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Olaf Sporns on connectome and brain connectivity

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What if we’ve been studying brain activity for decades without actually knowing how the brain is wired? Neuroscientist Olaf Sporns introduced the concept of the connectome, a complete structural map of the human brain’s network, and explains why understanding connectivity is the missing foundation beneath all of functional neuroscience. Subscribe for more from the Convergent Science Network podcast series. Olaf Sporns, one of the pioneers behind the human connectome concept, joins Paul Verschure at the BCBT summer school to explain why neuroscience needs a comprehensive wiring diagram of the brain. The connectome describes the full set of structural connections between brain regions or individual neurons , the network architecture that generates all the dynamic activity researchers have been measuring for years. The conversation addresses a fundamental gap in neuroscience: everyone records brain activity, but without knowing the underlying connectivity, we cannot explain where that activity comes from or how it is generated. Sporns traces the idea back to Ramon y Cajal while emphasizing that modern diffusion imaging now allows us to infer connectivity in living humans non-invasively for the first time. The discussion explores the relationship between structural connectivity and functional dynamics. Sporns argues that the connectome is not just an anatomical catalog but a framework for understanding how network architecture shapes cognition, behavior, and brain disorders. The challenge is scale , mapping individual neurons remains impossible in humans, but region-level connectivity is now within reach. Key topics include the methodological limitations of current imaging techniques, the difference between structural and functional connectivity, how network science tools from physics and mathematics apply to brain organization, and why the connectome project represents a shift from studying isolated brain regions to understanding the brain as an integrated network. Part of the Convergent Science Network podcast series from the BCBT Summer School.

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Both the triumphs of humanity and its most evil deeds have resulted from collaboration. In a time where humanity is required to aspire to the former and minimize the latter, the question arises of how collaboration arises and why it fails. Surprisingly, this phenomenon, so central to who we are, is not well understood. Hence, a collaborative effort is required to understand collaboration in its full biological, psychological, sociological, cultural, and economic complexity and to translate this understanding into operational impact. This series of podcasts is one step toward achieving these complementary goals. The Collaboration Podcast presents interviews with people who are central orchestrators of collaboration in various domains including business, government, science, art, health, sustainability, and the military. The discussions were conducted by Prof. Dr. Paul F.M.J. Verschure and members of the Program Advisory Committee of the Ernst Strungmann Forum on Collaboration (https://www.esforum.de/forums/ESF32_Collaboration.html) during 2021 and had the goal to sketch a map of opportunities, challenges, and obstacles in human collaboration. The forum took place in May 2022, and now we would like to share this series of interviews with a broader audience. The full report of the Forum will be published in 2023 by MIT Press. The podcast was produced by the Convergent Science Network (https://www.convergentsciencenetwork.org/). Context: The stability of social systems depends critically on realizing sustainable methods of “collaboration,” yet how and by which means collaboration is achieved is not clearly understood; neither are the conditions or processes that lead to its breakdown or failure. Collaboration can be understood as cooperation between agents toward mutually constructed goals. Part of the reason for our lack of understanding is that the phenomenon of collaboration is, by nature, a highly multidisciplinary problem, and effective research into its complexities has been difficult to achieve across the broad range of scientific and technical disciplines involved. The need for a fundamental understanding of collaboration, however, has become increasingly important. Not only does humankind demand answers as it attempts to address critical challenges at multiple scales (e.g., climate change, migration, enhanced automation, social and economic inequality), but ever-increasing technological and economic means of interconnecting people and societies are disrupting long-established, familiar patterns of how we interact. Radical technological changes that are ongoing have the potential to reshape collaboration in ways that are currently hard to predict or influence (e.g., by altering configurations in interaction, information creation, and modes of communication). On one hand, such changes could disrupt hitherto stable forms of collaboration by affecting critical communication channels and traditional roles, as can be observed in the rapidly changing patterns in governance, commerce, and social interaction. Conversely, technology could lead to the emergence of novel, successful forms of collaboration that deviate from traditional “hierarchical” architectures. Evidence of this can be seen in areas as diverse as highly automated manufacturing plants, the open science movement, collaborative software repositories, user-centered services, and the sharing of economy-based modes of organization. Without a fundamental understanding of the mechanisms, processes, and boundary conditions of collaboration, it is not possible to evaluate or predict which of these possible scenarios are sustainable or even plausible. The Forum “How Collaboration Arises and Why it Fails” (May 8–13, 2022, Location: Frankfurt am Main, Germany) Chairs: Andreas Roepstorff and Paul Verschure Program Advisory Committee: Jenna Bednar, Julia R. Lupp, Bhavani R. Rao , Andreas Roepstorff, Ferdinand von Siemens, and Paul Verschure

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  • fast_forward00:00:01 - So we don't have a podcast interview company we should because we would have
  • fast_forward00:00:07 - asked to write a prediction,
  • fast_forward00:00:09 - and I'll read the test we should check that I don't know whatever you said 10
  • fast_forward00:00:16 - years ago we interviewed you,
  • fast_forward00:00:18 - we can now find out I will look it up well if we can all look it up now it should be on the,
  • fast_forward00:00:28 - CS network work, um,
  • fast_forward00:00:34 - yeah, it's not identified, of course, I have the lecture here, no,
  • fast_forward00:00:46 - so, it's a real was a change. Cool. 11 years ago.
  • fast_forward00:00:51 - Yeah, it was 2nd of September 2014.
  • fast_forward00:00:58 - Exactly.
  • fast_forward00:01:07 - And my first slide was a Misty Oxford and Krubisa told me you should apply for
  • fast_forward00:01:14 - grads in asthma, 13 years.
  • fast_forward00:01:20 - And did it work?
  • fast_forward00:01:33 - So, looking here for…,
  • fast_forward00:01:39 - Well, Google's not helping. What are you going to do?
  • fast_forward00:01:44 - Maybe we can do a while for everybody.
  • fast_forward00:01:49 - Well, I think… So, 2014, right? So, let's… Here you can go to the archive.
  • fast_forward00:02:03 - This is 18...
  • fast_forward00:02:15 - But you already had robots, I remember. Oh, yeah.
  • fast_forward00:02:18 - You showed me robots. Then you showed me the walking neural circuits. I remember that.
  • fast_forward00:02:29 - So you were probably way ahead of your time.
  • fast_forward00:02:34 - But nobody cared no okay so let me see what I have here do we have,
  • fast_forward00:02:46 - we have these maybe cortical organization I don't see development really as a separate topic Tony,
  • fast_forward00:02:59 - shall I look at my own talk. Oh, Devo, Devo.
  • fast_forward00:03:04 - Oh, right. Actually, we talked about leptimian, mammalian, transitional,
  • fast_forward00:03:10 - the, how neurogenesis is cranking up.
  • fast_forward00:03:14 - I think some of the progenitors were discovered. Here you are. And, um.
  • fast_forward00:03:26 - This is the Convergent Science Network podcast.
  • fast_forward00:03:31 - Leading researchers in the domain of neuroscience, brain theory,
  • fast_forward00:03:35 - and technology are interviewed by Paul Verschur and Tony Prescott.
  • fast_forward00:03:40 - This is Paul Verschur, together with Tony Prescott of the Convergent Science
  • fast_forward00:03:44 - Network podcast of the BCBT Summer School.
  • fast_forward00:03:49 - And today we're here with our speaker, Sultan Molnar.
  • fast_forward00:03:53 - And Sultan was speaking about the evolution and the development of the neocortex.
  • fast_forward00:03:59 - All right, scroll to the end and see what the prediction is. Yeah, yeah.
  • fast_forward00:04:02 - Really? The cortex. Well, we have math. So I'm fascinated.
  • fast_forward00:04:08 - He's fascinated.
  • fast_forward00:04:13 - So the last three months. The cortex will remain there. So I'm fascinated with
  • fast_forward00:04:18 - the association of these scattered residual cells to cognitive abnormalities.
  • fast_forward00:04:25 - So it's like when you have sloppy builders, they leave some of the building,
  • fast_forward00:04:27 - the scaffold, behind where the adult structure is. Cognitive abnormalities.
  • fast_forward00:04:31 - So it's like when you have sloppy builders, they leave some of the building,
  • fast_forward00:04:37 - the scaffold, behind when the adult structure is finished.
  • fast_forward00:04:41 - They haven't done a good job anyway in the adult structure because they left
  • fast_forward00:04:46 - the scaffold inside and then they can't remove it.
  • fast_forward00:04:49 - So I'm fascinated with these and that's why I'm so interested in.
  • fast_forward00:04:53 - I agree with Willis from 1664 that many of the cognitive... I'm very good.
  • fast_forward00:04:59 - ...the brain developmental abnormalities and they are... They are...
  • fast_forward00:05:02 - Stop this fucking thing.
  • fast_forward00:05:03 - ...and these short-sized cord cells, or the remnants of them,
  • fast_forward00:05:07 - they tell us quite a bit about how the brain is constructed.
  • fast_forward00:05:15 - And simply because these are the earliest generated cells, to understand them
  • fast_forward00:05:19 - and understand their evolutionary origin.
  • fast_forward00:05:22 - That's why I do quite a bit of comparative work.
  • fast_forward00:05:25 - So although it's a bit more clinically driven, what I want to emphasize is that
  • fast_forward00:05:30 - sometimes it's good to just step back and look at the bigger overall picture.
  • fast_forward00:05:37 - And although it's a simplification, but this subplate is maybe the reptilian
  • fast_forward00:05:42 - framework of our mammalian brain.
  • fast_forward00:05:46 - If we're going to meet up with you in Oxford four years from now,
  • fast_forward00:05:50 - we're going to remind you of this discussion of the day.
  • fast_forward00:05:54 - And we're going to tell you, look, four years ago you made this prediction.
  • fast_forward00:05:57 - Now we're going to go check and see if it came out.
  • fast_forward00:06:00 - What's this one prediction you would like to make you feel most passionate about today in your work?
  • fast_forward00:06:06 - So if in the next four years I could monitor and modulate these transient scaffold
  • fast_forward00:06:15 - cells in the mammalian brain and show that by modulating their function could
  • fast_forward00:06:22 - alter cognitive development,
  • fast_forward00:06:24 - then I would be very, very happy.
  • fast_forward00:06:27 - And if I could extend it to some neuropathology, so histology or even imaging,
  • fast_forward00:06:33 - we have seven Tesla machines.
  • fast_forward00:06:35 - And if I could show that abnormal cortical development will have an impact on
  • fast_forward00:06:41 - these subgrade cells or vice versa, and then I would be very happy.
  • fast_forward00:06:45 - Okay, great. Sultan Lohner, thank you very much for this conversation.
  • fast_forward00:06:49 - Thank you. A little bit unspecific. Yeah, he's so a bit wishy-washy there, right?
  • fast_forward00:06:56 - Okay, so, well, we got work to do now.
  • fast_forward00:07:03 - So, are you up for this, Sultan? Are you ready? Yeah, are you?
  • fast_forward00:07:08 - No, we're recording. We're ready to go. Even the... Oh, sorry,
  • fast_forward00:07:12 - Leah, about the comments.
  • fast_forward00:07:17 - So okay we're back here in 2025 with the Congressional Science Network podcast
  • fast_forward00:07:24 - and it's still Tony Prescott and myself and we're back again with Sultan Mulder
  • fast_forward00:07:29 - who was speaking at our ACBT school.
  • fast_forward00:07:36 - On neurodevelopment and it's also interesting of course that more than 10 years
  • fast_forward00:07:41 - ago we also had an interview We also participated in our summer school then.
  • fast_forward00:07:45 - And one of the things you started out with as an overview in your overview statement
  • fast_forward00:07:53 - was that the brain development is prolonged, right? So it's a continuous process.
  • fast_forward00:08:01 - And also you drew this strong link to evolution and development, right?
  • fast_forward00:08:06 - So when you say prolonged, what do you exactly mean with prolonged,
  • fast_forward00:08:10 - the prolongation how long,
  • fast_forward00:08:14 - So if we compare the human brain development and the proportions of the times
  • fast_forward00:08:21 - allocated to setting up connections,
  • fast_forward00:08:23 - existence of the transient projections with the consolidating adult connectivity,
  • fast_forward00:08:33 - it's extremely long.
  • fast_forward00:08:35 - So we have a lot of time to self-organize based on the input we receive and
  • fast_forward00:08:43 - I think some of this is not present in some of the models we use today so some of the the.
  • fast_forward00:08:52 - Marine models, some of these steps that, for instance, thalamic projections
  • fast_forward00:08:57 - arrive to the cortex and then they accumulate and then they start interacting
  • fast_forward00:09:02 - with the forming cortical circuits, these are within hours or days maximum.
  • fast_forward00:09:07 - Whereas in human, this will go on for several months in utero life.
  • fast_forward00:09:14 - And also, it will continue within the first postnatal years.
  • fast_forward00:09:20 - And I think we are just not used to it, that we have this long period of coexistence
  • fast_forward00:09:27 - of the transient circuits with the adult circuits.
  • fast_forward00:09:32 - So I think we will probably need better models to study these transient circuits.
  • fast_forward00:09:37 - But does that also imply, well, two things.
  • fast_forward00:09:40 - First, how do we measure time in this case? Is it like relative time?
  • fast_forward00:09:44 - That means relative to life expectancy?
  • fast_forward00:09:46 - Right? And then maybe the relationship might be different. because what's the
  • fast_forward00:09:50 - life expectancy of a mouse and also their developmental time so let's say 30,
  • fast_forward00:09:56 - 40, 40 percent of the time they're in development,
  • fast_forward00:10:00 - humans might, if we take like 70 or something like this you also talk about 40,
  • fast_forward00:10:05 - 50 percent of that time is in a developmental phase in some sense if you look
  • fast_forward00:10:11 - at life expectancy of the organism isn't that not becoming constant?
  • fast_forward00:10:17 - I think Barbara Finley established the website called Translating Time.
  • fast_forward00:10:23 - And I think there are all sorts of species where they have the data on certain
  • fast_forward00:10:29 - steps of development they lined up.
  • fast_forward00:10:33 - And I think you can predict what is the relative maturity of a newborn ferret to a newborn,
  • fast_forward00:10:41 - But the question you asked, I don't think anybody ever looked at.
  • fast_forward00:10:47 - To see the developmental time in relation to the life.
  • fast_forward00:10:51 - Like for this brain volume scaling with body size, right?
  • fast_forward00:10:55 - So maybe developmental time scales with life expectancy, right?
  • fast_forward00:10:59 - And then we have an invariant relationship.
  • fast_forward00:11:00 - And then maybe it's a surprise that none of them make surprise.
  • fast_forward00:11:04 - It would be very interesting. Good question.
  • fast_forward00:11:08 - But if you had to make a bet, What would be your bet?
  • fast_forward00:11:11 - Would it be constant, or do you expect that there is a difference between,
  • fast_forward00:11:15 - let's say, rodents and primates?
  • fast_forward00:11:18 - So, looking at this Translating Time website of Barbara Finley and colleagues,
  • fast_forward00:11:24 - I wouldn't make any bets, because we assume that the development is universal
  • fast_forward00:11:33 - and you can compare the time. No.
  • fast_forward00:11:35 - There are some structures where you have a faster development,
  • fast_forward00:11:39 - and evolution is speeding things up, and maybe the cortical development is actually slower.
  • fast_forward00:11:47 - So, for instance, a marsupial, a mododelfis domestica, when it's born,
  • fast_forward00:11:52 - it's like embryonic day 11 mouse, or.
  • fast_forward00:11:57 - But the brainstem is extremely mature in the spiral core because they have to
  • fast_forward00:12:03 - make it all the way from the uterus to the nipples because otherwise they don't get food.
  • fast_forward00:12:09 - So with their brainstem, they crawl up, pop onto the nipples,
  • fast_forward00:12:13 - and then they start developing further.
  • fast_forward00:12:16 - And then their cortex will develop a bit later.
  • fast_forward00:12:19 - So the brainstem is maturing much earlier than the cerebral cortex in these animals.
  • fast_forward00:12:26 - So I wouldn't be surprised if some subcortical brain structures would develop
  • fast_forward00:12:35 - with a different speed compared to the cortex.
  • fast_forward00:12:39 - So I think you answered the question almost in your topic.
  • fast_forward00:12:43 - There's chimpanzees, you said their brain is mature in two years.
  • fast_forward00:12:46 - Well, the size, yeah. But their life is back on.
  • fast_forward00:12:52 - Yeah, but that's size, right? That's not, I say, white matter tracks and connectivity and so on.
  • fast_forward00:12:57 - Neuropeal and the thickness of the cortex and this kind of thing,
  • fast_forward00:13:00 - it plateaus at two, whereas we plateau at 11 or 12.
  • fast_forward00:13:05 - And our living expeditence is only double or triple, yeah.
  • fast_forward00:13:11 - Okay. So maybe, maybe, but I will look into this because it would be interesting.
  • fast_forward00:13:17 - Yeah, but it's got a second implication, then, is if you say it is prolongated,
  • fast_forward00:13:22 - that then raises the question, is it prolongated as some self-organizing process,
  • fast_forward00:13:28 - or is it prolongated by virtue of having some meta-controllers that ensure that
  • fast_forward00:13:34 - it develops as a stable system?
  • fast_forward00:13:37 - Because imagine it's just a self-organizing process.
  • fast_forward00:13:41 - The more time you give it, the higher the risk, and it will become stable.
  • fast_forward00:13:45 - So does it suggest that there is a meta-level developmental controller at work?
  • fast_forward00:13:51 - I think what is probably happening is that it's not a homogeneous maturation across the cortex.
  • fast_forward00:13:58 - So I think some cortical areas crystallize way before some others.
  • fast_forward00:14:03 - So for instance, the frontal regions, they don't myelinate until you are 21 or even later.
  • fast_forward00:14:10 - So probably there is a reason why we leave it so late.
  • fast_forward00:14:14 - And also there is a sequence how these connections develop.
  • fast_forward00:14:19 - So, for instance, the thalmic projections get to the proximity of the cortex
  • fast_forward00:14:23 - very early on, they accumulate in the subplate, before they make their final
  • fast_forward00:14:28 - move, eventually, to the ultimate target cells.
  • fast_forward00:14:36 - But in certain areas, this happens much earlier than in others.
  • fast_forward00:14:41 - And then with the propagations, of course, it suggests there's a finish and
  • fast_forward00:14:45 - a start, right? Exactly, and also then the connectivity back from the cortex
  • fast_forward00:14:49 - to the thalamus is even more,
  • fast_forward00:14:52 - The first descending pathways are from subplate, but they are overtaken by layer five projections.
  • fast_forward00:14:59 - And in fact, layer five is the first cell type which is entering the thalamus.
  • fast_forward00:15:04 - The subplate and the layer six projections, they somehow slow down and they
  • fast_forward00:15:12 - accumulate outside the thalamus, so they are in the proximity,
  • fast_forward00:15:16 - but they don't quite enter the thalamus.
  • fast_forward00:15:19 - And in the mouse, although they were there at embryonic day 15,
  • fast_forward00:15:22 - they only enter, for instance, the naturogenic nerve nucleus about post later day 10.
  • fast_forward00:15:28 - Can you imagine how long it is that they wait outside before they go in?
  • fast_forward00:15:32 - You enucleate the animal or you block the activity of the retina,
  • fast_forward00:15:37 - then they move in immediately.
  • fast_forward00:15:39 - So there's something interesting, some regulation is going on.
  • fast_forward00:15:42 - How do you interpret that?
  • fast_forward00:15:45 - I don't know how to interpret it, but basically the activity pattern within
  • fast_forward00:15:49 - the thalamus has an impact on the kinetics and how these corticothalamic loops close.
  • fast_forward00:15:56 - And maybe there's a reason why you do why you close these loops.
  • fast_forward00:16:01 - What I was worried about with respect to thalamus is that, of course,
  • fast_forward00:16:06 - these recurrent projections have to target both specific or non-specific nuclei
  • fast_forward00:16:11 - and the reticular nucleus.
  • fast_forward00:16:13 - So you have to do both. And this sounds to me like a really tricky problem to solve.
  • fast_forward00:16:19 - Because you don't only have to worry about the feed-forward projection because
  • fast_forward00:16:23 - once you hit the reticular nucleus, you really start to have divergent inhibitory
  • fast_forward00:16:27 - effects which you could imagine could destabilize this whole.
  • fast_forward00:16:33 - So would that be a reason to not innervate fully that you first want to have
  • fast_forward00:16:38 - this feed-forward pathway converge in some way in order not to destabilize?
  • fast_forward00:16:43 - Is that a way to think about it?
  • fast_forward00:16:44 - Actually, you put your finger exactly. this is the thoramic reticular endocleus,
  • fast_forward00:16:49 - is the suspected location of the weighting of this corticofagulose.
  • fast_forward00:16:55 - So, unfortunately, nobody did, including us. We haven't done a really nice,
  • fast_forward00:17:00 - reliable tracing on this.
  • fast_forward00:17:02 - We used transgenic animals where we had enhanced green fluorescent protein expressed
  • fast_forward00:17:09 - in the subset of these cells, and you can see that the green fibers accumulate
  • fast_forward00:17:14 - outside the thalamus, and they wait there,
  • fast_forward00:17:17 - probably at the site of the thalamic reticulonucleus, and then they move in.
  • fast_forward00:17:21 - What is also interesting, they do have functional connections with the thalamic reticular nucleus.
  • fast_forward00:17:27 - But more than 20 years ago, I
  • fast_forward00:17:30 - stimulated the cortex and looked at the voltage-sensitive dye recordings.
  • fast_forward00:17:37 - What do the corticothalamic projections do close to the thalamus?
  • fast_forward00:17:41 - And they do drive the thalamic reticular cells at very early stages,
  • fast_forward00:17:45 - probably when they are not even inhibitory in it.
  • fast_forward00:17:48 - So there are all sorts of transient circuits, not only the subplate and the thalamocortical,
  • fast_forward00:17:54 - but also the corticofugals, thalamic reticulum and the gleeus, and then the thalamus.
  • fast_forward00:17:59 - The first person who suggested that you have these circuits was Karla Schatz and Pasko Rakic.
  • fast_forward00:18:05 - They did some proline, old-fashioned proline, ulterior tracing from the cortex
  • fast_forward00:18:11 - in the developing macaque, and they noticed that the radioactivity was waiting
  • fast_forward00:18:15 - outside the thalamus before they moved in.
  • fast_forward00:18:18 - So we did a bit more work on the rodent, and it's clear that something funny
  • fast_forward00:18:24 - is going on outside the thalamus.
  • fast_forward00:18:26 - So these loops don't get close. And I would go even further.
  • fast_forward00:18:30 - You know, if you want to understand these cognitive abnormalities where you
  • fast_forward00:18:34 - have these loops, it's not enough just to look at the subplate.
  • fast_forward00:18:38 - You also have to look at what's going on outside the thalamus.
  • fast_forward00:18:41 - And it was, I think, Ray Killary who first suggested that these thalamic reticular
  • fast_forward00:18:47 - cells, they were also much more numerous during development.
  • fast_forward00:18:51 - And they are kind of like the subplate of the thalamus, they shrink.
  • fast_forward00:18:56 - And so it would be a very good idea to have a look at the relative numbers in
  • fast_forward00:19:01 - cognitive disorders, just as it was done for the suck.
  • fast_forward00:19:04 - So are you saying that what's happening in the cortex is maybe not unique to
  • fast_forward00:19:10 - cortex, but there's a similar developmental mechanism showing on other structures?
  • fast_forward00:19:14 - So for the thalon cortical projection, the suck plate is the transient zone
  • fast_forward00:19:19 - where they accumulate and then they move in. For the corticofubules,
  • fast_forward00:19:23 - it's maybe the thalamic reticular.
  • fast_forward00:19:25 - So that's kind of like the subplate of the thalamus for these fibers.
  • fast_forward00:19:30 - So there are several transient cell populations, and the thalamic reticular,
  • fast_forward00:19:36 - peri-reticular nuclei, they are the other transient.
  • fast_forward00:19:42 - But if we were to look elsewhere in the brain, wouldn't we see things like subplates.
  • fast_forward00:19:48 - Showing the growth of the migration of the neurons.
  • fast_forward00:19:52 - I think in the spinal cord, they describe the border neurons.
  • fast_forward00:19:57 - They are also transient, and they were attributed to some developmental role,
  • fast_forward00:20:04 - but we don't know whether in certain pathologies you have more or less cells remaining.
  • fast_forward00:20:10 - So, finally, particularly nobody looked at it in cognitive disorders,
  • fast_forward00:20:14 - and I think it would be very... I'd say superior colliculus,
  • fast_forward00:20:18 - which is another laminar structure. Right.
  • fast_forward00:20:21 - I'm not aware of any transient layers in the autonomic reticulum.
  • fast_forward00:20:27 - But it would be good to do some proper 3D systematic birth dating and then look
  • fast_forward00:20:35 - at what are the hotspots, which cell groups disappear in large numbers.
  • fast_forward00:20:41 - And even the presence and absence of the a preferential cell death in rodent
  • fast_forward00:20:49 - subplate is debated still, because we don't use the proper entire brain reconstruction.
  • fast_forward00:20:56 - So we don't agree what percentage of these cells disappear.
  • fast_forward00:21:01 - Some would say that they all stay.
  • fast_forward00:21:05 - Juan de Carlos and.
  • fast_forward00:21:10 - Laura, Mascarake, they would suggest that most of them stay, and Chiaqui,
  • fast_forward00:21:16 - Okhtaka, Maruyama in Tokyo, they would say that most of these cells will stay,
  • fast_forward00:21:20 - whereas I would say there is a preferential cell death between postnatal day
  • fast_forward00:21:26 - 2 to 8, and this is when some populations decline in number,
  • fast_forward00:21:32 - and others, their relative proportions increase.
  • fast_forward00:21:36 - And we, about 15 years ago, we pulled out markers which labeled these more permanent cells.
  • fast_forward00:21:43 - But how can you have a disagreement on that? Because that seems to be a very
  • fast_forward00:21:46 - objective measurement. It's very objective. So how can you disagree?
  • fast_forward00:21:50 - Because we, so I think the reason why we disagree is because even subplate cells,
  • fast_forward00:21:56 - they have subpopulations.
  • fast_forward00:21:58 - So you have some subplate cells which are born at tempion in day 10,
  • fast_forward00:22:02 - others 10.5, 11, et cetera.
  • fast_forward00:22:05 - And I think maybe the early-born cells behave differently from the later-born
  • fast_forward00:22:11 - subplates. So, with the classification issue.
  • fast_forward00:22:14 - It is, and also subtypes. And what would be really good is to have markers for
  • fast_forward00:22:19 - the early, late-generated, permanent, non-permanent cells. But we are getting there.
  • fast_forward00:22:26 - What Tony was suggesting could be an interesting way to think about the forebrain
  • fast_forward00:22:31 - development, right? You have a bunch of subplates that you position,
  • fast_forward00:22:36 - and then from there, you grow the substructure.
  • fast_forward00:22:39 - So it could be a way to think about how neurogenesis plays out for the forebrain.
  • fast_forward00:22:44 - But then you were saying, well, it's not so clear whether it's actually true
  • fast_forward00:22:47 - for any other structure but the cortex. Right? So...
  • fast_forward00:22:52 - What's your hypothesis? What direction does it go in? Because imagine we say,
  • fast_forward00:22:56 - oh, cortex is an exception, right? This doesn't hold for these other structures.
  • fast_forward00:22:59 - They still have to be developed in some way.
  • fast_forward00:23:01 - So these structures are the precocious, very early generated cells,
  • fast_forward00:23:07 - and they form a continuous layer,
  • fast_forward00:23:12 - which is providing a supporting scuffle on which the rest of the cortex will develop.
  • fast_forward00:23:21 - So I don't think that these cells really interfere with neurogenesis,
  • fast_forward00:23:26 - but they do interfere with regulation of migration and also stabilization of later connections.
  • fast_forward00:23:32 - So you have a zone where you have relatively mature cells.
  • fast_forward00:23:38 - They can already communicate with other cells.
  • fast_forward00:23:41 - They set up some connectivity, even at an early stage when some of the neurons
  • fast_forward00:23:47 - are not generated yet, not in position, and also the connections are not functional.
  • fast_forward00:23:53 - So they receive some transient connectivity. They have the waves, activity.
  • fast_forward00:23:57 - These are the first regions of the brain where you have synapses.
  • fast_forward00:24:02 - And then when the cortex is finished, then the connectivity is moving on.
  • fast_forward00:24:08 - So the thalamic fibers move into the cortex, corticofubules into the thalamus,
  • fast_forward00:24:12 - and then these its transient cell
  • fast_forward00:24:14 - populations in sub-plate and in thalomic reticular nucleus, they reduce.
  • fast_forward00:24:19 - And many of them will disappear. So I think this process could be inhibited
  • fast_forward00:24:28 - by altering the development.
  • fast_forward00:24:31 - So if you remove sensory input or you.
  • fast_forward00:24:39 - Block cell death, maybe you would end up with a very different circuit.
  • fast_forward00:24:45 - So then, on the other hand, like you mentioned in your talk,
  • fast_forward00:24:50 - is that from the subplate, not all neurons disappear.
  • fast_forward00:24:54 - Right. But there's a number of neurons that remain that are distributed,
  • fast_forward00:24:59 - if I understand it correctly, relatively evenly across the whole cortical sheet,
  • fast_forward00:25:04 - playing a very fundamental regulatory function.
  • fast_forward00:25:08 - Right, so how should we call these cells? How are they embedded in the cortical
  • fast_forward00:25:12 - circuits in the adult brain?
  • fast_forward00:25:14 - How should we think of them also in that control function?
  • fast_forward00:25:17 - So I was also very surprised to see that nature,
  • fast_forward00:25:23 - is using these cells for these fundamental functions, because I believe that
  • fast_forward00:25:29 - these cells are extremely important in regulating local arousal,
  • fast_forward00:25:37 - attention, perhaps log of sleep,
  • fast_forward00:25:40 - and why leave it to a cell population, which is very important during development,
  • fast_forward00:25:47 - but only have a couple of scattered cells in the white matter, or a sublayer,
  • fast_forward00:25:53 - one or two cell layer, a thick sublayer in layer 6, 6V.
  • fast_forward00:25:58 - So, but it looks like these cells are the one.
  • fast_forward00:26:04 - Really fundamental. So evolution is reusing, repurposing these cells in the adult.
  • fast_forward00:26:10 - But morphologically, what do they look like? They are just like any other neurons.
  • fast_forward00:26:16 - You have multiple morphology, multipolar.
  • fast_forward00:26:20 - Some of them, they have transient epical dendrites, which is reaching layer
  • fast_forward00:26:25 - one during development.
  • fast_forward00:26:27 - And then at certain stages, these projections neurons, they retract this epical
  • fast_forward00:26:33 - tuft, which is quite common for other cell populations as well.
  • fast_forward00:26:38 - You also have bipolar, multipolar, neurogliaform.
  • fast_forward00:26:44 - You can have glutamatergic and goboergic subplate cells.
  • fast_forward00:26:48 - Some of the early goboergic subplate cells have very long-range collectivity,
  • fast_forward00:26:54 - which is also very interesting because maybe they have some kind of a hub role.
  • fast_forward00:26:59 - So they're very heterogeneous. Very heterogeneous, and they come from all sorts
  • fast_forward00:27:03 - of different locations, and we don't know which cell type is the one which is
  • fast_forward00:27:09 - causing, perhaps, the cognitive dysfunctions when you have more surviving.
  • fast_forward00:27:14 - Those studies were done very early with relatively simple markers,
  • fast_forward00:27:19 - like NADPH, diaphorase, and.
  • fast_forward00:27:23 - But that implies, Soltan, that maybe these neurons are not even homogeneous systems.
  • fast_forward00:27:28 - It might be also the subsystems, right? Correct, yeah. Okay.
  • fast_forward00:27:32 - And where do the exons go?
  • fast_forward00:27:34 - So it depends on which cell to help. So for instance, we have a couple of Cree
  • fast_forward00:27:39 - lines in mouse where you have a...
  • fast_forward00:27:44 - You think that you have a subpopulation of these cells, like the LD1A3 cells
  • fast_forward00:27:52 - in the subplate, maybe it's like 15% of the subplate cells or layer 6B cells.
  • fast_forward00:27:58 - And yet, we've found out that they have four different types within that the
  • fast_forward00:28:04 - LD1A3, which is only the 15% of the subplate.
  • fast_forward00:28:09 - So even if you have a genetically defined subplate population.
  • fast_forward00:28:16 - So it's getting a bit complicated, because you can only monitor or modulate
  • fast_forward00:28:22 - these cells where you have control over them.
  • fast_forward00:28:24 - And even this DRD1A Cree line, which is quite selective, is heterogeneous.
  • fast_forward00:28:31 - Then you have the CTGF Cree, reconnected tissue growth factor Cree expressing,
  • fast_forward00:28:37 - and that is slightly different population. So you asked me, where are the projections?
  • fast_forward00:28:42 - We studied both of these. The DID1A Cree is very interesting because they have
  • fast_forward00:28:47 - projections up to layer 5 and also up to marginal zone,
  • fast_forward00:28:53 - but they also have projections out, sub-cerebral projections to the higher-order
  • fast_forward00:28:59 - thalamus, which is selective to the higher-order thalamus, and also some to
  • fast_forward00:29:03 - the superior goniculus.
  • fast_forward00:29:04 - And they have actually quite a wide range connectivity within the cortex.
  • fast_forward00:29:12 - And interestingly, the other cell types, the CTGF Cree, they don't have this
  • fast_forward00:29:19 - widespread and no selective connectivity.
  • fast_forward00:29:22 - So the DRD1A Cree cells, it turns out that they are exactly the cell type which is OREX-insensitive.
  • fast_forward00:29:31 - The CTGF, they are not.
  • fast_forward00:29:33 - So that's why we study especially the DRD1A Cree, because I think they have
  • fast_forward00:29:39 - a very strong grasp on these corticothalamo-cortical pathways and they regulate the activity.
  • fast_forward00:29:48 - And that's why we believe that they have a role in arousal, attention, and maybe even sleep.
  • fast_forward00:29:55 - Okay, but wouldn't one hypothesis be.
  • fast_forward00:30:00 - These are all subplate neurons or cells, so they can take on multiple functions
  • fast_forward00:30:11 - early on in development.
  • fast_forward00:30:13 - So couldn't you interpret them as sort of a default solution,
  • fast_forward00:30:16 - like, okay, I have a little cortical circuit.
  • fast_forward00:30:19 - The cortical circuit is generating various gradients signaling some piece is
  • fast_forward00:30:25 - missing. and now these progenitor cells turn into the function that little sub-circuit requires.
  • fast_forward00:30:31 - You see what I'm saying? It's like filling in gaps, filling in developmental gaps in the circuit.
  • fast_forward00:30:36 - So they cannot, you cannot produce more, but you can maybe regulate their survival. Exactly.
  • fast_forward00:30:42 - They have a circuit, but it is not fully functional so that the gradients.
  • fast_forward00:30:48 - That are being generated in the circuit indicates that we miss cell type X,
  • fast_forward00:30:53 - and now the progenitor neuron turns itself into cell type X in order to just
  • fast_forward00:30:57 - make sure this column or this little subservient can survive.
  • fast_forward00:31:00 - Yeah, so I completely agree. But again, you used the term that progenitor turns into.
  • fast_forward00:31:05 - No, these cells are already there, but they don't disappear.
  • fast_forward00:31:09 - So exactly. Okay, okay. So yeah, you know the difference.
  • fast_forward00:31:13 - So basically, I completely agree with this. So you can envisage that these cognitive
  • fast_forward00:31:19 - disorder, the conditions, they have more subplate cells because the sock plate is implicated.
  • fast_forward00:31:25 - But you can also imagine a situation that the cortical plate is altered, it's sick.
  • fast_forward00:31:31 - It cannot develop, therefore, you keep more of them. Exactly.
  • fast_forward00:31:37 - And this is not the primary cause, it's kind of a, yeah.
  • fast_forward00:31:41 - So we don't know, exactly. So what would be interesting is to manipulate some of the.
  • fast_forward00:31:49 - Cortical cells, and have a look
  • fast_forward00:31:52 - at what kind of impact they have on the survival of the subplate cells.
  • fast_forward00:31:57 - But it's interesting because it's a hypothesis that it would be orthogonal to
  • fast_forward00:32:01 - yours because it puts the cause at the cortical level and not at some subcortical
  • fast_forward00:32:09 - projection somewhere doing something.
  • fast_forward00:32:11 - Right, but the outcome is the same.
  • fast_forward00:32:14 - You have more subplate cells and they have this sensitivity and abnormal connectivity,
  • fast_forward00:32:21 - which will then have an impact on the cognitive function.
  • fast_forward00:32:24 - But I just wanted to tell you that there is evidence for this,
  • fast_forward00:32:28 - some kind of correlation.
  • fast_forward00:32:30 - So with Bashir Ahmed, who.
  • fast_forward00:32:34 - Is retired but then joined my lab to do some project, he looked at macaque cortex and correlated the,
  • fast_forward00:32:46 - Well, his question was very simple. We have variations in the interstitial white
  • fast_forward00:32:51 - matter cells in salt, psi, and gyri.
  • fast_forward00:32:54 - And he wanted to know what cell type would follow this variation in the subplate
  • fast_forward00:33:00 - feminal cells in the cortex.
  • fast_forward00:33:02 - And layer five, and the proportions of layer five and number of layer five cells
  • fast_forward00:33:09 - is very strongly correlating with the proportions of the subplate cells.
  • fast_forward00:33:14 - So here we go. So there is a matching between 5 and 6B or interstitial white matter cells.
  • fast_forward00:33:22 - So maybe we have to look for the cause in 5.
  • fast_forward00:33:26 - Yeah. So there is a possibility. It would be a more minimal interpretation,
  • fast_forward00:33:31 - right? Right. In terms of functional impact.
  • fast_forward00:33:34 - But on the other hand, we also looked at some of the susceptibility genes of
  • fast_forward00:33:38 - autism and schizophrenia. and we looked at where are these genes expressed in the developing cortex.
  • fast_forward00:33:48 - And the strongest affiliation was the subplate. So that would argue that actually
  • fast_forward00:33:53 - the subplate is the primary cause of the abnormalities.
  • fast_forward00:33:57 - But in the autism case, so morphologically in terms of cortical circuits,
  • fast_forward00:34:03 - it's this ratio of short and long-range projections that is effective.
  • fast_forward00:34:08 - So there's a reduction of long-range interactions. I mean, this is one of the
  • fast_forward00:34:13 - anatomical signatures, if I'm correct, right?
  • fast_forward00:34:16 - So then if we look at the subplate neurons that remain, how could they have
  • fast_forward00:34:22 - such an impact on the cortical morphology or connectivity?
  • fast_forward00:34:27 - Or would you see this as independent, unrelated?
  • fast_forward00:34:32 - Or to take any other pathology you looked at, right? So how could they influence
  • fast_forward00:34:37 - these other signatures that we might find in cortical circuits?
  • fast_forward00:34:44 - What's the cause and what's the effect here, right?
  • fast_forward00:34:50 - So, if you have abnormally high density of these cells or you change their distribution.
  • fast_forward00:34:58 - I can explain why you have cognitive dysfunction, because these cells feed into
  • fast_forward00:35:03 - layer five marginal zone, and also you have lots of cortical-cortical connections.
  • fast_forward00:35:09 - So if you have more of these cells, then that could argue for some of these
  • fast_forward00:35:15 - cognitive dysfunctions.
  • fast_forward00:35:16 - The other way around, when you are saying that you have a damaged developing
  • fast_forward00:35:21 - cortex and therefore you have more cells surviving,
  • fast_forward00:35:26 - that could be also explained with the connectivity, but we don't know where the primary cause was.
  • fast_forward00:35:32 - So whatever the case, it's a good idea to study these cells.
  • fast_forward00:35:37 - In your talk, you showed various examples, right?
  • fast_forward00:35:40 - Right. But we don't know what was the cause. Okay, so that's correlational at this stage.
  • fast_forward00:35:45 - So Agbarian looked a lot of schizophrenia cases, and indeed there was always
  • fast_forward00:35:51 - elevated level of these interstitial white matter cells, and especially in the prefrontal areas.
  • fast_forward00:35:59 - And I also showed some studies for the autism, exactly the same,
  • fast_forward00:36:03 - that you have more cells. But the cause, it was not really explained.
  • fast_forward00:36:08 - Okay. So in mouse, it would be very easy to do some experiments.
  • fast_forward00:36:11 - I would manipulate some of the cortical plate cells and have a look whether
  • fast_forward00:36:16 - I have more interstitial white metal cells.
  • fast_forward00:36:22 - So I think we looked at layer 5 silenced brains, where genetically I silenced
  • fast_forward00:36:28 - layer 5 by removing some 25 member of the snare complex, but I didn't see any
  • fast_forward00:36:33 - change in the subplate in these.
  • fast_forward00:36:35 - But maybe we didn't look hard enough or not the right area, so I wouldn't bury that still.
  • fast_forward00:36:42 - But you were saying that these subplate cells are responsive to erection. Correct.
  • fast_forward00:36:49 - So does that suggest, I think you're suggesting some sort of attentional type
  • fast_forward00:36:55 - function for all these circuits.
  • fast_forward00:36:59 - But is that a hypothesis about what they're doing when they're initially there?
  • fast_forward00:37:03 - So they arrive, they network with each other, possibly other parts of the brain,
  • fast_forward00:37:08 - and already in the very early trial, they have some function before the rest
  • fast_forward00:37:14 - of the cortex has developed.
  • fast_forward00:37:16 - But we don't know what that function is, but can we speculate that it might
  • fast_forward00:37:20 - be? to be with arousal or attention.
  • fast_forward00:37:22 - I mean, what would you suggest? I think it's probably, it's kicking in a bit later.
  • fast_forward00:37:28 - I like these neuromodulatory functions. I don't know what is the earliest time
  • fast_forward00:37:33 - when they have orexin sensitivity.
  • fast_forward00:37:36 - We did not study that. What we did study was that if you silence these cells
  • fast_forward00:37:44 - genetically and then you apply orexin, the orexin has a different effect on the cortex.
  • fast_forward00:37:51 - So, the orexin effect is mediated through this subpopulation of layer 6B neurons.
  • fast_forward00:38:02 - And that's why it's such an interesting potential target for therapy,
  • fast_forward00:38:06 - because you could alter anxiety without affecting the rest of the brain.
  • fast_forward00:38:12 - And why do you think that's later developing? Why isn't that for you, Clare?
  • fast_forward00:38:21 - The major target of these OREX-sinergic fibers is the prefrontal cortex.
  • fast_forward00:38:27 - So I don't know when it is, what is the earliest time when applying OREX-ing
  • fast_forward00:38:33 - would have an effect on the prefrontal. So I think we could check it.
  • fast_forward00:38:38 - But we know that before the rest of the cortical microsecond is assembled,
  • fast_forward00:38:44 - these neurons are already present, the neural network are already active.
  • fast_forward00:38:48 - Right, but these are mostly for glutamate and the thermic input.
  • fast_forward00:38:54 - So I don't know when they become sensitive to all these neuromodulators.
  • fast_forward00:38:59 - So we don't know if they're sensitive to sensory input? To sensory input,
  • fast_forward00:39:04 - for sure. They are very early on.
  • fast_forward00:39:06 - So Patrick Kennel showed it in ferret, and ferrets develop very early.
  • fast_forward00:39:11 - So a newborn ferret would be extremely immature, and Patrick showed that auditory
  • fast_forward00:39:17 - signals are mediated through subplates in the newborn ferret.
  • fast_forward00:39:21 - Without the corticoplates in the auditory cortex fully developed,
  • fast_forward00:39:27 - so the subplate is the first cell group which will mediate the sensory input,
  • fast_forward00:39:34 - whether this is proper sensory input,
  • fast_forward00:39:38 - I mean, sensory-driven activity, or just spontaneous activity in the receptor.
  • fast_forward00:39:45 - Right, but they have the connectivity. They have the connectivity to stimulate the subplates, yeah.
  • fast_forward00:39:52 - I mean, for example, if we would look at the visual, say B1 in the newborn infant,
  • fast_forward00:39:58 - so the subplate cells would be there at birth or after that.
  • fast_forward00:40:03 - Even before? They'll have some sensitivity.
  • fast_forward00:40:05 - Well, the reason I picked B1 is that there isn't any visual input before the birth.
  • fast_forward00:40:11 - So you open your eyes there's light
  • fast_forward00:40:15 - now you already have a circuit here that is
  • fast_forward00:40:18 - ready to respond to something but I bring any idea what that response is I think
  • fast_forward00:40:24 - the visual cortex by that time is almost fully wired up and you remember there
  • fast_forward00:40:31 - was a huge debate whether ocular dominance columns are ready in the primate before birth or not and.
  • fast_forward00:40:40 - In fact In fact, I think the result of the debate, but I'm not so,
  • fast_forward00:40:45 - I don't read the research literature on this, but I think it was that in primate,
  • fast_forward00:40:51 - the ocular dominance columns are there, but to stabilize them,
  • fast_forward00:40:54 - you need coherent visual input,
  • fast_forward00:40:57 - later on, so it is surprising that the spontaneous activity can sort things out like this.
  • fast_forward00:41:06 - So, but, but subplate is playing a very important in utero, life setting up all these connections.
  • fast_forward00:41:18 - So in auditory cortex for sure, they have a very important role,
  • fast_forward00:41:21 - and also in developing oculodominus columns, they have a role,
  • fast_forward00:41:28 - and also I showed some experiments from.
  • fast_forward00:41:33 - Patrick Ganod and Kyle Kaila, when they, in the rat, they destroyed selectively
  • fast_forward00:41:41 - the subplate cells, and they showed that no barrels developed in the barrel cortex.
  • fast_forward00:41:47 - So all these three modalities, it has been shown that subplates have an important role.
  • fast_forward00:41:55 - But Soltan, to go back to Tony's point about erection, why is that significant?
  • fast_forward00:42:01 - Because orexin as a peptide can have all sorts of effects and we barely i think
  • fast_forward00:42:07 - we don't really understand the full portfolio of of of impact it can have right
  • fast_forward00:42:13 - it can in in principle again modulate how other modulators work and so on right
  • fast_forward00:42:18 - so so why is this orexin observation,
  • fast_forward00:42:21 - then really telling us something about how the circuit operates,
  • fast_forward00:42:26 - I'm just trying to understand, right? I'm confused at this stage.
  • fast_forward00:42:30 - So your brain is wired up, and
  • fast_forward00:42:37 - in different contexts, you have to activate different parts of your brain.
  • fast_forward00:42:42 - So you behave very different when you have no sensory conflict.
  • fast_forward00:42:48 - You think you understand everything, and also when you have some kind of unusual stimulus.
  • fast_forward00:42:56 - So I believe that this orexin system has a role in activating the system,
  • fast_forward00:43:07 - which is very important in resolving these conflicts,
  • fast_forward00:43:13 - and you have unusual stimulus.
  • fast_forward00:43:15 - So this arousal is waking up these higher-order corticotheloma cortical circuits,
  • fast_forward00:43:21 - and you begin to pay more attention to that stimulus until you resolve it.
  • fast_forward00:43:27 - So the reason why we became interested in orexin, because there is a very strong
  • fast_forward00:43:33 - selectivity in the responsiveness of these cells.
  • fast_forward00:43:36 - So it has been known for a while from a group in Geneva, I think more than 20 years,
  • fast_forward00:43:45 - that these projection neurons in layer 6b are the only projection neurons which
  • fast_forward00:43:49 - have aurex insensitivity.
  • fast_forward00:43:51 - Now, it turns out that the aurex insensitive ones are the ones which communicate
  • fast_forward00:43:58 - with the layer 5 and marginal zone and the higher-order thalamus.
  • fast_forward00:44:03 - So they are perfectly positioned to wake up the whole system.
  • fast_forward00:44:08 - Now, the very same neurons, they also have response to neurotensin and dopamine.
  • fast_forward00:44:14 - So somehow they are kind of a neuromodulatory hubs.
  • fast_forward00:44:17 - So they are, in number, they are very low. But, you know, you only need one
  • fast_forward00:44:23 - conductor in an orchestra, no?
  • fast_forward00:44:25 - Yeah, but would that be sufficient? Because you could say, look,
  • fast_forward00:44:29 - they impact the sleep-wake cycle, very slow. Right, the slow process.
  • fast_forward00:44:34 - Or you could say, so they set the overall operating mode. Like,
  • fast_forward00:44:38 - are we awake or are we asleep?
  • fast_forward00:44:40 - Or you could say it's a tension. But if it's a tension, it's actually a pretty
  • fast_forward00:44:42 - fast system. And there we have other neuromodulators, the one we think,
  • fast_forward00:44:46 - right? You could think about noradrenaline, or your locus aurelius,
  • fast_forward00:44:49 - you have the ruffin nucleus, there's a four-brain acetylcholine.
  • fast_forward00:44:52 - Lots of them have sort of attentional effects, right?
  • fast_forward00:44:56 - So do you see it in this fast system, or in the slow system, or both? Both. Both.
  • fast_forward00:45:02 - And I think it could be in many different ways.
  • fast_forward00:45:07 - As you know, for instance, if we just talk about OREXA, So you have about less
  • fast_forward00:45:13 - than 10,000 cells in your lateral hypothermose.
  • fast_forward00:45:16 - Then they go everywhere in the brain, subcerebral and also in the cortex.
  • fast_forward00:45:21 - In the cortex, they go mostly to the frontal part of the cortex.
  • fast_forward00:45:27 - When you fall asleep, the front and the back of the brain, they have different
  • fast_forward00:45:35 - velocity how you fall asleep.
  • fast_forward00:45:37 - It's not a universal thing. So that's why I became really interested in the
  • fast_forward00:45:43 - possibility that these remnant cells of the subplate can have this very important adult function.
  • fast_forward00:45:49 - And the other beauty of this whole observation is that finally we can link the
  • fast_forward00:45:56 - developmental abnormality with the circuit which has this function in the adult. Okay.
  • fast_forward00:46:03 - So how many of these subplate nerves, these remaining subplate nerves, and have orexin as a.
  • fast_forward00:46:10 - Orexins and their own transmitter or peptide. They don't excrete, they respond.
  • fast_forward00:46:14 - All the orexin is produced in the lateral hypotherms, and then it's flooding the rain.
  • fast_forward00:46:20 - So diffusion is right. It can be both.
  • fast_forward00:46:24 - It can be synoptic release, and also it can be more like endocrine release.
  • fast_forward00:46:30 - And it's interesting that if you look at the orexin GFD mouse where all the
  • fast_forward00:46:38 - fibers are green, which have orexin, they don't respect 6B. They go everywhere in the cortex.
  • fast_forward00:46:45 - But the receptors on the projection neurons are only in 6B.
  • fast_forward00:46:49 - There are some interneurons which respond to orexin, but for projection neurons,
  • fast_forward00:46:55 - these are exclusively just in 6B.
  • fast_forward00:46:58 - So I was so surprised to
  • fast_forward00:47:01 - see then that I always consider the hypothalamus It's an ancient swamp of neuromodulators
  • fast_forward00:47:12 - which are occasionally released and they look after your very ancient functions,
  • fast_forward00:47:21 - you know, eating or mating or these kind of things.
  • fast_forward00:47:25 - But it seems that these lateral hypothalamic neuromodulators,
  • fast_forward00:47:31 - they know what they are doing.
  • fast_forward00:47:33 - They target very key structures which regulate the state of your brain to process
  • fast_forward00:47:41 - higher cognitive functions.
  • fast_forward00:47:42 - So probably we had this hypothalamic system even when we were in the reptilian stage.
  • fast_forward00:47:51 - And we started evolving a huge telencephalic vesicle.
  • fast_forward00:47:56 - And some of the receptors for these hypothermic, they are strategically positioned
  • fast_forward00:48:02 - to take advantage of this brain state regulation.
  • fast_forward00:48:08 - So, but then, if it's this hypothalamic regulation.
  • fast_forward00:48:16 - Is it setting an operating mode, or can it act very fast?
  • fast_forward00:48:22 - I think this is a very important question.
  • fast_forward00:48:27 - So, we don't know. Okay. I don't know. I predict that you will have two types,
  • fast_forward00:48:32 - a bit slower and a direct.
  • fast_forward00:48:34 - The reason why I'm saying that there is a direct, because you can do a CRE-dependent rabies tracing.
  • fast_forward00:48:43 - So if you want to know which cells talk to these subplate remnant cells,
  • fast_forward00:48:50 - you can express CRE recombinase.
  • fast_forward00:48:53 - You inject a rabies receptor, which will be expressed only in these tartar cells.
  • fast_forward00:48:59 - Then a few weeks later, you inject your rabies virus and you detect which cells
  • fast_forward00:49:04 - talk directly to these layer 6B cells.
  • fast_forward00:49:07 - So Tim Zolnik in Berlin and us in Oxford, we looked at this in different starter cell populations.
  • fast_forward00:49:14 - And the DLD1A Cree frontal cortical subplate remnant 6B cells,
  • fast_forward00:49:22 - they receive direct lateral hypothalamic input from the OREX synergic cells.
  • fast_forward00:49:28 - So, that's why I believe that probably it can be fast and also slow, both.
  • fast_forward00:49:34 - So, these lateral hypothalamic cells, they have the potential to directly talk
  • fast_forward00:49:39 - to these six-week cells.
  • fast_forward00:49:40 - But then you also mentioned that they modulate the simulcortical interactions.
  • fast_forward00:49:46 - So that was actually not a part of your talk that you emphasized quite a bit. Right.
  • fast_forward00:49:51 - This sort of the role of the thalamic cortical projections as if you want a
  • fast_forward00:49:54 - backbone of a lot of the also more advanced cognitive functions of the homo genus, right?
  • fast_forward00:50:01 - So how should I look at this interaction between these hypostalamic-driven systems
  • fast_forward00:50:07 - and the thalamic cortical one? Are these things competing?
  • fast_forward00:50:10 - Are they syllogistic? What's their relationship? So basically,
  • fast_forward00:50:16 - I think they are quite separate in a way that you have, imagine that you have
  • fast_forward00:50:22 - this corticotheloma cortical system.
  • fast_forward00:50:25 - So the layer 5, layer 6 projections, they have very selective connectivity to
  • fast_forward00:50:31 - the higher order thalamus.
  • fast_forward00:50:33 - So the part of the thalamus which is not receiving direct sensory input, like the Bluvinar.
  • fast_forward00:50:39 - And the orexian system is selectively targeting this part of the thalamus and
  • fast_forward00:50:46 - the input cells which project to that part of the thalamus.
  • fast_forward00:50:52 - So I think the orexian system is selectively waking up this corticotheloma cortical via the 6B.
  • fast_forward00:51:00 - And that could probably open up these channels to resolve things which we don't
  • fast_forward00:51:10 - find a clear answer immediately.
  • fast_forward00:51:14 - So for instance, I would predict that if you use the so-called odbo paradigm,
  • fast_forward00:51:21 - that you suddenly change a very...
  • fast_forward00:51:25 - Preventable, steroid-insipal stimulus, and then this system would wake up.
  • fast_forward00:51:31 - And we don't have evidence for that, but this is what we would like to study.
  • fast_forward00:51:39 - But we do have evidence that if you inactivate the Slayer 6B cells,
  • fast_forward00:51:48 - then you actually reduce anxiety in the animals.
  • fast_forward00:51:53 - Yeah, but so, You also mentioned that the thalmocortical system was sort of
  • fast_forward00:52:00 - structured in a hierarchical fashion, right? That was one other point that you made.
  • fast_forward00:52:05 - And you saw sort of a bifurcation in that. Let's say we have simple functions,
  • fast_forward00:52:11 - we have complex functions.
  • fast_forward00:52:12 - So then, and these must also be modulated in some way.
  • fast_forward00:52:18 - So now you're saying the Eurexian system is more, let's say,
  • fast_forward00:52:22 - a non-specific wake-up call to that system. but also to switch it into a mode
  • fast_forward00:52:27 - of, let's say, problem solving.
  • fast_forward00:52:29 - So this is, is that the right way to think about it? Right.
  • fast_forward00:52:33 - So, but then you're saying, sorry to interrupt, but then you're saying that
  • fast_forward00:52:37 - the hypothalamus says we got a problem that I don't know how to solve. Right?
  • fast_forward00:52:45 - So how to show this directly? Because this looks like a very nice hypothesis.
  • fast_forward00:52:52 - So I think it can now be resolved by pushing down some really long electrodes
  • fast_forward00:53:01 - which penetrate all these structures.
  • fast_forward00:53:04 - So not only through the cortex and through layer 6b, but then you don't stop.
  • fast_forward00:53:09 - You keep going through the first-order and higher-order thalamic nuclei and
  • fast_forward00:53:14 - perhaps even, and then record the activity pattern after you confirm the position of certain electrodes.
  • fast_forward00:53:25 - You show when they are really active in what behavior or situation.
  • fast_forward00:53:30 - So in vivo, awake, behaving with these electrodes in the strategic location could resolve this.
  • fast_forward00:53:36 - So I would predict that when you have some state transitions from, you know,
  • fast_forward00:53:43 - a bit dormant, predictable stimuli into something unexpected,
  • fast_forward00:53:48 - the B6 B cells and higher on the theromic will be much more active.
  • fast_forward00:53:53 - That's my prediction, but I have no evidence so far.
  • fast_forward00:53:57 - Yeah, but this isn't a bit counterintuitive because you could also argue arousal
  • fast_forward00:54:02 - means there's an unpredicted event.
  • fast_forward00:54:05 - That means also very primitive behavioral systems start to kick in because now
  • fast_forward00:54:09 - defense comes in, freezing might come in, or a defensive attack might come in.
  • fast_forward00:54:14 - And in some, all these, these, these behavioral systems in some sense also are
  • fast_forward00:54:20 - effective because they essentially shut down cortical porosity for a little
  • fast_forward00:54:25 - bit, because it will take too long.
  • fast_forward00:54:27 - It's small, it has to integrate, it has to deliberate, right?
  • fast_forward00:54:30 - So I got to act, it has to survive.
  • fast_forward00:54:32 - But it isn't a bit counterintuitive to link an arousal link system.
  • fast_forward00:54:37 - To actually a state switch in the cortex that will move it towards the phase
  • fast_forward00:54:42 - of delimeration, which makes you vulnerable.
  • fast_forward00:54:46 - Yeah, but that's why we are human. We have a huge higher-order thonomic system.
  • fast_forward00:54:52 - That's why we can resolve things.
  • fast_forward00:54:55 - And you still have to activate this system for that.
  • fast_forward00:54:59 - So this theory of attention and arousal through this system is not excluding
  • fast_forward00:55:08 - all the other possibilities which we might have.
  • fast_forward00:55:11 - For me, it was surprising to see just how specific the receptor distribution
  • fast_forward00:55:18 - is of some of these neuromodulators.
  • fast_forward00:55:21 - So there is a reason why this layer 6b subletramnat is a neuromodulatory hub.
  • fast_forward00:55:29 - And it turns out that even psychedelics act on this cell group preferentially.
  • fast_forward00:55:36 - So they can also open up channels for all sorts of associations when you apply psychedelics.
  • fast_forward00:55:45 - So layer 5 and layer 6b have the most interesting receptor distribution.
  • fast_forward00:55:52 - So it cannot be a coincidence.
  • fast_forward00:55:54 - There has to be some functional excreditation. Yeah, but to me,
  • fast_forward00:55:57 - more switching in the opposite direction of what you were describing.
  • fast_forward00:56:01 - For me, it's more like, let's shut down the frontal cortical part because that's just a risk.
  • fast_forward00:56:07 - Let's get the hell out of here. Let's freeze. Okay? Right.
  • fast_forward00:56:13 - So that's my counter-hypothesis. Right. Okay.
  • fast_forward00:56:18 - But when you are in an unusual environment, then you need to switch this on.
  • fast_forward00:56:25 - But you don't want to switch it on too long and too strong, because then you
  • fast_forward00:56:32 - might have anxiety. So that is, all these states can be actually continued.
  • fast_forward00:56:40 - Arousal, attention, arousal. Of course, it's interleaving.
  • fast_forward00:56:45 - Sure, but for me, an arousal system also brings you back more into a primitive
  • fast_forward00:56:52 - behavioral control because it's non-specific.
  • fast_forward00:56:55 - And if it's non-specific, I don't know what to do, so I better fall back on
  • fast_forward00:56:58 - non-stero-type behavior.
  • fast_forward00:57:00 - If it's specific, it means there's no arousal, I can just commit myself to the
  • fast_forward00:57:05 - test. I'm not under threat.
  • fast_forward00:57:06 - Now I can deliberate. I can weigh my options and so on, right?
  • fast_forward00:57:10 - So this is why I was, to each counterintuitive, therefore, to link that system
  • fast_forward00:57:15 - to actually the liberation.
  • fast_forward00:57:18 - Well, time will tell how these interact. Of course. We select, yeah.
  • fast_forward00:57:21 - But at the moment, we just have this. But what do we know behaviorally, like in animal studies?
  • fast_forward00:57:26 - If you inhibit this Eurexin system or you stimulate Eurexin system,
  • fast_forward00:57:31 - what's the behavioral result?
  • fast_forward00:57:33 - So, interestingly, orexin got its name from Professor Yanagisava because he
  • fast_forward00:57:44 - believed that orexin has something to do with appetite and food intake.
  • fast_forward00:57:50 - It turns out that, probably not, orexin was causing arousal in these animals
  • fast_forward00:57:57 - and therefore they were eating more at that time.
  • fast_forward00:58:00 - So it's more of a sustained arousal which forexin is.
  • fast_forward00:58:09 - Now, orexin has probably another 50 or 100 targets in addition to the cortex,
  • fast_forward00:58:15 - so it's very difficult to kind of study the function of the orexin selective to the cortex.
  • fast_forward00:58:24 - But in our case, when we silenced the recipient cells of this orexin signal
  • fast_forward00:58:30 - to the cortex, it had a strong anxiolytic effect.
  • fast_forward00:58:34 - And that's what we would like to study a bit more. Our study was not ideal because
  • fast_forward00:58:38 - we silenced the entire cortical mantle, and also the population we selected, the DRD1A3 cells,
  • fast_forward00:58:47 - is not a clear cell population because you have some contamination in other structures.
  • fast_forward00:58:56 - But now we can actually target sub-regions of this and have a look whether we
  • fast_forward00:59:01 - can actually alter anxiety. So, that's one of the research projects we are doing right now. Right.
  • fast_forward00:59:10 - So, Sultan, earlier we listened to the prediction you made more than 10 years ago.
  • fast_forward00:59:18 - And the answer was a bit aspirational, no? So, we're 10 years further down the
  • fast_forward00:59:25 - road, and of course you gained a lot of experience and understanding in the meantime.
  • fast_forward00:59:29 - Time so if we're now going to get back to
  • fast_forward00:59:32 - you in Oxford three years from now what's the specific hypothesis you want to
  • fast_forward00:59:37 - see validated in three years time what's a specific one that is a do or die
  • fast_forward00:59:42 - that's that's the whole of your career going down the june if you fail right
  • fast_forward00:59:47 - so what's what's the one that you really want to see tested.
  • fast_forward00:59:51 - So when we met last time, we were talking about this reptilian framework of
  • fast_forward00:59:55 - the developing mammalian brain.
  • fast_forward00:59:58 - And I think what became clear is that, yes, there are some cells which have
  • fast_forward01:00:07 - this very ancient origin.
  • fast_forward01:00:09 - But it also became clear that in human, you continue to produce these cells.
  • fast_forward01:00:15 - So it's not just an early-generated cell group.
  • fast_forward01:00:18 - You continually add. So a couple of weeks ago,
  • fast_forward01:00:22 - Tom Novakovsky, UCSF, published that in human, the short progenitors,
  • fast_forward01:00:28 - they produce subplate cells later, and they get added to this archaic cell population.
  • fast_forward01:00:35 - So it seems like if you have a bigger brain, you need a bigger scaffold,
  • fast_forward01:00:40 - and therefore you keep producing it longer.
  • fast_forward01:00:43 - So that was a very interesting discovery recently.
  • fast_forward01:00:46 - So we still maintain that they have evolutionary origin, but there is inhuman,
  • fast_forward01:00:51 - at least you have a later generated cell, population.
  • fast_forward01:00:57 - Now, 10 years ago when we talked, I was dreaming about showing these modulatory
  • fast_forward01:01:04 - functions of the residual subgate cells, and I think we delivered on that.
  • fast_forward01:01:08 - Mm-hmm, yeah, true. So if we chronically manipulate this cell group,
  • fast_forward01:01:13 - then we can actually change arousal anxiety and sleep.
  • fast_forward01:01:19 - We didn't believe that this was possible, but the byproduct of that study,
  • fast_forward01:01:27 - is that we also manipulated layer five cells, and with Vlad Vyazovsky we discovered
  • fast_forward01:01:32 - that if you manipulate layer five.
  • fast_forward01:01:36 - Then you have a strong manipulation of sleep. So 10, 20 years ago,
  • fast_forward01:01:43 - the dominant idea was that sleep is bottom-up.
  • fast_forward01:01:47 - So all these sub-cerebral structures like hypothalamus brainstem,
  • fast_forward01:01:51 - they regulate sleep, and they tell the cortex when to go to sleep.
  • fast_forward01:01:55 - Now we know that the cortex has a big say in when it's going to sleep.
  • fast_forward01:02:00 - So, and it's layer five and layer six B, which is actually regulating this and
  • fast_forward01:02:07 - perhaps some other interneuron populations.
  • fast_forward01:02:10 - So that was also a big breakthrough.
  • fast_forward01:02:14 - And now what I would love to do in the next couple of years is to find a way to selectively,
  • fast_forward01:02:23 - manipulate the number of these cell groups and then have a look at the behavior of the animal.
  • fast_forward01:02:29 - So one possibility is to change the mTOR pathway, and we have been doing it
  • fast_forward01:02:36 - with Britta Einkholt and Matthew Larkham at Charity in Berlin,
  • fast_forward01:02:41 - and what we want to do is to manipulate these early generated cells and their
  • fast_forward01:02:48 - preferential cell death and have an animal model where you have more cells.
  • fast_forward01:02:53 - And actually, I think we accomplished that because we now have a model where
  • fast_forward01:02:58 - you have about 30% more layer 6B cells, and now we are looking at the blue layer.
  • fast_forward01:03:04 - So it will be very interesting to see. What's your prediction on behavior?
  • fast_forward01:03:08 - So I think you will have to use probably very sensitive behavioral tests, novelty preference or.
  • fast_forward01:03:25 - Arousal or attention driven tests.
  • fast_forward01:03:30 - So these are not easy to set up in mouse. So I believe that this will show some,
  • fast_forward01:03:37 - alterations in these animals.
  • fast_forward01:03:39 - Would you predict improved performance in, let's say, a complex mace or compromised performance?
  • fast_forward01:03:46 - For the contrary, I expect that they will be a bit more timid,
  • fast_forward01:03:50 - or they will have a bit more anxiety.
  • fast_forward01:03:58 - More shy, and probably they will have very subtle alterations.
  • fast_forward01:04:07 - So it will be interesting to see whether these are the endophenotypes of autism or schizophrenia.
  • fast_forward01:04:13 - And perhaps you can even study hallucinations or even delusions in these animals.
  • fast_forward01:04:21 - There are some methods how to do that in mice.
  • fast_forward01:04:25 - So that would be very interesting. But my dream is to actually to have human
  • fast_forward01:04:30 - markers for some of the cells which matter the most, to have a look at human
  • fast_forward01:04:36 - cases and identify, which you can do now.
  • fast_forward01:04:39 - With spatial transcriptomics you can pull out the cell types from the interstitial
  • fast_forward01:04:44 - white letter and have a look which cell type is the most vulnerable in this cognitive condition.
  • fast_forward01:04:52 - Perhaps there are several types of schizophrenia and also...
  • fast_forward01:04:56 - Exactly. But then Sultan, last question.
  • fast_forward01:04:59 - Sultan's law, right? So you're now in this business for a long time.
  • fast_forward01:05:03 - You're active in one of the leading universes in the world, running one of the
  • fast_forward01:05:08 - leading labs in neurodevelopment.
  • fast_forward01:05:10 - So if younger researchers would like to follow your trajectory,
  • fast_forward01:05:16 - what is Sultan's law that they should follow?
  • fast_forward01:05:20 - No, I think it's probably very exceptional that somebody is sticking to one question.
  • fast_forward01:05:28 - Most people change fields very frequently, and that's probably good for you to change.
  • fast_forward01:05:34 - But I'm just fascinated with this problem, and I think this problem is a very
  • fast_forward01:05:39 - good entry point to learn quite a bit about the brain.
  • fast_forward01:05:44 - So I might start with this cell group, but look at my research.
  • fast_forward01:05:48 - It had to go to all sorts of other areas because of this cell group.
  • fast_forward01:05:53 - And unfortunately, you have to learn.
  • fast_forward01:05:56 - So for instance, I was not very keen on doing behavior, but now we have to do
  • fast_forward01:06:01 - it. I was not familiar with local
  • fast_forward01:06:04 - or global sleep, but now I have collaborations going on. And also, um.
  • fast_forward01:06:11 - I was not doing spatial transcriptomics, but I have to do it to get to the answers.
  • fast_forward01:06:18 - So although I'm asking the similar questions, but I think for the progress,
  • fast_forward01:06:23 - I had to change my research quite a bit.
  • fast_forward01:06:25 - Fantastic. Well, Sultan Molnar, thank you very much for this conversation.
  • fast_forward01:06:29 - Thank you very much, Paul, and looking forward to seeing you in the next 10
  • fast_forward01:06:32 - years. Exactly. You will.
  • fast_forward01:06:36 - Wonderful. Well, thank you. I learned a lot from this. Very good.
  • fast_forward01:06:40 - But it's indeed it's amazing right how this all came together in this 10 year
  • fast_forward01:06:44 - period I will go back and listen to it's astonishing recording and see what
  • fast_forward01:06:49 - we predicted and where are we mm-hmm,
  • fast_forward01:06:53 - But I think that there's an interesting discussion to be had here,
  • fast_forward01:06:56 - because also you see that your behavioral prediction, these are non-specific effects.
  • fast_forward01:07:01 - It's arousal, risk of birth. But do we prove the circuits?
  • fast_forward01:07:06 - No. No, no, no. I think there are some suggestions, but we don't know what is
  • fast_forward01:07:12 - the circuit of attention or arousal, or we don't even know the regulation of global or local sleep.
  • fast_forward01:07:19 - So that's actually a really important point which perfectly matches my theory
  • fast_forward01:07:26 - of consciousness because the whole point I'm making is that cortex the thalmocortical
  • fast_forward01:07:30 - system is also just selectively switching off parts of its circuits.
  • fast_forward01:07:37 - Putting them to sleep so they go in low frequency burst mode because that's
  • fast_forward01:07:43 - how you also create the content that you are dealing with is by sort of dynamically
  • fast_forward01:07:49 - switching off subcircuits.
  • fast_forward01:07:51 - And that fits in your thalocortical story rather well, I think.
  • fast_forward01:07:55 - But then the 6B is really well positioned to bring the subliminal to liminal. Exactly.
  • fast_forward01:08:01 - By switching off the competition. And then this is how that becomes the dominant scene.
  • fast_forward01:08:08 - So if we sleep, we are misunderstanding the thalocortical part of sleep.
  • fast_forward01:08:13 - I think it's just a generic feature of managing cortical dynamics by switching things on and off.
  • fast_forward01:08:19 - It's just in case of sleep, it's in a more global switch-off state.
  • fast_forward01:08:23 - But during wakefulness, exactly the same thing happens.
  • fast_forward01:08:27 - As soon as you hit the bursting mode of the thalamic relay endurance,
  • fast_forward01:08:31 - okay, you put that circuit to sleep.
  • fast_forward01:08:33 - It cannot process anything. It's off.
  • fast_forward01:08:36 - And to me, this is like a sleep spindle. It's essentially the same mechanism.
  • fast_forward01:08:41 - And consciousness is floating in that dynamic state.
  • fast_forward01:08:47 - Your theory is very similar to Matthew Larkin, who is a kind of a consciousness expert.
  • fast_forward01:08:54 - And that's why he is taking 6B very seriously.
  • fast_forward01:08:58 - Because it might be layer 5 producing all these bursts and things,
  • fast_forward01:09:02 - but it's 6B which is telling it when and how to do it. Exactly.
  • fast_forward01:09:07 - And I could imagine that your subplate neurons might be much more integrated
  • fast_forward01:09:13 - with that part of the story.
  • fast_forward01:09:15 - Right? So that modulation.
  • fast_forward01:09:18 - Anyway, so there's a lot of stuff discussed there. I think it's very interesting
  • fast_forward01:09:25 - to think about these bigger issues.
  • fast_forward01:09:29 - Well, that's what... But life is short, so we had to get on with it.
  • fast_forward01:09:33 - Well, the thing is to build a bridge.
  • fast_forward01:09:36 - So anyway, that was great. So it's great that you're still here tomorrow.
  • fast_forward01:09:41 - So we can still chat a bit.
  • fast_forward01:09:44 - And then you stay longer here in Alicanto or you go back? No,
  • fast_forward01:09:48 - no, no, we go back tomorrow. Oh, you have too much stuff going on here.
  • fast_forward01:09:51 - We have the medical admissions now. So we have like 60 students, half an hour each.
  • fast_forward01:10:00 - But it's an important process. Of course. Because you have to select the next,
  • fast_forward01:10:07 - generation and also it's not an easy course so you want to make sure that you
  • fast_forward01:10:11 - select people who are outstanding.
  • fast_forward01:10:14 - But do you see a shift in the demographics of these students?
  • fast_forward01:10:18 - We still have pretty good, but to be a junior doctor in.

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