Dynamic Remodeling of Dentate Gyrus Microglia Underlies Adult Depression-Like Outcomes Following Adolescent High-Fat...

Adolescent overconsumption of calorie-dense fatty foods is a major public health concern, as its adverse effects on brain function often persist into adulthood. However, the precise cellular and molecular mechanisms by which early-life dietary excess leads to enduring mood disorders remain poorly understood. Previous work from our group and others indicates that loss of dentate gyrus microglia following earlier overactivation is a critical step in depression-like pathology. Because high-fat intake is known to potently stimulate these immune cells, we examined whether such dynamic microglial changes underlie the depression-like behaviors triggered by adolescent high-fat diet (HFD) exposure. Our experimental data clearly show that a sub-chronic 12-day HFD, starting at postnatal day 28, not only induced depression-like behaviors in adult mice but also reduced the microglial population within the dentate gyrus. This marked reduction is associated with early microglial injury, as indicated by a substantial increase in TUNEL-positive cells. Importantly, preventing the initial microglial response with minocycline effectively blocked this damaging cascade, thereby averting both microglial loss and depression-like behaviors in adulthood. Conversely, a low-dose lipopolysaccharide (LPS) injection administered in adulthood, which effectively restored microglial numbers, successfully reversed these established behavioral deficits. Taken together, these findings show that adolescent HFD triggers a detrimental sequence of microglial activation, damage, and eventual depletion within the dentate gyrus. This terminal loss is a key driver of adult depression, strongly suggesting that strategies to reverse microglial decline may represent a viable therapeutic approach for depression associated with early-life nutritional adversity.