Viral tracing reveals molecule responsible for adult-born neuron signaling
A common theme that underlies neurological, neurodegenerative or neuropsychiatric diseases and brain or spinal cord injuries is that the affected neurons are dysfunctional or dead. Therefore, to restore normal function, researchers have been using stem cell therapies to form new neurons. However, ensuring long-term survival and proper connectivity of newborn neurons in vivo, or in mouse models,is very challenging. This is especially true in adults since only two brain regions are known to possess some regenerative potential and very little is known about the mechanisms that control those processes.
Researchers at Baylor College of Medicine and the Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital (NRI) have now identified a novel role for a soluble neuropeptide (small protein-like molecules used by neurons for communication), Corticotrophin Release Hormone (CRH), in the survival and integration of adult-born neurons in the mouse brain.
The findings appear in the current edition of Developmental Cell.
"We have hit a point in the research where we can generate and isolate neural stem cells from other somatic cell lineages, and we are making rapid strides in understanding how to differentiate them to excitatory or inhibitory neural subtypes. But the key to future therapies is to learn how neurons are wired up, make appropriate synapses (junctions between neurons) and to understand the signals that guide these synapses to be made, broken or maintained," said NRI researcher and corresponding author of this study Dr. Benjamin Arenkiel, who is also an assistant professor in the departments of Molecular Human Genetics and Neuroscience at Baylor and a McNair Scholar.
Arenkiel's team used a relatively new technique to trace functional connections between neurons. They selectively injected adult-born neurons in the olfactory bulb with a modified, non-infectious form of the rabies virus. This recombinant form of rabies virus is capable of jumping between infected cells and their immediate presynaptic partner cells. Using this and other techniques, researchers made the novel observation that adult-born neurons received extensive inputs from a specific group of CRH-releasing local interneurons that acts as a guidance/value cue, which ensures that newly formed neurons are connected to their appropriate neighboring neuron(s).
This is the first time that local neuropeptide signaling has been shown to be important in the integration of adult-born neurons in a pre-existing neuronal circuit.
"This study suggests that if we could find ways to regulate CRH signaling, we would be one step closer to repairing defective or injured neurons. It also provides us a molecular handle to ensure the survival and proper integration of neurons using stem cell therapies," said Isabella Garcia, MD/PhD, Programin Developmental Biology.
"Moreover, cutting-edge technologies used in this study provide a path for future exploration and potential manipulation of other neuropeptide signaling pathways either individually or in a combinatorial manner to repair adult neuronal circuitry," Arenkiel added.
Others who took part in this study include: Kathleen Quast, Longwen Huang, Alexander Herman, Jennifer Selever and Jan Deussing, Max Planck Institute of Psychiatry; and Nicholas Justice, University of Texas Health Science Center at Houston.
Funding for this work comes from the McNair Foundation and the National Institutes of Neurological Disorders and Stroke at the NIH (R01NS078294) to Arenkiel and (F31NS081805) to Garcia.
About Texas Children’s Hospital
Texas Children’s Hospital, a not-for-profit health care organization, is committed to creating a healthier future for children and women throughout the global community by leading in patient care, education and research. Consistently ranked as the best children’s hospital in Texas, and among the top in the nation, Texas Children’s has garnered widespread recognition for its expertise and breakthroughs in pediatric and women’s health. The hospital includes the Jan and Dan Duncan Neurological Research Institute; the Feigin Center for pediatric research; Texas Children’s Pavilion for Women, a comprehensive obstetrics/gynecology facility focusing on high-risk births; Texas Children’s Hospital West Campus, a community hospital in suburban West Houston; and Texas Children’s Hospital The Woodlands, a second community hospital planned to open in 2017. The organization also created the nation’s first HMO for children, has the largest pediatric primary care network in the country and a global health program that’s channeling care to children and women all over the world. Texas Children’s Hospital is affiliated with Baylor College of Medicine. For more information, go to www.texaschildrens.org. Get the latest news by visiting the online newsroom and Twitter at twitter.com/texaschildrens.