Functions of adult-born neurons in hippocampal memory interference and indexing

Abstract

The dentate gyrus-CA3 circuit of the hippocampus is continuously modified by the integration of adult-born dentate granule cells (abDGCs). All abDGCs undergo a prolonged period of maturation, during which they exhibit heightened synaptic plasticity and refinement of electrophysiological properties and connectivity. Consistent with theoretical models and the known functions of the dentate gyrus-CA3 circuit, acute or chronic manipulations of abDGCs support a role for abDGCs in the regulation of memory interference. In this Review, we integrate insights from studies that examine the maturation of abDGCs and their integration into the circuit with network mechanisms that support memory discrimination, consolidation and clearance. We propose that adult hippocampal neurogenesis enables the generation of a library of experiences, each registered in mature abDGC physiology and connectivity. Mature abDGCs recruit inhibitory microcircuits to support pattern separation and memory indexing.

Fig. 1 ∣. Development, experience and maturation of adult-born DGCs.

a, Left: during the first 2 weeks after their birth, immature abDGCs (orange circle) are low-spiking and are innervated by depolarizing GABA synapses (GABA⁺) from INs (gray circle), which subsequently promotes glutamatergic synapse formation from hilar mossy cells (MC). Mossy cells both directly innervate DGCs and provide disynaptic depolarization through synapses onto GABA⁺ interneurons. Middle: during the sensitive period 4–6 weeks after their birth, experience modifies inputs onto abDGCs. abDGCs receive inputs from medial EC (MEC) and, more strongly, from LEC. MEC and LEC synapses onto abDGCs are established via synaptic competition (see c), and their strength can be efficiently altered (LTP or long-term depression (LTD)) as a result of network activity and the animal’s experience (for example, enriched environment; see top inset). Additional excitatory input onto abDGCs comes from medial septum and diagonal band of Broca cholinergic neurons (MS/DB). Inhibitory microcircuits are also established during this period. This includes inhibitory GABAergic (GABA⁻) input from dendritically targeting SST⁺ INs in the hilus (HIPP), somatic-targeting PV⁺ INs in the granule cell layer (GCL; not shown and MOPP INs in the molecular layer (MOL). Interneurons receive input from MEC, LEC and mossy cells and thereby provide feedforward inhibition onto abDGCs. The abDGCs begin to establish glutamatergic (mossy fiber) synapses onto CA3 pyramidal cells (PC, blue) and progressively recruit PV⁺ INs to exert feedforward inhibition onto CA3. Right: after 6 weeks, additional inhibitory GABA⁺ synapses form, and the now-mature DGCs (pink circles) become highly input-specific. Mature DGCs provide lateral inhibition onto other DGCs via PV⁺ INs and may self-attenuate spiking via recruitment of feedback inhibition. b, Inhibitory microcircuit motifs. Feedforward inhibition: in EC–DG feedforward inhibition, interneurons are recruited by MEC and LEC inputs and mossy cell collaterals (not shown) to inhibit abDGCs. In DG–CA3 feedforward inhibition, abDGCs recruit PV⁺ INs to inhibit CA3 neurons. Feedback inhibition: DGCs undergo auto-inhibition via recruitment of interneurons by DGCs. Lateral inhibition: mDGCs recruit interneurons to inhibit neighboring DGCs. c, Synaptic competition: immature abDGCs (orange) compete with mDGCs (red) for PP inputs from LEC and MEC. Immature DGCs initially form multisynaptic boutons with pre-existing PP–DGC synapses (left) before forming monosynaptic connections with those PP terminals (right).

Fig. 2 ∣. Adult-born DGCs reduce memory interference and promote consolidation through inhibitory microcircuits.

a, Schematic of contextual fear conditioning paradigm using two similar but nonidentical contexts (here indicated by two different shades of blue). With high levels of adult neurogenesis, mice efficiently discriminate between the two similar contexts, as indicated by increased freezing in the shock-paired chamber (indicated in light blue) but not in the non-paired but similar chamber (indicated in dark blue). With low levels of neurogenesis, discrimination is impaired, as indicated by similar levels of freezing in the two chambers. b, Adult-born DGCs (outlined with dotted border) facilitate separation of DG engrams encoding similar contexts. Top: EC inputs are decorrelated in DG via feedforward inhibition and lateral inhibition; abDGCs, competing with mature DGCs for perforant path inputs, exert high levels of lateral inhibition onto other DGCs through local inhibitory microcircuits; this facilitates sparse activity in the DG and thereby enables the establishment of non-overlapping engrams for the shock-associated context (light blue) and the similar but neutral context (dark blue); white cells do not encode either context. abDGCs recruit feedforward inhibition to transfer engrams of both contexts in non-overlapping populations of CA3 (triangles). Following decorrelation of engrams of both contexts in DG–CA3, each representation is consolidated in independent cortical ensembles. Through these mechanisms, high levels of adult neurogenesis can reduce memory interference. Bottom: with low levels of neurogenesis, similar contexts are represented by overlapping engrams (light and dark blue shades) in the DG and CA3 owing to inefficient synaptic competition, decreased feedforward inhibition, decreased lateral inhibition and reduced sparsification of DG activity. This increased interference in turn results in overlap and linkage of representations of both contexts in the cortex.

Fig. 3 ∣. Proposed role of adult-born DGCs in indexing and pattern separation.

a, Refinement of abDGC input specificity during the sensitive period. Immature abDGCs (orange) mature into abDGCs (red) with high input-selectivity and respond to specific features experienced during the sensitive period (here only stimulus 2 of stimuli 0–3). b, Schematic of indexing. Overlapping experiences (A and B) are encoded in distinct engrams (or ‘indexes’) in the hippocampus (green). These indexes are linked to detailed representations of A and B that are distributed in downstream cortical and subcortical regions (yellow), much like the way a library index card corresponds to a book on the shelves of the library. c, Experiences A (blue) and B (yellow) represented by unique permutations of inputs (examples: 0–9) in association sensory cortices are relayed to the EC. A and B are transformed into distinct non-overlapping engrams or indexes in the DG through decorrelation of EC inputs in the DG, where inhibitory microcircuits sparsify DG activity through a winner-take-all circuit motif. Different combinations of mature abDGCs (outlined in black) are flexibly allocated into each engram (or index), with shared features recruiting the same DGCs (here: features 0 and 1). Feature-responsive DGCs (yellow and blue) inhibit neighboring DGCs (gray) to further refine the engram through the winner-take-all mechanism. Immature, <6-week-old abDGCs (outlined in yellow) encode novel features of B (here features 6 and 7) and contribute to the index of B while also exerting lateral inhibition. DGC recruitment of feedforward inhibition onto CA3 facilitates the transfer of the ensemble onto non-overlapping pyramidal cells in CA3 (triangles). The balance between DG and EC inputs in CA3 dictates whether pattern completion or separation occurs. The DG–CA3 engram represents an index of the memory, but does not encode all of its features; these are instead stored in the corresponding linked cortical traces (yellow and black squares). Activation of the index in DG–CA3 reinstates the cortical memory trace through pattern completion to mediate retrieval.