Impact of the COVID-19 pandemic on adults with Fetal Alcohol Spectrum Disorder: linking immune function to mental health status.

Prenatal alcohol exposure (PAE) is known to cause a variety of cognitive, behavioral, and neurological changes. Importantly, mental health problems are also overrepresented in individuals with Fetal Alcohol Spectrum Disorder (FASD), the group of neurodevelopmental conditions that can occur following PAE. Approximately 90% of individuals with FASD report experiencing mental health problems over their lifespan, compared to approximately 30% in the overall population. Individuals with FASD also display impairments in coping skills and increased vulnerability to stress. Here, we investigated whether the COVID-19 pandemic would have a differential impact on mental health and inflammation-to-mood associations in adults with FASD, compared to unexposed controls (no PAE). We capitalized on our pre-pandemic study examining health and immune function and invited past-participants to enroll in the current study. Participants completed mental health assessments and COVID-related questionnaires by phone. In addition, blood samples collected at baseline (pre-pandemic) were used to probe for inflammation-to-mood associations. Overall, our results indicate that lower SES was predictive of higher coronavirus anxiety scores, with no differences between adults with FASD and controls. In addition, while there were no differences in depression or anxiety measures at baseline (pre-pandemic) or during the pandemic, examination of inflammation-to-mood associations identified differential relationships in adults with FASD compared to unexposed controls. Specifically, there was a positive association between baseline neutrophil counts and both baseline and pandemic mental health scores in unexposed controls only. In addition, for unexposed controls there was also a negative association between baseline interferon-É£ (IFN-É£) and pandemic mental health scores. By contrast, only adults with FASD showed positive associations between baseline interleukin-12p70 (IL-12p70), IL-8, soluble intercellular adhesion molecule-1 (sICAM-1), and soluble vascular cell adhesion molecule-1 (sVCAM-1) and pandemic mental health scores. Taken together, to our knowledge, this study is the first to examine the impact of the pandemic in adults with FASD. And while it may be too soon to predict the long-term effects of the pandemic on mental health, our data suggest that it will be important that future work also takes into account how immune function may be modulating mental health outcomes in this population.

Modulatory role of prenatal alcohol exposure and adolescent stress on the response to arthritis challenge in adult female rats.

BACKGROUND: There are known environmental risk factors associated with rheumatoid arthritis; however, less is known regarding how the prenatal environment impacts later-life risk for rheumatoid arthritis. Based on preliminary clinical data suggesting that individuals with fetal alcohol spectrum disorder (FASD) are at higher risk for autoimmune disorders, this study investigated the modulatory impact of prenatal alcohol exposure (PAE) on the inflammatory disease profile in an adjuvant-induced arthritis rat model. METHODS: Pregnant rats received liquid ethanol or control diet throughout gestation. To model the increased exposure to stressors often experienced by individuals with FASD, adolescent offspring were exposed to chronic mild stress (CMS) or remained undisturbed. In adulthood, experimental arthritis was initiated and rats terminated either at the peak or following resolution from inflammation to assess endocrine, immune, and histopathological outcomes. FINDINGS: PAE rats had an increased incidence and severity of, and impaired recovery from, arthritis. Increased joint damage was observed in PAE animals, even in the face of apparent recovery from the clinical signs of arthritis, while it appeared that oestradiol may have a protective role. Moreover, with the combination of PAE and adolescent stress, increased macrophage density was detected in the synovium of PAE but not control rats. INTERPRETATION: These findings demonstrate that PAE alters the severity and course of arthritis, highlighting the potential immunomodulatory impact of adverse prenatal exposures. In particular, these data have implications for understanding preliminary data that suggest a heightened propensity for autoimmune disorders in individuals with FASD. FUNDING: This work was supported by: National Institutes of Health/National Institute on Alcohol Abuse and Alcoholism [R37 AA007789] and Kids Brain Health Network (KBHN; Canadian Networks of Centres of Excellence) to JW, a Natural Sciences and Engineering Research Council of Canada (NSERC) CGS-D to TSB and NIH/NIAAA R01 AA022460 to JW and TSB.

Altered social recognition memory and hypothalamic neuropeptide expression in adolescent male and female rats following prenatal alcohol exposure and/or early-life adversity.

Prenatal alcohol exposure (PAE) and early-life adversity (ELA) both negatively impact social neurobehavioral development, including social recognition memory. Importantly, while individuals with PAE are more likely to experience ELA, relatively few studies have assessed the interaction of these two early insults on adolescent social behavior development. Here, we combine animal models of PAE and ELA to investigate both their unique and interactive effects on social neurobehavioral function in early and late adolescent male and female rats. Behavioral testing was followed by assessment of hypothalamic expression of oxytocin (OT) and vasopressin (AVP), key neuropeptides in the regulation of social behavior. Our results indicate that PAE and ELA have unique sex- and age-specific effects on social recognition memory and OT/AVP expression, with more pronounced neurobehavioral changes observed in males than in females in both early and late adolescence. Specifically, ELA impaired social recognition in early adolescent females regardless of prenatal treatment, while males showed deficits in both early and late adolescence in response to unique and interactive effects of PAE and ELA. Neurobiological data suggest that these perinatal insults differentially impact the OT and AVP systems in a sexually dimorphic manner, such that the OT system appears to be particularly sensitive to PAE in males while the AVP system appears to be more vulnerable to ELA in females. Taken together, our data provide novel insight into how the early postnatal environment may mediate outcomes of PAE as well as the power of animal models to interrogate the relationship between these pre- and postnatal insults.

Glucocorticoid receptor expression in the stress-limbic circuitry is differentially affected by prenatal alcohol exposure and adolescent stress.

The dense expression of glucocorticoid receptors (GR) within the amygdala, medial prefrontal cortex (mPFC) and paraventricular nucleus of hypothalamus (PVN) mediates many aspects of emotional and stress regulation. Importantly, both prenatal alcohol exposure (PAE) and adolescent stress are known to induce emotional and stress dysregulation. Little is known, however, about how PAE and/or adolescent stress may alter the expression of GR in the amygdala, mPFC, and PVN. To fill this gap, we exposed PAE and control adolescent male and female rats to chronic mild stress (CMS) and assessed GR mRNA expression in the amygdala, mPFC, and PVN immediately following stress or in adulthood. We found that the effects of PAE on GR expression were more prevalent in the amygdala, while effects of adolescent stress on GR expression were more prevalent in the mPFC. Moreover, PAE effects in the amygdala were more pronounced during adolescence and adolescent stress effects in the mPFC were more pronounced in adulthood. GR expression in the PVN was affected by both PAE and adolescent stress. Finally, PAE and/or adolescent stress effects were distinct between males and females. Together, these results suggest that PAE and adolescent CMS induce dynamic alterations in GR expression in the amygdala, mPFC, and PVN, which manifest differently depending on the brain area, age, and sex of the animal. Additionally, these data indicate that PAE-induced hyperresponsiveness to stress and increased vulnerability to mental health problems may be mediated by different neural mechanisms depending on the sex and age of the animal.

Role of corticosterone in anxiety- and depressive-like behavior and HPA regulation following prenatal alcohol exposure.

Prenatal alcohol exposure (PAE) is known to cause dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, including hyperresponsivity to stressors. Dysregulation of the HPA axis plays a role in vulnerability to stress-related disorders, such as anxiety and depression. Thus, the effects of PAE on HPA function may result in increased vulnerability to the effects of stress and, in turn, lead to the development of stress-related disorders. Indeed, individuals prenatally exposed to alcohol have an increased risk of developing anxiety and depression. However, it is unclear whether hypersecretion of corticosterone (CORT) in response to stress per se is involved with mediating differential effects of stress in PAE and control animals. To investigate the role of CORT in mediating effects of stress in both adult females and males following PAE, adrenalectomy with CORT replacement (ADXR) was utilized to produce similar CORT levels among prenatal treatment groups before exposure to chronic unpredictable stress (CUS). Anxiety-like behavior was evaluated using the open field and elevated plus maze, and depressive-like behavior was examined in the forced swim test. Mineralocorticoid receptor (MR) and glucocorticoid receptor (GR) mRNA expression was assessed in the medial prefrontal cortex (mPFC), amygdala, and hippocampal formation. Under the non-CUS condition, PAE alone differentially altered anxiety-like behavior in sham but not ADXR females and males, with females showing decreased anxiety-like behavior but males exhibiting increased anxiety-like behavior compared to their control counterparts. There were no effects of PAE alone on depressive-like in females or males. PAE also decreased GR mRNA expression in the hippocampal formation in females but had no effects on MR or GR mRNA expression in any brain region in males. CUS had differential effects on anxiety- and depressive-like behavior in PAE and control animals, and these effects were sex dependent. Importantly, ADXR unmasked differences between PAE and control animals, demonstrating that CORT may play a differential role in modulating behavior and HPA activity/regulation in PAE and control animals, and may do so in a sex-dependent manner.

Prenatal alcohol exposure disrupts male adolescent social behavior and oxytocin receptor binding in rodents.

Social behavior deficits resulting from prenatal alcohol exposure (PAE) emerge early in life and become more pronounced across development. Maturational changes associated with adolescence, including pubertal onset, can have significant consequences for social behavior development, making adolescence a unique period of increased vulnerability to social behavior dysfunction. Unfortunately, little is known about the underlying neurobiology supporting PAE-related social behavior impairments, particularly in the context of adolescence, when the transition to a more complex social environment may exacerbate existing deficits in social behavior function. Here we perform a comprehensive evaluation of social behavior development in PAE animals during two different periods in adolescence using three separate but related tests of social behavior in increasingly complex social contexts: the social interaction test, the social recognition memory test (i.e. habituation-dishabituation test), and the social discrimination test. Additionally, we investigated the underlying neurobiology of the oxytocin (OT) and vasopressin (AVP) systems following PAE, given their well-documented role in mediating social behavior. Our results demonstrate that compared to controls, early adolescent PAE animals showed impairments on the social recognition memory test and increased OT receptor binding in limbic networks, while late adolescent PAE animals exhibited impairments on the social discrimination test and increased OTR binding in forebrain reward systems. Taken together, these data indicate that PAE impairs adolescent social behavior - especially with increasing complexity of the social context - and that impairments are associated with altered development of the OT but not the AVP system.

Fragmented QRS complexes after acute myocardial infarction are independently associated with unfavorable left ventricular remodeling.

BACKGROUND: Recovery of left ventricular ejection fraction (LVEF) after acute myocardial infarction (MI) is not universal and is difficult to predict. Fragmented QRS (fQRS) complexes are thought to be markers of myocardial scar. We hypothesized that fQRS complexes on 12­lead surface ECGs during the initial post-MI period would be associated with adverse LV remodeling over the following year. METHODS: Change in LVEF between the early (0-2 month) and later (2-12 month) post-MI periods was assessed in two independent cohorts of post-MI patients with initial LV dysfunction. A decline or no recovery in LVEF (ΔLVEF ≤0%) was used as a primary outcome. fQRS complexes were measured on 12­lead ECGs within a week of acute MI. A subset of patients underwent cardiac magnetic resonance imaging (CMR) for scar quantification. RESULTS: Of 705 patients in the combined cohort, 27% experienced the primary outcome (average ΔLVEF of -4%). fQRS complexes were associated with a two-fold higher risk of no LVEF recovery, independent of prior MI or CABG, baseline LVEF, MI location and QRS duration or axis. Of 113 patients undergoing CMR, fQRS was associated with increased peri-infarct zone late gadolinium enhancement (13 ±â€¯5% vs 11 ±â€¯4%, p = 0.02), but not core infarct. CONCLUSIONS: Despite contemporary post-MI therapy, >1 in 4 patients will show a decline in LVEF during follow-up. Fragmented QRS complexes on 12­lead surface ECG early post-MI may be a valuable marker of unfavorable LV remodeling and correlate to increased peri-infarct scar on CMR imaging.

Interactive effects of prenatal alcohol exposure and chronic stress in adulthood on anxiety-like behavior and central stress-related receptor mRNA expression: Sex- and time-dependent effects.

Children and adults prenatally exposed to alcohol show higher rates of mental health problems than unexposed individuals, with depression and anxiety being among the more commonly encountered disorders. Previous studies in rats showed that prenatal alcohol exposure (PAE) can indeed increase depressive- and anxiety-like behavior in adulthood; however, depression and anxiety are often observed in the context of stress and/or a dysregulated stress response system (the hypothalamic-pituitary-adrenal [HPA] axis). PAE can dysregulate the HPA axis, resulting in hyperresponsivity to stress. In turn, this may predispose individuals prenatally exposed to alcohol to the adverse effects of stress compared to unexposed individuals. We have shown previously that PAE animals may be more sensitive to the effects of chronic stress on behavior, showing increased anxiety- and depressive-like behavior following chronic unpredictable stress (CUS) exposure. Here, we investigated the independent and interactive effects of PAE and adult CUS on anxiety-like behavior and receptor systems (corticotropin-releasing hormone receptor type 1 [CRHR1], mineralocorticoid receptor [MR], and glucocorticoid receptor [GR]), and underlying stress and emotional regulation, and whether exposure to CUS differentially results in immediate or delayed effects. Adult male and female offspring from PAE, pair-fed (PF), and ad libitum-fed control (C) dams were exposed to either 10 days of CUS or left undisturbed. Behavioral testing began 1 or 14 days post-CUS, and brains were collected following testing. Anxiety-like behaviors were evaluated using the open field, elevated plus maze and dark-light emergence tests. CRHR1, MR, and GR mRNA expression were assessed in the medial prefrontal cortex (mPFC), amygdala, and hippocampal formation, brain areas key to both stress and emotional regulation. We found that PAE differentially increased anxiety-like behavior and altered GR mRNA in males and females compared to their control counterparts. Furthermore, depending on the timing of testing, CUS unmasked alterations in GR and CRHR1 mRNA expression in the mPFC and amygdala in PAE males, and MR mRNA in the hippocampal formation in PAE females compared to their C counterparts. Overall, the changes observed in these receptor systems may underlie the increase in anxiety-like behavior following PAE and CUS exposure in adulthood. That CUS differentially affected brain and behavioral outcome of PAE and C animals, and did so in a sexually-dimorphic manner, has important implications for understanding the etiology of psychopathology in individuals prenatally exposed to alcohol.

Chronic Stress Alters Behavior in the Forced Swim Test and Underlying Neural Activity in Animals Exposed to Alcohol Prenatally: Sex- and Time-Dependent Effects.

Dysregulation of the hypothalamic-pituitary-adrenal (HPA) stress response has been suggested to play a role in vulnerability to stress-related disorders, such as depression. Prenatal alcohol exposure (PAE) may result in HPA dysregulation, which in turn may predispose individuals to the effects of stress exposure throughout life, and increase their risk of developing depression compared to unexposed individuals. We examined the immediate and delayed effects of chronic unpredictable stress (CUS) in adulthood on behavior of PAE animals in the forced swim test (FST) and the neurocircuitry underlying behavioral, emotional, and stress regulation. Adult male and female offspring from PAE and control conditions were tested for 2 days in the FST, with testing initiated either 1 day (CUS-1; immediate) or 14 days (CUS-14; delayed) post-CUS. Following testing, c-fos mRNA expression of the medial prefrontal cortex (mPFC), amygdala, hippocampal formation, and the paraventricular nucleus of the hypothalamus was assessed. Our results indicate that PAE and CUS interact to differentially alter FST behaviors and neural activation of several brain areas in males and females, and effects may depend on whether testing is immediate or delayed post-CUS. PAE males showed decreased time immobile (Day 1 of FST) following immediate testing, while PAE females showed increased time immobile (Day 2 of FST) following delayed testing compared to their respective control counterparts. Moreover, in males, PAE decreased c-fos mRNA expression in the lateral and central nuclei of the amygdala in the non-CUS condition, and increased c-fos mRNA expression in the CA1 in the CUS-14 condition. By contrast in females, c-fos mRNA expression in the Cg1 was decreased in PAE animals (independent of CUS) and decreased in all mPFC subregions in CUS-14 animals (independent of prenatal treatment). Constrained principal component analysis, used to identify neural and behavioral networks, revealed that PAE altered the activation of these networks and modulated the effects of CUS on these networks in a sex- and time-dependent manner. This dysregulation of the neurocircuitry underlying behavioral, emotional and stress regulation, may ultimately contribute to an increased vulnerability to psychopathologies, such as depression, that are often observed following PAE.

Impact of adolescent stress on the expression of stress-related receptors in the hippocampus of animals exposed to alcohol prenatally.

Many functions of the hippocampus are affected by prenatal alcohol exposure (PAE). In particular, dysregulation of the stress response is especially important because individuals with PAE carry increased risks for exposure to stressful environments throughout life. Little is known, though, about how adolescent stress in the context of PAE-related stress system dysregulation may further alter hippocampal development. Here, we investigate the short- and long-term effects of adolescent chronic mild stress (CMS) on mRNA expression of stress-related mineralocorticoid (MR), glucocorticoid (GR), and type 1 CRH (CRHR1) receptors in the dorsal and ventral hippocampal formation of PAE and control rats. Our results indicate that PAE affects the expression of stress-related receptors in the hippocampus; however, PAE effects were more prominent during adolescence, as MR and CRHR1 mRNA expression were altered in both male and female PAE animals, with GR mRNA expression alterations observed only in PAE female. In adulthood, the effects of PAE were restricted to alterations in CRHR1 mRNA expression in females, while there were no effects in males. In contrast, the effects of adolescent CMS were more pronounced in adulthood, long after stress exposure termination. Importantly, PAE animals were less responsive to adolescent CMS, with effects only on CRHR1 in PAE animals compared to the altered MR, GR, and CRHR1 mRNA expression observed in controls. Together, our results show that PAE and adolescent CMS induce dynamic alterations in the expression of stress-related receptors in the hippocampal formation that manifest differently depending on the age and sex of the animal.

Comparison of Digitalis Sensitivities of Na+/K+-ATPases from Human and Pig Kidneys.

Digitalis drugs are selective inhibitors of the plasma membrane Na+/K+-ATPase. There are many studies on molecular mechanisms of digitalis interaction with purified pig kidney enzyme, with the tacit assumption that it is a good model of human kidney enzyme. However, previous studies on crude or recombinant human kidney enzymes are limited, and have not resulted in consistent findings on their digitalis sensitivities. Hence, we prepared comparably purified enzymes from human and pig kidneys and determined inhibitory constants of digoxin, ouabain, ouabagenin, bufalin, and marinobufagenin (MBG) on enzyme activity under optimal turnover conditions. We found that each compound had the same potency against the two enzymes, indicating that (i) the pig enzyme is an appropriate model of the human enzyme, and (ii) prior discrepant findings on human kidney enzymes were either due to structural differences between the natural and recombinant enzymes or because potencies were determined using binding constants of digitalis for enzymes under nonphysiological conditions. In conjunction with previous findings, our newly determined inhibitory constants of digitalis compounds for human kidney enzymes indicate that (i) of the compounds that have long been advocated to be endogenous hormones, only bufalin and MBG may act as such at kidney tubules, and (ii) beneficial effects of digoxin, the only digitalis with extensive clinical use, does not involve its inhibitory effect on renal tubular Na+/K+-ATPase.

Prenatal Alcohol Exposure and Pair Feeding Differentially Impact Puberty and Reproductive Development in Female Rats: Role of the Kisspeptin System.

BACKGROUND: Reproductive maturation is initiated with the onset of puberty, which activates the hypothalamic-pituitary-gonadal axis and coincidences with increased expression of the hormone kisspeptin within the hypothalamus. Maturational events are sensitive to environmental factors, including alcohol, which is known to delay reproductive development. We hypothesized that, similar to alcohol's adverse effects during reproductive maturation, prenatal alcohol exposure (PAE) would alter pubertal markers, sex hormone profiles, and kisspeptin expression in the hypothalamus. METHODS: Female offspring from control (C), pair-fed (PF), and PAE groups were sacrificed prior to puberty onset (postnatal day [PND] 30), during puberty [PND 35], or in adulthood [PND 65]. Estradiol (E2 ), progesterone (P4 ), prolactin, and luteinizing hormone levels, and Kiss1 mRNA expression were measured in the arcuate (ARC) and anteroventral periventricular (AVPV) nuclei of the hypothalamus. Pubertal markers (vaginal opening [VO], uterus/body wt ratio) were assessed. RESULTS: Our findings indicate that (i) PAE inhibits the expected increases in E2 levels with age and delays maturational increases of P4 levels; (ii) PAE and pair feeding have similar adverse effects on VO and uterus/body wt ratio; (iii) differential relationships between PRL and P4 suggest that different mechanisms may underlie delayed maturation in PAE and PF; that is, PF females have low PRL levels and no increase in P4 with age, whereas PAE animals, despite low PRL, show the expected age-related increase in P4 ; and (iv) there is higher mean density of Kiss1 mRNA in the ARC of adult PAE females and altered Kiss1 expression in the AVPV of both PAE and PF females. CONCLUSIONS: PAE and pair feeding have some overlapping but important differential effects on hormonal profiles and Kiss1 mRNA expression during reproductive development. Preadolescent alterations in Kiss1 expression in the AVPV and ARC, which may change the balance of function in these 2 nuclei, may differentially contribute to delayed reproductive maturation in PAE and PF compared to C females.

Short- and long-term effects of stress during adolescence on emotionality and HPA function of animals exposed to alcohol prenatally.

Prenatal alcohol exposure (PAE) is associated with extremely high rates of psychopathologies, which may be mediated by the hypothalamic-pituitary-adrenal (HPA) dysregulation observed in exposed individuals. Of relevance, PAE carries an increased risk of exposure to stressful environments throughout life. Importantly, stressful experiences during adolescence increase vulnerability to psychopathologies. However, little is known about how adolescent stressful experiences in the context of PAE-induced HPA dysregulation may further alter the developmental trajectory and potentially contribute to the disproportionally high rate of psychopathologies observed in this population. Here we investigate the short- and long-term effects of adolescent chronic mild stress (CMS) on the emergence of anxiety-/depressive-like behaviors (open-field and forced swim test - FST) and on HPA activity (corticosterone and type 1 CRH receptor - CRHR1) in PAE male and female rats. Under non-CMS conditions, open field results indicate that PAE induced inappropriate behavior (increased time in center) in males and females, with increased activity in female adolescents, but anxiety-like behavior in adult PAE females. Conversely, FST results indicate that PAE induced depressive-like behavior in adolescent males. Exposure to CMS resulted in increased activity in adolescent males and anxiety-like behaviors in adult females. Moreover, PAE and/or CMS altered corticosterone and CRHR1 expression in the mPFC and amygdala. Together, these results suggest that PAE and adolescent CMS induce dynamic neurobehavioral alterations that manifest differently depending on the age and sex of the animal. These results highlight the importance of using both sexes as well as an ontogenetic approach when investigating the effects of environmental adversity.

Exposure to Chronic Mild Stress Differentially Alters Corticotropin-Releasing Hormone and Arginine Vasopressin mRNA Expression in the Stress-Responsive Neurocircuitry of Male and Female Rats Prenatally Exposed to Alcohol.

BACKGROUND: Prenatal alcohol exposure (PAE) results in dysregulation of the offspring hypothalamic-pituitary-adrenal (HPA) axis, increasing sensitivity to stressors and vulnerability to stress-related disorders. We have previously shown that exposure to chronic mild stress (CMS) in adulthood significantly increases anxiety-like behaviors (elevated plus maze) in PAE males and females compared to controls. To explore neurobiological mechanisms linking HPA dysregulation and altered anxiety-like behavior, we investigated neuropeptide (corticotropin-releasing hormone [CRH] and arginine vasopressin [AVP]) expression in brain areas involved in the stress neurocircuitry of animals from this previous behavioral study. METHODS: Adult PAE, pair-fed (PF), and ad libitum fed control (C) male and female offspring exposed to CMS or remaining undisturbed (non-CMS) were terminated 30 minutes following behavioral testing. RESULTS: In the paraventricular nucleus, CMS increased CRH mRNA levels in PAE compared to PF and C males and increased AVP mRNA levels in PAE compared to C males, with no differential effects for CRH or AVP in females. In the central nucleus of the amygdala, there was an increase in CRH mRNA expression overall, regardless of CMS condition or sex, in PAE compared to C animals. Moreover, in PF males, CMS increased AVP mRNA levels in the paraventricular nucleus, resulting in a decreased CRH/AVP ratio compared to PAE males, and decreased amygdala CRH mRNA compared to that in the non-CMS condition. CONCLUSIONS: CMS differentially altered central HPA peptide expression in PAE and PF animals compared to their control counterparts, with a possible shift toward greater CRH mediation of HPA regulation in PAE males, and greater AVP mediation of HPA regulation in PF males. However, changes in CRH and AVP expression do not align fully with the anxiogenic profile observed in our previous behavior study, suggesting that other neuronal substrates and limbic forebrain regions also contribute to increased anxiety-like behavior following CMS.

Neurocircuitry underlying stress and emotional regulation in animals prenatally exposed to alcohol and subjected to chronic mild stress in adulthood.

Individuals exposed to alcohol during gestation show higher rates of psychopathologies. The hyperresponsivity to stress induced by prenatal alcohol exposure (PAE) may be related to this increased rate of psychopathologies, especially because this population is more likely to be exposed to stressful environments throughout life. However, alcohol-induced changes in the overlapping neurocircuitries that underlie stress and the expression of psychopathologies are not fully understood. Here, we performed a comprehensive analysis of the neural activity within central areas known to play key roles in both emotional and stress regulation. Adult male and female offspring from PAE, pair-fed, and ad libitum-fed control conditions were exposed to chronic mild stress (CMS). Following CMS, the neural activity (c-fos mRNA) of the amygdala, ventral hippocampal formation, medial prefrontal cortex (mPFC), and paraventricular nucleus of hypothalamus (PVN) was assessed in response to an acute stress (elevated plus maze). Our results demonstrate that, overall, PAE decreased neural activity within the amygdala and hippocampal formation in males and increased neural activity within the amygdala and mPFC in females. CMS reduced neural activity within the mPFC and PVN in PAE males, but reduced activity in all areas analyzed in control males. By contrast, CMS reduced neural activity in the mPFC in PAE females and had no effects in control females. Furthermore, the constrained principal component analysis revealed that these patterns of neural activity resulted in differential activation of the functional neural networks in males compared to females, indicating sexually dimorphic effects of PAE and CMS. Importantly, the altered networks of brain activation in PAE animals may underlie the hyperresponsivity to stress and increased psychopathologies observed among individuals prenatally exposed to alcohol.

Pulmonary interstitial glycogenosis in a patient ultimately diagnosed with Noonan syndrome.

We describe an infant prenatally diagnosed with hydrops fetalis ultimately found to have Noonan syndrome (NS). Prior to genetic confirmation of diagnosis, lung biopsy was performed which revealed widespread pulmonary interstitial glycogenosis (PIG), abnormal alveolarization, and mild inflammation. Although genetic alterations have been identified in NS, the mutations are heterogeneous and the diagnosis remains one of clinical suspicion. The combination of PIG and NS has not yet been documented in the literature. While the underlying pathophysiologic mechanism of PIG is unclear, we suggest that the mitogen-activated protein kinase signal transduction pathway members (PTPN11, KRAS, SOS1, RAF1, SHOC2, NRAS) involved in cellular growth factor signaling, which are affected in NS, can provide clues. In addition, this case demonstrates that empiric corticosteroids can be considered in complicated cases since biopsy did reveal an inflammatory component, not typically noted in PIG.

Vitamin D levels are associated with cardiac autonomic activity in healthy humans.

UNLABELLED: Vitamin D deficiency (≤50nmol/L 25-hydroxy vitamin D) is a cardiovascular (CV) risk factor that affects approximately one billion people worldwide, particularly those affected by chronic kidney disease (CKD). Individuals with CKD demonstrate abnormal cardiac autonomic nervous system activity, which has been linked to the significant rates of CV-related mortality in this population. Whether vitamin D deficiency has a direct association with regulation of cardiac autonomic activity has never been explored in humans. METHODS: Thirty-four (34) healthy, normotensive subjects were studied and categorized based on 25-hydroxy vitamin D deficiency (deficient vs. non-deficient, n = 7 vs. 27), as well as 1,25-dihydroxy vitamin D levels (above vs. below 25th percentile, n = 8 vs. 26). Power spectral analysis of electrocardiogram recordings provided measures of cardiac autonomic activity across low frequency (LF) and high frequency (HF, representative of vagal contribution) bands, representative of the sympathetic and vagal limbs of the autonomic nervous system when transformed to normalized units (nu), respectively, as well as overall cardiosympathovagal balance (LF:HF) during graded angiotensin II (AngII) challenge (3 ng/kg/min × 30 min, 6 ng/kg/min × 30 min). RESULTS: At baseline, significant suppression of sympathovagal balance was observed in the 25-hydroxy vitamin D-deficient participants (LF:HF, p = 0.02 vs. non-deficient), although no other differences were observed throughout AngII challenge. Participants in the lowest 1,25-dihydroxy VD quartile experienced significant withdrawal of inhibitory vagal control, as well as altered overall sympathovagal balance throughout AngII challenge (HF, mean difference = -6.98 ± 3 nu, p = 0.05; LF:HF, mean difference = 0.34 ± 0.1, p = 0.043 vs. above 25th percentile). CONCLUSIONS: Vitamin D deficiency is associated with suppression of resting cardiac autonomic activity, while low 1,25-dihydroxy vitamin D levels are associated with unfavourable cardiac autonomic activity during an acute AngII stressor, offering a potential pathophysiological mechanism that may be acting to elevate CV risk in in populations with low vitamin D status.

Basal regulation of HPA and dopamine systems is altered differentially in males and females by prenatal alcohol exposure and chronic variable stress.

Effects of prenatal alcohol exposure (PAE) on central nervous system function include an increased prevalence of mental health problems, including substance use disorders (SUD). The hypothalamic-pituitary-adrenal (HPA) and dopamine (DA) systems have overlapping neurocircuitries and are both implicated in SUD. PAE alters both HPA and dopaminergic activity and regulation, resulting in increased HPA tone and an overall reduction in tonic DA activity. However, effects of PAE on the interaction between HPA and DA systems have not been investigated. The present study examined PAE effects on basal regulation of central stress and DA systems in key brain regions where these systems intersect. Adult Sprague-Dawley male and female offspring from prenatal alcohol-exposed (PAE), pairfed (PF), and ad libitum-fed control (C) groups were subjected to chronic variable stress (CVS) or remained as a no stress (non-CVS) control group. Corticotropin releasing hormone (CRH) mRNA, as well as glucocorticoid and DA receptor (DA-R) expression were measured under basal conditions 24h following the end of CVS. We show, for the first time, that regulation of basal HPA and DA systems, and likely, HPA-DA interactions, are altered differentially in males and females by PAE and CVS. PAE augmented the typical attenuation in weight gain during CVS in males and caused increased weight loss in females. Increased basal corticosterone levels in control, but not PAE, females suggest that PAE alters the profile of basal hormone secretion throughout CVS. CVS downregulated basal CRH mRNA in the prefrontal cortex and throughout the bed nucleus of the stria terminalis (BNST) in PAE females but only in the posterior BNST of control females. PAE males and females exposed to CVS exhibited more widespread upregulation of basal mineralocorticoid receptor mRNA throughout the hippocampus, and an attenuated decrease in DA-R expression throughout the nucleus accumbens and striatum compared to CVS-exposed control males and females. Overall, these findings enhance our understanding of PAE effects on the cross-talk between HPA and DA systems, and provide insight into possible mechanisms underlying mental health problems that are related to stress and DA signaling, including SUD, which have a high prevalence among individuals with FASD.