Review
Early life stress as a risk factor for mental health: Role of neurotrophins from rodents to non-human primates

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Abstract

Early adverse events can enhance stress responsiveness and lead to greater susceptibility for psychopathology at adulthood. The epigenetic factors involved in transducing specific features of the rearing environment into stable changes in brain and behavioural plasticity have only begun to be elucidated. Neurotrophic factors, such as nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), are affected by stress and play a major role in brain development and in the trophism of specific neuronal networks involved in cognitive function and in mood disorders. In addition to the central nervous system, these effectors are produced by peripheral tissues, thus being in a position to integrate the response to external challenges. In this paper we will review data, obtained from animal models, indicating that early maternal deprivation stress can affect neurotrophin levels. Maladaptive or repeated activation of NGF and BDNF, early during postnatal life, may influence stress sensitivity at adulthood and increase vulnerability for stress-related psychopathology.

Introduction

Stressful events experienced early during postnatal life can influence the development of individual differences in vulnerability to psychopathology throughout life (Heim and Nemeroff, 2001). Severe conditions such as physical or sexual abuse, in addition to persistent emotional neglect or family conflict, can compromise growth, intellectual development and lead to increased risk for adult obesity, depression and anxiety disorders (Cicchetti and Toth, 1995, Heim and Nemeroff, 2001).

The relationship between quality of early life and health at adulthood is still an open question. During the early postnatal phases the brain is experience-seeking and provided with a considerable plasticity which allows a fine tuning between the external environment and the developing organism (Greenough, 1987). One possible hypothesis posed is that adversity early in life is able to enhance or inhibit the experience-dependent maturation of structures underlying emotional functioning and endocrine responses to stress, such as the cortico-limbic system, leading to increased stress responding at adulthood (Tronick and Weinberg, 1997, Heim et al., 2000, Schore, 2000, Heim and Nemeroff, 2001, Meaney, 2001, Seckl and Meaney, 2004). Depressed patients with a history of childhood abuse are often characterized by a hyperactive hypothalamic–pituitary–adrenal (HPA) axis, a major component of the stress response (Heim and Nemeroff, 2001). In addition, childhood abuse or neglect has been associated with abnormalities in brain regions involved in emotional disorders, including an overall volume loss in hippocampus, corpus callosum and prefrontal cortex, altered cortical symmetry in cortical regions and reduced neuronal density and integrity in the anterior cingulate (Bremner et al., 1997, Stein et al., 1997, Driessen et al., 2000, Carrion et al., 2001, De Bellis et al., 2002, Teicher et al., 2004).

In order to explain how psychopathology comes about at adulthood, a diathesis-stress model has been proposed. According to this model, a genetic vulnerability or predisposition (diathesis) interacts with the environment and life events (stressors) to trigger behaviours or psychological disorders (Zubin and Spring, 1977). Many psychiatric disorders can be accounted for by this ‘two hit model’ in which genetic or environmental factors disrupt early central nervous system (CNS) development leading to a long-term vulnerability to a “second hit” that then leads to the onset of psychiatric symptoms (Maynard et al., 2001). The signaling pathways involved in cellular differentiation, could be targets for a “first hit” during early development. These same pathways, redeployed for neuronal maintenance and plasticity, may be targets for a “second hit” in the adolescent or adult brain. Thus, if the same pathways in both the developing and the mature organism are targets of stress we have a way of integrating genetic, developmental, and environmental factors that contribute to vulnerability and pathogenesis of psychopathology (Norman and Malla, 1993, Pani et al., 2000, Maynard et al., 2001). In this context, the cascade of events initiated by stressful experiences at adulthood represents a major vulnerability factor and its deleterious effects can be aggravated in individuals who have experienced adversities early in life.

The importance of the interaction between genetic and experiential factors in the development of psychopathology has become recognized by preclinical and clinical researchers over the last 10 years (Yehuda et al., 1997, Heim and Nemeroff, 1999). The latest theoretical approaches are based on the notion that genes influence the susceptibility to environmental “pathogens” (Caspi and Moffitt, 2006). In one of the most influential studies involving gene–environment interactions, Caspi and coworkers (Caspi et al., 2003) have shown that a functional polymorphism in the promoter region of the serotonin transporter (5-HTT) gene would moderate the influence of stressful life events on vulnerability to depression. Individuals with one or two copies of the 5-HTT ‘short’ allele exhibited more depressive symptoms, diagnosable depression, and suicidality following stressful life events than individuals with two copies of the ‘long’ allele (Caspi et al., 2003). Additional support for the importance of gene–environment interactions in susceptibility to psychopathology is emerging. In two studies of attention-deficit hyperactivity disorder, polymorphisms in the dopamine system interacted with antenatal risk factors (such as low birth weight and maternal use of alcohol) to predict key symptoms associated with the disorder (for a review see Caspi and Moffitt, 2006).

The study of gene–environment interactions has been the province of epidemiology, in which genotypes, environmental pathogens exposures and disorder outcomes are studied as they naturally occur in the human population (Caspi and Moffitt, 2006). However, research in the neuroscience field has now a major goal to achieve, that is to complement psychiatric genetic epidemiology by specifying the more proximal role of nervous system reactivity in the gene–environment interactions. Indeed, there are a number of still open questions that need to be addressed, including the quality and quantity of experience that can predispose an individual towards psychopathology and the specific neural substrates affected. Appropriate animal models, in which early environmental and experiential factors can be manipulated under controlled conditions are needed to answer these questions (Suomi, 1991, Cirulli et al., 2003a). In recent years there has been a growing emphasis on developing complex models that incorporate a number of variables which can be manipulated by the experimenter providing new opportunities for translation from basic to clinical research. In this review we will provide examples of studies performed with the common aim of understanding the effects of the early rearing environment in shaping brain development and emotional functioning. While rodents offer a great opportunity to ask questions that can be answered in a short-time scale and allow for the analysis of neurobiological substrates, non-human primates, although offering a number of challenges in terms of understanding brain function, provide the closest match to humans in terms of genetic, behavioural, biological and social similarity. In addition, non-human primates’ relatively long lifespan, extended infancy, and socio-affective behaviour parallel many aspects of human development (Suomi, 1997). The challenge that basic science needs to meet is to make use of a comparative approach to benefit the most from what each model, notwithstanding its constraints, can tell us about the mechanisms that lead from environmental adversity to increased risk for mental health.

Section snippets

Development and vulnerability for anxiety and mood disorders: role of early social relationships

While there is now clear evidence documenting the relationship between childhood abuse and neglect (or other early adverse events) with individual vulnerability to psychiatric diseases, such as anxiety and depression, clinical studies cannot produce sufficient evidence on cause–effect relationships (Cirulli et al., 2003a). A major goal of these studies is to define times in development and strategies for intervening to prevent or reverse the effects of adverse early life experiences.

The

Animal models of early stressful experiences

Animal models are fundamental to gain insights into the behavioural and physiological mechanisms underlying the short- and long-term effects of early experiences on emotional reactivity, the stress response and susceptibility to disease. Successful animal models have been generated targeting experiential factors with robust effects that are relatively consistent across species. Amongst these we can enlist studies involving separating mother and infants in mammals (Table 1). Animal models have

General conclusions

The comparative approach used in these studies has revealed important changes in the levels of NGF and BDNF both as a function of age and as a consequence of the quality of the rearing environment.

The preliminary findings obtained in rhesus macaques suggest that changes in plasma levels of neurotrophins might function as peripheral markers of early adversity, being differentially affected by changes in the rearing environment. Peripheral levels of NGF in monkeys reared without adults might

Acknowledgments

Supported by the ISS-NIH Collaborative Project (0F14) to F.C. and E.A. and by the Italian Ministry of Health, Ricerca Finalizzata ex art. 12—2006. This research was also supported by funds from the Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health. The authors thank A. Ruggiero, S. Miletta, F. Capone and L.T. Bonsignore for technical assistance, F. Chiarotti for statistical advice.

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