Relationship between hair cortisol concentrations and cognitive functioning in adolescents with ADHD.

Background: Our study aimed to explore whether the hair cortisol concentration (HCC), a measure of long-term cortisol output, is associated with poorer cognitive functioning in adolescents with attention deficit and hyperactivity disorder (ADHD). We further aimed to test the potential moderating effects of sex and childhood maltreatment.Methods: In this cross-sectional study, fifty-three adolescents with ADHD were studied. The ADHD Rating Scale (ADHD-RS) and Childhood Trauma Questionnaire (CTQ) were administered. Seven cognitive tasks from the Cambridge Neuropsychological Test Automated Battery (CANTAB) were administered, and two cognitive factors (attention and memory and executive functioning) were identified by confirmatory factor analysis. A 3-cm hair sample from the posterior vertex region of the head was obtained. HCCs were determined by a high-sensitivity enzyme immunoassay kit. Multiple linear regression analyses were used to explore the association between HCCs and either cognitive performance or ADHD severity while adjusting for sex, childhood maltreatment and the ADHD-RS total score.Results: Sex moderated the relationship between HCCs and attention/memory confirmatory factor analysis (CFA) scores, with better performance in boys with higher HCCs. HCCs were not associated with executive functioning or ADHD symptoms. Childhood maltreatment was associated with inattention symptoms in adolescents with ADHD.Conclusions: Our study suggests that HCCs are positively associated with attention and memory performance in adolescents with ADHD, with a moderating effect of sex (the relationship is strongest in boys).

We studied the relationship between cortisol and cognition in adolescents with ADHD.Hair cortisol concentrations (HCCs) were determined.We explored the moderating effects of sex and childhood trauma.Sex moderated the relationship between HCCs and attention and memory.Childhood trauma did not moderate the relationship between HCCs and cognition.

Animal models of PTSD: Comparison of the neuroendocrine and behavioral sequelae of immobilization and a modified single prolonged stress procedure that includes immobilization.

A single exposure to some stressors results in long-lasting consequences reminiscent of those found in post-traumatic stress disorder (PTSD), but results are very often controversial. Although there is no consensus regarding the best animal models of PTSD, the single prolonged stress (SPS) model, consisting of sequential exposure within the same day to various stressors (typically restraint, forced swim, and ether), has gained acceptance. However, results, particularly those related to the hypothalamic-pituitary-adrenal (HPA) axis, are inconsistent and there is no evidence that SPS is clearly distinct from models using a single severe stressor. In the present study, we compared in male rats the behavioral and neuroendocrine (HPA) consequences of exposure to immobilization on boards (IMO) with a SPS-like model (SPSi) in which IMO and isoflurane were substituted for restraint and ether, respectively. Both procedures caused a similar impact on food intake and body weight as well as on sensitization of the HPA response to a novel environment (hole-board) on the following day. Reduction of activity/exploration in the hole-board was also similar with both stressors, although the impact of sudden noise was higher in SPSi than IMO. Neither IMO nor SPSi significantly affected contextual fear conditioning acquisition, although a similar trend for impaired fear extinction was observed compared to controls. Exposure to additional stressors in the SPSi did not interfere with homotypic adaptation of the HPA axis to IMO. Thus, only modest neuroendocrine and behavioral differences were observed between IMO and SPSi and more studies comparing putative PTSD models are needed.

Differential Hypothalamic-pituitary-adrenal Response to Stress among Rat Strains: Methodological Considerations and Relevance for Neuropsychiatric Research.

The hormones of the hypothalamic-pituitary-adrenal (HPA) axis, particularly glucocorticoids (GCs), play a critical role in the behavioral and physiological consequences of exposure to stress. For this reason, numerous studies have described differences in HPA function between different rodent strains/lines obtained by genetic selection of certain characteristics not directly related to the HPA axis. These studies have demonstrated a complex and poorly understood relationship between HPA function and certain relevant behavioral characteristics. The present review first remarks important methodological considerations regarding the evaluation and interpretation of resting and stress levels of HPA hormones. Then, it presents works in which differences in HPA function between Lewis and Fischer rats were explored as a model for how to approach other strain comparisons. After that, differences in the HPA axis between classical strain pairs (e.g. High and Low anxiety rats, Roman high- and low-avoidance, Wistar Kyoto versus Spontaneously Hypertensive or other strains, Flinder Sensitive and Flinder Resistant lines) are described. Finally, after discussing the relationship between HPA differences and relevant behavioral traits (anxiety-like and depression-like behavior and coping style), an example for main methodological and interpretative concerns and how to test strain differences is offered.

The relationship between sex, personality traits, and the hypothalamic-pituitary-adrenocortical axis.

The aim of our study was to examine whether there are sex-based differences in the relationship between personality traits and hypothalamic-pituitary-adrenal (HPA) axis measures. A total of 106 healthy volunteers (56.6% women; age: 48.0 ± 15.8 years) were studied. The revised temperament and character inventory (TCI-R) and the Childhood Trauma Questionnaire (CTQ) were administered. HPA axis function was assessed using three dynamic measures: the cortisol awakening response (CAR), the diurnal cortisol slope, and the cortisol suppression ratio with 0.25 mg of dexamethasone (DSTR). Female sex was associated with an increased CAR and a more flattened diurnal cortisol slope, although a negative significant interaction between harm avoidance and female sex was found. Regarding the DSTR, perseverance was associated with increased cortisol suppression after dexamethasone; sex did not affect this association. Our study suggests that the relationship between specific personality traits (harm avoidance) and HPA axis measures (CAR, diurnal slope) differs according to sex.

Stress-related biomarkers and cognitive functioning in adolescents with ADHD: Effect of childhood maltreatment.

Our study aimed to explore whether stress-related hormones (hypothalamic-pituitary-adrenal [HPA] axis hormones and prolactin) are associated with poorer cognitive functioning in adolescents with attention deficit and hyperactivity disorder (ADHD) and to test the potential moderating effect of childhood maltreatment. Seventy-six adolescents with ADHD were studied. The ADHD rating scale (ADHD-RS) and Childhood Trauma Questionnaire (CTQ) were administered. Seven cognitive tasks from the Cambridge Neuropsychological Test Automated Battery (CANTAB) were administered, and two cognitive factors (attention and memory as well as executive functioning) were identified by confirmatory factor analysis. Stress-related hormone levels were assessed at the clinic (plasma prolactin and cortisol levels and salivary cortisol levels) before cognitive testing and at home for two consecutive days (cortisol awakening response [CAR] and diurnal cortisol slope). Multiple linear regression analyses were used to explore the association between hormone levels and ADHD severity or cognitive functioning while adjusting for sex and childhood maltreatment. Regarding hormonal measurements obtained at the clinic, female sex moderated the relationship between salivary cortisol levels and executive functioning, whereas childhood maltreatment moderated the relationship between salivary cortisol levels and inattention symptoms of patients with ADHD. Prolactin levels were not associated with cognitive functioning or the severity of ADHD. Regarding HPA axis measurements performed at home, lower cortisol levels at awakening were associated with poorer executive functioning. Neither CAR nor the cortisol diurnal slope were associated with cognitive functioning or ADHD severity. Our study suggests that HPA axis hormone levels are associated with the severity of cognitive and inattention symptoms of patients with ADHD and that childhood maltreatment and sex exert distinct moderating effects depending on the symptom type.

Non-communicable diseases among women survivors of intimate partner violence: Critical review from a chronic stress framework.

A neurobiological framework of chronic stress proposes that the stress-response system can be functionally altered by the repeated presentation of highly stressful situations over time. These functional alterations mainly affect brain processing and include the dysregulation of the hypothalamic-pituitary-adrenal axis and associated processes. In the present critical review, we translate these results to inform the clinical presentation of women survivors of intimate partner violence (IPV). We approach IPV as a scenario of chronic stress where women are repetitively exposed to threat and coping behaviours that progressively shape their neurobiological response to stress. The changes at the central and peripheral levels in turn correlate with the phenotypes of non-communicable diseases. The reviewed studies clarify the extent of the impact of IPV on women's health in large (N > 10,000) population-based designs, and provide observations on experimental neuroendocrine, immune, neurocognitive and neuroimaging research linking alterations of the stress-response system and disease. This evidence supports the prevention of violence against women as a fundamental action to reduce the prevalence of non-communicable diseases.

Male long-Evans rats: An outbred model of marked hypothalamic-pituitary-adrenal hyperactivity.

Rat and mouse strains differ in behavioral and physiological characteristics, and such differences can contribute to explain discrepant results between laboratories and better select the most appropriate strain for a particular purpose. Differences in the activity of the hypothalamic-pituitary-adrenal (HPA) axis are particularly important given the pivotal role of this system in determining consequences of exposure to stressors. In this regard, Long-Evans (LE) rats are widely used in stress research, but there is no specific study aiming at thoroughly characterizing HPA activity in LE versus other extensively used strains. In a first experiment, LE showed higher resting ACTH and corticosterone levels only at certain points of the circadian rhythm, but much greater ACTH responsiveness to stressors (novel environment and forced swim) than Sprague-Dawley (SD) rats. Accordingly, enhanced corticotropin-releasing hormone (CRH) expression in the paraventricular nucleus of the hypothalamus and reduced expression of glucocorticoid receptors were observed in the hippocampal formation. Additionally, they are hyperactive in novel environments, and prone to adopt passive-like behavior when compared to SD rats. Supporting that altered HPA function has a marked physiological impact, we observed in another set of animals much lower thymus weight in LE than SD rats. Finally, to demonstrate that LE rats are likely to have higher HPA responsiveness to stressors than most strains, we studied resting and stress levels of HPA hormones in LE versus Wistar and Fischer rats, the latter considered an example of high HPA responsiveness. Again, LE showed higher resting and stress levels of ACTH than both Wistar and Fischer rats. As ACTH responsiveness to stressors in LE rats is stronger than that previously reported when comparing other rat strains and they are commercially available, they could be an appropriate model for studying the behavioral and physiological implications of a hyper-active HPA axis under normal and pathological conditions.

Individual differences in the neuroendocrine response of male rats to emotional stressors are not trait-like and strongly depend on the intensity of the stressors.

Biological response to stressors is critical to understand stress-related pathologies and vulnerability to psychiatric diseases. It is assumed that we can identify trait-like characteristics in biological responsiveness by testing subjects in a particular stressful situation, but there is scarce information on this issue. We then studied, in a normal outbred population of adult male rats (n = 32), the response of well-characterized stress markers (ACTH, corticosterone and prolactin) to different types of stressors: two novel environments (open-field, OF1 and OF2), an elevated platform (EP), forced swim (SWIM) and immobilization (IMO). Based on both plasma ACTH and prolactin levels, the OF1 was the lowest intensity situation, followed by the OF2 and the EP, then SWIM and finally IMO. When correlations between the individual responses to the different stressors were studied, the magnitude of the correlations was most dependent on the similarities in intensity rather than on other characteristics of stressors, with good correlations between similar intensity stressors and no correlations at all were found between stressors markedly differing in intensity. In two additional confirmatory experiments (n = 37 and n = 20) with HPA hormones, we observed good correlation between the response to restraint and IMO, which were close in intensity, and no correlation between OF1 and SWIM. The present results suggest that individual neuroendocrine response to a particular stressor does not predict the response to another stressor greatly differing in intensity, thus precluding characterization of low or high responsive individuals to any stressor in a normal population. The present data have important implications for human studies.

Adaptability to acute stress among women survivors of intimate partner violence: protocol for a mixed-methods cross-sectional study in a laboratory setting (BRAW study).

INTRODUCTION: Intimate partner violence (IPV) is the most common and alarming form of violence against women, affecting around 30% of all women around the world. Using an integrative methodology, we approach IPV as a form of chronic exposure to severe stress that alters the stress-response system of exposed women. The aim of this study is to test the hypothesis that sustained exposure to IPV in women confers a vulnerability-to-stress profile characterised by higher neuroendocrine and behavioural responsiveness associated with a selective attentional processing bias towards threat. METHODS AND ANALYSIS: Women between 21 and 50 years old from the area of Barcelona (Spain) will be invited to participate. A sample of 82 women exposed to IPV and 41 women not exposed to IPV will be included and assessed for attentional bias and response to acute stress in a laboratory condition (the Trier Social Stress Task). The study will include quantitative and qualitative measures of cognitive performance, neuroendocrine activity and face-to-face interviews to obtain an integrative description of the stress-response profile of these women. Results are expected to help build resilience strategies with a long-lasting impression on women's healthy functioning. ETHICS AND DISSEMINATION: The study has obtained the approval of the local Ethics Committee ('Comité de Ética de Investigación Parc Taulí de Sabadell'; 2 018 551 V.1.2 June 2018). Besides the communication of results in peer-reviewed papers and scientific congresses, the project will inform guidelines and recommendations through policy-dialogues and workshops with relevant regional and national representatives for future work and prevention strategies. Participants will be invited to be an active part in the dissemination strategy focussed on raising awareness of coping limitations and abilities that women themselves will be able to identify throughout the study. TRIAL REGISTRATION DETAILS: The study has been registered at the ClinicalTrails.gov database (Identifier number: NCT03623555; Pre-results).

The Role of Sleep Quality, Trait Anxiety and Hypothalamic-Pituitary-Adrenal Axis Measures in Cognitive Abilities of Healthy Individuals.

Sleep plays a crucial role in cognitive processes. Sleep and wake memory consolidation seem to be regulated by glucocorticoids, pointing out the potential role of the hypothalamic-pituitary-adrenal (HPA) axis in the relationship between sleep quality and cognitive abilities. Trait anxiety is another factor that is likely to moderate the relationship between sleep and cognition, because poorer sleep quality and subtle HPA axis abnormalities have been reported in people with high trait anxiety. The current study aimed to explore whether HPA axis activity or trait anxiety moderate the relationship between sleep quality and cognitive abilities in healthy individuals. We studied 203 healthy individuals. We measured verbal and visual memory, working memory, processing speed, attention and executive function. Sleep quality was assessed with the Pittsburgh Sleep Quality Index. Trait anxiety was assessed with the State-Trait Anxiety Inventory. HPA axis measures included the cortisol awakening response (CAR), diurnal cortisol slope and cortisol levels during the day. Multiple linear regression analyses explored the relationship between sleep quality and cognition and tested potential moderating effects by HPA axis measures and trait anxiety. Poor sleep quality was associated with poorer performance in memory, processing speed and executive function tasks. In people with poorer sleep quality, a blunted CAR was associated with poorer verbal and visual memory and executive functions, and higher cortisol levels during the day were associated with poorer processing speed. Trait anxiety was a moderator of visual memory and executive functioning. These results suggest that subtle abnormalities in the HPA axis and higher trait anxiety contribute to the relationship between lower sleep quality and poorer cognitive functioning in healthy individuals.

Acute exposure of rats to a severe stressor alters the circadian pattern of corticosterone and sensitizes to a novel stressor: Relationship to pre-stress individual differences in resting corticosterone levels.

Traumatic events have been proposed to be associated with hypo-activity of the hypothalamic-pituitary-adrenal (HPA) axis, but data in animal models exposed to severe stressors are controversial and have important methodological concerns. Individual differences in resting or stress levels of corticosterone might explain some of the inconsistencies. We then studied this issue in male rats exposed to 2 h immobilization on boards (IMO), a severe stressor. Thirty-six rats were blood sampled under resting conditions four times a day on three non-consecutive days. Then, they were assigned to control (n = 14) or IMO (n = 22) to study the HPA response to IMO, the stressor-induced alterations in the circadian pattern of corticosterone (CPCORT), and the behavioral and HPA responsiveness to an open-field. Individual differences in pre-IMO resting corticosterone were inconsistent, but averaging data markedly improved consistency. The CPCORT was markedly altered on day 1 post-IMO (higher trough and lower peak levels), less altered on day 3 and apparently normal on day 7. Importantly, when rats were classified in low and high resting corticosterone groups (LCORT and HCORT, respectively), on the basis of the area under the curve (AUC) of the averaged pre-IMO data, AUC differences between LCORT and HCORT groups were maintained in controls but disappeared in IMO rats during the post-IMO week. Open-field hypo-activity and corticosterone sensitization were similar in LCORT and HCORT groups nine days after IMO. A single IMO exposure causes long-lasting HPA alterations, some of them dependent on pre-stress resting corticosterone levels, with no evidence for post-IMO resting corticosterone hypo-activity.

Modulation of KDM1A with vafidemstat rescues memory deficit and behavioral alterations.

Transcription disequilibria are characteristic of many neurodegenerative diseases. The activity-evoked transcription of immediate early genes (IEGs), important for neuronal plasticity, memory and behavior, is altered in CNS diseases and governed by epigenetic modulation. KDM1A, a histone 3 lysine 4 demethylase that forms part of transcription regulation complexes, has been implicated in the control of IEG transcription. Here we report the development of vafidemstat (ORY-2001), a brain penetrant inhibitor of KDM1A and MAOB. ORY-2001 efficiently inhibits brain KDM1A at doses suitable for long term treatment, and corrects memory deficit as assessed in the novel object recognition testing in the Senescence Accelerated Mouse Prone 8 (SAMP8) model for accelerated aging and Alzheimer's disease. Comparison with a selective KDM1A or MAOB inhibitor reveals that KDM1A inhibition is key for efficacy. ORY-2001 further corrects behavior alterations including aggression and social interaction deficits in SAMP8 mice and social avoidance in the rat rearing isolation model. ORY-2001 increases the responsiveness of IEGs, induces genes required for cognitive function and reduces a neuroinflammatory signature in SAMP8 mice. Multiple genes modulated by ORY-2001 are differentially expressed in Late Onset Alzheimer's Disease. Most strikingly, the amplifier of inflammation S100A9 is highly expressed in LOAD and in the hippocampus of SAMP8 mice, and down-regulated by ORY-2001. ORY-2001 is currently in multiple Phase IIa studies.

Focusing attention on biological markers of acute stressor intensity: Empirical evidence and limitations.

ARMARIO, A, J. Labad and R. Nadal. Focusing attention on biological markers of acute stressor intensity: empirical evidence and limitations. NEUROSCIENCE AND BIOBEHAVIORAL REVIEWS. The availability of biological markers that objectively quantify stress is a highly relevant issue. However, experimental evidence suggests that most physiological changes elicited by emotional stressors do not reflect their intensity and are not useful for this purpose. Thus, we review experimental evidence in animals and humans about the putative validity of neuroendocrine and sympathetic/parasympathetic variables to measure stress. Plasma levels of some hormones (e.g. ACTH, glucocorticoids, prolactin and catecholamines) have been found to reflect, at least under certain conditions, the intensity of emotional stressors in animals and probably in humans. However, the temporal resolution of hormone changes is insufficient to reflect the very dynamic psychological processes taking place while experiencing stressors. Cardiovascular parameters (e.g. heart rate and blood pressure) have much better temporal resolution but their validity as markers of stressor intensity either in animals or humans is problematic. Skin conductance and pupil dilation appear to be promising. Additional and more systematic studies are needed to demonstrate the actual validity of stress-induced physiological changes to quantify stress.

Neuropeptide-S-receptor deficiency affects sex-specific modulation of safety learning by pre-exposure to electric stimuli.

Neuropeptide S (NPS) is a neuropeptide involved in the regulation of fear. Because safety learning is impaired in patients suffering from anxiety-related psychiatric disorders, and polymorphisms of the human neuropeptide S receptor (NPSR) gene have also been associated with anxiety disorders, we wanted to investigate whether NPSR-deficiency interferes with safety learning, and how prior stress would affect this type of learning. We first investigated the effect of pre-exposure to two different types of stressors (electric stimuli or immobilization) on safety learning in female and male C57Bl/6 mice, and found that while stress induced by electric stimuli enhanced safety learning in males, there were no differences in safety learning following immobilization stress. To further investigate the role of the NPS system in stress-induced modulation of safety learning, we exposed NPSR-deficient mice to stress induced by electric stimuli 10 days before safety learning. In nonstressed male mice, NPSR-deficiency enhanced safety learning. As in male C57Bl/6 mice, pre-exposure to electric stimuli increased safety learning in male NPSR +/+ mice. This pre-exposure effect was blocked in NPSR-deficient male mice showing impaired, but still intact, safety learning in comparison to their NPSR +/+ and NPSR +/- littermates. There was neither a pre-exposure nor a genotype effect in female mice. Our findings provide evidence that pre-exposure to stress induced by electric stimuli enhances safety learning in male mice, and that NPSR-deficiency prevents the beneficial effect of stress exposure on safety learning. We propose an inverted U-shape relationship between stress and safety learning.

Sex-specific association between the cortisol awakening response and obsessive-compulsive symptoms in healthy individuals.

BACKGROUND: Previous studies have shown associations between obsessive-compulsive disorder (OCD) and hypothalamic-pituitary-adrenal axis activity (HPA). We aimed to investigate the association between obsessive-compulsive (OC) symptoms and HPA axis functionality in a non-clinical sample and to explore whether there are sex differences in this relationship. METHODS: One hundred eighty-three healthy individuals without any psychiatric diagnosis (80 men, 103 women; mean age 41.3 ± 17.9 years) were recruited from the general population. The Obsessive-Compulsive Inventory Revised (OCI-R) was used to assess OC symptoms. State-trait anxiety, perceived stress, and stressful life events were also assessed. Saliva cortisol levels were determined at 6 time points (awakening, 30 and 60 min post-awakening, 10:00 a.m., 23:00 p.m. and 10:00 a.m. the following day of 0.25 mg dexamethasone intake [that occurred at 23:00 p.m.]). Three HPA axis measures were calculated: cortisol awakening response (CAR), cortisol diurnal slope, and cortisol suppression ratio after dexamethasone (DSTR). Multiple linear regression analyses were used to explore the association between OC symptoms and HPA axis measures while adjusting for covariates. Our main analyses were focused on OCI-R total score, but we also explored associations with specific OC symptom dimensions. RESULTS: No significant differences were observed between males and females in OC symptoms, anxiety measures, stress, or cortisol measures. In the multiple linear regression analyses between overall OC symptoms and HPA axis measures, a female sex by OC symptoms significant interaction (standardized beta = - 0.322; p = 0.023) for the CAR (but not cortisol diurnal slope nor DSTR) was found. Regarding specific symptom dimensions, two other sex interactions were found: a blunted CAR was associated with obsessing symptoms in women, whereas a more flattened diurnal cortisol slope was associated with ordering symptoms in men. CONCLUSIONS: There are sex differences in the association between OC symptoms and HPA axis measures in healthy individuals.

Tratamiento con levotiroxina de los síntomas cognitivos persistentes en depresión mayor / Levothyroxine treatment for persistent cognitive symptoms in major depression

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Controllability affects endocrine response of adolescent male rats to stress as well as impulsivity and behavioral flexibility during adulthood.

Exposure to stress during adolescence exerts a long-term impact on behavior and might contribute to the development of several neuropsychiatric disorders. In adults, control over stress has been found to protect from the negative consequences of stress, but the influence of controllability at early ages has not been extensively studied. Here, we evaluated in a rodent model the effects of repeated exposure in adolescent male rats to controllable versus uncontrollable foot-shock stress (CST or UST, respectively). Rats were assigned to three groups: non-stress (stress-naïve), CST (exposed to 8 sessions of a two-way shuttle active avoidance task over a period of 22 days) and UST (receiving the same amount of shocks as CST, regardless of their actual behavior). During adulthood, different cohorts were tested in several tasks evaluating inhibitory control and cognitive flexibility: 5-choice serial reaction time, delay-discounting, gambling test and probabilistic reversal learning. Results showed that the hypothalamic-pituitary-adrenal response to the first shock session was similar in CST and UST animals, but the response to the 8th session was lower in CST animals. In adulthood, the UST animals presented impaired motor (but not cognitive) impulsivity and more perseverative behavior. The behavioral effects of UST were associated with increased number of D2 dopamine receptors in dorsomedial striatum, but not in other striatal regions. In summary, UST exposure during adolescence induced long-term impairments in impulsivity and compulsivity, whereas CST had only minor effects. These data support a critical role of stress uncontrollability on the long-lasting consequences of stress, as a risk factor for mental illnesses.

Clinical correlates of hypothalamic-pituitary-adrenal axis measures in individuals at risk for psychosis and with first-episode psychosis.

Hypothalamic-pituitary-adrenal (HPA) axis alterations in at-risk mental states (ARMS) resemble those observed in established psychosis but are less consistent. We aimed to explore HPA axis abnormalities in both first-episode psychosis (FEP) and ARMS patients, while controlling for psychopathological symptoms. We studied 21 ARMS, 34 FEP patients and 34 healthy subjects. Clinical assessment included psychopathological symptoms (positive, negative, disorganized, excited and depressive symptoms) and stress measures. Saliva cortisol levels were determined at awakening, 30' and 60' post-awakening, 10:00 h, 23:00 h and 10:00 h on the day after the administration of 0.25 mg of dexamethasone, which occurred at 23:00 h. Three HPA axis measures were calculated: cortisol awakening response (CAR), cortisol diurnal slope and cortisol suppression ratio of the dexamethasone suppression test (DST). There were no significant differences between groups in HPA axis measures. However, when exploring the relationship between HPA axis measures and psychopathological symptoms, in ARMS subjects (but not FEP patients), a flatter cortisol slope was associated with more prominent negative symptoms, whereas a blunted CAR was associated with excited symptoms. Although no significant differences in HPA axis measures were found between diagnostic groups, subtle abnormalities in the CAR or circadian cortisol rhythmicity might be important for the phenotype of ARMS individuals.

Early life stress in rats sex-dependently affects remote endocrine rather than behavioral consequences of adult exposure to contextual fear conditioning.

Exposure to electric foot-shocks can induce in rodents contextual fear conditioning, generalization of fear to other contexts and sensitization of the hypothalamic-pituitary-adrenal (HPA) axis to further stressors. All these aspects are relevant for the study of post-traumatic stress disorder. In the present work we evaluated in rats the sex differences and the role of early life stress (ELS) in fear memories, generalization and sensitization. During the first postnatal days subjects were exposed to restriction of nesting material along with exposure to a "substitute" mother. In the adulthood they were exposed to (i) a contextual fear conditioning to evaluate long-term memory and extinction and (ii) to a novel environment to study cognitive fear generalization and HPA axis heterotypic sensitization. ELS did not alter acquisition, expression or extinction of context fear conditioned behavior (freezing) in either sex, but reduced activity in novel environments only in males. Fear conditioning associated hypoactivity in novel environments (cognitive generalization) was greater in males than females but was not specifically affected by ELS. Although overall females showed greater basal and stress-induced levels of ACTH and corticosterone, an interaction between ELS, shock exposure and sex was found regarding HPA hormones. In males, ELS did not affect ACTH response in any situation, whereas in females, ELS reduced both shock-induced sensitization of ACTH and its conditioned response to the shock context. Also, shock-induced sensitization of corticosterone was only observed in males and ELS specifically reduced corticosterone response to stressors in males but not females. In conclusion, ELS seems to have only a minor impact on shock-induced behavioral conditioning, while affecting the unconditioned and conditioned responses of HPA hormones in a sex-dependent manner.