Effects of Voluntary Physical Rehabilitation on Neurogenesis In SVZ And Functional Recovery After Ischemic Stroke

So the advisors to this dissertation candidate should followup with human research testing this out. That is the minimum a competent university department should be doing. 

Effects of Voluntary Physical Rehabilitation on Neurogenesis In SVZ And Functional Recovery After Ischemic Stroke

 

Author InfoBalakrishnan, Anuranjani

ORCID® Identifier

http://orcid.org/0000-0002-4407-5165

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http://rave.ohiolink.edu/etdc/view?acc_num=wright1537186443944433

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Year and Degree

2018, Master of Science (MS), Wright State University, Microbiology and Immunology.

Abstract

Stroke is the leading cause of long-term disability and 87% of all strokes are due to ischemic strokes. In this current study, we examined whether voluntary physical rehabilitation can influence neurogenesis (measured by Doublecortin) in the subventricular zone and show improved motor functional recovery in 10-12 month female rats after ischemia. We saw a significant increase in the neurogenesis (measured by doublecortin) of all three regions (anterior, middle and posterior) of SVZ in the rehab animals compared to control group when using a two-way variance ANOVA test, although we were unable to see significant differences in paired t-tests of similar regions for control and rehab animals. The control animals showed a significant increase in contralateral functional recovery of 56% with rehab animals displaying a recovery of 23%. These findings suggest that the physical rehabilitation showed increased neurogenesis in the SVZ but did not translate to greater contralateral functional recovery.

Committee

Adrian M. Corbett, Ph.D. (Committee Chair)
Nancy J. Bigley, Ph.D. (Committee Member)
Debra Ann Mayes, Ph.D. (Committee Member)

Pages

88 p.

Subject Headings

Immunology; Neurobiology; Neurosciences; Physiology; Rehabilitation

Keywords

neurogenesis; doublecortin; rehabilitation; ischemic stroke; ipsilateral recovery; contralateral recovery; Montoya Staircase

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Copyright Info© 2018, some rights reserved. Effects of Voluntary Physical Rehabilitation on Neurogenesis In SVZ And Functional Recovery After Ischemic Stroke by Anuranjani Balakrishnan is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License. Based on a work at etd.ohiolink.edu.
This open access ETD is published by Wright State University and OhioLINK.

Intraventricular Infusion of a Low Fraction of Serum Enhances Neurogenesis and Improves Recovery in a Rodent Stroke Model

Is this interesting enough to be proposed for human clinical trials? I want to know whom in the world can answer that question and then follow thru with the research to prove it one way or another. But that won't occur because we have no stroke strategy or stroke leaders at all.
http://www.sciencedirect.com/science/article/pii/S0304394015302573

• Yi-Chen Li^a,
• Li-Kai Tsai^{b, ,} ,
• Tai-Horng Young^{a, ,}

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doi:10.1016/j.neulet.2015.11.020

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Highlights

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A serum fraction (100K) was easily derived from serum.

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100K/bFGF enhanced cell proliferation at SVZ area and infarcted brain.

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100K/bFGF increased the number of MAP-2 cells at infarcted brain in MCAO rat.

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100K/bFGF improved animals' motor coordination of MCAO rat.

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Abstract

Enhancing endogenous neurogenesis is a potential therapeutic strategy in stroke treatment. We have previously domonstrated that treatment with a fraction of serum with molecular weight of less than 100kDa (100K) combined with bFGF promoted neurogenesis of cultured stem and progenitor cells (NSPCs). In this study, we further evaluated the efficacy of intraventricular administration of 100K with bFGF (100K/bFGF) in a rat model of transient middle cerebral artery occlusion (MCAO). Rats administered 100K/bFGF on post-stroke day 1 exhibited a higher number of Ki67 and Nestin immunoreactive cells at the subventricular zone (SVZ) area and in the infarcted brain, indicating promotion of NSPCs proliferation. The 100K/bFGF treatment also predominantly increased the number of MAP-2 immunoreactive cells rather than GFAP immunoreactive cells at the SVZ area and in the infarcted regions, implying that 100K/bFGF dominated NSPCs differentiating into neurons rather than astrocytes. Importantly, treatment with 100K/bFGF significantly improved the animals' motor coordination. These findings demonstrated that treatment with a low serum fraction and bFGF benefited ischemic stroke likely through promotion of the proliferation and neuronal differentiation of endogenous NSPCs.

IL-10 regulates adult neurogenesis by modulating ERK and STAT3 activity

This seems to be good but WHO is going to follow up with translational research that creates dosages/application methods and timeframes for survivors?
http://journal.frontiersin.org/article/10.3389/fncel.2015.00057/full?

Leticia Pereira^1,2, Miriam Font-Nieves^1,2, Chris Van den Haute^3,4, Veerle Baekelandt³, Anna M. Planas^1,2 and Esther Pozas^1,2*

• ¹Unit of Brain Ischemia, Institut d’Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain
• ²Department of Brain Ischemia and Neurodegeneration, Institute of Biomedical Research of Barcelona, Consejo Superior de Investigaciones Científicas, Barcelona, Spain
• ³Laboratory for Neurobiology and Gene Therapy, Faculty of Medicine, KU Leuven, Leuven, Belgium
• ⁴Leuven Viral Vector Core, KU Leuven, Leuven, Belgium

The adult subventricular zone (SVZ) contains Nestin+ progenitors that differentiate mainly into neuroblasts. Our previous data showed that interleukin-10 (IL-10) regulates SVZ adult neurogenesis by up-regulating the expression of pro-neural genes and modulating cell cycle exit. Here we addressed the specific mechanism through which IL-10 carries out its signaling on SVZ progenitors. We found that, in vitro and in vivo, IL-10 targets Nestin+ progenitors and activates the phosphorylation of ERK and STAT3. The action of IL-10 on Nestin+ progenitors is reversed by treatment with a MEK/ERK inhibitor, thus restoring neurogenesis to normal levels. Silencing STAT3 expression by lentiviral vectors also impaired neurogenesis by blocking the effects of IL-10. Our findings unveil ERK and STAT3 as effectors of IL-10 in adult SVZ neurogenesis.

Introduction

Postnatal neurogenesis takes place in restricted regions or niches in the adult brain. The SVZ lining the LVs is one of the main neurogenenic niches in the adult brain. The niche is composed by supporting cells, the vasculature and three progenitor cell types: slow-cycling glial-like NSCs or type B cells (GFAP+); TACs or type C cells (Ki67+, and Mash1+), and the more differentiated neuroblasts (type A cells; PSA-NCAM+; DCX+; TUBB3+) that migrate over long distances through the RMS to reach the olfactory bulb, where they finally become mainly GABAergic interneurons (Lois and Alvarez-Buylla, 1994; Doetsch and Alvarez-Buylla, 1996; Doetsch et al., 1997; Merkle et al., 2004; Ihrie et al., 2011). Nestin labels type B and C cells and a sub-population of immature committed neuroblasts (Doetsch et al., 1997; Perez-Asensio et al., 2013). The SVZ niche is unique in spatial localization and molecular characteristics. The relationships between the different cell types, the cerebrospinal fluid (CSF), and the vasculature modulate the molecular signals that regulate self-renewal, proliferation, the identity of VZ-SVZ-derived progeny, the integration of some intrinsic mechanisms (Guillemot, 2007; Lim et al., 2009; Ihrie et al., 2011).

Interleukin-10 (IL-10) is a general anti-inflammatory molecule that contributes to maintaining the pro- and anti-inflammatory balance in the body (Pestka et al., 2004; Saraiva and O’Garra, 2010; Ouyang et al., 2011). Recently, we demonstrated a new physiological role of this cytokine as a relevant factor that regulates postnatal neurogenesis. We deciphered how IL-10 targets the population of Nestin+ progenitors located in the dorsal SVZ, where it regulates the expression of undifferentiated neural progenitor markers, cell cycle activity, and the production of new neuroblasts (Perez-Asensio et al., 2013).

Here we aimed to identify the specific intracellular mechanism through which IL-10 acts specifically on adult Nestin+ progenitors. Our results show that IL-10 regulates the activation of ERK and STAT3 in Nestin+ progenitors and that this activity is required for IL-10 to exert its actions on neural progenitors.

Full article at link.

Neurogenesis is enhanced by stroke in multiple new stem cell niches along the ventricular system at sites of high BBB permeability

What is your doctor doing with this knowledge to update your stroke protocols and get you closer to 100% recovery? Do not let your doctor deflect the question, your doctor is supposed to help you recover, demand that they do that.
http://www.sciencedirect.com/science/article/pii/S0969996114003623

• Ruihe Lin^a,
• Jingli Cai^a,
• Cody Nathan^a,
• Xiaotao Wei^a,
• Stephanie Schleidt^a,
• Robert Rosenwasser^b,
• Lorraine Iacovitti^{a, ,}

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doi:10.1016/j.nbd.2014.11.016

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Under a Creative Commons license

  Open Access

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Highlights

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Stem cell niches exist along the entire ventricular system in the adult rat brain.

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Stroke induces widespread neurogenesis and gliogenesis in all adult brain niches.

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Niches access systemic injury cues via a permeable BBB, made leakier by stroke.

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All stem cell niches are induced following bFGF infusion into the CSF.

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Abstract

Previous studies have established the subventricular (SVZ) and subgranular (SGZ) zones as sites of neurogenesis in the adult forebrain (Doetsch et al., 1999a; Doetsch, 2003a). Work from our laboratory further indicated that midline structures known as circumventricular organs (CVOs) also serve as adult neural stem cell (NSC) niches (Bennett et al., 2009, 2010). In the quiescent rat brain, NSC proliferation remains low in all of these sites. Therefore, we recently examined whether ischemic stroke injury (MCAO) or sustained intraventricular infusion of the mitogen bFGF could trigger an up-regulation in NSC proliferation, inducing neurogenesis and gliogenesis. Our data show that both stroke and bFGF induce a dramatic and long-lasting (14 day) rise in the proliferation (BrdU +) of nestin + Sox2 + GFAP + NSCs capable of differentiating into Olig2 + glial progenitors, GFAP + nestin-astrocyte progenitors and Dcx + neurons in the SVZ and CVOs. Moreover, because of the upsurge in NSC number, it was possible to detect for the first time several novel stem cell niches along the third (3V) and fourth (4V) ventricles. Importantly, a common feature of all brain niches was a rich vasculature with a blood–brain-barrier (BBB) that was highly permeable to systemically injected sodium fluorescein. These data indicate that stem cell niches are more extensive than once believed and exist at multiple sites along the entire ventricular system, consistent with the potential for widespread neurogenesis and gliogenesis in the adult brain, particularly after injury. We further suggest that because of their leaky BBB, stem cell niches are well-positioned to respond to systemic injury-related cues which may be important for stem-cell mediated brain repair.

Brain May be Able to Repair Itself from Within

Whom in the stroke world is leading the strategy to push this to a successful completion? Now if we can just have angiogenesis occur at the same time. Like  
1. Transcriptomics of post-stroke angiogenesis in the aged brain  
or 

2. A comparative study of NONOate based NO donors: Spermine NONOate is the best suited NO donor for angiogenesis  
or

3. Vascular remodeling after ischemic stroke: mechanisms and therapeutic potentials  
or

4. Brain Derived Neurotrophic Factor Key Element in Recovery from Stroke  
or

5.Safe and Effective Vascular Endothelial Cell Growth Factor (VEGF)-based Therapeutic Angiogenesis for Ischemic Stroke:

You really do expect your doctors and researchers to be able to do both of these at the same time? Don't you? This may be one of the few therapies for us chronic patients.
http://www.biosciencetechnology.com/news/2014/06/brain-may-be-able-repair-itself-within?et_cid=3974854&et_rid=648870051&type=headline
Duke researchers have found a new type of neuron in the adult brain that is capable of telling stem cells to make more new neurons. Though the experiments are in their early stages, the finding opens the tantalizing possibility that the brain may be able to repair itself from within.

Neuroscientists have suspected for some time that the brain has some capacity to direct the manufacturing of new neurons, but it was difficult to determine where these instructions are coming from, explained Chay Kuo, an assistant professor of cell biology, neurobiology and pediatrics.

In a study with mice, his team found a previously unknown population of neurons within the subventricular zone (SVZ) neurogenic niche of the adult brain, adjacent to the striatum. These neurons expressed the choline acetyltransferase (ChAT) enzyme, which is required to make the neurotransmitter acetylcholine. With optogenetic tools that allowed the team to tune the firing frequency of these ChAT+ neurons up and down with laser light, they were able to see clear changes in neural stem cell proliferation in the brain.

The findings appeared as an advance online publication in the journal Nature Neuroscience.

The mature ChAT+ neuron population is just one part of an undescribed neural circuit that apparently talks to stem cells and tells them to increase new neuron production, Kuo said. Researchers don't know all the parts of the circuit yet, nor the code it's using, but by controlling ChAT+ neurons' signals Kuo and his Duke colleagues have established that these neurons are necessary and sufficient to control the production of new neurons from the SVZ niche.

"We have been working to determine how neurogenesis is sustained in the adult brain. It is very unexpected and exciting to uncover this hidden gateway, a neural circuit that can directly instruct the stem cells to make more immature neurons," said Kuo, who is also the George W. Brumley, Jr. M.D. assistant professor of developmental biology and a member of the Duke Institute for Brain Sciences. "It has been this fascinating treasure hunt that appeared to dead-end on multiple occasions!"

Kuo said this project was initiated more than five years ago when lead author Patricia Paez-Gonzalez, a postdoctoral fellow, came across neuronal processes contacting neural stem cells while studying how the SVZ niche was assembled.

The young neurons produced by these signals were destined for the olfactory bulb in rodents, as the mouse has a large amount of its brain devoted to process the sense of smell and needs these new neurons to support learning. But in humans, with a much less impressive olfactory bulb, Kuo said it's possible new neurons are produced for other brain regions. One such region may be the striatum, which mediates motor and cognitive controls between the cortex and the complex basal ganglia.

"The brain gives up prime real estate around the lateral ventricles for the SVZ niche housing these stem cells," Kuo said. "Is it some kind of factory taking orders?" Postdoctoral fellow Brent Asrican made a key observation that orders from the novel ChAT+ neurons were heard clearly by SVZ stem cells.

Studies of stroke injury in rodents have noted SVZ cells apparently migrating into the neighboring striatum. And just last month in the journal Cell, a Swedish team observed newly made control neurons called interneurons in the human striatum for the first time. They reported that interestingly in Huntington's disease patients, this area seems to lack the newborn interneurons.

"This is a very important and relevant cell population that is controlling those stem cells," said Sally Temple, director of the Neural Stem Cell Institute of Rensselaer, NY, who was not involved in this research. "It's really interesting to see how innervations are coming into play now in the subventricular zone."

Kuo's team found this system by following cholinergic signaling, but other groups are arriving in the same niche by following dopaminergic and serotonergic signals, Temple said. "It's a really hot area because it's a beautiful stem cell niche to study. It's this gorgeous niche where you can observe cell-to-cell interactions."

These emerging threads have Kuo hopeful researchers will eventually be able to find the way to "engage certain circuits of the brain to lead to a hardware upgrade. Wouldn't it be nice if you could upgrade the brain hardware to keep up with the new software?" He said perhaps there will be a way to combine behavioral therapy and stem cell treatments after a brain injury to rebuild some of the damage.

The questions ahead are both upstream from the new ChAT+ neurons and downstream, Kuo says. Upstream, what brain signals tell ChAT+ neurons to start asking the stem cells for more young neurons? Downstream, what's the logic governing the response of the stem cells to different frequencies of ChAT+ electrical activity?

There's also the big issue of somehow being able to introduce new components into an existing neuronal circuit, a practice that parts of the brain might normally resist. "I think that some neural circuits welcome new members, and some don't," Kuo said.

Source: Duke University

Oligodendrogenesis after cerebral ischemia

What is your doctor doing to make sure this happens? And if your doctor doesn't know what oligodendrocytes do then you have an idiot for a doctor?

Oligodendrogenesis after cerebral ischemia

Ruilan Zhang¹, Michael Chopp^1,2 and Zheng Gang Zhang^1*

• ¹Department of Neurology, Henry Ford Hospital, Detroit, MI, USA
• ²Department of Physics, Oakland University, Rochester, MI, USA

Neural stem cells in the subventricular zone (SVZ) of the lateral ventricle of adult rodent brain generate oligodendrocyte progenitor cells (OPCs) that disperse throughout the corpus callosum and striatum where some of OPCs differentiate into mature oligodendrocytes. Studies in animal models of stroke demonstrate that cerebral ischemia induces oligodendrogenesis during brain repair processes. This article will review evidence of stroke-induced proliferation and differentiation of OPCs that are either resident in white matter or are derived from SVZ neural progenitor cells and of therapies that amplify endogenous oligodendrogenesis in ischemic brain.

Parenchymal Neuro-Glio-Genesis Versus Germinal Layer-Derived Neurogenesis: Two Faces of Central Nervous System Structural Plasticity

20 years later and we still have no idea how to get neurogenesis to work for us. Once again this chapter misses this research:
Astrocytes build blood vessel scaffolds for long distance neuron migrations
Damn are people that clueless that a stroke-addled person knows more about their field than the workers in that field.
http://cdn.intechopen.com/pdfs/44268/InTech-Parenchymal_neuro_glio_genesis_versus_germinal_layer_derived_neurogenesis_two_faces_of_central_nervous_system_structural_plasticity.pdf

Chapter 9

1. Introduction

The discovery of neural stem cells (NSCs) at the beginning of the nineties led many people toconsider definitively broken the dogma of a static central nervous system (CNS) made up ofnon-renewable elements [1-3]. In parallel, the occurrence and characterization of adult neurogenesis in the olfactory bulb and hippocampus [3-5] triggered new hopes for brain repair.

Twenty years after, the dream of regenerative medicine applied to brain/spinal cord injuries and neurodegenerative diseases is still very far [

6,7

]. As a matter of fact, adult neurogenesisin mammals occurs mainly within two restricted areas known as ‘neurogenic sites’ [3,8]: the forebrain subventricular zone (SVZ); reviewed in [9] and the hippocampal dentate gyrus (subgranular zone, SGZ); reviewed in [10]. As a direct consequence of such topographical localization, most of the CNS parenchyma out of the two ‘classic’ neurogenic sites remains substantially a non-renewable tissue. Actually, most of the traumatic/vascular injuries and neurodegenerative diseases do occur in ‘non-neurogenic’ regions and no efficacious therapies

capable of restoring CNS structure and functions through cell replacement are at present available. Thus, two decades after the discovery of NSCs and the reaching of a satisfactory characterization of adult neurogenic sites, a gap remains between the occurrence of stem/

progenitor cells in the CNS of adult mammals and their effective capability to serve in brain repair. Several aspects do converge in explaining this gap [

11

], partially accounting for the heterogeneity of CNS structural plasticity in mammals (summarized in Table 1)

Pictures at pages 2 and 3

 

Ciliary Neurotrophic Factor Receptor Regulation of Adult Forebrain Neurogenesis

We need as much neurogenesis as possible, so demand your doctor understand this and incorporate it into your stroke protocol.
http://www.jneurosci.org/content/33/3/1241.short

Abstract

Appropriately targeted manipulation of endogenous neural stem progenitor (NSP) cells may contribute to therapies for trauma, stroke, and neurodegenerative disease. A prerequisite to such therapies is a better understanding of the mechanisms regulating adult NSP cells in vivo. Indirect data suggest that endogenous ciliary neurotrophic factor (CNTF) receptor signaling may inhibit neuronal differentiation of NSP cells. We challenged subventricular zone (SVZ) cells in vivo with low concentrations of CNTF to anatomically characterize cells containing functional CNTF receptors. We found that type B “stem” cells are highly responsive, whereas type C “transit-amplifying” cells and type A neuroblasts are remarkably unresponsive, as are GFAP⁺ astrocytes found outside the SVZ. CNTF was identified in a subset of type B cells that label with acute BrdU administration. Disruption of in vivo CNTF receptor signaling in SVZ NSP cells, with a “floxed” CNTF receptor α (CNTFRα) mouse line and a gene construct driving Cre recombinase (Cre) expression in NSP cells, led to increases in SVZ-associated neuroblasts and new olfactory bulb neurons, as well as a neuron subtype-specific, adult-onset increase in olfactory bulb neuron populations. Adult-onset receptor disruption in SVZ NSP cells with a recombinant adeno-associated virus (AAV-Cre) also led to increased neurogenesis. However, the maintenance of type B cell populations was apparently unaffected by the receptor disruption. Together, the data suggest that endogenous CNTF receptor signaling in type B stem cells inhibits adult neurogenesis, and further suggest that the regulation may occur in a neuron subtype-specific manner.

Grafted human neural stem cells enhance several steps of endogenous neurogenesis and improve behavioral recovery after middle cerebral artery occlusion in rats

Oh no, we're creating  human brains in rats. Shades of Christine O’Donnell famously insisting that scientists were putting human brains into mice.
http://www.ncbi.nlm.nih.gov/pubmed/23276704

Abstract

Neural stem/progenitor cells (NSPCs) in subventricular zone (SVZ) produce new striatal neurons during several months after stroke, which may contribute to recovery. Intracerebral grafts of NSPCs can exert beneficial effects after stroke through neuronal replacement, trophic actions, neuroprotection, and modulation of inflammation. Here we have explored whether human fetal striatum-derived NSPC-grafts influence striatal neurogenesis and promote recovery in stroke-damaged brain. T cell-deficient rats were subjected to 1 h middle cerebral artery occlusion (MCAO). Human fetal NSPCs or vehicle were implanted into ipsilateral striatum 48 h after MCAO, animals were assessed behaviorally, and perfused at 6 or 14 weeks. Grafted human NSPCs survived in all rats, and a subpopulation had differentiated to neuroblasts or mature neurons at 6 and 14 weeks. Numbers of proliferating cells in SVZ and new migrating neuroblasts and mature neurons were higher, and numbers of activated microglia/macrophages were lower in the ischemic striatum of NSPC-grafted compared to vehicle-injected group both at 6 and 14 weeks. A fraction of grafted NSPCs projected axons from striatum to globus pallidus. The NSPC-grafted rats showed improved functional recovery in stepping and cylinder tests from 6 and 12 weeks, respectively. Our data show, for the first time, that intrastriatal implants of human fetal NSPCs exert a long-term enhancement of several steps of striatal neurogensis after stroke. The grafts also suppress striatal inflammation and ameliorate neurological deficits. Our findings support the idea that combination of NSPC transplantation and stimulation of neurogenesis from endogenous NSPCs may become a valuable strategy for functional restoration after stroke.

Neurogenesis and progenitor cells in the adult human brain: a comparison between hippocampal and subventricular progenitor proliferation

But we next need to know which starting place  will migrate neurons to the area of need.
http://onlinelibrary.wiley.com/doi/10.1002/dneu.22028/abstract

Abstract

For more than a decade we have known that the human brain harbours progenitor cells capable of becoming mature neurons in the adult human brain. Since the original landmark paper by Eriksson and colleagues in 1998 there have been many studies investigating the effect depression, epilepsy, Alzheimer's disease, Huntington's disease and Parkinson's disease have on the germinal zones in the adult human brain. Of particular interest is the demonstration that there are far fewer progenitor cells in the hippocampal subgranular zone (SGZ) compared with the subventricular zone (SVZ) in the human brain. Furthermore the quantity of progenitor cell proliferation in human neurodegenerative diseases differs from that of animal models of neurodegenerative diseases; there is minimal progenitor proliferation in the SGZ and extensive proliferation in the SVZ in the human. In this review we will present the data from a range of human and rodent studies from which we can compare the amount of proliferation of cells in the SVZ and SGZ in different neurodegenerative diseases.