Repeated Stress Research Articles

6579 Neuroendocrine Signatures of Social-Defeated Stress Expressed by Adrenal Hormones in Mice

Abstract Disclosure: J. Noh: None. J. Choi: None. S. Myung: None. M. Kim: None. M. Choi: None. While psychological stress is one of the prevalent contributors to depression, the precise role of metabolic phenotypes in the development of depression remains elusive. Abnormality in hypothalamus-pituitary-adrenal (HPA) axis is a classical feature of depression. Here, an animal model of social defeat stress (SDS) was established with five-week-old C57BL/6J mice to repeated episodes of social defeat for a period of 10 days, facilitated by an aggressive CD-1 mouse. Liquid chromatography-mass spectrometry-based profiling of 29 adrenocortical steroids and 6 medullary amines was employed for serum samples collected at 3, 5, 7, and 10 days during the modeling from both control (n = 28) and SDS (n = 32) group. In response to initial stress, corticosterone (B) and its two precursors were significantly increased (p < 0.03 for all) during 3 days, while 18-hydroxyB was remarkably elevated (p < 0.003 for 3 days and p < 0.005) in SDS mice. In contrast, dopamine (p < 0.03) and metanephrine (p < 0.008) were significantly increased during 5 days in SDS mice, while remarkably higher levels of norepinephrine were also observed during 7 days (p < 0.01). The SDS mice showed the increased levels of normetanephrine for all days of repeated stress exposure (p < 0.002 for all, except 10 days of p < 0.02). In this study, the HPA regulated negative feedback in short period, whereas sympathetic nervous system was continuously stimulated during repeated stress exposure. The present study may provide insight into the neuroendocrine effects of social stress on allostatic overload. Presentation: 6/2/2024

Unpredictable Repeated Stress in Rainbow Trout (Oncorhynchus mykiss) Shifted the Immune Response against a Fish Parasite.

Farmed fish are regularly subjected to various stressors due to farming practices, and their effect in the context of a disease outbreak is uncertain. This research evaluated the effects of unpredictable repeated stress in rainbow trout challenged with the ciliate Ichthyophthirius multifiliis, known to cause white spot disease in freshwater fish. Before and after the pathogen exposure, fish were handled with a random rotation of three procedures. At 7 days post-infection (dpi), the parasite burden was evaluated in fish and in the tank's water, and the local and systemic immune responses were investigated in the gill and spleen, respectively. The fish mortality was recorded until 12 dpi, when all the fish from the infected groups died. There was no statistical difference in parasite burden (fish and tank's water) and infection severity between the two infected fish groups. The immune gene expression analysis suggested a differential immune response between the gill and the spleen. In gills, a T helper cell type 2 immune response was initiated, whereas in spleen, a T helper cell type 1 immune response was observed. The stress has induced mainly upregulations of immune genes in the gill (cat-1, hep, il-10) and downregulations in the spleen (il-2, il-4/13a, il-8). Our results suggested that the unpredictable repeated stress protocol employed did not impair the fish immune system.

FT-IR Analysis Results of Rolling and Temperature Effects on Flexible Substrate

Abstract This research investigates the complexities of molecular structural analysis applied to film substrates post the rolling process, concentrating specifically on characterizing flexible substrate materials, particularly polyimide (PI) film. By deliberately adjusting the number of rolling cycles and temperature parameters, a meticulous series of scratch tests was conducted. Following this, comprehensive sample analyses were carried out employing Fourier Transform Infrared (FT-IR) spectroscopy, enabling a thorough exploration of the molecular composition and structural integrity of the substrates. Our experimental findings confirm that molecules with weaker bonds tend to dissociate under physical stresses like rolling. While the dissociation of bonds does not strictly correlate proportionally with the frequency of stress application, a weakening of bonds is observed, particularly after repeated stress applications, indicating the susceptibility of molecular bonds to external stress.

Repeated stress to the skin amplifies neutrophil infiltration in a keratin 17- and PKCα-dependent manner.

Neutrophils are the first immune cells to reach inflamed sites and contribute to the pathogenesis of chronic inflammatory skin diseases. Yet, little is known about the pattern of neutrophil infiltration in inflamed skin in vivo and the mechanisms mediating their recruitment. Here, we provide insight into the dynamics of neutrophil infiltration in skin in response to acute or repeated inflammatory stress, highlighting a novel keratinocyte- and keratin 17 (K17)-dependent mechanism that regulates neutrophil recruitment to inflamed skin. We used the phorbol ester TPA and UVB, alone or in combination, to induce sterile inflammation in mouse skin. A single TPA treatment results in a neutrophil influx in the dermis that peaks at 12 h and resolves within 24 h. A subsequent TPA treatment or a UVB challenge, when applied 24 h but not 48 h later, accelerates, amplifies, and prolongs neutrophil infiltration. This transient amplification response (TAR) is mediated by local signals in inflamed skin, can be recapitulated in ex vivo culture, and involves the K17-dependent sustainment of protein kinase Cα (PKCα) activity and release of chemoattractants by stressed keratinocytes. K17 binds RACK1, a scaffold protein essential for PKCα activity. The N-terminal head domain of K17 is crucial for its association with RACK1 and regulation of PKCα activity. Analysis of RNAseq data reveals a signature consistent with TAR and PKCα activation in inflammatory skin diseases. These findings uncover a novel, keratin-dependent mechanism that amplifies neutrophil recruitment in skin under stress, with direct implications for inflammatory skin disorders.

Glucocorticoid signaling mediates stress-induced migraine-like behaviors in a preclinical mouse model.

Stress is one of the most common precipitating factors in migraine and is identified as a trigger in nearly 70% of patients. Responses to stress include release of glucocorticoids as an adaptive mechanism, but this may also contribute to migraine attacks. Here, we investigated the role of glucocorticoids on stress-induced migraine-like behaviors. We have shown previously that repeated stress in mice evokes migraine-like behavioral responses and priming to a nitric oxide donor. Metyrapone, mifepristone, and corticosterone (CORT) were used to investigate whether CORT contributes to the stress-induced effects. Facial mechanical hypersensitivity was evaluated by von Frey testing and grimace scoring assessed the presence of non-evoked pain. We also measured serum CORT levels in control, stress, and daily CORT injected groups of both male and female mice. Metyrapone blocked stress-induced responses and priming in male and female mice. However, repeated CORT injections in the absence of stress only led to migraine-like behaviors in females. Both female and male mice showed similar patterns of serum CORT in response to stress or exogenous administration. Finally, administration of mifepristone, the glucocorticoid receptor antagonist, prior to each stress session blocked stress-induced behavioral responses in male and female mice. These findings demonstrate that while CORT synthesis and receptor activation is necessary for the behavioral responses triggered by repeated stress, it is only sufficient in females. Better understanding of how glucocorticoids contribute to migraine may lead to new therapeutic opportunities.

Sex-specific role of high-fat diet and stress on behavior, energy metabolism, and the ventromedial hypothalamus

BackgroundScientific evidence highlights the influence of biological sex on the relationship between stress and metabolic dysfunctions. However, there is limited understanding of how diet and stress concurrently contribute to metabolic dysregulation in both males and females. Our study aimed to investigate the combined effects of high-fat diet (HFD) induced obesity and repeated stress on fear-related behaviors, metabolic, immune, and hypothalamic outcomes in male and female mice.MethodsTo investigate this, we used a highly reliable rodent behavioral model that faithfully recapitulates key aspects of post-traumatic stress disorder (PTSD)-like fear. We subjected mice to footshock stressor followed by a weekly singular footshock stressor or no stressor for 14 weeks while on either an HFD or chow diet. At weeks 10 and 14 we conducted glucose tolerance and insulin sensitivity measurements. Additionally, we placed the mice in metabolic chambers to perform indirect calorimetric measurements. Finally, we collected brain and peripheral tissues for cellular analysis.ResultsWe observed that HFD-induced obesity disrupted fear memory extinction, increased glucose intolerance, and affected energy expenditure specifically in male mice. Conversely, female mice on HFD exhibited reduced respiratory exchange ratio (RER), and a significant defect in glucose tolerance only when subjected to repeated stress. Furthermore, the combination of repeated stress and HFD led to sex-specific alterations in proinflammatory markers and hematopoietic stem cells across various peripheral metabolic tissues. Single-nuclei RNA sequencing (snRNAseq) analysis of the ventromedial hypothalamus (VMH) revealed microglial activation in female mice on HFD, while male mice on HFD exhibited astrocytic activation under repeated stress.ConclusionsOverall, our findings provide insights into complex interplay between repeated stress, high-fat diet regimen, and their cumulative effects on health, including their potential contribution to the development of PTSD-like stress and metabolic dysfunctions, emphasizing the need for further research to fully understand these interconnected pathways and their implications for health.

Cortisol dynamics and GR-dependent feedback regulation in zebrafish larvae exposed to repeated stress.

Zebrafish larvae show a rapid increase in cortisol in response to acute stressors, followed by a decline. While these responses are documented, both the duration of the refractory period to repeated stressors and the role of glucocorticoid receptors (GR) in specific phases of the glucocorticoid negative feedback are still being clarified. We explored these questions using water vortices as stressors, combined with GR blockage and measurements of whole-body cortisol in zebrafish larvae subjected to single and repeated stress protocols. Cortisol levels were elevated 10 min after stress onset and returned to baseline within 30-40 min, depending on the stressor strength. In response to homotypic stress, cortisol levels rose above baseline if the second stressor occurred 60 or 120 min after the first, but not with a 30-min interval. This suggests a rapid cortisol-mediated feedback loop with a refractory period of at least 30 min. Treatment with a GR blocker delayed the return to baseline and suppressed the refractory period, indicating GR-dependent early-phase feedback regulation. These findings are consistent with mammalian models and provide a framework for further analyses of early-life cortisol responses and feedback in zebrafish larvae, ideal for non-invasive imaging and high-throughput screening.

Levels of Corticosterone and Glucose in Blood of Rats under Conditions of Chronic Unpredictable Stress of Different Duration

INTRODUCTION: Mammals are almost constantly exposed to a variety of stressors. The changes in the concentration of corticosterone and the level of glucose in blood of animals under such conditions seems relevant for understanding the influence of repeated stress effects on endocrine and metabolic processes. AIM: To study the concentrations of corticosterone and glucose in blood of rats in different time periods of prolonged low-intensity unpredictable stress. MATERIALS AND METHODS: Experiments were carried out on 42 male Wistar rats. Individuals of the experimental groups were subjected to 7-day cycles of alternating stressors using a modified model of chronic unpredictable mild stress with presentation of different stressors. The concentration of corticosterone and glucose in blood was determined at 1, 2, 3 and 4 weeks of observation. RESULTS: A pronounced decrease in corticosterone levels was found in rats at 1 week of stress exposure, followed by a slow recovery by the end of 4th week. Blood glucose level increased at 2 weeks of exposure. CONCLUSION: The data obtained illustrate the specificity of changes in the levels of glucose and corticosterone in the blood of mammals in different time periods of chronic stress. These changes characterize the dysregulation of the integrative physiological systems in relatively early periods of chronic stress with the subsequent development of adaptation in the later stages of repeated stress exposures.

Repeated stress triggers seeking of a starvation-like state in anxiety-prone female mice.

Elevated anxiety often precedes anorexia nervosa and persists after weight restoration. Patients with anorexia nervosa often describe self-starvation as pleasant, potentially because food restriction can be anxiolytic. Here, we tested whether repeated stress can cause animals to prefer a starvation-like state. We developed a virtual reality place preference paradigm in which head-fixed mice can voluntarily seek a starvation-like state induced by optogenetic stimulation of hypothalamic agouti-related peptide (AgRP) neurons. Prior to stress exposure, males but not females showed a mild aversion to AgRP stimulation. Strikingly, following multiple days of stress, a subset of females developed a strong preference for AgRP stimulation that was predicted by high baseline anxiety. Such stress-induced changes in preference were reflected in changes in facial expressions during AgRP stimulation. Our study suggests that stress may cause females predisposed to anxiety to seek a starvation state and provides a powerful experimental framework for investigating the underlying neural mechanisms.

Repeated exposure to multiple concurrent stressors alters visual processing in the adult posterior parietal cortex

Chronic stress is well known to erode cognitive functions. Yet, our understanding of how repeated stress exposure impacts one of the fundamental bases of cognition: sensory processing, remains limited. The posterior parietal cortex (PPC) is a high order visual region, known for its role in visually guided decision making, multimodal integration, attention, and working memory. Here, we used functional measures to determine how repeated exposure to multiple concurrent stressors (RMS) affects sensory processing in the PPC in adult male mice. A longitudinal experimental design, repeatedly surveying the same population of neurons using in vivo two-photon imaging, revealed that RMS disrupts the balanced turnover of visually responsive cells in layer 2/3 of the PPC. Across the population, RMS-induced changes in visual responsiveness followed a bimodal distribution suggesting idiosyncratic stress effects. In cells that maintained their responsiveness across recording sessions, we found that stress reduced visual response magnitudes and feature selectivity. While we did not observe stress-induced elimination of excitatory synapses, noise correlation statistics indicated that RMS altered visual input to the neuronal population. The impact of RMS was restricted to visually evoked responses and was not evident in neuronal activity associated with locomotion onset. Together, our results indicate that despite no apparent synaptic reorganization, stress exposure in adulthood can disrupt sensory processing in the PPC, with the effects showing remarkable individual variation.

Level of Cytokines and C3 Complement in the Blood of Rats under Conditions of Chronic Unpredictable Stress of Different Durations.

The parameters of the cytokine profile and functional activity of the complement system in the blood of rats were studied during different time periods of chronic unpredictable mild stress using a model of sequentially alternating low-intensity stress effects for 1, 2, 3, and 4 weeks. In the dynamics of observation, a general tendency towards multidirectional fluctuations in the concentration of cytokines was revealed: an increase in IL-10, but a decrease in IL-4 in comparison with the control. Statistically significant changes in the level of IL-10 were noted after 2, 3, and 4 weeks, IL-4 - after 2 and 4 weeks of stress loads. The percentage of lysis of the C3 component in rats gradually increased by the 2nd week of chronic stress, but then decreased and practically did not differ from the control values (intact animals) by the end of the study. These results illustrate the specificity of changes in the indicators of the C component of the complement system and the cytokine profile of the blood reflecting activity of the cellular and humoral components of the immune response in rats exposed to repeated stress factors of different origins and duration.

Antidepressant Effect of Enzymatic Porcine Placenta Hydrolysate in Repeated Immobilization Stress-Induced Ovariectomized Female Mice.

When postmenopausal women are under stress conditions, this exacerbates mood disorders and issues with neuroimmune systems. The porcine placenta is known to relieve menopausal depression in clinical trials, but its underlying mechanisms for depression and anti-inflammatory functions remain poorly defined. The present study was designed to examine the anti-inflammatory effects of enzymatic porcine placenta hydrolysate (EPPH) on LPS-induced levels of nitric oxide (NO), prostaglandin E2 (PGE2), corticosterone (CORT), and pro-inflammatory cytokine interleukin-1 beta (IL-1β) in RAW 264.7 macrophage cells. In addition, the neurite outgrowth of PC12 cells was evaluated to examine the effects of EPPH on neurite growth. To mimic the symptoms of women with menopause-related depression, a stressed ovariectomized (OVX) female mouse model was used to evaluate the antidepressant effects of EPPH. The female mice were randomly divided into five groups: (1) the sham-operated (Sham) group, (2) the OVX + repeated stress + saline-treated (OVX + ST) group, (3) the OVX + repeated stress + estradiol (0.2 mg/kg)-treated (positive control) group, (4) the OVX + repeated stress + EPPH (300 mg/kg)-treated (300) group, and (5) the OVX + repeated stress + EPPH (1500 mg/kg)-treated (1500) group. Female mice were OVX and repeatedly immobilization-stressed for 2 weeks (2 h/day). A tail suspension test was conducted on the 13th day, followed by the forced swimming test on the 14th day to assess the antidepressant effects of EPPH. After the behavioral tests, the levels of CORT, PGE2, and IL-1β were evaluated. In addition, c-Fos expression in the paraventricular nucleus (PVN) was evaluated using immunohistochemistry. The concentrations of NO, PGE2, and IL-1β stimulated by LPS were significantly reduced via the addition of EPPH to RAW 264.7 cells. EPPH significantly promoted neurite outgrowth in PC12 cells compared to that of the controls. In the tail suspension test, the duration of immobility was reduced in mice treated with EPPH 1500 compared to the OVX + ST group. The EPPH 1500 group had significantly decreased levels of c-Fos-positive neurons in the PVN and reduced levels of CORT and IL-1β in the serum of the Sham group. These results suggested that the high dose of EPPH administration induced the antidepressant-like effect in the ovariectomized mice with repeated stress via downregulating the levels of CORT, IL-1β, and PGE2 in the serum through reducing the expression of c-Fos in the PVN regions.

Fatigue behavior of 4D printed materials: a review

Abstract4D printing presents a new direction in additive manufacturing through the incorporation of the time dimension into objects, thereby empowering them to modify their shape, properties, or functioning in stimulus to external influences. It is critical to investigate the fatigue behavior of these materials to comprehend their durability and reliability in the context of repeated stress or environmental changes. However, there has been limited effort to study this phenomenon. The purpose of this literature review is to consolidate the current understanding of the fatigue properties of 4D printed materials and identify areas where research is lacking. The impact of this work is to establish a foundation through a literature review for advancements in material science and manufacturing research that can improve the understanding of the fatigue behavior of 4D printed materials.

Static and Temporal Dynamic in Functional Connectivity of Large-scale Brain Networks During Acute Stress Regulate Stress Resilience Differently: The Promotion Role of Trait Resilience

Stress resilience has been largely regarded as a process in which individuals actively cope with and recover from stress. Over the past decade, the emergence of large-scale brain networks has provided a new perspective for the study of the neural mechanisms of stress. However, the role of inter-network functional-connectivity (FC) and its temporal fluctuations in stress resilience is still unclear. To bridge this knowledge gap, seventy-seven participants (age, 17–22 years, 37 women) were recruited for a ScanSTRESS brain imaging study. A static perspective was initially adopted, using changes in FC that obtained from stress vs. control condition during the entire stress induction phase as a static indicator. Further, changes in FC between different stress runs were analyzed as an index of temporal dynamics. Stress resilience was gauged using salivary cortisol levels, while trait resilience was measured via behavioral-activation-system (BAS) sensitivity. Results found that, for the static index, enhanced FC between the salience-network (SN), default-mode-network (DMN) and limbic-network (LBN) during acute stress could negatively signal stress resilience. For the temporal dynamics index, FC among the dorsal-attention-network (DAN), central-executive-network (CEN) and visual-network (VN) decreased significantly during repeated stress induction. Moreover, the decline of FC positively signaled stress resilience, and this relationship only exist in people with high BAS. The current research elucidates the intricate neural underpinnings of stress resilience, offering insights into the adaptive mechanisms underlying effective stress responses.

Adaptation to priming drought at six-leaf stage relieves maize yield loss to individual and combined drought and heat stressors around flowering

The frequency and magnitude of drought and heat events are predicted to increase, exerting adverse effects on maize yield. Repeated stress events may lead to critical stage or process shifts in maize yield response, but few studies document such shifts. In this experiment, maize plants were exposed to drought at the six-leaf period (V6) to investigate the priming effects on maize yield formation under control (CK), drought stress (DS), heat stress (HS), and combined drought and heat stress (DHS) occurring around flowering (AF). The stressors was significantly reduced maize yield by 10.0%–41.4% compared with T1 (V6CK+AFCK), with the exception of the T5 (V6DS+AFCK) treatment. Fortunately, compared with T1 (V6CK+AFCK), T2 (V6CK+AFDS), T3 (V6CK+AFHS), and T4 (V6CK+AFDHS) treatments around flowering, exposure to drought at V6 improved yield by 6.4%, 11.1%, 2.6%, and 33.4%, respectively. The increased yield in stressors around flowering was attributed to the enhancement of kernel numbers (KNS) and kernel weight (KW). However, KNS and KW showed variable responses to treatments. Drought exposure at V6 relieved KNS loss without stressors around flowering, as the fertilized florets increased by 2.7%. The KNS loss in DS and DHS treatment around flowering was reversed via seed setting, increased by 6.0% and 7.4%, resulting from strengthened sugar-starch conversion. Furthermore, the reduced KW in HS and DHS treatment around flowering was improved due to increased starch synthesis ability during kernel filling. Consequently, drought priming at the V6 stage increased seed setting, sugar-starch conversion, and starch synthesis ability, improving KNS and KW, offering a method to relieve yield loss under stressors around flowering.

Keratin 17- and PKCα-dependent amplification of neutrophil influx after repeated stress to skin

Abstract Neutrophils contribute to the pathogenesis of chronic inflammatory skin diseases. Little is known about the source and identity of the signals mediating their recruitment in inflamed skin. We used the phorbol ester TPA and UVB, alone or in combination, to induce sterile inflammation in mouse skin and assess whether keratinocyte-derived signals impact neutrophil recruitment. A single TPA treatment results in a neutrophil influx in the dermis that peaks at 12h and resolves within 24h. A second TPA treatment or a UVB challenge, when applied at 24h but not 48h later, accelerates, amplifies, and prolongs neutrophil infiltration. This transient amplification response (TAR) is mediated by local signals in inflamed skin, can be recapitulated in ex vivo culture, and involves the K17-dependent sustainment of Protein Kinase C α (PKCα) activity and release of neutrophil chemoattractants by stressed keratinocytes. We show that K17 binds RACK1, an essential scaffolding protein for PKCα activity. Analyses of RNAseq data reveal the presence of a transcriptomic signature consistent with TAR and PKCα activation in chronic inflammatory skin diseases including psoriasis, hidradenitis suppurativa, and atopic dermatitis. These findings uncover a novel, transient, and keratin-dependent mechanism that amplifies neutrophil recruitment to the skin under stress, with direct implications for inflammatory skin disorders.

Effects of oral administration of ondansetron, a 5-HT3 receptor antagonist, on anxiety-related behaviors and colonic hypercontractility in repeated stress-induced mice

PurposeChronic psychological stress develops and exacerbates irritable bowel syndrome (IBS). 5-hydroxytryptamine (5-HT) via activation of intestinal 5-HT3 receptors involves impairment of intestinal functions. This study aimed to investigate the effects of ondansetron, a 5-HT3 receptor antagonist, on locomotor activity, anxiety-related behaviors, and colonic functions in repeated water avoidance stress. Materials and methodsFood intake and fecal pellet output (FPO) of sham stress (SS), water avoidance stress (WS), and water avoidance stress with oral administration of ondansetron (1 mg/kg BW) (WA) groups were monitored along the water avoidance stress protocol for 10 consecutive days. On day 11, locomotor activity and anxiety-related behaviors were determined using an open field test. Contractile properties of colonic tissues in response to KCl and a cumulative dose of carbachol (CCh) were determined using in vitro organ bath technique. ResultsFPO was significantly increased in the WS group after 7 days of water avoidance stress, which was reversed in WA group. WS group decreased unsupported rearing behavior compared to WS group, which was not altered in the WA group. The colon of the WS group had a higher tonic contraction in response to CCh than the SS and WA groups, which was reversed with ondansetron pre-incubation. ConclusionsOral administration of ondansetron prevented increased FPO but did not affect anxiety-related behavior in repeated stress model. Colonic hypercontractility in the stressed mice was related to increased responses to cholinergic-induced contractions, which involved 5-HT3 receptors. Our findings suggest the modulatory roles of 5-HT3 receptors to mediate stress-induced colonic dysfunction.

Choice impulsivity after repeated social stress is associated with increased perineuronal nets in the medial prefrontal cortex

Repeated stress can predispose to substance abuse. However, behavioral and neurobiological adaptations that link stress to substance abuse remain unclear. This study investigates whether intermittent social defeat (ISD), a stress protocol that promotes drug-seeking behavior, alters intertemporal decision-making and cortical inhibitory function in the medial prefrontal cortex (mPFC). Male long evans rats were trained in a delay discounting task (DDT) where rats make a choice between a fast (1 s) small reward (1 sugar pellet) and a large reward (3 sugar pellets) that comes with a time delay (10 s or 20 s). A decreased preference for delayed rewards was used as an index of choice impulsivity. Rats were exposed to ISD and tested in the DDT 24 h after each stress episode, and one- and two-weeks after the last stress episode. Immunohistochemistry was performed in rat’s brains to evaluate perineuronal nets (PNNs) and parvalbumin GABA interneurons (PV) labeling as markers of inhibitory function in mPFC. ISD significantly decreased the preference for delayed large rewards in low impulsive, but not high impulsive, animals. ISD also increased the density of PNNs in the mPFC. These results suggest that increased choice impulsivity and cortical inhibition predispose animals to seek out rewards after stress.

Neuropsychological aspects of stress manifestation

Modern life, unfortunately, is not devoid of stressful situations. This article explores how stress affects various cognitive functions, making us more vulnerable. Memory, attention, decision-making, inhibition, and abstract thinking are just some aspects of the effects of stress. Studies show that prolonged or repeated stress can weaken the immune system, increasing inflammation and even destroying neurons in the hippocampus responsible for memory. Maturation of the frontal cortex, which is accompanied by an increase in gray matter volume and the number of synapses, can be disrupted by stress, leading to cognitive decline. Recent research on the impact of stressful situations on psychological and physical health is characterized by a wide range of methodological approaches and a variety of sources. Sapolsky R. highlights the impact of stress on memory-related processes, as well as on the formation of certain parts of the brain. In the work of D. Nakazawa, we get acquainted with neural development and the natural processes associated with this development. Thus, the latest research and publications in the field of stress psychology are an important contribution to our understanding of this complex problem and the development of practical recommendations for overcoming the negative effects of stress. Sleep is crucial for restoring energy and consolidating memory, but it also becomes a victim of stress. Lack of sleep and deterioration in its quality make us more vulnerable to the negative effects of stress. Children who have experienced stress risk losing even more neurons than their peers, as the natural neuronal pruning at puberty can be intensified. Chronic stress can lead to neurotic reactions, psychophysiological symptoms, and psychosomatic illnesses. This emphasizes the importance of nervous system rehabilitation and neuropsychological interventions.

Abstract 3391: Effects of repeated psychological stress on NNK-induced lung cancer development in young female mice

Abstract Lung cancer is the second most common cancer in both men and women in the US and the leading cause of cancer death. Among younger US women, lung cancer incidence rates have in recent years become higher than rates seen in men, despite comparable histories of tobacco use. The possible contribution of stress to higher lung cancer risk in young women has received little research attention despite preclinical evidence that exposure to stress-related neuroendocrine responses can cause DNA damage. The present study used a well-established lung cancer model in young female mice (in vivo exposure to NNK) along with a mouse stress model to explore their independent and combined effects on lung cancer development. In addition, we explored one possible biological pathway by chronic administration of a beta-adrenergic receptor blocker (propranolol). We also tested the use of in vivo imaging for repeated monitoring of tumor development over time. Cohort 1 (n=60) had 4 groups: Home cage control, NNK treatment alone, repeated stress (RS) alone and NNK+RS. Cohort 2 (n=60) had the same 4 groups with the addition of administration of propranolol in drinking water. Cohort 3 (n=48, imaging cohort) had 3 groups: Home cage control, NNK alone and NNK+RS. FVB/N (4-6 wk) were purchased from a commercial supplier and acclimated with gentle handling for two weeks. The repeated stress protocol began week-3 and continued for the duration of the study. It combined two well-established rodent models: social disruption stress via changes in cage mates at the time of cage cleaning (2x/week) and a 90-minute restraint stress immediately prior to cage change (1x/week). NNK or saline treatment began on week-4 (IP; 2x/week; 3 mg/injection) and continued for 4 weeks. 21 weeks after stress initiation, the mice in cohorts 1 and 2 were sacrificed, lungs removed, inflated and tumors counted and sized. Mice in cohort 3 were imaged by Hounsfield-calibrated micro-CT (μCT) at baseline, 14, 19 and 23 weeks. The entire lung space, excluding the heart, was defined as a volumetric region of interests (VOIs). The VOIs were subjected to thresholding to segment the lungs into air space and tissue space compartments. The volume of tissue space of each animal was ratioed against its own baseline tissue space volume. Results from Cohort 1 revealed significantly greater numbers and overall size of lung tumors in stressed mice that received NNK. No significant effects were seen in the absence of NNK. Results from Cohort 2 revealed no significant differences between stressed and unstressed groups treated with propranolol. Cohort 3 revealed a pattern of results with stressed mice generally showing the highest lung tumor volume levels (Hounsfield Units), which reached significance at 19 weeks in preliminary analyses. Conclusion: In this study, we found that repeated stress increased lung tumor burden in female mice treated with NNK, and that a beta-adrenergic pathway may be involved. Citation Format: Frank Jenkins, Laura P. Stabile, Jessie R. Nedrow, Kathryn Day, Joseph D. Latoche, Patrick M. Tarwater, Jessica Manculich, Dana H. Bovbjerg. Effects of repeated psychological stress on NNK-induced lung cancer development in young female mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3391.