Thursday, September 19, 2024
9/19/2024
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.
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