Young and excitable: the function of new neurons in the adult mammalian brain
Introduction
Stem cells residing in specialized niches in the adult brain continuously generate new neurons. In mammals, neurons are born in two germinal regions, in the subventricular zone (SVZ), which lies adjacent to the lateral wall of the lateral ventricle and generates olfactory bulb neurons, and in the subgranular zone (SGZ) of the hippocampal formation (Figure 1). In both the SVZ and the SGZ, the stem cells for adult neurogenesis are a subset of astrocytes, that is, glial cells classically associated with support functions in the brain [1]. In the SVZ, stem cell astrocytes divide to generate neuroblasts through rapidly dividing, transit-amplifying progenitors. From their site of origin in the SVZ, the newly generated neuroblasts migrate along the rostral migratory stream (RMS) as chains to reach the core of the olfactory bulb, where they turn radially and differentiate into granule and periglomerular inhibitory neurons (Figure 1, Figure 2). In contrast to the long-distance migration of olfactory bulb neurons, in the hippocampus, SGZ astrocytes give rise to intermediate progenitors, which mature locally into granule neurons of the dentate gyrus (Figure 3). The stem cell lineages and microenvironment supporting adult neurogenesis, as well as factors which modulate them, have recently been reviewed elsewhere [1, 2, 3]. Here, we focus on recent insights into the function of adult neurogenesis in mammals. We review the population dynamics and functional properties of new neurons and their potential roles in brain plasticity.
Section snippets
Function of new neurons in the olfactory bulb
Odorants and pheromones are detected by the olfactory system (Figure 1). Volatile odorants in the environment bind to olfactory sensory neurons (OSNs) in the main olfactory epithelium, the axons of which project to the main olfactory bulb (MOB) (Figure 1, Figure 2). OSNs expressing the same receptor converge onto one of two glomeruli in the MOB, where they synapse with the apical dendrites of mitral and tufted cells, the principal olfactory bulb output cells, which in turn project to olfactory
Integration of adult-generated neurons into the olfactory system
Approximately 1% of total olfactory bulb interneurons are added each day in the adult. Almost all become granule cells, with less than 3% differentiating into periglomerular cells [6, 9, 10, 11]. One-half of the adult-generated interneurons die between 15 and 45 days after their birth [10, 11], after they have elaborated complex dendritic morphology and spines. This early wave of cell death is activity-dependent, in contrast to neurogenesis. In mice, in which the cyclic nucleotide gated channel
The role of new olfactory bulb neurons
Olfactory cues are essential for survival, mediating reproductive and maternal behaviors, social cues, exploration, foraging for food and predator detection. Olfactory discrimination and learning and memory have been attributed to changes at reciprocal dendro–dendritic synapses between mitral/tufted cells and interneurons. The continual addition of interneurons, which modulate the spatial and temporal coding of olfactory information through lateral inhibition and synchronization of firing of
Function of the new neurons in the dentate gyrus of the hippocampus
The hippocampus is involved in the learning and memory of explicit information [31]. In addition, the hippocampal formation is very sensitive to stress and decreases in hippocampal volume have been observed in rodents after chronic stress and in humans afflicted with mood and anxiety disorders [32, 33]. The hippocampus extends along the septo–temporal axis (dorso–ventral in rodents and posterior–anterior in primates; Figure 3). Neurons from the entorhinal cortex project to the granule cells of
Electrophysiological properties of young neurons
Single cell recordings of young neurons have revealed that their electrophysiological properties are distinct from those of mature neurons but resemble those of immature neurons formed during development. GABA is an excitatory neurotransmitter for immature neurons [41]. New neurons can be depolarized using currents of very small amplitude, a feature probably attributable to the activity of low threshold calcium channels [42•]. Possibly as a result of this increased excitability, long-term
Impact of the young neurons on behavior
Attempts to assess the functional significance of adult hippocampal neurogenesis on behavior have relied on various ablation strategies. The first such study employed the methylation agent methylazoxymethanol (MAM) that when used at moderate doses kills dividing cells. Gould and co-workers [46, 47] showed that mice treated with MAM and therefore lacking hippocampal neurogenesis displayed a learning impairment in trace fear conditioning, a specific hippocampal-dependent learning paradigm.
Impact of behavior on young neurons
Neurogenesis can be modulated both positively and negatively by environmental factors such as enriched environment, learning and stress (reviewed by Schinder and Gage [56]). Recent behavioral manipulations suggest a link between hippocampal activity and neurogenesis. Specifically, an intense hippocampal-dependent learning paradigm increases the survival of newly formed dentate gyrus neurons [57]. By contrast, a non-hippocampal paradigm had no effect on survival. Furthermore, glutamate can act
Conclusions and future directions
Although great strides have been made into characterizing the integration of new neurons into adult neural circuits, the functional significance of adult neurogenesis remains elusive. New animal models are still needed, such as transgenic mice expressing GFP at various stages of differentiation of adult-generated neurons [63], as well as conditional mutants that enable the selective, inducible and reversible ablation of adult-generated neurons in the SVZ or SGZ [44, 64].
A better understanding
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
We apologize to all whose work we could not cite because of space limitations. R Hen is supported by the National Alliance for Research on Schizophrenia and Depression (NARSAD) and National Institute for Mental Health. F Doetsch is a Packard Foundation Fellow and is partially supported by the Anne and Bernard Spitzer Fund for Cell Replacement Therapy, and the Jerry and Emily Spiegel Laboratory for Cell Replacement Therapies. Thanks to P Riquelme J Richardson-Jones, A Sahay and M Saxe for
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