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192 Biobehavioral Resilience to Stress

subjects is unknown, although genes that regulate GRP signaling have been
implicated in autism (Ishikawa-Brush et al., 1997).
Because the GRP and stathmin genes are potential candidates for PTSD-
related phenotypes (e.g., vulnerability to alteration of fear memory encod-
ing or expression), researchers are now trying to determine whether stress
neuropeptides in either gene are relevant to amygdala function in normal
human subjects and in anxiety disorder patient populations. Targeting these

genes or their peptides for therapy may be difficult, however, as both have

fairly ubiquitous functions. For example, stathmin gene expression plays an
important role in cell mitosis and has been associated with oncogenesis and
malignant tumor growth in peripheral cells (e.g., Mistry, Bank & Atweh,

2005). Thus, manipulation of stathmin expression could produce unwanted,
perhaps even deleterious side eff ects.
Another pathway of interest for fear memory formation and expression
is the extracellular signal-regulated kinase (ERK) pathway. ERK is an intra-
cellular second messenger system that appears to be required for amygdala-
dependent fear acquisition and extinction (Apergis-Schoute, Debiec, Doyere,
LeDoux & Schafe, 2005; Lin, Chakravarti & Cutler, 2004; Lu, Walker &
Davis, 2001; Schafe et al., 2000). ERK signaling pathways produce transcrip-
tion factors to modulate gene expression. ERK signaling has been shown to
play a role in neuronal plasticity, is activated by acute stress (Meller et al.,
2003; Shen, Tsimberg, Salvadore & Meller, 2004), and might also play a role
in the mediation of responses to acute stress. Stress-induced enhancement of
fear learning appears to occur via activation of ERK signaling (perhaps via
CRF release; Sananbenesi, Fischer, Schrick, Spiess & Radulovic, 2003). Th us,
the molecules that regulate ERK signaling present an exciting new avenue for
the study of anxiety and fear.
As animal models improve our understanding of the cellular mecha-
nisms that underlie learned fear and anxiety responses, they will also help
to reveal additional gene candidates for the study of heritable vulnerability
versus resilience to stress. In the next section, we address the need for trans-
lational research to further explore CRF using cross-species behavioral indi-
ces of fear responding.

Combining Behavioral and Biological
Markers of PTSD Pathology

Several studies have documented exaggerated startle response in human

subjects with PTSD. Specifically, these individuals may demonstrate
increased baseline startle, increased startle in the presence of threaten-
ing or unpleasant stimuli (e.g., stimuli that predict shock, trauma-specifi c
stimuli), reduced threshold for startle responding, and reduced PPI (Butler
et al., 1990; Grillon et al., 1998, 1996; Morgan, Grillon, Southwick, Davis &

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