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186 Biobehavioral Resilience to Stress

phenotypic outcomes and could be shown to regulate one or more neuro-
biological pathways of known relevance to those outcomes. However, Moffi tt
et al. (2005) acknowledge that these criteria are difficult to meet because,

despite recent advances in the neurobiological study of stress and resilience

(Charney, 2004; Moffitt et al., 2005; Nemeroff et al., 2005), relatively little

is currently known about the effects of various environmental factors on
brain physiology. Moreover, experimental designs must take into account
human development and the possibility that gene–environment interactions

and their effects may change over the human lifespan (Fazel, Wheeler &
Danesh, 2005; Kohn, Levav, Garcia, Machuca & Tamashiro, 2005; Maercker,
Michael, Fehm, Becker & Margraf, 2004; Perkonigg et al., 2000). Preclinical
and clinical data suggest that during certain periods of early development,
gene– environment interactions have uniquely profound and lasting eff ects,
possibly through epigenetic and gene expression adaptations (Gardner,
Thrivikraman, Lightman, Plotsky & Lowry, 2005; Kramer et al., 2005; Ladd,

Huot, Th rivikraman, Nemeroff & Plotsky, 2004; Plotsky et al., 2005; Sanchez
et al., 2005; Weaver et al., 2005). Such periods of unique effect do not persist

into adulthood, but rather allow long-term alterations in the underlying neu-

robiology that will later define the individual adult phenotype (Kramer et al.,
2005; Rutter, 2005). These alterations may have potentially profound eff ects

on responsiveness to stress in adulthood because they aff ect neurocircuits
that control physiological responses to stress (e.g., corticotropin-releasing
factor [CRF]). For example, exposure to stress in childhood can produce
long-term changes in hypothalamic pituitary adrenal (HPA) axis reactivity,
cortisol diurnal rhythm, and serotonergic neurons in areas of the brain that
project to central autonomic and emotional motor control systems (Gardner
et al., 2005; Plotsky et al., 2005; Sanchez et al., 2005). In turn, these changes
in the brain produce changes in behavior. Animals exposed to environmen-
tal stress during early development demonstrate a more fearful phenotype

as their adults do. Th is effect is evident in an increased startle response*
concurrent with CRF and HPA changes, and in an altered pattern of social
interaction concurrent with changes in the serotonergic system (Gardner
et al., 2005; Plotsky et al., 2005; Sanchez et al., 2005). Mirescu, Peters, and

Gould (2004) have reported similar findings to suggest that neurogenesis in
adulthood is altered when individual mice are stressed at younger ages. In
human clinical research, history of childhood trauma is a well-documented
risk factor for PTSD onset subsequent to adult exposure to trauma (Yehuda,
Halligan & Grossman, 2001). Thus, PTSD studies of specific genotype infl u-

ences in adult subjects should account for childhood trauma and, if possible,

* The startle response is putatively a defensive behavior evolved to protect the body from
impact during attack (Graham, 1975; Yeomans et al., 2002).

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