Theo Palmer

In human brain development, neurogenesis ceases at birth and the vast majority of areas in the adult mammalian brain no longer produce new neurons, even in the face of debilitating injury or disease. However, there are distinct exceptions to the rule. In rodents and humans, the hippocampus is one of the few areas where neurogenesis continues throughout life. Among other roles, the hippocampus is most well known as the area of the brain that mediates short-term learning and memory. Hippocampal function is affected in many diseases with grave human consequences. The two most common presentations of this dysfunction are memory deficits that accompany Alzheimer’s disease and major depressive disorders. The fact that the addition/replacement of neurons uniquely occurs in the hippocampus suggests that neurogenesis itself plays a useful role within a pre-existing neural network. However, the mechanisms that regulate this process are not understood.

Our research examines regions of adult brain where neurogenesis occurs to understand how the brain regulates and utilizes this ability to add or replace neurons. In our anatomical studies in the adult rodent hippocampus, it has become clear that neurons are produced by neural stem cells that reside in a specialized environmental niche at the interface between neural tissues of the brain and a vascular bed of fine capillaries. It is likely that the areas permissive for neurogenesis in the adult are defined by a specific arrangement of cells and signals from both the CNS and the periphery. To define how these diverse cellular signals collaborate to control neurogenesis in the adult, we have been reconstructing neurogenesis in the brain and Petri dish using primary cultures of neural stem cells and precursor cells derived from humans, rats and mice. This work has allowed us to identify specific growth factors, such as vascular endothelial growth factor, insulin-like growth factor-1, sonic hedgehog and wingless family members that act on neural precursors to promote neurogenesis, but only when stem/progenitor cells are located within the correct local niche. By further defining this context-dependent regulation of neural stem cells at four levels (proliferation, differentiation, migration and survival), we hope to identify the specific cues that regulate where and when new neurons are made.

The local activation of neuronal replacement in other areas of the brain, or the reconstruction of a “neurogenic” niche through cell transplantation promise to be fundamentally important clinical tools for brain repair but an understanding of how neurogenesis is regulated and how is presence or absence influences cognition and behavior is critical for guiding these efforts. With sufficient insights into the natural utilization of neural stem cells, it will be possible to manipulate the workings of the mind to ameliorate the devastating effects of disease or injury.