Neuropeptides and Astrocytes Regulate Adult Neural Stem Cell Activity

Post by Lincoln Tracy 

What's the science?

The dentate gyrus is part of the hippocampus, an area of the brain that plays a critical role in memory formation. The dentate gyrus contains neural stem cells (brain cells that develop into other cell types) as well as a diverse range of other cell types, referred to as niche cells, such as granule cells, mossy cells, and astrocytes. These niche cells can release signals that act on neural stem cells to regulate neurogenesis, the process of generating new neurons. While previous research in the Song lab has identified that certain local niche cells can directly act on neural stem cells and regulate their behavior, it remains unknown if and how these niche cells interact within the dentate gyrus to regulate neural stem cells. This week in Neuron, Asrican and colleagues sought to address a range of challenges associated with determining the role of cholecystokinin signaling in regulating neural stem cells and neurogenesis within the hippocampus. 

How did they do it?

First, the authors selectively activated cholecystokinin neurons to examine the effect of endogenous cholecystokinin release on neural stem cells. To do this, they injected transgenic mice with adeno-associated viruses to selectively target cholecystokinin neurons within the dentate gyrus. Once the neurons had successfully been labeled, these neurons were activated via a chemogenetic approach. Next, they sought to address whether the cholesystokinin induced any direct or indirect effects on the neural stem cells, by recording their membrane potentials after GABAergic and glutamatergic signaling had been blocked. In addition, calcium imaging was performed to identify the effects of cholesystokinin on other cell types in the dentate gyrus, such as granule cells, local interneurons, and mossy cells. After these effects were identified, in vivo analysis of neural stem cell behavior was performed using immunohistology and stereological counting of neural stem cells and their progeny. Finally, adeno-associated viruses were used to reduce cholecystokinin levels in the dentate gyrus to assess the effect on neural stem cell behavior. RNA sequencing of the dentate gyrus was undertaken to explore the mechanisms by which reduced cholecystokinin levels impairs neural stem cell behavior. 

What did they find?

The authors showed that stimulating cholecystokinin neurons in the dentate gyrus induced neural stem cell depolarization. Interestingly, they found that it was the cholecystokinin that induced the depolarization, not GABA or glutamate transmission from these neurons. Moreover, cholecystokinin-induced neural stem cell depolarization requires the activation of glutamate receptors on the neural stem cells. The cholecystokinin induces astrocytes to release glutamate, which acts on receptors on the stem cells. In addition, the authors found that the cholecystokinin also excites parvalbumin neurons, which provide inhibitory inputs onto granule cells and mossy cells. Finally, the authors found that decreasing cholecystokinin release induces astrocyte reactivity and increases innate immune system activity. The resulting neuroinflammation leads to decreased proliferation of neural stem cells, most likely through proinflammatory cytokine signaling.  

What's the impact?

This study shows that promoting cholecystokinin release in the dentate gyrus supports neurogenesis through an astrocyte-mediated glutamatergic signaling pathway. In contrast, reducing cholecystokinin release in the dentate gyrus induces neuroinflammation which impairs the neurogenic potential of neural stem cells. The generation of new neurons in adult life also plays a critical role in cognitive functioning. Therefore, increasing cholecystokinin release to stimulate neurogenesis while also reducing inflammation may be utilized as a novel treatment strategy to treat conditions where abnormal neurogenesis and neuroinflammation occur.

Asrican et al. Neuropeptides modulate local astrocytes to regulate adult hippocampal neural stem cells. Neuron (2020). Access the original scientific publication here.