The continuous addition of new dentate granule cells, exquisitely regulated by brain activity, renders the hippocampus plastic. However, how neural circuits encode experiences to impact the addition of adult-born neurons remains unknown. Here, we used endoscopic Ca2+ imaging to track the real-time activity of individual dentate granule cells in freely-behaving mice. For the first time, we found that active dentate granule cells responded to a novel experience by preferentially increasing their Ca2+ event frequency. This elevated activity, which we found to be associated with object exploration, returned to baseline by one hour in the same environment, but could be dishabituated via introduction to a novel environment. To seamlessly transition between environments, we next established a freely-controllable virtual reality system for unrestrained mice. We again observed increased firing of active neurons in a virtual enriched environment. Interestingly, multiple novel virtual experiences accumulatively increased the number of newborn neurons when compared to a single experience. Finally, optogenetic silencing of existing dentate granule cells during novel environmental exploration perturbed experience-induced neuronal addition. Together, our study shows that the adult brain conveys novel, enriched experiences to increase the addition of adult-born hippocampal neurons by increasing the firing of active dentate granule cells.
Adult brains are constantly reshaping themselves from synapses to circuits as we encounter novel experiences from moment to moment. Importantly, this reshaping includes the addition of newborn hippocampal neurons. However, it remains largely unknown how our circuits encode experience-induced brain activity to govern the addition of new hippocampal neurons. By coupling in vivo Ca2+ imaging of dentate granule neurons with a novel unrestrained virtual reality system for rodents, we discovered that a new experience rapidly and robustly increased firing of active dentate granule neurons. Exploration in multiple novel virtual environments, as compared to a single environment, promoted dentate activation and accumulatively enhanced the addition of new hippocampal neurons. Finally, optogenetically silencing this activation during novel experiences perturbed experience-induced neuronal addition.
The authors declare no competing financial interests.
This work was supported by AG046875 and NS089770 to S.G., and 1F30MH110103 to G.W.K. We thank Walter Schmeling and Jeff Slechta of the University Machine Shop for assistance with the design and execution of the virtual reality system and Jason Wu for his assistance with experimental procedures. We also thank Drs. René Hen, Lorna Role, Grigori Enikolopov, Ramin Parsey, Amar Sahay, Il-Memming Park, Yan Gu, Michael Frohman, John Robinson and Qiaojie Xiong for their valuable feedback on this work.