There is now agreement that early life pain and stress are risk factors for subsequent changes in emotional,
mood and sensory systems. Nevertheless, painful events continue to occur in the context of neonatal
intensive care units (NICU) and other preventable settings. Similarly, a variety of less controllable stressful
situations, such as suboptimal parenting conditions, also contribute to subsequent dysfunction. However, the
mechanisms by which neonatal adversity leads to later anxiety, depression and sensory hypersensitivity
remain unclear. As the consequences of early life trauma tend to emerge during late childhood or early
adolescence, in order to design novel treatments and successful interventions, it is critical to examine the
effects of neonatal events on behavioral and brain function at various times during development. In order to
better understand how early life pain and stress can affect later brain function and behavior, this proposal uses
a “double-hit” model of trauma to test the hypothesis that neonatal trauma alters the developmental trajectory
of the amygdala, and subsequently hypothalamic-adrenal-pituitary axis function, including the role of
corticotrophin releasing factor (CRF) and corticosterone (CORT). In particular, we believe that neonatal
trauma alters CRF signaling in the amygdala and perhaps hypothalamus. When exposed to an “activating
trauma” later in life, the anxiogenic or depressive phenotype is expressed. Furthermore, alterations to the
amygdala will alter the descending pain system leading to tactile hypersensitivity and a predisposition towards
pain. In the current experiments, neonatal rats will be exposed to invasive heel pricks, inflammatory injury or
non-noxious handling over the first week of life. Fear conditioning and somatosensory function will then be
assessed at multiple ages including early childhood, adolescence and adulthood. Once the behavioral effects
are established, we will examine the role of amygdalar and hypothalamic CRF and CORT in these effects.
This will be accomplished by measuring CRF and CORT expression, as well as receptor distribution. This will
be followed by experiments that disrupt these signals using local and systemic pharmacology. We anticipate
that neonatal pain will lead to alterations in subsequent fear conditioning and sensory function. Moreover,
changes in CRF/CORT levels and receptor distribution in the amygdala will account for the observed
behavioral changes. Although previous work has demonstrated that early life adversity can affect subsequent
HPA axis function, the link between those changes and subsequent behavioral alterations that may lead to
behavioral dysfunction is not well established. Overall, these experiments will examine the consequences of
early-life trauma and offer insight into potential interventions protecting human well being.
