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Fries AB, Ziegler TE, Kurian JR, Jacoris S, Pollak SD. Early experience in humans is associated with changes in neuropeptides critical for regulating social behavior. Proc Natl Acad Sci U S A. 2005 Nov 22 ; 102(47):17237-40. Pubmed Abstract

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Primary Papers: Early experience in humans is associated with changes in neuropeptides critical for regulating social behavior.

Comment by:  Jogin H. Thakore
Submitted 30 November 2005
Posted 30 November 2005

Fries et al. have conducted a very interesting study into the social role of two neurohypophyseal peptides (oxytocin [OT] and vasopressin [AVP]). Most such studies are conducted in animals and have shed light on the importance of both in terms of social and emotional bonding. There is little doubt that the previously institutionalized group had suffered neglect, and their ability to secrete OT and their basal levels of AVP are reduced, indicating that their posterior pituitary and associated circuitry is not functioning optimally. A problem with this study is the fact that we are not told whether the children suffered from any sort of physical or sexual abuse. The latter is particularly important as children who were abused early in life, and were currently well, had stress (CRH-ACTH) responses which were similar to adults with depression (De Bellis, 1994). These findings may not seem very surprising as the effects of trauma or indeed illness may not manifest for many years. These small pieces of evidence add to the concept that many psychological and physical processes have their origins, though may only manifest in adult life.

De Bellis MD, Chrousos GP, Dorn LD, Burke L, Helmers K, Kling MA, Trickett PK, Putnam FW. Hypothalamic-pituitary-adrenal axis dysregulation in sexually abused girls. J Clin Endocrinol Metab. 1994 Feb;78(2):249-55. Abstract

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Primary Papers: Early experience in humans is associated with changes in neuropeptides critical for regulating social behavior.

Comment by:  James I. Koenig
Submitted 1 December 2005
Posted 1 December 2005

A variety of studies using a diverse array of species has established the importance of both oxytocin and vasopressin in non-human affiliative behaviors. The data provided by Fries and colleagues (Fries et al., 2005) in combination with recent data provided by Kosfeld et al. (Kosfeld et al., 2005; Zak et al., 2005) now begin to shed light on the role of these peptides in human social behaviors. While there are a number of caveats that can be attached to the findings of Fries and colleagues, the suppressed concentrations of vasopressin and oxytocin found in the urine of children exposed to impoverished early life conditions suggest that enduring changes occurred in the neurons of the hypothalamus that produce and secrete these hormones. The novelty of these data is that changing the social environment of these children elicits different responses in the hypothalamic systems responsible for producing oxytocin and vasopressin. This is a highly provocative finding! Whether urinary concentrations of these peptides are a reliable proxy for what happens in the brain loci intimately involved in social behavior remains to be established.

Fries and colleagues conclude that the early life impoverishment experienced by these children is responsible for the oxytocin and vasopressin changes reported in their paper. However, no information is provided about the prenatal in utero environment of the children. Data from our studies in rodents would suggest that adverse prenatal conditions compromise the development and function of brain oxytocinergic neurons involved in social behaviors, and that the quality of the postnatal environment is irrelevant in the genesis of these changes (Lee et al., 2003). The data provided by Fries and collaborators do not rule out such a possibility, but it would appear that the authors did not consider that the changes they have identified might have been generated even earlier in development. Collecting information about the pre-birth developmental conditions of the children Fries et al. studied may be impossible, but could provide a conduit to reconcile their data with our animal data. Obviously, more information about the dependence of human social behavior on the neurohypophyseal peptides is needed to thoroughly understand the differences and similarities between humans and non-human mammals in this important area.

Fries AB, Ziegler TE, Kurian JR, Jacoris S, Pollak SD. From The Cover: Early experience in humans is associated with changes in neuropeptides critical for regulating social behavior. Proc Natl Acad Sci U S A. 2005 Nov 22;102(47):17237-40. Abstract

Kosfeld M, Heinrichs M, Zak PJ, Fischbacher U, Fehr E. Oxytocin increases trust in humans. Nature. 2005 Jun 2;435(7042):673-6. Abstract

Lee PR, Brady D, Shapiro RA, Dorsa DM, Koenig JI (2003) Schizophrenia-related developmental insults alter social behaviors and neuropeptides in adult rats. Soc Neurosci Abstr 33:#754.714.

Zak PJ, Kurzban R, Matzner WT. Oxytocin is associated with human trustworthiness. Horm Behav. 2005 Dec;48(5):522-527. Epub 2005 Aug 18. Abstract

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Primary Papers: Early experience in humans is associated with changes in neuropeptides critical for regulating social behavior.

Comment by:  German TorresJudith Horowitz
Submitted 6 December 2005
Posted 6 December 2005

Hormonal Aspects of Neglect
One clearly recognized negative symptom of schizophrenia is the loss of interest in other people or surroundings. It is not exactly clear whether this social withdrawal is the result of neural irregularities laid down during fetal development or whether it develops after disruption of systems supporting higher-order cognitive function in the adolescent brain. In this context, the neuropeptides oxytocin and vasopressin have been shown to influence a number of forms of social behavior, including avoidance (Ferguson et al., 2002). Studies of rodents, particularly mice and certain vole species, have implicated the above neuropeptide hormones in the expression patterns of social recognition and social approach. The article of Fries et al. in the recent issue of PNAS further supports a neuropeptide basis of social behavior by showing that children reared in orphanages immediately after birth later display abnormal secretion of oxytocin and vasopressin in response to dynamic social interactions.

In their report, Fries and colleagues address the question of whether children with early negative experiences (e.g., lack of emotional and physical contact from primary caregivers) show differences in hormonal responsivity after being transferred to a relatively stable and nurturing social environment. The apparent answer to this question is that despite the transfer, neglected children still show lower baseline levels of vasopressin and lower socially interactive levels of oxytocin than levels obtained from family-reared children. Given that high levels of oxytocin and vasopressin correlate well with events related to social bonding and onset of maternal care (Young, 2002), the authors conclude that such low levels are the result of early social neglect. While their conclusion is likely to be correct, at least one consideration is noteworthy. Epidemiological observations suggest that adverse manipulations of the periconceptual, intrauterine, or fetal environment (commonly referred to as maternal constraints) influence the propensity to disease. For example, malnutrition during pregnancy and type of feeding to fetuses have long-term effects on cognitive function and insulin secretion (as reviewed by Gluckman and Hanson, 2004). Thus, it is conceivable that human development responds to undernutrition, maternal stress, and other adverse influences by altering the trajectory of hormone secretion which will result in a baby being born with characteristics similar to those studied by Fries and colleagues. In the absence of perinatal data or maternal health records, it is possible that epigenetic changes (e.g., histone acetylation and DNA methylation) could have influenced their findings.

What is the significance of oxytocin and vasopressin hormones to social withdrawal in schizophrenia? So far, no conclusive neuroendocrine studies have revealed changes in neuropeptide secretion following dynamic social interactions, nor have specific psychosocial factors been identified to explain social apathy in schizophrenia (Lewis and Levitt, 2002). These findings are also indirectly supported by genetic animal models of schizophrenia. For example, Chakragati mutants display characteristics of hyperactivity in a novel environment and importantly fail to show appropriate forms of social behavior, including proximity and approach responses (Torres et al., 2005). However, the oxytocin and vasopressin circuitry in Chakragati mice is not flawed, indicating that cellular connectivity alone is not enough to explain social withdrawal in these mice. While oxytocin and vasopressin may regulate social behavior, there is no doubt that other brain molecules (such as opioids) may also contribute to infant attachment behavior (Moles et al., 2004). Thus, it is unlikely that a symptom as complex as social withdrawal can be explained by an alteration of one principal cellular component.

Furthermore, when we look at the autistic spectrum of conditions such as classic autism and Asperger syndrome, where there are deficits in to-and-fro interactions and attachment to primary caregivers (Folstein and Rosen-Sheidley, 2001), there is no clear evidence that oxytocin or vasopressin systems influence abnormalities of social development. Along the same lines, there is no evidence that the above neurohypophyseal systems are involved in the excessive friendliness and overt social approach to strangers observed in children who have Williams-Beuren syndrome. Altogether, we have only an incomplete picture regarding the neural circuits underlying aberrant social behavior in humans. Nevertheless, the work presented by Fries et al. suggests that much might be learned by studying this rare group of socially neglected children. It appears that the risk of developing pervasive emotional difficulties in childhood is influenced not only by genetic and caregiver lifestyle factors, but also by environmental cues acting during the periconceptual and fetal phases of life.

Ferguson JN, Young LJ, Insel TR. The neuroendocrine basis of social recognition. Frontiers in Neuroendocrin. 2002 23: 200-224. Abstract Folstein SE, Rosen-Sheidley B. Genetics of autism: Complex aetiology for a heterogeneous disorder. Nature Gen 2001 2: 943-955. Abstract Fries AB, Ziegler TE, Kurian JR, Jacoris S, Pollak SD. Early experience in humans is associated with changes in neuropeptides critical for regulating social behavior. PNAS 2005 102: 17237-17240. Abstract Gluckman PD, Hanson MA. Living with the past: evolution, development, and patterns of disease. Science 2004 305: 1733-1736. Abstract Lewis DA, Levitt P. Schizophrenia as a disorder of neurodevelopment. Annu. Rev. Neurosci. 2002 25: 409-432. Abstract Moles A, Kieffer BL, D’Amato FR. Deficit in attachment behavior in mice lacking the μ-opioid receptor gene. Science 2004 304: 1983-1986. Abstract Torres G, Meeder BA, Hallas BH, Gross KW, Horowitz JM. Preliminary evidence for reduced social interactions in Chakragati mutants modeling certain symptoms of schizophrenia. Brain Res. 2005 1046: 180-186. Abstract Young LJ. The neurobiology of social recognition, approach and avoidance. Soc Biol Psychiatry 2002 51: 18-26. Abstract

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Primary Papers: Early experience in humans is associated with changes in neuropeptides critical for regulating social behavior.

Comment by:  Craig Morgan
Submitted 14 December 2005
Posted 14 December 2005

This is an intriguing study investigating the link between early childhood adversity and changes in certain neuropeptides implicated in the regulation of social behavior. This kind of research is of particular interest at the moment because of the recent resurgence of interest in the relationship between the social environment and schizophrenia (van Os and McGuffin, 2004), particularly the early social environment (Wicks et al., 2005; Tienari et al., 2004; Bebbington et al., 2004). Read and colleagues (2005), for example, in their recent review have concluded, somewhat controversially, that child abuse is a significant cause of schizophrenia. Is it possible that adverse early experiences impact on neurodevelopment in such a way as to increase vulnerability for later schizophrenia? The findings presented by Fries and colleagues (2005), by suggesting early experience affects neurobiology, offer a tentative "yes" in response to this question.

There is, however, a danger of getting carried away. Read and colleagues' (2005) rather extreme claims notwithstanding, the evidence that early adversity is a cause of adult schizophrenia is far from conclusive. Likewise, there is a long way to go before it can be concluded that early adversity links to later psychopathology through its effects on neurodevelopment. There are a number of methodological limitations to the study by Fries et al. (2005) that emphasize the need for caution in interpreting their data.

Firstly, it seems reasonable to suppose that children reared in institutional settings suffer various forms of neglect. What is more questionable is that care in an adoptive home is necessarily as good as that provided by biological parents to their children. It may be better than institutional care, but there is also evidence that adoptive homes do not always provide warm and nurturing environments. Fries et al. (2005), however, make the assumption that being reared as an adopted child in a nuclear family is no different from typical family environments. This is not necessarily true, and this undermines their claim that the study is a natural experiment. Consequently, not all the observed differences can be unequivocally attributed to the effects of institutional care. For example, it may be that the continuation of differences between the two groups in the production of vasopressin and oxytocin neuropeptides is a result of the failure of adoptive homes to provide fully supportive alternatives to institutional care.

Secondly, there might be alternative explanations for the findings. Children reared in orphanages are more likely to be born to parents of low socioeconomic status; does this increase the risk of insults in-uterus or during delivery that might impact on the production of neuropeptides? More obviously still, there may be genetic factors operating differentially in these groups. Other potential confounders include parental age. This study, however, does not make any allowances for potential confounding factors.

These are the usual cautionary notes, and probably sound overly picky. All I am suggesting is that we proceed cautiously. But that we should proceed and pursue these lines of inquiry in relation to schizophrenia—both associations between early adversity and later schizophrenia, and the neurobiology of early adversity—seems essential. While the study by Fries et al. (2005) may not quite provide a natural experiment, it points an exciting way forward.

Bebbington PE, Bhugra D, Brugha T, Singleton N, Farrell M, Jenkins R, Lewis G, Meltzer H. Psychosis, victimisation and childhood disadvantage: evidence from the second British National Survey of Psychiatric Morbidity. Br J Psychiatry. 2004 Sep;185:220-6. Abstract

Fries AB, Ziegler TE, Kurian JR, Jacoris S, Pollak SD. From The Cover: Early experience in humans is associated with changes in neuropeptides critical for regulating social behavior. Proc Natl Acad Sci U S A. 2005 Nov 22;102(47):17237-40. Abstract

Read J, van Os J, Morrison AP, Ross CA. Childhood trauma, psychosis and schizophrenia: a literature review with theoretical and clinical implications. Acta Psychiatr Scand. 2005 Nov;112(5):330-50. Abstract

Tienari P, Wynne LC, Sorri A, Lahti I, Laksy K, Moring J, Naarala M, Nieminen P, Wahlberg KE. Genotype-environment interaction in schizophrenia-spectrum disorder. Long-term follow-up study of Finnish adoptees. Br J Psychiatry. 2004 Mar;184:216-22. Abstract

van Os J, McGuffin P. Can the social environment cause schizophrenia? Br J Psychiatry. 2003 Apr;182:291-2. No abstract available. Abstract

Wicks S, Hjern A, Gunnell D, Lewis G, Dalman C. Social adversity in childhood and the risk of developing psychosis: a national cohort study. Am J Psychiatry. 2005 Sep;162(9):1652-7. Abstract

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Primary Papers: Early experience in humans is associated with changes in neuropeptides critical for regulating social behavior.

Comment by:  Tomiki Sumiyoshi
Submitted 19 December 2005
Posted 19 December 2005

Fries and colleagues (2005) reported decreased urine levels of neuropeptides, arginine vasopressin (AVP), and oxytocin in children reared in orphanage settings compared to those in infants who received normal caregiving from their parents. Since it has been suggested that previously institutionalized children frequently experience problems in establishing social bonds and regulating social behavior, as discussed by Fries and colleagues, these results provide an excellent addition to the growing evidence for the contribution of the neuropeptidergic systems to social behavior in mammalian species (e.g., Tanaka et al., 2003; Bielsky et al., 2005; Matsuoka et al., 2005; see Storm and Tecott, 2005 for review). Particularly impressive was the finding that infants who experienced early neglect showed lower basal levels of AVP than did family-reared children.

We (Matsuoka et al., 2005) recently found that NC-1900, an AVP analogue and agonist at AVP-V1a receptors, ameliorates social interaction deficits in rats chronically treated with MK-801, a non-competitive antagonist at N-methyl-D-aspartate (NMDA) receptors. This result from an animal model of schizophrenia is consistent with our earlier observation (Tanaka et al., 2003) that chronic administration of the NMDA antagonist phencyclidine reduces the density of V1a receptor binding sites in several brain regions, including the lateral septum, in rats showing social interaction deficits. These findings from our laboratory are in concert with those of Bielsky and colleagues (2005), who reported that re-expressing of V1a receptors in the lateral septum of V1a receptor knockout mice leads to complete recovery from impaired social recognition.

Although several issues await to be addressed before the neurobiology of social behavior in rodents can be generalized to humans (Storm and Tecott, 2005), further research into AVP, oxytocin, and receptor subtypes of these neuropeptides will facilitate the development of therapeutic tools to target disturbances of social behavior in patients with schizophrenia or related disorders.

Bielsky IF, Hu SB, Ren X, Terwilliger EF, Young LJ. The V1a vasopressin receptor is necessary and sufficient for normal social recognition: a gene replacement study. Neuron. 2005 Aug 18; 47(4):503-13. Abstract

Fries AB, Ziegler TE, Kurian JR, Jacoris S, Pollak SD. Early experience in humans is associated with changes in neuropeptides critical for regulating social behavior. Proc Natl Acad Sci USA. 2005 Nov 22; 102(47):17237-40. Abstract

Matsuoka T, Sumiyoshi T, Tanaka K, Tsunoda M, Uehara T, Itoh H, Kurachi M. NC-1900, an arginine-vasopressin analogue, ameliorates social behavior deficits and hyperlocomotion in MK-801-treated rats: therapeutic implications for schizophrenia. Brain Res. 2005 Aug 16; 1053(1-2):131-6. Abstract

Storm EE, Tecott LH. Social circuits: peptidergic regulation of mammalian social behavior. Neuron. 2005 Aug 18;47(4):483-6. Abstract

Tanaka K, Suzuki M, Sumiyoshi T, Murata M, Tsunoda M, Kurachi M. Subchronic phencyclidine administration alters central vasopressin receptor binding and social interaction in the rat. Brain Res. 2003 Dec 5;992(2):239-45. Abstract

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