Adult neurogenesis: integrating theories and separating functions

Abstract

The continuous incorporation of new neurons in the dentate gyrus of the adult hippocampus raises exciting questions about memory and learning, and has inspired new computational models to understand the function of adult neurogenesis. These theoretical approaches suggest distinct roles for new neurons as they slowly integrate into the existing dentate gyrus network: immature adult-born neurons seem to function as pattern integrators of temporally adjacent events, thereby enhancing pattern separation for events separated in time; whereas maturing adult-born neurons possibly contribute to pattern separation by being more amenable to learning new information, leading to dedicated groups of granule cells that respond to experienced environments. We review these hypothesized functions and supporting empirical research and point to new directions for future theoretical efforts.

Figure 1. Hippocampal and DG anatomy

(a) Cartoon schematic of the hippocampus and its principal input, the entorhinal cortex. (b) Schematic of the dentate gyrus and the hilus. The major neuron classes of the DG are labeled.

Figure 2. Maturation of adult-born neurons

(a) Seven- to 14-day-old neurons have limited dendritic arborization and receive only GABA inputs (red arrow), which are excitatory. Right: GFP labeled 10-day-old neuron. (b) Fourteen- to 21-day-old neurons begin to develop spines and receive glutamatergic inputs (blue arrows). GABA transitions from depolarizing to hyperpolarizing. Right: GFP-labeled 14-day-old neuron. (c) The 21- to 28-day-old neurons have significant spine formation and show increased plasticity of perforant path inputs; Right: GFP-labeled 21-day-old neuron. (d) By 56 days, neurons are comparable to embryonic-born GCs; Right: GFP-labeled 56-day-old neuron. (e) Cartoon schematic of maturation of basic neuronal electrophysiology properties. Period of potentially increased excitability is highlighted. F) Cartoon schematic of maturation of synaptic connectivity and plasticity. Period of potentially increased learning is highlighted. Image courtesy of Zhao et al., Journal of Neuroscience 2006[39].

Figure 3. How DG and new neurons may affect pattern separation

Each panel represents how a series of temporally discrete events (left) would be encoded by the hippocampus. (a) Events encoded by the hippocampus without the DG would not be adequately separated, leading to possible clustering of memories based on content. (b) Events encoded by the DG without neurogenesis would be highly separated. (c) Events encoded by the DG with neurogenesis would also be highly separated but would potentially retain their temporal structure. This temporal integration would be provided by the heterogeneous mix of immature neurons.

Figure 4. Alternative theories of neurogenesis depletion on the DG long-term

Each column represents how the DG would acquire information about events presented over extended time scales. (a) Without neurogenesis, the DG (and the rest of hippocampus) might continue to incorporate new information that, in effect, overwrites old information. Such a mechanism could lead to “catastrophic interference” in the network. (b) An alternative possibility is that, without neurogenesis, the DG network could quickly use its finite set of sparse codes for early events. All subsequent new memories would be encoded by utilizing already existing, and thus less optimal, sparse codes. (c) Most models of neurogenesis suggest that immature neurons are the most plastic in the network, allowing new information to be encoded by new neurons and leaving old information intact.

Figure 5. Role of DG and neurogenesis in hippocampal function

(a) According to theories based on the classic trisynaptic loop[23, 25, 88], the DG is the principal input to the hippocampus, positioning neurogenesis for a significant impact on memory formation. (b) An alternative possibility envisions that direct connections from EC to CA1 are sufficient for some hippocampal processing and loops through the CA3 and the DG are important under specific circumstances, such as one-shot learning[32, 89]. This positioning would suggest that DG modulates CA3 function and neurogenesis modulates this modulation.