Adult neurogenesis: integrating theories and separating functions

James B. Aimone, Wei Deng, Fred H. Gage
2010 Trends in Cognitive Sciences  
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
more » ... tion 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. The challenge of new neurons Although the nervous systems of other vertebrates exhibit varying degrees of widespread neurogenesis [1,2], in mammals neurogenesis almost completely ceases after development, with only two regions retaining an ongoing incorporation of new neurons throughout life [3] . One of these regions, the olfactory bulb, is populated by neurons that were originally born in the sub-ventricular zone (SVZ). Immature neurons migrate from the SVZ and give rise to several local interneuron populations in the olfactory bulb [4, 5] . By contrast, in the dentate gyrus (DG) region of the hippocampus, new neurons arise from a local population of neuronal progenitor cells (NPCs) and eventually become excitatory granule cells (GCs), the principal projection neurons of the DG [6]. From a theoretical point of view, the incorporation of new neurons into the adult brain represents a unique challenge: because the neural network responsible for memory is continuously changing with the addition of new neurons, the DG and hippocampus cannot be considered to be architecturally stable. The dynamic nature of the neural network underlying memory is emphasized by the tight regulation of neurogenesis rates and their correlation with hippocampus-related behaviors. For instance, learning and many factors known to be beneficial to memory (e.g. running, enrichment) also increase the numbers of new neurons [7-10]; likewise, factors that impair memory, such as aging, stress and several diseases, are associated with lower neurogenesis levels [11, 12] . Evidence increasingly indicates that neurogenesis is important for hippocampal function but the exact function of new neurons is unclear. Much of the work has used behavioral paradigms designed to show changes after full hippocampal lesions [13, 14] . Despite the development of effective animal models for neurogenesis knockdown, the results from these more global behavioral tests have been (perhaps predictably, in retrospect) inconclusive [6] . Instead, theoretical approaches using computational modeling suggest that there could be multiple functions for new neurons that are more subtle than previously thought; these functions can best be described as part of the hypothesized functions of the DG as opposed to an isolated process in hippocampal function. At different stages in its maturation, each new neuron has distinct properties and, at any given time, the DG population consists of GCs of many different ages. This heterogeneity has led to several proposed functions of new neurons. This review summarizes the literature supporting the view that the function of new neurons is dynamic. After a brief overview of the classic view of the DG's role in hippocampal function, we discuss the unique biological properties of immature neurons and the hypothesized computational functions of immature GCs. These young GCs, which are thought to be more excitable in the network, could complement the pattern separation function of mature GCs by adding a degree of similarity between events experienced close in time. Next, the biological events that affect longterm maturation are described along with how they relate to the proposed, long-term computational consequences of the addition of new neurons. Several models suggest that directing plasticity towards maturing neurons can preserve the DG's representations of old memories while maintaining its capacity to learn new information. In both cases, behavioral studies that support and challenge these proposed functions are discussed. The function of the DG in hippocampal processing Despite its large number of neurons and key position in the hippocampal formation (Figure 1) , the DG has not been investigated as extensively as the other principal hippocampal areas, the CA3 and CA1. Nevertheless, several functions have been proposed for the DG [15,16], most prominently that it is responsible for the pattern separation of cortical inputs to the hippocampus. The separation, or
doi:10.1016/j.tics.2010.04.003 pmid:20471301 pmcid:PMC2904863 fatcat:q4mmgl67gbcvzjlrxno6qqfu2a