Early-life adversity alters adult nucleus incertus neurons: implications for neuronal mechanisms of increased stress and compulsive behavior vulnerability

Early-life stress (ELS) arising from physical and emotional abuse disrupts normal brain development and impairs hypothalamic-pituitary-adrenal axis function, increasing the risk of psychopathological disorders and compulsive behaviors in adulthood. However, the underlying neural mechanisms remain unclear. The brainstem nucleus incertus (NI) is a highly stress-sensitive locus, involved in behavioral activation and stress-induced reward (food/alcohol) seeking, but its sensitivity to ELS remains unexplored. We used neonatal maternal separation stress in rats as a model for ELS and examined its impact on stress-related mRNA and neuropeptide expression in the NI, using fluorescent in situ hybridization and immunohistochemistry, respectively. Using whole-cell, patch-clamp recordings we determined the influence of ELS on the synaptic activity, excitability, and electrophysiological properties of NI neurons. Using c-Fos protein expression we also assessed the impact of ELS on the sensitivity of NI neurons to acute restraint stress in adulthood. ELS weakened the acute stress responsiveness of NI neurons, and caused dendritic shrinkage, impaired synaptic transmission and altered electrophysiological properties of NI neurons in a cell-type-specific manner. Additionally, ELS increased the expression of mRNA encoding corticotropin-releasing hormone receptor type 1 and the nerve-growth factor receptor, TrkA in adult NI. The multiple, cell-type specific changes in the expression of neuropeptides and molecules associated with stress and substance abuse in the NI, as well as impairments in NI neuron morphology and electrophysiology caused by ELS and observed in the adult brain, may contribute to the increased susceptibility to stress and compulsive behaviors observed in individuals with a history of ELS.