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Background: Early life stress (ELS) in macaques in the form of insecure maternal attachment putatively induces epigenetic adaptations resulting in a “thrifty phenotype” throughout the life cycle. For instance, ELS induces persistent increases in insulin resistance, hippocampal and corpus callosum atrophy and reduced “behavioral plasticity”, which, taken together, engenders an increased risk for mood and anxiety disorders in humans but also a putative sparing of calories. Herein, we test the hypothesis whether a thrifty phenotype induced by ELS is peripherally evident as hypotrophy of cardiac structure and function, raising the possibility that certain mood disorders may represent maladaptive physiological and central thrift adaptations. Methods: 14 adult bonnet macaques (6 males) exposed to the maternal variable foraging demand (VFD) model of ELS were compared to 20 non-VFD adult subjects (6 males). Left ventricle end-diastolic dimension (LVEDD), Left ventricle end-systolic dimension (LVESD) and stroke volume (SV) were calculated using echocardiography. Blood pressure and heart rate were measured only in females. Previously obtained neurobehavioral correlates available only in males were analyzed in the context of cardiac parameters. Results: Reduced LVESD (p

Introduction Early life stress (ELS) has been shown to play a role in establishing persistent maladaptive HPA axis modifications that may contribute to the pathogenesis of mood and anxiety disorders. Central glucocorticoid receptor (GR) messenger RNA (mRNA) expression may facilitate (mal)adaptive responsivity to ELS. The role of adult monocytic GR mRNA expression, a putative CNS proxy, during acute stress exposure was explored as well as the ELS marker, juvenile cerebrospinal fluid (CSF) corticotropin-releasing factor. Methods Six adult macaques (three of which were exposed to variable foraging demand, a form of ELS) underwent acute restraint. Baseline GR expression and plasma cortisol concentrations were separately measured followed by subsequent measurements following stress completion (t = 0 min, 4 h, 5 days and 7 days). Juvenile CSF CRF concentrations were available in five subjects to determine their developmental association with GR expression in response to stress. Results As expected acute restraint stress produced a significant increase in plasma cortisol concentrations most robustly observed at 4 h post-stress time point. There was a significant juvenile CSF CRF concentration x time interaction in predicting adult GR mRNA expression in response to stress (partial η2 = 0.80). During acute stress juvenile CRF concentrations negatively predicted GR expression and during recovery, “flipped” to positively predict expression. Juvenile CSF CRF concentrations positively correlated with the volatility of adult GR mRNA expression. Conclusions During acute stress, relatively high CSF CRF concentrations are associated with relatively rapid reductions in GR expression. Return to an ambient post-stress state was characterized by a direct relationship, consistent with increased HPA axis restraint in high CRF subjects. An ELS-associated allostatic adaptation suggests relative elevations of juvenile CSF CRF concentration set the stage for a relative hyper-volatility of adult GR mRNA expression in response to acute stress with potential long-term implications for HPA axis regulation.

Transforming growth factor-β1 (TGF-β1) is a multifunctional cytokine with anti-inflammatory, immunosuppressive, and neuroprotective properties. The hypothalamic-pituitary-adrenal axis and immune system exert bidirectional influences on each other, via cortisol and TGF-β1, but the exact nature of the interaction is not well characterized. The current study examined the effects, in bonnet macaques ( Macaca radiata), of two consecutive acute confinement stress periods in an unfamiliar room while mildly restrained, first without and then with dexamethasone pretreatment (0.01 mg/kg intramuscular). Preceding the confinement studies, a non-stress control condition obtained contemporaneous levels of cortisol and TGF-β1 in both plasma and cerebrospinal fluid to match the confinement stress studies. Subjects were reared under either normative or variable foraging demand conditions. Since there were no rearing effects at baseline or for any of the conditions tested—either for cortisol or TGF-β—the study analyses were conducted on the combined rearing groups. The stress condition increased both plasma and cerebrospinal fluid cortisol levels whereas dexamethasone pretreatment decreased cortisol concentrations to below baseline levels despite stress. The stress condition decreased TGF-β1 concentrations only in cerebrospinal fluid but not in serum. Together, the data suggested that stress-induced reductions of a centrally active neuroprotective cytokine occur in the face of hypothalamic-pituitary-adrenal axis activation, potentially facilitating glucocortoid-induced neurotoxicity. Stress-induced reductions of neuroprotective cytokines prompt exploration of protective measures against glucocorticoid-induced neurotoxicity.

Introduction Food insecurity is a major global contributor to developmental origins of adult disease. The allostatic load of maternal food uncertainty from variable foraging demand (VFD) activates corticotropin-releasing factor (CRF) without eliciting hypothalamic-pituitary-adrenal (HPA) activation measured on a group level. Individual homeostatic adaptations of the HPA axis may subserve second-order homeostasis, a process we provisionally term “social allostasis.” We postulate that maternal food insecurity induces a “superorganism” state through coordination of individual HPA axis response. Methods Twenty-four socially-housed bonnet macaque maternal-infant dyads were exposed to 16 weeks of alternating two-week epochs of low or high foraging demand shown to compromise normative maternal-infant rearing. Cerebrospinal fluid (CSF) CRF concentrations and plasma cortisol were measured pre- and post-VFD. Dyadic distance was measured, and blinded observers performed pre-VFD social ranking assessments. Results Despite marked individual cortisol responses (mean change = 20%) there was an absence of maternal HPA axis group mean response to VFD (0%). Whereas individual CSF CRF concentrations change = 56%, group mean did increase 25% (p = 0.002). Our "dyadic vulnerability" index (low infant weight, low maternal weight, subordinate maternal social status and reduced dyadic distance) predicted maternal cortisol decreases (p < 0.0001) whereas relatively “advantaged” dyads exhibited maternal cortisol increases in response to VFD exposure. Comment In response to a chronic stressor, relative dyadic vulnerability plays a significant role in determining the directionality and magnitude of individual maternal HPA axis responses in the service of maintaining a “superorganism” version of HPA axis homeostasis, provisionally termed “social allostasis.”

This paper is divided into two parts. Part I focuses on the manner in which the components of the face recognition system work together so that a perceiver, within several hundred milliseconds after seeing a familiar face, is able to both identify the face of the perceived and recall elements of the history of past encounters with the perceived. Face recognition plays a crucial role in enabling both human and nonhuman primates to interact in collaborative social groups. This critical function is accomplished through the unidirectional coded transfer of informational elements from one component to another. Although these informational elements themselves are not meaningful to the perceiving agent, they do nevertheless contain essential bits of information that are necessary for the final formation of the meaningful message. The structural components of the system are identified and the manner in which informational elements are coded and transferred sequentially from component to component in the brain of the perceiver is described. The independent, physically separated components in the face recognition system are bridged by an additional component, an “adaptor”, that mediates the transfer of informational elements from one component to another. The nature of the independent systems, and the manner by which the bridging or adaptor apparatus enables coded information transfer from one system to another is discussed. Part II focuses on the analysis of recognition in human-designed sign systems such as Braille and Morse code. Recognition in human-designed sign systems is notable for the stability of the link between sign and meaning. Face recognition is characterized as being subjective, indicating that the meaning of a sign (face) to a perceiver is variable and dependent on context, whereas human-devised sign recognition is characterized as being objective, indicating that the meaning of a sign is context independent and invariant. Human-designed sign systems require the presence in brain of a referent world. An example of a referent world is the set of letters of the alphabet. Representations of this set are installed in the brain through social mediated learning. Human-designed sets of signs (e.g., Braille, and written text) are created to correspond, via a code enabling adaptor structure, to referent worlds in the brain. Human-designed sign systems are the foundations for literacy, a capability only found in humans.

Four sequential, sub-processes are identified as the fundamental steps in the processing of signals by big-brained animals. These are, Detection of the signal, its Representation in correlated sensory brain structure, the Interpretation of the signal in another part of the brain and the Expression of the receiver’s response. We label this four-step spatiotemporal process DRIE. We support the view that when the context within which such signals are produced and received is relatively constant, the DRIE process can be ultimately assimilated into the genome, with the Interpretation sub-phase is markedly decreased in duration as speed and efficiency are maximized. With frequent repetition and learning, an analogous result can be attained epigenetically as exemplified in human word and text recognition, allowing tasks critical to primate social function to be accomplished with rapidity and accuracy.

Recent studies have indicated a gene by environment interaction between serotonin transporter gene (5-HTTLPR) polymorphism and childhood abuse on depressive symptoms. In addition, persistent elevation of cerebrospinal fluid (CSF) corticotropin-releasing factor (CRF) concentrations following early-life adversity has been posited to underlie the subsequent development of major depression. This pilot study tested the hypothesis that elevations of juvenile CSF CRF concentrations are, in part, determined by an interaction between polymorphisms of the 5-HTTLPR and early-life stress. Nine juvenile male bonnet macaques (Macaca radiata) had been raised under variable foraging demand (VFD) conditions, a nonhuman primate model of early-life stress, whereas nine subjects were normatively raised under LFD (low foraging demand) conditions. Genotyping revealed that four (44.4%) of the VFD-reared monkeys possessed at least one “s” allele whereas five VFD monkeys were of the l/l genotype. Of the nine LFD subjects, two (22%) had the s/l genotype and seven had the l/l genotype. A “juvenile” CSF sample was obtained at approximately three years of age. CSF CRF concentrations were elevated specifically in the VFD “s/s” and “s/l” allele group in comparison to each of the remaining three groups, indicating a gene by environment (GxE) interaction.

Background: Nonhuman primates have served as models for human cardiovascular (CV) and metabolic diseases. Recently, echocardiographic measurement of epicardial adipose tissue (EAT) thickness has been shown to be a reliable marker of visceral adiposity, and greater EAT is associated with increased CV risk, left ventricular (LV) hypertrophy, and metabolic syndrome. The objective of the present study was to determine EAT thickness in apparently healthy bonnet macaques and assess its relations with anthropometric and CV variables. Methods: Echocardiography was performed on 61 monkeys (41 females and 20 males, mean age 13.0 ± 4.7 years). EAT was measured on the right ventricular free wall in parasternal windows. Applanation tonometry was performed in 25 unselected monkeys using a SphygmoCor pulse wave system. Results: The mean EAT thickness was 2.4 ± 0.6 mm. EAT thickness was directly correlated with age (r = 0.26, P = 0.04), male gender (r = 0.47, P < 0.01), weight (r = 0.42, P < 0.01), crown–rump length (r = 0.45, P < 0.01), BMI (r = 0.38, P < 0.01), diastolic BP (r = 0.46, P = 0.01), and HR (r =−0.49, P < 0.01). EAT thickness also correlated with augmentation index (r = 0.42, P = 0.04), LV mass (r = 0.48, P < 0.01), and left atrial (LA) diameter (r = 0.26, P = 0.04). Intra- and interobserver coefficients of variation between measurements of EAT were 1.4% and 3.7%. On multivariate analysis adjusting for age, gender, weight, and CRL, EAT was independently related to age and weight (r2= 0.47, P < 0.01). Conclusion: This study found echocardiography to be a feasible and practical method to evaluate EAT in nonhuman primates. In bonnet macaques, EAT thickness correlates with LV and LA dimensions and augmentation index, and is independently related to age and weight. (ECHOCARDIOGRAPHY 2010;27:180-185)

Objectives: Macaques are used in cardiovascular and metabolic research. We determined echocardiographic-derived reference values of left ventricular (LV) systolic and diastolic function in healthy adult bonnet macaques (Macaca radiata). Methods: Transthoracic echocardiography was performed during ketamine sedation in 83 (67% female) healthy monkeys (age 7–26 years). Results: Technically adequate studies were obtained in all subjects and required 10.1 ± 1.3 min of scanning time. Age correlated inversely with the following Doppler indices: E (r = –0.44, p < 0.001), E/A (r = –0.26, p = 0.02), E′ (r = –0.45, p < 0.001, E′/A′ (r = –0.44, p < 0.001), E/E′ (r –0.25, p = 0.03), S′ (r = –0.33, p = 0.003), Vp (r = –0.26, p = 0.049). LV mass was more strongly correlated with crown rump length (r = 0.72, p < 0.001) and body surface area (r = 0.70, p < 0.001) than with body mass index (r = 0.47, p < 0.001) and weight (r = 0.63, p < 0.001). Conclusions: This study demonstrates echocardiography is feasible for characterizing LV function. Age-related changes in Doppler indices in primates are similar to those in humans. LV mass is more closely related to fat-free mass indices. We provide reference values for LV systolic and diastolic function in adult bonnet macaques across the captive life span.

Stress is a risk factor for chronic illnesses such as obesity, type 2 diabetes, and hypertension and has been postulated to cause the metabolic syndrome via perturbation of the hypothalamo-pituitary-adrenal (HPA) axis. In our model of early-life stress (variable foraging demand [VFD]), food insecurity is imposed on monkey mothers for 16 weeks beginning when their nursing offspring are 3–5 months of age. Under VFD, food availability is never restricted, and the infant's growth is unaffected. VFD rearing does, however, cause a range of neurobiological abnormalities, including dysregulation of the HPA axis, manifested in abnormal cerebrospinal fluid cortisol and corticotropin-releasing factor levels. We previously reported spontaneous occurrence of metabolic syndrome in 14% of normally reared peripubertal bonnet macaques given ad libitum access to standard monkey chow. Here, we show that compared with normally reared monkeys, peripubertal VFD juveniles exhibit greater weight, BMI, abdominal circumference, and glucagon-like peptide-1 and decreased glucose disposal rates during hyperinsulinemic-euglycemic clamps. Our data suggest that early-life stress during a critical period of neuro development can result in the peripubertal emergence of obesity and insulin resistance.

We have demonstrated, using proton magnetic resonance spectroscopy imaging ((1)H-MRSI), elevations of N-acetyl-aspartate/creatine (NAA/CR) in right dorsolateral prefrontal cortex (DLPFC) in patients with generalized anxiety disorder (GAD) in comparison to healthy volunteers. A recent study indicates that the volume of prefrontal cortical white matter may be disproportionately increased in man in comparison to other primate species, with evolutionary implications. We therefore re-analyzed the identical scans with a specific focus on the centrum semiovale (CSO) as a representative region of interest of cerebral white matter. The central hypothesis was, in accordance with our gray matter findings, that patients with GAD, in comparison to healthy controls, would exhibit either an increase in NAA in CSO, or alternatively demonstrate reductions in concentrations of choline (CHO)-containing compounds and/or creatine+phosphocreatine (CR). MRSI scans that were obtained from an earlier [Mathew, S.J., Mao, X., Coplan, J.D., Smith, E.L., Sackeim, H.A., Gorman, J.M., Shungu, D.C., 2004. Dorsolateral prefrontal cortical pathology in generalized anxiety disorder: a proton magnetic resonance spectroscopic imaging study. American Journal of Psychiatry 161, 1119-1121] sample of 15 patients with GAD [6 with early trauma (ET)] and 15 healthy age- and sex-matched volunteers were analyzed further for CSO metabolite alterations. Self-reported worry was scored using the Penn State Worry Questionnaire (PSWQ) and intelligence was assessed using the Wechsler Abbreviated Scale of Intelligence (WASI). Serial multislice/multivoxel MRSI scans had been performed on a 1.5-T MRI. Using absolute quantification methods for metabolite concentrations, we examined NAA, CHO and CR. GAD patients without ET exhibited bilaterally decreased concentrations of CHO and CR in CSO in comparison to healthy volunteers, whereas GAD patients with ET were indistinguishable from controls. In patients with GAD, high IQ was paired with greater worry, whereas in healthy volunteers, high IQ was associated with less worry. In all subjects, IQ inversely predicted left and right CSO CHO concentrations, independent of age, sex, group assignment and PSWQ scores. The CSO may therefore represent a neural substrate that exhibits reductions in CHO and CR metabolite concentrations that are inversely associated with GAD symptomatology and, in the case of CHO, with intelligence. These conclusions are deemed preliminary due to small sample size, with further study of cerebral WM in anxiety disorders suggested.

Two experiments were conducted to examine the effectiveness of presenting brief video of conspecifics to socially housed bonnet macaques as a reward for performing a joystick task. Using a joystick, subjects tracked a moving target with the cursor on a computer monitor. In Exp. 1, subjects completed significantly more joystick trials for food reward than for video reward or no reward. Subjects also preferred viewing video of another group (Other Group Video) to receiving no reward or to viewing video of their own group (Own Group Video). In Exp. 2, subjects were given two reward conditions, video of a familiar social group or video of a new social group. Two monkeys contributed the vast majority of trials, and both responded more frequently when the reward was video of the new social group. Results of these two experiments suggest that viewing video of conspecifics may serve as an effective reward for at least some socially housed primates and suggests that novelty of the individuals depicted in the video is an important factor contributing to the reward value of video.

Background Long-term behavioral, immunologic, and neurochemical alterations have been found in primates exposed to adverse early rearing. Methods Bonnet macaque ( Macaca radiata ) mother–infant dyads were exposed to uncertain requirements for food procurement (variable foraging demand, VFD) for a few months. Ten years later, these offspring and age- and gender-matched control subjects were studied using proton magnetic resonance spectroscopic imaging (MRSI). Results In anterior cingulate, VFD-reared subjects displayed significantly decreased N -acetylaspartate (NAA) resonance and significantly increased glutamate–glutamine–γ-aminobutyric acid (Glx) resonance relative to the stable neurometabolite creatine (Cr). Across all subjects, NAA/Cr and Glx/Cr ratios in the anterior cingulate were negatively correlated ( r = −.638, p = .014). In the medial temporal lobe, the ratio of choline-containing compounds to Cr was significantly increased in VFD subjects. Conclusions These findings indicate that adverse early rearing in primates has an enduring impact on adult MRSI measures considered reflective of neuronal integrity and metabolism, membrane structure and glial function, and cerebral glutamate content, and that these alterations occur in the same brain regions implicated in trauma-related psychiatric disorders.

The two neuropeptides corticotropin-releasing-factor (CRF) and oxytocin (OT) may produce opposing behavioral effects — elevations of the former have been associated with anxiety and social vigilance and reductions of the latter with reduced social affiliation. We sought to test the hypothesis that, within the primate macaque genus, the more gregarious, affiliative, and affectively stable bonnet species ( Macaca radiata ) would exhibit lower cerebrospinal fluid (CSF) CRF and higher CSF OT concentrations in comparison to its close relative, the temperamentally volatile and socially distant pigtail ( Macaca nemestrina ). Cisternal CSF samples were obtained from young adult male and female pigtail and bonnet macaques, and CRF and OT concentrations were measured by radioimmunoassay. Pigtail macaques exhibited significantly higher concentrations of CSF CRF and significant lower concentrations of CSF OT than bonnet macaques. Results were not attributable to age or sex differences in group composition. When included together in a multiple regression, CRF and OT showed a multiple R of 0.76, accounting for more than half of the species variance. Although species differences in the bioeffectiveness of these peptides may possibly confound the observed biobehavioral relationships, in the absence of any existing data to that effect, the current findings appear in accordance with the hypothesis and consistent with previously reported species–typical behaviors observed in these macaques.

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.

Adolescent bonnet macaques nursed as infants by mothers facing unpredictable requirements for food procurement (variable foraging demand, VFD) display persistent neurobiological disturbances. This study examined the long-term neurochemical and behavioral effects of adverse rearing initiated later in infancy than in previous cohorts of subjects to test the hypothesis that the timing of an early adverse experience would influence patterns of biobehavioral outcome. Cisternal cerebrospinal fluid (CSF) monoamine and corticotropin-releasing factor (CRF) concentrations were obtained from 20 bonnet macaques (11 VFD-reared and 9 normally reared controls) approximately 2 years after the end of differential rearing. VFD-reared primates displayed on multiple samplings significantly lower CSF CRF concentrations and higher CSF 5-hydroxyindoleacetic acid (5-HIAA) concentration compared to controls. In the VFD-reared, significant inverse correlations between CRF and all three monoamines were found (5-HIAA, 3-methoxy-4-hydroxyphenethyleneglycol and homovanillic acid), most prominently for 5-HIAA. In controls, but not VFD-reared subjects, CSF CRF was positively correlated with changes in "gregariousness" upon presentation of a fear stimulus. VFD-reared subjects displayed greater baseline hierarchical engagement than controls. In contrast to prior findings, in which rearing under VFD conditions at an earlier age led to increased CSF CRF compared with controls, CSF CRF was lower after later exposure to VFD rearing than in controls. Thus, the timing of exposure to VFD conditions early in life evidently determines whether CSF CRF was found to be elevated or decreased, within the context of increased serotonin metabolism, during the course of primate maturation.

Introduction: Issues in the Study of the Social Network.- 1 The Child's Social Network: Social Object, Social Functions, and Their Relationship.- 2 The Infant as a Focus for Family Reciprocity.- 3 Conceptualization of Father Influences in the Infancy Period.- 4 The Infant's Exposure to Talk by Familiar People: Mothers, Fathers, and Siblings in Different Environments.- 5 The Family as a System of Mutual Influences: Parental Beliefs, Distancing Behaviors, and Children's Representational Thinking.- 6 Self-Recognition in Chimpanzees and Man: A Developmental and Comparative Perspective.- 7 Only Children, Stereotypes, and Research.- 8 Interaction between Young Siblings in the Context of Family Relationships.- 9 Toddlers + Toys = An Autonomous Social System.- 10 The Effect of Adults on Peer Interactions.- 11 Differential Development of Various Social Relationships by Rhesus Monkey Infants.- 12 Young Children's Concepts of Social Relations: Social Functions and Social Objects.- 13 The Changing American Family and Its Implications for Infant Social Development: The Sample Case of Maternal Employment.- Author Index.

Three individually housed bonnet macaques, with long-term experience in performing a joystick task with a reward choice of either viewing color video of a single bonnet group or obtaining a banana-flavored food treat, were presented with images of a new group when they chose to view social video. The change produced absolute increases in responding for social video and enhanced preference for viewing social video relative to obtaining the food treat, supporting the view that the monkeys were strongly attending to the social content of the videos.

Background: The authors previously reported elevated cerebrospinal fluid (CSF) corticotropin-releasing factor (CRF) concentrations in juvenile primates nursed by mothers undergoing experimentally imposed unpredictable foraging conditions in comparison to normally reared controls. The purpose of the present study was to determine if these changes would endure into young adulthood. Methods: Cisternal CSF samples were obtained from those unpredictably reared young adult primates who had been previously studied as juveniles and age-matched ad libitum normally reared controls. Samples were assayed for CSF CRF. Results: Concentrations of CSF CRF were significantly elevated in the unpredictably reared sample in comparison to the ad libitum-reared control group. A significant positive correlation was noted between juvenile and young adult CSF CRF values within the unpredictably reared cohort. Conclusions: Disturbances of maternal-infant attachment processes have an enduring impact on primate CRF function into young adulthood. The CRF elevations following unpredictable maternal foraging conditions appear traitlike in nature.

Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis is a pathologic feature of certain mood and anxiety disorders that results in the increased production and secretion of corticotropin-releasing factor. There is increasing preclinical evidence that glutamate, an excitatory amino acid, plays an important role in the regulation of the HPA axis. Activation of glutamatergic projections to limbic structures such as the amygdala and brainstem structures such as the nucleus tractus solitarius is implicated in the stress response. There are laboratory and clinical suggestions that glutamatergic N-methyl-D-aspartate (NMDA) receptor antagonists function as antidepressants, and that chronic antidepressant treatments have a significant impact on NMDA receptor function. Clinical investigations of glutamate antagonists in patients with mood and anxiety disorders are in their infancy, with a few reports suggesting the presence of mood-elevating properties. Ultimately, HPA axis modulators, serotonin-enhancing agents, and glutamate antagonists might serve to increase neurotropic factors in key brain regions for affective and anxiety regulation, providing a putative final common pathway.

When primate infants are reared during the first half-year of life in an environment in which their mothers face uncertain requirements for food procurement (variable foraging demand [VFD]), long-lasting behavioral and neurodevelopmental consequences ensue, including increases in timidity and social subordinance as well as alterations in stress-related neuroendocrine profiles. We examined the nature and persistence of the effects of VFD rearing by exposing VFD-reared and normally reared adolescent bonnet macaques to a mild fear-provoking stimulus 2 years after the end of differential rearing. VFD-reared subjects at baseline were less gregarious than normally reared monkeys. VFDs also were considerably less responsive to the fear stimulus, and their behavior and affect returned to baseline levels more quickly than normally reared subjects. The extent and persistence of the sequelae of VFD rearing suggest parallels with predisposing factors in human anxiety disorders. © 2001 John Wiley & Sons, Inc. Dev Psychobiol 39: 40–45, 2001

There is increasing evidence for an important role of adverse early experience on the development of major psychiatric disorders in adulthood. Corticotropin-releasing factor (CRF), an endogenous neuropeptide, is the primary physiological regulator of the mammalian stress response. Grown nonhuman primates who were exposed as infants to adverse early rearing conditions were studied to determine if long-term alterations of CRF neuronal systems had occurred following the early stressor. In comparison to monkeys reared by mothers foraging under predictable conditions, infant monkeys raised by mothers foraging under unpredictable conditions exhibited persistently elevated cerebrospinal fluid (CSF) concentrations of CRF. Because hyperactivity of CRF-releasing neurons has been implicated in the pathophysiology of certain human affective and anxiety disorders, the present finding provides a potential neurobiological mechanism by which early-life stressors may contribute to adult psychopathology.

The study of grown nonhuman primates reared under randomly assigned, experimentally controlled rearing conditions provides a viable methodology not feasible in humans that delineates the behavioral and biologic correlates of adverse early rearing without genetic confounds. This article summarizes evidence that indicates that adverse, unpredictable rearing related to perturbations of the primate mother-infant attachment process leads to persistent anxiety- and depressive-like behaviors in the grown infant. These behaviors are accompanied by persistent disturbances of monoamine, neuroendocrine, and neuropeptidergic function.

Five individually housed, adult male bonnet macaques ( Macaca radiata ) that were highly experienced in single-target joystick tasks were trained to discriminate targets associated with food-pellet and live-social-video rewards; the social video afforded viewing of a social group of bonnet macaques. Most subjects more rapidly acquired the discrimination for their preferred reward. Following discrimination training, the remaining three subjects were given 34 weeks with a simultaneous choice between food-pellet and social-video; the subjects selected a reward by simply using a joystick to direct a cursor to contact the target associated with that reward. Despite some change over time, both types of reward remained effective for the extended period. Different daily patterns of responding for the two rewards were identified.

OBJECTIVE The authors determined the effects of antipanic treatment with fluoxetine on human growth hormone (GH) response to the alpha 2 agonist clonidine. METHOD Seventeen patients with panic disorder and 15 healthy volunteers were challenged with clonidine. Thirteen of the patients and 12 of the volunteers were given a second challenge with clonidine 12 weeks later. The patients received open fluoxetine and the healthy subjects received no treatment between challenges. Subjects with high baseline human GH levels (greater than 2 ng/ml) at the first and second challenges were excluded from further analysis. RESULTS The patients with panic disorder (N = 13 for the first challenge and N = 9 for the second) had significantly lower human GH responses to clonidine than the healthy subjects (N = 14 during the first challenge and N = 9 for the second) during both challenges, despite clinical improvement in eight of the nine patients at the time of the second challenge. CONCLUSIONS Blunted secretion of human GH in response to clonidine in patients with panic disorder persists despite clinical recovery.

Ethical and practical constraints limit the range of studies that can be performed on patients with anxiety disorders. A nonhuman primate model allows for a variety of experimental manipulations that cannot be attempted in humans. In this paper, we report on the further development of a nonhuman primate model of pathological anxiety, which we have labeled acute endogenous distress (AED). Bonnet macaques were challenged with the oral administration of the alpha-2 antagonist, yohimbine. Whereas our previous work has documented the behavioral response to yohimbine provocation, in this paper we report the drug's effects on the monkey's performance on a novel video computer device that presents well defined perceptual- motor tasks of varying difficulty. Under yohimbine challenge, animals virtually stopped initiating a complex task requiring sustained attention and perceptual-motor control; however, they showed no decrease in initiating and performing an easy task under the same pharmacological challenge, thus demonstrating that the effect was cognitive rather than motor in nature.

Bonnet macaques that had been reared from 3 to 6 months of age in experimental environments that appeared to adversely affect their ability to separate from mother to explore a novel physical environment in dyadic assessments shortly after the rearing experience were tested during late adolescence, an average of 2.5 years later, under conditions of increasing unfamiliarity and complexity of the social milieu. 6 monkeys, the low-foraging-demand (LFD) group, were reared by mothers having constant easy access to food during the experimental rearing period. Another 6 monkeys, the variable-foraging-demand (VFD) group, were reared by mothers having a foraging task that varied between easy and difficult in 2-week blocks during the experimental rearing period. Although no treatment group differences were evident during the initial rearing period, during subsequent social challenges VFD monkeys exhibited a diminished capacity for affiliative social engagement relative to LFD monkeys and were socially subordinate to LFD monkeys.

The video-task paradigm has been suggested as a means of providing enrichment for laboratory primates. The purpose of this study was to investigate the effect of providing multiple devices to socially housed pigtail macaques. Using different cage locations, the subjects were tested with conditions of access to a single device and with access to three identical devices. Differential preference among locations was strongly evident, but only when multiple devices were simultaneously accessible. Although a single device was never used to its theoretical maximum potential, overall device utilization was significantly higher with multiple devices available. Provision of a perch that equalized the substrate at all locations diminished, but did not eliminate, differential preference among locations.

It has been proposed that certain adverse early experiences may play a role in determining subsequent susceptibility to adult anxiety and affective disorders and this relationship may be the result of altered neurodevelopment of the noradrenergic and/or serotonergic systems. In this study of nonhuman primates, the predictability of foraging requirements for mothers during an early period of their infants' lives was manipulated. When the offspring were young adults, these early manipulations were related to differences in behavioral response to acute administration of two putative anxiety-provoking agents: the noradrenergic probe, yohimbine, and the serotonergic probe, mCPP. These long-term effects of the developmental environment on subsequent pharmacological responsivity suggest that both neuronal systems may be permanently altered by early experiential factors.

The diurnal pattern of joystick use by five individually caged bonnet macaque monkeys ( Macaca radiata ), with continuous access to a computer-controlled joystick task that required contacting a small stationary target with the cursor, was characterized by a dramatic peak occurring between 1500 and 1700 h and little activity during the morning hours. With 2 h limited daily access pseudorandomly scheduled across days, a similar pattern was found, although the number of trials completed during 2-h intervals of limited access was greater than that during the same intervals of continuous access. When an extended period of access at a fixed time each morning was compared to a similar period of fixed access time in the afternoon, the afternoon continued to be characterized by significantly higher levels of use.

A microchip that provided a unique identification number was injected into each forearm of all 8 members of a bonnet macaque (Macaca radiata) social group. The group was then given computer-controlled joystick tasks of increasing difficulty. The identification number of the arm used on each trial was input into the computer and used to determine individual performance and hand preference in more than 23,000 trials. Three subjects reversed hand preference as task difficulty was increased over time. All subjects exhibited nearly exclusive use of a single hand on the most difficult task; 6 used the right hand, and 2 used the left. Daily patterns of joystick activity for the group members differed somewhat from that of our individually housed monkeys.

Objective Obesity is associated with the insulin resistance metabolic syndrome, postulated to be mediated by stress-induced alterations within the hypothalamic–pituitary–adrenal (HPA) axis. In adult bonnet macaques we examined relationships between components of the metabolic syndrome, hippocampal neurometabolic asymmetry, an indicator of negative affect, and juvenile cerebrospinal fluid (csf) corticotropin-releasing factor (CRF) levels obtained after stress exposure associated with maternal food insecurity and in controls. Methods Eleven adult male monkeys (seven with early life stress) who had undergone csf-CRF analyses as juveniles had magnetic resonance spectroscopic imaging (MRSI) of bilateral hippocampus, morphometry (body mass index, BMI; sagittal abdominal diameter, SAD) and determination of fasting plasma glucose and insulin as adults. Neurometabolite ratios included N-acetyl-aspartate as numerator (NAA; a marker of neuronal integrity) and choline (Cho; cell turnover) and creatine (Cr; reference analyte) as denominators. Results Elevated juvenile csf-CRF levels positively predicted adult BMI and SAD and were associated with right > left shift of NAA ratio within the hippocampus. Adult visceral obesity and insulin level correlated with right > left shift in hippocampal NAA concentrations, controlling for age and denominator. Conclusion Juvenile csf-CRF levels, a neuropeptide associated with early life stress, predict adult visceral obesity and hippocampal asymmetry supporting the hypothesis that metabolic syndrome in adults may be related to early life stress. Furthermore, this study demonstrates asymmetrical hippocampal alterations related to obesity.

Increased neurogenesis in feeding centers of the murine hypothalamus is associated with weight loss in diet-induced obese rodents (Kokoeva et al., 2005 and Matrisciano et al., 2010), but this relationship has not been examined in other species. Postmortem hippocampal neurogenesis rates and premortem metabolic parameters were statistically analyzed in 8 chow-fed colony-reared adult bonnet macaques. Dentate gyrus neurogenesis, reflected by the immature neuronal marker, doublecortin (DCX), and expression of the antiapoptotic gene factor, B-cell lymphoma 2 (BCL-2), but not the precursor proliferation mitotic marker, Ki67, was inversely correlated with body weight and crown-rump length. DCX and BCL-2 each correlated positively with blood glucose level and lipid ratio (total cholesterol/high-density lipoprotein). This study demonstrates that markers of dentate gyrus neuroplasticity correlate with metabolic parameters in primates.

A number of studies have now indicated that monkeys of several species will perform hundreds of food-rewarded joystick tasks on a daily basis. Our goal in this study was to identify the level of joystick task performance that could be maintained by 10 sec. of live, color video of a conspecific social group contingent upon the completion of a joystick task. The subjects were five individually housed bonnet macaques that were highly experienced on joystick tasks. Performance with social-video reward was compared to that maintained by a 190-mg banana-flavored pellet reward and to a nonreward condition. Comparable levels of task activity were maintained by both video and pellet reward, whereas task activity nearly ceased in the absence of reward. Four of the five monkeys increased their levels of task activity between the first and second weeks of social-video reward.

To assess the developmental consequences of rearing environments for 12 infant bonnet macaques (Macaca radiata), infants from 2 environments, either low foraging demand (LFD) or variable foraging demand (VFD) for their mothers, were observed under 2 test conditions after the completion of the differential rearing treatment. One of the test conditions involved introduction of the rearing cohorts to a novel room; this was done in two series of four 1-hr sessions, a series before and a series after completion of the 2nd test condition. The 2nd test condition involved a 20.5-hr removal of each mother from the rearing cohort; this was repeated once a week for 3 weeks. The results of the novel room tests effectively differentiated rearing treatments in this study and suggested treatment group differences in attachment security. In contrast, the maternal separations failed to differentiate rearing treatments.

We tested the hypothesis that early life stress would persistently compromise neuronal viability of the hippocampus of the grown nonhuman primate. Neuronal viability was assessed through ascertainment of N-acetyl aspartate (NAA) – an amino acid considered reflective of neuronal density/functional integrity – using in vivo proton magnetic resonance spectroscopic imaging (MRSI). The subjects reported herein represent a re-analysis of a sample of nineteen adult male bonnet macaques that had been reared in infancy under induced stress by maternal variable foraging demand (VFD) (N = 10) or control rearing conditions (N = 9). The MRSI spectral readings were recorded using a GE 1.5 Tesla machine under anesthesia. Relative NAA values were derived using NAA as numerator and both choline (Cho) or creatine (Cr) as denominators. Left medial temporal lobe (MTL) NAA/Cho but not NAA/Cr was decreased in VFD subjects versus controls. An MTL NAA/Cho ratio deficit remained significant when controlling for multiple confounding variables. Regression analyses suggested that the NAA/Choline finding was due to independently low left NAA and high left choline. Right MTL showed no rearing effects for NAA, but right NAA was positively related to body mass, irrespective of denominator. The current data indicate that decreased left MTL NAA/Cho may reflect low neuronal viability of the hippocampus following early life stress in VFD-reared versus normally-reared subjects. Given the importance of the hippocampus in stress-mediated toxicity, validation of these data using absolute quantification is suggested and correlative neurohistological studies of hippocampus are warranted.

Deep brain stimulation (DBS) of the anterior limb of the internal capsule (ALIC) may be effective in treating depression. Parental verbal abuse has been linked to decreased fractional anisotropy (FA) of white matter and reduced FA correlated with depression and anxiety scores. Utilizing a nonhuman primate model of mood and anxiety disorders following disrupted mother-infant attachment, we examined whether adverse rearing conditions lead to white matter impairment of the ALIC. We examined white matter integrity using Diffusion Tensor Imaging (DTI) on a 3T-MRI. Twenty-one adult male Bonnet macaques participated in this study: 12 were reared under adverse [variable foraging demand (VFD)] conditions whereas 9 were reared under normative conditions. We examined ALIC, posterior limb of the internal capsule (PLIC) and occipital white matter. VFD rearing was associated with significant reductions in FA in the ALIC with no changes evident in the PLIC or occipital cortex white matter. Adverse rearing in monkeys persistently impaired frontal white matter tract integrity, a novel substrate for understanding affective susceptibility.

Male bonnet monkeys (Macaca radiata) were subjected to the variable foraging demand (VFD) early stress paradigm as infants, MRI scans were completed an average of 4 years later, and behavioral assessments of anxiety and ex-vivo corpus callosum (CC) measurements were made when animals were fully matured. VFD rearing was associated with smaller CC size, CC measurements were found to correlate with fearful behavior in adulthood, and ex-vivo CC assessments showed high consistency with earlier MRI measures. Region of interest (ROI) hippocampus and whole brain voxel-based morphometry assessments were also completed and VFD rearing was associated with reduced hippocampus and inferior and middle temporal gyri volumes. The animals were also characterized according to serotonin transporter genotype (5-HTTLPR), and the effect of genotype on imaging parameters was explored. The current findings highlight the importance of future research to better understand the effects of stress on brain development in multiple regions, including the corpus callosum, hippocampus, and other regions involved in emotion processing. Nonhuman primates provide a powerful model to unravel the mechanisms by which early stress and genetic makeup interact to produce long-term changes in brain development, stress reactivity, and risk for psychiatric disorders.

Early-life stress has emerged as a critical antecedent to a substantial portion of human mood and anxiety disorders. Animal models have been extensively utilized to determine the long-term impact of early-life stress on psychobiology and behavior. One such model, developed in nonhuman primates, focuses on the offspring of mothers confronting environmental uncertainty regarding the ease or difficulty of food procurement (variable foraging demand (VFD)) during their infants’ early development. VFD stress is transmitted to the offspring via disruption of maternal attachment. Psychopathology can be induced by this discrete period of maternal compromise, imparting pervasive and sustained biobehavioral effects within the developmental trajectory of the offspring.

12 bonnet macaque (Macaca radiata) mother-infant dyads were studied. For 14 weeks, beginning when the infants were a mean age of 11.2 weeks, the dyads were housed and observed under different foraging-demand conditions for the mothers: 6 dyads in a low-foraging-demand (LFD) condition and 6 dyads in a variable-foraging-demand (VFD) conditions. For VFD mothers, demand varied between low and high in 2-week blocks. Differences between the LFD and VFD groups were minimal during this period; there was, however, more maternal grooming and shorter separation bouts in the VFD group than in the LFD group. The dyads were then challenged by brief introductions to a novel environment. The challenge revealed that frequency of breaking dyadic contact and levels of play were significantly lower for the VFD infants than for the LFD infants, perhaps as a consequence of less secure attachment.

Differences were revealed in the age at which boys and girls attain developmental milestones during the first year of life and in the intervals between milestone attainments. Three of ten milestones were reached significantly earlier in boys than girls while none of the milestones appeared earier in girls than boys. Of the 45 intervals between milestones, seven were longer in boys and twelve were longer in girls. Data were recorded by the mothers of 4653 infants participating in the Copenhagen Consecutive Perinatal Cohort. Full-term gestation (38-41 weeks) and survival through the first year were the criteria for inclusion in the study. Nine potential confounding variables, including SES, birth weight and complications of pregnancy, were not responsible for the behavioral sex differences. This sexually dimorphic pattern of milestone achievement is discussed as supportive of hypothesized biologically-based sex differences in the ontogeny of social responsiveness and is consistent with sex differences ident...