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Proposal for a Clinical Study to Test the Effectiveness of a Neurogenic Approach in the Treatment of MSA and Parkinson’s Disease.

John Grinstein Ph.D..
www.jgrinstein.com
Food Biochemistry Research UK

Abstract

New neurons are generated from stem cells in the substantia nigra pars compacta. Previous studies have demonstrated that the entire population of dopaminergic neurons, in the substantia nigra, could be replaced during the lifespan of a mouse.

Following the introduction of the Neurogenic Dietary Program by our research team in 1998, we have undertaken a number of preliminary studies on small groups of MSA and Parkinson’s disease patients. These patients followed our Neurogenic Dietary Program for a period of 1 to 8 years.
These preliminary studies, have consistently demonstrated that neuronal regeneration, reactivation of damaged neurons an/or  neurogenesis, can occur in the adult human brain. Specifically, in the basal ganglia and other areas of the human brain affected in MSA and Parkinson’s Disease.

Introduction

The Brain Basal Ganglia comprises all of the large masses of gray matter at the base of the cerebral hemisphere; currently, the striate body (caudate and lentiform nuclei) and cell groups associated with the striate body, such as the subthalamic nucleus and substantia nigra.

Previous studies have shown the generation of dopaminergic projection neurons, of the type that are lost in Parkinson’s disease, from stem cells in the adult rodent brain and have shown that the rate of neurogenesis is increased after a lesion.

Our previous study comprises the follow up and conclusion from a number of case studies aiming to test whether neurogenesis can be induced in areas of the brain affected in MSA and Parkinson’s disease. These case studies have been reported by the patients’ physicians, caregivers, clinics and hospitals.

A statistical analysis of the results from these case studies, has demonstrated that in 80% of PD and 40% of MSA patients, with an identified chemically induced PD or MSA, the progression of the disease can be placed under control after a few months on The Neurogenic Program. However, in patients suffering from Idiopathic Parkinson’s disease, the progression of the disease is slowed but not halted. Here, the main improvement reported has been a noticeable decrease in the severity of the adverse reactions to the prescribed PD medications.

The present study has been designed to coordinate the results of our neurogenic program with 15 to 30 MSA and PD patients, following a neurogenic protocol for an initial period of 3 months.

Methods

To assess the degree of neuronal regeneration that can be induced through a specific type of neurogenic intervention, the following suggestions are indicated for Parkinson’s disease and MSA patients participating in the study:

1. –Assessment of Disability.
The assessment must be done once a week, in the early hours of the morning. On the day of the assessment, patients must be free of all Parkinson’s disease medication and of any medicinal extract for at least 12 hours. Each participant in the study should organize the video taping of the results from the disability tests performed each week.

2. - Degree of Disability.
To determine the degree of advancement of the disease, the patient and/or the caregiver must find out which movements or activities are the ones which are the most difficult to perform. The ability to perform each task will be evaluated through a PD disability scale, specially designed for this study. This examination measures, for example, the ability to stand up from a chair or get out of bed. It also studies walking, opening doors, dressing, writing, taking a bath, etc.

3. - Delay in the need for the early morning first dose of medication.
This test must be performed once a month and will measure the length of time, in the morning, during which the patient is able to function normally or with sufficient ability, without the need of the first morning dose of medication. This test also needs to be video-taped every time it is performed.

Results and Conclusions
1. - Neurogenic Activation.
An average improvement in the ability to perform the activities specified in the disability scale, and the delay in the need for the first dose of PD medication, will indicate the degree of self-enrichment in brain transmitter biosynthesis that has occurred during sleeping hours. This endogenous enhancement of neurotransmitter biosynthesis, carried out without the use of any PD drug or extract, can only occur as a result of an increase in the number or activity of brain dopaminergic neurons.

2. - Duration of the study.
DNA repair and neuronal regeneration are slow processes therefore; at least a period of 3 months on the Neurogenic Program is required to observe any noteworthy form of reduction in disability.

3. - Relevance of the Results.
Most neurological examinations, testing disability in PD and MSA, are used to establish the ability of a drug to improve mobility, for a limited number of hours, immediately after taking the drug being tested.

Here instead, we test the ability of a treatment to regenerate neurons. In our study, the disability tests are undertaken at a time when no drugs or extracts have been used whatsoever, for at least 12 hours. Therefore, with our treatment, the improvements are brought about, not because of the temporary effect of a drug, but because of the renewed and increased ability of the brain to fire up the secretion of the specific neurotransmitter substances that were deficient and had caused the disease.

An improvement of this kind will have a profound outcome, because it will demonstrate, in a conclusive way, that the progression of neurodegenerative diseases like PD and MSA can be reversed.

If a result of this type can be attained and demonstrated in a larger number of patients, it will become the first clear indication showing that PD and MSA do not necessarily have to be classified as progressive disorders.

Advances in brain neurogenesis research during the last decade, represents the most significant development so far, for the treatment of MSA and Parkinson’s Disease.

The methods used to demonstrate that neurogenesis actually occurs in the human brain, uses the most advanced molecular biology technology available at present.  Unfortunately, the significance of this development, has not yet been brought to the attention of neurologists and physicians in general.

Surprisingly, the outstanding results of this sophisticated research on neuroscience, due to a lack of understanding, has been by a few, erroneously categorized  in the field of complementary medicine.

We have not identified so far, a single publication on Neurogenesis Research,  in Journals of Alternative of Complementary Medicine

In order to enlighten on the subject of human brain neurogenesis we have included d in this newsletter abstracts from 19 references, from a total of more than 500 peer reviewed publications in the last decade, in journals of medicine and neuroscience.

The results on neurogenesis research might have been misinterpreted, because the induction of neurogenesis does not occur through the action of any drug or pharmaceutical chemical, instead the main factors known to induce human brain neurogenesis are:
1.- Enriched Living Environment,  
2.- Learning and Physical Activity
3.- The secretion of Trophic Brain Factors, synthesized  by astroglia and other types of glial cells, in the human brain
4.- Dietary interventions

At the end of the first 5 references, we have included a link to a PDF or Word file that will allow you to view the full text and all graphs of the article.
A PDF file will allow you to view an identical copy of the published article with all its figures and references. The word version is similar to the original.

MAIN REFERENCES AND ABSTRACTS:

MAIN REFERENCE

Scientific American May 1999. Pages 48 to 53
New Nerve Cells for the Adult Brain. Contrary to dogma, the human brain does produce new nerve cells in adulthood. Can our newfound capacity lead to better treatments for neurological diseases?
by Gerd Kempermann and Fred H. Gage

The adult brain, which repairs itself so poorly, might actually harbor great potential for neuronal regeneration. If investigators can learn how to induce existing stem cells to produce useful numbers of functional nerve cells in chosen parts of the brain, that advance could make it possible to ease any number of disorders involving neuronal damage and death; among them Alzheimer’s disease, Parkinson’s disease and disabilities that accompany stroke and trauma.

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ABSTRACTS

PNAS ( Proceedings of the National Academy of Science)
June 24, 2003. Vol 100; No 13.l. Pages 7925-7930
1.- Evidence for neurogenesis in the adult mammalian substantia nigra
Ming Zhao, Stefan Momma, Kioumars Delfani, Marie Carle´n, Robert M. Cassidy, Clas B. Johansson, Hjalmar Brismar, Oleg Shupliakov, Jonas Frise´n, and Ann Marie Janson

Departments of Neuroscience, ell and Molecular Biology, Medical Nobel Institute, and Woman and Child Health, Karolinska Institute, SE-171 77 Stockholm, Sweden
Communicated by Tomas Ho kfelt, Karolinska Institute, Stockholm, Sweden, April 3, 2003 (received for review November 8, 2002)

Abstract
New neurons are generated from stem cells in a few regions of the adult mammalian brain. Here we provide evidence for the generation of dopaminergic projection neurons of the type that are lost in Parkinson’s disease from stem cells in the adult rodent brain and show that the rate of neurogenesis is increased after a lesion.

The number of new neurons generated under physiological conditions in substantia nigra pars compacta was found to be several orders of magnitude smaller than in the granular cell layer of the dentate gyrus of the hippocampus. However, if the rate of neuronal turnover is constant, the entire population of dopaminergic neurons in substantia nigra could be replaced during the lifespan of a mouse. These data indicate that neurogenesis in the adult brain is more widespread than previously thought and may have implications for our understanding of the pathogenesis and treatment of neurodegenerative disorders such as Parkinson’s disease.

Introduction

The majority of neurons are born before or around birth. The first indications of neurogenesis in the adult mammalian brain were presented four decades ago, but it is only during the last years that it has been firmly established that new neurons are generated continuously from stem cells in certain regions of the adult brain in all studied mammals, including man (1–3). The most active neurogenic regions are the dentate gyrus (DG) of the hippocampus and the olfactory bulb. It has been estimated that 10,000 new neurons are added each day to the adult rat DG (4), and the rate of neurogenesis in the olfactory bulb is likely to be severalfold higher. In retrospect, it is quite remarkable that such pronounced processes went unnoticed for so long time, and it raises the question whether there may be a low level of neurogenesis in other brain regions, which has not yet been detected.

In addition to the neurogenesis in the olfactory bulb and DG, low numbers of new neurons have been suggested to be generated in other parts of the hippocampus as well as in the cortex (5–6), although the latter remains controversial (7). Moreover, neurogenesis has been demonstrated in several additional regions in response to injury (8–11). We asked whether new neurons are generated also in the substantia nigra pars compacta (SNpc) of the midbrain, the region where dopamine-producing neurons lost in Parkinson’s disease reside. We here report evidence for a slow turnover of dopaminergic projection neurons in the adult rodent brain, and that neurogenesis is increased after a partial injury.

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Nature Neuroscience
March 1999 Volume 2 Number 3 pp 266 – 270
2.- Running increases cell proliferation and neurogenesis in the adult mouse dentate gyrus.
Henriette van Praag1, Gerd Kempermann1, 2 & Fred H. Gage1
1. Laboratory of Genetics, The Salk Institute for Biological Studies, 10010 N. Torrey Pines Road, La Jolla, California 92037, USA
2. Department of Neurology, University of Regensburg, Universitätsstr. 84, D-93053 Regensburg, Germany

Abstract
Exposure to an enriched environment increases neurogenesis in the dentate gyrus of adult rodents. Environmental enrichment, however, typically consists of many components, such as expanded learning opportunities, increased social interaction, more physical activity and larger housing. We attempted to separate components by assigning adult mice to various conditions: water-maze learning (learner), swim-time-yoked control (swimmer), voluntary wheel running (runner), and enriched (enriched) and standard housing (control) groups. Neither maze training nor yoked swimming had any effect on bromodeoxyuridine (BrdU)-positive cell number. However, running doubled the number of surviving newborn cells, in amounts similar to enrichment conditions. Our findings demonstrate that voluntary exercise is sufficient for enhanced neurogenesis in the adult mouse dentate gyrus.

Selected Sections of this article:

Brain diseases such as Alzheimer's or Parkinson's and injury such as stroke have been considered to result in permanent loss of neurons with no possibility of cellular regeneration. This widely held belief has been challenged recently by extensive evidence that certain brain areas retain the capability to generate new neurons into adulthood in rodents, nonhuman primates and humans. The mechanisms by which these new neurons are generated and could contribute to brain repair are poorly understood. Recent studies indicate that exposure to an enriched environment produces not only a host of structural and functional changes in the brain, but also a significant increase in hippocampal neurogenesis. Enrichment, however, is a complex combination of inanimate and social stimulation, consisting of larger housing and more opportunity for social interaction, physical activity and learning than standard laboratory living conditions. It is not known which of these factors is critical for fostering survival of newborn dentate gyrus granule cells. Here we separated out components of the enriched environment and studied their effects on adult hippocampal cell proliferation and neurogenesis.

Enhanced neurogenesis in enriched animals has been associated with improved spatial memory performance. Conversely, learning itself may be a specific stimulus for neurogenesis. Maze training and enrichment may result in similar neurochemical alterations. Moreover, in food-storing birds, storage and retrieval experiences are correlated with changes in hippocampal size and neurogenesis.

An important confounding variable in assessing the immediate effects of learning on adult hippocampal neurogenesis is motor activity, which could affect cell proliferation, survival or differentiation. Indeed, exercise facilitates recovery from brain injury such as stroke and enhances cognitive function. Moreover, physical activity enhances neurotrophin levels and gene expression. In particular, the level of basic fibroblast growth factor (bFGF), which is important for the survival and differentiation of progenitor cells in vitro and in vivo, is elevated by exercise as well as by spatial learning. We designed our study to investigate the contribution of these variables, learning and physical activity, to generation of new dentate granule cells. Thus, we assigned mice to enriched-environment, hidden-platform water-maze learning, forced-exercise (yoked-swim controls), voluntary-exercise (running wheel) or standard-living (control) conditions.

We show that neither water-maze training nor yoked swimming had any effect on cell proliferation or neurogenesis. Exposure to an enriched environment increased the number of surviving newborn cells but did not affect proliferation, confirming our previous studies in C57BL/6 mice. Voluntary exercise in a running wheel increased cell proliferation, cell survival and net neurogenesis. Our findings suggest that physical activity is sufficient to enhance several aspects of adult hippocampal neurogenesis

Locomotion is highly correlated with the hippocampal theta rhythm. Mice usually make heavy use of their running wheel, going about 20,000–40,000 revolutions per day. Indeed, prolonged, locomotion-induced, synchronous electroencephalogram activity may alter neurochemistry. In turn, changes in neurotransmitter function may cause subtle, but important, changes in theta-rhythm frequency. For example, changes in serotonergic transmission can shift theta-rhythm frequency upward, enhance long-term potentiation as well as memory function, and possibly affect production of newborn granule cells (B.L. Jacobs, P. Tanapat, A.J. Reeves & E. Gould , Soc. Neurosci. Abstr. 24, 796.6 , 1998). In contrast, the length of the period of forced locomotion in our swimming tasks (approximately between 12 and 40 s per day) may be too short to cause long-lasting changes. Alternatively, these tasks may cause stress, counterbalancing the possible effects of activity on survival of BrdU-positive cells.

Maze training may evoke neurochemical events similar to those observed under enrichment conditions. However, in our study, basal rates of proliferation and neurogenesis did not change after one month of training in the Morris water maze. It is possible that two trials per day did not provide sufficient exposure to the task to elicit an effect. Short-term massed training, which induces a transient increase in hippocampal bFGF mRNA, may be more effective. Indeed, another report in this issue shows that Morris water maze training at four trials per day over four days in rats increases the number of surviving BrdU-positive cells. It is noteworthy, though, that some manipulations that increase neurogenesis are not necessarily compatible with learning. Blockade of NMDA receptors, which are normally required for learning, increases adult neurogenesis. In addition, adrenalectomy impairs memory function but elicits cell division in the dentate gyrus. Furthermore, pathological events such as seizures have been reported to stimulate proliferation and neurogenesis. Thus, upregulation of neurogenesis may be a rather general phenomenon, possibly increasing hippocampal storage capacity, whereas a specific learning task may influence existing cells.
In summary, our results demonstrate that voluntary exercise results in increased cell proliferation, survival and neuronal differentiation in the hippocampus of adult mice.

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Nat Neurosci 2(3): 260-5. (1999).
3.- Learning enhances adult neurogenesis in the hippocampal formation.
Gould, E., A. Beylin, et al.

Thousands of hippocampal neurons are born in adulthood, suggesting that new cells could be important for hippocampal function. To determine whether hippocampus-dependent learning affects adult-generated neurons, we examined the fate of new cells labeled with the thymidine analog bromodeoxyuridine following specific behavioral tasks. Here we report that the number of adult-generated neurons doubles in the rat dentate gyrus in response to training on associative learning tasks that require the hippocampus. In contrast, training on associative learning tasks that do not require the hippocampus did not alter the number of new cells. These findings indicate that adult-generated hippocampal neurons are specifically affected by, and potentially involved in, associative memory formation.

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Nature 417(6884): 39-44. (2002).
4.- Astroglia induce neurogenesis from adult neural stem cells.
Song, H., C. F. Stevens, et al.

During an investigation of the mechanisms through which the local environment controls the fate specification of adult neural stem cells, we discovered that adult astrocytes from hippocampus are capable of regulating neurogenesis by instructing the stem cells to adopt a neuronal fate. This role in fate specification was unexpected because, during development, neurons are generated before most of the astrocytes. Our findings, together with recent reports that astrocytes regulate synapse formation and synaptic transmission, reinforce the emerging view that astrocytes have an active regulatory role--rather than merely supportive roles traditionally assigned to them--in the mature central nervous system.

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Nat Med 4(11): 1313-7. (1998)
5.- Neurogenesis in the adult human hippocampus.Eriksson, P. S., E. Perfilieva, et al.

The genesis of new cells, including neurons, in the adult human brain has not yet been demonstrated. This study was undertaken to investigate whether neurogenesis occurs in the adult human brain, in regions previously identified as neurogenic in adult rodents and monkeys. Human brain tissue was obtained postmortem from patients who had been treated with the thymidine analog, bromodeoxyuridine (BrdU), that labels DNA during the S phase. Using immunofluorescent labeling for BrdU and for one of the neuronal markers, NeuN, calbindin or neuron specific enolase (NSE), we demonstrate that new neurons, as defined by these markers, are generated from dividing progenitor cells in the dentate gyrus of adult humans. Our results further indicate that the human hippocampus retains its ability to generate neurons throughout life.

Brain Res Bull 57(6): 809-16. (2002).
6.- Regulation of neurogenesis by neurotrophins in developing spinal sensory ganglia.
Farinas, I., M. Cano-Jaimez, et al.

Neurons and glia in spinal sensory ganglia derive from multipotent neural crest-derived stem cells. In contrast to neural progenitor cells in the central nervous system, neural crest progenitors coexist with differentiated sensory neurons all throughout the neurogenic period. Thus, developing sensory ganglia are advantageous for determining the possible influence of cell-cell interactions in the regulation of precursor proliferation and neurogenesis. Neurotrophins are important regulators of neuronal survival in the developing vertebrate nervous system and, in addition, they appear to influence precursor behavior in vitro. Studies in mice carrying mutations in neurotrophin genes provide a good system in which to analyze essential actions of these factors on the different developing neural populations.


J Neurobiol 51(2): 115-28. . (2002).
7.- The effects of social environment on adult neurogenesis in the female prairie vole.
Fowler, C. D., Y. Liu, et al

In the mammalian brain, adult neurogenesis has been found to occur primarily in the subventricular zone (SVZ) and dentate gyrus of the hippocampus (DG) and to be influenced by both exogenous and endogenous factors. In the present study, we examined the effects of male exposure or social isolation on neurogenesis in adult female prairie voles (Microtus ochrogaster). Newly proliferated cells labeled by a cell proliferation marker, 5-bromo-2'-deoxyuridine (BrdU), were found in the SVZ and DG, as well as in other brain areas, such as the amygdala, hypothalamus, neocortex, and caudate/putamen. Two days of male exposure significantly increased the number of BrdU-labeled cells in the amygdala and hypothalamus in comparison to social isolation. Three weeks later, group differences in BrdU labeling generally persisted in the amygdala, whereas in the hypothalamus, the male-exposed animals had more BrdU-labeled cells than did the female-exposed animals. In the SVZ, 2 days of social isolation increased the number of BrdU-labeled cells compared to female exposure, but this difference was no longer present 3 weeks later. We have also found that the vast majority of the BrdU-labeled cells contained a neuronal marker, indicating neuronal phenotypes. Finally, group differences in the number of cells undergoing apoptosis were subtle and did not seem to account for the observed differences in BrdU labeling. Together, our data indicate that social environment affects neuron proliferation in a stimulus- and site-specific manner in adult female prairie voles.

 

Brain Behav Immun 16(5): 602-9. . (2002).
8.- Adult brain neurogenesis and depression.
Jacobs, B. L

The waning and waxing of neurogenesis in brain areas such as the dentate gyrus is proposed as a key factor in the descent into and recovery from clinical depression, respectively. A decrease in neurogenesis could occur due to genetic factors, stress (especially because of the involvement of adrenal corticoids), and/or a decline in serotonergic neurotransmission. An increase in neurogenesis could be brought about by several factors, but especially those that activate the serotonin 5-HT(1A) receptor. The possible interaction of immune system factors, especially the proinflammatory cytokines, with adult brain neurogenesis is discussed.

Nat Med 4(5): 555-7. (1998).
9.- Closer to neurogenesis in adult humans.
Kempermann, G. and F. H. Gage


Bipolar Disord 4(1): 17-33 (2002).
10.- Regulation of adult hippocampal neurogenesis - implications for novel theories of major depression
Kempermann, G.

Major depression, whose biological origins have been difficult to grasp for decades, might result from a disturbance in neuronal plasticity. New theories begin to consider a fundamental role of adult hippocampal neurogenesis in this loss of plasticity. Could depression and other mood disorders therefore be 'stem cell disorders'? In this review, the potential role of adult hippocampal neurogenesis and of neuronal stem or progenitor cells in depression is discussed with regard to those aspects that are brought up by recent research on how adult hippocampal neurogenesis is regulated. What is known about this regulation today are mosaic pieces and indicates that regulation is complex and is modulated on several levels. Accordingly, emphasis is here laid on those regulatory feedback mechanisms and interdependencies that could help to explain how the pathogenic progression from a hypothesized disruptive cause can occur and lead to the complex clinical picture in mood disorders. While the 'neurogenic theory' of depression remains highly speculative today, it might stimulate the generation of sophisticated working hypotheses, useful animal experiments and the first step towards new therapeutic approaches.

J Neurochem 82(6): 1367-75. (2002).
11.- Evidence that brain-derived neurotrophic factor is required for basal neurogenesis and mediates, in part, the enhancement of neurogenesis by dietary restriction in the hippocampus of adult mice.
Lee, J., W. Duan, et al

To determine the role of brain-derived neurotrophic factor (BDNF) in the enhancement of hippocampal neurogenesis resulting from dietary restriction (DR), heterozygous BDNF knockout (BDNF +/-) mice and wild-type mice were maintained for 3 months on DR or ad libitum (AL) diets. Mice were then injected with bromodeoxyuridine (BrdU) and killed either 1 day or 4 weeks later. Levels of BDNF protein in neurons throughout the hippocampus were decreased in BDNF +/- mice, but were increased by DR in wild-type mice and to a lesser amount in BDNF +/- mice. One day after BrdU injection the number of BrdU-labeled cells in the dentate gyrus of the hippocampus was significantly decreased in BDNF +/- mice maintained on the AL diet, suggesting that BDNF signaling is important for proliferation of neural stem cells. DR had no effect on the proliferation of neural stem cells in wild-type or BDNF +/- mice. Four weeks after BrdU injection, numbers of surviving labeled cells were decreased in BDNF +/- mice maintained on either AL or DR diets. DR significantly improved survival of newly generated cells in wild-type mice, and also improved their survival in BDNF +/- mice, albeit to a lesser extent. The majority of BrdU-labeled cells in the dentate gyrus exhibited a neuronal phenotype at the 4-week time point. The reduced neurogenesis in BDNF +/- mice was associated with a significant reduction in the volume of the dentate gyrus. These findings suggest that BDNF plays an important role in the regulation of the basal level of neurogenesis in dentate gyrus of adult mice, and that by promoting the survival of newly generated neurons BDNF contributes to the enhancement of neurogenesis induced by DR.


J Neurochem 80(3): 539-47. (2002).
12.- Dietary restriction enhances neurotrophin expression and neurogenesis in the hippocampus of adult mice.
Lee, J., K. B. Seroogy, et al.

The adult brain contains small populations of neural precursor cells (NPC) that can give rise to new neurons and glia, and may play important roles in learning and memory, and recovery from injury. Growth factors can influence the proliferation, differentiation and survival of NPC, and may mediate responses of NPC to injury and environmental stimuli such as enriched environments and physical activity. We now report that neurotrophin expression and neurogenesis can be modified by a change in diet. When adult mice are maintained on a dietary restriction (DR) feeding regimen, numbers of newly generated cells in the dentate gyrus of the hippocampus are increased, apparently as the result of increased cell survival. The new cells exhibit phenotypes of neurons and astrocytes. Levels of expression of brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) are increased by DR, while levels of expression of high-affinity receptors for these neurotrophins (trkB and trkC) are unchanged. In addition, DR increases the ratio of full-length trkB to truncated trkB in the hippocampus. The ability of a change in diet to stimulate neurotrophin expression and enhance neurogenesis has important implications for dietary modification of neuroplasticity and responses of the brain to injury and disease.


Nature 405(6789): 951-5. (2000).
13.- Induction of neurogenesis in the neocortex of adult mice.
Magavi, S. S., B. R. Leavitt, et al.

Neurogenesis normally only occurs in limited areas of the adult mammalian brain--the hippocampus, olfactory bulb and epithelium, and at low levels in some regions of macaque cortex. Here we show that endogenous neural precursors can be induced in situ to differentiate into mature neurons, in regions of adult mammalian neocortex that do not normally undergo any neurogenesis. This differentiation occurs in a layer- and region-specific manner, and the neurons can re-form appropriate corticothalamic connections. We induced synchronous apoptotic degeneration of corticothalamic neurons in layer VI of anterior cortex of adult mice and examined the fates of dividing cells within cortex, using markers for DNA replication (5-bromodeoxyuridine; BrdU) and progressive neuronal differentiation. Newly made, BrdU-positive cells expressed NeuN, a mature neuronal marker, in regions of cortex undergoing targeted neuronal death and survived for at least 28 weeks. Subsets of BrdU+ precursors expressed Doublecortin, a protein found exclusively in migrating neurons, and Hu, an early neuronal marker. Retrograde labelling from thalamus demonstrated that BrdU+ neurons can form long-distance corticothalamic connections. Our results indicate that neuronal replacement therapies for neurodegenerative disease and CNS injury may be possible through manipulation of endogenous neural precursors in situ.
 

Brain Res Dev Brain Res 134(1-2): 57-76. (2002).
14.- Induction of neuronal type-specific neurogenesis in the cerebral cortex of adult mice: manipulation of neural precursors in situ.
Magavi, S. S. and J. D. Macklis

Over the past 3 decades, research exploring potential neuronal replacement therapies have focused on replacing lost neurons by transplanting cells or grafting tissue into diseased regions of the brain [Nat. Neurosci. 3 (2000) 67-78]. Over most of the past century of modern neuroscience, it was thought that the adult brain was completely incapable of generating new neurons. However, in the last decade, the development of new techniques has resulted in an explosion of new research showing that neurogenesis, the birth of new neurons, normally occurs in two limited and specific regions of the adult mammalian brain, and that there are significant numbers of multipotent neural precursors in many parts of the adult mammalian brain [Mol. Cell. Neurosci. 19 (1999) 474-486]. Recent findings from our laboratory demonstrate that it is possible to induce neurogenesis de novo in the adult mammalian brain, particularly in the neocortex where it does not normally occur, and that it may become possible to manipulate endogenous multipotent precursors in situ to replace lost or damaged neurons [Nature 405 (2000) 951-955; Neuron 25 (2000) 481-492]. Recruitment of new neurons can be induced in a region-specific, layer-specific, and neuronal type-specific manner, and newly recruited neurons can form long-distance connections to appropriate targets. Elucidation of the relevant molecular controls may both allow control over transplanted precursor cells and potentially allow the development of neuronal replacement therapies for neurodegenerative disease and other central nervous system injuries that do not require transplantation of exogenous cells.


Dev Neurosci 24(1): 59-70. (2002).
15.- Levels of amino acid neurotransmitters during neurogenesis and in histotypic cultures of mouse spinal cord.
Miranda-Contreras, L., P. Benitez-Diaz, et al.

The development of spinal cord interneurons and the formation of interneuronal synaptic connections has received little attention; the most comprehensively studied developing circuit has been the connection between motoneurons and the muscle they innervate. All motoneurons are cholinergic whereas spinal interneurons are mostly glutamatergic, glycinergic or GABAergic neurons. In this study, we show quantitative data, obtained by high-pressure liquid chromatography (HPLC), on the levels of amino acid neurotransmitters during mouse spinal cord neurogenesis, from embryonic day (E) 12 until postnatal day (P) 30. At E12, high levels of glutamate, glycine and taurine were already detected but between E16 and P3, significant increments in their contents were observed, indicating the occurrence of maximum synaptogenesis during this period. Important reductions in their contents were also observed in two stages: between E12-E16 and P3-P7. These results suggest that the apoptotic death of interneurons and motoneurons in the developing brain or the synapse refinement of neural circuitry during maturation reduced the number of synapses, thereby decreasing the levels of neurotransmitters. The contents of these neurotransmitters were also analyzed in primary cultures of mouse spinal cord prepared from embryos between E13 and E19. As deduced from light microscopy, ultrastructural studies, as well as results from HPLC analysis, the cultures derived from E15-E16 embryos showed the highest degree of histotypic features and neurotransmitter contents comparable with those obtained in situ. Although glycine, GABA and taurine levels reached about 80-90% of normal in situ values, the contents of aspartate and glutamate were lower by about 40%, which could be mainly due to deafferentation of both sensory and supraspinal afferent axon terminals. These results indicate that intrinsic synaptic circuits can be maintained in histotypic spinal cord cultures prepared from E15-E16 mouse embryos. Histotypic cultures of the spinal cord will serve as a good model for studies on the pathophysiology of amino-acid-based neurotransmission and repair strategies in many CNS disorders.


Nat Med 6(3): 271-7. (2000).
16.- In vitro neurogenesis by progenitor cells isolated from the adult human hippocampus."
Roy, N. S., S. Wang, et al.

Neurogenesis persists in the adult mammalian hippocampus. To identify and isolate neuronal progenitor cells of the adult human hippocampus, we transfected ventricular zone-free dissociates of surgically-excised dentate gyrus with DNA encoding humanized green fluorescent protein (hGFP), placed under the control of either the nestin enhancer (E/nestin) or the Talpha1 tubulin promoter (P/Talpha1), two regulatory regions that direct transcription in neural progenitor cells. The resultant P/Talpha1:hGFP+ and E/nestin:enhanced (E)GFP+ cells expressed betaIII-tubulin or microtubule-associated protein-2; many incorporated bromodeoxyuridine, indicating their genesis in vitro. Using fluorescence-activated cell sorting, the E/nestin:EGFP+ and P/Talpha1:hGFP+ cells were isolated to near purity, and matured antigenically and physiologically as neurons. Thus, the adult human hippocampus contains mitotically competent neuronal progenitors that can be selectively extracted. The isolation of these cells may provide a cellular substrate for re-populating the damaged or degenerated adult hippocampus.


Nature 410(6826): 372-6. (2001).
17.- Neurogenesis in the adult is involved in the formation of trace memories.
Shors, T. J., G. Miesegaes, et al.

The vertebrate brain continues to produce new neurons throughout life. In the rat hippocampus, several thousand are produced each day, many of which die within weeks. Associative learning can enhance their survival; however, until now it was unknown whether new neurons are involved in memory formation. Here we show that a substantial reduction in the number of newly generated neurons in the adult rat impairs hippocampal-dependent trace conditioning, a task in which an animal must associate stimuli that are separated in time. A similar reduction did not affect learning when the same stimuli are not separated in time, a task that is hippocampal-independent. The reduction in neurogenesis did not induce death of mature hippocampal neurons or permanently alter neurophysiological properties of the CA1 region, such as long-term potentiation. Moreover, recovery of cell production was associated with the ability to acquire trace memories. These results indicate that newly generated neurons in the adult are not only affected by the formation of a hippocampal-dependent memory, but also participate in it.


Nature 415(6875): 1030-4. (2002).
18.- Functional neurogenesis in the adult hippocampus.van Praag, H., A. F. Schinder, et al.

There is extensive evidence indicating that new neurons are generated in the dentate gyrus of the adult mammalian hippocampus, a region of the brain that is important for learning and memory. However, it is not known whether these new neurons become functional, as the methods used to study adult neurogenesis are limited to fixed tissue. We use here a retroviral vector expressing green fluorescent protein that only labels dividing cells, and that can be visualized in live hippocampal slices. We report that newly generated cells in the adult mouse hippocampus have neuronal morphology and can display passive membrane properties, action potentials and functional synaptic inputs similar to those found in mature dentate granule cells. Our findings demonstrate that newly generated cells mature into functional neurons in the adult mammalian brain.
 

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