Abstract

Thousands of neurons are born each day in the dentate gyrus (DG), but many of these cells die before reaching maturity. Both death and survival of adult-born neurons are regulated by neuronal activity in the DG. The immediate-early gene (IEG) zif268 appears to be an important mediator of these effects, as its expression can be induced by neural activity and knockout of zif268 impairs survival of adult-born neurons (Richardson et al., 1992; Veyrac et al., 2013). Despite the apparent importance of zif268 for adult neurogenesis, its behavior-induced expression has not been fully characterized in adult-born neurons. Here we characterize behavior-evoked expression of zif268 in mature and newborn dentate granule cells (DGCs). We first quantified zif268 expression in doublecortin-positive (DCX+) immature neurons and in the general granule cell population after brief exposure to a novel environment (NE). In the general granule cell population, zif268 expression peaked 1 h after NE exposure and returned to baseline by 8 h post-exposure. However, in the DCX+ cells, zif268 expression was suppressed relative to home cage for at least 8 h post-exposure. We next asked whether suppression of zif268 in DCX+ immature cells occurs in other behavioral paradigms that recruit the hippocampus. Exposure to Morris water maze (MWM) training, an enriched environment, or a NE caused approximately equal suppression of zif268 expression in DCX+ cells and approximately equal activation of zif268 expression among the general granule cell population. The same behavioral procedures activated zif268 expression in 6-week-old BrdU-labeled adult-born neurons, indicating that zif268 suppression is specific to immature neurons. Finally, we asked whether zif268 suppression varied as a function of age within the DCX+ population, which ranges in age from 0 to approximately 4 weeks. NE exposure had no significant effect on zif268 expression in 2- or 4-week-old BrdU-labeled neurons, but it significantly suppressed zif268 expression in 3-week-old neurons. In summary, behavioral experience transiently activated expression of zif268 in mature granule cells but caused a more long-lasting suppression of zif268 expression in immature, adult-born granule cells. We hypothesize that zif268 suppression inhibits memory-related synaptic plasticity in immature neurons or mediates learning-induced apoptosis of immature adult-born neurons.

Highlights

  • The dentate gyrus (DG) is one of the few brain regions that generates neurons in adulthood (Altman and Das, 1965; Cameron and McKay, 2001)

  • Opposite Effects of Novel Environment Exposure on Zif268 Expression in Immature and Mature Granule Cells First we assessed the time-course of zif268 expression in dentate granule cells (DGCs) after exposure to a novel environment (NE), a manipulation previously demonstrated to robustly induce immediate-early gene (IEG) expression in DGCs (Clark et al, 2012)

  • Our experiments yielded three main results: (1) Behavioral experience induces zif268 expression in mature granule cells but suppresses zif268 expression in immature adultborn granule cells; (2) zif268 suppression in immature granule cells is evoked by multiple types of behavioral experience; and (3) the time-course of behavior-induced changes in zif268 expression differs between young and mature granule cells, with behavior-induced zif268 suppression in immature neurons lasting longer than behavior-induced zif268 expression in mature granule neurons

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Summary

Introduction

The dentate gyrus (DG) is one of the few brain regions that generates neurons in adulthood (Altman and Das, 1965; Cameron and McKay, 2001). The probability of survival is influenced by local neural activity. Behavioral manipulations that stimulate neural activity in the hippocampus can increase the survival probability of newborn neurons, presumably through these mechanisms. The intracellular mechanisms through which newborn cell survival is regulated are not well understood, but a recent study implicates the immediate-early gene (IEG) zif268, known as egr. Zif268 is expressed in immature adultborn neurons, and newborn neuron survival is impaired in mice lacking a functional zif268 gene (Veyrac et al, 2013). Enhancement of newborn neuron survival by hippocampus-dependent learning is not observed in zif268 knockout mice (Veyrac et al, 2013). The data suggest that behavior-induced zif268 expression regulates survival of newborn neurons

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