In the recent article “Can Stem Cells Be Used to Enhance Cognition?” (2015) (html, pdf) , Goldberg and Blurton-Jones examine the potential to enhance cognition through (1) endogenous neurogenesis and (2) stem cell transplantation. This post is a summary of their findings.
This post goes into fairly deep technical detail. If you prefer, you can get the gist of the story in the summary section below.
An important but separate issue is whether neural stem cell implantation is ethical or desirable; social and ethical implications of this research are discussed elsewhere. 1 This post simply examines what is possible so far.
The equilibrium between cell loss and cell replacement is well maintained by stem cells in most adult tissues, except for the pancreas, heart, and brain. As the brain gets older, its ability to maintain itself through producing new neurons is reduced. (Rossi et al., 2008). This loss of this cell equilibrium in the brain is greatly correlated with age-related neurogenerative disorders like Parkinson’s and Alzheimer’s Disease.
Summary: multiple mechanisms connecting neurogenesis and cognition
The Role of Endogenous Neurogenesis in Cognition
Until recently, scientists did not have strong evidence that the brain generates new neurons. Then, in 1998, Eriksson e. al. demonstrated that humans exhibit adult neurogenesis in two key areas:
- The dentate gyrus of the hippocampus
- The Subventricular zone (SVZ) of the lateral ventricles 3
Since then, researchers have found that adult neurogenesis occurs in the hippocampus and SVZ throughout life 4, and that they form connections to other parts of the brain (emphasis is my own):
The existence of endogenous neural stem cells (NSCs) means that we can potentially insert new, healthy neurons where old neurons are dead or dysfunctional. It also means that we could add neurons to various regions of the brain to enhance their capability.
The role of the adult neurogenesis in cognition, as studied in the dentate gyrus of the hippocampus
The hippocampus plays a critical role in encoding and retrieving memories. The hippocampus would be one of the places in the brain where it would be most practical for neurogenesis to occur, since newly-formed neurons integrate more readily into the surrounding functional network:
Support for this finding came in 2006, when studies showed that newborn granule cells of the dentate gyrus are more highly activaeed by a novel exploration task compared with mature neurons of the same region (Ramirez-Amaya et al., 2006). Possibly as a result of this increased excitability, newborn granule neurons also integrate more readily into memory-associated engrams than mature granule cells (Ge et al., 2007 and Tashiro et al., 2006)
Additionally, researchers found the corresponding expected negative correlation: patients with damaged hippocampi (from chemotherapy radiation) experienced significantly decreased neurogenesis, and this correlated with difficulty with memory, executive function, attention, and visuospatial function. 6
Endogenous Stem Cells in Aging and Disease
Neurogenesis seems to be modulated by chemokines (part of the immune system’s signaling proteins) in blood plasma. Age-related decline of neurogenesis seems to be partially caused by an increase in chemokine levels in the blood:
Villeda et al. (2011) showed that aged blood could reduce both neurogenesis and cognitive function in young mice. Furthermore, aged mice injected with the plasma of young mice exhibited increased hippocampal neurogenesis. Interestingly, the effects of old and young plasma seem to be mediated via specific chemokines such as CCL11: injection of this chemokine alone into young mice impaired both neurogenesis and cognition. Thus the peripheral immune system and changes in inflammatory state that occur with age seem to play a critical role in age-associated changes in neurogenesis.
Improving Cognition by Enhancing Neurogenesis
Factors that modulate adult neurogenesis:
Things that are known to contribute to adult neurogenesis:
- Chronic low levels of the microglial-derived insulin-like growth factor 1 (IGF-1) and interferon
- Radial glia
- Astrocyte-derived molecules
- In addition to their direct involvement in neurogenesis, astrocyte-derived molecules also seem to make distinct contributions
- S100B – infusion of S100B for 7 days led to a significant increase in both neurognesis and hippocampla ependnt function (Kleindienst et al 2005)
- Reports have suggested, for example, that (CNS) central nervous system–specific T cells are required for spatial learning and the maintenance of hippocampal neurogenesis in adulthood (Ziv et al., 2006).
- However, evidence that the mood-improving effects of antidepressants did not depend on neurogenesis, but rather neuronal remodeling, arose in 2008; the blockade of neurogenesis failed to diminish the antidepressant activity of several SSRIs (Bessa et al., 2009).
- Trophic Factors
- Intrahippocampal infusion of BDNF also has been reported to increase neurogenesis in adult rats (Scharfman et al., 2005),
- other studies have shown that BDNF infusion can improve cognition (Blurton-Jones et al., 2009)
- HOWEVER the precise mechanistic relationship between BDNF neurogenesis and cognition has yet to be directly examined.
- Noninvasive methods
- BDNF and IGF-1 are thought to be the principle factors modulating the effects of exercise on learninga dn mood disorders,
- IGF-1 and VEGF are more strongly implicated in hippocampal neurogenesis (Ding et al., 2006 and Nichol et al., 2009).
- Both BDNF and IGF-1gene expression are elevated after only a few days of exercise in rats and are crucial to the cognitive benefits of exercise because blockade of growth factor signaling prevents exercise-induced improvements ( Berchtold et al., 2005 and Trejo et al., 2001)
Improving Cognition with Stem Cell Transplantation
Neural Stem Cell Transplantation in Aging
Injection of neural stem cells (NSCs) into the lateral ventricle improved spatial learning and memory in rats:
One of the first studies to examine the potential effect of NSC transplantation in aging injected human NSCs into the lateral ventricle of aged rats, leading to improved performance in spatial learning and memory as measured in the Morris water maze task (Qu et al., 2001).
Neural Stem Cell Transplantation in Neurological Disease
We found that murine NSC transplantation in the triple transgenic (3xTg-AD) model of AD improves cognition in Morris water maze and novel object recognition tasks via a BDNF-dependent mechanism (Blurton-Jones et al., 2009).
NSC transplantation can improve cognitive function following ablation of CA1 hippocampal neurons (Yamasaki et al., 2007)
Syngeneic NSCs were transplanted bilaterally into the striatum of aged α-synuclein mice, and 1 month later motor and cognitive behavior was examined. NSCs survive in the striatum and begin to differentiate into glia (glial fibrillary acidic protein) and neurons (doublecortin) (Figure 8.4). In these initial studies we found robust improvements not only in motor function but also in cognitive function, and, again, BDNF seems to be central to these improvements.
Stem Cell Transplantation in the Healthy Adult Brain
Until recently, few studies have shown an enhanced benefit of stem cell transplantation in regularly-functioning adult brains.
In 2013, Han et al. (2013) showed that human glial progenitor transplantation into the frontal cortex of immune-deficient neonatal mice led to significant enhancements in the cognitive function of adult and aged mice. In contrast, transplantation of murine glial progenitors had no such effect.
Question: Why did human glial progenitor cells improve cognition in mice but transplantation of the mouse-derived glial progenitor cells didn’t?
One potential explanation for the differential effect between human and murine progenitors may relate to species-specific differences in calcium wave propagation, a mechanism by which astrocytes communicate. Human glial progenitor calcium waves propagated at least threefold faster than did mouse cells, which may be attributable to their much larger size and structural complexity.
These differences also likely contributed to the heightened basal level of excitatory transmission and enhanced long-term potentiation that also were observed in this study.
Another study (Park et al 2013) modified NSCs to overexpress choline acetyltransferase (ChAT), which contributes to acetylcholine synthesis. Results:
Interestingly, this group found significant improvements in passive avoidance, Morris water maze performance, and spontaneous locomotor activity in aged mice receiving ChAT-expressing stem cells.
However, it is unknown how much the immune system plays a complicating factor in these studies.
Contribution of Different Transplanted Cell Types to Cognition
- The traditional goal of NSC was to replace dead/ dysfunctional neurons for neurological disorders. In the context of Parkinsons Disease, this has been disappointing, yielding only mild effects on motor movement and no significant effects on cognition.
- Arguments can be made for transplantation of NSCs and progenitors of other cell types (like astrocytes) that might influence cognition via more indirect mechanisms. (Again, see the complicating figure).
Glial Precursor and Astrocyte Transplantation
Most studies of glial progenitor transplantation focused on spinal cord disease and injury.
One exception: Bruckner and Arendt, (1992) compared capacity of fetal brain tissue and purified astrocytes to improve ethanol-induced cognitive deficits.
- Found that astrocytes, but not fetal brain tissue grafts, could restore memory (as measured via radial arm maze). 10
- Bradbury et al 1995 reported – astrocyte-induced cognitive imporvements likely resulted from altered immune and trophic activity.
- Finally, recent developments in cell reprogramming research have identified that astrocytes may be a more useful parent cell type than the commonly used skin fibroblast (Tian et al., 2011).
- Tumorigenesis. Because the neural stem cells replicate, they could be the seed of a tumor.
- Delivering Stem Cells to the Brain. There is no easy way to do it.
- increasing endogenous neurogenesis
- directly transplanting stem cells into the brain
Stem cells have direct and indirect influences on cognition through multiple mechanisms. There is a growing body of evidence that transplantation of neural stem cells does indeed have reliable positive effects on cognition, and is a promising method for both treating neurological disorders and improving cognition in healthy adults.
- For an initial look at the ethics of neural stem cell transplantation, see Master 2007. A framework for assessing the ethics of general cognitive enhancement is here. ↩
- For example, Wu et. al (2008) found that neural stem cells with transgenic expression of human nerve growth factor (hNGF) implanted into rat brains showed remarkably improved capacity to integrate into host tissue, and continued secretion of neurotrophic factor over time. For more details on their hNGF-expressing neural stem cells, see my rough notes from the paper. ↩
- Along with the subgranular zone of dentate gyrus, the subventricular zone serves as a source of neural stem cells in the process of adult neurogenesis. It harbors the largest population of proliferating cells in the adult brain of rodents, monkeys and humans. – Gates (2004) ↩
- (Ernst et al., 2014 and Spalding et al., 2013) ↩
- Ernst et al. (2014) ↩
- Raffa et al., 2006 and Staat and Segatore, 2005 ↩
- reviewed by Cotman et al., 2007, Cotman and Berchtold, 2002, van Praag, 2008 and van Praag et-al, 2005 ↩
- (Madsen et al., 2000, Perera et al., 2007, Li et al., 2009 and Peng et al., 2008 ↩
- Belarbi et al., 2012 ↩
- Bruckner and Arendt, (1992) ↩