Catering new neurons to environmental needs: Activity of granule cells regulates neurogenesis in the dentate gyrus

Abstract

The mammalian adult dentate gyrus generates new neurons. In a process called adult neurogenesis neural stem cells give rise to new neurons that mature and integrate into the existing neural network. By their addition and integration to the existing network, the new neurons form new circuits. In their immature stages the neurons are distinct in their morphology, physiology and protein expression from mature neurons in the dentate gyrus. Several lines of evidence implicate the immature neurons in learning and memory as well as other brain functions. Chapter two of this thesis summarizes the involvement of new neurons in memory formation during a critical period of their maturation. During this critical period the newly formed neurons are thought to play a unique role in supporting hippocampal function. The proliferation of neural stem cells is the first step of circuit formation by new neurons. This step of circuit formation by new neurons is regulated by several factors. Amongst them is activity of surrounding neurons. However, not all cellular players regulating proliferation in this fashion have been identified. To find out which cell types play which roles in the regulation of proliferation, optogenetics is suited. Optogenetics offers a method that can control specific cell types and thereby investigate their individual role in adult neurogenesis. Chapter three and four of this thesis focus on the practical aspects of implementing optogenetic methods. Chapter five of this thesis describes a study indicating a novel mechanism of control, namely how activity of spatially modulated cells (place cells) and granule cells may affect adult neurogenesis in the dentate gyrus. We found that place cell activity anatomically correlates with doublecortin expressing cells while this relationship was not present for interneurons. This supports the idea that place cell activity locally increases neurogenesis. When we optogenetically induced activity in granule cells, we found that proliferation increases significantly. Taken together, the results from the in vivo recordings and optogenetic activation of granule cells, we suggest that place cell activity induces proliferation of neuronal progenitor cells. Activity dependent control of neurogenesis supports the notion that new neurons are added when they are needed. The anticipated need is decided by activity, and this may be a way to add the minimal amount of new neurons to still allow the dentate gyrus to function with the best possible efficacy. Besides this, activity dependent control may regulate specifically in which anatomical loci new neurons are added. Specific addition of new neurons supports the idea that new neurons form specific new circuits, which are functionally relevant. In my thesis work I have implemented a technique that can be used to activate specific types of neurons and elucidate the involvement of granule cells in adult neurogenesis. We went on to use this technique to show that granule cell activity can induce increases in proliferation of progenitor cells in the dentate gyrus. This leads to increased neurogenesis. We show a previously undescribed mechanism of regulating adult neurogenesis. This new mechanism suggests new neurons are added in specific anatomical loci, allowing the formation of circuits that are suited to represent specific information.