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Article: Review: adult neurogenesis contributes to hippocampal plasticity

Toda, Tomohisa / Fred H. Gage

Cell and tissue research. 2018 Sept., v. 373, no. 3

2018

Abstract: Adult hippocampal neurogenesis is the process by which new functional neurons are added to the adult dentate gyrus of the hippocampus. Animal studies have shown that the degree of adult hippocampal neurogenesis is regulated by local environmental cues as ...

Abstract	Adult hippocampal neurogenesis is the process by which new functional neurons are added to the adult dentate gyrus of the hippocampus. Animal studies have shown that the degree of adult hippocampal neurogenesis is regulated by local environmental cues as well as neural network activities. Furthermore, accumulating evidence has suggested that adult hippocampal neurogenesis plays prominent roles in hippocampus-dependent brain functions. In this review, we summarize the mechanisms underlying the regulation of adult hippocampal neurogenesis at various developmental stages and propose how adult-born neurons contribute to structural and functional hippocampal plasticity.
Keywords	adults ; hippocampus ; neurogenesis ; neurons ; neuroplasticity ; plasticity
Language	English
Dates of publication	2018-09
Size	p. 693-709.
Publishing place	Springer Berlin Heidelberg
Document type	Article
Note	Review
ZDB-ID	125067-x
ISSN	1432-0878 ; 0302-766X
ISSN (online)	1432-0878
ISSN	0302-766X
DOI	10.1007/s00441-017-2735-4
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Prediction of response to drug therapy in psychiatric disorders

Shani Stern / Sara Linker / Krishna C. Vadodaria / Maria C. Marchetto / Fred H. Gage

Open Biology, Vol 8, Iss

2018 Volume 5

Abstract: Personalized medicine has become increasingly relevant to many medical fields, promising more efficient drug therapies and earlier intervention. The development of personalized medicine is coupled with the identification of biomarkers and classification ... ...

Abstract	Personalized medicine has become increasingly relevant to many medical fields, promising more efficient drug therapies and earlier intervention. The development of personalized medicine is coupled with the identification of biomarkers and classification algorithms that help predict the responses of different patients to different drugs. In the last 10 years, the Food and Drug Administration (FDA) has approved several genetically pre-screened drugs labelled as pharmacogenomics in the fields of oncology, pulmonary medicine, gastroenterology, haematology, neurology, rheumatology and even psychiatry. Clinicians have long cautioned that what may appear to be similar patient-reported symptoms may actually arise from different biological causes. With growing populations being diagnosed with different psychiatric conditions, it is critical for scientists and clinicians to develop precision medication tailored to individual conditions. Genome-wide association studies have highlighted the complicated nature of psychiatric disorders such as schizophrenia, bipolar disorder, major depression and autism spectrum disorder. Following these studies, association studies are needed to look for genomic markers of responsiveness to available drugs of individual patients within the population of a specific disorder. In addition to GWAS, the advent of new technologies such as brain imaging, cell reprogramming, sequencing and gene editing has given us the opportunity to look for more biomarkers that characterize a therapeutic response to a drug and to use all these biomarkers for determining treatment options. In this review, we discuss studies that were performed to find biomarkers of responsiveness to different available drugs for four brain disorders: bipolar disorder, schizophrenia, major depression and autism spectrum disorder. We provide recommendations for using an integrated method that will use available techniques for a better prediction of the most suitable drug.
Keywords	prediction ; classification ; bipolar disorder ; major depression ; autism spectrum disorder ; schizophrenia ; Biology (General) ; QH301-705.5
Subject code	150
Language	English
Publishing date	2018-05-01T00:00:00Z
Publisher	The Royal Society
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article: Serotonin in psychiatry: in vitro disease modeling using patient-derived neurons

Vadodaria, KrishnaC / Shani Stern / Maria C. Marchetto / Fred H. Gage

Cell and tissue research. 2018 Jan., v. 371, no. 1

2018

Abstract: Several lines of evidence implicate serotonin in the etiology of multiple psychiatric disorders, especially mood disorders, such as major depressive disorder (MDD) and bipolar disorder (BD). Much of our current understanding of biological mechanisms ... ...

Abstract	Several lines of evidence implicate serotonin in the etiology of multiple psychiatric disorders, especially mood disorders, such as major depressive disorder (MDD) and bipolar disorder (BD). Much of our current understanding of biological mechanisms underlying serotonergic alterations in mood disorders comes from animal studies. Innovation in induced pluripotent stem cell and transdifferentiation technologies for deriving neurons from adult humans has enabled the study of disease-relevant cellular phenotypes in vitro. In this context, human serotonergic neurons can now be generated using three recently published methodologies. In this mini-review, we broadly discuss evidence linking altered serotonergic neurotransmission in MDD and BD and focus on recently published methods for generating human serotonergic neurons in vitro.
Keywords	behavior disorders ; etiology ; humans ; mental depression ; neurons ; phenotype ; serotonin
Language	English
Dates of publication	2018-01
Size	p. 161-170.
Publishing place	Springer Berlin Heidelberg
Document type	Article
Note	Review
ZDB-ID	125067-x
ISSN	1432-0878 ; 0302-766X
ISSN (online)	1432-0878
ISSN	0302-766X
DOI	10.1007/s00441-017-2670-4
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Selection of distinct populations of dentate granule cells in response to inputs as a mechanism for pattern separation in mice

Wei Deng / Mark Mayford / Fred H Gage

eLife, Vol

2013 Volume 2

Abstract: The hippocampus is critical for episodic memory and computational studies have predicted specific functions for each hippocampal subregion. Particularly, the dentate gyrus (DG) is hypothesized to perform pattern separation by forming distinct ... ...

Abstract	The hippocampus is critical for episodic memory and computational studies have predicted specific functions for each hippocampal subregion. Particularly, the dentate gyrus (DG) is hypothesized to perform pattern separation by forming distinct representations of similar inputs. How pattern separation is achieved by the DG remains largely unclear. By examining neuronal activities at a population level, we revealed that, unlike CA1 neuron populations, dentate granule cell (DGC) ensembles activated by learning were not preferentially reactivated by memory recall. Moreover, when mice encountered an environment to which they had not been previously exposed, a novel DGC population—rather than the previously activated DGC ensembles that responded to past events—was selected to represent the new environmental inputs. This selection of a novel responsive DGC population could be triggered by small changes in environmental inputs. Therefore, selecting distinct DGC populations to represent similar but not identical inputs is a mechanism for pattern separation.
Keywords	learning and memory ; dentate gyrus ; pattern separation ; CA1 ; hippocampus ; Medicine ; R ; Science ; Q ; Biology (General) ; QH301-705.5
Language	English
Publishing date	2013-03-01T00:00:00Z
Publisher	eLife Sciences Publications Ltd
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: AAV ablates neurogenesis in the adult murine hippocampus

Stephen Johnston / Sarah L Parylak / Stacy Kim / Nolan Mac / Christina Lim / Iryna Gallina / Cooper Bloyd / Alexander Newberry / Christian D Saavedra / Ondrej Novak / J Tiago Gonçalves / Fred H Gage / Matthew Shtrahman

eLife, Vol

2021 Volume 10

Abstract: Recombinant adeno-associated virus (rAAV) has been widely used as a viral vector across mammalian biology and has been shown to be safe and effective in human gene therapy. We demonstrate that neural progenitor cells (NPCs) and immature dentate granule ... ...

Abstract	Recombinant adeno-associated virus (rAAV) has been widely used as a viral vector across mammalian biology and has been shown to be safe and effective in human gene therapy. We demonstrate that neural progenitor cells (NPCs) and immature dentate granule cells (DGCs) within the adult murine hippocampus are particularly sensitive to rAAV-induced cell death. Cell loss is dose dependent and nearly complete at experimentally relevant viral titers. rAAV-induced cell death is rapid and persistent, with loss of BrdU-labeled cells within 18 hr post-injection and no evidence of recovery of adult neurogenesis at 3 months post-injection. The remaining mature DGCs appear hyperactive 4 weeks post-injection based on immediate early gene expression, consistent with previous studies investigating the effects of attenuating adult neurogenesis. In vitro application of AAV or electroporation of AAV2 inverted terminal repeats (ITRs) is sufficient to induce cell death. Efficient transduction of the dentategyrus (DG)– without ablating adult neurogenesis– can be achieved by injection of rAAV2-retro serotyped virus into CA3. rAAV2-retro results in efficient retrograde labeling of mature DGCs and permits in vivo two-photon calcium imaging of dentate activity while leaving adult neurogenesis intact. These findings expand on recent reports implicating rAAV-linked toxicity in stem cells and other cell types and suggest that future work using rAAV as an experimental tool in the DG and as a gene therapy for diseases of the central nervous system should be carefully evaluated.
Keywords	hippocampus ; dentate gyrus ; adult neurogenesis ; adeno-associated virus (AAV) ; neural progenitor cell ; gene therapy ; Medicine ; R ; Science ; Q ; Biology (General) ; QH301-705.5
Subject code	610 ; 572
Language	English
Publishing date	2021-07-01T00:00:00Z
Publisher	eLife Sciences Publications Ltd
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Examining non-LTR retrotransposons in the context of the evolving primate brain

Sara B. Linker / Maria C. Marchetto / Iñigo Narvaiza / Ahmet M. Denli / Fred H. Gage

BMC Biology, Vol 15, Iss 1, Pp 1-

2017 Volume 8

Abstract: Abstract Researchers have long sought to understand the genetic basis of the cognitive differences between primates, with particular focus on the human brain. Although all mutational types have worked in concert with evolutionary forces to generate the ... ...

Abstract	Abstract Researchers have long sought to understand the genetic basis of the cognitive differences between primates, with particular focus on the human brain. Although all mutational types have worked in concert with evolutionary forces to generate the current human brain, in this review we will explore the impact of mobile elements, specifically non-LTR retrotransposons. Non-LTR retrotransposons have contributed coding and regulatory sequences to the genome throughout evolution. During primate evolution there have been multiple waves of LINE retrotransposition as well as the birth of new mobile elements such as the SINEs Alu and SVA and we will explore what kinds of impacts these may have had on the evolving human brain.
Keywords	Biology (General) ; QH301-705.5
Language	English
Publishing date	2017-08-01T00:00:00Z
Publisher	BMC
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Modeling psychiatric disorders through reprogramming

Kristen J. Brennand / Fred H. Gage

Disease Models & Mechanisms, Vol 5, Iss 1, Pp 26-

2012 Volume 32

Abstract: Psychiatric disorders, including autism spectrum disorders and schizophrenia, are extremely heritable complex genetic neurodevelopmental disorders. It is now possible to directly reprogram fibroblasts from psychiatric patients into human induced ... ...

Abstract	Psychiatric disorders, including autism spectrum disorders and schizophrenia, are extremely heritable complex genetic neurodevelopmental disorders. It is now possible to directly reprogram fibroblasts from psychiatric patients into human induced pluripotent stem cells (hiPSCs) and subsequently differentiate these disorder-specific hiPSCs into neurons. This means that researchers can generate nearly limitless quantities of live human neurons with genetic backgrounds that are known to result in psychiatric disorders, without knowing which genes are interacting to produce the disease state in each patient. With these new human-cell-based models, scientists can investigate the precise cell types that are affected in these disorders and elucidate the cellular and molecular defects that contribute to disease initiation and progression. Here, we present a short review of experiments using hiPSCs and other sophisticated in vitro approaches to study the pathways underlying psychiatric disorders.
Keywords	Medicine ; R ; Pathology ; RB1-214
Language	English
Publishing date	2012-01-01T00:00:00Z
Publisher	The Company of Biologists
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article: Generating human serotonergic neurons in vitro: Methodological advances

Vadodaria, Krishna C / Maria C. Marchetto / Jerome Mertens / Fred H. Gage

BioEssays. 2016 Nov., v. 38, no. 11

2016

Abstract: Technologies for deriving human neurons in vitro have transformed our ability to study cellular and molecular components of human neurotransmission. Three groups, including our own, have recently published methods for efficiently generating human ... ...

Abstract	Technologies for deriving human neurons in vitro have transformed our ability to study cellular and molecular components of human neurotransmission. Three groups, including our own, have recently published methods for efficiently generating human serotonergic neurons in vitro. Remarkably, serotonergic neurons derived from each method robustly produce serotonin, express raphe genes, are electrically active, and respond to selective serotonin reuptake inhibitors in vitro. Two of the methods utilize transdifferentiation technology by overexpressing key serotonergic transcription factors. The third and most recent method involves differentiating induced pluripotent stem cells (iPSCs) to serotonergic neurons using developmental patterning cues. In this miniâreview, we briefly describe the developmental programs governing serotonergic specification in vivo and how they have been harnessed to achieve serotonergic differentiation in vitro. We discuss the distinct and overlapping features of the recently published methodologies and their value in the context of in vitro disease modeling. Also see the video abstract here.
Keywords	gene overexpression ; genes ; humans ; induced pluripotent stem cells ; neurons ; serotonin ; transcription (genetics) ; transcription factors
Language	English
Dates of publication	2016-11
Size	p. 1123-1129.
Publishing place	John Wiley & Sons, Ltd
Document type	Article
Note	JOURNAL ARTICLE
ZDB-ID	50140-2
ISSN	1521-1878 ; 0265-9247
ISSN (online)	1521-1878
ISSN	0265-9247
DOI	10.1002/bies.201600127
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Distinct roles of NMDA receptors at different stages of granule cell development in the adult brain

Yangling Mu / Chunmei Zhao / Nicolas Toni / Jun Yao / Fred H Gage

eLife, Vol

2015 Volume 4

Abstract: NMDA receptor (NMDAR)-dependent forms of synaptic plasticity are thought to underlie the assembly of developing neuronal circuits and to play a crucial role in learning and memory. It remains unclear how NMDAR might contribute to the wiring of adult-born ...

Abstract	NMDA receptor (NMDAR)-dependent forms of synaptic plasticity are thought to underlie the assembly of developing neuronal circuits and to play a crucial role in learning and memory. It remains unclear how NMDAR might contribute to the wiring of adult-born granule cells (GCs). Here we demonstrate that nascent GCs lacking NMDARs but rescued from apoptosis by overexpressing the pro-survival protein Bcl2 were deficient in spine formation. Insufficient spinogenesis might be a general cause of cell death restricted within the NMDAR-dependent critical time window for GC survival. NMDAR loss also led to enhanced mushroom spine formation and synaptic AMPAR activity throughout the development of newborn GCs. Moreover, similar elevated synapse maturation in the absence of NMDARs was observed in neonate-generated GCs and CA1 pyramidal neurons. Together, these data suggest that NMDAR operates as a molecular monitor for controlling the activity-dependent establishment and maturation rate of synaptic connections between newborn neurons and others.
Keywords	NMDA receptor ; adult neurogenesis ; spine ; Medicine ; R ; Science ; Q ; Biology (General) ; QH301-705.5
Subject code	571
Language	English
Publishing date	2015-10-01T00:00:00Z
Publisher	eLife Sciences Publications Ltd
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Enhanced functional recovery in MRL/MpJ mice after spinal cord dorsal hemisection.

Sandrine Thuret / Michaela Thallmair / Laura L Horky / Fred H Gage

PLoS ONE, Vol 7, Iss 2, p e

2012 Volume 30904

Abstract: Adult MRL/MpJ mice have been shown to possess unique regeneration capabilities. They are able to heal an ear-punched hole or an injured heart with normal tissue architecture and without scar formation. Here we present functional and histological evidence ...

Abstract	Adult MRL/MpJ mice have been shown to possess unique regeneration capabilities. They are able to heal an ear-punched hole or an injured heart with normal tissue architecture and without scar formation. Here we present functional and histological evidence for enhanced recovery following spinal cord injury (SCI) in MRL/MpJ mice. A control group (C57BL/6 mice) and MRL/MpJ mice underwent a dorsal hemisection at T9 (thoracic vertebra 9). Our data show that MRL/MpJ mice recovered motor function significantly faster and more completely. We observed enhanced regeneration of the corticospinal tract (CST). Furthermore, we observed a reduced astrocytic response and fewer micro-cavities at the injury site, which appear to create a more growth-permissive environment for the injured axons. Our data suggest that the reduced astrocytic response is in part due to a lower lesion-induced increase of cell proliferation post-SCI, and a reduced astrocytic differentiation of the proliferating cells. Interestingly, we also found an increased number of proliferating microglia, which could be involved in the MRL/MpJ spinal cord repair mechanisms. Finally, to evaluate the molecular basis of faster spinal cord repair, we examined the difference in gene expression changes in MRL/MpJ and C57BL/6 mice after SCI. Our microarray data support our histological findings and reveal a transcriptional profile associated with a more efficient spinal cord repair in MRL/MpJ mice.
Keywords	Medicine ; R ; Science ; Q
Subject code	572
Language	English
Publishing date	2012-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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