Young and excitable: the function of new neurons in the adult mammalian brain

https://doi.org/10.1016/j.conb.2005.01.018Get rights and content

Adult neurogenesis occurs in most species and is regulated by a wide variety of environmental and pharmacological challenges. The functional integration of neurons generated in the adult was first demonstrated in songbirds more than two decades ago. In the adult mammalian brain, neurons are continuously generated in two structures, the olfactory bulb and the hippocampus. Current evidence suggests that adult-born immature neurons have distinct electrophysiological properties from old neurons, and proposed roles in a variety of functions including olfaction, learning and mood regulation.

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

References (66)

  • A.D. Garcia et al.

    GFAP-expressing progenitors are the principal source of constitutive neurogenesis in adult mouse forebrain

    Nat Neurosci

    (2004)
  • A.F. Schinder et al.

    A hypothesis about the role of adult neurogenesis in hippocampal function

    Physiology (Bethesda)

    (2004)
  • B. Leuner et al.

    Learning enhances the survival of new neurons beyond the time when the hippocampus is required for memory

    J Neurosci

    (2004)
  • S. Liu et al.

    Generation of functional inhibitory neurons in the adult rat hippocampus

    J Neurosci

    (2003)
  • L.S. Overstreet et al.

    A transgenic marker for newly born granule cells in dentate gyrus

    J Neurosci

    (2004)
  • F. Doetsch

    The glial identity of neural stem cells

    Nat Neurosci

    (2003)
  • G.M. Shepherd

    The Synaptic Organization of the Brain

    (2004)
  • M. Yokoi et al.

    Refinement of odor molecule tuning by dendrodendritic synaptic inhibition in the olfactory bulb

    Proc Natl Acad Sci USA

    (1995)
  • S.A. Bayer

    3H-Thymidine-radigraphic studies of neurogenesis in the rat olfactory bulb

    Exp Brain Res

    (1983)
  • J. Altman

    Autoradiographic and histological studies of postnatal neurogenesis. IV. Cell proliferation and migration in the anterior forebrain, with special reference to persisting neurogenesis in the olfactory bulb

    J Comp Neurol

    (1969)
  • M.S. Kaplan et al.

    Population dynamics of adult-formed granule neurons of the rat olfactory bulb

    J Comp Neurol

    (1985)
  • B. Winner et al.

    Long-term survival and cell death of newly generated neurons in the adult rat olfactory bulb

    Eur J Neurosci

    (2002)
  • L. Petreanu et al.

    Maturation and death of adult-born olfactory bulb granule neurons: role of olfaction

    J Neurosci

    (2002)
  • O. Belluzzi et al.

    Electrophysiological differentiation of new neurons in the olfactory bulb

    J Neurosci

    (2003)
  • A. Carleton et al.

    Becoming a new neuron in the adult olfactory bulb

    Nat Neurosci

    (2003)
  • D.D. Wang et al.

    Biophysical properties and ionic signature of neuronal progenitors of the postnatal subventricular zone in situ

    J Neurophysiol

    (2003)
  • D.D. Wang et al.

    GABA depolarizes neuronal progenitors of the postnatal subventricular zone via GABAA receptor activation

    J Physiol

    (2003)
  • A.J. Bolteus et al.

    GABA release and uptake regulate neuronal precursor migration in the postnatal subventricular zone

    J Neurosci

    (2004)
  • K. Kosaka et al.

    How simple is the organization of the olfactory glomerulus? The heterogeneity of so-called periglomerular cells

    Neurosci Res

    (1998)
  • M. Puopolo et al.

    Functional heterogeneity of periglomerular cells in the rat olfactory bulb

    Eur J Neurosci

    (1998)
  • F.S. Corotto et al.

    Odor deprivation leads to reduced neurogenesis and reduced neuronal survival in the olfactory bulb of the adult mouse

    Neuroscience

    (1994)
  • M. Biebl et al.

    Analysis of neurogenesis and programmed cell death reveals a self-renewing capacity in the adult rat brain

    Neurosci Lett

    (2000)
  • G. Gheusi et al.

    Importance of newly generated neurons in the adult olfactory bulb for odor discrimination

    Proc Natl Acad Sci USA

    (2000)

    • Cited by (209)

    • Fluoxetine increased adult neurogenesis is mediated by 5-HT3 receptor

      2023, Neuroscience Letters
      Citation Excerpt :

      Previous studies have analysed the effect of fluoxetine treatment on structural plasticity showing its ability to increase the expression of a key marker of structural plasticity, the Polysialylated form of the Neural Cell Adhesion Molecule (PSA-NCAM), in several brain regions including the hippocampus [13,14]. Some studies have analysed the distribution of the different serotonin receptors in the hippocampus, observing expression of the 5-HT1A receptor in stem cells and neural amplifying progenitors, 5-HT2A receptor was observed in the hilus, mostly associated to glial cells, and, by contrast, 5-HT2B and 5-HT2C receptors were observed in mature granule neurons [22,23]. 5-HT3 receptor expression was described in hilar interneurons [22].

    • Amphetamine exposure alters behaviors, and neuronal and neurochemical activation in the brain of female prairie voles

      2022, Neuroscience

    • Adult brain cytogenesis in the context of mood disorders: From neurogenesis to the emergent role of gliogenesis

      2021, Neuroscience and Biobehavioral Reviews
      Citation Excerpt :

      These new neurons extend their dendrites into the outer molecular layer, projecting their axons to the CA3. Hereafter, newborn neurons integrate into the preexisting neural circuits and perform specific brain functions (Doetsch and Hen, 2005; Ming and Song, 2005). This myriad of roles attributed to astrocytes and their presence throughout the brain makes them key targets, to uncover how neurogenesis can be potentiated and regulated, under physiological or pathological conditions.

    • Combining bioscaffolds and iPSCs in the treatment of neural trauma and Alzheimer’s disease

      2021, Methods in iPSC Technology

    • 3.29 - Functional Architecture of the Olfactory Bulb

      2020, The Senses: A Comprehensive Reference: Volume 1-7, Second Edition

    • Functions of subventricular zone neural precursor cells in stroke recovery

      2019, Behavioural Brain Research
    View all citing articles on Scopus
    View full text
    Copyright © 2005 Elsevier Ltd. All rights reserved.