Adult neurogenesis is the most dramatic form of plasticity in the adult brain and may play a role in learning and memory, especially in perceptually difficult tasks in complex natural environments. New neurons appear only in a few regions of the adult mammalian brain and become integrated into existing circuits. In the rodent olfactory bulb (OB), new neurons assume the identity of inhibitory interneurons, including granule cells (GCs). Little is known about the functional development of adult-born granule cells (abGCs) in vivo, including when they begin to respond to stimuli and how their responses change as they develop.I used a lentivirus to sparsely label abGCs with structural and activity markers, allowing me to examine their functional life history using multiphoton imaging. I found that many abGCs were responsive to odorants soon after they arrived in the OB and extended dendrites (7 to 10 days after viral labeling of migrating neuroblasts). Tracking identified abGCs over weeks revealed that the robust and broadly tuned responses of most newly arrived abGCs gradually became more selective over a period of about 3 weeks, but a small fraction achieved broader tuning with maturation. Enriching the olfactory environment of mice prolonged the period over which abGCs were strongly and broadly responsive to odorants. These data offer direct support for rapid integration of adult-born neurons into existing circuits, followed by experience-dependent refinement of their functional connectivity.Although previous work based on ex vivo quantification has shown that approximately half of young abGCs die before integrating into the OB circuit, longitudinal imaging revealed that less than 5% of the developing neurons die after extending their apical dendrites, and there was no correlation between odor-evoked dendritic responses and cell death. In contrast, dendritic pruning is associated with lower odor responsiveness and may be a mechanism for activity-dependent plasticity during synaptic development. Therefore, it is likely structural plasticity in general, including dendritic pruning and synaptic turnover, may be more important mechanisms for shaping the functional integration of abGCs than cell death. I modeled rates of cell addition and replacement in the OB, incorporating a range of estimates from the literature and our data and suggest that rates of cell addition and survival likely exceed rates of cell death throughout the lifespan, suggesting that ongoing neurogenesis leads to lifelong cell addition to the OB.AbGCs receive excitatory feedforward inputs from both the principal cells of the OB, mitral and tufted cells (M/TCs), as well as feedback from olfactory cortex. However, it is still unclear how these synapses are formed and refined in an input-specific manner to contribute to the functional activity of abGCs in vivo. By expressing channelrhodopsin in either feedforward or feedback inputs to abGCs and selectively activating these inputs in OB slices, I described the pattern of synaptic development and refinement of these inputs and related these inputs to action potential output in abGCs. I found that feedback inputs develop early, and there was no significant change in the amplitude of optogenetically-evoked minimal excitatory postsynaptic potentials or the estimated number of fibers converging onto single abGCs over development. Furthermore, activation of these inputs could already evoke action potentials in young abGCs. Additionally, young abGCs also fired action potentials in response to activation of feedforward inputs, at similar or slightly higher rates than mature abGCs, suggesting that feedforward inputs are functional much earlier than previously appreciated. We hypothesize that early on, high dendritic excitability in young abGCs together with inputs from mitral and tufted cells associated with many distinct glomeruli leads to broad odor responses in vivo. As abGCs mature, feedforward and feedback inputs may be refined to result in a set of inputs with more similar, selective odor tuning, providing more specificity for individual odor channels in mature abGCs, consistent with the proposed role of GCs in providing targeted lateral inhibition to mitral cells.I also investigated non cell-autonomous mechanisms of synapse development and refinement in abGCs. Microglia play key roles in these processes in the developing brain, but it is unknown whether they are similarly involved during adult neurogenesis. By transiently ablating microglia from the healthy adult mouse brain, I showed that microglia are necessary for the normal functional development of adult-born granule cells (abGCs) in the olfactory bulb. Microglia ablation reduced the odor responses of developing, but not preexisting GCs in vivo. Microglia preferentially target their motile processes to interact with mushroom spines on abGCs, and when microglia were absent, abGCs develop smaller spines and receive weaker excitatory synaptic inputs. These results suggest that ablating microglia may specifically interfere with synaptic refinement and the strengthening of correlated odor inputs while allowing dendritic excitability to decrease normally.These data have already been integrated into a new set of computational models of the olfactory bulb by several other groups, contributing to our understanding of the role of adult-born neurons in the olfactory circuit. Furthermore, insights into the mechanisms by which adult-born neurons integrate into existing brain could lay the groundwork for future efforts to enhance or repair brain plasticity.
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Functional development of adult-born neurons in the olfactory bulb
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