Snapshot: Adult Hippocampal Neurogenesis Krishna C

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1114 Cell SnapShot: Adult Hippocampal Neurogenesis Krishna C. Vadodaria1 and Fred H. Gage1 eray2,21 21 leirIc DOI http://dx.doi.org/10.1016/j.cell.2014.02.029 156, February 27,2014©2014 ElsevierInc. 1Laboratory of Genetics, Salk Institute for Biological Studies, La Jolla, CA 92037, USA

Dentate gyrus circuitry Stages of adult hippocampal neurogenesis Functional hippocampal neurogenesis Mouse Human Nestin GFAP DCX/PSA-NCAM Markers BLBP NeuN SVZ SGZ Sox2 Calretinin Calbindin Tbr2 Prox-1 Olfactory bulb Hippocampus >4 wk 3 wk Cognitive processes Pyramidal neuron Granule cell (newborn) Learning, memory, cognition, 2 wk Granule cell (adult) EC2 pattern separation, emotion Entorhinnal cortex layer 2 neuron CA1 EC3 Entorhinnal cortex 1 wk Computational predictions layer 3 neuron Basket NEUROGENIC NICHE cell Encryption of time in memories SUB 3 days Spatial/temporal pattern separation CA3 EC5 Type 1 Type 2 Memory resolution, orthogonalization

Days after birth 0 7 14 21 28 Fate choice ON DG Developmental Migration Synaptic integration stages Proliferation Immature Mature Radial and horizontal Type 2a and Type 3 granule granule The neurogenic niche type 1 NSCs 2b TAPS neuroblasts neuron neuron Sox2 Hes5 Pax6 NeuroD1 Prox1 Prox1

Transcription OFF Ascl1 Neurog2 Tbr2 Sox3 Sox11 CREB REST Brain activity factors FoxO3 REST TLX FoxG1 FoxG1 Glu GABA Age of neurons Birth 1 week 2–3 weeks 4–6 weeks after 8 weeks Separating similar but not identical patterns Endothelial Dopamine Responsiveness Immediate early gene expression cells ACh Apoptosis Rodent disease models with altered AHN 5HT Excitability Glutamate input Epilepsy GABA response Depolarized Hyperpolarized Neurodegenerative diseases: Type 1 Type 2 GABA input Dendritic Alzheimer’s, Parkinson’s, Huntington’s GABA input Somatic Neuropsychiatric disorders: Schizophrenia, major depression, posttraumatic See online version for legend and references. Differentiation/ stress disorder, autism spectrum disorders Blood vessel Regulators/stage Proliferation survival/maturation Cognitive defects Running, learning, calorie Learning, enriched environment, Behavioral/ restriction, seizure, ischemia activity Mental retardation environment Astrocyte Aging, stress, in ammation Stress Tools for studying adult neurogenesis Serotonin, dopamine, GABA, dopamine, glutamate, Transgenic conditional genetic overexpression/deletion acetylcholine, norepinephrine acetylcholine Focal irradiation Niche-speciﬁc contributors Neurotransmitters GABA Norepinephrine HSV1-TK+Ganciclovir (knockdown AHN) Vasculature, astrocytes, microglia, granule cells, local interneurons Diphtheria toxin (transgenic expression) IGF-1, FGF-2, Shh, BDNF-TrkB, NT3, Bax knockout mice (increase AHN) Growth factors/ Wnt3, VEGF Wnt3, FGF2 Local secreted factors morphogens Retrovirus-based gene delivery (morphology and Wnt, IGF, VEGF, BDNF, IL4, IFNγ, TGFβ, IL-6, IL1-β, IGFBP-6, TNFα Notch single-cell analysis) Modied rabies virus (mapping connectivity) GADD45b, miR-137, MBD1, MECP2, FMRP, DISC1, Molecular mediators DISC1 Cdk5, Klf9, Akt-mTOR Optogenetic control, channel rhodopsin; tetanus Endocrine regulators (Tx factors; toxin; Allatostatin+receptor (activity modulation) Thyroid, estrogen, endorphins, leptin, testosterone, corticosterone epigenetic regulators) FMRP HDACs Carbon-14 dating (human neurogenesis) SnapShot: Adult Hippocampal Neurogenesis Krishna C. Vadodaria1 and Fred H. Gage1 1Laboratory 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 subventricu- lar 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 microenviron- ment. Important contributors within the neurogenic niche include local astrocytes that secrete growth factors, microglia that phagocytose apopototic cells and have neuropro- tective 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 postdivi- sion (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, correspond- ing 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 (Kem- permann, 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.

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