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Posttraumatic Stress Disorder 189

The Startle Response as a Tool for Translational Research

The measurement of rodent startle response plasticity has face validity,

predictive validity, and construct validity for the study of startle plasticity
in human subjects (Davis, Walker & Myers, 2003; Funayama et al., 2001;
Grillon, 2002; Swerdlow, Braff, Taaid & Geyer, 1994). Unlike other anxiety

measures that depend on responsiveness to novel stimuli or environments,
startle behavior is relatively stable across repeated sessions and is thus ideal
for longitudinal and prospective studies of change in response to stress or

trauma. This stability is also observed in healthy human subjects, includ-
ing clinically stable psychiatric patients (e.g., Shalev et al., 2000). Th e startle
response may be helpful as an index of posttrauma behavioral recovery, and
may also be particularly useful as a means to develop animal models of PTSD
and resilience (Cohen & Zohar, 2004; Rothbaum & Davis, 2003).

Startle response paradigms offer multiple advantages over other preclin-
ical models of anxiety. For example, measures of startle plasticity are less

likely to be confounded by differences in locomotor activity (Davis, 1993;
Davis, Cassella, Wrean & Kehne, 1986). Startle behavior paradigms are
generally easier to use and to reproduce because they involve simple, well-

controlled stimuli. The neuroanatomical and neurochemical substrates that
mediate and modulate startle plasticity are already relatively well-defi ned.
These advantages support the development of more precise experimental

hypotheses and more robust interpretation of experimental results (Braff
et al., 2001; Davis, Falls, Campeau & Kim, 1993; Geyer et al., 2001; Heldt,
Sundin, Willott & Falls, 2000; Mansbach & Geyer, 1988; Risbrough, Hauger,
Pelleymounter & Geyer, 2003; Risbrough, Hauger, Roberts, Vale & Geyer,
2004; Swerdlow et al., 2001; Walker, Ressler, Lu & Davis, 2002).
A series of elegant FPS studies conducted by the Davis laboratory (see Walker
et al., 2002) found that extinction training is enhanced by the administration
of d-cycloserine (a glutamate partial agonist). A subsequent clinical study
found that d-cycloserine also significantly enhanced the effi cacy of extinc-

tion therapy in phobic patients (Ressler et al., 2004). Thus, the FPS-extinction

model has demonstrated predictive utility as a means to identify successful
pharmaceutical intervention to modulate extinction processes in human sub-
jects. Additional support for the usefulness of this model can be found in a
recent meta-analysis, which indicates that enhanced fear learning may be a
characteristic of clinical anxiety (Lissek et al., 2005). PTSD patients may also
have deficits in the ability to extinguish learned fear (Orr et al., 2000).

Startle Endophenotypes Specifi c
to the Genetic Basis of Human PTSD
In human subjects, baseline startle and inhibition of startle via PPI appear
to be heritable traits. PPI of the startle response occurs when a low-intensity

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