Environmental Influences on Adult Neurogenesis

The article below is the introduction to the current issue of Neural Plasticity, a special issue on adult neurogenesis - and the articles are open access! Enjoy.

Neural Plasticity
Volume 2014 (2014, Dec 18), Article ID 808643, 3 pages
http://dx.doi.org/10.1155/2014/808643

Editorial

Environmental Control of Adult Neurogenesis: From Hippocampal Homeostasis to Behavior and Disease

Sjoukje D. Kuipers [1,2,3], Clive R. Bramham [1,3], Heather A. Cameron [4], Carlos P. Fitzsimons [5], Aniko Korosi [5], and Paul J. Lucassen [5]

1. Department of Biomedicine, University of Bergen, 5009 Bergen, Norway 2. Department of Biology, University of Bergen, 5020 Bergen, Norway 3. K. G. Jebsen Centre for Research on Neuropsychiatric Disorders, 5009 Bergen, Norway 4. National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA 5. Swammerdam Institute for Life Sciences (SILS), Center for Neuroscience, University of Amsterdam, Science Parc 904, 1098 XH Amsterdam, The Netherlands

Copyright © 2014 Sjoukje D. Kuipers et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

There are few fields in neuroscience that have witnessed a faster development than the field of adult neurogenesis in the past decade. The discovery of stem cells present in the adult brain that give rise to new neurons has raised a lot of interest as it changed current concepts of brain plasticity and possible strategies for brain repair. While neurogenesis, today, has become a well-acknowledged phenomenon, many open questions remain. In this special issue, we have compiled a selection of articles that address several timely topics related to neurogenesis and discuss some of the unresolved questions concerning the functional relevance of adult neurogenesis, its regulation, and its role in the diseased brain.

The history of the field of adult neurogenesis is filled with controversies. By the end of the nineteenth century, largely due to influential scientists like y Cajal [1], it was firmly believed that no new neurons were added to the adult mammalian brain. A central dogma in neuroscience was that brains of mammals remained structurally constant from soon after birth. Neurogenesis was believed to occur only in early development and to rapidly decrease shortly thereafter. In the early 1960s, ground-breaking studies challenged this well-accepted doctrine by reporting the presence of newborn cells in various brain structures of young and adult rats, including the cerebral cortex, hippocampus, and olfactory bulb [2, 3]. These reports, however, were essentially ignored by the scientific community, and it was not until the end of the twentieth century, more than 100 years after the initial formulation of y Cajal’s tenacious dogma, that a novel concept could develop. In the late 1990s, a series of papers initiated an explosion of research on the existence, function, and implications of adult mammalian neurogenesis. Over the years, accumulating evidence has since established adult neurogenesis as a concept, and it is now widely accepted that the adult brain is far from being fixed but is rather a highly plastic organ in which new neurons are indeed added to the existing network throughout life in all mammals including humans. An overview of the controversial history of adult neurogenesis is reviewed in this issue by E. Fuchs and G. Flügge.

Today, we know that neurogenesis occurs in the adult central nervous system throughout life in at least a few discrete regions, like the hippocampus and subventricular zone. From rodents to primates, neurons are continuously produced in the subgranular zone of the hippocampal dentate gyrus. New neurons are also generated in the subventricular zone, the largest germinal zone of the adult mammalian brain, from which they extensively migrate along the rostral migratory stream into the olfactory bulb.

A highly dynamic process, adult neurogenesis is further regulated by several endogenous as well as exogenous factors, such as age, exercise, (early) stress, and disease [4–7]. Environmental stimuli (e.g., diet and stress) and social interactions can greatly affect adult neurogenesis at multiple levels. These include proliferation, fate specification, migration, integration, and survival. In this issue, T. Murphy and colleagues address dietary interventions as effective environmental modifiers of brain plasticity. The authors evaluate the gap in our mechanistic understanding and discuss recent findings from animal and human studies reporting beneficial effects of dietary factors on cognition, mood and anxiety, aging, and Alzheimer’s disease. Finally, they discuss the obstacles involved in harnessing these promising effects of diet on brain plasticity as seen in animal studies, into effective recommendations for humans and interventions to promote brain health. P. Peretto et al. review how the social environment impacts adult olfactory bulb neurogenesis. They discuss how social behaviors related to reproduction promote the proliferation and integration of newborn neurons into functional circuits. These social influences on adult olfactory bulb neurogenesis may ultimately enhance individuals’ fitness, as these “fresh” neurons contribute to critical activities such as parental behavior and partner recognition. Environmental influences on neurogenesis may already occur before conception but also continue during the peripartum period (pregnancy, birth, and lactation) which is characterized by numerous alterations in maternal neuroplasticity and neurogenesis, crucial for the physiological and mental health of the mother.

K. M. Hillerer et al. review common peripartum adaptations in mothers’ physiology and behavior, focusing on changes in neurogenesis and their possible underlying molecular mechanisms. From conception onwards, our physical and social environments trigger a series of physiological responses that modify our later responsivity by acting on the genetic blueprint to adjust developmental and lifelong programming of mental function. Early life represents a particularly sensitive period to the programming influences of environmental factors. Interestingly, the immune system plays an important role in the communication between the human body and its environment. While this holds true during both early development and adulthood, preliminary evidence suggests that early-life activation of the immune system can affect hippocampal neurogenesis and increase the risk for psychiatric disorder development later on. K. Musaelyan et al. further examine the effects associated with such immune system activation during early life, providing evidence to support a neurogenic hypothesis of immune developmental programming.

One of the most important and extensively studied environmental influences on neurogenesis is stress, both acute and chronic. Whereas brief stressful challenges appear beneficial for brain plasticity, allow adaptation, and in some instances even increase neurogenesis, chronic stress exerts deleterious inhibitory effects on plasticity, especially in the hippocampus. These detrimental influences are largely attributed to the elevation of glucocorticoids, through molecular mechanisms that are still not entirely clear. In the final part of their review, E. Fuchs and G. Flügge provide an overview of the influences of stress and stress hormones on the regulation of adult hippocampal neuroplasticity. The deleterious actions of chronic stress on neurogenesis have led to speculations regarding involvement of hippocampal neurogenesis in the aetiology of depression as well as antidepressants’ mode of action. In this issue, P. Rotheneichner et al. analyze the relationship between the various mechanisms of action of electroconvulsive therapy (ECT), a powerful second-line treatment for major depression disorders that strongly stimulates neurogenesis. They explore the intricate interactions between electroconvulsive shocks, hypothalamic-pituitary adrenal axis, neurogenesis, angiogenesis, and microglia activation as well the role of neurogenesis in age-related changes of ECT response in mice. J. L. Pawluski et al. instead explore the effects of fluoxetine, the most common antidepressant in the treatment of mood disorders, on hippocampal neuroplasticity and neurogenesis in female rats. They provide new evidence indicating that different modes of administration (oral versus minipump) of this antidepressant differentially modulate hippocampal neurogenesis in adult female rats.

Although somewhat counterintuitive, neurogenesis is especially responsive to neurodegeneration affecting the hippocampus. In fact, emerging evidence suggests that impaired neurogenesis may represent an early event in the course of various neurodegenerative disorders. From a functional perspective, adult neurogenesis provides new cells which are important for structural plasticity and network function. Newborn neurons in the adult hippocampus and subventricular zone participate in memory processing, mood regulation, and olfaction, functions commonly impaired in subjects suffering from Parkinson’s (PD) or Alzheimer’s disease (AD), two of the most common neurodegenerative disorders in humans. Disturbed regulation of new neuron production may exacerbate network vulnerability and promote early subtle disease manifestations. In this issue, M. Regensburg et al. summarize and interpret existing data on adult neurogenesis in patients with Parkinson’s disease and related animal models. A fundamental process in PD and AD, neuroinflammation, has been implicated in the progression of both diseases. Microglial cells, the major orchestrator of the brain inflammatory response, promote neuroprotective or neurotoxic microenvironments, thus controlling neuroprogenitor cell proliferation and neuronal fate. K. J. Doorn et al. address whether early microglial activation may play a role in the development of hippocampal pathology in Parkinson’s disease and study the proliferative responses occurring in the hippocampus of PD patients. Remarkably, they use double-labeling techniques to show that the proliferation in the PD hippocampus is largely due to microglial cells. A. Sierra et al. explore the interplay between microglia and neurogenesis and discuss both the beneficial and detrimental roles of microglial cells on adult hippocampal neurogenesis regulation, in the context of stress, aging and neurodegeneration, and particularly Alzheimer’s disease. Finally, M. W. Marlatt et al. discuss cell proliferation observed in the hippocampus of AD patients and describe the close proximity of dividing cells to amyloid plaques. Using novel triple immunocytochemical protocols, they further demonstrate that it is not astrocytes but rather the microglia cells, which appear to underlie the proliferative response in the AD hippocampus.

This special issue includes 11 exciting articles covering various aspects of adult neurogenesis, from its physiological regulation to its relevance for the pathophysiology of various brain disorders. We are convinced that this selection of papers will help the readers gain a better understanding of the crucial role of adult neurogenesis in both the healthy and diseased brain.

Sjoukje D. Kuipers
Clive R. Bramham
Heather A. Cameron
Carlos P. Fitzsimons
Aniko Korosi
Paul J. Lucassen

References

    S. R. y Cajal, Degeneration and Regeneration of the Nervous System, translated by R. M. Day from the 1913 Spanish, Oxford University Press, Oxford, UK, 1928.
    J. Altman, “Are new neurons formed in the brains of adult mammals?” Science, vol. 135, no. 3509, pp. 1127–1128, 1962. View at Publisher · View at Google Scholar · View at Scopus
    J. Altman and G. D. Das, “Autoradiographic and histological evidence of postnatal hippocampal neurogenesis in rats,” Journal of Comparative Neurology, vol. 124, no. 3, pp. 319–335, 1965. View at Publisher · View at Google Scholar · View at Scopus
    P. J. Lucassen, E. F. G. Naninck, J. B. van Goudoever, C. Fitzsimons, M. Joels, and A. Korosi, “Perinatal programming of hippocampal structure and function; emerging roles of stress, neurogenesis, epigenetics and early nutrition,” Trends in Neurosciences, vol. 36, no. 11, pp. 621–631, 2013.
    S. D. Kuipers, J. E. Schroeder, and A. Trentani, “Changes in hippocampal neurogenesis throughout early development,” Neurobiology of Aging, 2014. View at Publisher · View at Google Scholar
    P. J. Lucassen, P. Meerlo, A. S. Naylor et al., “Regulation of adult neurogenesis by stress, sleep disruption, exercise and inflammation: implications for depression and antidepressant action,” European Neuropsychopharmacology, vol. 20, no. 1, pp. 1–17, 2010. View at Publisher · View at Google Scholar · View at Scopus
    C. Zhao, W. Deng, and F. H. Gage, “Mechanisms and functional implications of adult neurogenesis,” Cell, vol. 132, no. 4, pp. 645–660, 2008. View at Publisher · View at Google Scholar · View at Scopus

In this recent article from Scientific American, Gary Stix takes a somewhat critical stance on the proliferation of books and video games purportedly explaining or increasing neuroplasticity. On the other hand, he summarizes some basic research that is moving our knowledge of neuroplasticity in the right direction.

The image above comes from Searching for the Mind with John Lieff, M.D.

Neuroplasticity: New Clues to Just How Much the Adult Brain Can Change

By Gary Stix | July 14, 2014

The views expressed are those of the author and are not necessarily those of Scientific American. 

A boy with ambylopia exercises his weaker eye

Popular neuroscience books have made much in recent years of the possibility that the adult brain is capable of restoring lost function or even enhancing cognition through sustained mental or physical activities. One piece of evidence often cited is a 14-year-old study that shows that London taxi drivers have enlarged hippocampi, brain areas that store a mental map of one’s surroundings. Taxi drivers, it is assumed, have better spatial memory because they must constantly distinguish the streets and landmarks of Shepherd’s Bush from those of Brixton.

A mini-industry now peddles books with titles like The Brain that Changes Itself or Rewire Your Brain: Think Your Way to a Better Life. Along with self-help guides, the value of games intended to enhance what is known as neuroplasticity are still a topic of heated debate because no one knows for sure whether or not they improve intelligence, memory, reaction times or any other facet of cognition.

Beyond the controversy, however, scientists have taken a number of steps in recent years to start to answer the basic biological questions that may ultimately lead to a deeper understanding of neuroplasticity. This type of research does not look at whether psychological tests used to assess cognitive deficits can be refashioned with cartoonlike graphics and marketed as games intended to improve mental skills. Rather, these studies attempt to provide a simple definition of how mutable the brain really is at all life stages, from infancy onward into adulthood.

One ongoing question that preoccupies the basic scientists pursuing this line of research is how routine everyday activities—sleep, wakefulness, even any sort of movement—may affect the ability to perceive things in the surrounding environment. One of the leaders in these efforts is Michael Stryker, who researches neuroplasticity at the University of California San Francisco. Stryker headed a group that in 2010 published a study on what happened when mice run on top of a Styrofoam ball floating on air. They found that neurons in a brain region that processes visual signals—the visual cortex—nearly doubled their firing rate when the mice ran on the ball.

The researchers probed further and earlier this year published on a particular circuit that acts as a sort of neural volume control in the visual cortex. It turns out that a certain type of neuron—the vasoactive intestinal peptide neurons (yes, they’re brain cells)— respond to incoming signals from a structure deep within the brain that signals that the animal is on the move. The VIP neurons then issue a call to turn up the firing of cells in the visual cortex. (As always with the brain, it’s not quite that straightforward: the VIP neurons squelch the activity of other neurons whose job is to turn down the “excitatory” neurons that rev up processing of visual information.)

“In the mouse the circuit happens to be hooked in the visual cortex to locomotion which puts it into a high-gain state,” Styker says. “That’s a sensible thing because when you move through the environment, you want the sensory system that tells you about things far away to be more active, to give a larger signal.” The researchers postulate that these neurons may form part of a general-purpose circuit able to detect an animal’s particular behavioral state and then respond to that input by regulating different parts of the cortex that process vision, hearing and other sensory information.

In late June, the investigators took their studies in a new direction with a publication that showed the possible clinical benefits of dialing up their newly identified neural knob. They did so in a study that demonstrated how the circuit that involves the VIP neurons plays a pivotal role in restoring visual acuity in a mouse that had been deprived of sight during a critical period in infancy when the animal must either use it or lose it. They sewed shut one eye in the young mouse for a time—effectively replicating amblyopia, a condition called “lazy eye” in human children that leads to vision loss. They waited until the mice had passed through the critical development stage, took out the stitches, and then switched on the VIP neurons in the behavioral plasticity circuit by having the mice go for a run. That restored vision to normal levels, but only if the animals were also exposed simultaneously to various forms of visual stimuli—either a grating pattern or random noise, similar to a television picture when a station is off the air.

The investigators have plans to see whether the same circuit in humans operates in a similar manner. One cautionary note to brain-game designers: the success in these experiments in eliciting plasticity—restoring vision, that is—was highly sensitive to the particular conditions under which the experiments were carried out. The visual cortex of a running rodent exposed to the grating pattern was better able to distinguish a similar geometric representation later, but not an image of snow-like noise.

What that means is that simply creating a game out of an n-back or Stroop test, or any other psychological assay for that matter, may not work that well in improving memory or self-control unless neuroscientists delve down with the same detailed level of analysis that Stryker and colleagues brought to bear. “We still don’t know what changes in circuitry are responsible for these phenomena of adult plasticity because we don’t have a really solid anatomical grasp of them,” Stryker says. Without the requisite insight, it may be that brain games make you into an ace at taking psychological tests designed to assess cognition, but these same tests may which have little or nothing to do with actually improving mental skills. You may spend all that time on sharpening cognition and end up as nothing more than a highly practiced test taker.

Stay tuned in coming years as brain science tries to sort out the plastic from the inelastic.

Image Source: National Eye Institute
About the Author: Gary Stix, a senior editor, commissions, writes, and edits features, news articles and Web blogs for SCIENTIFIC AMERICAN. His area of coverage is neuroscience. He also has frequently been the issue or section editor for special issues or reports on topics ranging from nanotechnology to obesity. He has worked for more than 20 years at SCIENTIFIC AMERICAN, following three years as a science journalist at IEEE Spectrum, the flagship publication for the Institute of Electrical and Electronics Engineers. He has an undergraduate degree in journalism from New York University. With his wife, Miriam Lacob, he wrote a general primer on technology called Who Gives a Gigabyte? Follow on Twitter @@gstix1.

Dr. Phillippe Goldin is known for his work on mindfulness and the brain. In this older lecture (from 2008) Dr. Goldin talks about why emotions are so important and the meaning of emotional intelligence. He goes on to explain the interplay of emotions and brain activity, including the implications of extreme emotions and how this leads to disease. The lecture unfolds into what happens to us emotionally and mentally when we develop empathy and compassion as a way of life. It's an older lecture, but it's still informative.

The Neuroscience of Emotions

Uploaded on Oct 13, 2008

Google Tech Talks
September 16, 2008


ABSTRACT

The ability to recognize and work with different emotions is fundamental to psychological flexibility and well-being. Neuroscience has contributed to the understanding of the neural bases of emotion, emotion regulation, and emotional intelligence, and has begun to elucidate the brain mechanisms involved in emotion processing. Of great interest is the degree to which these mechanisms demonstrate neuroplasticity in both anatomical and functional levels of the brain.

Speaker: Dr. Phillippe Goldin

Brain Plasticity with Michael Merzenich (Brain Science Podcast 105)

This is the January episode of the Dr. Ginger Campbell's fabulous Brain Science Podcast, #105, featuring a discussion with Michael Merzenich, author of Soft-Wired: How the New Science of Brain Plasticity Can Change Your Life.

One of the books not listed in the "further reading" section is The Mind and the Brain: Neuroplasticity and the Power of Mental Force, by Jeffrey Schwartz, but it too is an excellent book on this topic.

Brain Plasticity with Michael Merzenich (BSP 105)

Posted January 21, 2014 | Ginger Campbell, MD


Michael Merzenich

If you have read anything about brain plasticity you have seen the name Michael Merzenich. Dr. Merzenich is one of the pioneers in this field, having spent over 30 years documenting that the human brain (and that of other mammals) continues to change throughout life. I interviewed Dr. Merzenich several years ago (BSP 54), but the publication of his first book Soft-Wired: How the New Science of Brain Plasticity Can Change Your Life gave us another opportunity to talk about how we can apply these discoveries in our daily lives.

According to Dr. Merzenich,

"No matter how much you've struggled, no matter where you've been in your life, you're in charge of your life going forward. And you have the capacity; you have the resources to change things for the better—always have that capacity. And that's what the book is trying to emphasize. “ (BSP 105)

I found Soft-Wired very compelling because it combines a clear explanation of the science with many stories about real people facing a wide variety of cognitive challenges. The overall tone of the book is very optimistic even though it also considers the way bad choices can contribute to cognitive decline.

Ginger Campbell, MD
BSP 105 Brain Plasticity with Dr. Michael Merzenich (link takes you to the BSP site to listen to the podcast or listen at one of the ways below)

How to get this episode:

• FREE: audio mp3 (click to stream, right click to download)
• Buy Transcript for $1.
• Premium Subscribers now have unlimited access to all old episodes and transcripts.

The most recent 25 episodes of the Brain Science Podcast are still FREE. See the individual show notes for links the audio files.



Related Episodes:

• BSP 10: Introduction to Brain Plasticity.
• BSP 17: Discussion of The Wisdom Paradox: How Your Mind Can Grow Stronger As Your Brain Grows Older by Elkhonon Goldberg.
• BSP 28: Interview with Dr. Norman Doidge, author of The Brain That Changes Itself.
• BSP 33: Interview with Dr. John Ratey, author of Spark: The Revolutionary New Science of Exercise and the Brain.
• BSP 54: Interview with Dr. Michael Merzenich, author of Soft-Wired.
• BSP 87: Interview with Dr. Pam Greenwood, co-author of Nurturing the Older Brain and Mind.

Further Reading:

• Soft-Wired: How the New Science of Brain Plasticity Can Change Your Life by Dr. Michael Merzenich PhD. References for this book can be found at http://www.soft-wired.com/ref/.
• The Brain That Changes Itself: Stories of Personal Triumph from the Frontiers of Brain Science, by Norman Doidge.
• Nurturing the Older Brain and Mind by Pamela M. Greenwood and Raja Parasuraman.
• Spark: The Revolutionary New Science of Exercise and the Brain by John J. Ratey.
• The Wisdom Paradox: How Your Mind Can Grow Stronger As Your Brain Grows Older by Elkhonon Goldberg.
• Train Your Mind, Change Your Brain: How a New Science Reveals Our Extraordinary Potential to Transform Ourselves by Sharon Begley (featured in BSP 10).

In this interesting new article from Frontiers in Neuroscience: Neurogenesis, the authors offer an opinion piece on the limitations and potentials of cellular replacement and cellular plasticity in the context of brain repair - with a special focus on remote plasticity.

Full Citation: 
Quadrato G, Elnaggar MY, and Di Giovanni S. (2014, Feb 12). Adult neurogenesis in brain repair: cellular plasticity vs. cellular replacement. Frontiers in Neuroscience: Neurogenesis; 8:17. doi: 10.3389/fnins.2014.00017

Adult neurogenesis in brain repair: cellular plasticity vs. cellular replacement

Giorgia Quadrato [1], Mohamed Y. Elnaggar [1,2] and Simone Di Giovanni [1,3]

1. Laboratory for NeuroRegeneration and Repair, Center for Neurology, Hertie Institute for Clinical Brain Research, University of Tuebingen, Tuebingen, Germany
2. Graduate School for Cellular and Molecular Neuroscience, University of Tuebingen, Tuebingen, Germany
3. Molecular Neuroregeneration, Division of Brain Sciences, Department of Medicine, Imperial College London, London, UK

Introduction

The last decade has seen an exponential increase in research directed to the field of regenerative medicine aimed at using stem cells in the repair of damaged organs including the brain. The therapeutic use of stem cells for neurological disorders includes either the modulation of endogenous stem cells resident in the brain or the introduction of exogenous stem cells into the brain. The final goal of these attempts is to replace damaged dysfunctional cells with new functional neurons. Nevertheless, there are multiple concerns regarding the therapeutic efficacy of the cellular replacement approach both from endogenous and exogenous sources. Indeed the extensive heterogeneity of neuronal subtypes in the brain makes it difficult to drive stem cells to differentiate to specific neuronal subtypes (Hawrylycz et al., 2012), which is a major requirement for regaining the lost neurological function. Furthermore, the fact that the brain is a very complex 3D structure with highly complex hierarchically organized connections raises a question on whether new neurons formed outside the brain niche can be functionally integrated into the preexisting circuitry. An alternative approach to cellular replacement can be enhancing plasticity in newborn neurons in the neurogenic niche to take over a function of a remote brain region. This strategy may have a yet unknown potential as it overcomes the limitations of the cellular replacement approach. In this opinion paper, we discuss limitations and potential of cellular replacement and cellular plasticity in the context of brain repair with a special focus on remote plasticity.

Cellular Replacement Following Neurological Disorders

Cellular replacement upon brain damage involves two main strategies: (i) pharmacological or genetic modulation of endogenous neural stem cells (NSCs) and (ii) transplantation of exogenous stem cells.

NSCs resident in the adult brain are characterized by the ability to self-renew their own pool through cell proliferation and by the potential to differentiate into the three main cell types of Central nervous system (CNS): neurons, astrocytes, and oligodendrocytes (Gage, 2000).

Active neurogenesis occurs throughout adulthood in primates and various mammals including; rodents, rabbits, monkeys, and humans (Ming and Song, 2005; Martino et al., 2011). New functional neurons are produced under physiological conditions in two neurogenic niches: the subventricular zone (SVZ) in the lateral wall of the lateral ventricles and the subgranular zone (SGZ) of the dentate gyrus (DG) in the hippocampus (Gage, 2000). Moreover, various studies have shown the presence of “local” progenitors residing in various brain regions outside the stem cell niches including; neocortex, cerebellum, striatum, amygdala, substantia nigra, and hypothalamus (Ming and Song, 2005; Martino et al., 2011; Crociara et al., 2013).

Endogenous cellular replacement requires either: (i) increase in the number of newborn neurons in the neurogenic niches as compared to physiological conditions, (ii) migration of new neurons from the neurogenic niches to the damaged area, or (iii) production of the new neurons from local progenitor cells in the vicinity of the damaged brain. Indeed, various reports have demonstrated the occurrence of these three phenomenona following brain damage. Specifically, it has been shown that neurogenesis can be upregulated in neurogenic niches in response to different brain insults including ischemia (Jin et al., 2001; Harry, 2008; Osman et al., 2011), seizures (Parent and Lowenstein, 2002; Smith et al., 2005) and traumatic brain injury (Dash et al., 2001; Harry, 2008). Similarly, migration of newly generated neurons to the site of damage has been reported following brain ischemia (Arvidsson et al., 2002; Thored et al., 2007). Furthermore, neurogenesis following brain insults has been also reported in areas outside the neurogenic niches including the cortex, striatum, hippocampus, subcortical white matter, and corticospinal system (Sohur et al., 2006).

Although the reactive increase in neurogenesis that occurs following injury may indicate an attempt of the damaged brain to self-repair, this response fails in promoting functional recovery and in producing adequate amounts of newborn neurons that can survive and integrate.

Therefore increasing the number of functional neural precursor cells by increasing their survival rate, via pharmacological or genetic modulation, could be a promising strategy for brain repair.

The other cellular replacement strategy, following neurological insults, involves the transplantation of stem cells from exogenous sources into the damaged brain. The most commonly used stem cells are immortalized human neural stem cell lines, mesenchymal stem cells, embryonic stem cells, neuronal progenitors isolated from rodents or humans, and induced pluripotent stem cells (iPSCs) (Liu et al., 2009; Martino et al., 2011). The therapeutic potential of the transplanted stem cells have been validated in various models of diseases and injuries (Shihabuddin et al., 2000; Pluchino et al., 2003; Cummings et al., 2005; Jin et al., 2005). Although varying degrees of functional recovery have been observed, it does not always correlate with the number of newly integrated neurons resulting from the differentiation of the transplanted stem cells. Indeed there is general agreement that transplanted stem cells play various other roles beside cellular replacement in the diseased/damaged brain including neuroprotection and reduction of the inflammatory response via a bystander effect (Martino and Pluchino, 2006; Martino et al., 2011).

Limitation of the Cellular Replacement Approach

Stem cells-based cellular replacement from endogenous or exogenous sources has many limitations including those stemming from the heterogeneity of neuronal subtypes and the highly complex structure of the brain. During the development of the nervous system different types of neurons are produced in highly controlled manner both temporally and spatially. This process is conserved in different species and fate determination of neural progenitor cells result in several postmitotic progenies with distinct phenotypes (Cepko et al., 1996). Importantly, the molecular signature and the transcriptional regulation of different neuronal subtypes vary enormously between different anatomical regions in the brain (Hawrylycz et al., 2012) limiting the differentiation of transplanted stem cells into specific brain regions and neuronal subtypes. One way to overcome this limitation is to develop techniques to direct the differentiation of neural progenitor cells to a specific phenotype. This solution is not easily applicable due to the limited potential of adult neural progenitor cells to differentiate to most neuronal subtypes. Indeed the wide heterogeneity of neuronal subtypes in the central nervous system originates during embryonic development from earlier neural precursors cells.

The functional integration of the newly generated neurons in the existing brain circuits is another major limitation to the cell replacement approach for transplanted cells and for cells produced outside the neurogenic niche. This can be attributed to the fact that the brain is composed of highly entangled set of cells and connections with precise stable spatial organization. The introduction of new neurons in the existing brain structure requires complex processes including: (i) directed migration of the new neurons to the proper site of integration and (ii) directed neurite-growth over long distances, which have not been demonstrated in the adult brain outside the neurogenic niches.

Therefore, the introduction of new neurons directly to the site of damage in the brain either by exogenous or endogenous sources faces major challenges such as differentiation to the correct subtype and integration. This leaves to date the newborn neurons in the neurogenic niches as the only cell type shown to be able to functionally integrate in the adult brain circuitry.

Consequently, one fundamental question is how we can make use of the reactive pool of neural precursor cells residing in the neurogenic niches to take over the function of a remote damaged brain region. In order to address this question it will be important to gain knowledge from the plastic properties of the older brothers of neural stem cells, the postmitotic neurons.

Cellular Plasticity Following Neurological Disorders

Postmitotic neurons exhibit a certain degree of plasticity following brain ischemia and traumatic brain injuries. Indeed, despite the permanent structural damage and cellular loss, functional recovery is observed to a certain extent following brain damage (Chollet et al., 1991; Cao et al., 1998).

Neuroplasticity is defined as the brain's ability to reorganize itself by forming new functional synaptic connections throughout life. Continuous remodeling of neuronal connections and cortical maps in response to our experiences occurs to enable neurons to adapt to new situations (Taupin, 2008). Reorganization of brain networks plays also an important role allowing healthy neurons to compensate for damaged neurons (Sbordone et al., 1995; Cramer and Bastings, 2000; Demeurisse, 2000; Weidner et al., 2001). For instance, this functional compensation is evident following brain injury in the hemisphere contralateral to the lesion site. The contralateral hemisphere is reorganized and new connections are formed between intact neurons to take over some of the functions of the injured hemisphere (Takatsuru et al., 2009, 2011). Recent advances in functional imaging, e.g., positron emission tomographic and functional magnetic resonance imaging have indeed confirmed the occurrence of this reorganization (Calautti and Baron, 2003; Butefisch et al., 2006; Crosson et al., 2007; Ward, 2007). There is also clinical evidence that reorganization of the somatosensory cortex contralateral to the lesion site in stroke patients plays important role in the compensation of impaired functions (Chollet et al., 1991; Cao et al., 1998). Furthermore reorganization of brain networks has been reported in patients suffering from aphasia (speechlessness) in which the non-dominant right-hemisphere takes over the function of Wernicke's area (speech center normally present in the dominant left hemisphere) (Weiller et al., 1995).

Despite the consistent reports confirming circuitry reorganization in the brain following injury, the molecular and electrophysiological mechanisms controlling this fascinating phenomenon remain still elusive.

Another unexplored aspect of compensatory plasticity includes the question of whether newborn neurons are involved in the reorganization of brain circuitry that occurs following brain injury. However, because of their peculiar cellular and plastic properties, we believe that newborn neurons in the neurogenic niches are important players in this phenomenon.

Indeed it has been shown that newly generated neurons, as compared to mature granule cells, exhibit a lower threshold for induction of LTP (Schmidt-Hieber et al., 2004). This property, facilitating synaptic plasticity, makes young neurons ideally suited to adapt to the reorganization of brain networks and to take over a function that is normally played by other brain regions.

Importantly, following brain ischemia, newborn neurons react with a plastic response enhancing not only their proliferation rate but also exhibiting increased spine density and dendritic complexity as compared to resident hippocampal neurons (Liu et al., 1998; Niv et al., 2012).

So far it has not been investigated whether this plastic response includes changes in the pattern of brain connectivity of newborn neurons. However the recent application of retrograde monosynaptic tracing to study the connectome of the newly generated neurons (Deshpande et al., 2013) in neurogenic niches provides us with tools to address this important question.

The next step following the demonstration of the involvement of newborn neurons in brain reorganization would be to increase their plastic potential by increasing their number. This may be achieved, taking advantage of the increase in the proliferation rate of NPCs that normally occurs upon brain damage (Liu et al., 1998), by increasing their integration and survival rate.

Previous work has described a number of intrinsic and extrinsic factors required for newborn neurons survival (see Table 1). The modulation of such factors, important to regulate the survival and integration of newborn neurons in physiological condition, may become even more crucial following brain damage. Recently, cytoskeleton regulators such as Rho kinase and Rho-GTPases have been included among the most important intrinsic regulators of the adult neurogenesis (Christie et al., 2013; Vadodaria and Jessberger, 2013; Vadodaria et al., 2013). Interestingly, the modulation of the Rho-Pathway is also critical for growth cone collapse, neurite outgrowth and regeneration after neurotrauma in the CNS (McKerracher et al., 2012), making it an ideal target to enhance both cellular plasticity and survival. In this perspective the identification of molecular mechanisms that can be targeted to increase both the number and the plasticity of newborn neurons can increase the probability of functional reorganization of brain networks following injury.

TABLE 1

Table 1. Factors required for newborn neurons survival and integration in physiological conditions. 

Conclusions

The vast amount of information that have been gathered in the recent years about the use of neural stem cells in brain repair indicates that cellular replacement alone cannot lead to effective restoration of function due to the complex anatomical, histological, and functional organization of the brain.

In this perspective, due to their plastic potential and their innate ability to functionally integrate in brain circuits, newborn neurons produced inside the neurogenic niches are the most suitable targets for brain repair. Moreover, the importance of neurogenesis-related plasticity is further supported by the finding that hippocampal neurogenesis occurs in humans throughout adulthood with a modest decline during aging (Spalding et al., 2013). Indeed, the central location of the hippocampus in the medial temporal lobe in the human brain (Haines, 2004) may allow the communication of newborn neurons to various brain circuits.

In this scenario strategies that enhance the survival and the plasticity of newly generated neurons in the dentate gyrus may be the most effective to foster the functional reorganization of brain circuits following injury.

Acknowledgments

We thank the Hertie Foundation and the DFG (to Simone Di Giovanni) and the Fortüne Program of the University of Tübingen (to Giorgia Quadrato) for financial support. We apologize to authors whose original papers could not be cited due to space constraints.

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