Adult Stress Response Research Articles

A Causal Mediation Model for Longitudinal Mediators and Survival Outcomes with an Application to Animal Behavior.

In animal behavior studies, a common goal is to investigate the causal pathways between an exposure and outcome, and a mediator that lies in between. Causal mediation analysis provides a principled approach for such studies. Although many applications involve longitudinal data, the existing causal mediation models are not directly applicable to settings where the mediators are measured on irregular time grids. In this paper, we propose a causal mediation model that accommodates longitudinal mediators on arbitrary time grids and survival outcomes simultaneously. We take a functional data analysis perspective and view longitudinal mediators as realizations of underlying smooth stochastic processes. We define causal estimands of direct and indirect effects accordingly and provide corresponding identification assumptions. We employ a functional principal component analysis approach to estimate the mediator process and propose a Cox hazard model for the survival outcome that flexibly adjusts the mediator process. We then derive a g-computation formula to express the causal estimands using the model coefficients. The proposed method is applied to a longitudinal data set from the Amboseli Baboon Research Project to investigate the causal relationships between early adversity, adult physiological stress responses, and survival among wild female baboons. We find that adversity experienced in early life has a significant direct effect on females' life expectancy and survival probability, but find little evidence that these effects were mediated by markers of the stress response in adulthood. We further developed a sensitivity analysis method to assess the impact of potential violation to the key assumption of sequential ignorability. Supplementary materials accompanying this paper appear on-line.

Early stress-induced impaired microglial pruning of excitatory synapses on immature CRH-expressing neurons provokes aberrant adult stress responses.

SUMMARYSeveral mental illnesses, characterized by aberrant stress reactivity, often arise after early-life adversity (ELA). However, it is unclear how ELA affects stress-related brain circuit maturation, provoking these enduring vulnerabilities. We find that ELA increases functional excitatory synapses onto stress-sensitive hypothalamic corticotropin-releasing hormone (CRH)-expressing neurons, resulting from disrupted developmental synapse pruning by adjacent microglia. Microglial process dynamics and synaptic element engulfment were attenuated in ELA mice, associated with deficient signaling of the microglial phagocytic receptor MerTK. Accordingly, selective chronic chemogenetic activation of ELA microglia increased microglial process dynamics and reduced excitatory synapse density to control levels. Notably, selective early-life activation of ELA microglia normalized adult acute and chronic stress responses, including stress-induced hormone secretion and behavioral threat responses, as well as chronic adrenal hypertrophy of ELA mice. Thus, microglial actions during development are powerful contributors to mechanisms by which ELA sculpts the connectivity of stress-regulating neurons, promoting vulnerability to stress and stress-related mental illnesses.

Altered stress responses in adults born by Caesarean section

Birth by Caesarean-section (C-section), which increases the risk for metabolic and immune disorders, disrupts the normal initial microbial colonisation of the gut, in addition to preventing early priming of the stress and immune-systems.. Animal studies have shown there are enduring psychological processes in C-section born mice. However, the long-term impact of microbiota-gut-brain axis disruptions due to birth by C-section on psychological processes in humans is unknown. Forty age matched healthy young male university students born vaginally and 36 C-section delivered male students were recruited. Participants underwent an acute stressor, the Trier social stress test (TSST), during a term-time study visit. A subset of participants also completed a study visit during the university exam period, representing a naturalistic stressor. Participants completed a battery of cognitive tests and self-report measures assessing mood, anxiety, and perceived stress. Saliva, blood, and stool samples were collected for analysis of cortisol, peripheral immune profile, and the gut microbiota. Young adults born by C-section exhibit increased psychological vulnerability to acute stress and a prolonged period of exam-related stress. They did not exhibit an altered salivary cortisol awakening response to the TSST, but their measures of positive affect were significantly lower than controls throughout the procedure. Both C-section and vaginally-delivered participants performed equally well on cognitive assessments. Most of the initial effects of delivery mode on the gut microbiome did not persist into adulthood as the gut microbiota profile showed modest changes in composition in adult vaginally-delivered and C-sectioned delivered subjects. From an immune perspective, concentrations of IL-1β and 1L-10 were higher in C-section participants. These data confirm that there is a potential enduring effect of delivery mode on the psychological responses to acute stress during early adulthood. The mental health implications of these observations require further study regarding policies on C-section use.

Knockout of the hsd11b2 Gene Extends the Cortisol Stress Response in Both Zebrafish Larvae and Adults.

The Hsd11b2 enzyme converts cortisol into its inactive form, cortisone and regulates cortisol levels, in particular in response to stress. Taking advantage of CRISPR/Cas9 technology, we generated a hsd11b2 zebrafish mutant line to evaluate the involvement of this gene in stress response regulation. The absence of a functional Hsd11b2 affects survival of zebrafish, although homozygous hsd11b2−/− mutants can reach adulthood. Reproductive capability of hsd11b2−/− homozygous adult males is almost completely abrogated, while that of females is reduced. Interestingly, basal cortisol levels and glucocorticoid-dependent transcriptional activities are not affected by the mutation. In agreement with basal cortisol results, we also demonstrated that basal response to light (LMR-L/D) or mechanical (VSRA) stimuli is not significantly different in wild-type (hsd11b2+/+) compared to mutant larvae. However, after exposure to an acute stressor, the cortisol temporal patterns of synthesis and release are prolonged in both 5 days post fertilization larvae and one-year-old adult hsd11b2−/− zebrafish compared to wild-type siblings, showing at the same time, at 5 dpf, a higher magnitude in the stress response at 10 min post stress. All in all, this new zebrafish model represents a good tool for studying response to different stressors and to identify mechanisms that are induced by cortisol during stress response.

Consumption of peanut products improves memory and stress response in healthy adults from the ARISTOTLE study: A 6-month randomized controlled trial

Peanuts are rich in bioactive compounds that may have a positive impact on memory and stress response. To evaluate the effect of regular consumption of peanut products on cognitive functions and stress response in healthy young adults. A three-arm parallel-group randomized controlled trial was conducted in 63 healthy young adults that consumed 25g/day of skin roasted peanuts (SRP, n=21), 32g/d of peanut butter (PB, n=23) or 32g/d of a control butter made from peanut oil (free of phenolic compounds and fiber) (CB, n=19) for six months. Polyphenol intake, cognitive functions, and anxiety and depression scores were evaluated using validated tests. Fecal short-chain fatty acids (SCFAs) and plasma and fecal fatty acids were assessed by chromatographic methods. Urinary cortisol was quantified by an enzymatic method. Comparing the two interventions with the control, a significant reduction in anxiety scores was observed in the SRP compared to the CB group. After the intervention, consumers of SRP and PB had an improved immediate memory (p=0.046 and p=0.011). Lower anxiety scores were associated with SRP and PB (p<0.001 and p=0.002, respectively) and lower depression scores with SRP, PB and CB (p=0.007, p=0.003 and p=0.032, respectively). Memory functions and stress response were significantly correlated with polyphenol intake, fecal SCFAs, plasma and fecal very long chain saturated fatty acids (VLCSFAs). Regular peanut and peanut butter consumption may enhance memory function and stress response in a healthy young population. These effects seem to be associated with the intake of peanut polyphenols, increased levels of fecal SCFAs, and unexpectedly, VLCSFAs, which were also present in the control product.

Effects of Auricular Acupressure on Blood Pressure and Stress Responses in Adults with Prehypertension

Purpose: This study was done to examine the effects of auricular acupressure (AA) on blood pressure (BP) and stress responses in adults with prehypertension.Methods: This single-blind, randomized, placebo-controlled study was conducted from September 2019 to February 2020. Participants were recruited through bulletin board notices in D city. The experimental group (n=27) received 8 weeks of AA intervention on specific acupoints (shenmen, kidney, heart, occiput, adrenal gland) to reduce blood pressure and stress, whereas the control group (n=25) received AA unspecific acupoints (helix 1-5). The outcomes were measured using BP, perceived stress scale (PSS), cortisol, and heart rate variability (HRV). Collected data were analyzed using Fisher’s exact test, chi-square, Shapiro-Wilk normality test, paired t-test, independent t-test, Mann-Whitney U test, repeated measures ANOVA and Friedman test with the SPSS/WIN 24.0.Results: Statistical differences were found between the groups for systolic BP (x&lt;sup&gt;2&lt;/sup&gt;=85.64, p&lt;.001), diastolic BP (x&lt;sup&gt;2&lt;/sup&gt;=27.76, p=.001), PSS (F=9.439, p=.003), low frequency (F=5.22, p=.027), heart rate (F=3.208, p=.045), and HRV index (F=3.579, p=.035). Cortisol did not differ significantly between the experimental group and control group.Conclusion: The findings show that AA leads to improvements in BP and stress responses in adults with prehypertension. Therefore, AA can be used as an alternative nursing intervention for hypertension prevention and stress management.

Music listening does not inoculate the stress response in young and older adults.

Music listening does not inoculate the stress response in young and older adults.

Domestication affected stress and immune response markers in Perca fluviatilis in the early larval stage

It is already known that domestication modifies stress and immune responses in juveniles and adults of several fish species. However, there is a lack of information on whether these modulations result from adaptability along the life cycle or if they are pre-determined in very early developmental stages. To shed light on mechanisms that help to explain the process of domestication, a study was conducted to analyze comparatively Eurasian perch larval performance, stress, and immune status between wild and domesticated specimens. Eurasian perch larvae obtained from wild and domesticated (generation F5 reared in recirculating aquaculture systems) spawners were reared in the same conditions during the main rearing trial (MRT) and also subjected to a thermal challenge (TC). During the study, larval performance (including survival, growth performance, swim bladder inflation effectiveness, deformity rate), the expression of genes involved in immune and stress response, and the specific activity of oxidative stress enzymes (during MRT only) were analyzed. No significant differences in hatching rate, deformity rate, or swim bladder inflation effectiveness between wild and domesticated larvae were found, whereas specific growth rate, final total length, and wet body weight were significantly lower in wild larvae. Higher mortality was also observed in wild larvae during both MRT and TC. The data obtained in this study clearly indicated that during domestication, significant modifications in stress and immune response, such as complement component c3, were noted as early as just after hatching. Generally, domesticated fish were characterized by a lower stress response and improved immune response in comparison to the wild fish. This probably resulted from the domesticated larvae being better adapted to the conditions of artificial aquaculture. The data obtained provided information on how domestication affects fish in aquaculture, and they contribute to the development of efficient selective breeding programs of Eurasian perch and other freshwater teleosts.

Predator odor exposure increases social contact in adolescents and parental behavior in adulthood in Brandt’s voles

Research suggests that predation risk during adolescence can program adult stress response and emotional behavior; however, little is known about the short-term and lasting residual effects of this experience on social behavior. We explored this concept in social Brandt’s voles (Lasiopodomys brandtii). Adolescent male and female voles were exposed to distilled water, rabbit urine (as a non-predator stimulus), and cat urine for 60 min daily from postnatal day (PND) 28–49. Social play tests were conducted immediately following exposure on PND 28, 35, 42, and 49. In the social play test, repeated cat odor (CO) exposure enhanced the contact behavior of voles with their cagemate. Adolescent exposure to CO did not affect behavioral responses toward unrelated pups in the alloparental behavior test or same-sex individuals in the social interaction test. However, exposure to CO significantly enhanced the licking/grooming behavior of voles towards their own pups in the home cage parental behavior test. Repeated CO exposure significantly inhibited weight gain in male voles during adolescence. This effect was transmitted to the next generation, with lower weight gain in offspring before weaning. Following repeated CO exposure, males tended to have more female offspring whereas females produced more offspring, suggesting an adaptive strategy to increase inclusive fitness under predatory risk. These findings demonstrate that adolescent exposure to predatory risk augments adolescent social contact and adult parental behavior and suggest a role for improved inclusive fitness in mediating long-term outcomes.

How the Early Environment Influences Stress Responses in Adulthood

How the Early Environment Influences Stress Responses in Adulthood

Wnt signalling and endocytosis: Mechanisms, controversies and implications for stress responses.

Wnt signalling is one of a few conserved pathways that control diverse aspects of development and morphogenesis in all metazoan species. Endocytosis is a key mechanism that regulates the secretion and graded extracellular distribution of Wnt glycoproteins from the source cells, as well as Wnt signal transduction in the receiving cells. However, controversies exist regarding the requirement of clathrin-dependent endocytosis in Wnt signalling. Various lines of evidence from recent studies suggest that Wnt-β-catenin signalling is also involved in the regulation of cellular stress responses in adulthood, a role that is beyond its canonical functions in animal development. In this review, we summarise recent advances in the molecular and cellular mechanisms by which endocytosis modulates Wnt signalling. We also discuss how Wnt signalling could be repurposed to regulate mitochondrial stress response in the nematode Caenorhabditis elegans.

Supplemental Material for Music Listening Does Not Inoculate the Stress Response in Young and Older Adults

Supplemental Material for Music Listening Does Not Inoculate the Stress Response in Young and Older Adults

A history of juvenile mild malaria exacerbates chronic stress-evoked anxiety-like behavior, neuroinflammation, and decline of adult hippocampal neurogenesis in mice

Children residing in high malaria transmission regions are particularly susceptible to malaria. This early-life window is also a critical period for development and maturation of the nervous system, and inflammatory insults during this period may evoke a persistent increase in vulnerability for psychopathology. We employed a two-hit model of juvenile mild malaria and a two-week chronic unpredictable mild stress (CUMS) regime, commencing 60 days post-parasite clearance, to assess whether a history of juvenile infection predisposed the mice towards mood-related behavioral alterations and neurocognitive deficits. We showed that adult mice with a history of juvenile malaria (A-H/JMAL) exhibited heightened CUMS-associated anxiety-like behavior, with no observable change in cognitive behavior. In contrast, mice with a history of adult malaria did not exhibit such enhanced stress vulnerability. At baseline, A-H/JMAL mice showed increased activated microglia within the hippocampal dentate gyrus subfield. This was accompanied by a decrease in proliferating neuronal progenitors, with total number of immature hippocampal neurons unaltered. This neuroinflammatory and neurogenic decline was further exacerbated by CUMS. At day-14 post-CUMS, hippocampi of A-H/JMAL mice showed significantly higher microglial activation, and a concomitant decrease in progenitor proliferation and number of immature neurons. Taken together, these results suggest that a history of juvenile mild malaria leaves a neuroinflammatory mark within the hippocampal niche, and this may contribute to a heightened stress response in adulthood. Our findings lend credence to the idea that the burden of malaria in early-life results in sustained CNS changes that could contribute to increased vulnerability to adult-onset neuronal insults.

Social bonds do not mediate the relationship between early adversity and adult glucocorticoids in wild baboons

In humans and other animals, harsh conditions in early life can have profound effects on adult physiology, including the stress response. This relationship may be mediated by a lack of supportive relationships in adulthood. That is, early life adversity may inhibit the formation of supportive social ties, and weak social support is itself often linked to dysregulated stress responses. Here, we use prospective, longitudinal data from wild baboons in Kenya to test the links between early adversity, adult social bonds, and adult fecal glucocorticoid hormone concentrations (a measure of hypothalamic-pituitary-adrenal [HPA] axis activation and the stress response). Using a causal inference framework, we found that experiencing one or more sources of early adversity led to a 9 to 14% increase in females' glucocorticoid concentrations across adulthood. However, these effects were not mediated by weak social bonds: The direct effects of early adversity on adult glucocorticoid concentrations were 11 times stronger than the effects mediated by social bonds. This pattern occurred, in part, because the effect of social bonds on glucocorticoids was weak compared to the powerful effects of early adversity on glucocorticoid levels in adulthood. Hence, in female baboons, weak social bonds in adulthood are not enough to explain the effects of early adversity on glucocorticoid concentrations. Together, our results support the well-established notions that early adversity and weak social bonds both predict poor adult health. However, the magnitudes of these two effects differ considerably, and they may act independently of one another.

Early life stress alters transcriptomic patterning across reward circuitry in male and female mice

Abuse, neglect, and other forms of early life stress (ELS) significantly increase risk for psychiatric disorders including depression. In this study, we show that ELS in a postnatal sensitive period increases sensitivity to adult stress in female mice, consistent with our earlier findings in male mice. We used RNA-sequencing in the ventral tegmental area, nucleus accumbens, and prefrontal cortex of male and female mice to show that adult stress is distinctly represented in the brain’s transcriptome depending on ELS history. We identify: 1) biological pathways disrupted after ELS and associated with increased behavioral stress sensitivity, 2) putative transcriptional regulators of the effect of ELS on adult stress response, and 3) subsets of primed genes specifically associated with latent behavioral changes. We also provide transcriptomic evidence that ELS increases sensitivity to future stress through enhancement of known programs of cortical plasticity.

Early Life Stress Restricts Translational Reactivity in CA3 Neurons Associated With Altered Stress Responses in Adulthood.

Early life experiences program brain structure and function and contribute to behavioral endophenotypes in adulthood. Epigenetic control of gene expression by those experiences affect discrete brain regions involved in mood, cognitive function and regulation of hypothalamic-pituitary-adrenal (HPA) axis. In rodents, acute restraint stress increases the expression of the repressive histone H3 lysine 9 tri-methylation (H3K9me3) in hippocampal fields, including the CA3 pyramidal neurons. These CA3 neurons are crucially involved in cognitive function and mood regulation as well as activation of glucocorticoid (CORT) secretion. CA3 neurons also exhibit structural and functional changes after early-life stress (ELS) as well as after chronic stress in adulthood. Using a protocol of chronic ELS induced by limited bedding and nesting material followed by acute-swim stress (AS) in adulthood, we show that mice with a history of ELS display a blunted CORT response to AS, despite exhibiting activation of immediate early genes after stress similar to that found in control mice. We find that ELS induced persistently increased expression of the repressive H3K9me3 histone mark in the CA3 subfield at baseline that was subsequently decreased following AS. In contrast, AS induced a transient increase of this mark in control mice. Using translating ribosome affinity purification (TRAP) method to isolate CA3 translating mRNAs, we found that expression of genes of the epigenetic gene family, GABA/glutamate family, and glucocorticoid receptors binding genes were decreased transiently in control mice by AS and showed a persistent reduction in ELS mice. In most cases, AS in ELS mice did not induce gene expression changes. A stringent filtering of genes affected by AS in control and ELS mice revealed a noteworthy decrease in gene expression change in ELS mice compared to control. Only 18 genes were selectively regulated by AS in ELS mice and encompassed pathways such as circadian rhythm, inflammatory response, opioid receptors, and more genes included in the glucocorticoid receptor binding family. Thus, ELS programs a restricted translational response to stress in stress-sensitive CA3 neurons leading to persistent changes in gene expression, some of which mimic the transient effects of AS in control mice, while leaving in operation the immediate early gene response to AS.

Effects of post-weaning social isolation on social behaviors and oxytocinergic activity in male and female rats

AimsPost-weaning social deprivation is known to induce behavioral and neuronal alterations associated with anxiety and stress responses in adulthood. However, the effects of social deprivation on the development of sociability are poorly understood. We examined the effects of social deprivation on subsequent social behaviors and oxytocinergic activity using socially-isolated (approximately two months post-weaning) male and female rats. Main methodsThe behaviors were analyzed using a social preference test and a social approach test. Immunohistochemical investigations were conducted in the paraventricular nucleus (PVN) and supraoptic nucleus (SON) to examine the effects of social isolation on oxytocinergic activity in these regions. Oxytocinergic activity was measured by quantifying the number of oxytocin neurons expressing Fos following exposure to a novel conspecific. In all of the experiments of this study, ovariectomized females were used for social stimuli. Key findingsThe behavioral results show that isolation-reared females, but not males, displayed impaired social preference and decreased social approach towards ovariectomized females, compared with the pair-reared group, suggesting low priority of processing social versus non-social stimuli and low motivation for contact with a stranger, respectively. The immunohistochemical results show that social isolation decreased both the number and the ratio of Fos-positive cells in oxytocin neurons in the PVN in females, but not in males, following exposure to ovariectomized females. In the SON, the Fos-positive ratio was decreased in isolation-reared females, but not in males, compared with the pair-reared group. SignificancePost-weaning social isolation changed social behaviors and oxytocinergic activity in female rats, suggesting that in female rats post-weaning social experiences contribute to the development of sociability. These findings could impact the treatment of social dysfunction in humans.

Hemorrhage simulated by lower body negative pressure provokes an oxidative stress response in healthy young adults.

We characterize the systemic oxidative stress response in young, healthy human subjects with exposure to simulated hemorrhage via application of lower body negative pressure (LBNP). Prior work has demonstrated that LBNP and actual blood loss evoke similar hemodynamic and immune responses (i.e. white blood cell count), but it is unknown whether LBNP elicits oxidative stress resembling that produced by blood loss. We show that LBNP induces a 29% increase in F2-isoprostanes, a systemic marker of oxidative stress. The findings of this investigation may have important implications for the study of hemorrhage using LBNP, including future assessments of targeted interventions that may reduce oxidative stress, such as novel fluid resuscitation approaches.

Chronic adolescent stress sex-specifically alters the hippocampal transcriptome in adulthood.

Chronic adolescent stress alters behavior in a sex-specific manner at the end of adolescence and in adulthood. Although prolonged behavioral repercussions of chronic adolescent stress have been documented, the potential underlying mechanisms are incompletely understood. In this study we demonstrate that a history of chronic adolescent stress modified the adult stress response, as measured by corticosterone concentration, such that a history of chronic adolescent stress resulted in a blunted response to a novel acute stressor. In order to begin to address potential mechanistic underpinnings, we assessed the extent to which chronic adolescent stress impacted global DNA methylation. Reduced global hippocampal methylation was evident in females with a history of chronic adolescent stress; thus, it was possible that chronic adolescent stress altered global transcription in the whole hippocampi of adult male and female rats. In addition, because acute stress can stimulate a genomic response, we assessed the transcriptome following exposure to an acute novel stressor to determine the extent to which a history of chronic adolescent stress modifies the adult transcriptional response to an acute stressor in males and females. In addition to the reduction in global methylation, chronic adolescent stress resulted in distinct patterns of gene expression in the adult hippocampus that differentiated by sex. Furthermore, both sex and a history of chronic adolescent stress influenced the transcriptional response to an acute novel stressor in adulthood, suggesting both latent and functional effects of chronic adolescent stress at the level of gene transcription. Pathway analysis indicated that ESR1 and IFN-α may be particularly influential transcription factors mediating these transcriptional differences and suggest candidate mechanisms for future studies. Collectively, these studies demonstrate sex-specific and enduring effects of adolescent stress exposure that are more pronounced in females than in males.

Maternal separation induces long-term changes in mineralocorticoid receptor in rats subjected to chronic stress and treated with tianeptine

Purpose: The aim of this study was to analyze whether early maternal separation would result in long-term, persistent alterations in stress response in adulthood, altering mineralocorticoid receptor immunoreactivity (MR-ir) in the dorsal hippocampal areas [CA1, CA2, CA3 and dentate gyrus (DG)], paraventricular nucleus of the hypothalamus and medial and central nucleus of the amygdala, key structures involved in stress response regulation. We also analyzed whether chronic treatment with the antidepressant tianeptine reverses these possible changes.Material and methods: Male Wistar rats were subjected to daily maternal separation for 4.5 h during 3 weeks or left undisturbed. As adults, they were exposed to chronic stress during 24 days or left undisturbed, and they were also daily treated with tianeptine (10 mg/kg i.p.) or isotonic solution.Results: In the CA2 and DG areas of the dorsal hippocampus, there was an increase in MR-ir in non-maternally separated and chronic stressed groups. Tianeptine raised MR-ir in the CA3. In the DG, control and maternally separated + chronic stress groups treated with tianeptine showed more MR-ir than their respective vehicle groups. In the paraventricular nucleus, tianeptine decreased MR-ir in non-separated groups, but not in maternally separated rats.Conclusions: Our results support findings that early-life events induce long-term changes in stress response regulation, persistent into adulthood, which are manifested during challenges in later life, and that treatment with tianeptine, which tends to attenuate the hypothalamus-pituitary-adrenal axis dysregulation, depends on the individual experience of each rat.