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Physiol Behav. Author manuscript; available in PMC Aug 3, 2012.
Published in final edited form as:
PMCID: PMC3118860
NIHMSID: NIHMS280769
A novelty seeking phenotype is related to chronic hypothalamic-pituitary-adrenal activity reflected by hair cortisol
Mark L. Laudenslager,a Matthew J. Jorgensen,b Rachel Grzywa,a and Lynn A. Fairbanksc
a Department of Psychiatry, University of Colorado at Denver School of Medicine, Denver CO 80220
b Department of Pathology, Section on Comparative Medicine, Wake Forest University School of Medicine, Winston-Salem NC
c Department of Psychiatry & Biobehavioral Sciences, Semel Institute, University of California at Los Angeles, Los Angeles CA 90095
Corresponding Author: Mark L. Laudenslager, PhD, Department of Psychiatry, University of Colorado at Denver, School of Medicine, Denver CO 80220, Office Number 303-315-9276, FAX Number (303) -315-9125, mark.laudenslager/at/ucdenver.edu
Reduced hypothalamic pituitary adrenal (HPA) activity is associated with greater novelty seeking in humans. Hair cortisol represents an integrated proxy measure of total cortisol production/release over an extended period of time and may be a valuable tool for tracking the HPA system. Sampling approaches (collection of blood, saliva, urine, or feces) for socially housed nonhuman primates present a number of technical challenges for collection particularly when repeated sampling is necessary. Herein we describe a relationship between cortisol levels measured in hair collected from 230 socially housed female vervet (Chlorocebus aethiops sabaeus) monkeys and a free-choice novelty seeking phenotype. A predator-like object was placed at the periphery of the outdoor enclosures for 30 min and speed of approach (latency to approach within 1 m) and persistence of interest (number of 1 min intervals within 1 m) were scored. A composite Novelty Seeking score, combining these two measures, was calculated. The intra-class correlation coefficient (ICC=.68) for two different objects across years indicated that this score reflects a stable aspect of temperament. Hair samples were collected from each subject approximately 3–6 months following the second assessment; cortisol levels were determined from the hair. A significant inverse relationship of Novelty Seeking score with hair cortisol level (p < .01) was noted. The high hair cortisol groups had significantly lower Novelty Seeking scores than the low cortisol groups both years (p’s < .05). These results suggest that low average cortisol levels promote novelty seeking, while high average levels inhibit novelty seeking behavior.
Keywords: novelty seeking, risk taking, temperament, hair cortisol, nonhuman primate, vervet monkey, Chlorocebus aethiops sabaeus
Individual differences in novelty seeking and response to novelty are predictive of risk for multiple psychiatric disorders, including anxiety disorders or alcohol and substance abuse (14). Animal models have used a variety of novelty paradigms to understand the basic mechanisms involved, often with differing results depending on the type of novelty test. For example, rodent models of substance use disorders have found that inescapable or free-choice novelty paradigms evaluate different components of the addiction process (5) and reflect different neurochemical mechanisms (6). High rates of locomotion in an inescapable novelty test predict initial tendency to use or self-administer cocaine, while preference for novel places in a free-choice novelty test predicts the transition from use to addiction (7).
In nonhuman primates, inescapable novelty tests have been used to study emotionality and anxious temperament, modeled after studies of behavioral inhibition in children (3). Inescapable novelty paradigms typically involve removing infant or adolescent monkeys from their home environment, placing them in an unfamiliar cage or small room, confronting them with novel objects or an unfamiliar human, and measuring behavioral responses. These tests have been used to identify effects of early experience, genetic, hormonal, and neurobiological systems on defensive and fearful behavioral responses (812). Several studies have shown that levels of serum cortisol following the test sessions are positively associated with levels of anxiety-related behaviors such as freezing observed during the test (8, 9, 13).
Free-choice novelty tests, in contrast, have been used to measure novelty-seeking phenotype in nonhuman primates and differ significantly from inescapable challenges. In free-choice tests, the monkeys are presented with access to a novel area or novel object in the familiar home environment, and subjects are free to approach and explore, or to remain at a distance. Latency to enter a novel area or to approach a novel object by juvenile and adolescent primates in free-choice tests has been related to mildly stressful early experiences in macaques, vervets and squirrel monkeys (1417). Free-choice novelty tests in a pedigreed vervet monkey colony demonstrated that novelty-seeking is a heritable trait, with a portion of the genetic contribution attributable to the same polymorphism in the dopamine D4 receptor gene that has been related to novelty seeking in human primates (18). In contrast to results from inescapable novelty tests, there is little information on the relationship between free-choice novelty seeking and acute or chronic measures of hypothalamic-pituitary-adrenal axis (HPA) activity (16).
A normal response of the HPA axis to an acute stressor is marked by a rapid increase in plasma cortisol levels followed by a relatively rapid return to baseline (19). Both enhanced and/or blunted responses of the onset and/or offset of the HPA system suggest disrupted regulation which may lead to pathophysiology and behavioral disturbance in the organism (20). Identification of valid markers of long term HPA regulation/activation will add to understanding the relation of the HPA system to trait-like individual differences in response to novelty. Is there a valid measure that can be easily obtained from nonhuman primates which reflects long term activation of the HPA?
Cortisol measured in hair has been recently introduced to ethological research as a marker of long term activation of the HPA axis. Measurement of steroids in hair has been available for over three decades but generally required the use of mass spectrometry approaches (21, 22). Longitudinal evaluation of cortisol extracted from hair samples has the potential to serve as an alternative marker of chronic HPA activation (23) much like hemoglobin A1c reflects blood glucose control for an extended period of time (24). Development of commercially available, high sensitivity enzyme immunoassays has been used for measurement of cortisol in low concentration in saliva (25). These same assays permit rapid and reliable assessment of cortisol in hair collected from nonhuman primates (26). Hair cortisol level in the nonhuman primate was found to be higher in association with a phenotype of self injury and was correlated with salivary and plasma cortisol (27). Hair cortisol represents a reliable marker of longer term cortisol release in mammals. Importantly, hair cortisol levels are not impacted by the acute sampling distress as is the case for plasma steroids and other hormones, particularly for nonhuman primates (28).
Here we determine if there is a relationship between cortisol measured in hair collected from socially housed female vervet monkeys and their response to a free-choice novelty test using potentially threatening objects placed at the periphery of their home cage enclosures.
2.1. Subjects
Subjects were 230 female vervet monkeys (Chlorocebus aethiops sabaeus) (3–18 yr of age) living in 16 stable multigenerational, matrilineal social groups at the Vervet Research Colony (VRC). The VRC was originally established in Sepulveda, CA in 1975 with vervet monkeys captured from St. Kitts, West Indies. All subjects in the current study were born at the VRC and lived in social groups that were managed to reflect the natural social composition of vervet monkey groups in the wild. Infants and juveniles were raised by their mothers in one of 16 matrilineal social groups. Females remained in the social group with their mothers and female kin, while males were removed from the natal group at adolescence and transferred into new groups as adults for breeding. These procedures have produced a large, extended multi-generational pedigree (29, 30).
The monkeys were housed in outdoor enclosures varying in size from 30–117 square meters of ground area (mean = 61 m2), with adjacent indoor shelters. Each outdoor corral had one or two large platforms and multiple perches, climbing structures and enrichment devices. The social groups were undisturbed except for daily maintenance, behavioral tests, the annual veterinary exam, and clinical interventions as needed. The number of adult female subjects per social group varied from 6 to 26 (mean = 14.4, SD = 5.6). Of the 230 female subjects, two were pregnant and delivered 38 and 71 days after sample collection. Five others had given birth between 40–75 days prior to hair sample collection. None of these females were sampled within one month of delivery; a time frame associated with an increase in hair cortisol in this population (55) and humans (56). None had experienced experimental procedures or significant clinical interventions in the three months prior to sample collection. All procedures were approved by the UCLA and Department of Veterans Affairs Institutional Animal Care and Use committees.
2.2. Home Group Novelty Test
The Home Group Novelty test is a procedure to measure free-choice novelty seeking in the home enclosure (18). A novel and potentially threatening object was placed at the edge outside of the outdoor enclosure within reach of the animals but away from any of the preferred sitting or resting places. Novel objects were selected that were salient enough to arouse interest and curiosity, with some potential for fear. All subjects in the current analysis were tested twice, a year apart, using predator-like objects as the novel stimuli. During the test, the door to the indoor shelter was closed so all group members were present in the outdoor area. The novel object (a cloth snake in 2006 and a plastic tarantula in 2007) was placed in a wicker basket positioned outside the chain link fence of the home enclosure, at ground level. The latency to approach within one meter of the object, and the number of 1-minute intervals that each animal was observed within 1 meter of the object was scored for a 30-minute test session. A team of observers familiar with identifying individual monkeys made a consensus determination of who was within 1 meter for each interval. The area within 1 meter of the object only occupies a small portion of the home enclosure, and it requires voluntary action on the part of the monkeys to approach the object.
2.3. Hair cortisol
Hair samples were collected in December 2007 - January 2008, during the annual veterinary examination, 3–6 months after the second novelty test was completed. All members of a social group were transferred into a capture tunnel and anesthetized with 8-10mg/kg Ketamine hydrochloride. Using electric hair clippers, a 4 x 4 cm patch of hair was shaved from the center of the back between the shoulder blades, taking care not to damage the skin. The hair for each individual was wrapped in aluminum foil, stored in individual plastic bags, and stored in a dark, temperature controlled environment until overnight shipment to Colorado for analysis. This approach follows recommendations of the Society for Hair Testing (31).
Hair cortisol analysis followed the method of Davenport (26). All of the hair obtained from each subject was washed two times in 5 ml 99% isopropyl alcohol and allowed to dry for 4 or more days in glass tubes. From the washed hair a clump representing a mixture of long, short, and fine hairs was removed for grinding. The entire length of hair from proximal to distal end (5.6 + 0.7 cm, range = 4.5–6.7 cm) was ground in a ball mill (Retsch MM200) at 25 hz for 15 min, 50 mg of the powdered hair was extracted overnight in 1ml 100% HPLC grade methanol, and 0.6 ml of the extraction medium was dried under a nitrogen stream at 38°C for 45 min. The dried samples were reconstituted in 0.4 ml assay buffer used in the enzyme immunoassay (EIA) (Expanded range, high sensitivity salivary cortisol EIA, #3001, Salimetrics LLC). Twenty five microliters of the reconstituted samples in assay buffer were pipetted in duplicate to the wells of the microtiter plate and assayed according to manufacturer’s instructions (Salimetrics, LLC). Plates were read on a Biotek microtiter plate reader at 450 nm. Standard curves were determined using Gen Five software from which the unknowns were estimated. In order to establish assay reliability, a pool of ground human hair was extracted at the time of each assay and included on each plate with unknown samples. Within and between assay coefficients of variability for the pooled hair control were 4.0 and 9.1% respectively.
2.4. Data Analysis
The latency to approach and the number of 1-min intervals within 1 meter of the novel object were inversely correlated (snake, r = −0.42; tarantula, r = −0.48). A composite score combining these measures was computed for each year (range = 0 –60), with high scores indicating a greater tendency to explore the object: Novelty Seeking Score = (30 – latency) + (# intervals within 1 meter). The interclass correlation coefficient was used to assess the consistency of individual differences in Novelty Seeking across tests.
The association between Novelty Seeking and hair cortisol level was assessed by Pearson correlation. In order to identify a possible nonlinear relationship between novelty seeking and cortisol level, one way analysis of variance with hair cortisol group (low, middle, high) as the independent variable and Novelty Seeking score as the dependent variable was also run, including a test for linear contrasts between groups. A significant main effect of group was followed by pair-wise comparisons among groups, using Tukey tests. Both hair cortisol and novelty seeking data were screened for covariates, including age, dominance rank, group size, and reproductive status.
3.1. Novelty Seeking
Figure 1 compares Novelty Seeking scores for subjects for the 2006 (snake) and 2007 (tarantula) home group novelty tests. Of the 230 subjects, 197 (85.6%) approached the stimulus object during both tests, 9 (3.9%) did not approach the object in both tests, and 24 (10.4%) approached the stimulus object in one year but not the other. The intra-class correlation of Novelty Seeking scores was significant across years (r= 0.68, df = 229, p < 0.001) indicating the presence of a stable aspect of behavioral temperament that reflects reduced latency to approach and interest in novel and potentially risky stimuli.
Figure 1
Figure 1
Novelty Seeking scores for the snake (2006) and tarantula (2007) home group novelty tests. Individual differences were consistent across tests (ICC = 0.68) suggesting a trait-like temperamental characteristic.
Novelty seeking scores were inversely related to subject age for the range considered here (snake, r = −0.29, df=228, p<0.001; tarantula, r = −0.27, df=228, p<0.001). The high year to year consistency in scores remained after controlling age (ICC = 0.65, df=229, p<0.001). There were no significant effects of dominance rank on Novelty Seeking scores for either year (rank coded as high, middle, low: snake, r = 0.11, ns; tarantula, r = .004, ns), and Novelty Seeking was unrelated to the number of adult females in the group (snake, r = −.05, ns; tarantula, r = 0.01, ns).
3.2. Hair cortisol
Hair cortisol levels from samples collected approximately 3–6 months following the second novelty seeking test were normally distributed as shown in Figure 2. Hair cortisol levels ranged from 22.4 to 101.2 pg/mg (mean = 52.8, SD = 12.3), and was unrelated to female age (3–18 years of age) at the time of hair collection [Pearson’s r = 0.08, ns]. There were no significant effects of female dominance rank on hair cortisol levels (rank coded as high, middle, low: r = −0.01, df = 228, ns), and the seven females who delivered an infant two to three months before or after sample collection did not differ from the remaining females in mean level (t = 0.09, df = 228, ns).
Figure 2
Figure 2
Frequency distribution of hair cortisol observed in 230 vervet monkeys. The group was divided into three groups based on the upper and lower SD, lowest SD (n=28) ranges from 22.4 to 40 pg/mg, the midrange group (n=169) ranges 40.5 – 64 pg/mg, (more ...)
Hair cortisol level was inversely related to Novelty seeking score for both test years (snake, r = −0.26, df=228, p < .001; tarantula r, = −0.18, df=228, p < .01; mean Novelty Seeking score r = −0.25, df=228, p < .001). Controlling the effects of age did not change the relationship between hair cortisol levels and Novelty Seeking scores (snake, partial r = =−.25, df=227, p < .001; tarantula, partial r = −.17, df=227, p = 0.01)
3.3. Relation of Novelty Seeking and Hair Cortisol
In order to distinguish subjects with overall enhanced or blunted cortisol activity (19), subjects were divided into three subgroups based on the upper and lower standard deviations (SD) of the distribution. The lowest group (n=28) ranged from 22.4 to 40 pg/mg, the midrange group (n=169) ranged from 40.5 – 64 pg/mg, and the highest group (n=33) ranged from 65–101.2 pg/mg.
Mean (+SE) Novelty Seeking scores for the Low, Middle and High hair cortisol groups are shown in Figure 3 for the two stimulus objects. There was a significant main effect of hair cortisol group for both novel stimuli (snake: F(2,227) = 5.11, p < 0.01; tarantula: F(2,227) = 3.31, p = 0.04), and the unweighted linear term was also significant for both (snake: F(1,227) = 6.72, p = 0.01; tarantula: F(1,227) = 5.88, p = 0.02). Females in the high hair cortisol group falling in the upper SD of the cortisol distribution (>65 pg/mg), had significantly lower Novelty Seeking scores than the females from the low hair cortisol groups for both tests (Tukey test, p<0.05). The middle and low groups did not differ significantly from each other for either test. Controlling age did not alter the significance of the linear relationship between Novelty Seeking and hair cortisol for either year (p < 0.05). Removing the seven females who delivered an infant within two to three months of sample collection also did not alter the significance of the above results.
Figure 3
Figure 3
Mean (+SEM) Novelty Seeking Score for snake and tarantula home group novelty tests by hair cortisol level subgroups indicated in Figure 2. The low cortisol group differed significantly from the high cortisol group in both years (p<0.05).
The present results add further support to a growing literature regarding the utility of hair cortisol as a marker of underlying long term HPA activity (23, 26, 27, 3240). In the present study, reduced Novelty Seeking behavior in female vervet monkeys (indicated by fewer approaches and less time spent in proximity to a novel object introduced near the home enclosures) was associated with higher hair cortisol levels. In vervet monkeys, we have also shown that hair cortisol increases following a chronic stressor, is trait-like, and is heritable (55). In other nonhuman primate studies, hair cortisol levels of adult rhesus monkeys increased in response to the challenge of housing relocation, which was modulated by a history of behavioral pathologies (26, 27). Hair cortisol level of young rhesus monkeys predicts performance on cognitive tasks. Elevated hair cortisol level was associated with delayed response acquisition on a cognitive task (32).
Higher levels of novelty seeking behavior are associated with less HPA activation. For example the cortisol response to the combined dexamethasone/CRH challenge is reduced among individuals scoring high on novelty seeking assessments (41). In response to an anxiety provoking public speaking challenge in humans, the Trier Social Stress Test (TSST), individuals with a high novelty seeking temperament have a lower overall cortisol response to the TSST challenge (42). Mobbing behavior in the common marmoset (e.g., vocalization response in the presence of a predator) has been associated with lower salivary and hair cortisol levels (43,44). These results suggest that reduced HPA activity promotes a bold and fearless response to challenging circumstances.
In the present study, vervet females were sampled during the mating season and only a few were detectably pregnant. When hair was collected during the birth season in another environment, vervet females sampled within one month of delivery had significantly higher hair cortisol levels compared to females sampled earlier in pregnancy (55). The duration of pregnancy for vervet females is approximately 5.5 months, and the period of cortisol accumulation in hair for the females who were sampled within one month before or after delivery probably included most or all of the final third of pregnancy. The results of that study (55) supported the sensitivity of hair cortisol to increases in circulating cortisol in late pregnancy also shown in human studies (23,56).
Results from the present study, as well as another from our group (55), suggest that hair cortisol reflects a trait-like dimension of individual differences in HPA activity. Hair cortisol levels are responsive to environmental change, but individual differences within environments are heritable and trait-like. Here we demonstrate that hair cortisol is associated with a relatively stable behavioral measure of novelty seeking temperament. We do not have a precise estimate of hair growth rates or the time course of cortisol accumulation in vervet hair, but this study demonstrates that under stable conditions hair cortisol can be used to measure individual differences in HPA activity that have relevance for behavioral health and welfare.
What are potential contributions to individual differences in response to novelty that may underlie activation of the HPA? Experiences with mildly challenging situations early in development inoculate squirrel monkeys against overwhelming stress responses to challenges at a later age (45). Early maternal experiences affect novelty seeking behaviors in adolescent rhesus and vervet monkeys (14,46, 47) and environmental challenges that impact the maternal relationship lead to offspring that become independent of their mothers at an earlier age (48). Similar observations have been long known in rodents (49,50). Maternal patterns of interactions with offspring affect gene expression via epigenetic mechanisms (51). Finally there are a number of genetic contributions to variations in the responsivity of the HPA axis (5254). Thus multiple pathways, including early stressor exposure, maternal environment, and genetic background, affect responsivity to the environment and contribute to individual differences in novelty seeking as well as HPA activation.
5. Conclusions
The present observations demonstrate that novelty seeking is a persistent dimension of temperament for female vervet monkeys. In this study, female vervet monkeys with high hair cortisol levels were consistently lower in novelty seeking compared to females with low hair cortisol levels. Our observations add further support for the use of cortisol measured in hair as a marker of integrated cortisol release over a retrospective period. These results suggest that persistently high levels of HPA activity may inhibit novelty seeking and increase risk for pathology.
Acknowledgments
We wish to thank Adriana Jakobsen, Danielle Epstein, Clayton Clemment, Karin Blau, Sherry Briedenthal, Glenvile Morton, Dan Diekmann, and Raul Amaya for assistance with behavioral observations and hair collection. We would also like to thank Africa Armendariz and Crystal Natvig for their expert assistance in processing and analyzing the hair samples for this study. Finally, we thank Steven Shapiro for the loan of the ball grinder for processing initial samples in this study. Supported in part by NIH Grants R01-AA013973 (MLL), R01-MH61852 (LAF), R01-MH82147 (LAF), and P40-RR019963 (LAF) and the University of Colorado Denver, Department of Psychiatry, Developmental Psychobiology Endowment Fund (MLL).
Footnotes
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1. Cloninger CR, Sigvardsson S, Bohman M. Childhood Personality Predicts Alcohol Abuse in Young Adults. Alcoholism: Clinical and Experimental Research. 1988;12(4):494–505. [PubMed]
2. Howard MO, Kivlahan D, Walker RD. Cloninger's tridimensional theory of personality and psychopathology: applications to substance use disorders. Journal of Studies on Alcohol. 1997 Jan;58(1):48–66. [PubMed]
3. Kagan J, Snidman N. Early childhood predictors of adult anxiety disorders. Biological Psychiatry. 1999;9:547–50. [PubMed]
4. Svihra M, Katzman M. Behavioural inhibition: A predictor of anxiety. Paediatrics and Child Health. 2004;9:547–50. [PMC free article] [PubMed]
5. Kiebar J, Bevins R, Segar T, Bardo M. Individual differences in behavioral responses to novelty and amphetamine self-administration in male and female rats. Behavioral Pharmacology. 2001;12:267–75. [PubMed]
6. Zhu J, Bardo M, Bruntz R, Stairs D, Dwoskin L. Individual differences in response to novelty predict prefrontal cortex dopamine transporter function and cell surface expression. European Journal of Neuroscience. 2007;26:717–28. [PubMed]
7. Belin D, Nadege-Berson N, Balado E, Vincenzo Piazza P, Deroche-Gamonet V. High novelty preference rats are predisposed to compulsive cocaine self-administration. Neuropsychopharmacology. 2010 epublication. [PMC free article] [PubMed]
8. Capitanio JP, Rasmussen KL, Snyder DS, Laudenslager M, Reite M. Long-term follow-up of previously separated pigtail macaques: group and individual differences in response to novel situations. Journal of Child Psychology & Psychiatry & Allied Disciplines. 1986;27(4):531–8. [PubMed]
9. Kalin NH, Shelton SE, Rickman M, Davidson RJ. Individual differences in freezing and cortisol in infant and mother rhesus monkeys. Behavioral Neuroscience. 1998 Feb;112(1):251–4. [PubMed]
10. Kalin N, Shelton S, Fox A, Oakes T, Davidson R. Brain regions associated with the expression and contextual regulation of anxiety in primates. Biological Psychiatry. 2005;58:796–804. [PMC free article] [PubMed]
11. Williamson D, Coleman K, Bacanu S-A, Devlin B, Rogers J, Ryan N, Cameron J. Heritability of fearful-anxious endophenotypes in infant rhesus macaques: A preliminary report. Biological Psychiatry. 2003;53:284–91. [PubMed]
12. Rogers J, Shelton S, Shelledy W, Garcia R, Kalin N. Genetic influences on behavioral inhibition and anxiety in juvenile rhesus macaques. Genes Brain and Behavior. 2008;7:463–9. [PMC free article] [PubMed]
13. Bardi M, Bode A, Ramirez S, Brent L. Maternal care and development of stress responses in baboons. American Journal of Primatology. 2005;66:263–78. [PubMed]
14. Fairbanks LA, McGuire MT. Long-term effects of early mothering behavior on responsiveness to the environment in vervet monkeys. Developmental Psychobiology. 1988 Nov;21(7):711–24. [PubMed]
15. Fairbanks LA, McGuire MT. Maternal protectiveness and response to the unfamiliar in vervet monkeys. American Journal of Primatology. 1993;30:119–29.
16. Parker KJ, Rainwater KL, Buckmaster CL, Schatzberg AF, Lindley SE, Lyons DM, Parker KJ, Rainwater KL, Buckmaster CL, Schatzberg AF, Lindley SE, Lyons DM. Early life stress and novelty seeking behavior in adolescent monkeys. Psychoneuroendocrinology. 2007 Aug;32(7):785–92. [PMC free article] [PubMed]
17. Spencer-Booth Y, Hinde RA. Effects of brief separations from mothers during infancy on behaviour of rhesus monkeys 6–24 months later. Journal of Child Psychology and Psychiatry. 1971;12:157–72. [PubMed]
18. Bailey JN, Breidenthal SE, Jorgensen MJ, McCracken JT, Fairbanks LA. The association of DRD4 and novelty seeking is found in a nonhuman primate model. Psychiatric Genetics. 2007;17(1):23–7. [PubMed]
19. de Kloet ER. About stress hormones and resilience to psychopathology. Journal of Neuroendocrinology. 2008 Jun;20(6):885–92. [PubMed]
20. McEwen BS. Protection and damage from acute and chronic stress: allostasis and allostatic overload and relevance to the pathophysiology of psychiatric disorders. Annals of the New York Academy of Sciences. 2004;1032:1–7. [PubMed]
21. Cirimele V, Kintz P, Dumestre V, Goulle JP, Ludes B. Identification of ten corticosteroids in human hair by liquid chromatography-ionspray mass spectrometry. Forensic Science International. 2000 Jan 10;107(1–3):381–8. [PubMed]
22. Deshmukh N, Hussain I, Barker J, Petroczi A, Naughton DP, Deshmukh N, Hussain I, Barker J, Petroczi A, Naughton DP. Analysis of anabolic steroids in human hair using LC-MS/MS. Steroids. 2009 Oct;75(10):710–4. [PubMed]
23. Kirschbaum C, Tietze A, Skoluda N, Dettenborn L. Hair as a retrospective calendar of cortisolproduction: creased cortisol incorporation into hair in the third trimester of pregnancy. Psychoneuroendocrinology. 2009;34:32–7. [PubMed]
24. Saudek CD, Derr RL, Kalyani RR. Assessing Glycemia in Diabetes Using Self-monitoring Blood Glucose and Hemoglobin A1c. JAMA. 2006 April 12;295(14):1688–97. [PubMed]
25. Neu M, Goldstein M, Gao D, Laudenslager ML. Salivary cortisol in preterm infants: Validation of a simple method for collecting saliva for cortisol determination. Early Human Development. 2007 Jan;83(1):47–54. [PubMed]
26. Davenport MD, Tiefenbacher S, Lutz CK, Novak MA, Meyer JS. Analysis of endogenous cortisol concentrations in the hair of rhesus macaques. General & Comparative Endocrinology. 2006 Jul;147(3):255–61. [PubMed]
27. Davenport MD, Lutz CK, Tiefenbacher S, Novak MA, Meyer JS. A rhesus monkey model of self-injury: effects of relocation stress on behavior and neuroendocrine function. Biological Psychiatry. 2008 May 15;63(10):990–6. [PMC free article] [PubMed]
28. Herndon AG, Turner JJ, Perachio AA, Blank MS, Collins DC. Endocrine changes induced by venipuncture in Rhesus monkeys. Physiology Behavior. 1984;32:673–6. [PubMed]
29. Fairbanks LA, Newman TK, Bailey JN, Jorgensen MJ, Breidenthal SE, Ophoff RA, Comuzzie AG, Martin LJ, Rogers J. Genetic contributions to social impulsivity and aggressiveness in vervet monkeys. Biological Psychiatry. 2004 Mar 15;55(6):642–7. [PubMed]
30. Freimer NB, Service SK, Ophoff RA, Jasinska AJ, McKee K, Villeneuve A, Belisle A, Bailey JN, Breidenthal SE, Jorgensen MJ, Mann JJ, Cantor RM, Dewar K, Fairbanks LA. A quantitative trait locus for variation in dopamine metabolism mapped in a primate model using reference sequences from related species. Proceedings of the National Academy of Sciences of the United States of America. 2007 Oct 2;104(40):15811–6. [PubMed]
31. Wennig R. Potential problems with the interpretation of hair analysis results. Forensic Science International. 2000 Jan 10;107(1–3):5–12. [PubMed]
32. Dettmer AM, Novak MF, Novak MA, Meyer JS, Suomi SJ. Hair cortisol predicts object permanence performance in infant rhesus macaques (Macaca mulatta) Developmental Psychobiology. 2009 Dec;51(8):706–13. [PMC free article] [PubMed]
33. Accorsi PA, Carloni E, Valsecchi P, Viggiani R, Gamberoni M, Tamanini C, Seren E. Cortisol determination in hair and faeces from domestic cats and dogs. General & Comparative Endocrinology. 2008 Jan 15;155(2):398–402. [PubMed]
34. Van Uum SH, Sauve B, Fraser LA, Morley-Forster P, Paul TL, Koren G. Elevated content of cortisol in hair of patients with severe chronic pain: a novel biomarker for stress. Stress. 2008;11(6):483–8. [PubMed]
35. Sauve B, Koren G, Walsh G, Tokmakejian S, Van Uum SH. Measurement of cortisol in human hair as a biomarker of systemic exposure. Clinical & Investigative Medicine - Medecine Clinique et Experimentale. 2007;30(5):E183–91. [PubMed]
36. Kalra S, Einarson A, Karaskov T, Van Uum S, Koren G. The relationship between stress and hair cortisol in healthy pregnant women. Clinical & Investigative Medicine - Medecine Clinique et Experimentale. 2007;30(2):E103–7. [PubMed]
37. Yamada J, Stevens B, de Silva N, Gibbins S, Beyene J, Taddio A, Newman C, Koren G. Hair cortisol as a potential biologic marker of chronic stress in hospitalized neonates. Neonatology. 2007;92(1):42–9. [PubMed]
38. Raul JS, Cirimele V, Ludes B, Kintz P. Detection of physiological concentrations of cortisol and cortisone in human hair. Clinical Biochemistry. 2004 Dec;37(12):1105–11. [PubMed]
39. Gow R, Thomson S, Rieder M, Van Uum S, Koren G. An assessment of cortisol analysis in hair and its clinical applications. Forensic Science International. 2010 Mar 20;196(1–3):32–7. [PubMed]
40. Thomson S, Koren G, Fraser LA, Rieder M, Friedman TC, Van Uum SH, Van Uum SHM. Hair analysis provides a historical record of cortisol levels in Cushing's syndrome. Experimental & Clinical Endocrinology & Diabetes. 2010 Feb;118(2):133–8. [PMC free article] [PubMed]
41. Cross N, Rogers LJ. Mobbing vocalizations as a coping response in the common marmoset. Hormones & Behavior. 2006 Feb;49(2):237–45. [PubMed]
42. Clara E, Tommasi L, Rogers LJ. Social mobbing calls in common marmosets (Callithrix jacchus): effects of experience and associated cortisol levels. Animal Cognition. 2008 Apr;11(2):349–58. [PubMed]
43. Tyrka AR, Mello AF, Mello MF, Gagne GG, Grover KE, Anderson GM, Price LH, Carpenter LL. Temperament and hypothalamic-pituitary-adrenal axis function in healthy adults. Psychoneuroendocrinology. 2006 Oct;31(9):1036–45. [PubMed]
44. Tyrka AR, Wier LM, Anderson GM, Wilkinson CW, Price LH, Carpenter LL. Temperament and response to the Trier Social Stress Test. Acta Psychiatrica Scandinavica. 2007 May;115(5):395–402. [PubMed]
45. Lyons DM, Parker KJ, Lyons DM, Parker KJ. Stress inoculation-induced indications of resilience in monkeys. Journal of Traumatic Stress. 2007 Aug;20(4):423–33. [PubMed]
46. Simpson MJA. Effects of early experience on the behavior of yearling rhesus monkeys (Macaca mulatta) in the presence of a strange object: classification and correlation approaches. Primates. 1985;26:57–72.
47. Simpson MJA, Simpson AE. The emergence and maintenance of interdyad diffferences in the mother-infant relationships of rhesus macaques: A correlational study. International Journal of Primatology. 1986;7(4):379–99.
48. Laudenslager ML, Natvig C, Mikulich-Gilbertson SM, Blevins M, Corcoran C, Pierre PJ, Bennett AJ. Challenges to bonnet monkey (Macaca radiata) social groups: Mother-infant dyad and infant social interactions. Developmental Psychobiology. 2010 Jul;52(5):465–74. [PubMed]
49. Solomon GF, Levine S, Kraft JK. Early experience and immunity. Nature. 1968:220. [PubMed]
50. Wiener SG, Levine S. Perinatal malnutrition and early handling: interactive effects on the development of the pituitary-adrenal system. Developmental Psychobiology. 1978;11:335–52. [PubMed]
51. Kaffman A, Meaney MJ. Neurodevelopmental sequelae of postnatal maternal care in rodents: clinical and research implications of molecular insights. Journal of Child Psychology & Psychiatry & Allied Disciplines. 2007;48(3–4):224–442. [PubMed]
52. Derijk RH, de Kloet ER, Derijk RH, de Kloet ER. Corticosteroid receptor polymorphisms: determinants of vulnerability and resilience. European Journal of Pharmacology. 2008 Apr 7;583(2–3):303–11. [PubMed]
53. Wust S, Van Rossum EF, Federenko IS, Koper JW, Kumsta R, Hellhammer DH. Common polymorphisms in the glucocorticoid receptor gene are associated with adrenocortical responses to psychosocial stress.[see comment] Journal of Clinical Endocrinology & Metabolism. 2004;89(2):565–73. [PubMed]
54. Rosmond R, Rosmond R. The glucocorticoid receptor gene and its association to metabolic syndrome. Obesity Research. 2002 Oct;10(10):1078–86. [PubMed]
55. Fairbanks LA, Jorgensen MJ, Bailey JN, Breidenthal SE, Grzywa R, Laudenslager ML. Heritability and genetic correlation of hair cortisol in vervet monkeys in low and higher stress environments. Psychoneuroendocrinology. in press. [PMC free article] [PubMed]
56. D’Anna KL, Ross RG, Nativg C, Laudenslager ML. Hair cortisol levels as a retrospective marker of hypothalamic-pituitary axis activity throughout pregnancy: Comparison to salivary cortisol. Physiology and Behavior. in press. [PMC free article] [PubMed]