a subset of these interactors also modified hLRRK2(I2020T) induced dopaminergic neuronal loss in the fly brain and uncovered 16 candidates that modify dopaminergic cell loss. Our results suggest LRRK2 may be involved in a wide variety of cellular processes and the results from this screen provide an important genetic resource for further evaluation of LRRK2 function.

Maternal programming of sex-specific responses to predator odor stress in adult rats.

Prenatal stress mediated through the mother can lead to long-term adaptations in stress-related phenotypes in offspring. This study tested the long-lasting effect of prenatal exposure to predator odor, an ethologically relevant and psychogenic stressor, in the second half of pregnancy. As adults, the offspring of predator odor-exposed mothers showed increased anxiety-like behaviors in commonly used laboratory tasks assessing novelty-induced anxiety, increased defensive behavior in males and increased ACTH stress reactivity in females in response to predator odor. Female offspring from predator odor-exposed dams showed increased transcript abundance of glucocorticoid receptor (NR3C1) on the day of birth and FK506 binding protein 5 (FKBP5) in adulthood in the amygdala. The increase in FKBP5 expression was associated with decreased DNA methylation in Fkbp5 intron V. These results indicate a sex-specific response to maternal programming by prenatal predator odor exposure and a potential epigenetic mechanism linking these responses with modifications of the stress axis in females. These results are in accordance with the mismatch hypothesis stating that an animal's response to cues within its life history reflects environmental conditions anticipated during important developmental periods and should be adaptive when these conditions are concurring.

The Association of Asthma with Anxiety, Depression, and Mild Cognitive Impairment among Middle-Aged and Elderly Individuals in Saudi Arabia.

Asthma is a common chronic inflammatory condition with increasing global prevalence. There is some evidence highlighting the effect of asthma on brain functioning. In Saudi Arabia, limited studies have examined the relationship between asthma and mental health, including cognition and mood disorders in older adults in particular. In this study, we examine the association between asthma and mental health outcomes in middle-aged and elderly individuals in Riyadh, Saudi Arabia. In a cross-sectional study, 243 subjects were recruited from outpatient clinics between 2020-2021 (non-asthmatic: n = 159, asthmatic: n = 84). The Montreal Cognitive Assessment test, the Hospital Anxiety and Depression Scale, and the Asthma Control Test were used to assess cognition, anxiety and depression, and asthma control, respectively. Logistic regression analysis while controlling for covariates revealed an association between asthma and symptoms of anxiety and depression (OR = 2.40 [95% CI: 1.07-5.35]) and mild cognitive impairment (MCI) (OR = 1.80 [95% CI: 1.00-3.24]). Poorly controlled asthma increased the odds of anxiety cases (OR = 4.88 [95% CI: 1.09-17.2]). Stratifying analysis by age intervals revealed that asthma was associated with symptoms of anxiety and depression (OR = 2.5 [95% CI: 1.00-6.08]) in middle-aged patients only, while elderly asthmatics had increased odds of having MCI (OR = 7.4 [95% CI: 2.34-23.31]). These findings highlight the possible effects of asthma and its control on mental health among middle-aged and elderly individuals in Saudi Arabia.

Stress and DNA Methylation of Blood Leukocytes among Pregnant Latina Women.

Latinas experience physical and psychological stressors in pregnancy leading to increased morbidity and higher risk for adverse birth outcomes. Epigenetic changes, including DNA methylation (DNAm), have been proposed as markers to create more refined risk stratification, yet few of these studies have examined these changes in Latinas. We conducted a secondary analysis of stored blood leukocytes of Latina women (n = 58) enrolled in a larger National Institutes of Health funded R01 project (2011-2016). We examined DNAm on eight candidate stress genes to compare physically and psychologically stressed participants to healthy (low stress) participants. We found unique CpGs that were differentially methylated in stressed women early- and mid-pregnancy compared to the healthy group, though none remained significant after FDR correction. Both physical and psychological stress were associated with hypomethylation at two consecutive CpG sites on NR3C1 in early pregnancy and one CpG site on NR3C1 in mid-pregnancy before adjustment. Stress was also associated with hypomethylation at two CpG sites on FKBP5 in early and mid-pregnancy but were no longer significant after FDR adjustment. Though we did not find statistically significant differences in DNAm during pregnancy between stressed and healthy women in this sample, signals were consistent with previous findings. Future work in larger samples should further examine the associations between stress and DNAm in pregnancy as this mechanism may explain underlying perinatal health inequities.

Defining Physician-Nurse Efforts toward Collaboration as Perceived by Medical Students.

Collaboration between physicians and nurses is essential to healthcare delivery and is associated with high-quality patient care, greater patient satisfaction, and better health outcomes. Hence, it is imperative that doctors and nurses have a particular set of interprofessional collaboration skills. This descriptive cross-sectional study assessed how medical students in the pre-clinical and clinical years perceived attitudes toward collaboration between physicians and nurses in a hospital setting. The Jefferson Scale of Attitude toward Physician-nurse Collaboration (JSAPNC) was reverse-translated into Arabic for the current study. The results showed a total JSAPNC mean score of 46.55, lower than other medical students in other universities. In general, the results of the study showed no significant difference in the total JSAPNC score among medical students when analyzed according to age, clinical exposure, and year level, except in the two factors of JSAPNC: shared education and teamwork (p = 0.038) and caring as opposed to curing (p = 0.043). The findings of this study suggest the necessity of integrating interprofessional education (IPE) across the medical school curriculum because, as future physicians, medical students would be well equipped to treat their patients in partnership with their nursing colleagues.

Different Alterations in Gut Microbiota between Bifidobacterium longum and Fecal Microbiota Transplantation Treatments in Propionic Acid Rat Model of Autism.

Autism spectrum disorders (ASD) consist of a range of neurodevelopmental conditions accompanied by dysbiosis of gut microbiota. Therefore, a number of microbiota manipulation strategies were developed to restore their balance. However, a comprehensive comparison of the various methods on gut microbiota is still lacking. Here, we evaluated the effect of Bifidobacterium (BF) treatment and fecal microbiota transplantation (FT) on gut microbiota in a propionic acid (PPA) rat model of autism using 16S rRNA sequencing. Following PPA treatment, gut microbiota showed depletion of Bacteroidia and Akkermansia accompanied by a concomitant increase of Streptococcus, Lachnospiraceae, and Paraeggerthella. The dysbiosis was predicted to cause increased levels of porphyrin metabolism and impairments of acyl-CoA thioesterase and ubiquinone biosynthesis. On the contrary, BF and FT treatments resulted in a distinct increase of Clostridium, Bifidobacterium, Marvinbryantia, Butyricicoccus, and Dorea. The taxa in BF group positively correlated with vitamin B12 and flagella biosynthesis, while FT mainly enriched flagella biosynthesis. In contrast, BF and FT treatments negatively correlated with succinate biosynthesis, pyruvate metabolism, nitrogen metabolism, beta-Lactam resistance, and peptidoglycan biosynthesis. Therefore, the present study demonstrated that BF and FT treatments restored the PPA-induced dysbiosis in a treatment-specific manner.

The Efficacy of Fecal Transplantation and Bifidobacterium Supplementation in Ameliorating Propionic Acid-Induced Behavioral and Biochemical Autistic Features in Juvenile Male Rats.

Gut microbiota plays a major role in neurological disorders, including autism. Modulation of the gut microbiota through fecal microbiota transplantation (FMT) or probiotic administration, such as Bifidobacteria, is suggested to alleviate autistic symptoms; however, their effects on the brain are not fully examined. We tested both approaches in a propionic acid (PPA) rodent model of autism as treatment strategies. Autism was induced in Sprague-Dawley rats by administering PPA orally (250 mg/kg) for 3 days. Animals were later treated with either saline, FMT, or Bifidobacteria for 22 days. Control animals were treated with saline throughout the study. Social behavior and selected brain biochemical markers related to stress hormones, inflammation, and oxidative stress were assessed. PPA treatment induced social impairments, which was rescued by the treatments. In the brain, Bifidobacteria treatment increased oxytocin relative to control and PPA groups. Moreover, Bifidobacteria treatment rescued the PPA-induced increase in IFN-γ levels. Both treatments increased GST levels, which was diminished by the PPA treatment. These findings indicate the potential of gut microbiota-targeted therapeutics in ameliorating behavioral deficit and underlying neural biochemistry.

Fecal Transplant and Bifidobacterium Treatments Modulate Gut Clostridium Bacteria and Rescue Social Impairment and Hippocampal BDNF Expression in a Rodent Model of Autism.

Autism is associated with gastrointestinal dysfunction and gut microbiota dysbiosis, including an overall increase in Clostridium. Modulation of the gut microbiota is suggested to improve autistic symptoms. In this study, we explored the implementation of two different interventions that target the microbiota in a rodent model of autism and their effects on social behavior: the levels of different fecal Clostridium spp., and hippocampal transcript levels. Autism was induced in young Sprague Dawley male rats using oral gavage of propionic acid (PPA) for three days, while controls received saline. PPA-treated animals were divided to receive either saline, fecal transplant from healthy donor rats, or Bifidobacterium for 22 days, while controls continued to receive saline. We found that PPA attenuated social interaction in animals, which was rescued by the two interventions. PPA-treated animals had a significantly increased abundance of fecal C. perfringens with a concomitant decrease in Clostridium cluster IV, and exhibited high hippocampal Bdnf expression compared to controls. Fecal microbiota transplantation or Bifidobacterium treatment restored the balance of fecal Clostridium spp. and normalized the level of Bdnf expression. These findings highlight the involvement of the gut-brain axis in the etiology of autism and propose possible interventions in a preclinical model of autism.

Leaky gut biomarkers in casein- and gluten-rich diet fed rat model of autism.

It is proposed that gluten- and casein-rich diets (GRD and CRD) can synergistically exacerbate dysbiosis as comorbidity in autism by worsening leaky gut that affects the brain through the gut-brain axis. In this study, 35 young male rats were divided into 7 groups, Group 1 serves as control; Group 2, clindamycin (CL)-treated; and Group 3, propionic acid (PPA)-induced rodent model of autism. These three groups were fed standard diet until the end of the experiment. Groups 4-7 are rats treated similarly with CL and PPA, then fed on CRD or GRD until the end of the experiment. Serum zonulin, glutathione (GSH), lipid peroxides, and gut microbial composition were measured in the seven studied groups. Data demonstrate the significant increase in serum zonulin as marker of leaky gut in the CL-treated groups fed on CRD or GRD. Lipid peroxides were significantly higher in the serum of GRD-fed rats compared to CRD-fed or normal diet-fed rats. GSH was much lower in CL-treated groups fed on CRD or GRD compared to PPA-treated rats fed on both diets. Both diets differentially affected the diversity of the gut microbiota. This study demonstrates that CRD and GRD exacerbates leaky gut, according to serum zonulin, which was used as marker for increased gut permeability.

Perinatal high fat diet induces early activation of endocrine stress responsivity and anxiety-like behavior in neonates.

The maternal environment has a profound effect on the development of offspring, including responses to stress mediated by the hypothalamic-pituitary-adrenal (HPA) axis. In rodents, perinatal high fat diet (HFD) has been shown to program the HPA axis in a manner that persists throughout adulthood, however the effects of perinatal HFD on stress-related behaviors and physiology in neonates are limited. The first two weeks of life in rodents are known as the stress hyporesponsive period, during which animals do not respond to stressors that are otherwise known to elicit behavioral and physiological responses in mature animals. As neonates emerge from the hyporesponsive period, the maturing neural systems mediating the HPA axis leads to the suppression of ultrasonic vocalizations (USVs) and movement in the presence of threatening stimuli, such as male adult rat odor. In this study, we investigated the effects of perinatal HFD exposure, spanning the maternal pregestation, gestation and lactation period, on stress-related behaviors and physiology in neonatal rat offspring throughout the stress hyporesponsive period. During the stress hyporesponsive period, postnatal day (PND) 7, HFD pups had higher corticosterone levels in response to the presence of male odor, produced fewer USVs, and had an increase in basal corticotropin releasing hormone (Crh) transcript levels in the paraventricular nucleus of the hypothalamus. As pup emerged from the stress hyporesponsive period, PND 13, HFD offspring exhibited higher adrenocorticotropic hormone (ACTH) levels in response to male odor, increased anxiety-like behaviors as shown by increased USVs and immobility, and lower glucocorticoid receptor (Nr3c1) transcript abundance in the ventral hippocampus. These results indicate an alteration in the typical physiological and behavioral responses to stress during the hyporesponsive period of the HPA axis as a function of perinatal HFD exposure, which involves changes in the regulation of key genes mediating the HPA axis.

Maternal predator odour exposure programs metabolic responses in adult offspring.

A cardinal feature of the reaction to stress is the promotion of energy mobilization, enabling appropriate behavioural responses. Predator odours are naturalistic and ecologically relevant stressors present over evolutionary timescales. In this study, we asked whether maternal predator odour exposure could program long-term energy mobilization in C57BL/6 mice offspring. To test this hypothesis, we measured rates of oxygen consumption in prenatally predator odour exposed mice in adulthood while controlling for levels of locomotor activity at baseline and under stress. Circulating thyroid hormone levels and the transcript abundance of key regulators of the hypothalamic-pituitary-thyroid axis within the periventricular nucleus (PVN) of the hypothalamus and in the liver, including carriers and receptors and thyrotropin-releasing hormone, were measured as endocrine mediators facilitating energy availability. Prenatally predator odour exposed mice of both sexes mobilized more energy during lower energy demand periods of the day and under stressful conditions. Further, prenatally predator odour exposed mice displayed modifications of their hypothalamic-pituitary-thyroid axis through increased circulating thyroxine and thyroid hormone receptor α within the PVN and decreased transthyretin in the liver. Overall, these results suggest that maternal exposure to predator odour is sufficient to increase long-term energy mobilization in adult offspring.

Maternal Predator Odor Exposure in Mice Programs Adult Offspring Social Behavior and Increases Stress-Induced Behaviors in Semi-Naturalistic and Commonly-Used Laboratory Tasks.

Maternal stress has a profound impact on the long-term behavioral phenotype of offspring, including behavioral responses to stressful and social situations. In this study, we examined the effects of maternal exposure to predator odor, an ethologically relevant psychogenic stressor, on stress-induced behaviors in both semi-naturalistic and laboratory-based situations. Adult C57BL/6 mice offspring of dams exposed to predator odor during the last half of pregnancy showed increased anti-predatory behavior, more cautious foraging behavior and, in the elevated plus maze, avoidance of elevated open areas and elevated open areas following restraint stress challenge. These offspring also exhibited alterations in social behavior including reduced free interaction and increased initial investigation despite normal social recognition. These changes in behavior were associated with increased transcript abundance of corticotropin-releasing factor, mineralocorticoid receptor and oxytocin (Oxt) in the periventricular nucleus of the hypothalamus. Taken together, the findings are consistent with a long-term increase in ethologically-relevant behavioral and neural responses to stress in male and female offspring as a function of maternal predator odor exposure.