Abstract
Repairing the adult mammalian brain represents one of the greatest clinical challenges in medicine. Injury to the adult brain often results in substantial loss of neural tissue and permanent functional impairment. In contrast with the adult, during development, the mammalian brain exhibits a remarkable capacity to replace lost cells. A plethora of cell-intrinsic and extrinsic factors regulate the age-dependent loss of regenerative potential in the brain. As the developmental window closes, neural stem cells undergo epigenetic changes, limiting their proliferation and differentiation capacities, whereas, changes in the brain microenvironment pose additional challenges opposing regeneration, including inflammation and gliosis. Therefore, studying the regenerative mechanisms during development and identifying what impairs them with age may provide key insights into how to stimulate regeneration in the brain. Here, we will discuss how the mammalian brain engages regenerative mechanisms upon injury or neuron loss. Moreover, we will describe the age-dependent changes that affect these processes. We will conclude by discussing potential therapeutic approaches to overcome the age-dependent regenerative decline and stimulate regeneration.