Hippocampal neurogenesis persists throughout adult life and plays an important role in learning and memory. Although the influence of physical exercise on neurogenesis has been intensively studied, there is controversy in regard to how the impact of exercise may vary with its regime. Less is known about how distinct exercise paradigms may differentially affect the learning behavior. Here we found that, chronic moderate treadmill running led to an increase of cell proliferation, survival, neuronal differentiation, and migration. In contrast, intense running only promoted neuronal differentiation and migration, which was accompanied with lower expressions of vascular endothelial growth factor, brain-derived neurotrophic factor, insulin-like growth factor 1, and erythropoietin. In addition, the intensely but not mildly exercised animals exhibited a lower mitochondrial activity in the dentate gyrus. Correspondingly, neurogenesis induced by moderate but not intense exercise was sufficient to improve the animal’s ability in spatial pattern separation. Our data indicate that the effect of exercise on spatial learning is intensity-dependent and may involve mechanisms other than a simple increase in the number of new neurons.

Rewarding experiences are often well remembered, and such memory formation is known to be dependent on dopamine modulation of the neural substrates engaged in learning and memory; however, it is unknown how and where in the brain dopamine signals bias episodic memory toward preceding rather than subsequent events. Here we found that photostimulation of channelrhodopsin-2-expressing dopaminergic fibers in the dentate gyrus induced a long-term depression of cortical inputs, diminished theta oscillations, and impaired subsequent contextual learning. Computational modeling based on this dopamine modulation indicated an asymmetric association of events occurring before and after reward in memory tasks. In subsequent behavioral experiments, preexposure to a natural reward suppressed hippocampus-dependent memory formation, with an effective time window consistent with the duration of dopamine-induced changes of dentate activity. Overall, our results suggest a mechanism by which dopamine enables the hippocampus to encode memory with reduced interference from subsequent experience.T he brain structures crucial for memory formation are presumably under the control of the midbrain dopamine (DA) system, which selectively marks experiences that lead to reward (1, 2). In the striatum and the cortex, repetitive pairing of DA input after, but not before, sensorimotor stimulus within a narrow time window promotes structural and functional connectivity (3, 4), which may provide a cellular basis for reward to reinforce specifically an immediate past action. In the hippocampus, a structure that is instrumental in forming memories of contexts and objects making up the experiences (5, 6), DA must be present at the induction of long-term potentiation (LTP) to increase the magnitude of early-and late-phase LTP (7-10). When released during learning, DA also has been found to enhance the reactivation of newly formed neural ensembles (11). The requisite coincidence between the DA signal and the conditioning stimulation may serve to ensure that only inputs concurrent with or occurring shortly before reward are encoded in long-term memory. However, rewarding outcomes often may be delayed, and the involvement of the hippocampus is necessary when an event and its outcome are temporally discontinuous (12). This type of "memory" can be formed rapidly after even a single experience (5,6), and behavioral studies demonstrate that application of DA agonists in the hippocampus hours after training promotes memory maintenance (13,14), indicating that DA released from midbrain projections (Fig. S1) exerts distinct influences on the hippocampus to reinforce memory of earlier events selectively.Here we surveyed the dentate gyrus (DG) of the hippocampus to explore the possible sites and actions of DA. As the first stage of the intrahippocampal trisynaptic loop, the DG receives multiple processed sensory inputs from the entorhinal cortex (EC) and uses conjunctive encoding to integrate them for a memory representation (15). This region, together with area ...

Graphical AbstractHighlights d LTP in the dentate gyrus becomes more readily reversible during development d The age dependence of depotentiation is controlled by the GluN2A/GluN2B subunit ratio d The developmental enhancement of LTP reversal is associated with increased forgetting d Changes in the GluN2A/GluN2B subunit ratio affect rates of forgetting In BriefGe et al. report that the NMDA receptor GluN2A/GluN2B subunit ratio determines the sensitivity of strengthened neuronal connections to depotentiation. As the ratio rises during development, memories become more vulnerable to disruption by post-learning interference. These findings help to illuminate the mechanism by which forgetting rates may vary with age. SUMMARYRetroactive interference (RI) occurs when new incoming information impairs an existing memory, which is one of the primary sources of forgetting. Although long-term potentiation (LTP) reversal shows promise as the underlying neural correlate, the key molecules that control the sensitivity of memory circuits to RI are unknown, and the developmental trajectory of RI effects is unclear. Here we found that depotentiation in the hippocampal dentate gyrus (DG) depends on GluN2A-containing NMDA receptors (NMDARs). The susceptibility of LTP to disruption progressively increases with the rise in the GluN2A/GluN2B ratio during development.The vulnerability of hippocampus-dependent memory to interference from post-learning novelty exploration is subject to similar developmental regulation by NMDARs. Both GluN2A overexpression and GluN2B downregulation in the DG promote RIinduced forgetting. Altogether, our results suggest that a switch in GluN2 subunit predominance may confer age-related differences to depotentiation and underlie the developmental decline in memory resistance to RI.

The equal contribution footnote was missing for author Chao Huang. Chao Huang was one of the co-first author which had contributed equally to this work. The original article has been updated.

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