Dentate gyrus neurogenesis, integration and microRNAs

doi:10.1016/j.bbr.2011.03.048

Behavioural Brain Research

Volume 227, Issue 2, 14 February 2012, Pages 348-355

https://doi.org/10.1016/j.bbr.2011.03.048 Get rights and content

Abstract

Neurons are born and become a functional part of the synaptic circuitry in adult brains. The proliferative phase of neurogenesis has been extensively reviewed. We therefore focus this review on a few topics addressing the functional role of adult-generated newborn neurons in the dentate gyrus. We discuss the evidence for a link between neurogenesis and behavior. We then describe the steps in the integration of newborn neurons into a functioning mature synaptic circuit. Given the profound effects of neural activity on the differentiation and integration of newborn neurons, we discuss the role of activity-dependent gene expression in the birth and maturation of newborn neurons. The differentiation and maturation of newborn neurons likely involves the concerted action of many genes. Thus we focus on transcription factors that can direct large changes to the transcriptome, and microRNAs, a newly-discovered class of molecules that can effect the expression of hundreds of genes. How microRNAs affect the generation and integration of newborn neurons is just being explored, but there are compelling clues hinting at their involvement.

Highlights

► Neurogenesis is enhanced by activity and correlates to behavioral modification. ► The integration of newborn neurons into the synaptic circuitry is stereotyped and well described. ► We are beginning to understand the mechanisms through which large-scale transcriptional changes regulate the process of neurogenesis and integration.

Introduction

In the adult mammalian brain newborn neurons are born and then are integrated into the functioning synaptic circuitry. There are two major neurogenic regions of the brain – the subgranular layer of the dentate gyrus and the subventricular zone adjacent to the lateral ventricles. Newborn neurons of the subgranular layer become granule cells [1] whereas those derived from the subventricular zone migrate via the rostral migratory stream to become granule and periglomerular cells in the olfactory bulb [2]. In this review we discuss the evidence for dentate gyrus neurogenesis, how newborn neurons become integrated into the dentate gyrus, and some of the molecular mechanisms involved in this process. As newborn neurons integrate an array of cellular changes take place, therefore molecules that can orchestrate large-scale changes to the transcriptome such as transcription factors and possibly microRNAs are of particular interest.

Section snippets

Behavior and dentate gyrus neurogenesis

The proliferation of new neurons in the dentate gyrus and their chances of survival are influenced by environmental and endogenous factors, each of which can have profound effects on behavior. However, whether there is a causal relationship between the generation of new neurons and behaviors such as learning tasks is still debated. Two examples of a positive influence on neurogenesis are enriched environment and voluntary exercise or wheel running. Exposure to tunnels, toys, and running wheels

Integration of newborn neurons into the synaptic circuitry

In the adult rat, it has been estimated that 4000–9000 new cells are born every day [44], [45]. Of those surviving one week, about 75% differentiate into neurons [45], [46]. Of these, about half will die within the first month after birth whereas the other half appear to survive at least 6 months [47]. Thus it has been estimated that between 3.75% and 6% of neurons in the dentate gyrus are less than 1 month old [44], [45].

Although earlier studies focused on precursor cell proliferation,

Activity-dependent transcription

As progenitor cells undergo the transition into differentiated neurons and integrate into the synaptic circuitry, there are large-scale changes in gene expression [62]. Thus, there must be many molecular controls governing the stages of neurogenesis and subsequent circuit integration. One transcription factor governing this process, NeuroD1, is expressed in the dentate gyrus during the transition from precursor cells into neurons [63]. Both overexpression and knockdown of NeuroD1 indicate that

Conclusion

There is increasing evidence linking animal behavior to dentate gyrus neurogenesis in the adult animal. This link is exemplified by the ability of enriched environments, learning, and exercise to enhance adult neurogenesis and data suggesting that the behavioral effects of antidepressants are partially mediated by neurogenesis. However, understanding how adult neurogenesis contributes to learning and behavior is complicated by the difficulty in manipulating neurogenesis in isolation. That the

Acknowledgements

This work was supported by T32NS007381, F32MH079548, and a NARSAD Young Investigator Award (BWL), and MH46613 (GLW).

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ReviewDentate gyrus neurogenesis, integration and microRNAs

Abstract

Highlights

Introduction

Section snippets

Behavior and dentate gyrus neurogenesis

Integration of newborn neurons into the synaptic circuitry

Activity-dependent transcription

Conclusion

Acknowledgements

Physiol Behav

Neurosci Lett

Neurosci Lett

Neuroscience

Biol Psychiatry

Brain Behav Immun

Biol Psychiatry

Neuroscience

Eur J Pharmacol

Vitam Horm

Biol Psychiatry

Neuron

Neuron

Brain Res

Brain Res

Neuron

Neuron

Neuron

Curr Opin Neurobiol

Neurobiol Dis

Cell

Cell Stem Cell

Functional maturation of adult-generated granule cells

Hippocampus

Neurogenesis in adult subventricular zone

J Neurosci

Enriched environment and physical activity stimulate hippocampal but not olfactory bulb neurogenesis

Eur J Neurosci

More hippocampal neurons in adult mice living in an enriched environment

Nature

Environmental stimulation of 129/SvJ mice causes increased cell proliferation and neurogenesis in the adult dentate gyrus

Curr Biol

Enriched environment increases neurogenesis in the adult rat dentate gyrus and improves spatial memory

J Neurobiol

Running enhances neurogenesis, learning, and long-term potentiation in mice

Proc Natl Acad Sci USA

Hippocampal neurogenesis is not required for behavioral effects of environmental enrichment

Nat Neurosci

Selective enhancement of spatial learning under chronic psychosocial stress

Eur J Neurosci

Learning enhances adult neurogenesis in the hippocampal formation

Nat Neurosci

Differential effects of learning on neurogenesis: learning increases or decreases the number of newly born cells depending on their birth date

Mol Psychiatry

Dentate gyrus-specific knockdown of adult neurogenesis impairs spatial and object recognition memory in adult rats

Learn Mem

5-Fluorouracil chemotherapy affects spatial working memory and newborn neurons in the adult rat hippocampus

Eur J Neurosci

Effect of ablated hippocampal neurogenesis on the formation and extinction of contextual fear memory

Mol Brain

Ablation of hippocampal neurogenesis impairs contextual fear conditioning and synaptic plasticity in the dentate gyrus

Proc Natl Acad Sci USA

Causal relationship between stressful life events and the onset of major depression

Am J Psychiatry

Adrenal hormones suppress cell division in the adult rat dentate gyrus

J Neurosci

Stress and hippocampal plasticity

Annu Rev Neurosci

Antidepressants and neuroplasticity

Bipolar Disord

Adult brain neurogenesis and psychiatry: a novel theory of depression

Mol Psychiatry

Regulation of adult hippocampal neurogenesis – mplications for novel theories of major depression

Bipolar Disord

Stress-induced changes in cerebral metabolites, hippocampal volume, and cell proliferation are prevented by antidepressant treatment with tianeptine

Proc Natl Acad Sci USA

Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus

J Neurosci

Cell proliferation in adult hippocampus is decreased by inescapable stress: reversal by fluoxetine treatment

Neuropsychopharmacology

Review
Dentate gyrus neurogenesis, integration and microRNAs