Stress during development: Impact on neuroplasticity and relevance to psychopathology
Introduction
There is considerable evidence that adverse early life events have profound and persistent effects on brain functions and may represent a risk factor for the development of psychopathology later in life.
Epidemiological studies have revealed that stress or emotional trauma, particularly when experienced early in life, is associated with enhanced risk to develop depression (Heim et al., 2004). As an example, a large study has demonstrated that women with a history of sexual and physical abuse at childhood exhibited more symptoms of depression and anxiety than women who did not suffer from such adversities (McCauley et al., 1997). Similar risks may be associated with schizophrenia, a disease that is considered neurodevelopmental in origin (Brixey et al., 1993, Howes et al., 2004). The exposure of a pregnant woman to psychological stressors or traumatic experiences increases the likelihood that her children will develop schizophrenia later in life (Huttunen et al., 1994). A higher occurrence of schizophrenia was also detected in a large population of subjects whose mothers were pregnant during the German occupancy of Holland in 1940, when compared to subjects born in the same places before the stressful period (van Os and Selten, 1998). Moreover, other adverse life events, including famine, viral infections (during the second trimester of pregnancy) or birth complications, may also represent vulnerability factors for the onset of schizophrenia (Brown, 2006, Susser and Lin, 1992, Torrey et al., 1997, Wright et al., 1995). Mednick and associates found a greater than expected incidence of schizophrenia in the offspring of women who were in their second trimester of gestation at the peak of the 1957 influenza epidemic (Mednick et al., 1988). The risk for psychopathology can even be higher when considering other conditions, such as gestational exposure to alcohol or drugs of abuse: such as alcohol or cocaine: in this case, the consequences for the foetus are dramatic and may range from gross abnormalities to more subtle deficiencies such as learning disabilities (Arendt et al., 2004, Kodituwakku, 2006).
There is no doubt that stress may represent a major element of vulnerability for brain development and function. Regardless of its nature and origin, stress can be considered a threat to homeostasis and, for this reason, a series of physiological and/or behavioral responses are set in motion to reinstate the original condition. The pronounced effects of developmental (early life) stress throughout the lifespan may be related to the plasticity of the central nervous system as a function of experience. It is feasible to hypothesize that processing and adaptation to stress can be invariably different during early stages of life when neuronal development has not yet been completed.
The type or the timing of early in life events that are associated with enhanced risk for depression or anxiety may be different from those relevant to schizophrenia. In fact, according to the timing, the ‘adverse’ event can interfere with the maturation of a specific cell phenotype or a specific brain circuitry that might be selectively involved in the manifestation of the disease. Even symptoms, such as cognitive deficits, that may be common to different psychiatric diseases can originate from an altered function of different neuronal pathways.
Alternatively, similar events may lead to different psychopathological outcomes based on the genetic background. There is now compelling evidence that gene-environment interaction is a key feature in psychiatry (Caspi and Moffitt, 2006, van Os et al., 2005). On this basis environmental events, as those previously discussed, do not necessarily cause the disease, but it is the individuals’ behavioral response to the ‘adverse event’ that determines the final outcome. The diversity among individuals, which originates from their DNA sequences, will result in differences between individuals in their resiliency or vulnerability to environmental events at different stages of life. The pathological phenotype will therefore be determined by the convergence between environmental and genetic influence on a neuronal substrate whose function is critical for the disease manifestation. As an example, Caspi et al. have demonstrated that a functional polymorphism in the promoter region of the serotonin transporter gene, the major target of antidepressant drugs, can modulate the influence of stressful life events for the occurrence of depression (Caspi et al., 2003).
Bearing in mind the role of genes in modulating the effects of developmental adversities for psychopathology, a further degree of complexity is due to the fact that ongoing stress at adulthood can exacerbate or precipitate episodes of depression or schizophrenia. This suggests that early life stress may alter the vulnerability threshold of brain systems determining a sort of sensitization to subsequent stressors that might be required for the disease to become manifest.
The identification of neurobiological substrates that are affected by early in life adverse experience may have important diagnostic implications and could contribute to identify novel molecular targets for the development of more effective treatments of psychiatric disorders. To this regard, a number of animal models have been developed in order to investigate, under a controlled setting, the effects of exposure to adverse life events within specific time windows during development. Animal studies have clearly indicated that exposure to variable types of stressors during development produces persistent behavioral defects that are associated with hormonal, neurotransmitter and functional changes and resemble an array of psychopathological conditions.
In the present review, we will revise the results of these preclinical studies that, through the use of different animal models, have provided important hints to unravel some of the substrates that might participate in lifelong impairments of brain function following exposure to perinatal adversities. We have considered only stress-related events during development, although we are aware that other animal models that reproduce environmental pathogens known to determine permanent changes of brain function and increased psychopathology have been extensively characterized. To this end studies exist on the impact of maternal viral infection or specific neurotoxins, as well as of maternal obstetrical complications, on offspring behavior that may be relevant to psychiatric diseases, including schizophrenia and autism (Moore et al., 2006, Pearce, 2001, Robertson et al., 2006). We recapitulated major behavioral and functional abnormalities observed with different experimental paradigms of perinatal stress exposure as well as the hormonal changes associated with such defects. However, we have specifically focused our analysis on the alterations in neuroplasticity determined as a consequence of exposure to stressful experience during prenatal or early postnatal development. During the last decade, increasing evidence has suggested that psychiatric disorders, including major depression and schizophrenia, although characterized by altered neurotransmitter function, can be associated with reduced neuronal plasticity that might lead to enhanced vulnerability under challenging conditions (Fuchs et al., 2004, Harrison and Weinberger, 2005, Stephan et al., 2006). Such reduced plasticity may impact on the ability of the brain to perform specific tasks or activate specific neuronal pathways. For this reason we believe that a review of the evidence in support of a role for developmental adversities in long-term impairment of neuronal plasticity is warranted in an attempt to provide a comprehensive and detailed picture of the detrimental effects produced by adverse perinatal conditions on brain function, in order to reconcile our data with the findings obtained by other groups and present our theoretical line of reasoning on this subject.
Section snippets
Experimental paradigms
The negative influence exerted by adverse life events during gestation on brain development has received a great deal of attention since the proposal that psychiatric disorders may be developmental in origin. This has led to the development of animal models aimed at mimicking etiological aspects relevant to the disease and the investigation of the defects that originate from such manipulations. In the majority of the studies pregnant dams have been exposed to stress as adverse manipulation and
Programming of the HPA axis function
The hypothalamus-pituitary-adrenal (HPA) axis system is designed at controlling the organism's response to stress and regulating certain circadian activities. Corticotropin-releasing hormone (CRH)-producing neurons from the paraventricular nucleus (PVN) of the hypothalamus have their secretory terminals in the external zone of the median eminence of the pituitary where they regulate adrenocorticotrophic hormone (ACTH) release. ACTH, in turn, drives corticosterone (CORT) release from the rat
Concluding remarks
It is now well established that perinatal environment has an overwhelming impact on brain development. Pre- and postnatal stress conditions are widely embraced as paradigmatic examples of early in life adversities; however, other perinatal manipulations have been performed that can cause permanent perturbations lasting, through puberty, into adulthood. To this end, molecular and behavioral alterations have been observed in experimental models through immune challenge in utero (Meyer et al., 2005
Acknowledgments
We wish to thank Dr. Francesco Bedogni for collaborating at an initial stage of this work. Funded by the Italian Ministry of University and Research, the Italian Ministry of Health and the National Alliance for Research on Schizophrenia and Depression.
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