Early environmental regulation of glucocorticoid feedback sensitivity in young adult monkeys

Variations in maternal care induce in neonatal rodents life-long changes in glucocorticoid feedback regulation of the hypothalamic-pituitary-adrenal axis. This aspect of plasticity in neuroendocrine development has not been established in primates. We assessed, in young adult squirrel monkeys, postnatal rearing effects on cortisol-induced suppression of corticotropin-releasing factor (CRF) stimulated secretion of adrenocorticotropic hormone (ACTH). Offspring of randomly bred monkeys were periodically removed from natal groups between 13 and 21 weeks of age. In two other postnatal rearing conditions, systematic differences in maternal availability were produced by manipulating the effort required of lactating mothers to successfully find food. All offspring were subsequently administered, 3-5 years later on two occasions, an intravenous ovine CRF injection preceded 60 min earlier by placebo or cortisol pretreatment. The difference between CRF-stimulated time-integrated secretion of ACTH following placebo vs cortisol pretreatment served as an index of glucocorticoid negative feedback. Difference scores were greatest in monkeys previously separated from natal groups. This finding was not attributable to significant rearing condition differences in plasma cortisol levels achieved following pretreatment with exogenous cortisol, nor plasma ACTH levels produced when the CRF injection was preceded by pretreatment with placebo. The results suggest that postnatal experiences altered glucocorticoid feedback in monkeys at least through early adulthood. This conclusion supports retrospective reports indicating that, for humans with major mood and anxiety disorders, systematic differences in glucocorticoid feedback may reflect neural mechanisms in development linking early life stress with psychopathology in adulthood.     

Prenatal stress diminishes neurogenesis in the dentate gyrus of juvenile rhesus monkeys.

BACKGROUND: Early life stress, including during fetal development, has been hypothesized to predispose individuals to several illnesses and psychiatric disorders later in adulthood. METHODS: To determine whether prenatal stress alters neural, hormonal, and behavioral processes in nonhuman primates, pregnant rhesus monkeys were acutely stressed on a daily basis for 25% of their 24-week gestation with an acoustical startle protocol. At 2 to 3 years of age, hippocampal volume, neurogenesis in the dentate gyrus, and cortisol levels were evaluated in the offspring generated from stressed and control pregnancies. RESULTS: Prenatal stress, both early and late in pregnancy, resulted in a reduced hippocampal volume and an inhibition of neurogenesis in the dentate gyrus. These changes were associated with increased pituitary-adrenal activity, as reflected by higher cortisol levels after a dexamethasone suppression test, and also with behavioral profiles indicative of greater emotionality. CONCLUSIONS: These findings indicate that the prenatal environment can alter behavior, dysregulate neuroendocrine systems, and affect the hippocampal structure of primates in a persistent manner.     

Preliminary evidence that hippocampal volumes in monkeys predict stress levels of adrenocorticotropic hormone.

BACKGROUND: Hippocampal volumes previously determined in monkeys by magnetic resonance imaging are used to test the hypothesis that small hippocampi predict increased stress levels of adrenocorticotropic hormone (ACTH). METHODS: Plasma ACTH levels were measured after restraint stress in 19 male monkeys pretreated with saline or hydrocortisone. Monkeys were then randomized to an undisturbed control condition or intermittent social separations followed by new pair formations. After 17 months of exposure to the intermittent social manipulations, restraint stress tests were repeated to determine test/retest correlations. RESULTS: Individual differences in postrestraint stress ACTH levels over the 17-month test/retest interval were remarkably consistent for the saline (r(s) = .82, p = .0004) and hydrocortisone (r(s) = .78, p = .001) pretreatments. Social manipulations did not affect postrestraint stress ACTH levels, but monkeys with smaller hippocampal volumes responded to restraint after saline pretreatment with greater increases in ACTH levels with total brain volume variation controlled as a statistical covariate (beta = -.58, p = .031). Monkeys with smaller hippocampal volumes also responded with diminished sensitivity to glucocorticoid feedback determined by greater postrestraint ACTH levels after pretreatment with hydrocortisone (beta = -.68, p = .010). CONCLUSIONS: These findings support clinical reports that small hippocampi may be a risk factor for impaired regulation of the hypothalamic-pituitary-adrenal axis in humans with stress-related psychiatric disorders.     

Hippocampal volume in aging combat veterans with and without post-traumatic stress disorder: relation to risk and resilience factors

OBJECTIVE: To examine whether there are post-traumatic stress disorder (PTSD) related differences in hippocampal volume in middle-aged and elderly veterans and to examine the relationship of neuroendocrine activity, memory performance, and measures of risk and resilience for PTSD to hippocampal volume in this cohort. METHODS: Seventeen veterans with chronic PTSD and 16 veterans without chronic PTSD received an MRI scan followed by neuroendocrine assessment (24-h urinary cortisol excretion and the lysozyme IC(50-DEX), a measure of glucocorticoid receptor (GR) responsiveness), and cognitive testing. RESULTS: Veterans with PTSD did not differ from those without PTSD in hippocampal volume, but they did show significantly lower urinary cortisol levels, and poorer memory performance on the Wechsler Logical Memory test and Digit Span test. Smaller left hippocampal volumes were observed in veterans who developed PTSD in response to their first reported traumatic exposure, compared to veterans who had first experienced a traumatic event to which they did not develop PTSD, prior to experiencing a subsequent event that led to PTSD. In contrast, the two neuroendocrine measures were associated with risk factors related to early trauma exposure. CONCLUSION: Although hippocampal volume was not found to differ between subjects with and without PTSD, smaller hippocampal volumes in PTSD may be associated with specific risk and resilience factors. These may be distinct from vulnerability markers associated with increased responsiveness to glucocorticoids and/or other neuroendocrine measures that have been observed in combat-related PTSD.     

Prospective investigation of stress inoculation in young monkeys

BACKGROUND: Retrospective studies in humans have identified characteristics that promote stress resistance, including childhood exposure to moderately stressful events (ie, stress inoculation). OBJECTIVE: Because of limited opportunities for prospective studies in children, we tested whether exposure to moderate stress early in life produces later stress resistance in a primate model. DESIGN AND MAIN OUTCOME MEASURES: Twenty squirrel monkeys were randomized to intermittent stress inoculation (IS; n = 11) or a nonstress control condition (NS; n = 9) from postnatal weeks 17 to 27. At postnatal week 35, each mother-offspring dyad underwent testing in a moderately stressful novel environment for inferential measures of offspring anxiety (ie, maternal clinging, mother-offspring interactions, object exploration, and food consumption) and stress hormone concentrations (corticotropin [ACTH] and cortisol). At postnatal week 50, after acclimation to an initially stressful wire-mesh box attached to the home cage, independent young monkeys underwent testing for inferential measures of anxiety (ie, voluntary exploration and play) in the box. RESULTS: In the novel environment test, IS compared with NS offspring demonstrated diminished anxiety as measured by decreased maternal clinging (P =.02), enhanced exploratory behavior (P =.005), and increased food consumption (P =.02). Mothers of IS offspring accommodated offspring-initiated exploration (P =.009) and served as a secure base more often compared with NS mothers (P =.047). Compared with NS offspring, IS offspring had lower basal plasma ACTH (P =.001) and cortisol (P =.001) concentrations and lower corticotropin (P =.04) and cortisol (P =.03) concentrations after stress. In the subsequent home-cage wire-box test, IS offspring demonstrated enhanced exploratory (P<.001) and play (P =.008) behaviors compared with NS offspring. CONCLUSIONS: These results provide the first prospective evidence that moderately stressful early experiences strengthen socioemotional and neuroendocrine resistance to subsequent stressors. This preclinical model offers essential opportunities to improve our understanding and enhance prevention of human stress-related psychiatric disorders by elucidating the etiology and neurobiology of stress resistance.     

Linking the neuroendocrinology of post-traumatic stress disorder with recent neuroanatomic findings.

It has been hypothesized that stress damages the hippocampus and results in myriad other deleterious consequences owing to the toxic effects of cortisol, presumed to be released in excess in response to traumatic stress. Several studies have now demonstrated that hippocampal volumes of trauma survivors with post-traumatic stress disorder (PTSD) are reduced compared to those of nontraumatized persons. Interestingly, however, there is little evidence of increased cortisol release in either the acute or chronic aftermath of stress in trauma survivors who develop this disorder, raising questions about the etiology of the smaller hippocampal volumes as well as the relationship between the neuroendocrine and neuroanatomic alterations in PTSD. This article will review hypothalamic-pituitary-adrenal alterations in PTSD in an attempt to link the neuroendocrine findings with the observation of reduced hippocampal volume. It will be argued that the resolution of the neuroendocrine and neuroanatomic alterations in PTSD depends on understanding the pivotal role of glucocorticoids and their action at glucocorticoid receptors at target brain areas in response to stress and in PTSD.     

Longitudinal changes in amygdala,hippocampus and cortisol development following early caregiving adversity

Although decades of research have shown associations between early caregiving adversity, stress physiology and limbic brain volume (e.g., amygdala, hippocampus), the developmental trajectories of these phenotypes are not well characterized. In the current study, we used an accelerated longitudinal design to assess the development of stress physiology, amygdala, and hippocampal volume following early institutional care. Previously Institutionalized (PI; N = 93) and comparison (COMP; N = 161) youth (ages 4–20 years old) completed 1–3 waves of data collection, each spaced approximately 2 years apart, for diurnal cortisol (N = 239) and structural MRI (N = 156). We observed a developmental shift in morning cortisol in the PI group, with blunted levels in childhood and heightened levels in late adolescence. PI history was associated with reduced hippocampal volume and reduced growth rate of the amygdala, resulting in smaller volumes by adolescence. Amygdala and hippocampal volumes were also prospectively associated with future morning cortisol in both groups. These results indicate that adversity-related physiological and neural phenotypes are not stationary during development but instead exhibit dynamic and interdependent changes from early childhood to early adulthood.     

The role of early adverse experience and adulthood stress in the prediction of neuroendocrine stress reactivity in women: a multiple regression analysis

Sensitization of stress-responsive neurobiological systems as a possible consequence of early adverse experience has been implicated in the pathophysiology of mood and anxiety disorders. In addition to early adversities, adulthood stressors are also known to precipitate the manifestation of these disorders. The present study sought to evaluate the relative role of early adverse experience vs. stress experiences in adulthood in the prediction of neuroendocrine stress reactivity in women. A total of 49 women (normal volunteers, depressed patients, and women with a history of early abuse) underwent a battery of interviews and completed dimensional rating scales on stress experiences and psychopathology, and were subsequently exposed to a standardized psychosocial laboratory stressor. Outcome measures were plasma adrenocorticotropin (ACTH) and cortisol responses to the stress test. Multiple linear regression analyses were performed to identify the impact of demographic variables, childhood abuse, adulthood trauma, major life events in the past year, and daily hassles in the past month, as well as psychopathology on hormonal stress responsiveness. Peak ACTH responses to psychosocial stress were predicted by a history of childhood abuse, the number of separate abuse events, the number of adulthood traumas, and the severity of depression. Similar predictors were identified for peak cortisol responses. Although abused women reported more severe negative life events in adulthood than controls, life events did not affect neuroendocrine reactivity. The regression model explained 35% of the variance of ACTH responses. The interaction of childhood abuse and adulthood trauma was the most powerful predictor of ACTH responsiveness. Our findings suggest that a history of childhood abuse per se is related to increased neuroendocrine stress reactivity, which is further enhanced when additional trauma is experienced in adulthood.     

Cortisol levels in relation to hippocampal sub-regions in subjects with first episode schizophrenia

The etiology of hippocampal volumetric reductions in schizophrenia is largely unknown. In addition to genetic factors, environmental factors might also play a role. High levels of glucocorticoids are known to affect hippocampal volume in disorders such as Cushing's syndrome, but the relationship between cortisol and hippocampal volumes has not been studied in schizophrenia. We obtained diurnal salivary cortisol levels and MRI images to explore the link between cortisol levels and regional hippocampal volumes in healthy controls (N=29) and subjects with first episode schizophrenia (N=16) at the time of first admission. T1-weighted coronal MR images (slice thickness=1.5 mm) were acquired through the whole head using a 3D Fast SPGR IR Prep sequence on a 1.5 T GE imaging system. Using ANOVA, cumulative daily cortisol exposure calculated as area under the curve for each subject revealed significantly higher cortisol levels in the patient group [F(1,43)=4.4 p=0.04]. However, there were no statistically significant associations between the cortisol measures and regional hippocampal volumes in the subjects, except a trend level link between anterior hippocampal volume and cortisol in the positive direction, in parallel to previous findings in healthy adolescents. Our findings do not suggest a robust association between cortisol levels and hippocampal volumes in a first episode schizophrenia sample. Larger scale studies are needed to conclude a link between the two measures, yet it is possible that the negative association that was previously shown in other disorders may not apply to schizophrenia.     

Interaction with stressed mothers affects corticosterone levels in pups after reunion and impairs the response to dexamethasone in adult mice

BACKGROUND: Early adverse experiences are preeminent factors for the development of affective disorders. In the present study, we analyzed the effects of different postnatal manipulations applied either on the mother or on the offspring in mice. Maternal behavior and adrenocortical activity of both mothers and offspring at the end of postnatal stress and at adulthood were considered. METHODS: From postnatal day (PND) 1 to 14 mice underwent 15min of: (a) brief (15min) pups' exposure to clean bedding (CB: clean bedding), (b) mothers' exposure to the odor of a novel male (SM: stressed mother) or (c) mothers' exposure to a clean cage (CSM: control stressed mother), and (d) standard rearing (N-H: non-handled). The behavior of mouse dams during and after stress sessions was analyzed. Serum corticosterone of mothers and pups at the end of the stress session and 30min after reunion was assessed on PND 14. Moreover, anxiety levels and HPA-axis inhibitory feedback in response to dexamethasone administration were evaluated in adult male offspring. RESULTS: Overall, during the 14 days of treatment CB mothers when reunited with their pups showed higher maternal behavior than other dams. After the last stress (PND 14) SM and CSM maternal corticosterone levels increased as well as those of CB pups. While 30min of mother-infant interaction restored baseline corticosterone levels in SM and CSM mothers and in CB pups, SM and CSM offspring showed a decrease of corticosterone under baseline levels. At adulthood, SM and CSM males did not show the suppressive hormonal response to dexamethasone treatment. Moreover, adult CB and SM male mice displayed decreased anxiety in the open field. CONCLUSIONS: Maternal psychosocial stress during lactation seems to permanently affect the offspring's HPA functioning. These effects may be dissociated from the behavioral response as suggested by the decrease of anxiety in SM and CB adult mice.     

Prepubertal stress and hippocampal function: Sex‐specific effects

The chances of developing psychiatric disorders in adulthood are increased when stress is experienced early in life. In particular, stress experienced in the childhood or ‘prepubertal' phase is associated with the later development of disorders such as depression, anxiety, post‐traumatic stress disorder, and psychosis. Relatively little is known about the biological basis of this effect, but one hypothesis is that prepubertal stress produces long‐lasting changes in brain development, particularly in stress sensitive regions such as the hippocampus, leaving an individual vulnerable to disorders in adulthood. In this study, we used an animal model of prepubertal stress to investigate the hypothesis that prepubertal stress induces alterations in hippocampal function in adulthood. Male and female rats were exposed to a brief, variable prepubertal stress protocol (postnatal days 25–27), and their performance in two distinct hippocampal‐dependent tasks (contextual fear and spatial navigation) was compared with controls in adulthood. Prepubertal stress significantly impaired contextual fear responses in males and enhanced performance in spatial navigation in females. These results demonstrate that exposure to a brief period of stress in the prepubertal phase alters hippocampal‐dependent behaviors in adulthood in a sex‐specific manner. © 2014 Wiley Periodicals, Inc.     

Stress-induced changes in corticosteroid receptor expression in primate hippocampus and prefrontal cortex

Neurobiological studies of stress often focus on the hippocampus where cortisol binds with different affinities to two types of corticosteroid receptors, i.e., mineralocorticoid receptor (MR) and glucocorticoid receptor (GR). The hippocampus is involved in learning and memory, and regulates the neuroendocrine stress response, but other brain regions also play a role, especially prefrontal cortex. Here, we examine MR and GR expression in adult squirrel monkey prefrontal cortex and hippocampus after exposure to social stress in infancy or adulthood. In situ hybridization histochemistry with (35)S-labeled squirrel monkey riboprobes and quantitative film autoradiography were used to measure the relative distributions of MR and GR mRNA. Distinct cortical cell layer-specific patterns of MR expression differed from GR expression in three prefrontal regions. The relative distributions of MR and GR also differed in hippocampal Cornu Ammonis (CA) regions. In monkeys exposed to adult social stress compared to the no-stress control, GR expression was diminished in hippocampal CA1 (P=0.021), whereas MR was diminished in cell layer III of ventrolateral prefrontal cortex (P=0.049). In contrast, exposure to early life stress diminished GR but not MR expression in cell layers I and II of dorsolateral prefrontal cortex (P's<0.048). Similar reductions likewise occurred in ventrolateral prefrontal cortex, but the effects of early life stress on GR expression in this region were marginally not significant (P=0.053). These results provide new information on regional differences and the long-term effects of stress on MR and GR distributions in corticolimbic regions that control cognitive and neuroendocrine functions.     

Cortisol levels and hippocampus volumes in healthy preadolescent children.

BACKGROUND: Research in animal models has demonstrated that elevated levels of glucocorticoids can inflict damage within the hippocampus. In adult humans, elevated cortisol levels have been associated with reduced hippocampal volumes; however, normative data in children are not available. The objective of this study was to examine possible associations of serum cortisol levels with hippocampal volumes and morphology in healthy children. METHODS: Morning serum cortisol levels and hippocampus magnetic resonance imaging were measured in 17 healthy children (8 girls, 9 boys) between 7 and 12 years of age. RESULTS: Cortisol levels were not associated with total hippocampal volumes; however, with an analysis of surface morphology, significant associations were found for regionally specific portions of the hippocampus. Positive associations were detected for the anterior segment of the hippocampus and inverse associations along the lateral aspects of the hippocampus. CONCLUSIONS: Associations of cortisol levels with regionally specific variations in hippocampal morphology were detected during early development in healthy preadolescent children.     

Associations among parenting experiences during childhood and adolescence, hypothalamus-pituitary-adrenal axis hypoactivity, and hippocampal gray matter volume reduction in young adults

Recent human studies have indicated that adverse parenting experiences during childhood and adolescence are associated with adulthood hypothalamus-pituitary-adrenal (HPA) axis hypoactivity. Chronic HPA axis hypoactivity inhibits hippocampal gray matter (GM) development, as shown by animal studies. However, associations among adverse parenting experiences during childhood and adolescence, HPA axis activity, and brain development, particularly hippocampal development, are insufficiently investigated in humans. In this voxel-based structural magnetic resonance imaging study, using a cross-sectional design, we examined the associations among the scores of parental bonding instrument (PBI; a self-report scale to rate the attitudes of parents during the first 16 years), cortisol response determined by the dexamethasone/corticotropin-releasing hormone test, and regional or total hippocampal GM volume in forty healthy young adults with the following features: aged between 18 and 35 years, no cortisol hypersecretion in response to the dexamethasone test, no history of traumatic events, or no past or current conditions of significant medical illness or neuropsychiatric disorders. As a result, parental overprotection scores significantly negatively correlated with cortisol response. Additionally, a significant positive association was found between cortisol response and total or regional hippocampal GM volume. No significant association was observed between PBI scores and total or regional hippocampal GM volume. In conclusion, statistical associations were found between parental overprotection during childhood and adolescence and adulthood HPA axis hypoactivity, and between HPA axis hypoactivity and hippocampal GM volume reduction in healthy young adults, but no significant relationship was observed between any PBI scores and adulthood hippocampal GM volume.     

Mild early life stress enhances prefrontal-dependent response inhibition in monkeys.

BACKGROUND: Severely stressful early experiences have been implicated in the pathophysiology of psychiatric disorders. In contrast, exposure to mild early life stress (i.e., stress inoculation) strengthens emotional and neuroendocrine resistance to subsequent stressors. Herein we extend this research to examine the effects of mild early life stress on cognition. METHODS: Squirrel monkeys were randomized to a mild intermittent stress (IS; n = 11) or nonstress (NS; n = 9) condition from 17 to 27 weeks postpartum. At 1.5 years of age, monkeys were assessed for response inhibition on a test previously shown to reflect prefrontal-dependent cognitive function. RESULTS: IS monkeys demonstrated fewer response inhibition errors compared with NS monkeys. There were no rearing-related differences in aspects of performance that did not require inhibitory control. Compared with NS monkeys, IS monkeys had lower basal plasma pituitary-adrenal stress hormone levels. No rearing-related differences on neuroendocrine measures obtained 15 minutes after testing were found. CONCLUSIONS: Results from this experiment provide the first evidence that exposure to mildly stressful early experiences improves prefrontal-dependent response inhibition in primates. Combined with our previous data, findings from this animal model suggest that exposure to mild early life stress may enhance the development of brain systems that regulate emotional, neuroendocrine, and cognitive control.     

Behavioural and neuroendocrine adaptations to repeated stress during puberty in male golden hamsters

In adult animals, the consequences of stress are often severe and long lasting. Repeated subjugation in adult male golden hamsters inhibits aggression and increases submissive and avoidant behaviours. By contrast, subjugation during puberty enhances offensive aggression. The goals of this study were to characterize behavioural and neuroendocrine responses of naïve and repeatedly subjugated juveniles to social defeat and to assess potential recovery from social stress. From the onset of puberty on postnatal day 28 (P28) to mid puberty (P42), animals were either socially subjugated or placed in a clean and empty cage for 20 min daily. The subjugated and control groups were further divided into subgroups and sacrificed under basal conditions or after social defeat on P28, P35 (early puberty), P45 (mid puberty) and P70 (early adulthood). On P35 and P45, repeatedly subjugated juveniles showed a complete inhibition of olfactory investigation (i.e. risk assessment) towards aggressive adults. Repeatedly subjugated also animals had lower postdefeat cortisol levels than controls on P45. Interestingly, basal cortisol levels increased gradually during puberty but did not differ between treatment groups at any point. Repeated subjugation was also associated with increased tyrosine hydroxylase immunoreactivity (ir‐TH) within the extended medial amygdala. After a 4‐week recovery period, none of these variables differed between subjugated and control groups. In an additional experiment, subjugated adults also had increased ir‐TH in the medial extended amygdala, suggesting that these neurones are particularly responsive to social stress. In conclusion, puberty may be a developmental period characterized by behavioural and neuroendocrine plasticity in stress responsiveness. Furthermore, peri‐pubertal changes in stress hormones may explain why juvenile hamsters are more resilient to social stress than adults.     

Hippocampal volume and mood disorders after traumatic brain injury.

BACKGROUND: Recent evidence from clinical studies and animal models of traumatic brain injury (TBI) suggest that neuronal and glial loss might progress after the initial insult in selectively vulnerable regions of the brain such as the hippocampus. There is also evidence that hippocampal dysfunction plays a role in the pathogenesis of mood disorders. We examined the relationship between hippocampal damage and mood disorders after TBI and the effect of hippocampal atrophy on the outcome of TBI patients. METHODS: The study group consisted of 37 patients with closed head injury who were evaluated at baseline and at 3, 6, and 12 months after trauma. Psychiatric diagnosis was made with a structured clinical interview and DSM-IV criteria. Quantitative magnetic resonance imaging scans were obtained at 3-months follow-up. RESULTS: Patients with moderate to severe head injury had significantly lower hippocampal volumes than patients with mild TBI. Patients who developed mood disorders had significantly lower hippocampal volumes than patients without mood disturbance. Furthermore, there was a significant interaction between mood disorders diagnosis and severity of TBI, by which patients with moderate to severe TBI who developed mood disorders had significantly smaller hippocampal volumes than patients with equivalent severe TBI who did not develop mood disturbance. Finally, reduced hippocampal volumes were associated with poor vocational outcome at 1-year follow-up. CONCLUSIONS: Our findings are consistent with a "double-hit" mechanism by which neural and glial elements already affected by trauma are further compromised by the functional changes associated with mood disorders (e.g., the neurotoxic effects of increased levels of cortisol or excitotoxic damage resulting from overactivation of glutaminergic pathways). Finally, patients with greater hippocampal damage were less likely to return to a productive life 1 year after trauma.     

Changes in plasma levels of BDNF and NGF reveal a gender-selective vulnerability to early adversity in rhesus macaques

Early stressful events can increase vulnerability for psychopathology, although knowledge on the effectors is still limited. Here we tested the hypothesis that peripheral levels of brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF), which are involved in the response to stress and in the pathophysiology of anxiety and depression, might be affected in a non-human primate model of adverse rearing. Males and females rhesus macaques reared with their mothers (MR) or in peer-only groups (PR) were used as experimental subjects. BDNF, NGF, adrenocorticotropic hormone (ACTH), cortisol and growth hormone (GH) were determined at baseline on postnatal days (PND) 14, 30 and 60 by means of specific ELISA and RIA procedures. In addition, behavior was assessed on PND 7, 14, 21, 30 (Brazelton test) and 60 (home cage observation). Data indicate gender differences in basal levels of BDNF throughout development. Peer-rearing increased significantly BDNF levels only in females. In addition, while all peer-reared subjects showed high levels of stereotypies and self-directed behaviors, behavioral passivity was selectively increased in females. By contrast, NGF levels were increased in response to peer-rearing only in males, and correlated positively with other "classic" endocrine responses to stress, such as cortisol and GH. Our data identify BDNF and NGF as neuroendocrine markers underlying differential responses to maternal deprivation in males and females rhesus macaques. The selective changes in BDNF levels in females could help explain the greater vulnerability to mood disorders of this gender reported in humans.     

Hippocampal volume reduction and HPA-system activity in major depression

Structural imaging studies investigating hippocampal volumes in patients suffering from major depression have yielded mixed results. Here, 24 unipolar depressed in-patients and 14 healthy controls carefully matched for age, gender, and years of education underwent quantitative magnetic resonance imaging (MRI). Saliva cortisol was measured at 0800 and 1600 h in patients during a one-week wash-out and the following 4 weeks. Hippocampal volumes were significantly reduced in the patient group even after adjusting for intracranial brain volume (ICV) and age. Across groups, age was significantly negatively correlated with uncorrected hippocampal volumes. In patients, severity of disease (baseline HAMD scores) and baseline cortisol levels were not related to hippocampal volumes. However, there was a negative association between duration of the index episode before hospitalization and hippocampal volumes. Additionally, hippocampal volumes were significantly negatively correlated with duration of illness. Finally, we observed a trend for higher hippocampal volumes in those patients who showed a subsequent decrease in cortisol levels under pharmacotherapy.     

Transforming growth factor-beta 1 and cortisol in differentially reared primates

Exposure of primate infants to adverse rearing conditions during the first half year of life can result in enduring behavioral, neuroendocrine, and immunologic abnormalities. However, the effects of differential rearing on cytokines, some of which can regulate immune and inflammatory responses and modulate activity of the central nervous system and the hypothalamic-pituitary-adrenal (HPA) axis, are largely unexamined. The present study explored the relationship between circulating levels of transforming growth factor-beta 1 (TGF-beta 1) and cortisol in macaques reared either normally or under conditions of variable foraging demand (VFD). Under VFD rearing, for a period of 4 months, the infants' mothers intermittently had to expend more time and effort to obtain food than did the mothers of normally reared control subjects. Two years after cessation of the rearing experience, exposure to a moderate stressor (confinement in an unfamiliar room for 90 min) induced elevated levels of serum TGF-beta 1 and plasma cortisol in VFD-reared monkeys compared to normally reared controls. The correlation between TGF-beta 1 and cortisol levels was substantially higher in the normally reared subjects. Examination of the relationship between HPA axis and immune function will improve our understanding of the pathophysiological consequences of adverse rearing.