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 ...

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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.

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 four 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. 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.