Our experiences as children, particularly those with our attachment figures, have a disproportionately large
impact on our later development. Among the most powerful of these early experiences are aversive
circumstances or challenges. While most would consider early trauma to be a relatively uncommon experience
in modern human society, evidence suggests otherwise. More than half of adults living across a range of North
American and European countries report experiencing one or more significant early adverse experiences, often
involving disruption of the attachment relationship. Recent studies on how these essentially social experiences
become “embedded” in our biology have strongly implicated an upregulation of neuroimmune signaling and
inflammatory processes. While once thought to relate specifically to mood disorders, it is now clear that this
enhanced neural inflammatory activity has broad effects on stress reactivity, leading to a relatively
commonplace phenotype in adolescence marked by an “inflammatory burden” that increases susceptibility to
an array of stress-related mental disorders including, but not limited to, anxiety, schizophrenia, bipolar disorder,
depression, and posttraumatic stress disorder. However, we still know extremely little about the specific
developmental processes linking early stress to vulnerability in later life. Work with appropriate animal models
is required for this task. The guinea pig is a particularly well-suited rodent for studying attachment disruption.
Because guinea pigs are well-developed at birth, display strong evidence for an attachment process like that
seen in primates, and receive little active maternal care, effects of isolation from the mother can be confidently
attributed to attachment disruption as opposed to physical immaturity or changes in the mother's behavior
upon return of the pup. Moreover, isolation in a threatening environment induces a neuroinflammatory-based
behavioral reaction that sensitizes when animals are isolated again in infancy or adolescence. This effect thus
provides an opportunity to directly assess how physiological changes during early attachment disruption are
translated into specific neuroinflammatory mechanisms that sensitize behavioral stress reactivity in later life.
Proposed studies will examine the role of sympathetic nervous system activation, either alone or together with
stress levels of glucocorticoids, in initiating the sensitization process. On the basis of our preliminary results,
we propose that the activity of these stress mediators will result in enhanced sensitivity to the prostaglandin
PGE-2 via an EP-1 receptor-specific mechanism. We will examine behavioral sensitivity to PGE-2 and
upregulation of EP-1 in cells activated by isolation in essential threat-related neurocircuitry of medial prefrontal
cortex (mPFC), amygdala, and hypothalamus. The necessity of PGE-2 signaling and binding of EP-1--
particularly in mPFC--for behavioral sensitization to occur will be analyzed. Successful completion of these
studies will provide critical insight into how neuroinflammatory activity resulting from attachment disruption can
promote development of a phenotype prone to stress-related disorders in adolescence.