For a long time it was widely believed that the adult mammalian brain was incapable of generating new neurons. During early development, a significant amount of neurogenesis (production of new neurons) occurs in order to form the nervous system. This neurogenic program was thought to shut down during adulthood, rendering the brain lacking in neurogenic capabilities.
However, the prevailing views of adult neurogenesis have since changed drastically. Adult neurogenesis has become a central tenet of contemporary neuroscience. It turns out that specific niches of the brain contain neural stem cells that can give rise to mature neurons. These adult-generated neurons have been suggested to provide the neural plasticity necessary for learning and memory, as well as regulating emotions and mood.
Interestingly, emerging lines of work are showing that adult neural stem cells become activated in response to various injury and other pathological conditions that result in neuronal loss. In many cases, these stem cells migrate to the injury sites and seem to give rise to new neurons. This self-repair process is severely inefficient, since newly generated neurons do not survive long enough and are not able to integrate into preexisting structures correctly. The big question then is how can we enhance this endogenous regenerative pathway to achieve better brain repair.
In an intriguing new study published in Science Magazine, Jena Magnusson and colleagues searched for an internal mechanism in the brain that can enhance neural regeneration. Using a mouse model of stroke, they discovered a novel pathway by which non-neuronal support cells can be turned into neurons. This newly unveiled pathway represents a new therapeutic target upon which drugs can act to enhance the endogenous repair response, potentially fostering a novel paradigm in the field of regenerative medicine.
Surrounding neurons in the brain are support cells called glia. These non-neuronal cells perform various functions that help maintain and support the nervous system, such as stabilizing connections and protecting neurons against pathogens. One of these glial cells, astrocytes, has gathered significant interest in terms of understanding brain regeneration. Following traumatic injury, astrocytes swell up and release factors that form a physical barrier around the injury site. This so called “glial scar” is thought to be a major contributor to the brain’s profound regenerative failure. Thus, astrocytes are thought to have negative effects on endogenous neural replacement.
Corroborating known findings, Magnusson and colleagues found that new neurons were generated following stroke in a mouse model. Previously it was believed that neural stem cells from other regions of the brain migrated to the injury site to facilitate injury-induced neurogenesis. However, the authors of the study discovered that the newly generated neurons were actually derived from astrocytes using genetic tracing methods.
In addition to the finding that astrocytes carry the latent ability to become neurons, Magnusson and others also elucidated the biological pathway that underlies the neurogenic potential in astrocytes. During early development of the nervous system, a signaling pathway called Notch1 is critical for determining whether a cell will adopt a neuronal or glial phenotype. Notch1 signaling persists in the adult brain, where it seems to regulate the proliferative activity of neural stem cells. When Magnusson and others deactivated the Notch1 signaling pathway, they were able to artificially induce astrocytes to turn into neurons. Likewise, by activating Notch1, they were able to block neurogenesis.
These findings show an unexpected biological pathway by which the brain’s endogenous regenerative mechanisms can be enhanced. This creates the potential for future drugs or other therapies that may be able to manipulate this pathway, leading to better treatments against diseases or other pathological conditions by allowing the brain to more effectively replace lost or damaged neurons. In the realm of regenerative medicine, this is an exciting study that sets the stage for enhanced brain repair therapeutics.
