Early Life Adversity Produces Enduring Molecular and Functional Disruption of Developing Vagal Circuits

Early life adversity (ELA) is a significant preventable cause of poor health outcomes, raising the risk of mental and physical illness later in life. However, the specific mechanisms linking ELA to comorbidities in both the brain and body are still not well understood. To investigate this, researchers utilized a mouse model known as limited bedding and nesting (LBN) to simulate unpredictable maternal care.

The study measured vagally mediated autonomic stress responses through three noninvasive techniques assessing heart rate variability (HRV) over time. This marks the first time the development of the vagally-mediated autonomic stress response has been monitored in mice. Additionally, single-nucleus RNA sequencing was conducted on the vagal medulla right after the LBN exposure and during adulthood, followed by a spatial mapping of high-confidence differentially expressed genes.

The results revealed that ELA disrupted the development of vagal circuits, with pronounced sex-specific differences. Female mice experienced precocious maturation, but their vagal circuit development declined in adulthood. On the other hand, male mice initially showed blunted responses but eventually recovered to normal levels. The transcriptomic changes were also sex-dependent, with female neurons displaying signs of mitochondrial dysfunction, while males exhibited adaptive mitochondrial responses.

Spatial mapping of the data showed that adaptive male responses localized to the rostral and intermediate regions of the vagal medulla, whereas maladaptive female responses were found in the intermediate vagal medulla and loose nucleus ambiguus. These findings underscore the enduring, sex-specific alterations in vagal circuit development, primarily centered on mitochondrial pathways.