Neuroendocrine Responses Research Articles

Restoration of typical HPA-SAM co-activation following psychosocial intervention among preadolescent youth living in poverty.

Despite the added value of multisystem (relative to traditional single-system) approaches for characterizing biological processes linked to risk for psychopathology (e.g., neuroendocrine stress responsivity; Buss et al., 2019; Quas et al., 2014), no study to date has evaluated whether multisystem processes may serve as viable biological targets of intervention. Utilizing a multiple-levels-of-analysis approach (Cicchetti & Dawson, 2002), this person-centered study examined whether stress-adapted patterns of hypothalamus-pituitary-adrenal (HPA) axis and sympathetic-adrenomedullary (SAM) system co-activation were amenable to change following the Building a Strong Identity and Coping Skills intervention (BaSICS; Wadsworth et al., 2022). Preadolescents exposed to concentrated poverty (n = 112, M age = 11.78 years, 57.1% female, 54% assigned to intervention; 40% Hispanic, 63% Black, 20% White) completed questionnaires and the Trier Social Stress Test at both pre- and posttest. Multitrajectory modeling of cortisol and alpha-amylase levels identified four pretest and posttest HPA-SAM co-activation profiles. At pretest, youth exhibiting Asymmetric Nos. 1 & 2 HPA-SAM co-activation reported greater maladjustment relative to youth with Symmetric Nos. 1 & 2 co-activation. Youth exhibiting Asymmetric No. 1 co-activation at pretest were more likely to exhibit Symmetric No. 1 co-activation following BaSICS relative to control. Findings highlight the potential of BaSICS to restore neuroendocrine stress response function in impoverished youth, pointing to HPA-SAM co-activation as a potential biological target of preventive intervention in this population.

Unveiling the intricacies of irritable bowel syndrome.

Irritable bowel syndrome (IBS) remains a challenging condition both for patients and clinicians, characterized by its chronic nature and the elusive complexity of its underlying mechanisms. The multifaceted relationship between the neuroendocrine axis, gut microbiota, and inflammatory response has emerged as a focal point in recent research, offering new insights into the pathophysiology of IBS. The neuroendocrine axis plays a crucial role in maintaining the delicate balance between the brain and the gut, often referred to as the "gut-brain axis". This bidirectional communication is essential for regulating gastrointestinal function, stress responses, and overall homeostasis. Dysregulation of this axis, as highlighted by elevated cortisol and serotonin levels in IBS patients, suggests that neuroendocrine imbalances may significantly contribute to the severity of gastrointestinal symptoms. These findings underscore the need for a broader understanding of how stress and emotional factors influence IBS, potentially guiding more effective, personalized treatment approaches. Equally important is the role of the gut microbiota, a diverse and dynamic ecosystem that directly impacts gut health. This dysbiosis disrupts gut function and appears to exacerbate the neuroendocrine and inflammatory responses. These findings align with the growing recognition that gut microbiota is a critical player in IBS, influencing both the disease's onset and progression.

Human Pulmonary Neuroendocrine Cells Respond to House Dust Mite Extract With PAR-1 Dependent Release of CGRP.

Pulmonary neuroendocrine cells (PNEC) are rare airway epithelial cells that have recently gained attention as potential amplifiers of allergic asthma. However, studying PNEC function in humans has been challenging due to a lack of cell isolation methods, and little is known about human PNEC function in response to asthma-relevant stimuli. Here we developed and characterized an invitro human PNEC model and investigated the neuroendocrine response to extracts of the common aeroallergen house dust mite (HDM). PNEC-enriched cultures were generated from human induced pluripotent stem cells (iPNEC) and primary bronchial epithelial cells (ePNEC). Characterized PNEC cultures were exposed to HDM extract, a volatile chemical odorant (Bergamot oil), or the bacterial membrane component, lipopolysaccharide (LPS), and neuroendocrine gene expression and neuropeptide release determined. Both iPNEC and ePNEC models demonstrated similar baseline neuroendocrine characteristics and a stimuli-specific modulation of gene expression. Most notably, exposure to HDM but not Bergamot oil or LPS, leads to dose-dependent induction of the CGRP encoding gene, CALCB, and corresponding release of the neuropeptide. HDM-induced CALCB expression and CGRP release could be inhibited by a protease-activated receptor 1 (PAR1) antagonist or protease inhibitors and was mimicked by a PAR1 agonist. We have characterized a novel model of PNEC-enriched human airway epithelium and utilized this model to demonstrate a previously unrecognized role for human PNEC in mediating a direct neuroendocrine response to aeroallergen exposure.

Hormone regulation of corticotropin-releasing factor receptor 1 in the female mouse brain

Introduction: Corticotropin-releasing factor receptor 1 (CRFR1) is a key regulator of neuroendocrine and behavioral stress responses. Previous studies have demonstrated that CRFR1 in certain hypothalamic and preoptic brain areas is modified by chronic stress and during the postpartum period in female mice, although the potential hormonal contributors to these changes are unknown. Methods: This study focused on determining the contributions of hormones associated with stress and the maternal period (glucocorticoids, prolactin, estradiol/progesterone) on CRFR1 levels using a CRFR1-GFP reporter mouse line and immunohistochemistry. Results: Administration of dexamethasone, an agonist of the glucocorticoid receptor, elevated CRFR1 in the anteroventral periventricular nucleus (AVPV/PeN) and paraventricular hypothalamus (PVN) with no changes found in the medial preoptic area (MPOA) or arcuate nucleus. Treatment with prolactin for 5 days elevated CRFR1 levels in the MPOA with no changes in other regions. Finally, we utilized the hormone-simulated pseudopregnancy (HSP) paradigm to mimic changes in estradiol and progesterone across pregnancy and the early postpartum period. Female mice receiving HSP treatment, as well as mice receiving HSP treatment that then underwent 5 days of estrogen withdrawal (EW) showed alterations in CRFR1 relative to control groups that mirrored changes previously reported in postpartum mice. Specifically, CRFR1 levels increased in the AVPV/PeN and decreased in the MPOA and PVN, with no changes found in the arcuate nucleus. HSP- and EW-treated mice also showed decreases in tyrosine hydroxylase-expressing neurons in the AVPV/PeN. Discussion/Conclusion: Overall, these hormone-induced changes in stress-regulating CRFR1 neurons may impact behavioral and neuroendocrine stress responses.

Acute hyperglycemia is associated with intraventricular extension among patients with spontaneous intracerebral hemorrhage

ObjectiveAcute hyperglycemia following intracerebral hemorrhage (ICH) is associated with poor functional outcomes and may result from a neuroendocrine stress response. Given the proximity of neuroendocrine structures to the cerebral ventricles, we tested the hypothesis that intraventricular hemorrhage (IVH) is associated with hyperglycemia. Materials and methodsA post-hoc analysis of the ICH Deferoxamine (i-DEF) trial was conducted to determine predictors of IVH. Variables with significant differences (p < 0.1) in univariable tests between patients with and without IVH were entered into a logistic regression model along with age, sex, diabetes, hyperglycemia (admission glucose ≥140 mg/dL), and baseline intraparenchymal hemorrhage (IPH) volume. This model was then applied to an independent cohort of consecutive non-traumatic ICH patients admitted to a single referral center (2007 to 2018). ResultsAmong 294 patients in the i-DEF cohort with mean age 60 ± 12 years (IVH in 41 %), hyperglycemia (aOR 1.90, 95 % CI [1.06–3.38]), smoking history (aOR 1.90, 95 % CI [1.11–3.27]), and non-lobar ICH location (aOR 3.38, 95 % CI [1.49–7.69]) were independently associated with IVH. In the independent cohort consisting of 856 patients with mean age 71 ± 12 years (IVH in 37 %), hyperglycemia (aOR 2.23, 95 % CI [1.55–3.20]), non-lobar ICH location (aOR 2.50, 95 % CI [1.75–3.59]), and IPH volume (aOR 1.02, 95 % CI [1.01–1.02]) were associated with IVH. ConclusionsHyperglycemia is associated with IVH and may be a peripheral marker for the inflammatory response to hemorrhage within the ventricles. Further translational studies are needed to elucidate the pathophysiological basis for this phenomenon.

ECR Spotlight – Sandra Martins

ECR Spotlight is a series of interviews with early-career authors from a selection of papers published in Journal of Experimental Biology and aims to promote not only the diversity of early-career researchers (ECRs) working in experimental biology but also the huge variety of animals and physiological systems that are essential for the ‘comparative’ approach. Sandra Martins is an author on ‘ Immunological resilience of a temperate catshark to a simulated marine heat wave’, published in JEB. Sandra is a PhD student in the lab of Rui Rosa and Deborah Power from the University of Lisbon, Portugal, investigating how human activities impact shark health by uncovering the immune and neuroendocrine responses that help them adapt and thrive in a changing ocean.

Impact of adolescent high-fat diet and psychosocial stress on neuroendocrine stress responses and binge eating behavior in adult male Lewis rats.

Childhood obesity is a multifactorial disease affecting more than 160 million adolescents worldwide. Adolescent exposure to obesogenic environments, characterized by access to high-fat diets and stress, precipitates maladaptive eating habits in adulthood such as binge eating. Evidence suggests a strong association between Western-like high-saturated-fat (WD) food consumption and dysregulated hormone fluctuations. However, few studies have explored the long-term impact of adolescent WD and psychosocial stress on brain and behavior. This longitudinal study aimed to investigate the impact of adolescent exposure to an obesogenic diet on stress resiliency and increased susceptibility for binge-like eating behaviors. Adolescent male Lewis rats were given WD (41% fat; n=40) or control diet (CD, 16% fat; n=38) for 4 weeks before undergoing a stress paradigm of predator exposure and social instability (CDE, WDE, CDU, WDU; n=16/group). Subjects were provided intermittent WD access (24 h/week) to evaluate binge eating-like behavior in adulthood. Fecal corticosterone and testosterone were measured at four timepoints throughout adolescence and adulthood. WD rats exhibited increased body weight (p = 0.0217) and elevated testosterone in mid-adolescence (p=0.0312) and blunted stress-induced corticosterone response in mid-late adolescence (CDE:WDE, p=0.028). Adolescent hormone levels were negatively correlated with bingeing and explained the variability between adult rats expressing hyperphagic and hypophagic behaviors. These results demonstrate that exposure to WD in adolescence disrupts hormone fluctuations and stress responsivity, with effects persisting into adulthood. This underscores the importance of addressing obesogenic environments early to mitigate their lasting impact on hormone regulation and stress responsiveness.

Sex Differences in the Neuroendocrine Stress Response: A View from a CRH-Reporting Mouse Line.

Corticotropin-releasing hormone (CRH) neurons within the paraventricular hypothalamic nucleus (PVH) play a crucial role in initiating the neuroendocrine response to stress and are also pivotal in coordination of autonomic, metabolic, and behavioral stress reactions. Although the role of parvocellular CRHPVH neurons in activation of the hypothalamic-pituitary-adrenal (HPA) axis is well established, the distribution and function of CRH-expressing neurons across the whole central nervous system are less understood. Stress responses activate complex neural networks, which differ depending on the type of stressor and on the sex of the individual. Because of the technical difficulties of localizing CRH neurons throughout the rodent brain, several CRH reporter mouse lines have recently been developed. In this study, we used Crh-IRES-Cre;Ai9 reporter mice to examine whether CRH neurons are recruited in a stressor- or sex-specific manner, both within and outside the hypothalamus. In contrast to the clear sexual dimorphism of CRH-mRNA-expressing neurons, quantification of CRH-reporting, tdTomato-positive neurons in different stress-related brain areas revealed only subtle differences between male and female subjects. These results strongly imply that sex differences in CRH mRNA expression occur later in development under the influence of sex steroids and reflects the limitations of using genetic reporter constructs to reveal the current physiological/transcriptional status of a specific neuron population. Next, we compared the recruitment of stress-related, tdTomato-expressing (putative CRH) neurons in male and female Crh-IRES-Cre;Ai9 reporter mice that had been exposed to predator odor. In male mice, fox odor triggered more c-Fos in the CRH neurons of the paraventricular hypothalamic nucleus, central amygdala, and anterolateral bed nucleus of the stria terminalis compared to females. These results indicate that male mice are more sensitive to predator exposure due to a combination of hormonal, environmental, and behavioral factors.

Mitophagy Unveiled: Exploring the Nexus of Mitochondrial Health and Neuroendocrinopathy.

Mitochondria play a pivotal role in cellular metabolism, energy production, and apoptotic signaling, making mitophagy, the selective degradation of damaged mitochondria, crucial for mitochondrial health. Dysregulation of mitophagy has been implicated in various neuroendocrinopathies, yet the mechanisms linking these processes remain poorly understood. This review aims to explore the intersection between mitophagy and neuroendocrinopathy, addressing the critical gaps in knowledge regarding how mitochondrial dysfunction may contribute to the pathophysiology of neuroendocrine disorders. We conducted a comprehensive literature review of studies published on mitophagy and neuroendocrinopathies, focusing on data that elucidate the pathways involved and the clinical implications of mitochondrial health in neuroendocrine contexts. Our findings indicate that altered mitophagy may lead to the accumulation of dysfunctional mitochondria, contributing to neuroendocrine dysregulation. We present evidence linking impaired mitochondrial clearance to disease models of conditions such as metabolic syndrome, depression, and stress-related disorders, highlighting the potential for therapeutic interventions targeting mitophagy. While significant advances have been made in understanding mitochondrial biology, the direct interplay between mitophagy and neuroendocrinopathies remains underexplored. This review underscores the necessity for further research to elucidate these connections, which may offer novel insights into disease mechanisms and therapeutic strategies for treating maladaptive neuroendocrine responses.

Multimodal examination of daily stress rhythms in chronic Cannabis users.

Chronic cannabis users frequently report stress relief as their primary reason for use. The endocannabinoid system is involved in the neuroendocrine stress response, and diurnal cortisol rhythms may be disrupted in chronic cannabis users. The objectives were to determine whether cannabis users demonstrate disruptions in diurnal stress rhythms and examine the acute effects of cannabis on stress-related outcomes in cannabis users' natural environments. Eighty-two participants (39 cannabis users, 43 non-users) collected saliva samples to quantify cortisol concentrations and provided subjective stress ratings at 8 time points throughout the day. They wore a medical-grade wearable device for 24h that recorded physiological indicators of stress (heart rate variability, electrodermal activity). Cannabis users collected additional saliva samples before and after cannabis use to examine acute effects of cannabis use. Cannabis users exhibited significant dysregulations in diurnal cortisol rhythms, including a blunted cortisol awakening response, flattened diurnal cortisol slope, and elevated afternoon cortisol concentrations. There were no differences in diurnal heart rate variability or electrodermal activity except for elevated evening heart rate in cannabis users. Finally, there were significant decreases in cortisol, subjective stress, and electrodermal activity following acute cannabis use in cannabis users' natural environment. These results provide evidence of dysregulated diurnal cortisol rhythms in cannabis users that were related to later waking times and acute stress-relieving properties of cannabis use in naturalistic environments. Future research should examine the direction of the relationship between cannabis use and diurnal cortisol rhythms and potential implications for other psychological disorders.

The Influence of Regional Anesthesia on the Systemic Stress Response

Background: The systemic stress response to surgery is a complex physiological process characterized by neuroendocrine, sympathetic, and inflammatory activation. While necessary for survival, this response can lead to adverse outcomes such as hyperglycemia, immune suppression, cardiovascular complications, and delayed recovery. Regional anesthesia (RA) has been shown to modulate this stress response more effectively than general anesthesia (GA) by blocking nociceptive signaling and attenuating the release of stress mediators. Objectives: This review aims to elucidate how RA influences the systemic stress response, highlighting its clinical benefits in reducing postoperative pain, improving hemodynamic stability, minimizing inflammatory responses, and preserving immune function. Additionally, this review examines evidence from clinical trials supporting using RA to improve surgical outcomes, particularly in high-risk populations. Methods: A comprehensive narrative review of the literature was conducted to explore the physiological impact of RA on the systemic stress response and its associated clinical outcomes. Studies comparing RA to GA across various surgical procedures were evaluated, focusing on neuroendocrine modulation, sympathetic inhibition, inflammatory attenuation, and the implications for pain management, cardiovascular and pulmonary function, and immune preservation. Results: RA significantly attenuates the neuroendocrine response by reducing the release of cortisol and catecholamines, thereby improving hemodynamic stability and reducing myocardial oxygen consumption. RA also inhibits the sympathetic nervous system, leading to improved cardiovascular outcomes. Furthermore, RA mitigates the inflammatory response by reducing pro-inflammatory cytokine levels, reducing the risk of systemic inflammatory response syndrome (SIRS), sepsis, and pulmonary complications. Clinical studies and meta-analyses consistently demonstrate that RA reduces postoperative pain, opioid consumption, and the incidence of cardiovascular and pulmonary complications, particularly in elderly and high-risk patients. Conclusions: RA offers a significant advantage in modulating the systemic stress response to surgery, improving postoperative outcomes by reducing pain, enhancing cardiovascular stability, and preserving immune function. Its benefits are particularly pronounced in high-risk populations such as the elderly or those with pre-existing comorbidities. Given the growing evidence supporting its efficacy, RA should be considered a critical component of multimodal perioperative care strategies aimed at minimizing the systemic stress response and improving recovery. Future research should optimize RA techniques and identify patient-specific factors to enhance therapeutic benefits.

Is the Mannheim Multicomponent Stress Test a viable alternative to the Trier Social Stress Test?

BackgroundThe Trier Social Stress Test (TSST) is a widely used laboratory protocol to study acute stress reactivity, a hallmark of which is a meaningful increase in saliva cortisol (> 2.5 nmol/L) in most individuals, reflecting hypothalamic-pituitary-adrenal (HPA) axis activation. The Mannheim Multicomponent Stress Test (MMST) has potential as a low staff burden alternative to the TSST, with one study showing statistically significant increases in subjective stress, heart rate and saliva cortisol; however, uncertainty remains about the meaningfulness of these psychobiological responses. ObjectiveTo assess whether the MMST is a viable alternative to the TSST. MethodsUsing a between subjects design, 31 healthy adults were randomised to the standard TSST or the MMST using stratified block randomisation accounting for sex and trait anxiety. The standard TSST consisted of an anticipation phase, followed by a free speech and mental arithmetic task performed in front of a panel of trained actors. The MMST consisted of a computer based Paced Auditory Serial Addition Task (cognitive stressor) with additional motivational, emotional, and acoustic stressors in the presence of one unresponsive observer. ResultsGroup x time interactions showed that the MMST induced smaller psychobiological responses compared with the TSST (mixed model ANCOVA, P < 0.05). Post-hoc analyses revealed that the MMST induced a significant yet smaller state anxiety response (score range 20–80, MMST: 47 ± 12 vs. TSST: 57 ± 9; P < 0.01, Cohens d = 0.9) and peak heart rate response (MMST: 98 ± 17 vs. TSST: 110 ± 21 bpm; P < 0.05, Cohens d = 0.6) compared with the TSST. Despite observing stereotypical neuroendocrine responses to the TSST, the MMST did not increase saliva α-amylase or cortisol (Δ saliva cortisol, 0.1 ± 1.1 vs. TSST: 10.3 ± 12.8 nmol/L; between group difference P < 0.01, Cohens d = 1.1). Moreover, meaningful increases in saliva cortisol (> 2.5 nmol/L) were observed in 80% of participants after the TSST but in no participant after the MMST. ConclusionThe Mannheim Multicomponent Stress Test increased state anxiety and heart rate but not saliva cortisol. As such, the present results do not support the utility of the Mannheim Multicomponent Stress Test as a viable alternative to The Trier Social Stress Test.

Genome-Wide Association Study of Temporomandibular Disorder-Related Pain in Finnish Populations.

Temporomandibular disorders (TMD) are multifactorial musculoskeletal pain and dysfunctions in temporomandibular joints (TMJs) and masticatory muscles. Genetic factors play a role in TMD-related pain, but only a few genome-wide association studies (GWAS) have been conducted. The aim of this GWAS was to explore genetic factors associated with painful TMD in Finnish populations. Data from two epidemiological surveys, the Northern Finland Birth Cohort 1966 (NFBC1966) and the Health 2000 Survey in Finland, including altogether 468 cases and 6833 controls, were used. Case definition was based on pain on palpation of masticatory muscles and/or TMJs. GWASs of the whole data and stratified by sex were conducted from both cohorts using additive models, followed by meta-analysis of the two cohorts. Replications of the previously reported TMD risk loci (rs73460075, DMD; rs4794106, SGCA; rs73271865, SP4; rs60249166, RXP2; rs1531554, BAHCCI; rs5862730, OTUD4/SMAD1; rs10092633, SFRP1; rs34612513, SOX14/CLDN18; rs878962, TSPAN9) were also investigated. Four genome-wide significant loci were found in sex-stratified analysis of NFBC1966, including associations at three loci in males (rs1023114, PRIM2, p = 5 × 10-9; rs4244867, ALG10, p = 3 × 10-8; rs79841648, ADCYAP1, p = 4 × 10-9) and one locus in females (rs148476652, DNER, p = 4 × 10-9). However, the results could not be replicated in the Health 2000 Survey or in the meta-analysis of these two cohorts. The previous TMD GWAS associations did not replicate in our data either. Several TMD pain-associated variants were found in sex-stratified analysis of NFBC1966, suggesting the role of neuroendocrine stress responses and central nervous system. These findings need to be confirmed in future studies.

PACAP regulates neuroendocrine and behavioral stress responses via CRF-containing neurons of the rat hypothalamic paraventricular nucleus

AbstractPituitary adenylate cyclase-activating polypeptide (PACAP) is a neuropeptide widely distributed in the brain including the hypothalamic paraventricular nucleus (PVN) implying a regulatory role in stress function. Recent evidence indicates that one of the main targets of PACAP within the PVN are corticotropin-releasing factor (CRF) neurons, which are key regulators of the hypothalamic-pituitary-adrenal (HPA) axis. However, the neural correlates that mediate PACAP effects on stress function are not fully understood. In the present study, we characterized the neuronal mechanism by which PACAP regulates neuroendocrine and behavioral stress responses in rats. We found that intracerebroventricular administration of PACAP increased the swim stress-induced c-Fos expression in distinct brain areas of the stress and anxiety circuitry including the parvocellular part of the PVN and changed behavioral stress coping during forced swimming to a more passive coping style (i.e., indicated by increased floating and reduced struggling behavior). Subsequently, PACAP administration directly into the PVN mimicked these behavioral effects and potentiated the plasma ACTH response to forced swim stress suggesting an excitatory role of PACAP on HPA stress axis reactivity. In addition, immunohistochemical analysis revealed a considerable portion of stress-activated CRF neurons in the medial parvocellular part of the PVN that co-localized PAC1 receptors suggesting that PACAP-induced effects on stress function are likely mediated directly by activation of CRF neurons in the PVN. Thus, these findings suggest that the PVN may represent one of the key areas where PACAP regulates the neuroendocrine and behavioral stress response.

Behavioural and neuroendocrine responses in alpacas (Vicugna pacos) to the shearing procedure

Shearing is a necessary procedure which can cause stress in alpacas. Reactions to stressful situations can include behavioural and physiological changes in an animal's effort to maintain homeostasis. There has been limited investigation on stress mechanisms in terms of behaviour and physiological changes in alpacas, with a focus on heart rate and cortisol in faeces and saliva. This study aimed to determine alpaca behaviour and the concentrations of selected neuroendocrine indicators (cortisol, dopamine, noradrenaline, serotonin, thyroxine) at: pre-shearing (3 days before shearing), on the day of shearing and post-shearing (5 and 10 days after shearing). This study examined 20 alpacas. Compared with the behaviour observed before shearing, shearing performed by the standing method caused only an acute behavioural stress response on the day of shearing and no change 5 and 10 days after shearing. Higher stress activity during shearing was not strongly correlated with the intensity of their everyday reactions to the environment. In contrast, noradrenaline increased and thyroxine decreased after the shearing procedure, changes indicative of mid-term stress symptoms. There were significant correlations between some behavioural and neuroendocrine indicators, confirming the involvement of cortisol, serotonin and noradrenaline in the mechanisms of alpaca behavioural regulation.

Timing matters in stress appraisal: The relationship between retrospective appraisal and stress responses

BackgroundAlthough psychosocial stressors are known to impact task performance and trigger neuroendocrine responses, the dynamic nature of the stress appraisal process is often neglected in research. GoalThis study aims to explore whether self-reported appraisals at various time points can accurately represent an individual’s behavioral and physiological stress responses. MethodsA total of 137 participants were recruited to induce individual stress states using the Trier Social Stress Test (TSST). Self-reported appraisals were measured both before (anticipatory appraisal) and after the stressor (retrospective appraisal) to capture the dynamic process. Concurrently, participants' cortisol responses and task performances were documented. ResultsFindings indicate that anticipatory appraisal does not significantly reflect task performance. In contrast, retrospective appraisal is strongly associated with the performance of corresponding tasks. Regarding cortisol levels, significantly negative results of multiple regression analysis revealed that the retrospective appraisal of the speech task is the sole variable to represent the cortisol response under stress. DiscussionThe results highlight that retrospective appraisals could represent individuals’ behavioral and physiological responses to stressors more accurately than anticipatory appraisals. These findings provide empirical evidence for choosing the appropriate timing to acquire accurate self-reported appraisals and also help to build a mapping relationship between self-reported, behavioral, and physiological data.

Sex-specific and developmental effects of early life adversity on stress reactivity are rescued by postnatal knockdown of 5-HT1A autoreceptors.

Early Life Adversity (ELA) predisposes to stress hypersensitivity in adulthood, but neurobiological mechanisms that protect from the enduring effects of ELA are poorly understood. Serotonin 1A (5HT1A) autoreceptors in the raphé nuclei regulate adult stress vulnerability, but whether 5HT1A could be targeted to prevent ELA effects on susceptibility to future stressors is unknown. Here, we exposed mice with postnatal knockdown of 5HT1A autoreceptors to the limited bedding and nesting model of ELA from postnatal day (P)3-10 and tested behavioral, neuroendocrine, neurogenic, and neuroinflammatory responses to an acute swim stress in male and female mice in adolescence (P35) and in adulthood (P56). In females, ELA decreased raphé 5HT neuron activity in adulthood and increased passive coping with the acute swim stress, corticosterone levels, neuronal activity, and corticotropin-releasing factor (CRF) levels in the paraventricular nucleus (PVN) of the hypothalamus. ELA also reduced neurogenesis in the ventral dentate gyrus (vDG) of the hippocampus, an important mediator of individual differences in stress susceptibility, and increased microglia activation in the PVN and vDG. These effects of ELA were specific to females and manifested predominantly in adulthood, but not earlier on in adolescence. Postnatal knockdown of 5HT1A autoreceptors prevented these effects of ELA on 5HT neuron activity, stress reactivity, neurogenesis, and neuroinflammation in adult female mice. Our findings demonstrate that ELA induces long-lasting and sex-specific impairments in the serotonin system, stress reactivity, and vDG function, and identify 5HT1A autoreceptors as potential targets to prevent these enduring effects of ELA.

8611 Maternal Immune Activation During Mid-Gestation Leads to Impaired Neuroendocrine Stress Response and Blood-Brain Barrier Integrity in a Sex-Dependent Manner

Abstract Disclosure: J.A. Sheng: None. S.A. Tobet: None. Background and Hypothesis: Maternal immune activation (MIA) has been associated with increased risk for neuropsychiatric diseases in the offspring. Recently, our lab demonstrated toll-like receptor 7 (TLR7) activation during impaired stress-related behaviors (anxiety-, anhedonia-, social-like) (Sheng et al., 2023, Front. Neurosci.). Stress-related behaviors are regulated by neurons in the paraventricular nucleus of the hypothalamus (PVN), an anatomic region involved in the hypothalamic-pituitary-adrenal (HPA) stress response. We hypothesize immune system activation by TLR7 during mid-gestation impairs PVN neuroendocrine stress response and brain vasculature. Methods: Timed-pregnant female mice were administered the TLR7 agonist Resiquimod (RQ) or vehicle saline on embryonic day 12.5. Adult offspring underwent 20-minute acute restraint stress with 80-minutes of recovery to examine plasma corticosterone (ELISA assay) as an indicator of HPA function. Mice were transcardially perfused with fluorescein isothiocyanate (FITC; 100mg/mL) to visualize blood vessel integrity (FITC leakage; Frahm &amp; Tobet, 2015, Brain Struct. Funct.). Sections through the PVN of offspring were also immunolabeled for Glial Fibrillary Acidic Protein (GFAP; astrocytic end feet) and IBA-1 (microglia). Only data from brains of offspring that did not undergo restraint stress are presented for baseline changes in blood-brain barrier components by MIA. Results: Plasma corticosterone was elevated in RQ-offspring (males p&amp;lt;0.0001, females p&amp;lt;0.01 vs. VEH) following stressor and recovery, suggesting delayed negative feedback to the HPA axis. Blood-brain barrier integrity diminished in RQ-adult offspring who showed greater FITC leakage in the PVN as indicated by an increase in the ratio of extravascular to intravascular FITC (males p&amp;lt;0.001, females p&amp;lt;0.01). GFAP+ coverage of FITC-labeled vessels was greater in the PVN only in RQ males compared to VEH (p&amp;lt;0.001). Microglia were examined in relation to vasculature, and data show more IBA-1+ cells in the PVN with close proximity (within 2µm) to blood vessels after maternal injection of RQ in females compared to VEH (p&amp;lt;0.05). In RQ-adult males, the average size of IBA-1+ cells in the PVN were greater than VEH counterparts (p&amp;lt;0.05), but number and proximity of IBA-1+ cells to blood vessels were unchanged. No changes in these measures were seen in control brain regions. Conclusions: This study provides support for sex-dependent influences of fetal immune antecedents on brain development and adult neuroendocrine function that could indicate a locus for increased susceptibility to adult neuropsychiatric disorders. While the current experiments found significant post-pubertal changes selectively in adult PVN, ongoing studies are examining whether these effects are evident prior to puberty. Supported by ORWH-NIMH U54 SCORE-MH118919. Presentation: 6/1/2024

The post-Cartesian dilemma: Reuniting the mind and body through psychoneuroimmunology

While today, it might seem absurd to hear anyone claim that stress does not alter all aspects of the human experience, including behavioral, cognitive, affective, and physiological processes. Dr. Janice Kiecolt-Glaser started her career at a time when stress was primarily considered a neuroendocrine response with cardiovascular repercussions. She was part of a small group of innovative scientists who began to push the boundaries of stress research – many contemporary immunologists and virologist disputed their early results in 1980s and 90s – and, yet, they persevered by connecting psychological stress to altered immune function via stress-related neuroendocrine changes. As a clinical psychologist, she focused mainly on human research studies to advance the field of psychoneuroimmunology throughout her career. Her research demonstrates how adversity and psychosocial aspects of human experience alter physiological functioning, primarily immune, and health or, in other words, the embodiment of our lived experiences. This short review is a contextualized synthesis of Dr. Kiecolt-Glaser’s key contributions to the fields of psychoneuroimmunology and health psychology and her influence on my present day thinking and research approaches, as well as potential steps forward in our post-pandemic world.

Sex-specific behavioral, cardiac, and neuroendocrine responses to repeated witness social stress in adult rats

In humans, sex disparities exist in the prevalence of social stress-related disorders, yet our understanding of the predisposing factors and underlying mechanisms is still elusive. Also at the preclinical level, the investigation of sex differences in social stress responses is limited. In this study, adult male and female wild-type Groningen rats were repeatedly exposed to witness social defeat stress (WS) to assess sex-specific behavioral, neuroendocrine, and cardiac responses to the same social stress paradigm. Male and female rats bore witness to an aggressive social defeat episode between two males for nine consecutive days or were exposed to a control (CTR) procedure. Stress-related parameters were assessed in correspondence to the first and last WS/CTR exposure and also during subsequent exposure to the stress context alone in the absence of social defeat. During WS, rats of both sexes displayed larger amounts of burying behavior and smaller amounts of rearing and grooming behaviors, but with a greater extent in female witnesses. Cardiac autonomic responses to WS were similar between the sexes, yet only females displayed higher plasma corticosterone levels after the first WS exposure compared to CTRs, and had a larger corticosterone increase than male witnesses upon repeated WS. Exposure to the stress context alone (i.e., without the presence of the aggressive resident rat) elicited greater amount of burying behavior and more pronounced and persistent tachycardic responses in females than males with a history of WS. Our findings suggest sex-disparities in the response of adult rats to WS at multiple behavioral, cardiac, and neuroendocrine levels, highlighting the utility of this social stress paradigm for investigating predisposing factors and pathophysiological mechanisms underlying sex-specific vulnerabilities to stress-related pathologies.