Rodent pups emit ultrasonic vocalizations (USVs) to solicit maternal care, enhancing survival. Inflammatory stressors, such as maternal high-fat diet (mHFD) and neonatal lipopolysaccharide (nLPS) exposure, affect neonatal neurodevelopment and behavior. Although basic features of USVs are widely used to assess these impacts, their sonographic and syntax characteristics remain underexplored. We employed DeepSqueak, a deep learning system, for automated unsupervised USV classification and detailed analysis of temporal and syntax changes, comparing it to manual coding for call number, duration, and frequency. Offspring of Long Evans rat dams, fed a high-fat or control diet for three weeks premating and throughout gestation and lactation, received 0.05 mg/kg intraperitoneal nLPS or saline on postnatal days (PND) 3 and 5 (n = 5-6 per condition, total N = 41). On PND 7, USVs were recorded after a brief maternal separation. DeepSqueak yielded 97% concordance (p > 0.8 vs. manual); mHFD increased bout duration by 25% (p < 0.01), and nLPS increased calls per sequence by 30% (p < 0.05). DeepSqueak matched manual accuracy, with automated analysis revealing that mHFD and nLPS significantly prolonged sequence durations and altered syntax transition probabilities. These findings suggest that temporal and syntactic USV features are sensitive markers of early inflammatory stress.

The transition to parenthood is a unique period of adulthood during which the brain undergoes profound and rapid changes, particularly in birthing mothers. This transition is also associated with a risk of developing mental illness, likely due to intersections among the neurobiological changes and a host of psychosocial factors including one’s history of mental illness and lack of adequate support systems for parents. Emerging evidence indicates that perinatal depression and anxiety are associated with distinct neural alterations that overlap with the brain areas also involved in caregiving. Thus, there is a critical need to better understand the neurobiological mechanisms underlying perinatal mental illness for both maternal and child wellbeing. The goals of this review are to highlight key findings from current research on the ways in which human brain function and structure are associated with (1) perinatal depression, (2) perinatal anxiety, and (3) treatments aimed at promoting parental mental health. Advances in understanding the neuroplasticity associated with perinatal depression and anxiety will inform the development of targeted interventions and treatments aimed at supporting parental wellbeing, promoting healthy parent–infant relationships, and improving peripartum brain health.

Maternal health during pregnancy is a leading factor influencing offspring risk. This study investigated whether postnatal dietary supplementation could reduce oxidative stress and gut leakiness in a rat model of autism spectrum disorder (ASD). Male rat pups were prenatally exposed to valproic acid (VPA) or lipopolysaccharide (LPS) to induce ASD-like conditions. A total of 54 offspring of Wistar albino rats were divided into nine groups to evaluate various postnatal treatments, including an artichoke-based prebiotic (AR), probiotics (Pro), and omega-3 fatty acids (ω3). The experimental design also included control groups (saline, VPA-only, and LPS-only), as well as a protective regimen in which AR was administered both prenatally and postnatally. Oxidative stress and gut permeability "leakiness" were assessed using Enzyme-Linked Immunosorbent Assay (ELISA). Prenatal exposure to VPA and LPS was associated with increased oxidative stress levels in brain homogenates, accompanied by a significant decrease in glutathione (GSH). Additionally, elevated plasma levels of gut permeability biomarkers were observed. In the VPA model, treatment with artichoke-derived prebiotics - administered either prenatally, postnatally, or in combination with probiotics - effectively improved oxidative stress markers, as evidenced by a significant increase in GSH levels. Conversely, similar interventions in the LPS-induced maternal immune activation model did not significantly ameliorate oxidative stress, although a modest increase in GSH levels was noted. Plasma levels of gut permeability biomarkers did not show significant improvement in either model following treatment with artichoke-derived probiotics alone or in combination with probiotics and omega-3 fatty acids. However, intestinal fatty acid-binding protein levels were significantly reduced in all treatment groups across both models. In contrast, lipopolysaccharide-binding protein (LBP) levels were not significantly reduced by artichoke extract monotherapy in either model, although combination therapy with probiotics and/or omega-3s led to significant reductions in LBP. These results support the use of both VPA and LPS as complementary models for studying ASD. The VPA model, characterized by direct and predictable neurotoxic effects, appears to be more suitable for evaluating preventive interventions. In contrast, the LPS model more accurately captures the complex immune-inflammatory mechanisms implicated in ASD, highlighting the need for broader and more individualized treatment strategies. The differing responses to artichoke-based interventions in these models underscore the importance of considering ASD etiology when designing dietary and microbiome-targeted therapies.

Objectives:The present study aimed to evaluate the behavioral consequences of maternal immune activation (MIA) induced by lipopolysaccharide (LPS), in comparison to valproic acid (VPA), a widely used and reliable inducer of autism-like features in rats when administered during prenatal development. At the behavioral level, we further assessed the potential ameliorative effects of a standardized polyphenol-rich extract derived from the leaves of Cynara cardunculus L. (artichoke), used as a prebiotic - either independently or in combination with a probiotic mixture and/or omega-3 (ω3) fatty acids. Methods:Wistar albino rats prenatally exposed to LPS or VPA were evaluated for social behavior using the three-chamber social interaction test. Beginning at 7 days of age, male rat pups received specific doses of the artichoke as prebiotic (AR), probiotics (Pro), and ω3 supplements, depending on group assignment. A total of 54 neonatal male rats were divided into nine experimental groups: (1) Control group: received normal saline; (2) VPA-0 group: prenatally exposed to VPA only; (3) VPA-AR group: prenatally exposed to VPA, postnatally treated with AR; (4) VPA-AR.Pro group: prenatally exposed to VPA, postnatally treated with AR + Pro; (5) VPA.AR-AR group: received AR during gestation (protectively), and postnatal AR after VPA exposure; (6) LPS-0 group: prenatally exposed to LPS only; (7) LPS-AR group: prenatally exposed to LPS, postnatally treated with AR; (8) LPS-AR.Pro.ω3 group: prenatally exposed to LPS, postnatally treated with AR + Pro + ω3; (9) LPS.AR-AR group: received AR during gestation (protectively), and postnatal AR after LPS exposure. Results:LPS and prenatal VPA exposure significantly impair social interactions and promoting stereotypic-like behaviors. Notably, both pre- and postnatal administration of artichoke extract demonstrated significant potential in improving these behavioral deficits. MIA and prenatal VPA exposure have detrimental effects on neurobehavioral development, particularly impairing social interactions and promoting stereotypic-like behaviors consistent with ASD. Conclusions:These results provide evidence for the beneficial role of artichoke-derived prebiotics, alone or in combination with probiotics and ω3, in improving ASD-like symptoms in rodent models of autism.

BACKGROUND:Pregnancy outcomes are influenced by maternal distress but the pathways underlying these effects are still unknown. Mitochondria, crucial for energy production and stress adaptation, may link psychosocial stress to its biological effects, especially during pregnancy when energy demands significantly increase. This study explores two mitochondrial markers-circulating cell-free mitochondrial DNA (cf-mtDNA) and Growth Differentiation Factor-15 (GDF15)-as potential mitochondrial health indicators linking maternal distress to pregnancy outcomes in two longitudinal studies from the USA and Turkey. METHODS:We analyzed biological, demographic, and psychological data from women in two pregnancy studies: EPI (N = 187, USA) and BABIP (N = 198, Turkey). Data were collected at multiple timepoints during the perinatal period, including late 2nd and 3rd trimester, with EPI also including additional data at early 2nd trimester and 4-14 months postpartum. Prenatal maternal psychological distress was measured as perceived stress, anxiety, and depressive symptoms. Plasma cf-mtDNA and GDF15 levels were assessed using qPCR and ELISA, respectively. Statistical analyses included Wilcoxon signed-rank tests, Spearman correlations, and Mann-Whitney tests. RESULTS:Plasma cf-mtDNA levels did not significantly vary across pregnancy, while plasma GDF15 levels increased from early to late pregnancy and decreased postpartum. Late 2nd trimester plasma GDF15 was negatively correlated with pre-pregnancy BMI (p = 0.035) and gestational age (p = 0.0048) at birth. Early 2nd trimester maternal distress was associated with lower cf-mtDNA (all p-values < 0.05) and a trend for lower GDF15. Higher pre-pregnancy BMI and late-pregnancy maternal distress were linked to smaller postpartum GDF15 declines in EPI (all p-values < 0.05). CONCLUSIONS:This study identified distinct patterns of plasma cf-mtDNA and GDF15 levels during the perinatal period across studies from two countries, linking these mitochondrial markers to maternal distress and pregnancy outcomes.

BackgroundMost studies on emotions in the perinatal period have focused on psychopathology, identifying groups of women with distinct symptom trajectories, but research on typical, normative changes in emotions across the perinatal period is scarce. This study examines typical patterns of emotions in low-risk, healthy perinatal population.MethodsA prospective longitudinal study with 151 participants who completed emotion-related questionnaires (Positive and Negative Affect Schedule, Perceived Stress Scale, Edinburgh Postnatal Depression Scale, State-Trait Anxiety Inventory) six times during pregnancy and twice in the postpartum. Linear mixed effect models were used to test whether maternal emotions underwent significant changes across the perinatal period and whether those changes are affected by child sex and parity. Nonlinear temporal trends were fitted by natural cubic splines.ResultsFor all emotions, we observed significant nonlinear changes across the perinatal period. Negative affect and anxiety decreased and positive affect increased significantly from the first to the third trimester. Depressive symptoms showed a U-shaped pattern and perceived stress remained unchanged during pregnancy. Negative affect and anxiety increased significantly from the third trimester to the first postpartum week. After stratifying for parity, the increase in negative emotions with approaching childbirth occurred only in primiparae.ConclusionLow-risk pregnancy and the early postpartum period are associated with emotional changes which differ depending on parity. Health care providers should inform pregnant women about those common changes to help them develop realistic expectations and enhance their ability to cope with the demands of pregnancy and the early postpartum period.

Background/objectives:Autism spectrum disorder (ASD) is associated with excitatory-inhibitory imbalance and oxidative stress. GABA, an inhibitory neurotransmitter, and related nutritional therapies are promising in restoring these imbalances. GABAergic deficits and glutamate excitotoxicity are two essential signaling pathways that could be addressed to treat autism, thus medications targeting these pathways are critical for treating behavioral symptoms. In a rat model of autism produced by propionic acid (PPA), this study assessed the effects of GABA supplementation and combined nutritional therapy (probiotics, vitamin D3) and β-lactam as an activator of glutamate transporter. Methods:Sixty rats were randomly assigned into six groups: Group I (Control), Group II (PPA-treated), Group III (Control-GABA), Group IV (Control-Combination), Group V (PPA-GABA), and Group VI (PPA-Combination). Social behavior was evaluated using the three-chamber test. Selected biochemical variables related to oxidative stress (GST, Catalase, Lipid peroxides, GSH and Vitamin C), GABA and glutamate signaling (EAAT2, KCC2, NKCC1, GABA, VD3, Glutamate and GABRA5) were measured in the brain homogenates of the six groups. The hippocampus was examined histopathologically to assess cellular integrity. Results:The obtained data revealed that PPA treatment caused significant oxidative stress and neurotransmitter imbalances, characterized by reduced GABA and elevated glutamate levels. GABA supplementation alone produced moderate benefits in biochemical and behavioral markers, but combined therapy considerably restored GABA levels, reduced oxidative stress, and enhanced social interaction behaviors. Histopathology revealed that combination therapy mitigated neurodegenerative changes induced by PPA, preserving hippocampal cellular structure. Conclusion:This study demonstrated that combined therapy (GABA, probiotics, vitamin D3, and β-lactam) were more effective than GABA alone in enhancing neurochemical balance and lowering oxidative stress in a PPA-induced mouse model of autism, indicating promise for treating symptoms.

Objective:This study examined associations between mitochondrial markers-circulating cell-free mitochondrial DNA (cf-mtDNA) and Growth Differentiation Factor-15 (GDF15)-with maternal distress and pregnancy outcomes. Method:Participants were drawn from two pregnancy studies, EPI (N=187, USA) and BABIP (N=198, Turkey). Plasma cf-mtDNA and GDF15 levels were quantified using qPCR and ELISA assays. Results:Plasma cf-mtDNA levels did not significantly vary across pregnancy, while plasma GDF15 levels increased from early to late pregnancy and decreased postpartum. Late 2nd trimester plasma GDF15 was negatively correlated with pre-pregnancy BMI (p=0.035) and gestational age (p=0.0048) at birth. Early 2nd trimester maternal distress was associated with lower cf-mtDNA (p<0.05) and a trend for lower GDF15. Higher pre-pregnancy BMI and late-pregnancy maternal distress were linked to smaller postpartum GDF15 declines in EPI (p<0.05). Conclusion:This study reveals distinct plasma cf-mtDNA and GDF15 patterns during the perinatal period, linking mitochondrial markers to maternal distress and pregnancy outcomes.

Maternal body mass index (BMI) influences pregnancy and birth outcomes along with child metabolic and neurodevelopmental health and fetal sex may be a moderating factor in these effects. Alternations in autonomic nervous system (ANS) functioning, identified in heart rate (HR) measurements, could present early markers of these prenatal programming effects in both the mother and the developing fetus. This study examines the associations between pre-pregnancy BMI and maternal and fetal ANS functioning and infant postnatal behavioral outcomes stratified by fetal sex. Pregnant women (N=176) were recruited at gestational week (GW) T1: 12-22 and categorized into Normal (BMI< 25) or High BMI (BMI > 25). Women attended laboratory sessions at T2: GW 23-28, and T3: GW 34-36 to assess maternal and fetal HR and HR variability (HRV) at baseline and after a stressor at T3. Infant behavior was assessed at 4 months using the Infant Behavior Questionnaire-Revised. Women with high BMI bearing female fetuses had higher HR and lower HRV at both gestational time points. Later in the third trimester, female fetuses of high BMI women exhibited lower HRV when challenged with a stressor. At 4 months, female infants were rated as having lower scores on the Orienting/Regulatory scale. Our findings provide evidence of female sex-specific programming of maternal pre-pregnancy BMI on maternal ANS regulation and neurodevelopment identified in-utero and continuing into early infancy.

Allostatic load due to chronic exposure to physiological or psychological stressors lead to compromised capacity of the body to maintain homeostasis. Obesity as a metabolic stressor is associated with a suboptimal physiological milieu including an inflammatory state and a dysregulated stress axis. Perinatal maternal body mass index (BMI) impacts pregnancy, birth outcomes, and child metabolic and neurodevelopmental health. We examine the impacts of pre-pregnancy BMI on maternal phenotype characteristics throughout pregnancy and fetal heart rate measurements as an early marker of programming effects of altered autonomic nervous system and infant neurobehavioral outcomes with a focus on sex-dimorphic effects. Pregnant women (n=176) attended sessions at gestation weeks 12-22, 23-28, and 34-36, where blood was collected for cytokine analysis and DNA methylation, and Edinburgh post-partum depression scale was administered. On the latter two visits, heart rate assessment was carried out for mothers and fetuses. Maternal high BMI was associated with higher perinatal depression, increased inflammation, and reduced heart rate variability. DNA methylation of maternal blood indicated enrichment in immune related biological processes. Moreover, we observed a decrease in fetal heart rate variability in female fetuses of women of high BMI, indicating alteration in the neurobehavioral development of the fetus. In infancy, female infants of high BMI mothers had reduced behavioral regulation and orientation to stimulus. This work highlights that the metabolic stress associated with BMI could leave a molecular fingerprint that could explain other maternal physiological and psychological outcomes, which in turn program the fetal neurodevelopmental outcomes.

The prenatal period is a sensitive window of development that is open to both opportunity and risk for predicting later developmental outcomes. There are multiple stress-responsive physiological systems during pregnancy that may mediate the link between stress exposure and physical and mental health. Alterations in these systems during gestation due to elevated stress exposure can lead to poorer health in both the gestational parent and the offspring. In this symposium, we examine stress-responsive psychobiological systems during pregnancy and their association with differential developmental outcomes during gestation, at birth, and in infancy by a multinational group of researchers. The first presentation by the symposium chair, Özlü Aran (University of Denver, USA), will focus on the trajectories of placental corticotropin-releasing hormone (pCRH), a stress-responsive hormone released by placenta, and their association with birth outcomes as well as infant socioemotional development at 6 months postpartum. In the second presentation, Dr. Elif Aysimi Duman (Boğaziçi University, Turkey) will highlight intergenerational associations of parental early life stress and gestational parent prenatal cortisol awakening response with infant development at 4 months postpartum. This study underscores psychosocial risk (i.e., pregnancy-related worries) and protective factors (i.e., fetal bonding) in addition to prenatal HPA activity during gestation. In the third presentation, Dr. Sameera Abuaish (Princess Nourah bint Abdulrahman University, Saudi Arabia) will extend research findings beyond HPA axis by demonstrating the association between gestational parent body mass index (BMI) and prenatal mood and immune functioning, while also linking BMI to both fetal and infant outcomes. Consistent with the ISPNE’s 2023 symposium translational psychoneuroendocrinology themes, these presentations apply basic scientific methods to understand better health outcomes for gestational parents and their offspring with a focus on stress-responsive physiological systems during pregnancy. Together, they underscore the importance of early life stressors as well as prenatal stressors and their potential impact over generations among individuals across countries and cultures. Finally, these presentations will be discussed by a leading investigator, Dr. Jenalee Doom (University of Denver, USA), who has expertise on early life stress and the biological embedding of early experiences across development with a special focus on mental and physical health.

Background: Stress and negative mood in pregnancy have been linked to less favorable birth outcomes, but the mechanisms underlying this effect remain largely unknown. We examined associations between emotions in pregnancy, pro- and anti-inflammatory cytokines (IFN-gamma, IL-6, IL-8, IL-10, IL-12, IL-17, MCP-1, MIP-1R, TNF-alpha) and birth outcomes (gestational age at birth and birth weight) in a low-risk sample. Methods: At each trimester of pregnancy, participants (N = 74) completed the Positive and Negative Affect Schedule, Perceived Stress Scale, Edinburgh Postnatal Depression Scale, and State-Trait Anxiety Inventory. They provided blood samples in the third trimester. Multivariate regression with a reduction of dimensionality (orthogonal projection to latent structures) was used to assess associations between maternal emotions, cytokine levels, and birth outcomes. Results: We found significant positive associations between negative mood (depressive symptoms in the second and third trimesters and negative affect in the third trimester) and anti-inflammatory cytokine IL-10 levels, and negative associations between maternal distress in the second and third trimesters and pro-/anti-inflammatory cytokine ratios (IFN-gamma/IL-10, TNF-alpha/IL-10 and IL-6/IL-10). Higher levels of pro-inflammatory cytokines IFN-gamma, IL12, IL-17, and TNF-alpha were associated with younger gestational age at birth and lower birth weight. Limitations: We did not control for relevant factors such as social support, health-related behaviors, or cortisol levels. Conclusions: Negative mood in mid- and late pregnancy may shift cytokine balance toward the anti-inflammatory cytokine dominance. Our results provide further evidence for the negative association between pro-inflammatory cytokines in late pregnancy and gestational age at birth/birth weight, which we observed even in a low-risk population.

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.

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.

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.

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.

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.