Optogenetic silencing of a corticotropin-releasing factor pathway from the central amygdala to the bed nucleus of the stria terminalis disrupts sustained fear.

The lateral central nucleus of the amygdala (CeAL) and the dorsolateral bed nucleus of the stria terminalis (BNSTDL) coordinate the expression of shorter- and longer-lasting fears, respectively. Less is known about how these structures communicate with each other during fear acquisition. One pathway, from the CeAL to the BNSTDL, is thought to communicate via corticotropin-releasing factor (CRF), but studies have yet to examine its function in fear learning and memory. Thus, we developed an adeno-associated viral-based strategy to selectively target CRF neurons with the optogenetic silencer archaerhodopsin tp009 (CRF-ArchT) to examine the role of CeAL CRF neurons and projections to the BNSTDL during the acquisition of contextual fear. Expression of our CRF-ArchT vector injected into the amygdala was restricted to CeAL CRF neurons. Furthermore, CRF axonal projections from the CeAL clustered around BNSTDL CRF cells. Optogenetic silencing of CeAL CRF neurons during contextual fear acquisition disrupted retention test freezing 24 h later, but only at later time points (>6 min) during testing. Silencing CeAL CRF projections in the BNSTDL during contextual fear acquisition produced a similar effect. Baseline contextual freezing, the rate of fear acquisition, freezing in an alternate context after conditioning and responsivity to foot shock were unaffected by optogenetic silencing. Our results highlight how CeAL CRF neurons and projections to the BNSTDL consolidate longer-lasting components of a fear memory. Our findings have implications for understanding how discrete amygdalar CRF pathways modulate longer-lasting fear in anxiety- and trauma-related disorders.

Epigenetic modulation of chronic anxiety and pain by histone deacetylation.

Prolonged exposure of the central amygdala (CeA) to elevated corticosteroids (CORT) facilitates long-term anxiety and pain through activation of glucocorticoid receptors (GRs) and corticotropin-releasing factor (CRF). However, the mechanisms maintaining these responses are unknown. Since chronic phenotypes can be sustained by epigenetic mechanisms, including histone modifications such as deacetylation, we tested the hypothesis that histone deacetylation contributes to the maintenance of chronic anxiety and pain induced by prolonged exposure of the CeA to CORT. We found that bilateral infusions of a histone deacetylase inhibitor into the CeA attenuated anxiety-like behavior as well as somatic and visceral hypersensitivity resulting from elevated CORT exposure. Moreover, we delineated a novel pathway through which histone deacetylation could contribute to CORT regulation of GR and subsequent CRF expression in the CeA. Specifically, deacetylation of histone 3 at lysine 9 (H3K9), through the coordinated action of the NAD+-dependent protein deacetylase sirtuin-6 (SIRT6) and nuclear factor kappa B (NFκB), sequesters GR expression leading to disinhibition of CRF. Our results indicate that epigenetic programming in the amygdala, specifically histone modifications, is important in the maintenance of chronic anxiety and pain.

Reporting vaccine complications: what do obstetricians and gynecologists know about the Vaccine Adverse Event Reporting System?

BACKGROUND: Obstetrician-gynecologists are increasingly called upon to be vaccinators as an essential part of a woman's primary and preventive health care. Despite the established safety of vaccines, vaccine adverse events may occur. A national Vaccine Adverse Event Reporting System (VAERS) is a well-established mechanism to track adverse events. However, we hypothesized that many obstetrician-gynecologists are naive to the role and use of VAERS. METHODS: We devised a ten-question survey to a sample of ACOG fellows to assess their knowledge and understanding of VAERS. We performed descriptive and frequency analysis for each of the questions and used one-way analysis of variance for continuous and chi-squared for categorical variables. RESULTS: Of the 1000 fellows who received the survey, 377 responded. Only one respondent answered all nine knowledge questions correctly, and 9.2% of physicians had used VAERS. Older physicians were less familiar with VAERS in general and with the specific objectives of VAERS in particular (χ(2) = 10.7, P = .005). CONCLUSIONS: Obstetrician-gynecologist familiarity with VAERS is lacking. Only when the obstetrician-gynecologist is completely knowledgeable regarding standard vaccine practices, including the availability and use of programs such as VAERS, will providers be functioning as competent and complete vaccinators.

Postpartum care: Discussions and counseling for the peripartum period.

BACKGROUND: Traditionally, postpartum care is confined to inpatient care immediately post birth and one appointment approximately six weeks postpartum. Data supports a continuum of care model as best for the health of mother and baby. Despite most women having significant concerns about the postpartum period, these concerns are frequently incompletely addressed by providers. We surveyed prenatal and postpartum patients to understand their concerns and experiences discussing postpartum care with providers. METHODS: Cross sectional surveys were administered between June 2019 and May 2021. Principal component analysis was used to show higher than average (positive) or lower than average (negative) conversations with providers about postpartum care examined by race, education, and parity. Chi squared tests were conducted to examine the significance of specific postpartum concerns. RESULTS: 421/450 patient surveys were analyzed, based on completion. Most patients were White (193), had post graduate degrees (188), privately insured (236), married (248), first time pregnant (152), and used doctors as their primary provider (267). Patients with lower education, higher parity and Black patients without postgraduate degrees reported higher than average postpartum counseling. Additionally, most patients expressed significant concerns about postpartum exhaustion (65.8%), breastfeeding (62.3%), pain (61.2%), physical activity (54.9%) and the baby blues (50.4%). CONCLUSIONS: Postpartum concerns are incompletely and inconsistently addressed amongst patients based on race, parity, and education. A continuum of care approach, beginning in the third trimester, through the postpartum period, may provide better counseling to address all patients' concerns.

Provider practices for the prevention of eclampsia and attitudes toward magnesium sulfate: results of a nationwide survey.

OBJECTIVE: To survey OB-GYNs regarding their practice patterns and perspectives when it comes to using magnesium sulfate (magnesium) in the prevention of eclampsia. STUDY DESIGN: We conducted a cross-sectional web-based 18-item survey given to 564 practicing OB-GYNs in the Pregnancy-Related Care Research Network. The survey used clinical scenarios to look at provider practices for preventing eclampsia in patients who have preeclampsia and relative contraindications to magnesium. Next, we assessed provider attitudes toward magnesium and inquired about their experiences with complications related to its use. The survey also contained an embedded educational component that addressed the signs and symptoms of magnesium toxicity followed by a 2-item quiz for those providers who self-identified as having never treated magnesium toxicity. RESULTS: Nearly 30% of OB-GYNs contacted completed the survey. For patients with preeclampsia and a contraindication to magnesium such as myasthenia gravis, 44.4% of respondents would administer an alternative antiepileptic and 42.5% of them would administer no antiepileptic at all. For patients with pulmonary edema complicating preeclampsia, 32.5% would give magnesium at the usual dose, 33.1% would give magnesium at less than the usual dose, 12.3% would give an alternative antiepileptic and 22.1% would give no antiepileptic at all. For patients with laboratory evidence of renal compromise complicating preeclampsia, most respondents (89.6%) said they would give magnesium at less than the usual dose. Regarding complications of magnesium that clinicians have encountered, over one-third of respondents have administered calcium gluconate for magnesium toxicity in patients with preeclampsia. For those providers who have not treated magnesium toxicity and were prompted to receive the educational component and quiz, all knew the correct initial bolus dosing of magnesium and the majority were able to identify symptoms of toxicity. The majority (81.8%) of respondents said that continuous magnesium infusions cause an increased demand for dedicated personnel to care for the patients on them. Almost 57% of respondents endorsed the need for an alternative antiepileptic to magnesium in the prevention of eclampsia. Most write-in responses supporting this need cited a concern with magnesium's safety and side effects. CONCLUSION: There is wide variation among OB-GYNs regarding the prevention of eclampsia and complications of magnesium are not uncommon. The survey revealed that OB-GYNs are using alternative antiepileptics in scenarios where there is concern for magnesium's safety profile. In addition, over half of those surveyed believe there is a need for validated antiepileptics other than magnesium for the prevention of eclampsia in patients with preeclampsia. These findings suggest that OB-GYNs would support further research into alternative antiepileptics in the prevention of eclampsia.

Practices of sickle cell disease genetic screening and testing in the prenatal population.

BACKGROUND: Genetic screening and testing are technologies historically underutilized in Black populations despite predicting diseases like sickle cell disease (SCD), which is predominantly found in Blacks. We surveyed prenatal patients to understand choices, beliefs and experiences surrounding genetic screening and testing, specifically for SCD. METHODS: In this cross-sectional study, we surveyed 322 women during prenatal visits. Responses were analyzed to identify barriers to care and education about testing and screening for SCD. Patients rated whether they agreed or disagreed with statements regarding sickle cell health behaviors. We used χ2 tests to compare categorical variables by self-reported race. Binary logistic regression was used to determine the odds ratios and confidence intervals for each outcome. RESULTS: Women were a mean (SD) age of 33.3 (6.1). 42.9% of patients self-identified as White while 41.3% of patients self- identified as Black. Screening questions were adjusted for differences in race, insurance, and education levels to show significant differences in responses between Blacks and Whites for screening for SCD (p = 0.047, OR 95% CI = 0.455 [0.210-0.989]) and plans to meet with genetic counselors (p = 0.049, OR 95% CI = 0.299 [0.090-0.993]). The statements "if sickle cell is not in their family, then it is likely not in themselves or their children," was significantly different between Black and White populations (p = 0.011, OR 95% CI = 0.207 [0.081-0.526]). CONCLUSION: Our findings suggest gaps in screening, testing, education, and pregnancy management choices between Black and White patients. Research should focus on decreasing these healthcare gaps and improving education that address concerns about SCD for relevant populations.

Pattern of maternal circulating CRH in laboratory-housed squirrel and owl monkeys.

The anthropoid primate placenta appears to be unique in producing corticotropin-releasing hormone (CRH). Placental CRH is involved in an endocrine circuit key to the production of estrogens during pregnancy. CRH induces cortisol production by the maternal and fetal adrenal glands, leading to further placental CRH production. CRH also stimulates the fetal adrenal glands to produce dehydroepiandrostendione sulfate (DHEAS), which the placenta converts into estrogens. There are at least two patterns of maternal circulating CRH across gestation among anthropoids. Monkeys examined to date (Papio and Callithrix) have an early-to-mid gestational peak of circulating CRH, followed by a steady decline to a plateau level, with a possible rise near parturition. In contrast, humans and great apes have an exponential rise in circulating CRH peaking at parturition. To further document and compare patterns of maternal circulating CRH in anthropoid primates, we collected monthly blood samples from 14 squirrel monkeys (Saimiri boliviensis) and ten owl monkeys (Aotus nancymaae) during pregnancy. CRH immunoreactivity was measured from extracted plasma by using solid-phase radioimmunoassay. Both squirrel and owl monkeys displayed a mid-gestational peak in circulating CRH: days 45-65 of the 152-day gestation for squirrel monkeys (mean±SEM CRH=2,694±276 pg/ml) and days 60-80 of the 133-day gestation for owl monkeys (9,871±974 pg/ml). In squirrel monkeys, circulating CRH declined to 36% of mean peak value by 2 weeks before parturition and then appeared to increase; the best model for circulating CRH over gestation in squirrel monkeys was a cubic function, similar to previous results for baboons and marmosets. In owl monkeys, circulating CRH appeared to reach plateau with no subsequent significant decline approaching parturition, although a cubic function was the best fit. This study provides additional evidence for a mid-gestational peak of maternal circulating CRH in ancestral anthropoids that has been lost in the hominoid lineage.

US obstetrician-gynaecologist's prevention and management of obesity in pregnancy.

A survey regarding management of obesity in pregnancy was mailed to 787 practising members of the American College of Obstetricians and Gynecologists (ACOG); 433 responded of whom 353 practised obstetrics. Most (79.2%) had read ACOG Committee Opinion, 'Obesity in Pregnancy,' and rated it helpful (68.6%) or very helpful (17.2%). Most responding physicians (91.2%) use BMI to assess their patients weight status; fewer (63.4%) use pre-pregnancy BMI to modify their pregnancy weight gain recommendation. Having read the Committee Opinion and being a woman were independent factors associated with using pre-pregnancy BMI. Responding physicians that had read the Committee Opinion were more knowledgeable about obesity-related pregnancy complications; but even among those physicians, only 32.2% were aware that maternal obesity is a risk factor for fetal neural tube defects. The responding physicians appeared well-versed on appropriate practice for caesarean delivery for obese patients whether they had read the Committee Opinion or not.

Patient Attitudes toward Gestational Weight Gain and Exercise during Pregnancy.

Body mass index (BMI) and gestational weight gain (GWG) are important factors for neonatal and maternal health. Exercise helps women moderate their BMI and GWG, and provides health benefits to mother and child. This survey study assessed patients' perceptions of counseling they received during pregnancy, their sources of information about GWG, and their attitudes toward exercise during pregnancy. We distributed an anonymous survey to 200 pregnant women over the age of 18 at a tertiary care center in Danville, Pennsylvania. Survey questions included demographics, discussions with medical providers regarding GWG and exercise, and their exercise habits before and during pregnancy. 182 women (91%) responded. Most reported their provider discussed weight and diet (78.8%), expected GWG (81.6%), and exercise during pregnancy (79.8%); however, 28% of obese women and 25% of women who did not plan to exercise during pregnancy reported not receiving exercise counseling. Approximately 20% of women did not plan to exercise during pregnancy. Women decreased the number of days per week they exercised (40.6% with 3 or more days prepregnancy versus 30.7% during pregnancy, P = 0.002). Some patients who did not exercise prior to pregnancy (12%) expressed interest in a personal training session. Among women in the eight month or later, 42.4% were above GWG recommendations. Our study found barriers to adequate activity during pregnancy; 20% of pregnant women not receiving/remembering counseling regarding exercise. Interest in personal training from patients that did not exercise suggests they would benefit from increased efforts to encourage physical activity. Exercise and GWG counseling based in medical science as well as patient psychological needs will help efforts to reduce GWG and improve pregnancy outcomes.

Umbilical cord clamping practices of U.S. obstetricians.

BACKGROUND: Delayed umbilical cord clamping is associated with significant benefits to preterm and term newborns and is recommended for all infants by the World Health Organization and the American College of Obstetricians and Gynecologists (ACOG). Little is known about the cord management practices of U.S. obstetricians. OBJECTIVE: The objective of this study was to describe current cord clamping practices by U.S. obstetricians and investigate factors associated with delayed cord clamping. STUDY DESIGN: A cross-sectional survey was sent to 500 members of the American College of Obstetricians and Gynecologists. Umbilical cord practices were assessed, and factors related to delaying cord clamping were examined using Chi-square tests and multivariate logistic regression models. RESULTS: The overall response rate was 37% with 74% of those opening the email responding. Sixty-seven percent of respondents reported DCC by one minute or more after vaginal births at term. After preterm and near-term vaginal births, 73% and 79% said they waited at least 30 seconds before clamping. The factor most consistently and strongly related to delaying cord clamping in both bivariate and multivariate analyses was having the belief that the timing of clamping was important. Additional analysis revealed that believing the timing was important was positively associated with the physician's institution having a written policy on the cord clamping. CONCLUSIONS: In this study, a majority of respondents reported delaying cord clamping and indicated that employing strategies to implement the full uptake of this practice could be valuable. Findings suggest that institutional policies may influence attitudes on cord clamping.

Behavioral neuroscience: challenges for the era of molecular biology.

This is a great age to participate in biological inquiry. Behavioral neuroscience offers a rich perspective for molecular biologists. However, behavioral analysis is not simply an assay. Whereas molecular biology has become a unique tool in the armamentarium of behavioral neuroscience, the powerful methodology of molecular biology is no substitute for careful behavioral exploration.

Transgenerational transmission of pregestational and prenatal experience: maternal adversity, enrichment, and underlying epigenetic and environmental mechanisms.

Transgenerational transmission refers to positive and negative adaptations in brain function and behavior that affect following generations. In this paper, empirical findings regarding the transgenerational transmission of maternal adversity during three critical periods - childhood, pregestational adulthood and pregnancy - will be reviewed in terms of pregnancy outcomes, maternal care, offspring behavior and development, and physiological functioning. Research on the transgenerational transmission of enrichment and the implications for interventions to ameliorate the consequences of adversity will also be presented. In the final section, underlying epigenetic and environmental mechanisms that have been proposed to explain how experience is transferred across generations through transgenerational transmission will be reviewed. Directions for future research are suggested throughout.

Corticotropin-releasing factor 1 receptor-mediated mechanisms inhibit colonic hypersensitivity in rats.

The potential relationship between stress and irritable bowel syndrome (IBS) symptomatology suggests a possible role for stress-mediating hormones, such as corticotropin-releasing factor (CRF), in the altered perception of stimuli in IBS patients. In previous studies, Wistar-Kyoto (WKY) rats with genetic indices of high anxiety demonstrated colonic hypersensitivity coupled with a high basal level of CRF within the central nervous system. In the current study we tested the hypothesis that a selective, non-peptide CRF1 receptor antagonist, antalarmin, would inhibit hypersensitivity in the WKY rat colon. Colonic sensitivity was determined by monitoring a visceromotor behavioural response during innocuous levels of colorectal distention (30 mmHg). In high anxiety WKY rats we found that antalarmin (20 mg kg-1, i.p.) significantly decreased the visceromotor response induced by colorectal distention. In a second study central administration (i.c.v.) of CRF was used to induce colonic hypersensitivity in lower anxiety Fischer 344 (F-344) rats, and in this model, antalarmin significantly inhibited the CRF-induced colonic hypersensitivity. In summary, a selective CRF1 receptor antagonist, antalarmin, inhibits colonic hypersensitivity apparent in WKY rats or in F-344 rats given a central administration of CRF. Our findings suggest that CRF1 receptor antagonism may represent a novel therapeutic approach for the treatment of IBS.

A national survey of obstetricians' attitudes toward and practice of periviable intervention.

OBJECTIVE: Test the association between provider characteristics and antenatal interventions offered for periviable delivery. STUDY DESIGN: Six hundred surveys mailed to members of the College's Collaborative Ambulatory Research Network. Items queried physicians' practices regarding administering steroids, recommending cesarean (for breech) and offering induction (for ruptured membranes) at 23 weeks. RESULT: Three hundred and ten (52%) obstetricians (OBs) responded. Respondents reported institutional cutoffs of 23 weeks for resuscitation (34%) and 24 weeks for cesarean (35%), whereas personal preferences for cesarean were ⩾25 weeks (44%). At 23 weeks, two-thirds ordered steroids, 43% recommended cesarean and 23% offered induction. In multivariable analyses, institutional cutoffs and providers' personal preferences predicted steroid administration (odds ratio, OR=4.37; 95% confidence interval, CI=1.73 to 11.00; OR=0.30, 95% CI=0.13 to 0.70); institutional cutoffs and the impression that cesarean decreases neurodevelopmental disability predicted recommending cesarean (OR=3.09, 95% CI=1.13 to 8.44; OR=6.41, 95% CI=2.06 to 19.91). For offering induction, practice location and religious service attendance approached, but did not meet, statistical significance (P=0.06 and P=0.05). CONCLUSION: OBs' willingness to intervene can impact periviable outcomes. These findings suggest that personal and institutional factors may influence obstetrical counseling and decision-making.

Parabrachial lesions in rats disrupt sodium appetite induced by furosemide but not by calcium deprivation.

An appetite for CaCl2 and NaCl occurs in young rats after they are fed a diet lacking Ca or Na, respectively. Bilateral lesions of the parabrachial nuclei (PBN) disrupt normal taste aversion learning and essentially eliminate the expression of sodium appetite. Here we tested whether similar lesions of the PBN would disrupt the calcium-deprivation-induced appetite for CaCl2 or NaCl. Controls and rats with PBN lesions failed to exhibit a calcium-deprivation-induced appetite for CaCl2. Nevertheless, both groups did exhibit a significant calcium-deprivation-induced appetite for 0.5M NaCl. Thus, while damage to the second central gustatory relay in the PBN disrupts the appetite for 0.5M NaCl induced by furosemide, deoxycorticosterone acetate, and polyethylene glycol, the sodium appetite induced by dietary CaCl2 depletion remains intact.

Allostasis, amygdala, and anticipatory angst.

Regions of the amygdala are involved in anticipation of negative events. Chronic anticipation of negative events leads to what we call allostatic load, or arousal pathology. Two hormones appear to be involved in arousal pathology; corticotropin-releasing hormone in the brain and glucocorticoids. We suggest that increases in corticotropin-releasing hormone, by stress or glucocorticoids, in the amygdala may have functional consequences for allostatic load. Whereas, corticotropin-releasing hormone in the parvocellular region of the paraventricular nucleus of the hypothalamus is decreased by glucocorticoids thereby under negative feedback and homeostatic control, the central nucleus of the amygdala is to some extent under positive feedback and is increased by glucocorticoids, and perhaps under allostatic control. The human and animal literature suggest that a variety of psychopathologies (e.g., melancholia) may be tied to neurohormonal signals activating regions of the amygdala.

Estrogens and non-reproductive behaviors related to activity and fear.

Estrogens affect a variety of behaviors in addition to sexual responses, some of them related to motor activity and emotional reactivity. This is true in experimental animals and in humans. The literatures on these subjects are confusing because not all of the experimental results point in the same direction. Here we propose the following theoretical suggestion, hoping to account for the variety of reports extant: following the generally arousing effects of estrogens, their hormonal actions on motor activity and fear depend on context. In a safe environment, estrogen treatment causes increased activity. But in a novel environment or in contexts otherwise perceived as threatening, activity is reduced by estrogen, due to the hormone's arousing action, which heightens fear. Many hormone-dependent neural circuits involving several neuropeptides could provide mechanisms for this dynamic. We suggest a causal route could involve the activation of corticotropin releasing hormone gene expression in the brain. In sum, estrogenic effects on arousal states, as manifest differently according to details of the environmental context during behavioral test, could account for some of the discrepancies in the literature.

Regulation of corticotropin-releasing hormone receptor messenger ribonucleic acid in the rat brain and pituitary by glucocorticoids and stress.

Glucocorticoids and stress are known to influence the synthesis of corticotropin-releasing hormone (CRH) at a variety of sites in brain, including the hypothalamus and amygdala. The recent cloning of the CRH receptor (CRH-R) enabled us to determine whether glucocorticoids or stress influenced CRH action via regulation of CRH-R. We, therefore, used in situ hybridization to measure CRH-R messenger RNA (mRNA) levels in the hypothalamic paraventricular nucleus (PVN), anterior pituitary (AP), amygdala, and bed nucleus of the stria terminalis (BNST) under several conditions. Systemic corticosterone (CORT) treatment, both daily injection (5 mg/rat.day) up to 14 days and pellet implant (200 mg) for 14 days, decreased CRH-R mRNA in the PVN and lateral and basolateral nucleus of the amygdala (BLA). Corticosterone injection (10 mg/rat.day, for 7 days) decreased CRH-R mRNA in the AP. Adrenalectomy also decreased CRH-R mRNA in the PVN and AP, but did not alter it in the BLA. In both sham and adrenalectomized rats with CORT pellet replacement (39 mg; ADX+CORT rats), acute (2-h) and repeated (2 h daily for 14 days) immobilization stress (which produced a large increase in plasma CORT in sham rats) increased CRH-R mRNA in the PVN and decreased it in the AP, but did not affect CRH-R mRNA in the BLA. However, ADX+CORT rats consistently had higher levels of CRH-R mRNA in both the PVN and AP than sham rats after stress. Brain stem hemisection, which damaged all ascending catecholaminergic fibers with the exception of the locus ceruleus, attenuated immobilization stress-induced up-regulation of CRH-R mRNA ipsilaterally in the PVN. None of the treatments affected CRH-R mRNA levels in the central and medial nucleus of the amygdala or the BNST. These results suggest that high concentrations of CORT or CRH synergistically decrease CRH-R mRNA levels in the AP, and that at least high CORT has an inhibitory effect on PVN CRH-R mRNA levels. However, stress input can override such inhibitory effects and thus up-regulate CRH-R mRNA in the PVN. The extrahypothalamic regions, such as amygdala and BNST may have different sensitivities to CORT or CRH for the regulation of CRH-R mRNA.

Preterm birth: associated neuroendocrine, medical, and behavioral risk factors.

Increased CRH secretion by the placenta of pregnant women has been associated with preterm birth. Certain indices of risk, both medical and psychosocial in nature, have been linked to preterm delivery. Levels of total, bound, and free CRH, CRH-binding protein (CRH-BP), and cortisol were measured prospectively in a large sample of pregnant Danish women who delivered preterm and term infants. Measures of maternal serum hormones were taken at 7--23 and 27--37 weeks gestation and, for those who delivered at term, at 37--43 weeks gestation. At 7--23 weeks gestation, maternal levels of total CRH (P = 0.01), bound CRH (P = 0.03), and CRH-BP (P = 0.01) were higher in the preterm than in the term group. At 27--37 weeks gestation, levels of total CRH (P < 0.0001), bound CRH (P < 0.0001), free CRH (P < 0.0001), and cortisol (P < 0.0001) were all higher in the preterm than the term group, whereas levels of CRH-BP (P < 0.0001) were lower in the preterm than in the term group. The best medical and behavioral factors associated with preterm delivery were, respectively, previous preterm delivery (P < 0.0001) and engagement in certain risk-taking behaviors (P = 0.008). The positive relations between preterm delivery and various adverse medical and socioeconomic variables with increases in placental secretion of CRH suggest that the latter may participate in the pathophysiology of preterm delivery.

From normal fear to pathological anxiety.

In this article the authors address how pathological anxiety may develop from adaptive fear states. Fear responses (e.g., freezing, startle, heart rate and blood pressure changes, and increased vigilance) are functionally adaptive behavioral and perceptual responses elicited during danger to facilitate appropriate defensive responses that can reduce danger or injury (e.g., escape and avoidance). Fear is a central motive state of action tendencies subserved by fear circuits, with the amygdala playing a central role. Pathological anxiety is conceptualized as an exaggerated fear state in which hyperexcitability of fear circuits that include the amygdala and extended amygdala (i.e., bed nucleus of the stria terminalis) is expressed as hypervigilance and increased behavioral responsivity to fearful stimuli. Reduced thresholds for activation and hyperexcitability in fear circuits develop through sensitization- or kindling-like processes that involve neuropeptides, hormones, and other proteins. Hyperexcitability in fear circuits is expressed as pathological anxiety that is manifested in the various anxiety disorders.