L-lactate induces neurogenesis in the mouse ventricular-subventricular zone via the lactate receptor HCA₁

Adult neurogenesis occurs in two major niches in the brain: the subgranular zone of the hippocampal formation and the ventricular-subventricular zone. Neurogenesis in both niches is reduced in ageing and neurological disease involving dementia. Exercise can rescue memory by enhancing hippocampal neurogenesis, but whether exercise affects adult neurogenesis in the ventricular-subventricular zone remains unresolved. Previously, we reported that exercise induces angiogenesis through activation of the lactate receptor HCA1. The aim of the present study is to investigate HCA₁ -dependent effects on neurogenesis in the two main neurogenic niches.

Wild-type and HCA₁ knock-out mice received high intensity interval exercise, subcutaneous injections of L-lactate, or saline injections, five days per week for seven weeks. Well-established markers for proliferating cells (Ki-67) and immature neurons (doublecortin), were used to investigate neurogenesis in the subgranular zone and the ventricular-subventricular zone.

We demonstrated that neurogenesis in the ventricular-subventricular zone is enhanced by HCA₁ activation: Treatment with exercise or lactate resulted in increased neurogenesis in wild-type, but not in HCA₁ knock-out mice. In the subgranular zone, neurogenesis was induced by exercise in both genotypes, but unaffected by lactate treatment.

Our study demonstrates that neurogenesis in the two main neurogenic niches in the brain is regulated differently: Neurogenesis in both niches was induced by exercise, but only in the ventricular-subventricular zone was neurogenesis induced by lactate through HCA₁ activation. This opens for a role of HCA₁ in the physiological control of neurogenesis, and potentially in counteracting age-related cognitive decline.