Biology references for cortical pathways


Hi all,
HTM theory suggests a cortical microcircuit with some differences from the canonical microcircuit. If people would be able to share some of the paper references for the HTM information pathways, it would be greatly appreciated. Specifically, the recent suggestions that the main FF pathway up the hierarchy is from layer V and not III, and that the information for the coordinate transform is long range connections into layer VI (from where, laterals in layer VI?). Yes there are pathways diagrammed in the Thomson papers and the HBP database, but have targeted studies suggested/confirmed these hypotheses? Thanks in advance!



Hi Alex,
Regards to L5 being the main feed forward pathway going up the cortical hierarchy: This idea originated with Murray Sherman at the U Chicago. He has been promoting it for many years. He has written multiple papers on this topic and it is featured heavily in his most recent book. I know I read at least one other paper from another lab that specifically tested this hypothesis with a positive conclusion. Unfortunately I can’t recall the authors. I suspect with a bit of literature searching you can find some relevant papers. You can always email Murray and ask him the state of support.

Everyone agrees that both L2/3 and L5a project to the next region. The question is what are their relative roles. Sherman argues that the L5a pathway, which goes through relay cells in the thalamus, is the main “driver” pathway. Although the number of axons is numerically smaller than L2/3, those axons are large and form large synapses on the recipient layers L4 and L6a. Hence they can make the recipient neurons fire. The axons from L2/3 are numerically greater but form smaller synapses that are not proximal, therefore they play a “modulatory” role. Another supporting piece of evidence is that primary sensory regions only get input via the thalamus; there is no equivalent of a feed forward L2/3 path. If the primary driver input to primary sensory regions is via the thalamus then it would be very odd if that wasn’t true of higher regions which exhibit the exact same pathway and anatomy. Another piece of evidence is that the L5a/thalamic neurons seem to only target the higher region, whereas L2/3 cells project many places, not just to the next higher region.

We did some literature searches on the question of long range connections into L6 between “what” and “where” regions. Thomson stated these exist in her review paper. I read the papers she referenced and a bunch of others. The anatomical evidence was not conclusive. There seems to be a general level of agreement that what and where (motor and sensory) regions are highly interconnected. There seems to be evidence that most of these connections arrive in the lower layers. But I couldn’t find out which L6 cells receive this input. I also found evidence that these connections originated in multiple layers on the “where”/motor side, which somewhat contradicts what Thomson said. As is often the case, the different studies used different animals and protocols. This makes it extremely difficult to reach definitive answers.

I am sorry that I can’t cite specific papers, but as you know I have no memory for authors. It isn’t hard to find these papers with a bit of searching on Google Scholar or elsewhere.


In neuroscience circles, the paper by Constantinople and Bruno [1] has been very influential in lending credence to Sherman’s hypothesis that L5 is a primary FF pathway. Through their experiments, they argue convincingly that L2/3 cannot be the primary pathway. The L5/6 pathway is at least equally important. They show, for example, that L2/3 cannot be driving L5/6, which is the classical assumption. Their detailed timing studies show that L5/6 might actually become active slightly before L2/3. A quote from their paper:

L5 neurons make up a major output of the cortex, as they have the most substantial axonal innervation of subcortical and cortical structures.

Larkum has also argued for a while that the L5 pathway is highly significant for complex cortical processing [2]. At a conference in September he showed very convincing evidence that selectively disabling L5 cells in sensory areas prevented decisions and/or motor responses controlled by higher level and motor areas. This was convincing (to me at least) that L5 is required for higher level processing.

At some level arguing that these pathways “primary” vs “secondary” is purely a matter of semantics. Both pathways play important roles. What is clear though is that the L5/6 pathway is at least equal in importance to the L2/3 pathway. This evidence completely contradicts the classical “one pure feed-forward hierarchical pathway” model of recognition. As far as I know there are no published computational models that explain the role of L2/3 in combination with L5/6.


  1. C. M. Constantinople, R. M. Bruno, Deep Cortical Layers Are Activated Directly by Thalamus. Science (80-. ). 340, 1591–1594 (2013). Available at:

  2. M. Larkum, A cellular mechanism for cortical associations: an organizing principle for the cerebral cortex. Trends Neurosci. 36, 141–51 (2013). Available at:


Thank you @jeff and @subutai, this is very helpful.

Regarding the suggestion that L5 projects FF info and not L3, Jeff’s succinct summary of the evidence + the Constantinople and Bruno paper make a strong case. If I reach out to Sherman I’ll be sure to share his thoughts here.

It’ll be interesting to see the specifics of this Larkum study; I don’t think it’s any of his publications here.

“primary” vs “secondary” is purely a matter of semantics

This is a very good point. So much of the literature tries to fit observed connectivity into concise pathways because we favor simplicity, a bit too much perhaps. Similarly, Thomson has an interesting note on avoiding the terms ‘feedforward’ and ‘feedback’ because they’re “nonsensical” — the connectivity implies more complex circuits than one-way processing — but here I am preaching to the choir :wink:


On that page, I believe it is the first one, authored by Naoya:

Naoya Takahashi, Thomas Oertner, Peter Hegemann, Matthew E. Larkum. (2016) Perceptual Detection depends on Dendritic Mechanism in Cortical Pyramidal Cells. Science; In press

Looks like it got accepted to Science - cool! It should be coming out soon…