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A View from the NIH Office of Behavioral and Social Sciences Research - page 6 / 14





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ways that maximize the chances for motivating and sustaining positive, health-related change?

Investigators are beginning to address these ques- tions. For example, Caspi and Moffitt36 have been at the forefront of studies linking gene–environment interactions to psychiatric disorders in humans. Using data from the longitudinal Dunedin cohort study, they demonstrated that a particular, functional polymor- phism in the promoter region of the serotonin trans- porter gene moderates the depressogenic influence of stressful life events during childhood. They reported that childhood maltreatment predicted adult depres- sion only among individuals carrying the short allele genotype, but not among individuals carrying two cop- ies of the long allele. Notably, the genotype did not predict adult depression.37 These data illustrate that the social environment during childhood interacts with genetics to influence adult behavior and disease.

To support work at this leading edge of discovery, NIH has recently launched its NIH Roadmap Epigenomics Program40 as part of the NIH Roadmap. Among the goals of the NIH Roadmap Epigenomics Program are the following: (1) to coordinate and develop a series of reference epigenome maps, analogous to genome maps, which will be publicly available to facilitate research in human health and disease; (2) to evaluate the epigenetic mechanisms in aging, development, environmental exposure (including physical and chem- ical exposures), behavioral and social environments, and modifiers of stress; and (3) to develop new tech- nologies for the epigenetic analysis of single cells and the imaging of epigenetic activity in living organisms.

Programmatic Direction #2. Interdisciplinary Research

The biological pathways underlying gene–social en- vironment interactions are being explored as well. Meaney, Szyf, and colleagues38,39 have completed an elegant series of studies elucidating the mechanisms underlying the long-term effects of rat maternal behav- ior on the behavioral and neuroendocrine stress re- sponses of their offspring. They have reported that a particular style of maternal behavior (low maternal rat-pup licking and arched-back nursing) during the first week of postnatal life leads to increased and prolonged reactivity of the hypothalamic–pituitary– adrenal (HPA) axis in the offspring. These changes are associated with reduced glucocorticoid receptor-gene expression in the hippocampi of the offspring, which appears to be due to epigenetic changes (increased DNA methylation, altered histone acetylation) in the promoter region of the glucocorticoid receptor gene. Central infusion of the histone deacetylase inhibitor, trichostatin A, to the offspring during adulthood re- verses the previously defined differences in histone acetylation, DNA methylation, glucocorticoid-receptor expression, and HPA axis responses to stress, thus suggesting a causal relationship between patterns of maternal care and the epigenomic state, glucocorticoid- receptor expression, and stress responses in the off- spring. While the extent to which these findings might generalize to other instances of behavioral and environ- mental programming remains to be determined, these findings do suggest that an epigenetic mechanism may underlie the transmission of intergenerational effects of a behavioral stimulus— one that is potentially re- versible but can have dramatic downstream conse- quences (heightened neuroendocrine response to stress) across the offspring’s lifetime.

Thus, there is enormous potential for greater under- standing of gene–environment interactions and health through interdisciplinary partnerships among the be- havioral and social sciences and the biomedical sci- ences as the field of epigenetics/epigenomics emerges.

The staff at OBSSR recognize that solving the most pressing health problems will require a greater under- standing of the full range of factors that determine health—biological, behavioral, social, and environmental— and of their complex interrelationships. In some in- stances, a single research discipline is best suited to tackle specific health problems. However, most com- mon, serious, health problems cannot be adequately addressed solely within a single discipline, instead requiring a more comprehensive approach. New dis- coveries and innovative solutions may become possible when researchers in different disciplines meet at the interfaces and frontiers of those disciplines to pool their diverse bodies of knowledge. Interdisciplinary research and education are inspired by the drive to solve complex questions and problems, whether gener- ated by scientific curiosity or by pressing social need. Over time, collaboration among diverse scientists may shift from multidisciplinary and interdisciplinary work to a full transdisciplinary synthesis that has the poten- tial to produce new disciplines, as in psychoneuroim- munology, cognitive and social neurosciences, and behavioral genetics.

Research on stress and cancer is an excellent example of interdisciplinary research involving the behavioral and biomedical sciences. Antoni et al.41 recently integrated a number of biomedical, behavioral, and clinical studies into a proposed mechanistic cascade underlying the links among behavior, biology, and cancer. Evidence is accu- mulating to suggest that stress, depression, and lack of social support influence the risk of cancer. For example, the breakup of a marriage has been associated with a twofold increase in the risk of breast cancer,42 and long- term chronic depression appears to increase general cancer risks.43,44 Basic research in physiology established a long time ago that the stress response is characterized by the activation of the sympatho-adrenal system, which releases the catecholamines, epinephrine, and norepi- nephrine, and the HPA axis, which releases glucocorti-

S216 American Journal of Preventive Medicine, Volume 35, Number 2S


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