Adult Stress Research Articles

Dynamic changes in microglia morphology and higher resilience to stress-induced anxious-behavior in a model of prenatal exposure to glucocorticoids

Dynamic changes in microglia morphology and higher resilience to stress-induced anxious-behavior in a model of prenatal exposure to glucocorticoids

TpH2 expression after neonatal dexamethasone treatment and acute or chronic stress in adulthood

TpH2 expression after neonatal dexamethasone treatment and acute or chronic stress in adulthood

Youth Adversities Amplify the Association between Adult Stressors and Chronic Inflammation in a Domain Specific Manner: Nuancing the Early Life Sensitivity Model.

There is strong evidence that chronic, systemic inflammation hastens onset of the diseases of old age that ultimately lead to death. Importantly, several studies suggest that childhood adversity predicts chronic inflammation. Unfortunately, this research has been plagued by retrospective reports of childhood adversity, an absence of controls for adult stressors, and a failure to investigate various competing models of the link between childhood adversity and chronic inflammation. The present study was designed to address these limitations. Using 18 years of data collected from 413 African Americans (58% female) included in the Family and Community Health Study, hierarchical regression analyses provided support for a nuanced early life sensitivity explanation for the link between early adversity and adult chronic inflammation. Controlling for health risk behaviors and adult SES, late childhood (ages 10-12) adversity amplified the association between adult adversity (age 29) and chronic inflammation. This interaction operated in a domain-specific fashion. Harsh parenting amplified the relation between intimate partner hostility and inflammation, whereas early discrimination amplified the relation between adult discrimination and inflammation. These findings suggest that individuals may be primed to respond physiologically to adverse adult circumstances that resemble those experienced earlier in life.

SA48 - STRESS, DEPRESSIVE STATUS AND TELOMERE LENGTH: DOES SOCIAL INTERACTION AND COPING STRATEGY PLAY A MEDIATING ROLE?

Background Telomeres have been reported to be shorter in individuals exposed to psychosocial stress and in those with depression. Since negative environmental stress is a risk factor for depression, the present study tested whether stressors in childhood (CA) and recent adulthood (NLE) predicted telomere attrition directly and/or indirectly through individuals’ depressive status 3-6 years before TL measurement; and then if social interaction and coping strategies in adulthood influenced the relationship between depressive status and TL. Methods Participants were 337 individuals with a recent depression diagnosis and 574 screened controls that derived from a longitudinal population-based cohort study conducted in Stockholm, Sweden. Relative TL was determined using qPCR. Relationships between key variables stressors, depressive status, social interaction, coping strategies and TL were explored by path analysis in males and females, adjusting for age. Results The key variables were correlated in expected directions. In females, depressive status and age had direct negative effects on TL (p Discussion Our study consolidates previous findings that TL is shorter in depression. In other words, exposure to environmental stress is associated with higher risk of depression, which in turn associates with shorter TL. While in females there was no statistically significant pathway through social interaction or coping strategy, in males, depressive status was associated with TL through AVSI, AVAT and the coping strategy worry. In addition, in males CA had a significant indirect effect on TL through AVSI, AVAT and depressive status. This sex difference in pathways might be explained by the sex differences in social-cognitive styles, coping or reaction to stress and relationship provisions. Good social relationships play a positive role in reducing the impact of stress and in turn enhance well-being and health habits, whereas weak social interactions and corresponding improper coping relate with the dysregulation of stress- responsive biological systems e.g. the HPA axis and inflammation. Previous studies have linked the dysfunction of these biological systems to accelerated telomere erosion.

Correlates and Treatment Outcome of Risky Sexual Behaviour in Young Males with ADHD and Comorbid Alcohol Use Disorder: A Prospective Study

Background: Attention-deficit/hyperactivity disorder (ADHD) is associated with risky sexual behavior (RSB). Alcohol use and high perceived stress in young adulthood contributes to this association. Previous studies have not found methylphenidate to reduce RSB in ADHD, as the population had comorbidities such as mood disorders and antisocial personality disorder. We aimed to study (a) the association of RSB with ADHD and severity of alcohol use among adolescents and young adult males with ADHD who had comorbid alcohol use disorder and (b) the effect of treatment of ADHD using methylphenidate on RSB in this population at 3- and 6-month follow-ups. Methodology: The study had 31 participants who were selected by screening for RSBs using the sexual behavior section of the HIV Risk-taking Behavior Scale (HRBS) manual among a cohort of individuals with ADHD and early onset alcohol use. These individuals were also administered WHO ADHD self-report scale (ASRS), alcohol-use disorders identification test (AUDIT), perceived stress scale (PSS), and HRBS-sexual behavior section. They were then treated with methylphenidate and these assessments were repeated at 3 and 6 months. Results: Those having ADHD with RSB had higher total ADHD score ( P = .007) and inattention score ( p = .0001) than those without RSB. There was a significant correlation between the ADHD total score with alcohol-use severity ( r = 0.47), with RSB ( r = 0.34), and ADHD hyperactivity scores with alcohol-use severity ( r = 0.49) and with RSB ( r = 0.34). There was also a significant reduction of ADHD total, inattention and hyperactivity scores, alcohol-use severity scores, RSB and perceived stress scores with use of methylphenidate at 3- and 6-month follow-ups. Multiple logistic regression predicted reduction in ADHD total scores to reduce RSB (odds ratio [OR] = 1.26, P = .01). Conclusion: RSB was associated with severity of ADHD and alcohol use. Methylphenidate not only reduced ADHD severity but also alcohol-use severity and RSB, whose reduction was predicted by reduction in ADHD severity.

Common Environmental Factors May Underpin the Comorbidity Between Generalized Anxiety Disorder and Mood Disorders Via Activated Nitro-oxidative Pathways.

Generalized Anxiety Disorder (GAD) commonly co-occurs with mood disorders, especially Major Depressive Disorder (MDD) and bipolar disorder (BD), which are accompanied by activated neuro-immune and neuro-oxidative pathways. The aim of this narrative review is to review the phenomenological similarities and dissimilarities and the shared pathways between GAD and mood disorders. We searched PubMed, Scopus, and Google Scholar for articles published in English from 1980 to present. GAD and mood disorders, either MDD or BD, show some phenomenological overlaps and a high degree of comorbidity, especially between GAD and MDD. Both GAD and mood disorders are also frequently comorbid with other anxiety disorders, substance use disorders and medical conditions, including cardio- vascular disorder (CVD). Mood disorders have a worse prognosis when GAD is present. GAD and mood disorders are associated with female sex and may partly share genetic variants of risk. Moreover, both GAD and mood disorders frequently share similar environmental risks factors including Early Life Time Trauma (ELT) and Psychological Stressors in Adulthood (PSA). Increased nitro-oxidative stress and lipid peroxidation coupled to lowered lipid-associated antioxidant defenses are evident in GAD, MDD and type I bipolar patients. Patients with comorbid GAD and MDD show significantly higher nitro- oxidative biomarkers as compared with patients presenting with either GAD or MDD as well as patients with BD with or without co-occurring GAD. Activated immune-inflammatory processes characterized by increased levels of CRP and pro-inflammatory cytokines are other shared pathways that underpin GAD and mood disorders. Moreover, these pathways may explain comorbidities with medical disorders including CVD. Aberrations in HPA-axis, GABA and glutamate neurotransmission, NMDA and mu opioid-receptors and neuroimaging fields have yielded more inconsistent findings. In conclusion, here we propose a new model explaining GAD and the comorbidity between GAD and mood disorders. Common triggers such as ELT/PSA may underpin GAD and its comorbidity with mood disorders via activated neuro-oxidative, neuro-nitrosative and neuro-immune pathways.

Maternal Protein Malnutrition: Current and Future Perspectives of Spirulina Supplementation in Neuroprotection.

Malnutrition has been widely recognized as a grave burden restricting the progress of underdeveloped and developing countries. Maternal, neonatal and postnatal nutritional immunity provides an effective approach to decrease the risk of malnutrition associated stress in adulthood. Particularly, maternal nutritional status is a critical contributor for determining the long-term health aspects of an offspring. Maternal malnutrition leads to increased risk of life, poor immune system, delayed motor development and cognitive dysfunction in the children. An effective immunomodulatory intervention using nutraceutical could be used to enhance immunity against infections. The immune system in early life possesses enormous dynamic capacity to manage both genetic and environment driven processes and can adapt to rapidly changing environmental exposures. These immunomodulatory stimuli or potent nutraceutical strategy can make use of early life plasticity to target pathways of immune ontogeny, which in turn could increase the immunity against infectious diseases arising from malnutrition. This review provides appreciable human and animal data showing enduring effects of protein deprivation on CNS development, oxidative stress and inflammation and associated behavioral and cognitive impairments. Relevant studies on nutritional supplementation and rehabilitation using Spirulina as a potent protein source and neuroprotectant against protein malnutrition (PMN) induced deleterious changes have also been discussed. However, there are many futuristic issues that need to be resolved for proper modulation of these therapeutic interventions to prevent malnutrition.

Neonatal Maternal Deprivation Followed by Adult Stress Enhances Adrenergic Signaling to Advance Visceral Hypersensitivity

The pathophysiology of visceral pain in patients with irritable bowel syndrome remains largely unknown. Our previous study showed that neonatal maternal deprivation (NMD) does not induce visceral hypersensitivity at the age of 6 weeks in rats. The aim of this study was to determine whether NMD followed by adult stress at the age of 6 weeks induces visceral pain in rats and to investigate the roles of adrenergic signaling in visceral pain. Here we showed that NMD rats exhibited visceral hypersensitivity 6 h and 24 h after the termination of adult multiple stressors (AMSs). The plasma level of norepinephrine was significantly increased in NMD rats after AMSs. Whole-cell patch-clamp recording showed that the excitability of dorsal root ganglion (DRG) neurons from NMD rats with AMSs was remarkably increased. The expression of β2 adrenergic receptors at the protein and mRNA levels was markedly higher in NMD rats with AMSs than in rats with NMD alone. Inhibition of β2 adrenergic receptors with propranolol or butoxamine enhanced the colorectal distention threshold and application of butoxamine also reversed the enhanced hypersensitivity of DRG neurons. Overall, our data demonstrate that AMS induces visceral hypersensitivity in NMD rats, in part due to enhanced NE-β2 adrenergic signaling in DRGs.

Association of Childhood Adversity With Differential Susceptibility of Transdiagnostic Psychopathology to Environmental Stress in Adulthood

Multivariable comorbidity research indicates that childhood adversity increases the risk for the development of common mental disorders. This risk is explained by underlying internalizing and externalizing transdiagnostic constructs that are amplified by environmental stressors. The differential susceptibility model suggests that this interaction of risk and environment is bidirectional: at-risk individuals will have worse outcomes in high-stress environments but better outcomes in in low-stress environments. To test the differential susceptibility model by examining how a history of adverse childhood experiences moderates the association between life stress and transdiagnostic psychopathology. Data came from the US National Epidemiological Survey on Alcohol and Related Conditions (NESARC), a population-based observational longitudinal survey administered to adults (≥18 years of age). Participants completed the survey at wave 1 (from 2001 through 2002) and wave 2 (from 2004 through 2005). Responses from 34 458 participants were used for the analyses from March 3, 2017, through October 8, 2018. Latent variables for internalizing-fear, internalizing-distress, externalizing, and general psychopathology were created to represent continuous levels of psychopathology in each wave. Latent variables were also created to represent continuous levels of life stress at each wave. Level of childhood adversity was characterized based on the number of types of childhood adversity experienced (no [0 types], low [1-2 types], and high [≥3 types] exposure). Analyses examined how the interaction between level of childhood adversity and adult life stress was associated with change in adult transdiagnostic psychopathology factors. Of the 34 458 participants included in the analysis (58.0% women and 42.0% men; mean [SD] age, 46.0 [17.4] years at wave 1 and 49.0 [17.3] years at wave 2), 40.5% had no adverse childhood experiences, 34.6% had 1 to 2, and 24.9% had 3 or more. At wave 1, 61.5% of the sample endorsed at least 1 stressful life event and 27.2% met criteria for at least 1 mental disorder; at wave 2, these figures were 64.7% and 29.7%, respectively. Childhood adversity moderated the association between changes in adult life stress and changes in all transdiagnostic psychopathology factors. Specifically, higher levels of childhood adversity had a stronger association between adult life stress and adult transdiagnostic psychopathology factors. Further, significant differences between childhood adversity groups occurred in the mean scores of all transdiagnostic psychopathology factors for both increases and decreases in life stress, providing preliminary evidence of differential susceptibility. Results provide empirical support for childhood adversity as a differential susceptibility factor engendering heightened functional and dysfunctional reactivity to later stress.

Serotonin Signaling Trough Prelimbic 5-HT1A Receptors Modulates CSDS-Induced Behavioral Changes in Adult Female Voles

BackgroundMost previous studies have focused on the effects of social defeat in male juvenile individuals. Whether chronic social defeat stress in adulthood affects female emotion and the underlying mechanisms remains unclear.MethodsUsing highly aggressive adult female mandarin voles (Microtus mandarinus), the present study aimed to determine the effects of chronic social defeat stress on anxiety- and depression-like behaviors in adult female rodents and investigate the neurobiological mechanisms underlying these effects.ResultsExposure of adult female voles to social defeat stress for 14 days reduced the time spent in the central area of the open field test and in the open arms of the elevated plus maze and lengthened the immobility time in the tail suspension and forced swimming tests, indicating increased anxiety- and depression-like behaviors. Meanwhile, defeated voles exhibited increased neural activity in the prelimbic cortex of the medial prefrontal cortex. Furthermore, chronic social defeat stress reduced serotonin projections and levels of serotonin 1A receptors in the medial prefrontal cortex-prelimbic cortex. Intra-prelimbic cortex microinjections of the serotonin 1A receptor agonist 8-OH-DPAT reversed the alterations in emotional behaviors, whereas injections of the serotonin 1A receptor antagonist WAY-100635 into the prelimbic cortex of control voles increased the levels of anxiety- and depression-like behaviors.ConclusionsTaken together, our results demonstrated that chronic social defeat stress increased anxiety- and depression-like behaviors in adult female voles, and these effects were mediated by the action of serotonin on the serotonin 1A receptors in the prelimbic cortex. The serotonin system may be a promising target to treat emotional disorders induced by chronic social defeat stress.

Exploring the Potential of RET Kinase Inhibition for Irritable Bowel Syndrome: A Preclinical Investigation in Rodent Models of Colonic Hypersensitivity.

Abdominal pain represents a significant complaint in patients with irritable bowel syndrome (IBS). While the etiology of IBS is incompletely understood, prior exposure to gastrointestinal inflammation or psychologic stress is frequently associated with the development of symptoms. Inflammation or stress-induced expression of growth factors or cytokines may contribute to the pathophysiology of IBS. Here, we aimed to investigate the therapeutic potential of inhibiting the receptor of glial cell line-derived neurotrophic factor, rearranged during transfection (RET), in experimental models of inflammation and stress-induced visceral hypersensitivity resembling IBS sequelae. In RET-cyan fluorescent protein [(CFP) RetCFP/+] mice, thoracic and lumbosacral dorsal root ganglia were shown to express RET, which colocalized with calcitonin gene-related peptide. To understand the role of RET in visceral nociception, we employed GSK3179106 as a potent, selective, and gut-restricted RET kinase inhibitor. Colonic hyperalgesia, quantified as exaggerated visceromotor response to graded pressures (0-60 mm Hg) of isobaric colorectal distension (CRD), was produced in multiple rat models induced 1) by colonic irritation, 2) following acute colonic inflammation, 3) by adulthood stress, and 4) by early life stress. In all the rat models, RET inhibition with GSK3179106 attenuated the number of abdominal contractions induced by CRD. Our findings identify a role for RET in visceral nociception. Inhibition of RET kinase with a potent, selective, and gut-restricted small molecule may represent a novel therapeutic strategy for the treatment of IBS through the attenuation of post-inflammatory and stress-induced visceral hypersensitivity.

EFFECT OF CHILDHOOD ADVERSITY ON PSYCHOLOGICAL AND BIOLOGICAL MARKERS OF STRESS IN MIDDLE AND LATER LIFE

A growing number of studies have identified significant linkages between adverse childhood experiences and health outcomes in later life. Guided by a broad theoretical framework of the life course perspective, these studies have postulated that childhood adversities are the seedbed for vulnerabilities that may accumulate across the life course. This symposium includes four presentations that build on such existing knowledge, and its primary aim is to investigate the effects of early childhood adversities on psychological and biological markers of stress in middle and later adulthood. Using nationally representative samples, the four presentations focus on examining various aspects of psychological and biological markers of stress in later adulthood, including biomarkers of inflammation, alpha amylase, grip strength, and daily emotional reactivity. Particularly, biomarker data such as inflammation have key strengths: providing objective data about health and functioning in contrast to measurements based on self-reports and indicating potential risk of future disease. This symposium also addresses a wide range of childhood adversities, including neglect and abuse, low socioeconomic status, and early parental loss and provides insights around how different types and characteristics of adverse childhood experiences may unfold differently across the life course. Additionally, this symposium consists of a group of multidisciplinary presenters with diverse scholarly and cultural backgrounds. For example, one of the presentations discusses the experience of older Korean adults and offers a chance to understand cross-cultural differences.

Influence of trait anxiety, child maltreatment, and adulthood life events on depressive symptoms.

BackgroundVarious personality traits mediate the association between childhood stress and depressive symptoms in adulthood. The aim of this study was to clarify the indirect effects of the experience of child maltreatment on depressive symptoms and appraisal of life events in adulthood through trait anxiety.Subjects and methodsA total of 404 participants who were volunteer subjects from the community were studied using the following self-administered questionnaire surveys: Patient Health Questionnaire-9, which measures depressive symptoms; State-Trait Anxiety Inventory Form Y, which measures trait anxiety; the Child Abuse and Trauma Scale, which measures child maltreatment; and Life Experiences Survey, which measures negative and positive appraisal of adulthood life events.ResultsStructural equation modeling demonstrated that the experience of child maltreatment increased depressive symptoms in adulthood as well as the negative appraisal of life events in adulthood through an increase in trait anxiety. Furthermore, trait anxiety affected depressive symptoms in adulthood through its influence on the negative appraisal of adulthood life events. The following indirect effect was also significant: the experience of child maltreatment increased the negative appraisal of adulthood life events via trait anxiety and subsequently influenced adult depressive symptoms.LimitationsThe subjects of this study are volunteer subjects from the community including healthy people, and hence the results may not be generalizable to major depressive patients. Recall bias should be considered when interpreting the results. Because this study is a cross-sectional study, the causality between the experience of child maltreatment and depression is not clear.ConclusionThis study suggests that trait anxiety may play a mediating role in the influence of the experience of child maltreatment on depressive symptoms in adulthood and negative appraisal of adulthood life events.

A life course perspective of victimization, child welfare involvement, cumulative stress and mental health for mothers on probation and parole.

Women involved in the criminal justice system experience multiple forms of adversity over their lifetimes. These events may include childhood abuse, involvement in the child welfare system as children, intimate partner violence victimization during adulthood, and punitive interactions with the child welfare system as mothers. Community supervision (e.g. probation or parole) entails particular stressors, such as obtaining basic needs and employment. A majority of women under community supervision also experience depression and anxiety. The current study used the Stress Process Model to investigate associations between childhood and adulthood stressors (including childhood abuse, intimate partner violence and child welfare system involvement), recent stressful life events, and symptoms of depression and anxiety for mothers (n = 348) on probation and parole. All of the mothers had experienced some form of childhood and/or adulthood victimization. Structural equation modeling was conducted to examine how childhood abuse, adulthood victimization, and child welfare system involvement as a child and a mother were associated with recent stressful life events and symptoms of depression and anxiety. Results indicated multiple direct and indirect relationships from childhood and adulthood stressors to mental health symptoms as women navigated probation and parole. For example, adverse childhood experiences were associated with elevated anxiety and depression symptoms via higher levels of recent stressful life events and adverse adulthood experiences. These findings highlight relationships between childhood abuse and adulthood factors and the mental health of mothers involved in the criminal justice system, with implications for theory, practice, and research.

A developmental cascade model for early adolescent-onset substance use: the role of early childhood stress.

Backgrounds and aimsDespite the link between stress and addictive behavior in adulthood, little is known about how early life stress in families predicts the early emergence of substance use in adolescence. This study tested a developmental cascade model, proposing that early stressful life events and negative parent–child interaction covary, and both disrupt the refinement of inhibitory control, which evolves into problem behavior in middle/late childhood and subsequent substance use exploration in early adolescence.MethodsData came from the Early Steps Multisite study, a community sample of at‐risk families in the metropolitan US areas of Pittsburgh (Pennsylvania), Eugene (Oregon) and Charlottesville (Virginia) with children aged 2 years at the start of the study and 14 years at the last measurement (n = 364). Structural equation modeling was used to test the proposed model.ResultsEarly stressful life events and negative parent–child interaction assessed at ages 2–5 were negatively related to inhibitory control at ages 7 and 8. Low levels of inhibitory control were prognostic of childhood problem behavior at ages 9 and 10. Finally, late childhood problem behavior was associated with substance use at age 14. Parental drug use was directly related to substance use at age 14.ConclusionsEarly life stress may disrupt child inhibitory control, which can cascade into behavioral and peer problem behavior in childhood and, in turn, heighten the risk for early adolescent substance use.

Vulnerability to stress in mouse offspring is ameliorated when pregnant dams are provided a chewing stick during prenatal stress

ObjectiveTo investigate whether maternal chewing during prenatal stress alters the responsivity of young offspring to novel stress, we examined the expression of hippocampal glucocorticoid receptors and mineralocorticoid receptors, and the levels of hypothalamic corticotropin-releasing hormone in young adult mouse offspring of dams exposed to restraint stress during pregnancy. DesignTo induce stress, the dams were placed in a ventilated restraint tube for 45 min each day from day 12 of pregnancy through parturition. While restrained in the tube, one group of dams was provided a wooden stick for chewing. Hippocampal expression of glucocorticoid receptor and mineralocorticoid receptor messenger ribonucleic acid was assessed in 1-month-old pups. Hypothalamic expression of corticotropin-releasing hormone messenger ribonucleic acid was examined before and after exposing the offspring to a novel stressor. ResultsPrenatal stress significantly decreased hippocampal expression of both glucocorticoid receptor and mineralocorticoid receptor messenger ribonucleic acid in the offspring, and increased the expression of corticotropin-releasing hormone messenger ribonucleic acid in the hypothalamic paraventricular nucleus in the offspring after novel stress exposure. Maternal chewing during exposure to prenatal stress attenuated the decreased hippocampal expression of both glucocorticoid receptor and mineralocorticoid receptor messenger ribonucleic acid, and the increased corticotropin-releasing hormone messenger ribonucleic acid expression in the hypothalamic paraventricular nucleus in the offspring. ConclusionsDownregulation of hippocampal glucocorticoid receptor and mineralocorticoid receptor expression in offspring due to prenatal stress, which may be associated with increased susceptibility to novel stress in adulthood, are attenuated by allowing the dams to chew on a wooden stick.

SSRIs target prefrontal to\xa0raphe circuits during development modulating synaptic connectivity and emotional behavior

Antidepressants that block the serotonin transporter, (Slc6a4/SERT), selective serotonin reuptake inhibitors (SSRIs) improve mood in adults but have paradoxical long-term effects when administered during perinatal periods, increasing the risk to develop anxiety and depression. The basis for this developmental effect is not known. Here, we show that during an early postnatal period in mice (P0–P10), Slc6a4/SERT is transiently expressed in a subset of layer 5–6 pyramidal neurons of the prefrontal cortex (PFC). PFC-SERT+ neurons establish glutamatergic synapses with subcortical targets, including the serotonin (5-HT) and GABA neurons of the dorsal raphe nucleus (DRN). PFC-to-DRN circuits develop postnatally, coinciding with the period of PFC Slc6a4/SERT expression. Complete or cortex-specific ablation of SERT increases the number of functional PFC glutamate synapses on both 5-HT and GABA neurons in the DRN. This PFC-to-DRN hyperinnervation is replicated by early-life exposure to the SSRI, fluoxetine (from P2 to P14), that also causes anxiety/depressive-like symptoms. We show that pharmacogenetic manipulation of PFC-SERT+ neuron activity bidirectionally modulates these symptoms, suggesting that PFC hypofunctionality has a causal role in these altered responses to stress. Overall, our data identify specific PFC descending circuits that are targets of antidepressant drugs during development. We demonstrate that developmental expression of SERT in this subset of PFC neurons controls synaptic maturation of PFC-to-DRN circuits, and that remodeling of these circuits in early life modulates behavioral responses to stress in adulthood.

Parkinson's Disease-Linked LRRK2-G2019S Mutation Alters Synaptic Plasticity and Promotes Resilience to Chronic Social Stress in Young Adulthood.

The G2019S mutation in leucine-rich repeat kinase 2 (LRRK2) is a prevalent cause of late-onset Parkinson's disease, producing psychiatric and motor symptoms, including depression, that are indistinguishable from sporadic cases. Here we tested how this mutation impacts depression-related behaviors and associated synaptic responses and plasticity in mice expressing a Lrrk2-G2019S knock-in mutation. Young adult male G2019S knock-in and wild-type mice were subjected to chronic social defeat stress (CSDS), a validated depression model, and other tests of anhedonia, anxiety, and motor learning. We found that G2019S mice were highly resilient to CSDS, failing to exhibit social avoidance compared to wild-type mice, many of which exhibited prominent social avoidance and were thus susceptible to CSDS. In the absence of CSDS, no behavioral differences between genotypes were found. Whole-cell recordings of spiny projection neurons (SPNs) in the nucleus accumbens revealed that glutamatergic synapses in G2019S mice lacked functional calcium-permeable AMPARs, and following CSDS, failed to accumulate inwardly rectifying AMPAR responses characteristic of susceptible mice. Based on this abnormal AMPAR response profile, we asked whether long-term potentiation (LTP) of corticostriatal synaptic strength was affected. We found that both D1 receptor (D1R)- and D2R-SPNs in G2019S mutants were unable to express LTP, with D2R-SPNs abnormally expressing long-term depression following an LTP-induction protocol. Thus, G2019S promotes resilience to chronic social stress in young adulthood, likely reflecting synapses constrained in their ability to undergo experience-dependent plasticity. These unexpected findings may indicate early adaptive coping mechanisms imparted by the G2019S mutation.SIGNIFICANCE STATEMENT The G2019S mutation in LRRK2 causes late-onset Parkinson's disease (PD). LRRK2 is highly expressed in striatal neurons throughout life, but it is unclear how mutant LRRK2 affects striatal neuron function and behaviors in young adulthood. We addressed this question using Lrrk2-G2019S knock-in mice. The data show that young adult G2019S mice were unusually resilient to a depression-like syndrome resulting from chronic social stress. Further, mutant striatal synapses were incapable of forms of synaptic plasticity normally accompanying depression-like behavior and important for supporting the full range of cognitive function. These data suggest that in humans, LRRK2 mutation may affect striatal circuit function in ways that alter normal responses to stress and could be relevant for treatment strategies for non-motor PD symptoms.

Psychosocial Stress Over the Lifespan, Psychological Factors, and Cardiometabolic Risk in the Community.

The complex relationship between psychosocial stress over the lifetime, psychological factors, and cardiometabolic risk is still poorly understood. Accordingly, our aims were (1) to independently assess the associations between childhood adversity, life-event stress in remote (earlier than the last 5 years), and recent adulthood and cardiometabolic risk, and (2) to determine the role of psychological factors including personality, coping, and depression in these associations. The sample included 2674 adults, aged 35 to 66 years, randomly selected from urban area. Participants underwent a physical examination including the assessment of obesity markers, blood pressure, and blood lipid and glucose levels. Stress during adulthood was determined using the severity scores of 52 stressful life events. Information on adverse childhood experiences and major depressive disorders was collected using semistructured interviews, whereas personality traits and coping mechanisms were evaluated through questionnaires. Both childhood adversity and stress in remote adulthood were associated with elevated body mass index (β [95% confidence interval {CI}] = 0.249 [0.029 to 0.468]; 0.020 [0.006 to 0.034]), waist circumference (β [95% CI] = 0.061 [0.024 to 0.099]; 0.08 [0.04 to 0.11]), and the global cardiometabolic risk score (β [95% CI] = 0.278 [0.017 to 0.540]; 0.017 [0.001 to 0.033]) after adjustment for sociodemographic, lifestyle, and psychological factors. In addition, childhood adversity was associated with low high density lipoprotein levels (β [95% CI] = -0.021 [-0.042 to 0.000]), as well as increased fat mass and systolic blood pressure levels (β [95% CI] = 0.506 [0.165 to 0.846]; 0.952 [0.165 to 1.740]) and stress in remote adulthood with apolipoprotein B levels (β [95% CI] = 0.607 [0.312 to 0.901]). Psychological factors did not account for these associations and were not effect modifiers. Our data demonstrate that psychosocial stress during childhood and remote adulthood favor adiposity and abnormal lipid metabolism.

Abstract 133: Endothelial-Specific Interference With PPARγ Increases the Susceptibility to Angiotensin II-Induced Endothelial Dysfunction in Adult Offspring Born from AVP-Infused Pregnancies

Mutations in the ligand-activated transcription factor PPARγ result in hypertension, and synthetic agonists of PPARγ reduce blood pressure. Previously we found that mice expressing dominant-negative (DN) PPARγ driven by an endothelium-specific promoter (E-DN) exhibit vascular dysfunction. Preeclampsia (PE) is a hypertensive disorder of pregnancy which carries cardiovascular risk to offspring. PE is also associated with vascular dysfunction. We hypothesized a role for endothelial PPARγ in the pathogenesis of PE and its sequelae. C57BL/6J dams were bred with E-DN sires, and symptoms of PE were induced by infusion of vasopressin (AVP, 24 ng/hr sc) throughout gestation. Phenotypes of PE were first assessed in pregnant dams and then in adult offspring. Compared to saline infusion (SAL), AVP elevated maternal blood pressure (SBP: 116±3 vs 107±3, p<0.05) at gestational day (GD) 14-15 and urine protein (70±6 vs 27±4 mg/mL, p<0.05) at GD17. Offspring were phenotyped in adulthood. Data were stratified to sex, genotype, and exposure to AVP or SAL. At 20 weeks of age, SBP and vasorelaxation responses to acetylcholine were similar in offspring exposed to PE compared to mice born from SAL pregnancies. Adult offspring were next exposed to a sub-pressor dose of Angiotensin II (ANG; 120ng/kg/hr) for 14 days. Adult male ANG-treated E-DN born to PE pregnancies, but not NT mice exhibited significant impairment in ACh-induced relaxation in carotid artery (% relaxation: 62±10 vs 86±11, p<0.05). Adult female ANG-treated E-DN exposed to PE also exhibited a trend for impaired endothelial function compared to NT controls (% relaxation: 63±9 vs 72±10). Endothelial dysfunction in male ANG-treated E-DN born to PE pregnancies was attenuated by tempol (relaxation improved from 56±9% vs 81±12%, p<0.05), indicative of oxidative stress, and by a Rho-kinase inhibitor (relaxation improved from 73±11% vs 89±12%, p<0.05). This data suggests that interference with endothelial PPARγ in pups born from PE pregnancies increases the risk for endothelial dysfunction upon exposure to a cardiovascular stressor in adulthood. Thus, conditions which impair PPARγ activity, such as obesity and diabetes, may predispose adult offspring born from PE pregnancy to cardiovascular disease.