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

Abstract

Early life adversity (ELA) is a leading preventable contributor to morbidity and mortality, increasing risk for mental and physical illness later in life. However, mechanisms linking ELA to comorbid outcomes within both the brain and body remain poorly understood. We tested whether ELA disrupts functional and molecular development of vagal circuitry, a key pathway for brain-body communication, using the limited bedding and nesting (LBN) mouse model of unpredictable maternal care. We measured vagally mediated autonomic stress responses longitudinally using three noninvasive measures of heart rate variability (HRV). This is the first time the development of the vagally-mediated autonomic stress response has been measured in mice. We also performed single-nucleus RNA sequencing of the vagal medulla immediately after LBN and in adulthood, followed by spatial mapping of high-confidence differentially expressed genes. ELA altered trajectories of all HRV measures, with pronounced sex differences. ELA females showed precocious maturation followed by adult declines, whereas males initially exhibited blunted responses but recovered to control levels. Transcriptomic changes were also sex dependent, with female neurons exhibiting signatures of mitochondrial dysfunction, while males showed adaptive mitochondrial responses. Spatial mapping revealed rostro-caudal organization, localizing adaptive male responses to the rostral and intermediate vagal medulla and maladaptive female responses to the intermediate vagal medulla and loose nucleus ambiguus. These findings demonstrate enduring, sex-specific alterations in vagal circuit development centered on mitochondrial pathways.