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Serotonin transporter gene variation, infant abuse, and responsiveness to stress in rhesus macaque mothers and infants
Open accessAbstract
A functional polymorphism in the promoter region of the serotonin transporter (5-HTTLPR) gene has been associated with variation in anxiety and hypothalamus-pituitary-adrenal (HPA) axis function in humans and rhesus macaques. Individuals carrying the short allele are at a higher risk for developmental psychopathology, and this risk is magnified in short allele carriers who have experienced early life stress. This study investigated the relationship between 5-HTTLPR allelic variation, infant abuse, and behavioral and hormonal responses to stress in rhesus macaques. Subjects were 10 abusive mothers and their infants, and 10 nonabusive mother-infant pairs. Mothers and infants were genotyped for the rh5-HTTLPR, and studied in the first 6 months of infant life. For mothers and infants, we measured social group behavior, behavioral responses to handling procedures, and plasma concentrations of ACTH and cortisol under basal conditions and in response to stress tests. The proportion of individuals carrying the short rh5-HTTLPR allele was significantly higher among abusive mothers than controls. Among mothers and infants, the short allele was associated with higher basal cortisol levels and greater hormonal stress responses in the infants. In addition, infants who carried the short rh5-HTTLPR allele had higher anxiety scores than infants homozygous for the long allele. The rh5-HTTLPR genotype also interacted with early adverse experience to impact HPA axis function in the infants. These results are consistent with those of previous studies which demonstrate associations between serotonergic activity and anxiety and stress reactivity, and add additional evidence suggesting that genetic variation in serotonergic function may contribute to the occurrence of abusive parenting in rhesus macaques and modulate emotional behavior and HPA axis function.
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“Social buffering of the infant is a dynamic process that wanes as individuals across species mature and become independent (Gee et al., 2014, Levine, 2001, McCormack et al., 2009, Sanchez, 2006, Stanton and Levine, 1990, Suchecki et al., 1995, van Oers et al., 1998) (Fig. 1).”
From Early life adversity during the infant sensitive period for attachment: Programming of behavioral neurobiology of threat processing and social behavior (2017) · cites this paper as McCormack et al., 2009
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Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene
Caspi, A., Sugden, K., Moffitt, T. E., Taylor, A., Craig, I. W., Harrington, H., McClay, J., Mill, J., Martin, J., Braithwaite, A., et al. (2003) · Science · doi:10.1126/science.1083968 · Cited by 8,120 · cited 1×
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A FIELD STUDY OF THE SOCIOBIOLOGY OF RHESUS MONKEYS, MACACA MULATTA *
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“Data collection included infant abuse, other mother–infant interactions (time spent in contact and frequencies of: contacts made and broken, rejections, and restrains), as well as the social and nonsocial behavior of the infants (frequencies of vocalizations, anxiety behavior, agonistic interactions with others, and s…”
Method
Cited by
Sorted by citations
Adolescent risk taking, impulsivity, and brain development: Implications for prevention
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“, 1997), and enhanced stress response (McCormack et al., 2009), future studies need to examine the impact of maternal HFD consumption on neuronal development, stress response, and cognition.”
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“Similarly, rhesus macaques with the S allele who experience ELA show heightened stress responses, reduced serotonergic function, and greater anxiety than L allele carriers [170], and mice with disrupted 5-HTT show enhanced ACTH levels in response to stress [171].”
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The neuroendocrinology of primate maternal behavior
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“(McCormack et al., 2009) suggests that genetically based variation in brain serotonergic function may also play a role in the manifestation of abusive parenting and its transmission across generations.”
BackgroundMaternal early life experiences and parenting: the mediating role of cortisol and executive function
Gonzalez, A., Jenkins, J. M., Steiner, M., & Fleming, A. S. (2012) · Journal of the American Academy of Child & Adolescent Psychiatry · doi:10.1016/j.jaac.2012.04.003 · Cited by 146
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“Although there is no solid evidence of a true SHRP in rhesus monkeys, socially familiar cues, specifically the presence of a nurturing mother, do buffer the HPA axis stress responses in infant rhesus macaques (McCormack et al., 2009; Sanchez, 2006).”
Self-citationKinnally, E. L., Tarara, E. R., Mason, W. A., Mendoza, S. P., Abel, K., Lyons, L. A., & Capitanio, J. P. (2009) · Genes Brain & Behavior · doi:10.1111/j.1601-183x.2009.00533.x · Cited by 125
“This is consistent with our previous work [Kinnally et al. 2008; Kinnally et al.(in press)], but inconsistent with other work in rhesus macaques (Barr et al. 2004; Bennett et al. 2002; Champoux et al. 2002; McCormack et al. 2009; Spinelli et al. 2007).”
InfluentialHowell, B., McCormack, K. M., Grand, A. P., Sawyer, N. T., Zhang, X., Maestripieri, D., Hu, X. P., & Sánchez, M. M. (2013) · Biology of Mood & Anxiety Disorders · doi:10.1186/2045-5380-3-21 · Cited by 112
“Using this model we have previously reported increased emotional reactivity in maltreated infants and juveniles [7,9,70] and social alterations including delayed independence from the mother and less play during infancy [6,71], as well as increased social aggression during adolescence [72].”
InfluentialSelf-citationGenetics of anxiety disorders: the complex road from DSM to DNA
Smoller, J. W., Block, S. R., & Young, M. M. (2009) · Depression and Anxiety · doi:10.1002/da.20623 · Cited by 104
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Elbau, I., Cruceanu, C., & Binder, E. B. (2019) · Biological Psychiatry · doi:10.1016/j.biopsych.2019.04.025 · Cited by 98
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“Social buffering of the infant is a dynamic process that wanes s individuals across species mature and become independent Gee et al., 2014; Levine, 2001; McCormack et al., 2009; Sanchez, 006; Stanton and Levine, 1990; Suchecki et al., 1995; van Oers t al., 1998) (Fig.”
Steroid hormones, stress and the adolescent brain: A comparative perspective
Brown, G. R., & Spencer, K. A. (2012) · Neuroscience · doi:10.1016/j.neuroscience.2012.12.016 · Cited by 88
“In 23 primates, basal CORT levels rise during adolescence (e.g., chimpanzees, Pan troglodytes: 24 Seraphin et al., 2008; rhesus macaques, McCormack et al., 2009) , and studies of human 25 adolescents have reported enhanced stress reactivity in adolescents compared to children (e.g., 1 Gunnar et…”
Wilkinson, P. O., & Goodyer, I. M. (2011) · Development and Psychopathology · doi:10.1017/s0954579411000472 · Cited by 95
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BackgroundResultInfluentialKofink, D., Boks, M. P. M., Timmers, H. T. M., & Kas, M. J. (2013) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2013.03.020 · Cited by 83
Maternal influences on primate social development
Dario Maestripieri, A. (2018) · Behavioral Ecology and Sociobiology · doi:10.1007/s00265-018-2547-x · Cited by 77
Howell, B. R., Grand, A. P., McCormack, K. M., Shi, Y., LaPrarie, J. L., Maestripieri, D., Styner, M. A., & Sanchez, M. M. (2014) · Developmental Psychobiology · doi:10.1002/dev.21237 · Cited by 72
“…and inclusion/exclusion criteria described in detail for this species in previous publications (e.g. Maestripieri, 1998; McCormack et al., 2006; McCormack et al., 2009; Troisi & D’Amato, 1983), infants were classified as abused if the mother was observed exhibiting at least 3 instances of the…”
Self-citationNuman, M. (2020) · doi:10.1093/oso/9780190848675.001.0001 · Cited by 106
Higham, J. P., Barr, C. S., Hoffman, C. L., Mandalaywala, T. M., Parker, K. J., & Maestripieri, D. (2011) · Behavioral Neuroscience · doi:10.1037/a0022695 · Cited by 69
“Genetic polymorphisms (e.g., in or related to dopamine receptor genes and the serotonin transporter gene; Fairbanks et al., 2006; McCormack et al., 2009) and neuroendocrine variables (e.g., reproductive and stress hormones, endogenous opioids and oxytocin (OT), and monoamine neurotransmitters;…”
The role of childhood abuse in HPA-axis reactivity in Social Anxiety Disorder: A pilot study
Elzinga, B. M., Spinhoven, P., Berretty, E. W., de Jong, P., & Roelofs, K. (2009) · Biological Psychology · doi:10.1016/j.biopsycho.2009.09.006 · Cited by 73
“Interestingly, some of these same genes also appear to be associated with alterations in HPA-axis reactivity after stress exposure (Binder et al., 2008; McCormack et al., 2009; see also Ouellet-Morin et al., 2008).”
BackgroundGettler, L. T. (2016) · Current Anthropology · doi:10.1086/686149 · Cited by 66
“Finally, these researchers (Champoux et al. 2002; Jedema et al. 2009) and others (McCormack et al. 2009) have found a number of significant serotonin transporter gene X rearing environment interactions that predict monkeys’ behaviors from infancy through adulthood.”
BackgroundAïn, S. A., Perry, R. E., Nuñez, B. S., Kayser, K. E., Hochman, C., Brehman, E., LaComb, M., Wilson, D. A., & Sullivan, R. M. (2016) · Social Neuroscience · doi:10.1080/17470919.2016.1159605 · Cited by 65
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Cross-fostering: Elucidating the effects of gene×environment interactions on phenotypic development
McCarty, R. C. (2016) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2016.12.025 · Cited by 65
Howell, B., & Sánchez, M. M. (2011) · Development and Psychopathology · doi:10.1017/s0954579411000460 · Cited by 59
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“Rhesus macaque mothers who demonstrate abusive mothering traits also show short allele variants of the serotonin transporter gene which is further associated with increased basal cortisol levels (McCormack et al., 2009).”
Homberg, J. R., & van den Hove, D. (2012) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2012.08.003 · Cited by 53
“abuse, to impact upon HPA axis function in the infants (McCormack et al., 2009).”
Akkermann, K., Kaasik, K., Kiive, E., Nordquist, N., Oreland, L., & Harro, J. (2011) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2011.09.013 · Cited by 56
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“Behavioral observations were collected in each mother-infant pair by four experienced coders from observation towers located at each social compound during the first three months postpartum using an adaptation of a well-established rhesus monkey ethogram (Altmann, 1962) and following previously published procedures (M…”
BackgroundMethodInfluentialSelf-citationThe neurobiology of safety and threat learning in infancy
Dębiec, J., & Sullivan, R. M. (2016) · Neurobiology of Learning and Memory · doi:10.1016/j.nlm.2016.10.015 · Cited by 49
Nonhuman Primate Models of Depression: Effects of Early Experience and Stress
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“, 2004) or monoaminergic (Barr et al., 2004b; McCormack et al., 2009) neurotransmitter system components.”
BackgroundEarly Experience Affects the Strength of Vigilance for Threat in Rhesus Monkey Infants
Mandalaywala, T. M., Parker, K. J., & Maestripieri, D. (2014) · Psychological Science · doi:10.1177/0956797614544175 · Cited by 44
“Infants who possess this same variant often demonstrate impaired emotion regulation and heightened anxiety, but only when exposed to early life adversity (e.g., McCormack et al., 2009; Spinelli et al., 2012).”
A comparative approach to affect and cooperation
Massen, J. J. M., Behrens, F., Martin, J. S., Stocker, M., & Brosnan, S. F. (2019) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2019.09.027 · Cited by 45
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“…stress responses and modulate vulnerability to the deleterious effects of early life stress, both in humans (Caspi et al. 2003; Zalsman et al. 2006; Stein et al. 2008; Caspi et al. 2010) and nonhuman primates (Bennett et al. 2002; Champoux et al. 2002; Barr et al. 2004; McCormack et al. 2009).”
Morin, E. L., Howell, B. R., Feczko, E., Earl, E., Pincus, M., Reding, K., Kovacs-Balint, Z. A., Meyer, J. S., Styner, M., Fair, D., et al. (2020) · Development and Psychopathology · doi:10.1017/s0954579420001133 · Cited by 37
“…impact on development of amygdala FC, which may underlie the increased emotional reactivity reported in maltreated animals (Howell et al., 2014; McCormack et al., 2009; McCormack et al., 2006; Morin et al., 2019; Morin et al., 2018); and (b) whether the prolonged exposure to high cortisol…”
BackgroundMethodInfluentialKoch, H. R., McCormack, K. M., Sánchez, M. M., & Dario Maestripieri, A. (2012) · Developmental Psychobiology · doi:10.1002/dev.21093 · Cited by 37
“…function under both basal conditions and in response to stress, that the altered response to stress was different in male and female infants, and that this was primarily a short-term effect that was detectable in the first year or life but not in subsequent years (see also McCormack et al., 2009).”
BackgroundSelf-citationLiving in a dangerous world decreases maternal care: A study in serotonin transporter knockout mice
Heiming, R. S., Bodden, C., Jansen, F., Lewejohann, L., Kaiser, S., Lesch, K., Palme, R., & Sachser, N. (2011) · Hormones and Behavior · doi:10.1016/j.yhbeh.2011.07.006 · Cited by 36
“Indeed, variation in the frequency and intensity of maternal care, in particular maternal licking and grooming (LG) of pups, is amajor source of interindividual differences in behavioral profile and stress responsiveness in adulthood (Kaufman et al., 2004; McCormack et al., 2009; Meaney, 2001).”
Martin, J. S., Jaeggi, A. V., & Koski, S. E. (2022) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2022.104980 · Cited by 38
“, 2016) and rhesus macaques (Macaca mulatta; McCormack et al., 2009) to southern field crickets (Gryllus bimaculatus; Abbey-Lee et al.”
BackgroundVaske, J. C., Newsome, J., & WRIGHT, J. P. (2012) · Development and Psychopathology · doi:10.1017/s0954579411000769 · Cited by 35
“…allele exhibit lower levels of 5-hydroxyindoleacetic acid, exhibit higher levels of ACTH responses to stress, and exhibit more aggressive and anxious behaviors in response to stress than maltreated subjects who do not carry a copy of the short allele (Maestripieri, 2005; McCormack et al., 2009).”
BackgroundHormonal effects of maltreatment in Nazca booby nestlings: Implications for the “cycle of violence”
Grace, J. K., Dean, K. M., Ottinger, M. A., & Anderson, D. J. (2011) · Hormones and Behavior · doi:10.1016/j.yhbeh.2011.03.007 · Cited by 33
“, 2003); (2) young acquire maltreatment behavior through observational learning (Chapman and Scott, 2001); and (3) maltreatment is a genetically heritable trait (Caspi et al., 2002; Kaufman et al., 2004; McCormack et al., 2009; Widom and Brzustowicz, 2006).”
Drury, S. S., Howell, B., Jones, C., Esteves, K. C., Morin, E. L., Schlesinger, R. P., Meyer, J. S., Baker, K. C., & Sánchez, M. M. (2017) · Development and Psychopathology · doi:10.1017/s0954579417001225 · Cited by 33
“0.8) from observation towers using established ethograms and procedures (Altmann, 1962; Howell et al., 2017, in press; Maestripieri & Carroll, 1998; McCormack et al., 2009, 2015; McCormack, Sanchez, Bardi, & Maestripieri, 2006).”
MethodInfluentialGlucocorticoids as Predictors of Treatment Response in Depression
Horstmann, S., & Binder, E. B. (2011) · Harvard Review of Psychiatry · doi:10.3109/10673229.2011.586550 · Cited by 31
Early-life social adversity and developmental processes in nonhuman primates
French, J. A., & Carp, S. B. (2015) · Current Opinion in Behavioral Sciences · doi:10.1016/j.cobeha.2015.11.004 · Cited by 34
“Increased rates of distress calls are also observed in infant macaques that experienced abuse compared to infants who were not abused [9].”
McCormack, K. M., Howell, B., Guzman, D., Villongco, C., Pears, K. C., Kim, H. K., Gunnar, M. R., & Sánchez, M. M. (2014) · American Journal of Primatology · doi:10.1002/ajp.22307 · Cited by 32
“…by four experienced coders from observation towers situated over each social compound, during thefirst 3months postpartumusing an adaptation of a well‐established rhesus monkey ethogram [Altmann, 1962], following previously published procedures [Maestripieri, 1998; McCormack et al., 2006, 2009].”
Self-citationMaternal effects on offspring stress physiology in wild chimpanzees
Murray, C. M., Stanton, M. A., Wellens, K. R., Santymire, R. M., Heintz, M. R., & Lonsdorf, E. V. (2016) · American Journal of Primatology · doi:10.1002/ajp.22525 · Cited by 32
“While carefully controlled research in captive or sanctuary settings has begun to unravel maternal effects on offspring stress physiology in primates [e.g., Coe et al., 2003; McCormack et al., 2009], much less is known about this process in wild populations or among chimpanzees.”
BackgroundZhang, B. (2017) · PubMed Central · doi:10.13918/j.issn.2095-8137.2017.002 · Cited by 32
“Similar results was revealed in 5-HTT genotype, as short promoter region of the serotonin transporter (5-HTTLPR) allele was related to increased anxious behavior in primates (McCormack et al., 2009) and highest emotional problem scores in human (Kumsta et al.”
ResultComparative perspectives on human gender development and evolution
Meredith, S. L. (2014) · American Journal of Physical Anthropology · doi:10.1002/ajpa.22660 · Cited by 33
“…the first 6 months of life, l/l infants showed no cortisol or ACTH elevations in response to a short-term stressor if their mothers were present, but l/s infants did, and the increase was most pronounced for l/s Yearbook of Physical Anthropology infants who were abused (McCormack et al., 2009).”
BackgroundBales, K. L. (2017) · Current Opinion in Psychology · doi:10.1016/j.copsyc.2017.02.026 · Cited by 31
The developmental consequences of early adverse care on infant macaques: A cross-fostering study
McCormack, K. M., Howell, B., Higgins, M. K., Bramlett, S. N., Guzman, D., Morin, E. L., Villongco, C., Liu, Y., Meyer, J. S., & Sánchez, M. M. (2022) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2022.105947 · Cited by 30
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“2007), infant abuse (McCormack et al. 2009), and prenatal alcohol exposure (Kraemer et al.”
BackgroundChen, G., Novak, M. A., Meyer, J. S., Kelly, B. J., Vallender, E. J., & Miller, G. M. (2010) · Genes Brain & Behavior · doi:10.1111/j.1601-183x.2010.00564.x · Cited by 30
Embree, M., Michopoulos, V., Votaw, J. R., Voll, R. J., Mun, J.-Y., Stehouwer, J. S., Goodman, M. M., Wilson, M. E., & Sánchez, M. M. (2012) · Neuroscience · doi:10.1016/j.neuroscience.2012.10.016 · Cited by 29
“The 5HTTLPR short allelic variant has been associated with vulnerabilities to psychopathology and pathophysiology in humans and nonhuman primates (for review, see Nordquist and Oreland, 2010; Lesch, 2011), including HPA dysregulation (McCormack et al., 2009), metabolic and reproductive consequences (Hoffman et al.”
BackgroundEffects of early maternal care on adolescent attention bias to threat in nonhuman primates
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“rejection, for which the highest rates occur in the first two to three months of life (Maestripieri, 1998; Maestripieri and Carroll, 1998; McCormack et al., 2006; McCormack et al., 2009).”
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“…physical abuse and maternal rejection (thought to be a form of neglect) (Maestripieri and Carroll, 1998; McCormack et al., 2006), which cause infant distress and elevations in stress hormones (Drury et al., 2017; Brittany R. Howell et al., 2013; Koch et al., 2014; McCormack et al., 2009, 2006).”
BackgroundMethodBayesian updating during development predicts genotypic differences in plasticity
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“2005), whereas high rates of maternal rejection (sometimes associated with infant abuse) can result in a short-term increase in HPA responsiveness followed by a long-term decrease (McCormack et al. 2009; Sanchez et al. 2010).”
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Suomi, S. J., Chaffin, A. C., & Higley, J. D. (2011) · Springer eBooks · doi:10.1007/978-1-4614-0176-6_11 · Cited by 20
“In a study of mother–infant interactions, among both the mothers and their infants, possession of the short allele was associated with higher basal levels of cortisol and greater hormonal responses to stress in the infants (McCormack et al. 2009).”
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“Blood samples collected under these training/ habituation conditions and within 10 min reflect basal hormone levels since elevations in plasma cortisol concentrations are minimal/undetectable, as demonstrated by previous studies of rhesus monkeys done at the YNPRC, including infants (McCormack et al., 2009; Sanchez et…”
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“In addition, higher cortisol in response to a stressor was reported in infant macaques carrying the s allele and raised by abusive mothers (Mccormack et al., 2009).”
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“Recently, McCormack et al. (2009) demonstrated that infants with the “at-risk” short allele for serotonin transporter who are not abused as infants exhibit lower CORT reactivity than those that are abused, and infants who lack the short allele but who are abused as infants exhibit higher levels of…”
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“Moreover, previous reports of interactions between stress and individual genotypes on HPA axis activity (Barr et al. 2004b; Bet et al. 2009; Chen et al. 2010a; Gillespie et al. 2009; McCormack et al. 2009; Tyrka et al. 2009; Witt et al. 2011) support the hypothesis of inherent genetic risk being elevated by a history…”
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“In this model, infant MALT is de fi ned by co-morbid experience of maternal physical abuse and rejection of the infant during the fi rst three months of life causing pain, emotional distress, and elevations in stress hormones [20, 21, 23, 25 – 27 , 39 – 41 ].”
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Metadata
- Authors
- McCormack, K., Newman, T. K., Higley, J. D., Maestripieri, D., & Sanchez, M. M.
- Affiliations
- Spelman College (US)
- University of Cape Town (ZA)
- Brigham Young University (US)
- Corresponding author
- McCormack, K.
- Venue
- Hormones and Behavior
- Publisher
- Elsevier BV
- Published
- 2009-04
- Volume
- 55
- Issue
- 4
- Pages
- 538-547
- ISSN
- 0018-506X (ISSN-L)
- PMC
- PMC3954512
- OpenAlex
- W2068680756
- Cited by
- 161
- References
- 73
- Citations by year
- 2026: 4 · 2025: 5 · 2024: 6 · 2023: 4 · 2022: 7 · 2021: 2 · 2020: 21 · 2019: 8 · 2018: 10 · 2017: 5 · 2016: 11 · 2015: 7 · 2014: 9 · 2013: 11 · 2012: 17
- FWCI
- 6.36
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Hormones and Behavior (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- National Institute of Mental Health (MH62577, MH65046, P50MH058922, MH58922, MH63097, K02MH063097, R01MH062577, MH065046, R21MH065046)
- National Institute of General Medical Sciences (K12-GM 00680, K12GM000680)
- National Center for Research Resources (RR-00 165, P51RR000165)
- National Institute on Minority Health and Health Disparities (P20MD000215, MD000215)
- Topics
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Neuroendocrine regulation and behavior
- Keywords
- serotonin transporter gene, 5-HTTLPR, infant abuse, abusive parenting, rhesus monkeys, hypothalamic-pituitary-adrenal axis, cortisol, ACTH, stress reactivity, anxiety, early life stress, gene-environment interaction
- MeSH terms
- Adrenocorticotropic Hormone, Aging, Animals, Anxiety, Female, Hormones, Hydrocortisone, Hypothalamo-Hypophyseal System, Macaca mulatta, Maternal Behavior, Maternal Deprivation, Mothers, Pituitary-Adrenal System, Social Behavior, Stress, Psychological, Time Factors, Genetic Variation, Sequence Analysis, DNA, Serotonin Plasma Membrane Transport Proteins
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