1114
Cell 156, February 27, 2014 ©2014 Elsevier Inc.
DOI http://dx.doi.org/10.1016/j.cell.2014.02.029
See online version for legend and references.
CA1
DG
EC2
EC5
Glu GABA Dopamine ACh 5HT
Thyroid, estrogen, endorphins, leptin, testosterone, corticosterone
Endocrine regulators
Wnt, IGF, VEGF, BDNF, IL4, IFNγ, TGFβ, IL-6, IL1-β, IGFBP-6, TNFα
Local secreted factors
Vasculature, astrocytes, microglia, granule cells, local interneurons
Niche-specific contributors
Blood vessel
Type 2
Endothelial cells
SUB
EC3
Human
Brain activity
Hippocampus
The neurogenic niche
SGZ
Astrocyte
Type 1
CA3
Pyramidal neuron Granule cell (newborn) Granule cell (adult) Entorhinnal cortex layer 2 neuron Entorhinnal cortex layer 3 neuron
Olfactory bulb
SVZ
Mouse
Dentate gyrus circuitry
BLBP Sox2
7 Fate choice
Molecular mediators (Tx factors; epigenetic regulators)
Growth factors/ morphogens
Neurotransmitters
Behavioral/ environment
Regulators/stage
Somatic
FoxG1
FoxG1 after 8 weeks
GABA IGF-1, FGF-2, Shh, Wnt3, VEGF
FMRP
GADD45b, miR-137, DISC1
HDACs
MBD1, MECP2, FMRP, DISC1, Cdk5, Klf9, Akt-mTOR
Norepinephrine BDNF-TrkB, NT3, Wnt3, FGF2
Serotonin, dopamine, acetylcholine, norepinephrine
Notch
Stress GABA, dopamine, glutamate, acetylcholine
Aging, stress, inflammation
Learning, enriched environment, activity
Hyperpolarized
Immediate early gene expression
4–6 weeks
REST
Prox1
Mature granule neuron
Running, learning, calorie restriction, seizure, ischemia
2–3 weeks
Prox1 CREB
Immature granule neuron
Differentiation/ survival/maturation
1 week
28
>4 wk
Synaptic integration
21
3 wk
Prox-1
Calbindin
NeuN Calretinin
Proliferation
Dendritic
Depolarized
Birth
FoxO3 REST TLX
Age of neurons Responsiveness Apoptosis Excitability Glutamate input GABA response GABA input GABA input
Transcription factors
NeuroD1 Sox3 Sox11
14
Sox2 Hes5 Pax6 Ascl1 Neurog2 Tbr2
Migration
2 wk
Type 3 neuroblasts
Proliferation
0
Type 2
3 days
1 wk
Tbr2
DCX/PSA-NCAM
Radial and horizontal Type 2a and type 1 NSCs 2b TAPS
Developmental stages
Days after birth
Type 1
Basket NEUROGENIC NICHE cell
Markers
GFAP
Nestin
Stages of adult hippocampal neurogenesis
Krishna C. Vadodaria1 and Fred H. Gage1 1 Laboratory of Genetics, Salk Institute for Biological Studies, La Jolla, CA 92037, USA
SnapShot: Adult Hippocampal Neurogenesis
Transgenic conditional genetic overexpression/deletion Focal irradiation HSV1-TK+Ganciclovir (knockdown AHN) Diphtheria toxin (transgenic expression) Bax knockout mice (increase AHN) Retrovirus-based gene delivery (morphology and single-cell analysis) Modified rabies virus (mapping connectivity) Optogenetic control, channel rhodopsin; tetanus toxin; Allatostatin+receptor (activity modulation) Carbon-14 dating (human neurogenesis)
Tools for studying adult neurogenesis
Cognitive defects Mental retardation
Epilepsy Neurodegenerative diseases: Alzheimer’s, Parkinson’s, Huntington’s Neuropsychiatric disorders: Schizophrenia, major depression, posttraumatic stress disorder, autism spectrum disorders
Rodent disease models with altered AHN
Separating similar but not identical patterns
OFF
ON
Encryption of time in memories Spatial/temporal pattern separation Memory resolution, orthogonalization
Computational predictions
Learning, memory, cognition, pattern separation, emotion
Cognitive processes
Functional hippocampal neurogenesis
SnapShot: Adult Hippocampal Neurogenesis Krishna C. Vadodaria1 and Fred H. Gage1 1 Laboratory of Genetics, Salk Institute for Biological Studies, La Jolla, CA 92037, USA Adult neurogenesis, largely described over the last two decades, represents a unique form of structural plasticity. In mammals, life-long neurogenesis occurs in the subventricular zone (SVZ) of the lateral ventricles and in the subgranular zone (SGZ) of the hippocampal dentate gyrus (DG). In the SGZ, neural stem/precursor cells (NSPCs) go through a distinct developmental timeline, giving rise to dividing neuroblasts, which generate immature neurons that must then survive and integrate into the existing DG circuitry. This process is dynamically regulated by extrinsic and intrinsic factors. Recent evidence indicates a role for adult-born neurons in cognitive and emotion-related hippocampal functions, notably pattern separation and anxiety-like behavior. In this SnapShot, we highlight key features of adult hippocampal neurogenesis (AHN), providing an overview of the adult neurogenic niche, developmental stages in AHN, intrinsic and extrinsic regulators, functional roles of adult-born hippocampal neurons, and AHN in humans (Gage et al., 2008). The Neurogenic Niche of the DG Although NSPCs have been isolated from nonneurogenic brain regions, only NSPCs in the SVZ and SGZ generate neurons in vivo, suggesting a key role of the microenvironment. Important contributors within the neurogenic niche include local astrocytes that secrete growth factors, microglia that phagocytose apopototic cells and have neuroprotective effects via the secretion of chemokines and cytokines, as well as the vasculature that enables new neuron production. Panel 1 illustrates the DG cytoarchitechture, with important contributors to the neurogenic niche: vasculature, microglia, and astrocytes, along with the secreted factors. Developmental Stages of Adult Hippocampal Neurogenesis Radial glia-like neural stem/precursor cells residing in the SGZ are considered relatively quiescent. This self-renewing pool of cells asymmetrically divides, giving rise to the transit-amplifying and proliferative pool of neuroblasts. A small percentage of these proliferating cells survive, differentiating into immature neurons. Within 7–10 days postdivision (dpd), cells begin to adopt a neuronal fate and morphology, sending out axons to the hippocampal CA3 region via the mossy fiber tract and extending dendrites into the DG molecular layer, receiving input from the entorhinnal cortex via the perforant path. Dendritic spines appear around 14 dpd and increase up to and beyond 28 dpd, corresponding to a critical maturation period. Early on, GABAergic input promotes excitation and is important for early aspects of neuronal maturation. As neurons mature, they receive synaptic glutamatergic input (3 weeks) and shift to GABA-induced inhibitory responses. During this time, newborn neurons are hyperexcitable, but within 8 weeks, they become indistinguishable from developmentally born DG neurons. Panel 2 illustrates the developmental stages of neurogenesis with the key features highlighted, along with widely used stage-specific markers (Duan et al., 2008). Key Regulators Extrinsic and intrinsic factors regulate AHN. Table 2 in Panel 2 shows notable extrinsic regulators such as running, environmental enrichment, and dietary components (Kempermann, 2011). In contrast, stress, aging, and inflammation negatively impact the process. Intrinsic neuromodulators such as neurotransmitters, growth factors or morphogens, and cell-intrinsic molecular mediators, play a part in modulating adult neurogenesis at basal levels, as well as downstream of extrinsic regulators. Functional Role of Adult-Born Hippocampal Neurons Collective evidence suggests a prominent role in cognitive processes, including learning, memory, and emotion. Experimental data ascribed a specific role for newborn neurons in the orthogonalization functions of the DG (Panel 3) (Aimone et al., 2010). As compared to relatively silenced (hyperpolarized) mature granule cells, the hyperexcitability of newborn neurons during the critical maturational period is thought to enable encoding of a nuanced spatial/temporal context to memory (pattern separation), allowing greater separation of patterns that are closely related in space or time and possibly greater resolution in memories (Panel 3) (Deng et al., 2010). Additional studies suggest that AHN may play a role in modulating anxiety-like behavior via the HPA axis, possibly downstream of stimuli such as stress or antidepressant treatment (Sahay et al., 2011). AHN is widespread in mammalian species and has been shown to occur in humans even into the fifth decade of life (Eriksson et al., 1998; Spalding et al., 2013), raising the possibility that it may play an even greater role in cognition, memory, and emotion-related behaviors in humans. Acknowledgments This work is supported by The Mathers Foundation, JPB Foundation, and MH090258. KCV is currently supported by a Swiss National Science Foundation (SNSF) postdoctoral fellowship. References Aimone, J.B., Deng, W., and Gage, F.H. (2010). Adult neurogenesis: integrating theories and separating functions. Trends Cogn. Sci. 14, 325–337. Deng, W., Aimone, J.B., and Gage, F.H. (2010). New neurons and new memories: how does adult hippocampal neurogenesis affect learning and memory? Nat. Rev. Neurosci. 11, 339–350. Duan, X., Kang, E., Liu, C.Y., Ming, G.L., and Song, H. (2008). Development of neural stem cell in the adult brain. Curr. Opin. Neurobiol. 18, 108–115. Eriksson, P.S., Perfilieva, E., Björk-Eriksson, T., Alborn, A.M., Nordborg, C., Peterson, D.A., and Gage, F.H. (1998). Neurogenesis in the adult human hippocampus. Nat. Med. 4, 1313–1317. Gage, F.H., Kempermann, G., and Song, H. (2008). Adult Neurogenesis (Cold Spring Harbor Monograph Series 52). Kempermann, G. (2011). Seven principles in the regulation of adult neurogenesis. Eur. J. Neurosci. 33, 1018–1024. Sahay, A., Wilson, D.A., and Hen, R. (2011). Pattern separation: a common function for new neurons in hippocampus and olfactory bulb. Neuron 70, 582–588. Spalding, K.L., Bergmann, O., Alkass, K., Bernard, S., Salehpour, M., Huttner, H.B., Boström, E., Westerlund, I., Vial, C., Buchholz, B.A., et al. (2013). Dynamics of hippocampal neurogenesis in adult humans. Cell 153, 1219–1227.
1114.e1 Cell 156, February 27, 2014 ©2014 Elsevier Inc. DOI http://dx.doi.org/10.1016/j.cell.2014.02.029
Cell 156, February 27, 2014 ©2014 Elsevier Inc.
DOI http://dx.doi.org/10.1016/j.cell.2014.02.029
See online version for legend and references.
CA1
DG
EC2
EC5
Glu GABA Dopamine ACh 5HT
Thyroid, estrogen, endorphins, leptin, testosterone, corticosterone
Endocrine regulators
Wnt, IGF, VEGF, BDNF, IL4, IFNγ, TGFβ, IL-6, IL1-β, IGFBP-6, TNFα
Local secreted factors
Vasculature, astrocytes, microglia, granule cells, local interneurons
Niche-specific contributors
Blood vessel
Type 2
Endothelial cells
SUB
EC3
Human
Brain activity
Hippocampus
The neurogenic niche
SGZ
Astrocyte
Type 1
CA3
Pyramidal neuron Granule cell (newborn) Granule cell (adult) Entorhinnal cortex layer 2 neuron Entorhinnal cortex layer 3 neuron
Olfactory bulb
SVZ
Mouse
Dentate gyrus circuitry
BLBP Sox2
7 Fate choice
Molecular mediators (Tx factors; epigenetic regulators)
Growth factors/ morphogens
Neurotransmitters
Behavioral/ environment
Regulators/stage
Somatic
FoxG1
FoxG1 after 8 weeks
GABA IGF-1, FGF-2, Shh, Wnt3, VEGF
FMRP
GADD45b, miR-137, DISC1
HDACs
MBD1, MECP2, FMRP, DISC1, Cdk5, Klf9, Akt-mTOR
Norepinephrine BDNF-TrkB, NT3, Wnt3, FGF2
Serotonin, dopamine, acetylcholine, norepinephrine
Notch
Stress GABA, dopamine, glutamate, acetylcholine
Aging, stress, inflammation
Learning, enriched environment, activity
Hyperpolarized
Immediate early gene expression
4–6 weeks
REST
Prox1
Mature granule neuron
Running, learning, calorie restriction, seizure, ischemia
2–3 weeks
Prox1 CREB
Immature granule neuron
Differentiation/ survival/maturation
1 week
28
>4 wk
Synaptic integration
21
3 wk
Prox-1
Calbindin
NeuN Calretinin
Proliferation
Dendritic
Depolarized
Birth
FoxO3 REST TLX
Age of neurons Responsiveness Apoptosis Excitability Glutamate input GABA response GABA input GABA input
Transcription factors
NeuroD1 Sox3 Sox11
14
Sox2 Hes5 Pax6 Ascl1 Neurog2 Tbr2
Migration
2 wk
Type 3 neuroblasts
Proliferation
0
Type 2
3 days
1 wk
Tbr2
DCX/PSA-NCAM
Radial and horizontal Type 2a and type 1 NSCs 2b TAPS
Developmental stages
Days after birth
Type 1
Basket NEUROGENIC NICHE cell
Markers
GFAP
Nestin
Stages of adult hippocampal neurogenesis
Krishna C. Vadodaria1 and Fred H. Gage1 1 Laboratory of Genetics, Salk Institute for Biological Studies, La Jolla, CA 92037, USA
SnapShot: Adult Hippocampal Neurogenesis
Transgenic conditional genetic overexpression/deletion Focal irradiation HSV1-TK+Ganciclovir (knockdown AHN) Diphtheria toxin (transgenic expression) Bax knockout mice (increase AHN) Retrovirus-based gene delivery (morphology and single-cell analysis) Modified rabies virus (mapping connectivity) Optogenetic control, channel rhodopsin; tetanus toxin; Allatostatin+receptor (activity modulation) Carbon-14 dating (human neurogenesis)
Tools for studying adult neurogenesis
Cognitive defects Mental retardation
Epilepsy Neurodegenerative diseases: Alzheimer’s, Parkinson’s, Huntington’s Neuropsychiatric disorders: Schizophrenia, major depression, posttraumatic stress disorder, autism spectrum disorders
Rodent disease models with altered AHN
Separating similar but not identical patterns
OFF
ON
Encryption of time in memories Spatial/temporal pattern separation Memory resolution, orthogonalization
Computational predictions
Learning, memory, cognition, pattern separation, emotion
Cognitive processes
Functional hippocampal neurogenesis
SnapShot: Adult Hippocampal Neurogenesis Krishna C. Vadodaria1 and Fred H. Gage1 1 Laboratory of Genetics, Salk Institute for Biological Studies, La Jolla, CA 92037, USA Adult neurogenesis, largely described over the last two decades, represents a unique form of structural plasticity. In mammals, life-long neurogenesis occurs in the subventricular zone (SVZ) of the lateral ventricles and in the subgranular zone (SGZ) of the hippocampal dentate gyrus (DG). In the SGZ, neural stem/precursor cells (NSPCs) go through a distinct developmental timeline, giving rise to dividing neuroblasts, which generate immature neurons that must then survive and integrate into the existing DG circuitry. This process is dynamically regulated by extrinsic and intrinsic factors. Recent evidence indicates a role for adult-born neurons in cognitive and emotion-related hippocampal functions, notably pattern separation and anxiety-like behavior. In this SnapShot, we highlight key features of adult hippocampal neurogenesis (AHN), providing an overview of the adult neurogenic niche, developmental stages in AHN, intrinsic and extrinsic regulators, functional roles of adult-born hippocampal neurons, and AHN in humans (Gage et al., 2008). The Neurogenic Niche of the DG Although NSPCs have been isolated from nonneurogenic brain regions, only NSPCs in the SVZ and SGZ generate neurons in vivo, suggesting a key role of the microenvironment. Important contributors within the neurogenic niche include local astrocytes that secrete growth factors, microglia that phagocytose apopototic cells and have neuroprotective effects via the secretion of chemokines and cytokines, as well as the vasculature that enables new neuron production. Panel 1 illustrates the DG cytoarchitechture, with important contributors to the neurogenic niche: vasculature, microglia, and astrocytes, along with the secreted factors. Developmental Stages of Adult Hippocampal Neurogenesis Radial glia-like neural stem/precursor cells residing in the SGZ are considered relatively quiescent. This self-renewing pool of cells asymmetrically divides, giving rise to the transit-amplifying and proliferative pool of neuroblasts. A small percentage of these proliferating cells survive, differentiating into immature neurons. Within 7–10 days postdivision (dpd), cells begin to adopt a neuronal fate and morphology, sending out axons to the hippocampal CA3 region via the mossy fiber tract and extending dendrites into the DG molecular layer, receiving input from the entorhinnal cortex via the perforant path. Dendritic spines appear around 14 dpd and increase up to and beyond 28 dpd, corresponding to a critical maturation period. Early on, GABAergic input promotes excitation and is important for early aspects of neuronal maturation. As neurons mature, they receive synaptic glutamatergic input (3 weeks) and shift to GABA-induced inhibitory responses. During this time, newborn neurons are hyperexcitable, but within 8 weeks, they become indistinguishable from developmentally born DG neurons. Panel 2 illustrates the developmental stages of neurogenesis with the key features highlighted, along with widely used stage-specific markers (Duan et al., 2008). Key Regulators Extrinsic and intrinsic factors regulate AHN. Table 2 in Panel 2 shows notable extrinsic regulators such as running, environmental enrichment, and dietary components (Kempermann, 2011). In contrast, stress, aging, and inflammation negatively impact the process. Intrinsic neuromodulators such as neurotransmitters, growth factors or morphogens, and cell-intrinsic molecular mediators, play a part in modulating adult neurogenesis at basal levels, as well as downstream of extrinsic regulators. Functional Role of Adult-Born Hippocampal Neurons Collective evidence suggests a prominent role in cognitive processes, including learning, memory, and emotion. Experimental data ascribed a specific role for newborn neurons in the orthogonalization functions of the DG (Panel 3) (Aimone et al., 2010). As compared to relatively silenced (hyperpolarized) mature granule cells, the hyperexcitability of newborn neurons during the critical maturational period is thought to enable encoding of a nuanced spatial/temporal context to memory (pattern separation), allowing greater separation of patterns that are closely related in space or time and possibly greater resolution in memories (Panel 3) (Deng et al., 2010). Additional studies suggest that AHN may play a role in modulating anxiety-like behavior via the HPA axis, possibly downstream of stimuli such as stress or antidepressant treatment (Sahay et al., 2011). AHN is widespread in mammalian species and has been shown to occur in humans even into the fifth decade of life (Eriksson et al., 1998; Spalding et al., 2013), raising the possibility that it may play an even greater role in cognition, memory, and emotion-related behaviors in humans. Acknowledgments This work is supported by The Mathers Foundation, JPB Foundation, and MH090258. KCV is currently supported by a Swiss National Science Foundation (SNSF) postdoctoral fellowship. References Aimone, J.B., Deng, W., and Gage, F.H. (2010). Adult neurogenesis: integrating theories and separating functions. Trends Cogn. Sci. 14, 325–337. Deng, W., Aimone, J.B., and Gage, F.H. (2010). New neurons and new memories: how does adult hippocampal neurogenesis affect learning and memory? Nat. Rev. Neurosci. 11, 339–350. Duan, X., Kang, E., Liu, C.Y., Ming, G.L., and Song, H. (2008). Development of neural stem cell in the adult brain. Curr. Opin. Neurobiol. 18, 108–115. Eriksson, P.S., Perfilieva, E., Björk-Eriksson, T., Alborn, A.M., Nordborg, C., Peterson, D.A., and Gage, F.H. (1998). Neurogenesis in the adult human hippocampus. Nat. Med. 4, 1313–1317. Gage, F.H., Kempermann, G., and Song, H. (2008). Adult Neurogenesis (Cold Spring Harbor Monograph Series 52). Kempermann, G. (2011). Seven principles in the regulation of adult neurogenesis. Eur. J. Neurosci. 33, 1018–1024. Sahay, A., Wilson, D.A., and Hen, R. (2011). Pattern separation: a common function for new neurons in hippocampus and olfactory bulb. Neuron 70, 582–588. Spalding, K.L., Bergmann, O., Alkass, K., Bernard, S., Salehpour, M., Huttner, H.B., Boström, E., Westerlund, I., Vial, C., Buchholz, B.A., et al. (2013). Dynamics of hippocampal neurogenesis in adult humans. Cell 153, 1219–1227.
1114.e1 Cell 156, February 27, 2014 ©2014 Elsevier Inc. DOI http://dx.doi.org/10.1016/j.cell.2014.02.029
