Unique potential of immature adult-born neurons for the remodeling of CA3 spatial maps.

Mammalian hippocampal circuits undergo extensive remodeling through adult neurogenesis. While this process has been widely studied, the specific contribution of adult-born granule cells (aGCs) to spatial operations in the hippocampus remains unknown. Here, we show that optogenetic activation of 4-week-old (young) aGCs in free-foraging mice produces a non-reversible reconfiguration of spatial maps in proximal CA3 while rarely evoking neural activity. Stimulation of the same neuronal cohort on subsequent days recruits CA3 neurons with increased efficacy but fails to induce further remapping. In contrast, stimulation of 8-week-old (mature) aGCs can reliably activate CA3 cells but produces no alterations in spatial maps. Our results reveal a unique role of young aGCs in remodeling CA3 representations, a potential that can be depleted and is lost with maturation. This ability could contribute to generate orthogonalized downstream codes supporting pattern separation.

Dynamic interplay between GABAergic networks and developing neurons in the adult hippocampus.

Neurogenesis is a powerful mechanism for structural and functional remodeling that occurs in restricted areas of the adult brain. Although different neurotransmitters regulate various aspects of the progression from neural stem cell quiescence to neuronal maturation, GABA is the main player. The developmental switch from excitation to inhibition combined with a heterogeneous population of GABAergic interneurons that target different subcellular compartments provides multiple points for the regulation of development and function of new neurons. This complexity is enhanced by feedback and feedforward networks that act as sensors and controllers of circuit activity, impinging directly or indirectly onto developing granule cells and, subsequently, on mature neurons. Newly generated granule cells ultimately connect with input and output partners in a manner that is largely sculpted by the activity of local circuits.

GABAergic Interneurons Control Adult Neurogenesis but Astrocytes Have the Last Word.

Adult neurogenesis depends on the decision of neural stem cells to leave quiescence and become neurons. In this issue, Asrican et al. show that the neuropeptide cholecystokinin released by interneurons promotes the neuronal fate through astrocytic signaling.

Rejuvenating the Brain With Chronic Exercise Through Adult Neurogenesis.

The aging brain presents a general decline in plasticity that also affects hippocampal neurogenesis. Besides the well-known reduction in the rate of neuronal generation, development of new neurons is largely delayed in the aging brain. We have recently shown that this slow development is accelerated when middle-aged mice perform voluntary exercise in a running wheel. It is unclear whether the effects of exercise on neurogenic plasticity are persistent in time in a manner that might influence neuronal cohorts generated over an extended time span. To clarify these issues, we examined the effects of exercise length in 3-week-old neurons and found that their development is accelerated only when running occurs for long (3-4 weeks) but not short periods (1 week). Furthermore, chronic running acted with similar efficiency on neurons that were born at the onset, within, or at the end of the exercise period, lasting until 3 months. Interestingly, no effects were observed on neurons born 1 month after exercise had ended. Our results indicate that multiple neuronal cohorts born throughout the exercise span integrate very rapidly in the aging brain, such that the effects of running will accumulate and expand network assembly promoted by neurogenesis. These networks are likely to be more complex than those assembled in a sedentary mouse due to the faster and more efficient integration of new neurons.

Experience-Dependent Structural Plasticity of Adult-Born Neurons in the Aging Hippocampus.

Synaptic modification in cortical structures underlies the acquisition of novel information that results in learning and memory formation. In the adult dentate gyrus, circuit remodeling is boosted by the generation of new granule cells (GCs) that contribute to specific aspects of memory encoding. These forms of plasticity decrease in the aging brain, where both the rate of adult neurogenesis and the speed of morphological maturation of newly generated neurons decline. In the young-adult brain, a brief novel experience accelerates the integration of new neurons. The extent to which such degree of plasticity is preserved in the aging hippocampus remains unclear. In this work, we characterized the time course of functional integration of adult-born GCs in middle-aged mice. We performed whole-cell recordings in developing GCs from Ascl1CreERT2;CAGfloxStopTom mice and found a late onset of functional excitatory synaptogenesis, which occurred at 4 weeks (vs. 2 weeks in young-adult mice). Overall mature excitability and maximal glutamatergic connectivity were achieved at 10 weeks. In contrast, large mossy fiber boutons (MFBs) in CA3 displayed mature morphological features including filopodial extensions at 4 weeks, suggesting that efferent connectivity develops faster than afference. Notably, new GCs from middle-aged mice exposed to enriched environment for 7 days showed an advanced degree of maturity at 3 weeks, revealed by the high frequency of excitatory postsynaptic responses, complex dendritic trees, and large size of MFBs with filopodial extensions. These findings demonstrate that adult-born neurons act as sensors that transduce behavioral stimuli into major network remodeling in the aging brain.

High Plasticity of New Granule Cells in the Aging Hippocampus.

During aging, the brain undergoes changes that impair cognitive capacity and circuit plasticity, including a marked decrease in production of adult-born hippocampal neurons. It is unclear whether development and integration of those new neurons are also affected by age. Here, we show that adult-born granule cells (GCs) in aging mice are scarce and exhibit slow development, but they display a remarkable potential for structural plasticity. Retrovirally labeled 3-week-old GCs in middle-aged mice were small, underdeveloped, and disconnected. Neuronal development and integration were accelerated by voluntary exercise or environmental enrichment. Similar effects were observed via knockdown of Lrig1, an endogenous negative modulator of neurotrophin receptors. Consistently, blocking neurotrophin signaling by Lrig1 overexpression abolished the positive effects of exercise. These results demonstrate an unparalleled degree of plasticity in the aging brain mediated by neurotrophins, whereby new GCs remain immature until becoming rapidly recruited to the network by activity.

Role of Mitochondrial Metabolism in the Control of Early Lineage Progression and Aging Phenotypes in Adult Hippocampal Neurogenesis.

Precise regulation of cellular metabolism is hypothesized to constitute a vital component of the developmental sequence underlying the life-long generation of hippocampal neurons from quiescent neural stem cells (NSCs). The identity of stage-specific metabolic programs and their impact on adult neurogenesis are largely unknown. We show that the adult hippocampal neurogenic lineage is critically dependent on the mitochondrial electron transport chain and oxidative phosphorylation machinery at the stage of the fast proliferating intermediate progenitor cell. Perturbation of mitochondrial complex function by ablation of the mitochondrial transcription factor A (Tfam) reproduces multiple hallmarks of aging in hippocampal neurogenesis, whereas pharmacological enhancement of mitochondrial function ameliorates age-associated neurogenesis defects. Together with the finding of age-associated alterations in mitochondrial function and morphology in NSCs, these data link mitochondrial complex function to efficient lineage progression of adult NSCs and identify mitochondrial function as a potential target to ameliorate neurogenesis-defects in the aging hippocampus.

A disynaptic feedback network activated by experience promotes the integration of new granule cells.

Experience shapes the development and connectivity of adult-born granule cells (GCs) through mechanisms that are poorly understood. We examined the remodeling of dentate gyrus microcircuits in mice in an enriched environment (EE). Short exposure to EE during early development of new GCs accelerated their functional integration. This effect was mimicked by in vivo chemogenetic activation of a limited population of mature GCs. Slice recordings showed that mature GCs recruit parvalbumin γ-aminobutyric acid-releasing interneurons (PV-INs) that feed back onto developing GCs. Accordingly, chemogenetic stimulation of PV-INs or direct depolarization of developing GCs accelerated GC integration, whereas inactivation of PV-INs prevented the effects of EE. Our results reveal a mechanism for dynamic remodeling in which experience activates dentate networks that "prime" young GCs through a disynaptic feedback loop mediated by PV-INs.

Effects of spaced learning in the water maze on development of dentate granule cells generated in adult mice.

New dentate granule cells (GCs) are generated in the hippocampus throughout life. These adult-born neurons are required for spatial learning in the Morris water maze (MWM). In rats, spatial learning shapes the network by regulating their number and dendritic development. Here, we explored whether such modulatory effects exist in mice. New GCs were tagged using thymidine analogs or a GFP-expressing retrovirus. Animals were exposed to a reference memory protocol for 10-14 days (spaced training) at different times after newborn cells labeling. Cell proliferation, cell survival, cell death, neuronal phenotype, and dendritic and spine development were examined using immunohistochemistry. Surprisingly, spatial learning did not modify any of the parameters under scrutiny including cell number and dendritic morphology. These results suggest that although new GCs are required in mice for spatial learning in the MWM, they are, at least for the developmental intervals analyzed here, refractory to behavioral stimuli generated in the course of learning in the MWM.

Delayed coupling to feedback inhibition during a critical period for the integration of adult-born granule cells.

Developing granule cells (GCs) of the adult dentate gyrus undergo a critical period of enhanced activity and synaptic plasticity before becoming mature. The impact of developing GCs on the activity of preexisting dentate circuits remains unknown. Here we combine optogenetics, acute slice electrophysiology, and in vivo chemogenetics to activate GCs at different stages of maturation to study the recruitment of local target networks. We show that immature (4-week-old) GCs can efficiently drive distal CA3 targets but poorly activate proximal interneurons responsible for feedback inhibition (FBI). As new GCs transition toward maturity, they reliably recruit GABAergic feedback loops that restrict spiking of neighbor GCs, a mechanism that would promote sparse coding. Such inhibitory loop impinges only weakly in new cohorts of young GCs. A computational model reveals that the delayed coupling of new GCs to FBI could be crucial to achieve a fine-grain representation of novel inputs in the dentate gyrus.

The timing for neuronal maturation in the adult hippocampus is modulated by local network activity.

The adult hippocampus continuously generates new cohorts of immature neurons with increased excitability and plasticity. The window for the expression of those unique properties in each cohort is determined by the time required to acquire a mature neuronal phenotype. Here, we show that local network activity regulates the rate of maturation of adult-born neurons along the septotemporal axis of the hippocampus. Confocal microscopy and patch-clamp recordings were combined to assess marker expression, morphological development, and functional properties in retrovirally labeled neurons over time. The septal dentate gyrus displayed higher levels of basal network activity and faster rates of newborn neuron maturation than the temporal region. Voluntary exercise enhanced network activity only in the temporal region and, in turn, accelerated neuronal development. Finally, neurons developing within a highly active environment exhibited a delayed maturation when their intrinsic electrical activity was reduced by the cell-autonomous overexpression of Kir2.1, an inward-rectifying potassium channel. Our findings reveal a novel type of activity-dependent plasticity acting on the timing of neuronal maturation and functional integration of newly generated neurons along the longitudinal axis of the adult hippocampus.