Persistent elevations of cerebrospinal fluid concentrations of corticotropin-releasing factor in adult nonhuman primates exposed to early-life stressors: implications for the pathophysiology of mood and anxiety disorders.

Abstract

There is increasing evidence for an important role of adverse early experience on the development of major psychiatric disorders in adulthood. Corticotropinreleasing 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.Considerable evidence from genetic, neurochemical, pharmacological, and neuroanatomical studies obtained over the past three decades supports a biological basis for many of the major neuropsychiatric disorders (1). Prior to the modern era of biological psychiatry, psychoanalytic theory pioneered by Freud prevailed. Freud's theories emphasized the importance of early rearing conflicts in the pathogenesis of adult psychopathology (2). More recent studies indicate that psychosocial factors, including abuse and neglect in early life as well as untoward life events in adulthood, contribute to the development of mood and anxiety disorders (3, 4). An integration of biological and developmental approaches may illuminate further the role of adverse early life experience on subsequent neurodevelopment. Using random-assignment study designs, nonhuman primate models of psychopathology, produced by an unpredictable early rearing environment, provide for the experimental exclusion of genetic influences on development, a strategy rarely feasible in humans (5-9).The present study presents evidence for persistent hyperactivity of corticotropin-releasing factor (CRF)-releasing neurons in the central nervous system (CNS) of grown nonhuman primates who, as infants, were reared by mothers exposed to environmental unpredictability. A neurochemically based hypothesis is proposed whereby emotionally adverse early experiences may antecede psychiatric disorders through the induction of persistently elevated neuronal release of CRF.The CRF-containing parvocellular neurons of the hypothalamic paraventricular nucleus (PVN) represent the cephalicThe publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact. component of the hypothalamic-pituitary-adrenal (HPA) axis, which serves as the primary endocrine response of mammalian organisms to stress (10-12). Hypothalamic CRF release increases HPA axis activity by ...

Suicide attempters: biological stressmarkers and adverse life events

“…Similarly, Heim et al [18] found that severe stress (sexual and physical abuse) early in life is associated with persistent sensitization of the HPA axis, which in turn is related to an increased risk for adulthood psychopathological conditions. These findings are consistent with results from several animal studies [8,28]. De Bellis [12] considered feelings of neglect or reports of having been neglected during childhood and adolescence as reflecting a chronic stressor that causes anxiety-and depressive disorders during child and/or adulthood, and most likely, a dysregulation of the biological stress system.…”

Fluvoxamine Reduces Responsiveness of HPA Axis in Adult Female BPD Patients with a History of Sustained Childhood Abuse

“…The effect exerted by maternal deprivation resulted in the altered expression of the hippocampal mineralo (MR) and glucocorticoid receptor (GR) sites (Oitzl et al, 2000) in a manner that would explain the enhanced HPA responsiveness (De Kloet et al, 1998). In other studies, early stress was found to induce an increase in the number of hypothalamic CRH neurons and an increase in CRH and AVP m-RNA expression (Coplan et al, 1996(Coplan et al, , 2001De Goeij et al, 1992;Hatalski et al, 1998;Lim, 2000;Plotsky and Meaney, 1993). An elevated AVP/CRH release is likely to enhance the expression of pro-opiomelanocortin (POMC) synthesis and the release of its peptide product ACTH in the pituitary corticotrophs.…”

“…(Heim et al, 2000a, b). Clinical and preclinical studies suggest that an enhanced expression of CRH and its potent coregulator arginine vasopressin (AVP) in the hypothalamic nucleus paraventricularis (PVN) is involved in the pathogenesis of this hyper-responsiveness of the HPA axis (Coplan et al, 1996;Hatalski et al, 1998;von Bardeleben et al, 1985). This hyper-responsiveness of the HPA axis may render the abused BPD patients very susceptible to stress, and in case of sustained stress to depression comparable with subjects with a heritable predisposition for MDD .…”

Neurosteroids in the context of stress: Implications for depressive disorders

“…Both animal and human studies indicate that chronic or severe stress exposure, especially early in life (Coplan et al, 1996), can result in persistent alterations in neurobiological systems that are stress responsive (Bremner & Vermetten, 2001;Heim et al, 2001). There is particularly compelling evidence that such long-term adaptation to either early life stress or to chronic on-going stress occurs for HPA axis regulation (Lemieux & Coe, 1995;Resnick et al, 1995;Coplan et al, 1996;Ladd et al, 1996;Kaufman et al, 1997, Heim et al, 2001Szikszay & Benedek, 1989;D'Amore et al, 1993;Heim et al, 2002;Bennett et al, 2004), and there is also evidence that it occurs for noradrenergic regulation (Bremner et al, 1996;Young & Breslau, 2004).…”