Abstract

Early Life Stress Responses in Selectively Bred Rats: How Genetic Temperament Determines Development of the HPA Axis

Maras P, Hebda-Bauer EK, Watson SJ, Akil H
52nd Annual Meeting of Society for Neuroscience. 2023.

Heritable personality traits are a strong predictor of vulnerability or resilience to developing psychiatric disorders, including anxiety and depression. An individual’s underlying temperament, however, is strongly influenced by environmental factors, and stressful life events, especially those experienced during early life, provide another major risk for mood disorders. Understanding the complex ways genetic and environmental factors interact to regulate emotion has remained a challenge. To this end, our laboratory has developed a genetic model of temperament by selectively breeding rats based on locomotor response to novelty, a behavioral trait that corresponds to stable differences in emotionality and stress reactivity. Rats bred for high (bHR) or low (bLR) locomotor responses reflect externalizing or internalizing temperaments, respectively, and previous studies have demonstrated that bHRs and bLRs respond quite differently to stress in adulthood. Importantly, the hypothalamic-pituitary-adrenal (HPA) axis, the primary mediator of stress responses, undergoes significant functional organization during early postnatal life, and differences in HPA development may set the stage for lifelong differences in stress reactivity. The goal of the current set of experiments was to characterize the functional development of the HPA axis in bHRs and bLRs. Through a series of experiments, we compared plasma corticosterone (CORT) levels following an acute isolation stress and discovered that, compared to bLRs, bHRs had elevated CORT responses throughout much of early life, evident by postnatal day 12. Even though bHRs had a higher peak stress response, CORT levels in both lines returned to baseline by 60 minutes after the end of isolation, indicating similar efficiency in negative feedback processes. Furthermore, CORT levels in response to an adrenocorticotropic hormone challenge were comparable in bHRs and bLRs, suggesting that their differences in CORT responses to stress reflect differences in how upstream neural circuits respond to the stressful stimuli. Using hairpin chain reaction-based fluorescent in situ hybridization (HCR FISH) methods, ongoing experiments are comparing mRNA expression of c-fos (marker of neural activation), as well as multiple stress-related molecules, following isolation stress in bHR and bLR pups. Together, these data will shed light on how underlying genetic differences can shape the development of the stress system and ultimately determine risk for stress-related psychiatric disorders.