Monday, August 3, 2009

Neocortex, Allocortex, and Nuclei, and the Remapping of Their Connections
The mammalian brain is made up of many parts, each pretty much unique.  However, these various parts, or at least the "gray matter" of them, can be roughly grouped into three classes of structure, or even more roughly into two: nucleus and cortex.  The word "cortex" comes from the Latin, meaning "bark", "rind", "shell" or "husk".  In the case of gray matter, it usually denotes a relatively thin layer of gray matter covering thicker white: such as the neocortex, the piriform cortex, or many other cortical areas in mammals and other vertebrates.  In a recent post, I described the neocortex, comparing and contrasting it with other forms, which are loosely grouped together as "allocortex".  (Meaning "other cortex" with a connotation for "other" of "like but not identical".  This from the Greek prefix "allo-" which we may contrast with the alternative prefix "hetero-" which means "unlike".)

The class of structure I haven't touched on yet is the nucleus: defined by Wiki as "a brain structure consisting of a relatively compact cluster of neurons." Quoting further:
The term "nucleus" is in some cases used rather loosely, to mean simply an identifiably distinct group of neurons, even if they are spread over an extended area.  The reticular nucleus of the thalamus, for example, is a thin layer of inhibitory neurons that surrounds the thalamus.
In this respect, the word parallels "allocortex", which also covers a variety of forms.  Only the Neocortex has a very precise description, and even here only by excluding the parts of the hippocampus in which neurons mature from the outside in as they do in the neocortex.  In addition, the cortical structure of the Cerebellum should probably be given its own term, considering the very old and very sophisticated developmental mechanisms unique to it.  I'm not going to discuss the Cerebellum in this post, it deserves its own, along with more detailed research than I've done to date on its evolution.

In several posts, I've discussed the general nature of the "gray matter", focusing on "neuropil", which is generally defined as a tangled mass of neurites, glial and sometimes neural somas, and glial extensions (which would be called neurites if they were possessed by neurons rather than glia).  The neuropil is where the real work of calculation takes place, since is contains most of the active dendritic arbor (one way or another) as well as most of the synapses and a goodly part of the axonic arbor.  The relationship between the mass of neural somas and the neuropil varies by region of the brain, being different in at least some details for just about each region studied.

In many parts of the brain and Central Nervous System (CNS) a set of similar structures call glomeruli turn up.  These have been extensively studied and described in the olfactory system, where they are part of the olfactory bulb, which forms a "way station" of sorts between the olfactory epithelium which contains the actual sensory cells, and the deeper parts of the brain, including the piriform cortex and the amygdala and hypothalamus.

Glomeruli have also been studied in the cerebellum (Wiki only describes them in these two spots, as well as superficially similar structures in the kidney), but studies have been made of similar structures in many places in the CNS, including, for instance, the trigeminal nucleus.[1]  In general, a glomerulus can be described as a tangle of neuropil surrounded by a tighter structure of neural and glial somas cells with extensions of both into the central part.  In many (perhaps most) types of glomeruli, diffusion of neurohormones through the central part is easy and fast enough that most of the neurites inhabit the same extracellular concentrations of signaling molecules, at least on a time-scale of seconds or more.  The tight structure of the surrounding cell bodies, along with (presumably) greater uptake rates by glial cell membranes, would tend to isolate the concentrations within any one glomerulus from even its nearest neighbors.  In contrast to the typical neuropil of the neocortex, where concentrations of emitted extra-synaptic neurohormones might vary over micron scales or less, it seems likely that the extra-synaptic concentrations of glomeruli are pretty much normalized.

All of these brain structures depend on the axon bundles (called "tracts" in the brain, although they are called "nerves" in the periphery, per Wiki) to transmit information between the more detailed calculations in the neuropil.  ... Indeed, in the more traditional view, the primary calculation was simply whether/when to fire an action potential, which was regarded as the key to the brain's activity.  Recent research has thoroughly undercut this view, as I've discussed in several posts.  However, even with this new information, the "wiring" of axonal connections is critical to the working of the brain.

Which brings us to a very important research paper,[13] published in last Friday's Science Magazine: Pre-Target Axon Sorting Establishes the Neural Map Topography (by Takeshi Imai, Takahiro Yamazaki, Reiko Kobayakawa, Ko Kobayakawa, Takaya Abe, Misao Suzuki, and Hitoshi Sakano).  This paper is, unfortunately, behind a paywall, but I'm going to describe the finding in general terms, then go on to its importance, especially in terms of how we can generalize from the olfactory system to the brain in general.

We need to start with a brief description of how the olfactory sense in mammals works: it begins with the olfactory epithelium, which is a structure inside the nose, where mucus with absorbed volatiles comes in contact with olfactory sensory neurons (OSNs).  (There is a organ called the vomeronasal organ which is the input to the accessory olfactory system which I'm not going to discuss here.)  Each OSN expresses one specific odorant receptor (OR), of which there are around a thousand in mice, rabbits, and other mammals that have retained the ancestral focus on this sense.  (Humans have about 350.[23])  Actually, this is the number of genes, there are two copies, one from each parent, and any specific cell only expresses one of those copies.[13] 

The distribution of OSNs expressing any one OR within the olfactory epithelium tends to be quite specific, pretty much identical from one member of a species to another.  Although the surface of the olfactory epithelium is rather convoluted, it can be unfolded into a roughly planar surface, extending from dorsomedial (upper/inner) to ventrolateral (lower/outer) in one dimension, and anterior to posterior (front to back) in the other.  The OSNs expressing a specific OR will all lie in a rather narrow stripe extending all the way from anterior to posterior, but only a small part of the dorsomedial to ventrolateral dimension.[13] 

Now, as mentioned above, the olfactory bulb serves as a "way station" between the olfactory epithelium and the deeper (higher) regions of the brain.  What happens is that there's one glomerulus (on each side) in the olfactory bulb for each specific OR, and axons from all the OSN's expressing that OR end up at that glomerulus.  The surface of the olfactory bulb, like the olfactory epithelium, can be mapped as a rough plane, and the dorsal-ventral axis seems to map clearly to the dorsomedial-ventrolateral axis of the olfactory epithelium.  So any glomerulus will show up at a location on the dorsal/ventral axis of the olfactory bulb that corresponds to the location of the stripe on the olfactory epithelium.  (Actually, there are two sections to the olfactory bulb, the "Main olfactory bulb" and the "Accessory olfactory bulb", part of the accessory olfactory system, but this is not really critical to the discussion at hand and will be left out.)

But it's much more complex along the other axis.  There are many different OSN's occupying the same stripe of the olfactory epithelium, and there will be many glomeruli occupying a similar (mapped) stripe within the olfactory bulb.  How do the neurons sort themselvs out so that all of those expressing one OR end up at the same glomerulus?  What Imai, Yamazaki, et al. have demonstrated is that the axons actually sort themselves into their proper order while growing from the epithelium towards the bulb.

They do this using varying gradients of expression of Neuropilin-1, a multi-purpose receptor for several agonists, including "the secreted repulsive ligand Semaphorin-3A (Sema3A)." This ligand is "expressed not only in the target, but also in OSNs.  Single-cell microarray analysis revealed that Nrp1 and Sema3A genes are regulated in a complementary manner by OR-derived cAMP signals".[13]  That means that the more the ligand is expressed, the less the receptor is, and vice versa.  By appropriate responses of the growing axons, the axons can sort themselves into the proper order before ever reaching their target in the olfactory bulb (OB)[19]:
We found that pre-target axon sorting plays an important role in the organization of the topographic map.  Nrp1 and its repulsive ligand Sema3A are both expressed in OSNs and are involved in axon sorting before targeting on the OB.  Within the axon bundles of D-zone OSNs, DII-A axons (Nrp1 low, Sema3A high) are sorted to the central compartment of the bundle, whereas DII-P axons (Nrp1 high, Sema3A low) are sorted to the lateral-peripheral compartment.  This sorting appears to occur, at least in part, by the repulsive interaction between Sema3A and Nrp1.  In addition to the repulsive interactions, Sema3A and Nrp1 signals may induce homophilic adhesion of axons with Nrp1 itself ([ref]) or with other molecules such as L1 ([ref]).  Furthermore, additional guidance receptors such as Plexin-A1 ([ref]) may be involved in the sorting of DII-A and DII-P axons (fig.  S7).  We assume that similar mechanisms are also at work in the sorting of DI and DII axons (Fig.  1B).

Once OSN axons are sorted in the bundle, they need to be oriented along the correct axis before projecting onto a topographic map on the OB.  This probably requires positional cues that are derived from the target or that are found along the pathway between the olfactory epithelium and the OB.  In the Sema3A total knockout, Nrp1-positive DII-P axons spread rather uniformly across diameter of the bundle (Fig.  5B) and consequently mistarget to the anterior region in the OB (
[refs]).  The effect is different in the OSN-specific Sema3A knockout, where DII-P axons at least gravitate toward the lateral region in the bundle (Fig.  5B).  Thus, Sema3A expressed by cells outside of the bundle likely functions as an additional guidance cue to orient the sorted axons along the correct axis for projection onto OB.  In early embryos, but not in postnatal mice, Sema3A is expressed in the anterior OB (Fig.  5A).  Furthermore, Sema3A is found in ensheathing glial cells along the medial side of the axon bundles (Fig.  5A) ([ref]).  Involvement of such intermediate cues has been reported for the thalamocortical projection ([refs]).[13]
What this means is that the growing axons use varying expressions of the same ligands and receptors as their targets to orient and sort themselves into a rough approximation of the distribution of their targets, before the axon bundle ever reaches that target.  In addition, there is evidence that similar varying expression (or at least secretion) of the ligands involved is provided by supporting glial cells.  (Both neurons and glial cells have the ability to localize their secretion of various signaling molecules, as discussed in Nerve Cells and Glial Cells: Redefining the Foundation of Intelligence)

The implications are important.  In a recent review: Development of Continuous and Discrete Neural Maps (by Liqun Luo1 and John G.  Flanagan), which is open access, the differences between discrete neural maps such as found in the olfactory system, and continuous neural maps such as found in the retina and early visual areas of the brain, are discussed in detail.  "Since visual retinotopic and olfactory glomerular maps represent two ends of a continuum that includes many other types of neural map in between, these emerging general principles may be widely applicable to map formation throughout the nervous system."[11] The mechanisms used are very similar, although the precise means by which each OR maps to a specific concentration ratio of ligands and receptors appears to require more research.  (My guess would be that the ORs actually release varying levels of cyclic Adenosine MonoPhosphate (cAMP) a signaling molecule used within the cell for a wide variety of purposes.  Their levels of release in guiding axon growth are probably (IMO) independent of the level of release found when operating as olfactory receptors, presumably a different mode of stimulation is used during developmental nerve growth.)

What these facts demonstrate is that the axon tracts linking any two parts of the brain, can rearrange themselves from the source mapping to the target mapping.  In the case of the olfactory epithelium, the "mapping" on the anterior/posterior axis appears to be random,[13] for other systems, where it isn't actually random, such mapping can be treated as though it was.

Technically, only one of the two dimensions involved here is remapped, with the dorsomedial-ventrolateral axis of the olfactory epithelium mapping directly (ie without the need for remapping) to the dorsal/ventral axis of the olfactory bulb.  So we can't use this as actual proof that brain regions can remap more than one dimension.  However, if a mechanism like this can be developed once, it can be developed more times, and it's completely plausible that several dimensions of an n-dimensional space could be remapped between communicating brain regions.  This is especially important in the neocortex, where the kind of complex and abstract n-dimensional transformations these functions support could be critical to making intelligence as we know it work.

I've discussed these ideas in Concepts, Cognition, and Anthropomorphism; this remapping process represents a critical enabling function for this kind of operation.  The fact that it shows up in the olfactory system, arguably older than the neocortex, suggests that the development of this capability, or at least certain critical refinements of it, may have been a sine qua non for the development of the neocortex.  Of course, until research into the presence (or absence) of such remapping is done in lizards, turtles, and amphibians, we can't actually know that the entire mechanism wasn't inherited from an earlier ancestor.  Indeed, it may have been present in the earliest jawed fishes.  Still, the appearance and expansion of the neocortex is significant, and until the needed research has been done, it might be best to tentatively assume that some improvements in neural remapping took place just prior to the development of the neocortex.

As for the nuclei, it may well be that these structures are primitive, in the sense that they don't require such remapping, or at least didn't in early vertebrates.  Perhaps the default structure for early nuclei was for each incoming axon to arborize over the entire nucleus, picking and choosing its target cells entirely on the basis of local interactions.  But once the remapping capability had been developed, it seems very likely it would have been reused for tracts targeting those nuclei where it would have been useful.  Thus, we can't assume that nuclei in the mammalian brain don't involve such remapping processes.

Imai, T., Yamazaki, T., Kobayakawa, R., Kobayakawa, K., Abe, T., Suzuki, M., & Sakano, H. (2009). Pre-Target Axon Sorting Establishes the Neural Map Topography Science, 325 (5940), 585-590 DOI: 10.1126/science.1173596

Links:  Only a few of these are actually called out in the text. I've only included the link called out in this leader.  Use the "back" key if you came by clicking a footnote. 

1.  Synaptic organization of the substantia gelatinosa glomeruli in the spinal trigeminal nucleus of the adult cat paywall

2.  From Pheromones to Behavior paywall

3.  Evolutionary Convergence of Higher Brain Centers Spanning the Protostome-Deuterostome Boundary paywall

4.  Lungfish evolution and development paywall

5.  Forebrain evolution in bony fishes paywall

6.  Dendritic neurotransmitter release and its modulation in accessory olfactory bulb circuits

7.  Localization and Targeting of Voltage-Gated Ion Channels in Mammalian Central Neurons

8.  Primary innervation of the avian and mammalian cochlear nucleus

9.  Origin and function of olfactory bulb interneuron diversity paywall

10.  Distribution and phenotypes of unipolar brush cells in relation to the granule cell system of the rat cochlear nucleus

11.  Development of Continuous and Discrete Neural Maps

12.  Contributions of Theoretical Modeling to the Understanding of Neural Map Development

13.  Pre-Target Axon Sorting Establishes the Neural Map Topography paywall

14.  Requirement for Slit-1 and Robo-2 in Zonal Segregation of Olfactory Sensory Neuron Axons in the Main Olfactory Bulb

15.  Odorant Receptor–Derived cAMP Signals Direct Axonal Targeting free registration required

16.  Roles of odorant receptors in projecting axons in the mouse olfactory system paywall

17.  Tenascin-C Is an Inhibitory Boundary Molecule in the Developing Olfactory Bulb paywall

18.  Axons find their way in the snow paywall

19.  Odorant receptors at the growth cone are coupled to localized cAMP and Ca2+ increases

20.  Neural map specification by gradients paywall

21.  Innate versus learned odour processing in the mouse olfactory bulb paywall

22.  Odor maps in the olfactory cortex

23.  Neurobiology: Odorant receptors make scents paywall

24.  Brain

25.  Cholinergic Modulation of Dopaminergic Neurons in the Mouse Olfactory Bulb

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