The brain may be able to repair itself from within, Duke researchers discover

June 3, 2014

In this artist’s representation of the adult subependymal neurogenic niche (viewed from underneath the ependyma), electrical signals generated by the ChAT+ neuron give rise to newborn migrating neuroblasts, seen moving over the underside of ependymal cells ( credit: O‚ÄôReilly Science Art)

Duke researchers have found a new type of neuron in the adult brain that is capable of telling stem cells to make more new neurons.

Neuroscientists have suspected for some time that the brain has some capacity to direct the manufacturing of new neurons, but it was difficult to determine where these instructions are coming from, explains Chay Kuo, M.D. Ph.D., an assistant professor of cell biology, neurobiology and pediatrics.

In a study with mice, his team found a previously unknown population of neurons within the subventricular zone (SVZ) neurogenic niche of the adult brain, adjacent to the striatum.

These neurons expressed the choline acetyltransferase (ChAT) enzyme, which is required to make the neurotransmitter acetylcholine. With optogenetic tools that allowed the team to tune the firing frequency of these ChAT+ neurons up and down with laser light, they were able to see clear changes in neural stem cell proliferation in the brain.

The findings appeared as an advance online publication June 1 in the journal Nature Neuroscience.

The mature ChAT+ neuron population is just one part of an undescribed neural circuit that apparently talks to stem cells and tells them to increase new neuron production, Kuo said. Researchers don’t know all the parts of the circuit yet, nor the code it’s using, but by controlling ChAT+ neurons’ signals Kuo and his Duke colleagues have established that these neurons are necessary and sufficient to control the production of new neurons from the SVZ niche.

Studies of stroke injury in rodents have noted SVZ cells apparently migrating into the neighboring striatum. And just last month in the journal Cell, a Swedish team observed newly made control neurons called interneurons in the human striatum for the first time. They reported that interestingly in Huntington’s disease patients, this area seems to lack the newborn interneurons.

Kuo’s team found this system by following cholinergic signaling, but other groups are arriving in the same niche by following dopaminergic and serotonergic signals, Temple said. “It’s a really hot area because it’s a beautiful stem cell niche to study. It’s this gorgeous niche where you can observe cell-to-cell interactions.”

These emerging threads have Kuo hopeful researchers will eventually be able to find the way to “engage certain circuits of the brain to lead to a hardware upgrade. Wouldn’t it be nice if you could upgrade the brain hardware to keep up with the new software?” He said perhaps there will be a way to combine behavioral therapy and stem cell treatments after a brain injury to rebuild some of the damage.

This research was supported by the National Institutes of Health, David & Lucile Packard Foundation, and George Brumley Jr. Endowment.

Abstract of Nature Neuroscience paper

Postnatal and adult subventricular zone (SVZ) neurogenesis is believed to be primarily controlled by neural stem cell (NSC)-intrinsic mechanisms, interacting with extracellular and niche-driven cues. Although behavioral experiments and disease states have suggested possibilities for higher level inputs, it is unknown whether neural activity patterns from discrete circuits can directly regulate SVZ neurogenesis. We identified a previously unknown population of choline acetyltransferase (ChAT)+ neurons residing in the rodent SVZ neurogenic niche. These neurons showed morphological and functional differences from neighboring striatal counterparts and released acetylcholine locally in an activity-dependent fashion. Optogenetic inhibition and stimulation of subependymal ChAT+ neurons in vivo indicated that they were necessary and sufficient to control neurogenic proliferation. Furthermore, whole-cell recordings and biochemical experiments revealed direct SVZ NSC responses to local acetylcholine release, synergizing with fibroblast growth factor receptor activation to increase neuroblast production. These results reveal an unknown gateway connecting SVZ neurogenesis to neuronal activity-dependent control and suggest possibilities for modulating neuroregenerative capacities in health and disease.