A septo-temporal molecular gradient of sfrp3 in the dentate gyrus differentially regulates quiescent adult hippocampal neural stem cell activation

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Abstract

Background

A converging body of evidence indicates that levels of adult hippocampal neurogenesis vary along the septo-temporal axis of the dentate gyrus, but the molecular mechanisms underlying this regional heterogeneity are not known. We previously identified a niche mechanism regulating proliferation and neuronal development in the adult mouse dentate gyrus resulting from the activity-regulated expression of secreted frizzled-related protein 3 ( sfrp3) by mature neurons, which suppresses activation of radial glia-like neural stem cells (RGLs) through inhibition of Wingless/INT (WNT) protein signaling.

Results

Here, we show that activation rates within the quiescent RGL population decrease gradually along the septo-temporal axis in the adult mouse dentate gyrus, as defined by MCM2 expression in RGLs. Using in situ hybridization and quantitative real-time PCR, we identified an inverse septal-to-temporal increase in the expression of sfrp3 that emerges during postnatal development. Elimination of sfrp3 and its molecular gradient leads to increased RGL activation, preferentially in the temporal region of the adult dentate gyrus.

Conclusions

Our study identifies a niche mechanism that contributes to the graded distribution of neurogenesis in the adult dentate gyrus and has important implications for understanding functional differences associated with adult hippocampal neurogenesis along the septo-temporal axis.

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Most cited references 46

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Adult hippocampal neurogenesis buffers stress responses and depressive behavior

Jason Snyder, Amélie Soumier, Michelle Brewer … (2011)

Summary Glucocorticoids are released in response to stressful experiences and serve many beneficial homeostatic functions. However, dysregulation of glucocorticoids is associated with cognitive impairments and depressive illness 1, 2 . In the hippocampus, a brain region densely populated with receptors for stress hormones, stress and glucocorticoids strongly inhibit adult neurogenesis 3 . Decreased neurogenesis has been implicated in the pathogenesis of anxiety and depression, but direct evidence for this role is lacking 4, 5 . Here we show that adult-born hippocampal neurons are required for normal expression of the endocrine and behavioral components of the stress response. Using transgenic and radiation methods to specifically inhibit adult neurogenesis, we find that glucocorticoid levels are slower to recover after moderate stress and are less suppressed by dexamethasone in neurogenesis-deficient mice compared with intact mice, consistent with a role for the hippocampus in regulation of the hypothalamic-pituitary-adrenal (HPA) axis 6, 7 . Relative to controls, neurogenesis-deficient mice showed increased food avoidance in a novel environment after acute stress, increased behavioral despair in the forced swim test, and decreased sucrose preference, a measure of anhedonia. These findings identify a small subset of neurons within the dentate gyrus that are critical for hippocampal negative control of the HPA axis and support a direct role for adult neurogenesis in depressive illness.

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Regional dissociations within the hippocampus--memory and anxiety.

D Bannerman, J. N. P. Rawlins, S B McHugh … (2004)

The amnestic effects of hippocampal lesions are well documented, leading to numerous memory-based theories of hippocampal function. It is debatable, however, whether any one of these theories can satisfactorily account for all the consequences of hippocampal damage: Hippocampal lesions also result in behavioural disinhibition and reduced anxiety. A growing number of studies now suggest that these diverse behavioural effects may be associated with different hippocampal subregions. There is evidence for at least two distinct functional domains, although recent neuroanatomical studies suggest this may be an underestimate. Selective lesion studies show that the hippocampus is functionally subdivided along the septotemporal axis into dorsal and ventral regions, each associated with a distinct set of behaviours. Dorsal hippocampus has a preferential role in certain forms of learning and memory, notably spatial learning, but ventral hippocampus may have a preferential role in brain processes associated with anxiety-related behaviours. The latter's role in emotional processing is also distinct from that of the amygdala, which is associated specifically with fear. Gray and McNaughton's theory can in principle incorporate these apparently distinct hippocampal functions, and provides a plausible unitary account for the multiple facets of hippocampal function.

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Adult hippocampal neurogenesis in depression.

Amar Sahay, Rene Hen (2007)

The development of new treatments for depression is predicated upon identification of neural substrates and mechanisms that underlie its etiology and pathophysiology. The heterogeneity of depression indicates that its origin may lie in dysfunction of multiple brain regions. Here we evaluate adult hippocampal neurogenesis as a candidate mechanism for the etiology of depression and as a substrate for antidepressant action. Current evidence indicates that adult hippocampal neurogenesis may not be a major contributor to the development of depression, but may be required for some of the behavioral effects of antidepressants. We next revisit the functional differentiation of the hippocampus along the septo-temporal axis within the context of adult hippocampal neurogenesis and suggest that neurogenesis in the ventral dentate gyrus may be preferentially involved in regulation of emotion. Finally, we speculate on how increased adult hippocampal neurogenesis may modulate dentate gyrus function to confer the behavioral effects of antidepressants.

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Author and article information

Contributors

Guo-li Ming: gming1@jhmi.edu

Journal

Journal ID (nlm-ta): Mol Brain

Journal ID (iso-abbrev): Mol Brain

Title: Molecular Brain

Publisher: BioMed Central (London )

ISSN (Electronic): 1756-6606

Publication date (Electronic): 4 September 2015

Publication date PMC-release: 4 September 2015

Publication date Collection: 2015

Volume: 8

Electronic Location Identifier: 52

Affiliations

[ ]Tsinghua-Peking Joint Center for Life Sciences, Tsinghua University, Beijing, 100084 P.R. China

[ ]Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205 USA

[ ]Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205 USA

[ ]Department of Neurologic Surgery, Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN 55905 USA

[ ]The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205 USA

[ ]Institutes of Brain Science and State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, 200032 China

[ ]Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205 USA

[ ]Present Address: Broad CIRM Center and Department of Stem Cell Biology and Regenerative Medicine, Zilkha Neurogenetic Institute, University of Southern California Keck School of Medicine, Los Angeles, CA 90033 USA

[ ]Present Address: Whitehead Institute for Biomedical Research, Cambridge, MA 02142 USA

Article

Publisher ID: 143

DOI: 10.1186/s13041-015-0143-9

PMC ID: 4559945

PubMed ID: 26337530

SO-VID: 6a269d1e-f952-417b-8089-4453809d0d59

License:

Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 22 February 2015

Date accepted : 25 August 2015

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ScienceOpen disciplines: Neurosciences

Keywords: adult hippocampal neurogenesis,molecular gradient,neural stem cells,septo-temporal axis,wnt,niche

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ScienceOpen disciplines: Neurosciences

Keywords: adult hippocampal neurogenesis, molecular gradient, neural stem cells, septo-temporal axis, wnt, niche

A septo-temporal molecular gradient of sfrp3 in the dentate gyrus differentially regulates quiescent adult hippocampal neural stem cell activation

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Abstract

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Most cited references 46

Adult hippocampal neurogenesis buffers stress responses and depressive behavior

Regional dissociations within the hippocampus--memory and anxiety.

Adult hippocampal neurogenesis in depression.

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