Monday, June 30, 2008

Microglial origin

Continuation of the Glia series:
Here is what the authors on the topic in Encyclopedia of the Human Brain, Guido Stoll, Sebastian Jander and Michael Schroeter have to say on the topic, p. 34 Vol 3:
The origin of ramified microglia has been a long-standing controversial issue, although most authorities would accept that microglia are bone marrow derived and belong to the monocyte/macrophage lineage. The observation that the decline of blood-derived amoeboid cells (macrophages) in the CNS during the first postnatal weeks was accompanied by a dramatic increase in the number of ramified microglia was suggestive for a transition of amoeboid cells into resident ramified microglia. Based on morphological grounds, however, transitional forms between these brain macrophages and resting microglia could not be detected in the developing brain. Moreover, in an attempt to directly address the issue of transition, young mice received bone marrow transplants from transgenic mice, thereby allowing the distinction between host and donor cells in tissues. In these chimeric animals only 10% of parenchymal microglia in the CNS displayed the transgenic signal. In adult animals attempts to directly demonstrate the replacement of ramified parenchymal microglia from bone marrow-derived precursors have so far yielded inconclusive results. Ramified microglia in the adult CNS are an extremely sessile cell population exhibiting virtually no turnover from circulating monocytic precursor cells. In contrast to the parenchymal microglia, the perivascular microglia are definitely bone marrow derived and regularly replaced in the adult CNS as demonstrated by use of chimeric rats by Hickey and Kimura.

The view that parenchymal microglia are bone marrow derived has been challenged. Based on their finding that astroglial cultures initiated from newborn mouse neopallium contained bipotential progenitor cells that could give rise to both astrocytes and microglia, Fedoroff and colleagues put forward the idea that parenchymal microglia are of neuroectodermal origin as are all other glia. This view was further supported by the observation that the majority of microglia lacked the transgenic signal after bone marrow transplantation as described previously. Despite the uncertainty about their origin, microglia share most surface molecules with bone marrow-derived monocytes/ macrophages."

Neuroectoderm is a term researchers are using to replace 'neural crest derived tissue'.
I found a little picture of Fedoroff in a 2007 newsletter from U of Sask. (12 page pdf), a picture taken way back in 1963, and featured as an archival photo.

A written description below identifies Fedoroff as the man standing in the photo.
Alas, I was unable to retrieve the reference cited, which is in a book:
Fedoroff S (1995). Development of microglia. In Neouroglia (H. Ketterman and B.R. Ransom, Eds.), pp 162-181. Oxford University Press, NY.

I couldn't find very much that has been published on the topic, or any other papers by Fedoroff that discuss neuroectodermal origin of microglia.

The three chapter authors appear to be quite busy.. here is another chapter they have written elsewhere.

Saturday, June 28, 2008

Monkey intentions and control of a robotic arm
In a brief departure from a current catch-up I'm doing on glia, I want to catch up some old posts, thoughts, themes and developments to do with the brain as movement simulator.

In reference to blogposts The devil is in the Details (Dec 18/07), More on Learning (Dec 21/07), and The User Illusion, Dec. 22/07:

Today Deric Bownds Mindblog post featured a short piece about a big big topic:
Science Hack - monkey brain moving robotic arm. Readers can follow the links and find the great little video - as usual, a food reward proved to be the most effective for getting a monkey to neuroplasticize its brain... this monkey can't move its own arm but it learned to move the robotic one to reach food and put it into its own mouth. Remarkable. It appears that with the right motivation a brain can learn whatever it needs to.

Additional Reading:
Differences Between Intention-Based and Stimulus-Based Actions (12 page pdf)

Friday, June 27, 2008


ResearchBlogging.orgIn reference to About Glia:

I just waded through the entire chapter on astroglia in Encyclopedia of the Human Brain. I discovered it was written by two researchers in France, Nicole Baumann and Danielle Pham-Dinh. The chapter is extensive (from p. 251-268 in Vol. 1) and I've still only scratched the surface of what is available in this large reference work on glia.

Here is the concluding section of their chapter:
The importance of glia has become increasingly clear with the development of molecular biology and cell culture techniques. With technical progress, the roles of glia in neuronal migration in the development of neuronal pathways as well as in synaptic functions have bee deciphered. Increasingly, the molecules involved in developmental processes and in the adult are being identified; molecules necessary for the migration of neurons on radial glia or Bergmann* cells are made by neurons or glia with multiple interactions. Molecular studies of developmental mutants and human pathologies have led to the identification of the involvement of glia in numerous defects of migration that lead to microcephaly and other developmental diseases.

In many cases, axonal guidance seems to involve preformed glial pathways that may remain and create glial boundaries. Increasingly these neuroglial interactions are being identified in relation to neuronal functions. Because of their mobility and plasticity, glial cells appear to be increasingly involved in the functions of the cabled neuronal network. Synapses throughout the brain are ensheathed by astrocytes. Astrocytes help to maintain synaptic functions by buffering ion concentrations, clearing released neurotransmitters, and providing metabolic substrates to synapses. As recently reviewed, glia should be envisaged as integral modulary elements of tripartite synapses because they are now playing an active role in synaptic transmission and are fully involved in neuron-astrocyte circuits in the processing of information in the brain. They are indispensable in obtaining nutrients from the blood and helping to maintain the blood-brain barrier. For energy metabolism, these glial cells take up glucose from the brain capillaries and transform it into lactate and other fuels absolutely necessary for the neurons to function. The metabolic coupling between glia and neurons is increasingly obvious in view of the development of the methods of investigation, even in vivo; astrocytes contribute to the deoxyglucose signal in PET, which may give new insights into the interpretation of this signal in neurological and psychiatric disorders. Astrocytes are necessary to avoid the excitotoxic role of glutamate through the glutamate-glutamine cycle, which is pivotal, as are probably other neurotransmitter cycles. One of the recent developments is the way in which communication can occur through glial cells by calcium waves; this seminal discovery has been followed by a wealth of work demonstrating that calcium signaling can extend even to neurons and can be bidirectional. It is possible that astrocytes may provide new means of communication in the nervous system and new pathways not yet clearly defined. No doubt, there are enormous gaps to fill in relation to their functions in vivo; hints have been provided, for example, by the observation that they are modulated by circadian rhythms and hormonal states.

Although myelin repair and synaptic remodeling and regeneration can occur, many enigmas still remain, especially in humans, in which the factors may be different from those in the murine species. Thus, studies in primates and in vivo systems cannot be omitted at this stage in view of therapeutic implications.

The dysfunction of glial cells is possibly at the origin of many of the degenerative diseases of the nervous system and the major brain tumors (glioma). Although the neuroimmunological role of astrocytes as antigen presenting cells is still unclear in the CNS under in vivo conditions, their role in neurodegenerative diseases seems increasingly evident because they are implicated in the suppression of oxidative stress. No doubt, in the near future, we will understand more about the cross talk between glial cells and neurons in normal and pathological states. Already, abnormal astrocytes and oligodendrocytes appear to be involved in cognitive functions as evidenced from leukodystrophies related to oligodendrocyte or astrocyte genetic disorders. Recently the primary genetic defect of Alexander disease was demonstrated in astrocytes where mutations of GFAP lead to a secondary demyelinating disease, enlightening the pivotal role of astrocyte on oligodendrocyte and myelin maintenance.

Progress in neuroscience has shown that neurons and glia do not represent just the addition of independent compartments and that the cooperation of both cell populations is essential for development and functions of the nervous system. As mentioned by Peschanski, the time has come for "neurogliobiology" because neurons and glia (including astrocytes, oligodendrocytes and microglia) in the nervous system are indissociable partners."

* Bergmann cells are a subtype of astrocyte located in the cerebellum; they help maintain synapse junctions between Purkinje cells and climbing fibers.

Additional reading:
1. Also by Nicole Baumann and Danielle Pham-Dinh: Biology of Oligodendrocyte and Myelin in the Mammalian Central Nervous System. They seem to be the go-to people for basic fundamentals on glia.
Baumann, N., Pham-Dinh, D. (2001). Biology of Oligodendrocyte and Myelin in the Mammalian Central Nervous System. Physiological Reviews, 81(2), 871-927.

Sunday, June 22, 2008

About glia

This is the first post of several I intend to make about glia, a class of neural (but not neuronal) cells that I really don't know enough about yet. Now, having become rather interested in synapses, I've come to see the need to know more about the cell basics.

I started out with the Encyclopedia of the Human Brain. In Volume 3, p. 480, I gained a sense of proportion. Glial numbers exceed neurons by a factor of 10 to 1. They account for 50% of the volume of the entire brain. Volume, not numbers. They are tinier.

p. 406, I learned a bit about four main types:

- Glia are far more abundant than neurons in the brain
- Glia of the brain and spinal cord are classified into four types:
1. astrocytes
2. oligodendrocytes
3. microglia
4. ependymal cells

- are starshaped glial cells found in both gray and white matter
- have a role in the mechanical support of neurons
- contribute to metabolic regulation of the micro environment of the brain
- participate in its response to injury

- are confined mainly to white matter
- are responsible for the myelination of brain axons (as Schwann cells are in the PNS)

- are small cells found in gray and white matter
- serve as the phagocytes of the brain
- migrate as necessary to damaged areas where they consume pathogens and neuronal debris

Ependymal cells
- line the ventricles of the brain
- at a specialized structure called the choroid plexus (one of which is found in each ventricle) they form a secretory epithelium that produces the CSF that fills the ventricles and bathes the entire CNS

There is some debate about their origins. For now I'm going to go with neural crest being their parent progenitor, but will bring the different opinions here later. Microglia pose the biggest departure, because they are scavengers, macrophagic in behavior, thought to come possibly from a hemopoietic source. However, I wouldn't put it past neural crest to be quite capable of making a version of brain cell that behaves just like a macrophagic cell that originates with mesoderm.

Further reading:

1. NIH Public Access: Glial cells: Old cells with new twists (2008) (mostly about oligodendrocytes)

2. Neurophilosophy: Nerve glue comes unstuck
- Background on Rudolf Ludwig Karl Virchow (who was responsible for suggesting that glial cells were merely filler, and whose other claim to fame was that washing one's hands to prevent spread of infection was not important.)

3. A Wikipedia link explaining membrane proteins, connexins (small) and connexons (larger, 6 connexins from each cell forming a gap junction between two cells)

4. Neurophilosophy: Starring role in the brain for astrocytes

5. Neurophilosophy: Astrocytes take center stage in brain function

6. Neurophilosophy: Getting a grip on cerebral bloodflow

7. Neurophilosophy: Six iconoclastic discoveries about the brain

(How can you tell I'm a huge Neurophilosophy fan?)

8. Fifty-eight page paper about oligodendroctyes by Nicole Baumann and Danielle Pham-Dihn: Biology of Oligodendrocyte and Myelin in the Mammalian Central Nervous System (2001)

(These two authors also have a chapter on astrocytes in Encyclopedia of the Human Brain)

Wednesday, June 18, 2008

Synapse Proteomics

Lily Tomlin, in her comedic role as Trudy the bag lady, in the 1991 film Searching for Signs of Intelligent Life in the Universe, mentioned that she thought she likely suffered from a few "lapses in the synapses."

In all seriousness though, both Deric at Mindblog and Mo at Neurophilosophy have referred recently to work being done on synaptic complexity.

1. Deric's post, Increasing complexity of nerve synapses during evolution refers to this Nicholas Wade article in the New York Times, Brain Power May Lie in Complexity of Synapses, which looks at the possibility that the more complex the synapses are, the more brain power there is likely to be.
(Image from the Nicholas Wade NYT article, originally from the journal Nature Neuroscience.)
The NYT article looks at this paper, Evolutionary Expansion and anatomical specialization of synapse proteome complexity by Emes RD, Grant S, et al.

2. Meanwhile, Mo at Neurophilosophy wrote this blogpost: Synapse proteomics & Brain Evolution about the same paper.

In the first part of a series of posts here called Nervous System Basics (see Part I), I wanted to draw attention to the fact that there are 100 billion neurons, 1-10 trillion glial cells, and 100 trillion chemical synapses.

This is just so hard to imagine (i.e., form a mental construct about). And those are just the numbers associated with the complexity due to numbers of microscopic-sized physical structures. Now add large numbers of complexities in the synapses themselves, at a molecular (beyond ordinary microscopic-sized) order of magnitude, and you might catch a glimpse of how complex our brains truly are.


1. It's not just about brain size or numbers of neurons:
From the Wade NYT piece:
"A human brain... is three times the volume of a chimpanzee’s... (however) in fact the synapses get considerably more complex going up the evolutionary scale, Dr. Grant and colleagues reported online Sunday in Nature Neuroscience. In worms and flies, the synapses mediate simple forms of learning, but in higher animals they are built from a much richer array of protein components and conduct complex learning and pattern recognition..."

(From Mo's Neurophilosophy post:)
"a new study which used bioinformatics to compare the synapses of distantly related species suggests that size may not be the most important factor in human brain evolution after all. Instead, the new findings, which were published online in Nature Neuroscience on Sunday, suggest that it is an increase in the complexity and number of synapses that was crucial for the emergence of complex behaviours and cognition."

2. Each synapse has a role in adding complexity and therefore brainpower:
"If the synapses are thought of as the chips in a computer, then brainpower is shaped by the sophistication of each chip, as well as by their numbers. “From the evolutionary perspective, the big brains of vertebrates not only have more synapses and neurons, but each of these synapses is more powerful.." (- Wade quoting Dr.Grant)

(From Mo's post:)
"On the receiving end of the synapses of mammals, immediately beneath the membrane, there is a dense network of proteins called the postsynaptic density (PSD). The PSD contains more than 1,000 proteins, which can broadly be divided into 3 different classes: the components of around 12 parallel but converging signaling pathways.."

3. Synapses preceded nervous systems:
(Wade again:)
"He included yeast cells in his cross-species survey and found that they contain many proteins equivalent to those in human synapses, even though yeast is a single-celled microbe with no nervous system. The yeast proteins, used for sensing changes in the environment, suggest that the origin of the nervous system, or at least of synapses, began in this way."

4. Synaptic problems ("lapses in the synapses") may be responsible for mental disorders (Wade again:)
"The roots of several mental disorders lie in defects in the synaptic proteins, more than 50 of which have been linked to diseases like schizophrenia, Dr. Grant said."

5. Synapses might "evolve" by 'tweaking' themselves? :

In Mo's post, there is a link to this page, on postsynaptic density or PSD. In it is stated the definition; "The postsynaptic density is a multiprotein complex containing membrane proteins, signaling molecules and core PSD proteins." Mo says,
"The PSD contains more than 1,000 proteins, which can broadly be divided into 3 different classes: the components of around 12 parallel but converging signaling pathways, with the components of each one clustered to form an enormous macromolecular complex; the cytoskeletal and scaffolding proteins which tether the complexes to precise locations at the membrane, in close proximity to the receptors which activate them; and the enzymes which regulate the movements and functions of the complexes and their individual components within the membrane.

The regulatory enzymes act by making minor modifications in the structure of the signaling pathway components. One apparently ubiquitous form of modification involves the addition of a small molecule called a phosphate group to a specific site on the target protein. This process, phosphorylation, is catalyzed by enzymes called a kinases. It is reversible, and acts like a switch - the phosphate groups can be removed by another group of enzymes called phosphatases, and the addition or removal of a phosphate group activates or inhibits a target protein.

These signaling pathways are incredibly complex - the enzymes all act on multiple targets, and differ in their effects on each. Furthermore, they are subject to the same regulatory mechanisms as the proteins they regulate. They too can have phosphate groups or other small molecules added or removed, and in some cases, activate or inhibit themselves by catalyzing modifications of their own structure."

(This is really clear, and I'd like to thank you Mo, for being such a good writer on such a difficult topic that even a regular person like me can catch a glimpse of some immense implications...)

6. Proteomics (i.e., the study of proteins) might help researchers unravel synaptic mysteries and reveal more about how the brain "works": (Mo again:)
"The interactions between these signaling pathways are very poorly understood, largely because researchers were until recently only able to investigate one or two of the components at any one time. This is where proteomics comes into its own, because it allows for simultaneous analysis of hundreds or thousands of molecules, enabling researchers to begin teasing apart the pathways and networks instead of plucking individual components out one at a time."

Additional Links/Reading:
1. Genes to Cognition program headed by Seth Grant
2. Grant S; Organization of brain complexity - synapse proteome form and function (2006, open access)
3. Genes2Cognition
4. Grant S; The synapse proteome and phosphoproteome: a new paradigm for synapse biology (2006, 5-page pdf)
5. Hensch TK, Fagiolini M; Excitatory-Inhibitory Balance: Synapses, Circuits, Systems (2003): Chapter 1, The Organization and Integrative Function of the Post-Synaptic Proteome, is by Grant S et al.
6. Ziff EB; Getting to synaptic complexes through systems biology (2006)
7. Short (5 minute) YouTube video: Neurons and Neuro-transmitters
8. Press release June 2009, from the Sanger Institute where Seth Grant works: Origins of the Brain: Complex Synapses drove brain evolution
9. Emes R and Grant SG et al; Evolutionary expansion and anatomical specialization of synapse proteome complexity, Nature Neuroscience, June 2008, open access 8-page pdf

Saturday, June 7, 2008

More about neurogenesis

There are some other posts here that include the topic of neurogenesis:
1. History of Neuroplasticity
2. And it's about brain parts: like hippocampus
3. Nervous Systems Basics VIII: PLASTICITY

Here is a new study on the matter; Spatial Relational Memory Requires Hippocampal Adult Neurogenesis.

Abstract: The dentate gyrus of the hippocampus is one of the few regions of the mammalian brain where new neurons are generated throughout adulthood. This adult neurogenesis has been proposed as a novel mechanism that mediates spatial memory. However, data showing a causal relationship between neurogenesis and spatial memory are controversial. Here, we developed an inducible transgenic strategy allowing specific ablation of adult-born hippocampal neurons. This resulted in an impairment of spatial relational memory, which supports a capacity for flexible, inferential memory expression. In contrast, less complex forms of spatial knowledge were unaltered. These findings demonstrate that adult-born neurons are necessary for complex forms of hippocampus-mediated learning.
(Thank you, Deric Bownds at Mindblog.)

The best general reader book I've found on the topic of neuroplasticity and neurogenesis is the one by Sharon Begley, Train Your Mind, Change Your Brain: How a New Science Reveals Our Extraordinary Potential to Transform Ourselves .

The best general reader book I ever found on the topic of spatial brainmaps is Sandra Blakeslee's book,The Body Has a Mind of Its Own: How Body Maps in Your Brain Help You Do (Almost) Everything Better. (This same author helped Ramachandran write his now-classic Phantoms in the Brain: Probing the Mysteries of the Human Mind.)

Both these authors' books have been discussed or the authors have been interviewed by Ginger Campbell at Brainscience Podcast; there are links to a discussion of Sharon Begley's book (episode 10), and Sandra Blakeslee's interview (episode 23, also #21), and others on neuroplasticity.

More reading:
1. The Reinvention of Self, a 2006 article by Jonah Lehrer in Seed about Elizabeth Gould's pioneering research into neurogenesis in marmosets

Sunday, June 1, 2008

"Sky-blue place" IV: Descending modulation

In reference to:
Locus Ceruleus: "Sky-blue place"
"Sky-blue place" II: Projections
"Sky-blue place" III: Input

This will be the last post in this series.
I think I've turned over most of the stones I could find learning about this cool little brain spot that seems to know just when to wake up the brain and when to be quiet.

I want to bring forward a few more juicy tidbits here, however, from Textbook of Pain 5th Ed.

1. The PAG (periaqueductal grey) and locus ceruleus seem to enhance one another's function: (p. 394:)
"Concurrent delivery".. (of "ethylketocyclazocine,""reported to have μ-agonist properties"), "at doses that together were less than injected in either site alone, produced a significant, naloxone-reversible increase in response latency. These observations were argued to reflect a synergic interaction between these two anatomically distinct systems (Bodnar et al 1991)."
If something is naloxone-reversible it means it has an opioid effect of some kind.

2. Anterior insular cortex projects to LC: (p. 127:)
"Dorsolateral pontine systems may also contribute to cortical control of spinal nociceptive transmission. Increasing GABA levels in the anterior insular cortex produces an analgesic effect that is blocked by intrathecal administration of α-adrenergic antagonists. Because this cortical region projects to the locus coeruleus as well as the RVM, it was suggested that inhibition of the insular outflow disinhibits noradrenergic neurons of the locus coeruleus (Jasmin et al 2003b). This could be through an action in the pons or via the RVM."

I missed this when I did the projections post.
(Note: RVM = rostral ventromedial medulla)

3. Linkage to affective states: (p. 234:)
"Chapman (2004) described how processing of nociceptive signals produces affect in multiple neurotransmitter pathways that project to the cortex. Noradrenergic, serotonergic, dopaminergic and acetylcholinergic fibres and pathways are involved. Drawing on an extensive literature on the biology of emotions (e.g. Gray 1987), noradrenergic pathways are recognized as linked most closely to negative emotional states. Of particular importance are nociceptive afferent systems operating and transmitting through the limbic brain-in particular the locus coeruleus, the dorsal noradrenergic bundle, the ventral noradrenergic bundle, and the hypothalamo-pituitary-adrenocortical axis-to all of the neocortex. These are not specific in their activation to nociception, but are also responsive to non-nociceptive, aversive emotional states. These systems are recognized as fostering survival by allowing biological vigilance to threatening and harmful stimuli, both external and internal. Chapman proposes that the affective dimensions of pain can best be conceptualized as involving a two-stage mechanism. The immediate experience would be akin to hypervigilance or fear, with this rapid response giving rise through efferent messages to visceral and other event-related, autonomic activity that creates a strong negative subjective experience and an affective response involving images and symbols."

4. Supraspinal analgesia: (p. 431:)
"Fibres descending from the RVM to the dorsal horn of the spinal cord are mostly serotonergic, enkephalinergic, glycinergic and GABAergic. The nucleus raphe magnus contained within the RVM and the noradrenergic nuclei (locus coeruleus, subcoeruleus, A5 and A7 cell groups) are major PAG relays for noradrenergic and serotonergic descending pathways, respectively, to the dorsal horn (Kwiat & Basbaum 1992). Rather than the RVM being a homogeneous population of serotonergic neurons, GABA- (and glycine-) releasing neurons are now thought to constitute a significant proportion of spinally projecting RVM fibres (Antal et al 1996). The pharmacology of noradrenergic and serotonergic modulation in the dorsal horn is complex but opioids can also interact with noradrenergic mechanisms and there are many studies showing that the effector mechanism and location for the major noradrenaline target receptor-the α2 adrenoceptor-is very similar to that of opioid receptors."

Here is a picture of where LC is to be found in the brain (see red arrow, image from Atlas of Functional Neuroanatomy and modified).

Look at how tiny it is. (I think if you click on the picture you can enlarge it some more.)

Here is a link to a set of notes I made on this little brain part.