Discovered: How The Brain Repairs Itself After a Stroke

A PSYBLOG writeup on this; readable even for your doctor.
http://www.spring.org.uk/2014/10/discovered-how-the-brain-repairs-itself-after-a-stroke.php

The actual research on this: 
A latent neurogenic program in astrocytes regulated by Notch signaling in the mouse

Discovered: How The Brain Repairs Itself After a Stroke

What is your doctor doing to enhance this process in your brain?
What protocol is being followed?
The readable blog article here:

Discovered: How The Brain Repairs Itself After a Stroke

The research it is based on here:

A latent neurogenic program in astrocytes regulated by Notch signaling in the mouse

Jagged1 is necessary for postnatal and adult neurogenesis in the dentate gyrus

How is your doctor ensuring you get Jagged1 and notch proliferation to help your neurogenesis? Do they have any idea what it is? Or why it's important to your recovery?
http://www.sciencedirect.com/science/article/pii/S0012160614000724

• Alfonso Lavado^, ,
• Guillermo Oliver^,

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http://dx.doi.org/10.1016/j.ydbio.2014.02.004

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Highlights

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Jagged1 is not necessary for embryonic dentate gyrus formation

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Jagged1 is required for postnatal and adult neurogenesis in the dentate gyrus

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Notch/Jagged1 is required for progenitor proliferation and maintenance

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Abstract

Understanding the mechanisms that control the maintenance of neural stem cells is crucial for the study of neurogenesis. In the brain, granule cell neurogenesis occurs during development and adulthood, and the generation of new neurons in the adult subgranular zone of the dentate gyrus contributes to learning. Notch signaling plays an important role during postnatal and adult subgranular zone neurogenesis, and it has been suggested as a potential candidate to couple cell proliferation with stem cell maintenance. Here we show that conditional inactivation of Jagged1 affects neural stem cell maintenance and proliferation during postnatal and adult neurogenesis of the subgranular zone. As a result, granule cell production is severely impaired. Our results provide additional support to the proposal that Notch/Jagged1 activity is required for neural stem cell maintenance during granule cell neurogenesis and suggest a link between maintenance and proliferation of these cells during the early stages of neurogenesis.

Loss of Dickkopf-1 Restores Neurogenesis in Old Age and Counteracts Cognitive Decline

Your doctor should be able to take this and create a stroke protocol for you. But your incompetent? doctor will DO NOTHING! 

Loss of Dickkopf-1 Restores Neurogenesis in Old Age and Counteracts Cognitive Decline

Summary

Memory impairment has been associated with age-related decline in adult hippocampal neurogenesis. Although Notch, bone morphogenetic protein, and Wnt signaling pathways are known to regulate multiple aspects of adult neural stem cell function, the molecular basis of declining neurogenesis in the aging hippocampus remains unknown. Here, we show that expression of the Wnt antagonist Dickkopf-1 (Dkk1) increases with age and that its loss enhances neurogenesis in the hippocampus. Neural progenitors with inducible loss of Dkk1 increase their Wnt activity, which leads to enhanced self-renewal and increased generation of immature neurons. This Wnt-expanded progeny subsequently matures into glutamatergic granule neurons with increased dendritic complexity. As a result, mice deficient in Dkk1 exhibit enhanced spatial working memory and memory consolidation and also show improvements in affective behavior. Taken together, our findings show that upregulating Wnt signaling by reducing Dkk1 expression can counteract age-related decrease in neurogenesis and its associated cognitive decline.

BCL6 controls neurogenesis through Sirt1-dependent epigenetic repression of selective Notch targets

So have your researcher notch up another mark for his/her figurative gun.
http://www.nature.com/neuro/journal/vaop/ncurrent/full/nn.3264.html

Abstract

• Abstract
• Author information
• Supplementary information

During neurogenesis, neural stem/progenitor cells (NPCs) undergo an irreversible fate transition to become neurons. The Notch pathway is important for this process, and repression of Notch-dependent Hes genes is essential for triggering differentiation. However, Notch signaling often remains active throughout neuronal differentiation, implying a change in the transcriptional responsiveness to Notch during the neurogenic transition. We identified Bcl6, an oncogene, as encoding a proneurogenic factor that is required for proper neurogenesis of the mouse cerebral cortex. BCL6 promoted the neurogenic conversion by switching the composition of Notch-dependent transcriptional complexes at the Hes5 promoter. BCL6 triggered exclusion of the co-activator Mastermind-like 1 and recruitment of the NAD⁺-dependent deacetylase Sirt1, which was required for BCL6-dependent neurogenesis. The resulting epigenetic silencing of Hes5 led to neuronal differentiation despite active Notch signaling. Our findings suggest a role for BCL6 in neurogenesis and uncover Notch-BCL6-Sirt1 interactions that may affect other aspects of physiology and disease.

Signaling mechanisms regulating adult neural stem cells and neurogenesis

I only put this out here because of the sonic hedgehog. You'll have to get your doctor to buy the full article.
 http://www.sciencedirect.com/science/article/pii/S0304416512002577

Abstract

Background

Adult neurogenesis occurs throughout life in discrete regions of the mammalian brain and is tightly regulated via both extrinsic environmental influences and intrinsic genetic factors. In recent years, several crucial signaling pathways have been identified in regulating self-renewal, proliferation, and differentiation of neural stem cells, as well as migration and functional integration of developing neurons in the adult brain.

Scope of review

Here we review our current understanding of signaling mechanisms, including Wnt, notch, sonic hedgehog, growth and neurotrophic factors, bone morphogenetic proteins, neurotransmitters, transcription factors, and epigenetic modulators, and crosstalk between these signaling pathways in the regulation of adult neurogenesis. We also highlight emerging principles in the vastly growing field of adult neural stem cell biology and neural plasticity.

Major conclusions

Recent methodological advances have enabled the field to identify signaling mechanisms that fine-tune and coordinate neurogenesis in the adult brain, leading to a better characterization of both cell-intrinsic and environmental cues defining the neurogenic niche. Significant questions related to niche cell identity and underlying regulatory mechanisms remain to be fully addressed and will be the focus of future studies.

General significance

A full understanding of the role and function of individual signaling pathways in regulating neural stem cells and generation and integration of newborn neurons in the adult brain may lead to targeted new therapies for neurological diseases in humans. This article is part of a Special Issue entitled Biochemistry of Stem Cells.

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Highlights

► Adult neurogenesis is regulated via both extrinsic environmental influences and intrinsic genetic factors. ► We review individual signaling mechanisms and their cross-talk in regulating adult neurogenesis. ► We highlight emerging principles in the growing field of adult neural stem cell biology.

So after your doctor has digested this article, ask him/her how they are going to use it to help your neurogenesis along.  Don't be afraid, they'll probably just ask if you want one for a pet.

Formation of the Collateral Circulation is Regulated by Vascular Endothelial Growth Factor-A and A Disintegrin and Metalloprotease Family Members 10 and 1

We are going to need this if we ever expect to repopulate our dead brain areas or wherever we lay down stem cells.  If you go down the stem cell route ask your doctor how  those cells are going to get a blood supply. Be insistent. 

Formation of the Collateral Circulation is Regulated by Vascular Endothelial Growth Factor-A and A Disintegrin and Metalloprotease Family Members 10 and 1

Abstract

Rationale: The density of native (pre-existing) collaterals varies widely and is a significant determinant of variation in severity of stroke, myocardial infarction and peripheral artery disease. However, little is known about mechanisms responsible for formation of the collateral circulation in healthy tissues.

Objective: We previously found that variation in VEGF expression causes differences in collateral density of newborn and adult mice. Herein, we sought to determine mechanisms of collaterogenesis in the embryo and the role of VEGF in this process.

Methods and Results: Pial collaterals begin forming between embryonic day (E) 13.5 and 14.5 as sprout-like extensions from arterioles of existing cerebral artery trees. Global VEGF-A overexpressing mice (Vegf ^hi/+) formed more-and Vegf ^lo/+ formed fewer-collaterals during embryogenesis, in association with differences in vascular patterning. Conditional global reduction of Vegf or Flk1 only during collaterogenesis significantly reduced collateral formation, but now without affecting vascular patterning, and the effects remained in adulthood. Endothelial-specific Vegf reduction had no effect on collaterogenesis. Endothelial-specific reduction of a disintegrin-and-metalloprotease-domain-10 (Adam10) and inhibition of γ-secretase increased collateral formation, consistent with their roles in VEGF-induced Notch1 activation and suppression of "pro-sprouting" signals. Endothelial-specific knockdown of Adam17 reduced collateral formation, consistent with its roles in endothelial cell migration and embryonic vascular stabilization, but not in activation of ligand-bound Notch1. These effects also remained in adulthood.

Conclusions: Formation of pial collaterals occurs during a narrow developmental window via a sprouting angiogenesis-like mechanism, requires paracrine VEGF-stimulation of Flk1-Notch signaling, and adult collateral number is dependent on embryonic collaterogenesis.

POU-III Transcription Factors (Brn1, Brn2, and Oct6) Influence Neurogenesis, Molecular Identity, and Migratory Destination of Upper-Layer Cells of the Cerebral Cortex

I like the migration destination. 

POU-III Transcription Factors (Brn1, Brn2, and Oct6) Influence Neurogenesis, Molecular Identity, and Migratory Destination of Upper-Layer Cells of the Cerebral Cortex

Abstract

The upper layers (II–IV) are the most prominent distinguishing feature of mammalian neocortex compared with avian or reptilian dorsal cortex, and are vastly expanded in primates. Although the time-dependent embryonic generation of upper-layer cells is genetically instructed within their parental progenitors, mechanisms governing cell-intrinsic fate transitions remain obscure. POU-homeodomain transcription factors Pou3f3 and Pou3f2 (Brn1 and Brn2) are known to label postmitotic upper-layer cells, and are redundantly required for their production. We find that the onset of Pou3f3/2 expression actually occurs in ventricular zone (VZ) progenitors, and that Pou3f3/2 subsequently label neural progeny switching from deep-layer Ctip2⁺ identity to Satb2⁺ upper-layer fate as they migrate to proper superficial positions. By using an Engrailed dominant-negative repressor, we show that sustained neurogenesis after the deep- to upper-layer transition requires the proneual action of Pou3fs in VZ progenitors. Conversely, single-gene overexpression of any Pou3f in early neural progenitors is sufficient to specify the precocious birth of Satb2⁺ daughter neurons that extend axons to the contralateral hemisphere, as well as exhibit robust pia-directed migration that is characteristic of upper-layer cells. Finally, we demonstrate that Pou3fs influence multiple stages of neurogenesis by suppressing Notch effector Hes5, and promoting the expression of proneural transcription factors Tbr2 and Tbr1.

Notch signaling and neural connectivity

Let's listen in on notch and hear what signals its putting out. More on brain connectivity.
 http://www.sciencedirect.com/science/article/pii/S0959437X12000470
 The cell surface receptor Notch contributes to the development of nearly every tissue in most metazoans by controlling the fates and differentiation of cells. Recent results have now established that Notch also regulates the connectivity of the nervous system, and does so at a variety of levels, including specification of neuronal identity, division, survival and migration, as well as axon guidance, morphogenesis of dendritic arbors and weighting of synapse strength. To these ends, Notch engages at least two signal transduction pathways, one that controls nuclear gene expression and another that directly targets the cytoskeleton. Coordinating the many functions of Notch to produce neural structure is thus a pivotal aspect of building and maintaining the nervous system.

Direct Stimulation of Adult Neural Stem/Progenitor Cells In Vitro and Neurogenesis In Vivo by Salvianolic Acid B

Some actual TCM research. 

Direct Stimulation of Adult Neural Stem/Progenitor Cells In Vitro and Neurogenesis In Vivo by Salvianolic Acid B

Introduction Top

Ischemic brain damage is one of the most dangerous ailments that lead to learning and memory disability, physical dysfunction and even death. Up to now, no effective treatment has been reported [1]. Neurons as terminally differentiated cells cannot regenerate after injury in traditional view. However, appropriate exercise training can facilitate some neurological function recovery after stroke in clinical practice [2], [3], with the evidence that neurogenesis occurs in the adult brain. Neural stem/precursor cells (NSPCs) had been found and confirmed in adult brain in past decades that it can differentiate into neurons or glial cells as a result of neurogenesis [4]–[7], NSPCs can be stimulated in several pathological conditions, such as neurological diseases, cerebral ischemic in adult brain, and many reports showed that they are an excellent candidate for developing therapeutic strategies to repair the injured CNS [8], [9]. Although the NSPCs would be stimulated to proliferation and differentiation during the brain injury, often this response is not sufficient to overcome the damage. It is essential to study the signalling mechanisms that are activated by small molecular materials in the NSPCs to enhance their response pharmacologically. NSPCs proliferation and neurogensis involves a series of intracellular signaling pathways [10], [11]. Among these pathways, the activation of Notch, mitogen-activated protein kinases (MAPKs) and phosphatidylinositol-3-kinase (PI3K)/Akt pathways are known to play major roles in cell growth and survival responses [12]–[14]. Numerous studies have shown that small molecular materials such as growth factors [15], retinoic acid [16] and Traditional Chinese Medicine (TCM) active constituent [17], [18] can regulate the biological characteristics of neural stem cell and promote neurogenesis. Therefore, regulation of neurogenesis by NSPCs is anticipated as a noble therapeutic strategy for brain damage.
Herbs have been used for treating diseases for centuries, and a lot of natural compounds that with neural beneficial from medicinal plants had been discovered [19]. Treatment of stroke by TCM has a wealth of clinical experience and theoretical basis, and a large number of effective clinical prescriptions have been accumulated. In recent years a large number of studies have shown that TCM prescription and its active ingredient can improve cerebral ischemic injury in experimental animal [20], [21]. Ginsenoside Rb1 and Rg1, for example, improved spatial learning and increase hippocampal synaptophysin level in mice [22]. Curcumin had been demonstrated to stimulate developmental and adult hippocampal neurogenesis, and a biological activity that may enhance neural plasticity and repair [23]. A recent report has shown that NeuroAid (MLC601 and MLC901), a Traditional Chinese Medicine is used in China for patients after stroke, reduced the increase in escape latency and in swim distance induced by ischemia [24]. With an extensive clinical experience, there are ample opportunities to discover natural compounds that effectively promote the proliferation of NSPCs and neurogenesis from TCM.

Results Top

Salvianolic acid B induced the proliferation of cultured NSPCs in vitro

Forty-five herbal compounds, which are extensively used clinically for treating stroke in China, were screened in an in vitro proliferation assay to identify compounds that could induce proliferation of NSPCs. As shown in Fig. 1, among these natural compounds screened, berberine and Sal B displayed marked activity promoting NSPCs proliferation. In the following study, the proliferative effect of berberine and Sal B were systematically investigated but the action of berberine was proved to be an illusion by BrdU incorporation assay (See Figure S1 in the Supporting Information).
To study the proliferation-inducing effect of Sal B in detail, we investigated effects of Sal B on the viability of NSPCs in vitro using the MTS assay, NSPCs were treated with Sal B at different concentrations and for different durations. We investigated Sal B at 5, 10, 20, 30, 40, 50 µM dose exposure for 24 hours, and at 20 µM dose incubated for 24, 48, 72 hours on promoting NSPCs proliferation. The results showed that the viability of NSPCs significantly increased as the dose (P<0.01, F_{(6, 35)} = 103.06) and time increases (P<0.01, Fig. 2A–B). The number and size of neurospheres were increased by addition of 20 µM of Sal B (Figure 2C–D). These results suggested that Sal B significantly increased the viability of NSPCs in dose- and time- dependent manners.

Botch Promotes Neurogenesis by Antagonizing Notch

Lets antagonize everybody until stroke recovery is solved.
http://www.sciencedirect.com/science/article/pii/S1534580712000925

Summary

Regulation of self-renewal and differentiation of neural stem cells is still poorly understood. Here we investigate the role of a developmentally expressed protein, Botch, which blocks Notch, in neocortical development. Downregulation of Botch in vivo leads to cellular retention in the ventricular and subventricular zones, whereas overexpression of Botch drives neural stem cells into the intermediate zone and cortical plate. In vitro neurosphere and differentiation assays indicate that Botch regulates neurogenesis by promoting neuronal differentiation. Botch prevents cell surface presentation of Notch by inhibiting the S1 furin-like cleavage of Notch, maintaining Notch in the immature full-length form. Understanding the function of Botch expands our knowledge regarding both the regulation of Notch signaling and the complex signaling mediating neuronal development.

Graphical abstract

Folic acid enhances Notch signaling, hippocampal neurogenesis, and cognitive function in a rat model of cerebral ischemia

Not sure how useful this is since the rats were pre-treated with folic acid prior to their induced stroke.
http://www.ingentaconnect.com/content/maney/nns/pre-prints/1476830511Y.0000000025

Abstract:

Increasing neurogenesis may restore cognitive functions that are impaired in ischemia stroke. Folic acid has been reported to play an important role in neuronal development and reduce the risk of ischemic stroke in primary prevention. Folic acid supplementation stimulates Notch signaling and cell proliferation in neural progenitor cells cultured from neonatal brain. The present study determined whether folic acid supplementation stimulates Notch signaling and neurogenesis and improves cognitive function after ischemic stroke in adult brain. Rats were randomly assigned to four groups: sham operation plus vehicle (Sham), middle cerebral artery occlusion plus vehicle (MCAO), MCAO plus low-dose folic acid (4 mg/(kg day)), and MCAO plus high folic acid (12 mg/(kg day)). The vehicle and folic acid were administered by oral gavage for 28 days prior to sham or MCAO operation and up to 14 days after surgery. Newborn hippocampal neurons were detected at 3, 7, and 14 days post-MCAO. Cognitive function (learning and memory in Y-maze tests) and the protein expression levels of components of the Notch signaling system (Notch1, Hes1, and Hes5) were measured at 7 days post-MCAO. The results showed that MCAO impaired Y-maze performance and stimulated Notch signaling and hippocampal neurogenesis in brain. Folic acid prevented the impairment of Y-maze performance. The nutrient also increased further the expression of Notch1, Hes1, and Hes5 and the number of the newborn hippocampal neurons. Folic acid enhances the stimulation by ischemia of Notch signaling and hippocampal neurogenesis in adult brain and lessens the impairment of cognitive function that occurs after experimental stroke.

Researchers Identify Role of Protein Important for Stem Cell Growth; Study Leads to Recovery in Animal Model of Stroke

Only 5 years old, we should have useable results by now.
http://www.ninds.nih.gov/news_and_events/news_articles/news_article_stroke_Notch.htm

For release: Wednesday, August 30, 2006

For the first time, researchers have found that a protein signal important in embryonic development promotes survival and proliferation of stem cells. Stimulating receptors for this protein, called Notch, led to functional recovery in rats with brain damage from stroke. The results suggest potential new ways of treating stroke and neurodegenerative diseases.

The study was conducted by Ronald D.G. McKay, Ph.D., Andreas Androutsellis-Theotokis, Ph.D., and colleagues at the National Institute of Neurological Disorders and Stroke (NINDS) in Bethesda, Maryland, and published in the August 17, 2006, issue of Nature.*

"This is a new role for the Notch receptor," Dr. McKay says. Previous studies have shown that Notch is important for proper development of embryos, and that it regulates chemical chain reactions, or pathways, that are central to cancer and diabetes. However, this is the first study to show that Notch controls stem cell division and survival and that it can prompt functional recovery after brain injury in an animal model.

Dr. McKay and his colleagues tested chemicals that increase Notch activity in cultured neural stem cells (NSCs). NSCs can form all of the cells that make up the nervous system, but they do not normally develop into other kinds of tissue. The researchers found that one of these chemicals, Dll4, rapidly reduced cell death. They also found that Notch is part of the pathway by which insulin controls cell survival, and they identified several other genes that control cells' responses to Notch. Pumping Dll4 into the brains of normal rats for 7 days increased the number of dividing cells. Many of the newly generated cells showed a marker that is common on immature neurons. These cells survived for at least 45 days in an immature state. These findings suggest that Notch may be important for maintaining populations of stem cells in the brain and other parts of the body.

The researchers also tested Dll4 in cultures of human embryonic stem cells and pancreatic stem cells and found that it improved survival and proliferation of those cells. The results suggested that Notch may be an important control signal for many different kinds of stem cells.

Next, the researchers used a pump to deliver Dll4 and a growth factor called fibroblast growth factor 2 (FGF2) into the brains of rats that had experienced a stroke. The combination of Dll4 and FGF2 increased the number of dividing cells in the brain. Furthermore, rats given this treatment showed a significant improvement in their motor scores (ability to move) during a 45-day test period. In contrast, rats given either Dll4 or FGF2 alone showed no change in their motor scores.

“This study shows that stem cell regeneration is intimately related to mechanisms controlling cancer and diabetes,” says Dr. McKay. The finding suggests that knowledge gained from studying these diseases may lead to improved methods of cultivating stem cells. This is particularly important for embryonic stem cells, which are currently very difficult to grow in culture.

"People often ask, 'If we've got stem cells in our bodies, why don't we recover?'" says Dr. McKay. "If you have a significant injury in the cerebral cortex, you have no time to repair it under natural conditions. The system seems to be designed to immediately limit the injury." These protective responses often override the body's ability to repair itself. The new study shows that raising the activity of Notch can significantly increase the proliferation of cells after an injury and might improve the chances of recovery.

While the study found significant functional recovery in animals treated with Dll4, very few of the newly generated cells appeared to be mature neurons or astrocytes. Therefore it is unclear exactly how the treatment helped the rats recover. The researchers are now planning experiments to define how Notch activation leads to recovery. They also need to learn how to get the cells to the damaged part of the brain and how Notch affects the vascular and immune systems, which are important for normal brain function.

The NINDS is a component of the National Institutes of Health (NIH) in Bethesda, Maryland, and is the nation’s primary supporter of biomedical research on the brain and nervous system. The NIH is comprised of 27 Institutes and Centers and is a component of the U. S. Department of Health and Human Services. It is the primary Federal agency for conducting and supporting basic, clinical, and translational medical research, and investigates the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit http://www.nih.gov.

Transcription factor Lhx2 is necessary and sufficient to suppress astrogliogenesis and promote neurogenesis in the developing hippocampus

I think I need a scientist to translate this one. 

Transcription factor Lhx2 is necessary and sufficient to suppress astrogliogenesis and promote neurogenesis in the developing hippocampus

Abstract

The sequential production of neurons and astrocytes from neuroepithelial precursors is a fundamental feature of central nervous system development. We report that LIM-homeodomain (LIM-HD) transcription factor Lhx2 regulates this transition in the developing hippocampus. Disrupting Lhx2 function in the embryonic hippocampus by in utero electroporation and in organotypic slice culture caused the premature production of astrocytes at stages when neurons are normally generated. Lhx2 function is therefore necessary to suppress astrogliogenesis during the neurogenic period. Furthermore, Lhx2 overexpression was sufficient to suppress astrogliogenesis and prolong the neurogenic period. We provide evidence that Lhx2 overexpression can counteract the instructive astrogliogenic effect of Notch activation. Lhx2 overexpression was also able to override and suppress the activation of the GFAP promoter by Nfia, a Notch-regulated transcription factor that is required for gliogenesis. Thus, Lhx2 appears to act as a “brake” on Notch/Nfia-mediated astrogliogenesis. This critical role for Lhx2 is spatially restricted to the hippocampus, because loss of Lhx2 function in the neocortex did not result in premature astrogliogenesis at the expense of neurogenesis. Our results therefore place Lhx2 as a central regulator of the neuron-glia cell fate decision in the hippocampus and reveal a striking regional specificity of this fundamental function within the dorsal telencephalon.