Genomic modules and intramodular network concordance in susceptible and resilient male mice across models of stress.

The multifactorial etiology of stress-related disorders necessitates a constant interrogation of the molecular convergences in preclinical models of stress that use disparate paradigms as stressors spanning from environmental challenges to genetic predisposition to hormonal signaling. Using RNA-sequencing, we investigated the genomic signatures in the ventral hippocampus common to mouse models of stress. Chronic oral corticosterone (CORT) induced increased anxiety- and depression-like behavior in wild-type male mice and male mice heterozygous for the gene coding for brain-derived neurotrophic factor Val66Met, a variant associated with genetic susceptibility to stress. In a separate set of male mice, chronic social defeat stress (CSDS) led to a susceptible or a resilient population, whose proportion was dependent on housing conditions, namely standard housing or enriched environment. Rank-rank-hypergeometric overlap (RRHO), a threshold-free approach that ranks genes by their p value and effect size direction, was used to identify genes from a continuous gradient of significancy that were concordant across groups. In mice treated with CORT and in standard-housed susceptible mice, differentially expressed genes (DEGs) were concordant for gene networks involved in neurotransmission, cytoskeleton function, and vascularization. Weighted gene co-expression analysis generated 54 gene hub modules and revealed two modules in which both CORT and CSDS-induced enrichment in DEGs, whose function was concordant with the RRHO predictions, and correlated with behavioral resilience or susceptibility. These data showed transcriptional concordance across models in which the stress coping depends upon hormonal, environmental, or genetic factors revealing common genomic drivers that embody the multifaceted nature of stress-related disorders.

Dextran sulfate sodium-induced colitis in C57BL/6J mice increases their susceptibility to chronic unpredictable mild stress that induces depressive-like behavior.

AIMS: In patients with colitis, the high comorbidity of depressive disorders is well-known, but the detailed mechanisms remain unresolved. In this study, we examined whether colitis induced by dextran sulfate sodium (DSS) increased the susceptibility to chronic unpredictable mild stress (CUMS) in C57BL/6J mice with resilience to CUMS. MAIN METHODS: To induce experimental colitis and depressive-like behaviors, male 7-weeks old C57BL/6J mice were administered ad libitum 1% DSS solution for 11 days, and subjected to various mild stressors in a chronic, inevitable and unpredictable way according to a random schedule for 21 days, respectively. KEY FINDINGS: In naïve mice exposed to CUMS, their immobility times in a forced swim (FS) test were almost equal to those in control mice. The DSS administration to naïve mice induced colitis without depressive-like behavior, and at 18 days after termination of the DSS administration, the colitis had recovered to control levels, while altered diversity and composition of bacterial genera such as Bacteroides spp., Alistipes spp., etc., were found in the gut microbiota. Exposure of mice with DSS-induced colitis to CUMS (DSS + CUMS) significantly increased the immobility times in the FS test. In the gut microbiota of DSS + CUMS mice, the alteration profile of the relative abundance of bacterial genera differed from in the DSS ones. SIGNIFICANCE: These findings indicate that mice with colitis exhibit increased susceptibility to psychological stress, resulting in induction of depressive-like behavior, and this might be due, at least in part, to altered characteristics of the gut microbiota.

Association between ambient air pollution and perceived stress in pregnant women.

Air pollution may influence prenatal maternal stress, but research evidence is scarce. Using data from a prospective cohort study conducted on pregnant women (n = 2153), we explored the association between air pollution and perceived stress, which was assessed using the 14-item Perceived Stress Scale (PSS), among pregnant women. Average exposures to particulate matter with an aerodynamic diameter of < 2.5 µm (PM2.5) or < 10 µm (PM10), nitrogen dioxide (NO2), and ozone (O3) for each trimester and the entire pregnancy were estimated at maternal residential addresses using land-use regression models. Linear regression models were applied to estimate associations between PSS scores and exposures to each air pollutant. After adjustment for potential confounders, interquartile-range (IQR) increases in whole pregnancy exposures to PM2.5, PM10, and O3 in the third trimester were associated with 0.37 (95% confidence interval [CI] 0.01, 0.74), 0.54 (95% CI 0.11, 0.97), and 0.30 (95% CI 0.07, 0.54) point increases in prenatal PSS scores, respectively. Furthermore, these associations were more evident in women with child-bearing age and a lower level of education. Also, the association between PSS scores and PM10 was stronger in the spring. Our findings support the relationship between air pollution and prenatal maternal stress.

Lymphocyte Index of Peripheral Blood in Rats at Different Stages of the Post-Stress Period under Conditions of Antigenic Exposure and Injection of Lipopolysaccharide.

Changes in the Shaganin lymphocyte index (ratio of the number of lymphocytes to segmented neutrophils) in the peripheral blood of rats after intraperitoneal administration of LPS (100 µg/kg) at the end of a single stress exposure in a model of 24-h restraint stress were studied. The lymphocyte index was analyzed 3 h later, on the 1st and 8th days after the stress load. Immobilization was accompanied by a decrease in this parameter 3 h after exposure. One day after the stress load, an increase in the lymphocyte index was noted, which remained on the 8th day of observation. LPS injection did not affect the changes in this parameter caused by 24-h immobilization on the 1st and 8th days of the study, but prevented a pronounced increase in the lymphocyte index on the 1st day after the stress load. The data obtained expand the existing scientific understanding of the specificity of the involvement of immunomodulatory substances in the implementation of adaptive-compensatory processes in mammals under conditions of emotional stress.

Neuropsychological adverse drug reactions of Remdesivir: analysis using VigiBase, the WHO global database of individual case safety reports.

OBJECTIVE: Although remdesivir (GS-5734) has recently demonstrated clinical benefits against the pandemic outbreak of coronavirus disease 2019 (COVID-19), neuropsychological adverse reactions (ADRs) remain to be examined in real-world settings. Therefore, we aimed to identify and characterize the neuropsychological ADRs associated with remdesivir use. MATERIALS AND METHODS: We obtained data for this international pharmacovigilance cohort study from individual case safety reports (ICSRs) in a World Health Organization database (VigiBase) from the first report on remdesivir on February 17, 2020, until August 30, 2020 (n=1,403,532). ADRs reported to be relevant to remdesivir were compared with the full database by using a Bayesian neural network method to calculate the information component (IC). RESULTS: A total of 2,107 reported cases of neuropsychological ADRs suspected to be associated with remdesivir were identified from among all ICSRs in the database during the observation period. Although 108 neuropsychological ADRs (64 neurologic events and 44 psychologic events) were reported in association with the medication, no statistically significant pharmacovigilance signal could be detected; the IC025 value was negative for all of the neuropsychological dysfunctions (anxiety [n=13, 0.62%], seizures [n=12, 0.57%], lethargy [n=6, 0.28%], agitation [n=5, 0.25%], cerebral infarction [n=3, 0.14%], ischemic stroke [n=3, 0.14%], and hemiparesis [n=3, 0.14%]). CONCLUSIONS: Our study demonstrates that remdesivir, a novel drug applied to the treatment of COVID-19, does not have a significant association with adverse neurologic or psychiatric reactions in the real-world setting.

A Reliable High-Throughput Screening Model for Antidepressant.

Depression is the most frequent affective disorder and is the leading cause of disability worldwide. In order to screen antidepressants and explore molecular mechanisms, a variety of animal models were used in experiments, but there is no reliable high-throughput screening method. Zebrafish is a common model organism for mental illness such as depression. In our research, we established chronic unpredictable mild stress (CUMS) models in C57BL/6 mice and zebrafish; the similarities in behavior and pathology suggest that zebrafish can replace rodents as high-throughput screening organisms. Stress mice (ip., 1 mg/kg/d, 3 days) and zebrafish (10 mg/L, 20 min) were treated with reserpine. As a result, reserpine caused depression-like behavior in mice, which was consistent with the results of the CUMS mice model. Additionally, reserpine reduced the locomotor ability and exploratory behavior of zebrafish, which was consistent with the results of the CUMS zebrafish model. Further analysis of the metabolic differences showed that the reserpine-induced zebrafish depression model was similar to the reserpine mice model and the CUMS mice model in the tyrosine metabolism pathway. The above results showed that the reserpine-induced depression zebrafish model was similar to the CUMS model from phenotype to internal metabolic changes and can replace the CUMS model for antidepressants screening. Moreover, the results from this model were obtained in a short time, which can shorten the cycle of drug screening and achieve high-throughput screening. Therefore, we believe it is a reliable high-throughput screening model.

The Association Between Second-hand Smoke Exposure and Psychiatric Distress Among Naturally Pregnant Women and Pregnant Women After Assisted Reproductive Technology Treatment: a Birth Cohort Study.

Second-hand smoke (SHS) has been shown to be associated with psychiatric distress in pregnant women spontaneously conceived (SC), but this has never been investigated in pregnant women with assisted reproductive technology (ART) treatment. This study aimed to investigate and compare the associations of SHS with psychiatric distress among SC and ART pregnant women. Participants (1467 SC and 857 ART women) were from the sub-study of Chinese National Birth Cohort (CNBC) in Anhui Province. SHS was assessed by the self-reported questionnaire. The symptoms of depression, anxiety, stress, and poor sleep quality were assessed using CES-D, SAS, CPSS, and PSQI questionnaire. Multivariable linear regression was used to determine the association between SHS and psychiatric distress in each trimester. In SC women, SHS (yes or no) was associated with depression and anxiety symptoms in the 3rd trimester (ß = 0.90, 95% CI 0.07-1.73 for depression and ß = 1.21, 95% CI 0.39-2.04 for anxiety) and stress symptom and poor sleep quality in both the 2nd and 3rd trimesters (ß = 0.85, 95% CI 0.20-1.49 in the 2nd trimester and ß = 0.69, 95% CI 0.07-1.32 in the 3rd trimester for stress, and ß = 1.32, 95% CI 0.68-1.96 in the 2nd trimester and ß = 1.38, 95% CI 0.64-2.11 in the 3rd trimester for poor sleep quality). By contrast, in ART women, SHS was associated with depression and stress symptoms in the 1st trimester (ß = 1.97, 95% CI 0.59-3.35 for depression and ß = 1.18, 95% CI 0.24-2.12 for stress) and poor sleep quality throughout the pregnancy (ß = 0.64, 95% CI 0.22-1.06 in the 1st trimester, ß = 0.77, 95% CI 0.35-1.18 in the 2nd trimester, and ß = 0.99, 95% CI 0.50-1.48 in the 3rd trimester, respectively). Our findings indicate a universal and detrimental effect of SHS on psychiatric health among both SC and ART pregnant women. However, the SHS impact may be more substantial at the early stage of pregnancy for ART women and at later stages for SC women. This implies the importance of reducing SHS exposure during pregnancy and the necessary to be aware of the difference in the effect of SHS on psychiatric distress between SC and ART women.

Hippocampal mitogen-activated protein kinase phosphatase-1 regulates behavioral and systemic effects of chronic corticosterone administration.

Clinical reports indicate a bidirectional relationship between mental illness and chronic systemic diseases. However, brain mechanisms linking chronic stress and development of mood disorders to accompanying peripheral organ dysfunction are still not well characterized in animal models. In the current study, we investigated whether activation of hippocampal mitogen-activated protein kinase phosphatase-1 (MKP-1), a key factor in depression pathophysiology, also acts as a mediator of systemic effects of stress. First, we demonstrated that treatment with the glucocorticoid receptor (GR) agonist dexamethasone or acute restraint stress (ARS) significantly increased Mkp-1 mRNA levels within the rat hippocampus. Conversely, administration of the GR antagonist mifepristone 30 min before ARS produced a partial blockade of Mkp-1 upregulation, suggesting that stress activates MKP-1, at least in part, through upstream GR signaling. Chronic corticosterone (CORT) administration evoked comparable increases in hippocampal MKP-1 protein levels and produced a robust increase in behavioral emotionality. In addition to behavioral deficits, chronic CORT treatment also produced systemic pathophysiological effects. Elevated levels of renal inflammation protein markers (NGAL and IL18) were observed suggesting tissue damage and early kidney impairment. In a rescue experiment, the effects of CORT on development of depressive-like behaviors and increased NGAL and IL18 protein levels in the kidney were blocked by CRISPR-mediated knockdown of hippocampal Mkp-1 prior to CORT exposure. In sum, these findings further demonstrate that MKP-1 is necessary for development of enhanced behavioral emotionality, while also suggesting a role in stress mechanisms linking brain dysfunction and systemic illness such as kidney disease.

Neurotensin 1 receptor in the prelimbic cortex regulates anxiety-like behavior in rats.

The central neurotensin system has been implicated in reward, memory processes, also in the regulation of anxiety. However, the neural substrates where neurotensin acts to regulate anxiety have not been fully identified. The prelimbic region of medial prefrontal cortex (PrL) holds a key position in the modulation of anxiety-related behaviors and expresses neurotensin 1 receptor (NTS1). This study investigated the effects of activation or blockade of NTS1 in the PrL on anxiety-like behaviors of rats. Our results demonstrated that infusion of a selective NTS1 agonist or neurotensin into the PrL produced anxiogenic-like effects. Administration of a NTS1 antagonist into the PrL did not affect anxiety-like behaviors of normal rats, but attenuated anxiogenic effects induced by restraint stress. Moreover, we employed molecular approaches to downregulate the expression of NTS1 in the PrL, and found that downregulation of NTS1 in the PrL induced anxiolytic effects in restraint stress rats, also confirming the pharmacological results. Together, these findings suggest that NTS1 in the PrL is actively involved in the regulation of anxiety.

Exploring Community Psychosocial Stress Related to Per- and Poly-Fluoroalkyl Substances (PFAS) Contamination: Lessons Learned from a Qualitative Study.

The purpose of this study was to qualitatively explore the per- and poly-fluoroalkyl substances (PFAS) exposure experience and associated stressors, to inform public health efforts to support psychosocial health and resilience in affected communities. Semi-structured interviews (n = 9) were conducted from July-September 2019 with community members and state public health department representatives from areas with PFAS-contaminated drinking water. Thematic analysis was completed and themes were described and summarized. Reported stressors included health concerns and uncertainty, institutional delegitimization and associated distrust, and financial burdens. Interviewees provided several strategies to reduce stress and promote stress coping capacity and resilience, including showing empathy and validating the normalcy of experiencing stress; building trust through visible action and sustained community engagement; providing information and actionable guidance; discussing stress carefully; fostering stress coping capacity and resilience with opportunities to build social capital and restore agency; and building capacity among government agencies and health care providers to address psychosocial stress. While communities affected by PFAS contamination will face unavoidable stressors, positive interactions with government responders and health care providers may help reduce negative stress. More research on how best to integrate community psychosocial health and stress coping and resilience concepts into the public health response to environmental contamination could be helpful in addressing these stressors.

Chronically infused angiotensin II induces depressive-like behavior via microglia activation.

Brain inflammation is one of hypotheses explaining complex pathomechanisms of depression. Angiotensin II (ANGII), which is associated with hypertension, also induces brain inflammation. However, there is no animal study showing the direct relationship between ANGII and depression. To address this issue, ANGII-containing osmotic pumps were implanted into adult male C57BL/6 mice subcutaneously for subacute (7 days) and chronic (at least 21 days) periods and behavioral and molecular analyses were conducted. Chronic infusion of ANGII into mice induced depressive-like behaviors, including the tail suspension test and forced swimming test, which were reversed by imipramine. Chronic infusion of ANGII also induced microglial activation in the hippocampus with increase of Il-1ß mRNA and decrease of Arg1 mRNA. In addition, chronic ANGII infusion activated the hypothalamic-pituitary-adrenal axis (HPA axis) and resulted in decreased hippocampal glucocorticoid receptor level. However, subacute ANGII infusion did not induce significant molecular and behavioral changes in mice compared to that of control. The molecular and behavioral changes by chronic ANGII infusion were reversed by co-treatment of minocycline or telmisartan. In addition, ANGII treatment also induced the pro-inflammatory changes in BV-2 microglial cells. Our results indicate that ANGII can induce depressive-like behaviors via microglial activation in the hippocampus and HPA axis hyperactivation in mice. These might suggest possible mechanism on depressive symptom in chronic hypertensive state.

HIV-1 Tat Dysregulates the Hypothalamic-Pituitary-Adrenal Stress Axis and Potentiates Oxycodone-Mediated Psychomotor and Anxiety-Like Behavior of Male Mice.

Human immunodeficiency virus (HIV) is associated with co-morbid affective and stress-sensitive neuropsychiatric disorders that may be related to dysfunction of the hypothalamic-pituitary-adrenal (HPA) stress axis. The HPA axis is perturbed in up to 46% of HIV patients, but the mechanisms are not known. The neurotoxic HIV-1 regulatory protein, trans-activator of transcription (Tat), may contribute. We hypothesized that HPA dysregulation may contribute to Tat-mediated interactions with oxycodone, a clinically-used opioid often prescribed to HIV patients. In transgenic male mice, Tat expression produced significantly higher basal corticosterone levels with adrenal insufficiency in response to a natural stressor or pharmacological blockade of HPA feedback, recapitulating the clinical phenotype. On acute exposure, HIV-1 Tat interacted with oxycodone to potentiate psychomotor and anxiety like-behavior in an open field and light-dark transition tasks, whereas repeated exposure sensitized stress-related psychomotor behavior and the HPA stress response. Pharmacological blockade of glucocorticoid receptors (GR) partially-restored the stress response and decreased oxycodone-mediated psychomotor behavior in Tat-expressing mice, implicating GR in these effects. Blocking corticotrophin-releasing factor (CRF) receptors reduced anxiety-like behavior in mice that were exposed to oxycodone. Together, these effects support the notion that Tat exposure can dysregulate the HPA axis, potentially raising vulnerability to stress-related substance use and affective disorders.

Eriodictyol produces antidepressant-like effects and ameliorates cognitive impairments induced by chronic stress.

Eriodictyol, a natural flavonoid compound identified in numerous medicinal plants, has been reported to have anti-inflammatory, antioxidative and antiproliferative activities and exert protective effects on the neurons, thus drawing attention to its therapeutic potential. However, the effect of eriodictyol on depression remains unclear. In the present study, we investigated the behavioral effects of chronic eriodictyol treatment in rat models of depression induced by lipopolysaccharide (LPS, 1 mg/kg) challenge and chronic unpredictable mild stress (CUMS). We found that chronic eriodictyol (10, 30, and 100 mg/kg) treatment by oral gavage once daily for 14 days dose-dependently produced antidepressant effect in the forced swim test (FST), but did not alter locomotor activity in the open field test. Moreover, oral administration with eriodictyol (100 mg/kg) for 28 days reversed the depressive- and anxiety-like behaviors induced by LPS or CUMS, as evidenced by significantly increased sucrose preference in the sucrose preference test, reduced immobility time in the FST, and reduced latency to feeding in the novelty-suppressed feeding test. In addition, co-administration of subthreshold doses of eriodictyol (30 mg/kg) and transient potential vanilloid 1 receptor antagonist capsazepine (1.5 mg/kg) produced a synergistic effect in these tests. Chronic eriodictyol administration at a dose of 100 mg/kg also rescued the memory deficits induced by CUMS as indicated by the increased exploration index in the novel object recognition test. Altogether, these results demonstrate that eriodictyol attenuates depressive- and anxiety-like behaviors and cognitive impairments in rats, and might be a potential therapeutic avenue for depression.

Neonatal exposure to ketamine disrupts developmental synapse unsilencing and predisposes adult mice for stressor-evoked anxiety.

Accumulating evidence suggests long-lasting impairments in brain development and cognition caused by neonatal exposure to general anesthetics. To date, very little is known about potential abnormal psychiatric manifestations attributable to neonatal anesthesia. In this study, we used ketamine to induce anesthesia in neonatal mice. By applying mild stressors one day before behavioral tests, we found that adult mice exhibit significant anxiety-like behaviors that were indistinguishable at basal level. Recruitment of AMPA (a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) type glutamate receptors into silent synapses is a prominent cellular process during neonatal neurodevelopment. We found that exposure to ketamine significantly disrupted synapse unsilencing, and impaired the expression of unsilencing-mediated long-term potentiation (LTP). Pharmacologically enhancement of neural activities by AMPAkine drug CX546 [1-(1,4-benzodioxan-6-ylcarbonyl) piperidine] effectively rescued disrupted developmental synapse unsilencing and LTP at neonatal age, and prevented stressor-evoked anxiety-like behaviors in adult mice. Together, our results indicate that neonatal exposure to ketamine may predispose individuals for psychiatric conditions via disrupting synapse unsilencing, and potentiation of neural activities during the anesthesia-recovery period may be an effective approach to manage adverse effects on brain development. This article is part of the special issue on 'Stress, Addiction and Plasticity'.

Changes in c-fos and p-CREB signaling following exposure to forced swim stress or exogenous corticosterone during morphine-induced place preference are dependent on glucocorticoid receptor in the basolateral amygdala.

Neural circuitry comprising the nucleus accumbens (NAc), prefrontal cortex (PFC), amygdala (AMY), and hippocampus (HIP) are the main components of the reward circuit. Our previous behavioral data showed that forced swim stress (FSS) and corticosterone administration could inhibit the acquisition of morphine-induced conditioned place preference (CPP), and this effect was blocked by intra-basolateral amygdala (BLA) administration of RU38486, glucocorticoid receptor (GR) antagonist. Therefore, we tried to evaluate the effect of intra-BLA administration of the GR antagonist during the conditioning phase on the c-fos and p-CREB/CREB ratio expression in the AMY, NAc, PFC, and HIP of rats that underwent FSS or received exogenous corticosterone (10 mg/kg; i.p.) before morphine injection (5 mg/kg; s.c.) during 3 conditioning days. Our results showed that morphine-induced CPP could increase c-fos level and p-CREB/CREB ratio in all regions (except in the HIP). In addition, c-fos expression was elevated by FSS in all regions and blockade of GR decreased this effect. In the PFC, in addition to FSS, corticosterone could raise c-fos expression, which was blocked by RU38486. In conclusion, it seems that the intra-BLA administration of RU38486 differently modulates the effect of morphine-induced CPP on the expression of c-fos and p-CREB/CREB ratio in animals that underwent FSS or corticosterone administration.

Beneficial effects of benzodiazepine on masticatory muscle dysfunction induced by chronic stress and occlusal instability in an experimental animal study.

Psychological stress and occlusal alteration are important etiologic factors for temporomandibular/masticatory muscular disorders. In particular, the exact physiologic mechanism underlying the relation by occlusal alteration and temporomandibular disorders remains unclear. Our purpose was to test the hypothesis that benzodiazepine therapy is able to prevent metabolic and vascular changes in the medial pterygoid muscle of rats under chronic stress after 14 days of unilateral exodontia. Adult Wistar rats were submitted to unpredictable chronic mild stress (10 days) and/or unilateral exodontia and their plasma and medial pterygoid muscles were removed for analysis. A pre-treatment with diazepam was used to verify its effect on stress. The parameters evaluated included anxiety behavior, plasma levels of corticosterone, metabolic activity by succinate dehydrogenase, capillary density by laminin staining and ultrastructural findings by transmission electron microscopy. Occlusal instability induced anxiety-like behavior on elevated plus-maze test and diazepam administration blocked the appearance of this behavior. Unilateral exodontia promoted in the contralateral muscle an increase of oxidative fibers and capillaries and modification of sarcoplasmic reticulum. Chronic stress caused increased glycolytic metabolism, reduced capillary density and morphological changes in mitochondria on both sides. Association of both factors induced a glycolytic pattern in muscle and hemodynamic changes. Pharmacological manipulation with diazepam inhibited the changes in the medial pterygoid muscle after stress. Our results reveal a preventive benzodiazepine treatment for stress and occlusal instability conditions affecting masticatory muscle disorders. In addition, provide insights into the mechanisms by which chronic stress and exodontia might be involved in the pathophysiology of masticatory muscular dysfunctions.

Neuroinflammatory and Behavioral Outcomes Measured in Adult Offspring of Mice Exposed Prenatally to E-Cigarette Aerosols.

BACKGROUND: In an effort to decrease the rates of smoking conventional tobacco cigarettes, electronic cigarettes (e-cigarettes) have been proposed as an effective smoking cessation tool. However, little is known about their toxicological impacts. This is concerning given that e-cigarette use is perceived as less harmful than conventional tobacco cigarettes during pregnancy for both the mother and fetus. OBJECTIVE: The goal of this study was to test the neurodevelopmental consequences of maternal e-cigarette use on adult offspring behavior and neuroimmune outcomes. METHODS: Pregnant female CD-1 mice were randomly assigned to one of three treatment groups (n=8-10 per group) and exposed daily to either filtered air, propylene glycol and vegetable glycerol (50:50 PG/VG vehicle), or to PG/VG with 16mg/mL nicotine (+Nic). Whole-body exposures were carried out for 3 h/d, 7 d/week, from gestational day (GD)0.5 until GD17.5. Adult male and female offspring (8 weeks old) were assessed across a battery of behavioral assessments followed by region-specific quantification of brain cytokines using multiplex immunoassays. RESULTS: Adult offspring of both sexes exposed to +Nic exhibited elevated locomotor activity in the elevated plus maze and altered stress-coping strategies in the forced swim task. Moreover, male and female offspring exposed to PG/VG with and without nicotine had a 5.2% lower object discrimination score in the novel object recognition task. In addition to differences in offspring behavior, maternal e-cigarette exposure with nicotine led to a reduction in interleukin (IL)-4 and interferon-gamma (IFNγ) in the diencephalon, as well as lower levels of hippocampal IFNγ (females only). E-cigarette exposure without nicotine resulted in a 2-fold increase of IL-6 in the cerebellum. DISCUSSION: These findings support previous adverse findings of e-cigarette exposure on neurodevelopment in a mouse model and provide substantial evidence of persistent adverse behavioral and neuroimmunological consequences to adult offspring following maternal e-cigarette exposure during pregnancy. https://doi.org/10.1289/EHP6067.

Prenatal tobacco and marijuana co-use: Sex-specific influences on infant cortisol stress response.

Although tobacco (TOB) and marijuana (MJ) are often co-used in pregnancy, little is known regarding the joint impact of MJ + TOB on offspring development, including the developing neuroendocrine stress system. Further, despite evidence for sex-specific impacts of prenatal exposures in preclinical models, the sex-specific impact of prenatal MJ + TOB exposure on offspring neuroendocrine regulation in humans is also unknown. In the current study, overall and sex-specific influences of MJ + TOB co-use on offspring cortisol regulation were investigated over the first postnatal month. 111 mother-infant pairs from a low-income, racially and ethnically diverse sample participated. Based on Timeline Followback data with biochemical verification, three groups were identified: (1) prenatal MJ + TOB, (2) TOB only, and (3) controls. Baseline cortisol and cortisol stress response were assessed at seven points over the first postnatal month using a handling paradigm in which saliva cortisol was assessed before, during, and following a standard neurobehavioral assessment (NICU Network Neurobehavioral Scale). A significant exposure group by offspring sex interaction emerged for baseline cortisol over the first postnatal month (p = .043); MJ + TOB-exposed males showed 35-36% attenuation of baseline cortisol levels vs. unexposed and TOB-exposed males (ps ≤ .003), while no effects of exposure emerged for females. Both MJ + TOB and TOB-exposed infants showed a 22% attenuation of cortisol stress response over the first postnatal month vs. unexposed infants (ps < .03), with evidence for sex-specific effects in exploratory analyses. Although results are preliminary, this is the first human study to investigate the impact of prenatal MJ exposure on infant cortisol and the first to reveal a sex-specific impact of prenatal MJ + TOB on cortisol regulation in humans. Future, larger-scale studies are needed to elucidate mechanisms and consequences of sex-specific effects of MJ and MJ + TOB on the developing neuroendocrine stress system.

Perinatal exposure to bisphenol A at the intersection of stress, anxiety, and depression.

Endocrine-disrupting compounds (EDCs) are common contaminants in our environment that interfere with typical endocrine function. EDCs can act on steroid and nuclear receptors or alter hormone production. One particular EDC of critical concern is bisphenol A (BPA) due to its potential harm during the perinatal period of development. Previous studies suggest that perinatal exposure to BPA alters several neurotransmitter systems and disrupts behaviors associated with depression and anxiety in the rodent offspring later in life. Thus, dysregulation in neurotransmission may translate to behavioral phenotypes observed in mood and arousal. Many of the systems disrupted by BPA also overlap with the stress system, although little evidence exists on the effects of perinatal BPA exposure in relation to stress and behavior. The purpose of this review is to explore studies involved in perinatal BPA exposure and the stress response at neurochemical and behavioral endpoints. Although more research is needed, we suggest that perinatal BPA exposure is likely inducing variations in behavioral phenotypes that modulate their action through dysregulation of neurotransmitter systems sensitive to stress and endocrine disruption.

A selective D2 dopamine receptor agonist alleviates depression through up-regulation of tyrosine hydroxylase and increased neurogenesis in hippocampus of the prenatally stressed rats.

Prenatal stress (PNS) has its negative impact on both the infant hippocampal neurogenesis and pregnancy outcomes in the neonates that serves as a risk factor for postnatal depression in adult offsprings. Therefore, main objectives of the present study were to evaluate the effect of maternal chronic unpredictable mild stress (CUMS) on behavioural changes, levels of oxidative stress, changes in selective developmental signaling genes and neurogenesis in the adult brain of Wistar rats and its reversal through a selective non-ergoline D2 type dopamine receptor (D2R) agonist Ropinirole (ROPI). Effects of ROPI treatment on CUMS induced adult rats offspring were measured by assessment of behavioural tests (sucrose preference test and forced swim test), biomarkers of oxidative stress, protein expression of tyrosine hydroxylase (TH), mRNA expression of SHH, GSK-3ß, ß-catenin, Notch, brain-derived neurotrophic factor (BDNF), Dopamine receptor 2 (Drd2) and bromodeoxyuridine (BrdU) cell proliferation assay. The oxidative stress, protein and mRNA expression were determined in the hippocampus and prefrontal cortex while the BrdU cell proliferation was observed in the hippocampus of rat brain. PNS induced changes resulted in depression validated by the depression-like behaviours, increased oxidative stress, decreased TH expression, altered expression of selective developmental genes, along with the reduced hippocampal neurogenesis and BDNF expression in the brain of adult offsprings. Chronic ROPI treatment reversed those effects and was equally effective like Imipramine (IMI) treatment. So, the present study suggested that ROPI can be used as an antidepressant drug for the treatment of depressive disorders.