Adolescent Ethanol Exposure Disrupts the Mature Phenotype of Surviving Neuroprogenitors in Female Mice

ABSTRACT

Rodent models of human adolescent binge drinking persistently reduce adult neurogenesis and induce innate immune signaling cascades, suggesting long‐lasting dysfunction in the hippocampal neurogenic niche. Nevertheless, many neuroprogenitors survive, and the impact of adolescent ethanol on the mature phenotype of these surviving neurons is unknown, resulting in an unstudied cellular population that could impact hippocampal function. To label a cohort of immature neurons, we used doublecortin‐CreERT2 transgenic mice crossed with Rosa26‐CAG‐tdTomato reporter mice, resulting in tamoxifen‐induced labeling of newborn neurons. Female offspring underwent adolescent intermittent ethanol (AIE) (5 g/kg ethanol or water by gavage, 2‐day‐on/2‐day‐off from postnatal day 29–58 ± 1), followed by a multi‐month ethanol‐free period. AIE increased dendritic branch width and cellular migratory distance, increased hilar axonal varicosities, reduced dendritic spine density, and shifted action potential generation with escalating current injections in tdTomato+ cells. Although tdTomato+ expression was also decreased in AIE relative to CON mice, there was no significant change in the number of tdTomato+ somata. AIE also reduced microglial territory in the polymorphic and molecular layers despite no change in cell number. Furthermore, microglia entwined in the dendritic trees of surviving adolescent neuroprogenitors exhibited increased sphericity, potentially indicative of a shift towards a more reactive morphological phenotype. Surviving neuroprogenitors exhibited no changes in labeling of the vesicular acetylcholine transporter, despite robust cholinergic innervation proximal to the mature dendritic tree that reduced rapidly with increasing distance from dendritic arbors. These results suggest that AIE causes lasting changes in the architectural and physiological phenotype of surviving adolescent neuroprogenitors, which may be related to disrupted neuronal‐microglial dynamics and have critical consequences for both hippocampal circuitry and function.