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Elena Galea on astrocytes and glia

Episode 4 15.03.2019

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Season 2019

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What if half the brain’s cells are doing something essential that neuroscience has barely begun to investigate? Elena Galea makes the case that astrocytes, long dismissed as passive glue, are active computational elements that tile the brain in a precise three-dimensional matrix, modulate neural circuits, control blood flow, and may hold the key to understanding memory and higher brain function. Subscribe for more from the Convergent Science Network podcast series. Elena Galea joins Paul Verschure and Tony Prescott to explain why the old category of “glia” should be abandoned. Astrocytes, oligodendrocytes, microglia, and NG2 cells are molecularly and functionally distinct , lumping them together has obscured decades of potential discovery. Galea describes how modern labeling techniques reveal astrocytes not as star-shaped cells with long processes but as dense bushy structures approximately 50 microns across, tiling the brain in a Voronoi tessellation pattern that extends uniformly through gray and white matter. The conversation dives into what astrocytes actually do beyond metabolic support. They release glutamate on a timescale of seconds, buffer and potentially redistribute potassium, modulate inhibitory and excitatory circuit responses with surprising precision, and control capillary dilation within hundreds of milliseconds of neural activity. Galea argues this goes well beyond homeostasis , astrocytes gate, modulate, and potentially synchronize neural activity within local circuits. Yet the field remains in its infancy: only one percent of systems neuroscience presentations address non-neuronal cells, and the long-term plasticity mechanisms in astrocytes, analogous to LTP in neurons, remain completely uncharacterized. Key topics include why astrocyte research has lagged behind neuronal studies by decades, how techniques have constrained concepts in the field, the role of astrocytes in memory consolidation revealed by chemogenetic manipulation, the multiplexing capacity of astrocytes that simultaneously regulate synapses and blood vessels, and why understanding the brain’s dark matter may require rethinking neural circuit models from the ground up. Part of the Convergent Science Network podcast series from the BCBT Summer School.

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astrocytes Brain Cells glia Neural Activity

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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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00:00:03 - This is the Convergent Science Network podcast. Leading researchers in the domain
00:00:10 - of neuroscience, brain theory and technology are interviewed by Paul Verschoor and Tony Prescott.
00:00:21 - This is Paul Verschoor for the Convergent Science Network podcast
00:00:25 - here at the barcelona cognition brain
00:00:29 - and technology summer school of 2018 and um i'm with me elena galea welcome
00:00:35 - to the podcast elena thank you very much happy to be here great um and your
00:00:41 - your talk was about the astrocytes and also was immediately um,
00:00:48 - instructed not to call them glia anymore because they're astrocytes.
00:00:53 - So maybe this is also a good starting point for a discussion, right?
00:00:57 - So why do we have to drop this notion glia and focus on astrocytes?
00:01:03 - Well, because it doesn't make any sense to classify cells between neurons and
00:01:09 - non-neuronal cells because the non-neuronal cells are so different among themselves.
00:01:14 - So this is like saying in the whole body.
00:01:18 - That the body is divided into heart and the rest of the organs, intestines and liver.
00:01:24 - It makes no sense because those organs are so different.
00:01:27 - They have different problems and different features. You have to focus on them individually.
00:01:33 - So the non-neuronal cells include cells that are so different in their functions
00:01:39 - and in molecular phenotype, in their contribution to pathology,
00:01:44 - contribution to higher brain functions,
00:01:46 - that just classifying them,
00:01:49 - just putting them together in a single concept,
00:01:52 - it just doesn't force us to look into the details. I think details are very, very important.
00:01:59 - Names are very, very important because they guide research and they guide the
00:02:05 - understanding of problems.
00:02:08 - So it makes sense one century ago to see neurons and the rest of the brain.
00:02:12 - Now it doesn't make sense any longer.
00:02:15 - Okay, so basically you're saying with many cell types that build the brain,
00:02:21 - some of those are spiking.
00:02:22 - They generate action potentials. Those are what we call neurons.
00:02:25 - But then the many other cells, which is a very variable set of cells that formerly
00:02:30 - were known as LEA, the non-neuronal cells, but it is not in any way descriptive of this variability.
00:02:38 - And then among this highly variable set of cells, We have a subtype called estrocytes, right?
00:02:44 - So what then sets the estrocytes apart from these other non-neuronal cells?
00:02:49 - Well, first, molecularly, they're different already.
00:02:52 - They have a different identity.
00:02:55 - And they carry functions that the others don't. They don't generate myelin,
00:03:01 - like oligodendrocytes.
00:03:03 - They don't deliver blood, like the vascular cells. cells, they don't protect
00:03:09 - neurons from some danger like microglia.
00:03:14 - So at least they don't do what other things do.
00:03:17 - And perhaps they do things like providing lactate to neurons,
00:03:23 - removing potassium from the extracellular medium.
00:03:28 - They transform glutamate into glutamine. So they have very, very specific functions.
00:03:36 - On the astrocytes too and none on the rest of the cells too.
00:03:39 - So this is what is important to focus on them.
00:03:44 - But they stand apart also on purely morphological grounds?
00:03:51 - Morphologically, yes, depending on what comparison you carry out.
00:03:58 - Because there are other cells in the brain called NG2 oligodendrocytes.
00:04:03 - They are like between astrocytes and microglia.
00:04:07 - So if you compare an astrocyte with a neuron, they're very different.
00:04:10 - So neurons have their dangerous spines and axons, while astrocytes are very
00:04:16 - complicated cells, bushy cells with very intricate distal processes.
00:04:23 - But NG2 have also primary, secondary processes and some dense distal processes.
00:04:31 - So they are intermediate. And in microglia, they have very low processes,
00:04:35 - and they don't have the distal processes.
00:04:37 - So it seems that there is a morphological gradient in the brain that differentiates,
00:04:46 - neurons from microglia, but not so much NG2 from astrocytes.
00:04:51 - Vascular cells are very different from the rest of the cells.
00:04:54 - All the goals are very similar to neurons in many ways.
00:04:57 - So, depending on the comparisons you tell us, that the morphological differences
00:05:03 - are larger or smaller, but yeah, morphologically, they're very,
00:05:07 - very different, absolutely.
00:05:10 - Molecularly and morphologically, very different. So, in the human brain,
00:05:13 - we have about 90 billion neurons, right, according to the most recent counts.
00:05:20 - Do we have then 90 billion non-neuronal cells?
00:05:27 - Marisa, I don't know, what is her name? Herculano. So those people,
00:05:30 - that's a fantastic word. There are papers.
00:05:34 - She has analyzed that with very objective technology.
00:05:38 - And so the answers are there. I don't think the answer is that equal amount of neurons. 50-50?
00:05:46 - I think it's 50-50. Depends on the animal and depends on the area of the brain.
00:05:52 - So I don't think it's 50-50.
00:05:54 - She has calculated those. Those numbers.
00:05:57 - But now, the often non-neuronal... Do you think this is relevant?
00:06:01 - Like numbers of... Well, just plenty of ratios.
00:06:04 - Ratios. It was like... Well, you gave some numbers actually in your talk, right?
00:06:08 - Where you said that... Where do I have... On average... In humans...
00:06:14 - On average, like two astrocytes per each 10 neurons. I think that's an average calculation.
00:06:21 - On average. In mouse, it was 1 to 20 neurons per astrocyte, right?
00:06:25 - You said. Yeah, or 1 to 20 or 2 to a… it's in that world park.
00:06:31 - It's in difference for humans as well, I would say. Yeah, probably. So it would be the same.
00:06:36 - But what I meant is that there was, for many years, the notion that astrocytes
00:06:41 - were 10 times more abundant than neurons. Exactly.
00:06:45 - First, this is not true. And I don't think the numbers are so relevant in the
00:06:51 - sense that the fact that you have more of something makes that something more
00:06:55 - relevant, perhaps not necessarily.
00:06:59 - I think it's the function that is more relevant.
00:07:02 - You may have something that is just present in very low amounts,
00:07:08 - but it's for some reason incredibly important for the function of the brain.
00:07:12 - So numbers are interesting, but I don't think that is so relevant.
00:07:15 - And definitely, astrocytes are not 10 times more abundant in the brain than...
00:07:20 - But as the non-neuronal cells, how abundant are the astrocytes compared to the
00:07:25 - other non-neuronal cells? I don't have the numbers. Herculano has them.
00:07:29 - But just in your imagination, astrocytes are a relatively small subpopulation
00:07:38 - of cells making up the brain?
00:07:42 - So they're not that dominant? if I know it's directed so and then is if you
00:07:48 - look at the non-neuronal cell types,
00:07:50 - is there anything special about their distribution in the nervous system if
00:07:55 - we go for more primitive parts of the brain like the brain stem and the spinal
00:07:59 - cord or two more frontal areas do you see any kind of differentiation across
00:08:04 - these non-neuronal cell types I don't think that this has been analyzed.
00:08:09 - We spoke about tiling, and I think tiling is a feature of astrocytes that neurons don't have.
00:08:18 - And perhaps there is more tiling the more frontal we go.
00:08:23 - So the more developed...
00:08:28 - The area, the more tiling. Regular, if you want. More regularly and perhaps tighter.
00:08:34 - So the tiling function, whatever it is, is more developed. That's perhaps the case.
00:08:39 - But those kind of analysis have been performed.
00:08:42 - And from an evolutionary perspective, if we go to, say, primitive vertebrates,
00:08:47 - let's say, lamprey or fish,
00:08:51 - or we go to invertebrates, Do we see any kind of patterning of the non-neuronal cell types?
00:09:00 - I'm not sure about that. I know the difference between mice and humans,
00:09:07 - that astrocytes are more complicated structurally in humans than in astrocytes,
00:09:13 - and there are more subtypes.
00:09:14 - And I don't know exactly, but I think in invertebrates, yeah,
00:09:18 - there are astrocytes. but I'm not sure about their colonization or whether they
00:09:25 - are But it also means people might not have really looked at that. No.
00:09:29 - Okay. So that's interesting, right? Because one thing that you also made clear
00:09:36 - in your talk is that the whole idea already of the morphology of astrocytes has changed a lot.
00:09:41 - Because initially because of just the immunocyte chemistry available.
00:09:45 - Because there are better techniques now to the astrocytes, yeah?
00:09:47 - Initially And actually, they look like very sort of punctuated,
00:09:50 - star-like... Star-like cells.
00:09:52 - It's mostly with long processes. Yeah.
00:09:55 - And they're not. They're like balls of a lot of hairs.
00:10:00 - Exactly. That's the way they are. Right. And that's probably indicative of their
00:10:02 - function. Really? In the way... Yeah, absolutely.
00:10:05 - So, and that's also some of your own work that you showed. Yeah.
00:10:10 - To get to the tiling, so it looks like we have these bushy astrocytes that are
00:10:19 - forming sort of a tessellated pattern throughout the brain,
00:10:24 - which is structured in a three-dimensional way.
00:10:30 - So do you also think this tiling is highly structured in three dimensions?
00:10:34 - Oh, absolutely. Like bricks? Absolutely. Like we shouldn't hit the boxes?
00:10:38 - Absolutely. It's like a boronite tessellation.
00:10:40 - Absolutely, it is. I know. We have published a paper, actually,
00:10:44 - where the tiling of astrocytes, it's really well modeled when you do borneotisolation of the brain.
00:10:52 - So you take the brain and you just do this kind of tisolation from,
00:10:58 - you just have seeds there and then you stabilize the distances between the seeds
00:11:05 - and you draw walls there.
00:11:07 - And that way you divide the...
00:11:10 - The brain, like a given volume in different voronoi volumes,
00:11:14 - and it's identical to the desolation, to the natural desolation of astrocytes.
00:11:21 - Indicating that, I think this is indicative of the way they grow.
00:11:26 - So probably when they grow, either from radionuclidea or from clonal expansion
00:11:31 - from local astrocytes, they sort of grow until they find another astrocyte.
00:11:37 - And that's actually how voronoi's deflation occurs and develops.
00:11:43 - But that's for the neocortex, mainly, no?
00:11:46 - Yeah, that's probably the neocortex, and probably the rest of the brain is like
00:11:50 - that, but with more mistakes, with lower quality, perhaps.
00:11:55 - So my idea that's in the neocortex, the signaling that determines the tannin,
00:12:02 - I mean, the synodyms that I think are repulsive pathways,
00:12:06 - like hip frames or semaphore frames, probably is more developed and works better.
00:12:15 - But in the rest of the brain, that occurs, but perhaps in a more primitive fashion,
00:12:20 - more, taking a picture, in a more primitive fashion.
00:12:26 - So, probably the same elements all over the brain, but with different quality.
00:12:33 - Okay. So, the ester sites, they have this really dense projective field of processes,
00:12:41 - which is, you said, about 50 micron across?
00:12:45 - The whole size, yeah. So, the ball is the diameter, yes, up to 50 microns.
00:12:51 - Okay. The whole ball from 35 to 50. 50 is a good number.
00:12:58 - So would that be compatible to something like a cortical column?
00:13:05 - Um...
00:13:09 - I think columns are, aren't they larger? I'm not sure about this.
00:13:15 - And they're wider, I think they're wider than that. But do you see it aligned
00:13:19 - with, let's say, the structures that neurons would be like?
00:13:23 - There is one paper where they do fate analysis,
00:13:27 - so they label the astrocytes, and they see in the adults where they are with
00:13:33 - radial glia, and they do see columns, but they are not all over the place.
00:13:39 - So, it's not that columns have astrocytes associated to that column, all the columns.
00:13:46 - The notion is that some of the columns have astrocytes, indicating that the
00:13:51 - origin of astrocytes is mixed.
00:13:54 - Some of them come from the radial clea that gives rise to the column,
00:13:59 - and some of them come from elsewhere.
00:14:02 - And that creates a complex pattern. And the astrocytes would only be in the
00:14:07 - gray matter of the nervous system. No, there are also white matter astrocytes.
00:14:10 - Absolutely. They're different as well as they are.
00:14:13 - And they have a different morphology and different molecular phenotype too.
00:14:18 - But there's essentially just a continuous matrix, if you want,
00:14:22 - of astrocytes. So if I take a brain.
00:14:27 - If I could visualize all the exercise in that brain, it would be just the whole
00:14:31 - volume would be covered with sort of very regularly spaced exercise.
00:14:37 - Yeah, absolutely. With the different densities, different morphologies, depending on the area.
00:14:43 - But it would be a continuous. Yeah, that's a nice experiment to do with a clear
00:14:47 - brain technique. Absolutely.
00:14:48 - Before you were thinking about that. Yeah, that's a good experiment.
00:14:51 - But that would be the prediction.
00:14:52 - To stain estros exclusively. And yeah, you will, we will see,
00:14:56 - uh, different tiling of astrocytes all over the brain. Yeah, absolutely.
00:15:01 - That would be nice. So a nice picture to have. So would that structure then,
00:15:05 - so what's the density then, if you take just a bit of brain,
00:15:09 - a cubic millimeter, right?
00:15:13 - In your mind, then these, these mushy astrocytes would really fill up that That
00:15:19 - whole volume and then the neurons and the blood vessels are sort of squeezed inside that matrix?
00:15:29 - Everything is squeezed there. And probably the arrangement of all the cell types
00:15:36 - is highly coordinated and regulated.
00:15:39 - And vessels probably play a big role too.
00:15:43 - So everything, the vessels grow and everything adapts to the rest of the space.
00:15:48 - And creates their own surface there.
00:15:52 - But then, couldn't you speculate that these astrocytes are there to give some
00:15:57 - sort of uniform mechanical support to the rest of the system, right? That could be it.
00:16:04 - So I think that when astrocytes were described as a glue, initially named glia.
00:16:14 - Glue is not a bad term for astrocytes, actually, in the sense that they're all over the place.
00:16:21 - The difference is that glue implies it's a passive support, and this is possible.
00:16:27 - Perhaps there is some, as you say, structural support for the rest of the structures.
00:16:33 - But I do think myself that that structure is also actively exchanging information
00:16:38 - with the rest of the cells. So, it's not just a passive thing there that you
00:16:43 - may have break or real glue. It's an active glue.
00:16:46 - So, whether it has also supportive elements and guiding elements to its structures, it is possible.
00:16:53 - Because would you know of any other cell type, non-neuronal or neuronal,
00:17:00 - that would have this feature of such a uniform distribution locally and globally, right?
00:17:08 - Microglia too. Microglia is all over the place, exactly.
00:17:13 - Also like a three-dimensional matrix. Yeah, yeah, yeah, yeah.
00:17:16 - And NG2 cells, which I find fascinating.
00:17:19 - And we don't know much about them, but they are all over the place, are highly abundant.
00:17:24 - And they're also, they have a tile. Microglia and NG2, they are also tiled.
00:17:31 - They're also territorial.
00:17:33 - It's just neurons that are not territorial, but yes, they are.
00:17:36 - And then if you could state them, you actually see them beautifully arranged,
00:17:39 - regularly arranged all over the brain. Right. Absolutely.
00:17:43 - So in some sense, you want to have a very strongly symmetric structure to distribute
00:17:48 - all mechanical forces so that you can allow neurons to be, let's say,
00:17:52 - asymmetric in how they process things. That's an interesting idea.
00:17:56 - Uh-huh. Okay. You think like an engineer.
00:18:02 - I don't know. Do I? that's a continuing thought but why not um well but so i think myself about.
00:18:11 - For me, the timeline, it's about information processing.
00:18:16 - Well, that's indeed the next question, right? For me, that's the idea.
00:18:20 - So they segregate information processing in a set of neurons.
00:18:27 - Either they synchronize that activity or they provide energy for a given set of neurons.
00:18:32 - So for me, that's the notion. It is related to information processing.
00:18:37 - Like in a circuit, it's a mini circuit. And I have no idea what they do there,
00:18:44 - but tallying is more associated to synchronization of activities in a given module in the brain.
00:18:52 - Okay, so let's look now at that function, right?
00:18:56 - So here we have the disaster sites, equally tessellated.
00:19:04 - It um we don't know what
00:19:07 - they do and it's actually a significant chunk
00:19:11 - of the of the cell volume of the brain that's
00:19:14 - correct so you spoke of the dark matter of of the brain and now we can start
00:19:21 - to speculate about what they do because actually we don't know much about that
00:19:24 - no so why has it taken us so long to even start to worry about what they might
00:19:29 - do functionally why no we we i that's a great question.
00:19:33 - I realize, and actually this is sort of a recent understanding about things, research.
00:19:42 - Develops very, very slowly, incredibly slowly, which is for the people that
00:19:48 - are not very patient, that includes me, that's very striking.
00:19:52 - So it takes us years to find something relevant, events, and sometimes the techniques
00:20:00 - are a limitation or an advance.
00:20:03 - So in the case of astrocytes, we spoke about this this morning,
00:20:06 - the reason why we know so much about calcium astrocytes is because we have calcium
00:20:10 - imaging, and that was fantastic.
00:20:13 - And since we don't have imaging or another readout for another phenomenon that
00:20:18 - may be more relevant, then we cannot talk about that phenomenon.
00:20:22 - So sometimes techniques determine concepts.
00:20:26 - We have to be very aware of that. So as to why it has taken so long, I think a big problem is,
00:20:34 - in addition to science being slow in nature, that the neuronal people haven't
00:20:43 - been interested in non-neuronal cells. Even...
00:20:48 - If we look at the number of references, I have a student, my student,
00:20:52 - Abel, I just defended his thesis.
00:20:55 - He had a picture about the number of citations, so the number of articles related
00:21:00 - to astrocytes, the number of articles related to glia.
00:21:03 - They're per year. So we have like 20,000 articles for neurons versus,
00:21:10 - I don't remember, 2,000 articles for astrocytes.
00:21:13 - So then that explains a lot. So the number of people working on neurons is larger
00:21:20 - than the number of people working on astrocytes.
00:21:22 - That determines also how fast discovery goes.
00:21:26 - And the second thing is that neuronal people are not interested in astrocytes.
00:21:31 - That's it. And then many of the neurons, the advance in neurons is earlier because
00:21:39 - the axon potentials were discovered in the 50s.
00:21:42 - Advancement in astrocytes started to happen in the 90s when we discovered Gaussian
00:21:50 - imaging for astrocytes.
00:21:51 - So we have been studying neurons for 50 years already.
00:21:58 - By the time we start to realize astrocytes do something else, other than being a glue.
00:22:03 - So that can explain a lot of things. The techniques are different.
00:22:06 - But I think a big problem is that neuronal people are not interested in non-neuronal stuff.
00:22:11 - But conversely, you can also say that astrocyte people don't care too much about
00:22:14 - the neurons. Yeah, exactly.
00:22:16 - But the impact of that in the neuronal field is minimal.
00:22:20 - I think the impact of all these people working on neurons of not caring about
00:22:26 - astrocytes is much larger. Yeah, but I think that's a very common impression
00:22:30 - people have, that whatever they do is not considered relevant by their colleagues.
00:22:35 - Right, it's true. I think it's just a sign of general fragmentation.
00:22:38 - But in our case, we have numbers. So systems neuroscience concerns mostly neurons.
00:22:45 - So in the big meetings that are specialized in systems neuroscience,
00:22:51 - we calculated that only 1% of presentations are dedicated to non-neuronal cells.
00:22:57 - You know, maybe the problem here is that right now there is not a clear proposition
00:23:03 - what astrocytes could contribute functionally to neural systems, right?
00:23:08 - And I think this is the big challenge. In some sense, if you say 2,000 papers
00:23:12 - a year on astrocytes, then you can also wonder, okay, what the hell are these
00:23:16 - papers about, given that their overall understanding is still so limited. Right.
00:23:21 - So the question is how astrocytes contribute to higher brain function.
00:23:25 - That should be our challenge, right? That's our challenge.
00:23:27 - Beyond clearing the test, which is very important, or beyond providing fuel
00:23:34 - to neurons, which is very important too, but it did do something else that is
00:23:38 - relevant to higher brain functions.
00:23:39 - And if we didn't have astrocytes, we wouldn't have those functions.
00:23:43 - So let's take a look. What do we know about the interaction between astrocytes
00:23:49 - and neurons? What are the outstanding features that astrocytes have that might
00:23:54 - be relevant if you are a neuron?
00:24:00 - Let's go for the data. So the data shows that you manipulate astrocytes and
00:24:06 - you change the response of neurons.
00:24:08 - So before any further interpretation of why astrocytes are necessary for neurons.
00:24:12 - So, in local circuits or in networks, doing things to astrocytes,
00:24:20 - manipulating their responses,
00:24:22 - changes the circuit without, changes the network without.
00:24:29 - That's a fact. That's the evidence, the experimental evidence.
00:24:34 - And I could say, look, if I just occlude the blood vessel, also something happens
00:24:38 - to neurons, but it's not necessarily informative.
00:24:41 - No, but one thing is that it's different if neurons suffer because they lack
00:24:48 - basic support, they lack oxygen.
00:24:52 - And another thing is that the neurons don't have action potentials or they have
00:24:59 - reduced action potentials because astrocytes are releasing different amounts of neurotransmitters.
00:25:06 - So, the signaling that is involved there is very different.
00:25:13 - Yeah, but for instance, what I was looking for, as was discussed,
00:25:17 - there's direct exchange of key ions that neurons need to be active,
00:25:24 - to change their membrane potentials, to generate action.
00:25:29 - But like there's sodium exchange you have potassium exchange.
00:25:34 - There's a calcium exchange between neurons and estrocytes right so apparently these ions are,
00:25:44 - exchanging so what are estrocytes doing with it what is our estrocytes doing
00:25:49 - with potassium are they buffering it are they they're buffering using it are
00:25:53 - they they're buffering just they bring it out of the estrosolar space to the
00:25:58 - blood that's the the standard knowledge that you have a lot of potassium channels.
00:26:04 - And in diseases, it's well known that it's a good therapeutic target in the
00:26:09 - sense that they get dysregulated, meaning that probably if they don't buffer potassium correctly,
00:26:16 - that contributes to disease and to neuronal activity.
00:26:20 - So the interpretation goes again to a more homostatic direction,
00:26:22 - like, okay, it's sort of just removing the potassium from extracellular space.
00:26:28 - Right. But another interpretation, it's like basic computation. mutation.
00:26:33 - So the fact that we spoke about it, filtering, so if there is a circuit,
00:26:41 - imagine that it's a circuit and neurons are part of the circuit and astros are
00:26:46 - part of the circuit as another element.
00:26:48 - So they may be doing things to that circuit. That's what I'm trying to figure out.
00:26:51 - Like they're maybe gating, changing gain, changing extras on the...
00:26:59 - Could they release potassium again in the extracellular space?
00:27:04 - They could release potassium. They could release glutamate. That goes back.
00:27:07 - It's like a third neuron that goes back to the neuron and changes the way the
00:27:12 - neuron responds to the next stimuli.
00:27:14 - So it means that the astrocyte essentially can control whether a neuron will
00:27:20 - respond at all to the next stimulus. It would modulate.
00:27:23 - I think it's better to modulate. In an extreme case, it could actually prevent
00:27:26 - it. Yeah, exactly. Exactly.
00:27:28 - Or anything could change. In the studies in the local circuits,
00:27:36 - it is known that depending on the input, so the inhibitory neurons, for instance,
00:27:43 - depending on the kind of response they have,
00:27:47 - they produce different responses and astrocytes that in turn relay different
00:27:53 - outposts to, etc. That's well known.
00:27:59 - And that's pretty delicate. So it's not just homostasis.
00:28:04 - It is pretty balanced reading of the neuronal activity and routing it to the
00:28:14 - other neuron in the circuit.
00:28:17 - So for me, this is beyond homostasis.
00:28:21 - This is the astros are acting like another neuron. and they can may change actually
00:28:28 - the output the global output of the receding circuit can be changed by astrocytes
00:28:34 - in a precise manner beyond like.
00:28:41 - Vascular cells delivering oxygen to neurons they can change that for you that
00:28:47 - doesn't mean that astrocytes may contribute to,
00:28:51 - Higher brain functions, being just there, there are metabolic roles.
00:28:56 - I think it would be great if exercise would help out.
00:29:02 - So I have no objections against that. So it's more about looking at what they
00:29:06 - can really do and what spatial temporal scale that could play out. That's such a question.
00:29:10 - If we talk about the potassium dynamics, this could play out at,
00:29:15 - let's say, millisecond level, the buffering and release of potassium.
00:29:19 - Or do you see this as a slow process?
00:29:23 - I think it's more of a slow process, but I have to look into it. And glutamate?
00:29:27 - Glutamate, the glutamate uptake, I think it goes in the millisecond scale.
00:29:32 - Glutamate release, it's in the second scale.
00:29:36 - So when the astrocytes respond to neurons by releasing glutamate, that takes seconds.
00:29:42 - But in hundreds of milliseconds and then in tens of seconds.
00:29:47 - And this releases the nonspecific in extracellular space?
00:29:50 - Well, it's sort of paracrine. Let's say paracrine, which is not a bad term because
00:29:56 - there are neurons like the neurodegenerative neurons that work in a paracrine
00:30:01 - manner in volume transmission.
00:30:04 - So sometimes relevant things happen globally, not just locally.
00:30:09 - And probably local control is different from global control.
00:30:12 - They both have different roles. So you're saying there's no evidence that astrocytes
00:30:19 - would have the specificity to have a very highly,
00:30:22 - highly temporally precise and locally specific or global….
00:30:44 - So the point is to look at what kind of global roles, synchronization,
00:30:50 - different neurons at the same time, are relevant for astrocytes to control.
00:30:57 - Now we talk about different neurotransmitters and presumptuosum.
00:31:01 - Are these only evantotropic receptors that astrocytes have?
00:31:05 - Or do you also see metabotropic receptors?
00:31:08 - Oh, they have metabotropic receptors for glutamate, for instance.
00:31:12 - They are typically present in astrocytes.
00:31:16 - Doesn't it make you suspicious that there is actually a real functional role for this?
00:31:20 - Because that would mean that you really actively, in a very specific way,
00:31:25 - are regulating processes in the astrocytes depending on the presence of glutamate. Oh, absolutely.
00:31:31 - So this would be also a little bit beyond just buffering, no?
00:31:35 - No, absolutely not. Yes, even transport of glutamate signals to some functions,
00:31:41 - even just the mere transport.
00:31:44 - So what kind of reactions do you see in astrocytes to glutamate?
00:31:48 - You may have changes, for instance, in the physical changes in the way the astrocytes wrap neuron.
00:31:57 - So the same way that spines change their morphology in order to get closer to
00:32:03 - our spine to retract, that has been described also in astrocytes in those distal
00:32:08 - processes in relationship with neuron.
00:32:11 - And this is regulated by glutamate and calcium. So you would argue that the
00:32:15 - glutamate also regulates issue on the formation of these synaptic structures
00:32:22 - that would then create post-synaptic neural processes plus gastrocytes.
00:32:27 - Yes, and an area of gastrocytes that I'm very interested in,
00:32:32 - and it hasn't been explored, are long-term changes.
00:32:36 - So we know that gastrocytes...
00:32:40 - Modulate memory, because when we manipulate the astrocytes with chemogenetics or transgenic tools,
00:32:46 - there are different stages that has been done with chemogenetics,
00:32:50 - and different stages in the memory paradigm from acquisition,
00:32:56 - consolidation, replay, so that exactly where they're acting is getting characterized.
00:33:04 - But we don't know exactly what are the long-term changes in astrocytes,
00:33:10 - the same way that neurons have long-term potentials, LTP, which causes changes
00:33:16 - in the molecular makeup of the neurons.
00:33:18 - That hasn't been characterized in astrocytes.
00:33:21 - And I do think this is an area that I'm interested, very interested,
00:33:25 - because I think that can be very fruitful to understand. To understand.
00:33:29 - Because for instance, there is this whole problem at the neuron side.
00:33:32 - If I build a synapse, how do I stabilize my synapse?
00:33:36 - And there is the idea that this also has to do with intercellular processes
00:33:41 - that depend on the molecules, like chemokinase 2, as an example,
00:33:45 - and John Lisman hypothesis.
00:33:48 - But that would suggest that you need similar kind of memory processes at the
00:33:53 - level of the astrocyte if they form part of that synapse.
00:33:56 - Yes. So, is there anything known about this kind of intercellular signaling
00:34:02 - pathways in estrocytes?
00:34:04 - No, not at all. Okay. That's a totally infant area of study.
00:34:09 - So, you're saying one of these 2,000 papers a year are all about, right? Yes.
00:34:12 - But then the other possible control that estrocytes have is capillaries.
00:34:18 - Absolutely. They can directly control blood flow and exchange,
00:34:23 - right? They do. The blood-brain barrier.
00:34:25 - They do. So how do you think that can be or is used and on what timescale is it used by astrocytes?
00:34:34 - I think, well, that's what the data shows in the time of milliseconds.
00:34:41 - Absolutely, that happens. So when a neuron in somatosensory stimulation,
00:34:48 - so a neuron in mice, the whiskers touch, the neuron detects that it has action
00:34:55 - potentials and calcium inactivation,
00:34:58 - then seconds later, milliseconds later, hundreds of milliseconds,
00:35:01 - seconds, astrocytes see it, and they transduce that to the vessel. That's a fact.
00:35:08 - And it's interesting when we talk about this this morning that they could do this earlier,
00:35:15 - before the task happens because there is a prediction that is going to happen
00:35:20 - and so it prepares the territory for a better response later on. But yeah, absolutely.
00:35:26 - The relationship of gastrocytes and vessels, for me, is very important. It's very, very clear.
00:35:31 - And I think astrocytes multiplex, so they can talk. And structurally,
00:35:35 - they are different because the distal processes are one thing,
00:35:42 - and the amphid is another morphological structure that is different and wraps the vessels.
00:35:52 - And it doesn't have the bulbous structure.
00:35:55 - Very dense network, this lattice in the distal process.
00:36:00 - It's just like a, yeah, it's like a sheet.
00:36:03 - Totally, it wraps the message. So the astrocytes have the multiplex.
00:36:09 - They're able to multitask, and one task is regulating the connection between
00:36:16 - vessels and the rest of the brain. Absolutely.
00:36:20 - What's the delay? So when we have neural activity, with what delay do the astrocytes
00:36:27 - start to then change blood vessel response?
00:36:30 - And what species is it in? Hundreds of milliseconds.
00:36:35 - And that's a long lasting? How long does this?
00:36:38 - I would say seconds. I'm not sure about that, but seconds. Okay,
00:36:42 - and then I would assume that this is not, if you have one spike,
00:36:47 - I don't think the astrocyte will start to change the dilation of the capillary.
00:36:54 - Oh, that you need to make a threshold?
00:36:56 - I probably, I don't know about it, but probably. So would you say then that
00:37:02 - the astrocyte looking at some average lower response and giving this average,
00:37:08 - it would control the capillary?
00:37:10 - That's a great question. I don't think it's none. Okay. Whether or not it responds
00:37:14 - to, because usually the experiments are more one-to-one.
00:37:19 - Bad balancing that has been analyzed, whether you need the minimum of neurons
00:37:24 - to be stimulated in order to produce.
00:37:26 - Now, one reason I'm asking is, of course, a lot of the work on magnetic resonance
00:37:30 - imaging and how you can use that to assess a function in the brain is by looking
00:37:37 - at this bold signal that's derived from blood flow.
00:37:39 - Right. And then there's a belief that this is related to neural activity.
00:37:45 - But now we see that this is actually mediated by astrocytes.
00:37:48 - Well, it could be mediated by astrocytes.
00:37:49 - The astrocytes consume oxygen, that's the point, but not all the time. So it's not that thing.
00:37:55 - Well, BOL signaling is actually very complicated because what it really shows
00:38:00 - is that it's hemodynamic response.
00:38:04 - So it is an increase in blood flow, but actually oxygen consumption doesn't increase.
00:38:09 - It's the paradox of BOL that was described several years ago.
00:38:15 - So meaning that oxygen consumption doesn't change very much.
00:38:19 - What changes is that there is more blood flow.
00:38:22 - And as a result, the ratio of hemoglobin that is oxidized versus the hemoglobin
00:38:27 - that is not oxidized changes. This is what you're looking.
00:38:30 - You're looking at increasing flow. You're looking at increasing oxygen consumption.
00:38:34 - Both is really difficult to interpret. But in general, it has been used as a
00:38:40 - surrogate for neuronal activation.
00:38:43 - And this is what I think is wrong. Not totally wrong, it's just neurons can
00:38:47 - contribute to the signal too. Not all the time.
00:38:51 - So my point is that we need to get into the details.
00:38:55 - I think the paradigm is very relevant because the notion that the task-dependent
00:39:00 - activity is the model of brain activity is wrong.
00:39:05 - So we need to look into different ways.
00:39:08 - Models, including that one of high glutamateric activation, but also brain,
00:39:14 - increasing brain activity.
00:39:16 - I'm sure that the both signaling increasing brain activity is very different.
00:39:21 - Gustavo Leco works on that, from task-dependent activity, changes during the
00:39:28 - day, changes in different nuclei.
00:39:30 - So we need to get out of average measurements and very specific models that
00:39:36 - we think are the models of all the reactivity because the devil's in the details here.
00:39:42 - And I'm sure that in very specific circuits and in very specific moments,
00:39:48 - astrocytes consume a lot of oxygen.
00:39:51 - So there are some papers and literature where people look at this relationship
00:39:55 - between reactivity, astrocyte response, and blood flow that are mainly done
00:40:01 - with optogenetics. And they're being questioned.
00:40:04 - Why don't they actually tell us Because whether they're formative or not,
00:40:08 - I almost understand people questioning because for many neuroscientists,
00:40:11 - they have a lot at stake to just believe in the dogma that, you know,
00:40:16 - the bold signal reflects neural activity.
00:40:18 - Right. But what is the truth of the matter in your view?
00:40:24 - Is it like the neural contribution will be like a tiny fraction of the bold
00:40:29 - signal, let's say 10%? or it will strongly vary on conditions.
00:40:34 - Because it's high variability, it's uninterpretable.
00:40:38 - So where do you... I think that the right measurements need to be done.
00:40:43 - I wouldn't be able to calculate.
00:40:47 - And this is like the traditional biophysics and the brain physiology.
00:40:53 - So we need to really calculate that.
00:40:56 - But you could also use... But I wouldn't dare to say that astrocytes use more
00:41:03 - oxygen than neurons or vice versa.
00:41:05 - So it is clear that action potentials are very demanding of energy.
00:41:12 - That's absolutely very clear.
00:41:14 - The needs, energetic needs of astrocytes are not known, for instance.
00:41:20 - We don't know. No, there are pathways and there are phenomena in astrocytes
00:41:26 - that require ATP, bermanic, oxytocin, calcium removal.
00:41:31 - So there are many pumps in the astrocytes.
00:41:35 - Perhaps we can say that they don't do as much ATP as neurons, but I wouldn't say.
00:41:41 - Dare to estimate it unless I do the calculations.
00:41:45 - So the energy requirements of the astrocytes are not known at all.
00:41:50 - Is it measurable for you? I think it could be measurable. Yeah,
00:41:54 - I think we just, it's like they have been measured in neurons. So why not?
00:41:58 - And the thing that we know now is that at least they are able to produce ATP
00:42:03 - through fatty acid oxidation that we think they do, which is very,
00:42:08 - it's very efficient because there's a lot of ATP.
00:42:10 - But we think that they don't produce, they don't have fatty oxidation all the time.
00:42:16 - We think they're versatile. The beauty of astrocytes, if I can introduce this
00:42:21 - word, beauty, in a scientific talk, is that they're versatile.
00:42:26 - So they use whatever they have, and they have glycolysis.
00:42:29 - And probably because the ATP produced by glycolysis is necessary for certain
00:42:35 - pathways that are locally by the membrane and related to the release of glutamate
00:42:42 - or to uptake of glutamate.
00:42:45 - But they do generate enough ATP to provide the other oxidation at some points in the life.
00:42:52 - I'm not sure when because we haven't carried out experiments in vivo, but I'm sure they do.
00:42:57 - And in certain moments, but I don't, I wouldn't dare to say whether that accounts
00:43:03 - for what percentage of ranoxetamines.
00:43:07 - Astrocytes can operate in an energetically efficient regime,
00:43:12 - but they can also be energetically inefficient.
00:43:17 - It can be both. You say at some point in their life. I think that they can use
00:43:21 - only glycolysis. And what happens there is they don't die.
00:43:25 - But one thing is not to die, and I think it's to be doing well. To be useful.
00:43:30 - To be performing right. One thing is survival, and I think it's the right performance.
00:43:35 - No, because again, we'd argue against this homeostasis interpretation,
00:43:39 - because if it was homeostasis,
00:43:41 - you would expect that substrate to be very energetically efficient,
00:43:46 - because otherwise, how can you be usefully contributing to maintaining homeostasis
00:43:50 - of your neurons if you burn a lot of energy yourself and produce waste products and so on?
00:43:55 - That's actually correct. Yeah, I think we need to understand the energy metabolism
00:43:58 - and astrocytes, not just when they use, what pathway, in what moment.
00:44:04 - Also, I think this notion that ATP is not stored perhaps is not true,
00:44:09 - so there is something that is very labile, you produce ATP and then either you
00:44:13 - don't use it or it's gone.
00:44:15 - So perhaps the astrocytes store ATP too. So that allows them to resort to glycolysis
00:44:23 - when neurons need a lot of oxygen, then within the oxygen goes to neurons, not to astrocytes.
00:44:28 - But the astrocytes are still there doing something.
00:44:31 - So perhaps they can use ATP from other sources.
00:44:34 - So there are questions there that need to be answered.
00:44:38 - And I do believe that energy is very, very important and that many of the anatomical
00:44:46 - designs in nature are determined by energy usage and energy usage optimization.
00:44:55 - So that could be probably a very fruitful area of research to try to understand
00:45:01 - how astrocytes, the interplay of energy metabolism between astrocytes and neurons,
00:45:06 - and how much oxygen each one uses.
00:45:09 - So is there any evidence that astrocytes can really, let's say,
00:45:14 - turn circuits on and off, and then it also happens under a realistic condition?
00:45:18 - I would, more experimentally, I have to find the papers. I would say yes.
00:45:24 - Probably if you ask this question to Alfonso Arago, all the leaders in the field,
00:45:29 - yeah, I think they can actually turn.
00:45:31 - So that means energy management. Well, yeah, because of the energy,
00:45:37 - but also because they stop releasing a given biotransmitter than neurons do.
00:45:44 - Yes, I think they can, yeah. Mm-hmm. Yes. Right, okay.
00:45:48 - Not just because of the energy, but because of the signaling. Right. Yeah.
00:45:53 - But the other thing that I always find very exciting about estrocytes,
00:45:58 - also because I'm ignorant, are the gap junctions, right?
00:46:02 - So they have gap junctions that allows potassium to disperse across membranes between estrocytes.
00:46:11 - And that would, in theory, set up possibilities for a more rapid signal transduction
00:46:19 - than what you would get if you have action potentials going over axons.
00:46:23 - Would you agree with that?
00:46:24 - I'm not sure about that because the unit is not.
00:46:27 - So the potassium that is diffused out of the astrocytes would have reached enough
00:46:35 - concentration to change the neuronal activity in other neurons that are farther away?
00:46:41 - No, let's just worry about the network of astrocytes and they're coupled with
00:46:44 - these gap junctions, right?
00:46:46 - Right, but in order to have an effect on neurons, you need to have really reached
00:46:51 - certain levels of potassium. So I tend to think about diffusion as not being
00:46:58 - very controlled, it's just passive, they are removed.
00:47:01 - It depends on the gradients, right? Right, exactly.
00:47:04 - That has to be modeled. So the answer could be… Yeah, but look,
00:47:11 - if neurons are reactive, they are transiently buffering a lot of potassium, right? Right.
00:47:18 - So that could possibly set up these kinds of gradients.
00:47:23 - No, because then you would have, so then the potassium in the exercise network
00:47:28 - would be rapidly attracted to these areas where there is activity.
00:47:34 - But a gradient, for me, is a process that is regulated in a fine manner,
00:47:40 - and this is incompatible for me with diffusion. Isn't that incompatible?
00:47:48 - So I tend to think that diffusion is just, yeah. But that could be modeled, I think.
00:47:55 - That idea could be put into a model and tested different levels of potassium
00:48:03 - production and potassium removal by estrogen to see that creates gradients.
00:48:08 - Yeah. And those gradients change neural activity. Yes.
00:48:12 - Maybe they, what you mentioned about the priming of neural activity.
00:48:17 - Maybe this is created by gradients of potassium around a given circuit that
00:48:23 - makes the neurons respond more or less, or beyond a threshold or not reaching the threshold.
00:48:29 - So maybe that's, but that can be modeled.
00:48:33 - Yeah, because what you would have, let's say you have neurons and become very
00:48:36 - active, so they start to buffer a lot of potassium rapidly.
00:48:42 - This might then deprive their neighbors from also becoming active because there's no potassium around.
00:48:49 - And then the astrocytes allow potassium to flow in from other parts of the network that are, let's say.
00:48:57 - So in some sense, it also will give you a competitive system,
00:49:01 - because if I have different islands of activity, via the exercise,
00:49:07 - I can actually compete over the potassium. I see. Right?
00:49:11 - And then this would play out very quickly if the gradients are big enough.
00:49:17 - So would you buy this kind of fantasy scenario, or do you think this is really
00:49:20 - completely… I would like to see the models.
00:49:25 - Okay. I would like to see the models that support that kind of scenario.
00:49:30 - Okay. Because the same thing might also be then going on with your sodium.
00:49:35 - Exactly. But the sodium doesn't diffuse over the gap junctions,
00:49:39 - right? That stays local in the astrocyte.
00:49:40 - Right. It's taken out of the astrocytes. It's true that it's taken out of the astrocytes, yes.
00:49:44 - So it's only the potassium that could do this. Yes. So the other thing I was
00:49:48 - thinking about that is exciting about these potassium networks
00:49:52 - or communication channels across the astrocyte network is it might give you
00:50:02 - a channel to start to prime different areas of the brain, right?
00:50:05 - So you mentioned this also earlier where you say, well, we expect a vision.
00:50:09 - And there are experiments that also have shown already that you have anticipatory
00:50:13 - changes in the volt signal that do not correlate to neural activity.
00:50:18 - And this would suggest that this is driven by the astrocytes.
00:50:22 - Then the question, how can the astrocytes know, right?
00:50:25 - So there must be some communication channel that says, look,
00:50:28 - we expect a visual stimulus, so increased blood flow.
00:50:31 - Well, but this is also the prediction brain, that the brain has already the
00:50:37 - information about the outer world and is renewing that information all the time.
00:50:41 - And whenever new information comes in, they just reset.
00:50:47 - And perhaps astrocytes are already in that circuit, meaning that they are actively
00:50:52 - processing information all the time.
00:50:55 - So premonition is part of the system that is replaying the information all the time.
00:51:04 - Don't you agree with that? Well, I was more thinking about that you just have,
00:51:07 - let's say, a conditional event that you're conditioned.
00:51:10 - When you hear a sound, there will be a visual stimulus five seconds later.
00:51:15 - So I hear the sound. And now in an anticipatory response to this association,
00:51:19 - I start to prime my visual area through the exercise to say,
00:51:23 - okay, we're going to get a visual stimulus, wake up.
00:51:26 - So you can sort of put areas in idle mode, like low energy consumptions,
00:51:33 - and then reactivate it from there by just three exercise network.
00:51:37 - It could be, yeah. Is there any data that would support that idea? No.
00:51:42 - Except this anticipatory bolt response innovation. Exactly. Was that Critchfield?
00:51:48 - I don't know. I don't remember. Yeah. Okay. So it could be one of the reasons for tylene.
00:51:55 - So that creates different islands of energy usage or potassium gradients along the brain.
00:52:02 - If I'm an estrocyte network, could I control the diffusion of the potassium?
00:52:09 - Can I open and close my gap junctions?
00:52:12 - Are they actively controlled or are they just passive? Nothing, they're passive.
00:52:17 - Yes. So now we made a little index of different possible functions of the estrocytes.
00:52:27 - And you also mentioned this glymphatic system.
00:52:31 - And that, of course, pushes us a little bit more in the direction of homeostasis.
00:52:35 - I've seen that's homeostasis, clearly. So why was this glymphatic system relevant
00:52:41 - in this discussion? Why do you think this is an important insight in terms of
00:52:46 - what astrocytes could be doing?
00:52:49 - Well, because it's, I think, a very important issue as to how the brain removes waste.
00:52:57 - And this is highly, highly relevant for normal function. It is highly relevant for diseases.
00:53:06 - So I think it is worth mentioning. And it's a very recent discovery,
00:53:10 - so it's worth mentioning.
00:53:11 - And moreover, it is probably regulated by the brain itself.
00:53:17 - So it's not really clear at this point, but the locus coeruleus and others,
00:53:23 - some of these nuclei that are globally broadcast, broadcasting throughout the
00:53:30 - brain, probably regulate that too.
00:53:34 - And there are studies showing that this can regulate also.
00:53:38 - You spoke about gradients of potassium determining circuit activation.
00:53:43 - There are studies showing that these fluxes inside the brain control,
00:53:54 - the glucose availability, the availability of nutrients.
00:54:01 - So they're not trivial. They're not just things that are there.
00:54:04 - They're very relevant to brain
00:54:06 - physiology. So the astrocytes are sort of regulating blood-brain barrier.
00:54:10 - This sets up a convective flow of what?
00:54:15 - Of liquid.
00:54:18 - It's liquid that moves from the artery side to the venous side.
00:54:23 - It's just inter-solar space.
00:54:26 - What's the liquid? It's a solutes, salts probably. It's convection.
00:54:32 - It's pure convection. And it's probably water.
00:54:37 - So it's really like you're washing out the brain. You're washing out the brain.
00:54:41 - It's going to flow towards.
00:54:42 - It flows to the venous side that eventually goes to the lymphatic system. Uh-huh.
00:54:49 - It's actually beautiful physiology.
00:54:53 - I'm very fond of myself in addition to computation, to brain physiology studies.
00:54:59 - And these studies are actually very elegant because it's actually very simple.
00:55:04 - Technically, they use fluorescent tracers and they just put them on one side
00:55:09 - and see where they can find them.
00:55:11 - And then they find their way out of the brain and they can track their pathway. way.
00:55:16 - So they absolutely there is water, the brain is clean every day with a lot of
00:55:24 - things get out and that is mediated by the astrocytes in the sense that they are a wall.
00:55:30 - At least they're a wall that those things have to cross and that wall probably
00:55:36 - is also selectively regulating the passage and when that wall is not working
00:55:42 - well then that passage doesn't occur.
00:55:44 - And that changes also during day and night. I find it fascinating.
00:55:50 - The finding that this clearance works only at night is fantastic,
00:55:57 - meaning that the intracellular volume of the brain changes during the day and
00:56:03 - during the night. Right.
00:56:04 - So, it's not sure if the estrocytes shrink or something, and that changes the
00:56:09 - convection towards the venous side of the brain.
00:56:15 - Well, distances are covered in that way, you think.
00:56:18 - I'm not sure. So, what's the density of this venous density?
00:56:21 - I'm not sure, but probably that answer can be found in the literature,
00:56:25 - yeah. But it's fantastic.
00:56:27 - But it also means that there must be different chambers along the artery,
00:56:31 - no? Because you must accumulate this fluid that's being released.
00:56:37 - It must be extracted from the blood, stored, and then released.
00:56:41 - Well, it comes from the CSF. The CSF is in contact with that liquid.
00:56:47 - But that's all physiology is well known. It comes from the CSF.
00:56:51 - The CSF is circulating all the time and it's in contact with the intracellular space.
00:56:58 - Probably they have different contents, but there is a flow. There is a flow
00:57:03 - from the putter in between the arteries and the astrocytes that goes in a different
00:57:10 - direction from the blood. This is interesting also.
00:57:13 - So the blood goes in one direction and that flow goes in the opposite direction.
00:57:16 - And eventually, because of these convection forces, crosses,
00:57:21 - the brain came out to the venous side.
00:57:23 - But the astrocytes must be controlling both walls.
00:57:26 - Yeah, they do, absolutely, yeah. So they must be controlling the artery wall. Absolutely.
00:57:32 - And then this CSF chamber. Yes, absolutely. Okay.
00:57:39 - So do you know when in sleep to sleep? In which sleep stage?
00:57:43 - I'm not sure. I'm sure they have looked at it, but I don't have the data.
00:57:50 - But as it occurs, the paper has very beautiful pictures and it's very traumatic.
00:57:56 - The way that those fluorescent tracers go through the brain at night,
00:58:03 - but they don't go through the brain during the day in mice.
00:58:07 - It's really, really traumatic, the change. But so now at the more behavioral level,
00:58:13 - you highlighted the number of correlations we are aware of with respect to exercise
00:58:20 - activity and behavior, like in sensor processing,
00:58:25 - state switching, and fear response regulation. Yes.
00:58:30 - So, which of these results for you are most informative about the possible functional
00:58:38 - role of astrocytes? Our brain states.
00:58:41 - I think network activity regulation.
00:58:44 - Because of this global notion, I think the findings in the local circuits are
00:58:51 - just a part of a larger role.
00:58:54 - So they find them because they look. But I think the astrocytes are more important
00:58:59 - in the regulation of networks.
00:59:02 - So they are more relevant to these brain state transitions. That's my thing.
00:59:08 - If I would study something, I would study the role of astrocytes in neuromodulation.
00:59:15 - So global phenomena, neuromodulation, brain state, slow oscillations,
00:59:20 - that would be, for me, the… So in the brain state example,
00:59:24 - you use optogenetics to stimulate… Astrocytes, Kira post-cancer, the paper.
00:59:36 - Yeah, right, exactly.
00:59:37 - And Raphael, Justin, and Kira. Right, exactly. But you're stimulating in the… which area are we?
00:59:43 - Is it the somatosensory cortex, or was it the barrel cortex?
00:59:47 - Yeah, I think it's the somatosensory cortex. Yeah, it's the cortex.
00:59:51 - So we're measuring LFPs.
00:59:56 - What we then see is that after a five-second stimulation.
01:00:01 - You essentially see a peak at about 100 seconds later of really low frequency,
01:00:10 - like below, let's say here, half to two hertz or a million delta range, right?
01:00:15 - Right. Which is a frequency range that under the control condition does not appear, right?
01:00:21 - So this here. Right, there's a change in the power.
01:00:25 - So… at the low frequency, that is increasing, stimulating. Like there's actually
01:00:30 - no power in a control condition.
01:00:32 - Exactly. And it jumps up when you stimulate the astrocytes with optogenetics. Exactly.
01:00:38 - But now, isn't that a surprise? That's no surprise.
01:00:42 - Because if you drive the astrocytes, you stimulate the astrocytes for that long,
01:00:46 - you might lead to, let's say, pathological change in the local.
01:00:50 - But not quite pathological. I wouldn't say pathological.
01:00:53 - It's not known. Well, low delta would correlate with really deep sleep or deep anesthesia, right?
01:01:01 - So those would mean these neurons are deprived of just any ion to do anything.
01:01:07 - That's such a good thing. So essentially shutting down.
01:01:09 - So this is like you have just shut down the neurons by depleting them of any resource.
01:01:15 - What would be the right control to use?
01:01:18 - Well if you want to see state change you want to look at oscillatory frequencies
01:01:23 - that you know have functional relevance right so you want to look at.
01:01:28 - Frequencies that's either in gamma or in theta or alpha but certainly above
01:01:32 - delta because delta would reflect deep sleep so my question is can we speak
01:01:37 - of a state that is functionally relevant so you have to look at a power of a
01:01:44 - frequency range that you know has functional relevance Right.
01:01:48 - This finding has been reproduced, actually, it is an early study.
01:01:57 - People have shown that if we remove the capacity of astrocytes to respond to
01:02:02 - the nucleus basalis, the nucleus basalis are minor, they also regulate brain state.
01:02:07 - And this has been measured with local field potentials.
01:02:10 - But that's very different. But the result is very similar.
01:02:14 - In this case, they are not stimulating us with optogenetics because optogenetics
01:02:19 - didn't exist. I think we're talking about a study from 2000-something.
01:02:25 - I don't remember the year.
01:02:26 - But the result is similar in the sense that the astrocytes don't have calcium responses.
01:02:32 - The nucleus basalis of minor doesn't regulate the brain states.
01:02:39 - The nucleus basalis of minor would be the cholinergic projection.
01:02:43 - Right, but meaning, talking about, so in that case, we cannot talk about astrocytes
01:02:49 - stimulation depleting neurons from things they need, from shedding, because it's actually,
01:02:57 - they aren't actually, it's just the opposite experiments.
01:03:00 - Astrocytes are not being stimulated. They just don't respond.
01:03:03 - Therefore, they cannot be depleting neurons from anything.
01:03:07 - And it's the same result in the sense that they regulate brain states.
01:03:10 - But now, in this optogenetic experiment, what does it mean to activate an astrocyte?
01:03:17 - Because they're genetically manipulated to respond to light,
01:03:21 - right? That's a key question.
01:03:24 - How are they coupled? To which receptors are they coupled? No, it's not known.
01:03:27 - That's a key question. That's the finding. They express Whereas our carotidopsin,
01:03:35 - there, they stimulate with light, and they see the calcium increases.
01:03:39 - But how it happens… The calcium inside the astrocyte increases?
01:03:44 - The calcium transients inside the astrocyte increase, and the only thing that
01:03:48 - they know is that their carotidopsin hyperpolarizes cells and the neurons that
01:03:55 - triggers the neurons are inhibited.
01:03:57 - But in astrocytes, there are also voltage-dependent channels,
01:04:03 - but not as active as in neurons.
01:04:05 - So probably the astrocytes are detecting the hydropolarization somehow,
01:04:11 - and that triggers somehow an
01:04:14 - increase in calcium concentration in the saddle. But it's not known how.
01:04:19 - First thing. Second thing, it happens mostly in the processes.
01:04:23 - So, it's a very important thing.
01:04:29 - Whether the calcium increases are happening in processes,
01:04:34 - in the distal processes, or in the primary process, or in the soma,
01:04:39 - because the mechanisms that regulate calcium release are very different in different compartments.
01:04:46 - And interestingly enough, with our pyrrhodopsin, they happen mostly in the processes,
01:04:53 - indicating that those voltage-dependent channels are perhaps richer there, but it's not known.
01:04:59 - And I think this is a limitation. It's very interesting because it's actually
01:05:04 - interesting to be able to stimulate as-processed-reverence-in-assault type in
01:05:10 - a time-specific manner and not using transgenic mice that are,
01:05:16 - it's a really elegant tool but the fact that we don't know exactly how it works
01:05:22 - I think is a limitation because we don't know the physiological relevance of the response.
01:05:27 - It is a limitation. This is a bit problematic then, right?
01:05:30 - Because we do we can speak of a state change but we don't know whether we have
01:05:35 - induced some pathological state of the tissue.
01:05:38 - I don't know. It's also sort of not sufficiently controlled.
01:05:42 - It's probably you need to refine the technique, understand mechanisms better,
01:05:45 - and find the same things in other approaches.
01:05:49 - So we're still in the dark then about where in the dark is the glass, right?
01:05:55 - But now in your case you are also interested in finding well,
01:06:00 - there's another problem we see here.
01:06:02 - Everything is so much tied to calcium imaging, right? It's too much.
01:06:07 - Probably yes and this of course is also biasing very much how we think about
01:06:12 - because we think oh these guys are really slow,
01:06:14 - right but this might be due to the way we observe them so what do you expect
01:06:20 - if we would have the magic imaging techniques,
01:06:24 - or measurement techniques to some kind of.
01:06:28 - Electrophysiologically like techniques do you expect them to be as fast as neurons
01:06:33 - in terms of time constants at work or do you really Would your prediction be
01:06:37 - that they are a system that are slower than neurons? I would say they're slower.
01:06:42 - Perhaps they are faster than seconds.
01:06:46 - So maybe we can move now the time scale from hundreds of milliseconds to tens of milliseconds.
01:06:52 - But still, that's slower than neurons. Yes.
01:06:56 - Right. I would say they're slower. And my point is that we have to find the
01:07:03 - moments where the brain needs that time scale.
01:07:07 - So we don't need to make astrocytes faster than they are. That's a mistake.
01:07:12 - So the field has been trying for a very long time to make astrocytes look like
01:07:16 - neurons. So that's a mistake.
01:07:17 - We just have to find what they are. And once we characterize them without forcing
01:07:22 - the interpretations, try to find out where that time scale is relevant for.
01:07:29 - Is it relevant to any phenomenon in the brain? I think this is the way to go.
01:07:34 - So these These very ultra-fast representations of neurons that last a few milliseconds,
01:07:41 - that astrocytes have nothing to do with it, obviously, because that's beyond their time scope.
01:07:46 - But other phenomena in the brain that happen there, where the astrocytes can
01:07:52 - be useful, that's, I think, the way to go. Okay.
01:07:56 - So now, could you imagine astrocytes as a substrate of memory?
01:08:02 - Like, his memory is to carry information over time, and you do that by stable structural change.
01:08:09 - Do you think exercise has the properties, the basic, also, biomechanical and
01:08:17 - the biochemical tools to form memories and store information over time?
01:08:22 - I think it's a biophysical question whether they have something that can have
01:08:27 - many different positions to store information. So, that's the question,
01:08:32 - and the question is, can different calcium transients do that?
01:08:37 - We don't know. We have to ask that question and analyze it.
01:08:42 - Because the question is, of course, then, if they provide context in which neurons
01:08:45 - operate, this context might have to also be associative. Right.
01:08:52 - The question is whether this context is just supportive, metabolically supportive,
01:08:58 - or more or structurally supported, or it's really an intelligent support and
01:09:04 - it's doing something for neurons. Right.
01:09:09 - There are the questions of what are the variables that neurons encode is not
01:09:16 - totally clarified because they know that some variables like odor or sounds or colors.
01:09:23 - I know that the neurons encode those variables and in their presentations that
01:09:29 - are happening in the time scale of milliseconds. seconds, but there are other
01:09:33 - variables than ever, for instance.
01:09:36 - There are many other variables that the brain uses, and I don't think we have
01:09:40 - discovered them, and perhaps some of those variables are bolder,
01:09:45 - and that is the role I'm afraid to precise.
01:09:51 - But they're very important too, like associations, contests,
01:09:56 - providing averages, perhaps they do that.
01:09:59 - They carry out the statistics of the brain in this model of prediction coding,
01:10:04 - where the brain is so tied in doing the statistics about how their predictions
01:10:09 - are confirmed by experience. But that's a lot of error calculation.
01:10:13 - And some of the papers that describe that, some of the parameters around the error calculation...
01:10:22 - Placing it in a timescale of seconds, actually. Some of them are really fast,
01:10:26 - and some of them are slower, the ones that require more computation.
01:10:31 - And that perhaps is this kind of buffering. Well, probably.
01:10:35 - It's perhaps what the kind of things that astrocytes do.
01:10:38 - So they're not hunting the code for concepts or for colors or for others.
01:10:44 - I think those neurons do that, and that is related to the lack of specialization
01:10:50 - of astrocytes. So neurons are highly specialized.
01:10:53 - And for me, that means that they encode for many different things, plays and music.
01:10:58 - I don't think astrocytes do that. I think astrocytes do general things,
01:11:02 - general computations, providing general context, net time scale of seconds.
01:11:10 - So the question is what variables are encoding.
01:11:14 - That's the question. But I think there are different variables that are broader,
01:11:18 - there, but those variables are probably important, too.
01:11:23 - One way to get a handle on that is, of course, you could look at the different
01:11:26 - pathologies where astrocytes are involved.
01:11:29 - So what are the outstanding pathologies? They're involved in all pathologies.
01:11:34 - Any brain pathology has,
01:11:40 - sick astrocytes. The question there, so they're morphologically changed and molecularly changed.
01:11:46 - The question is, what is the contribution of that astrocyte to the pathology.
01:11:50 - How many diseases are there that specifically attack the astrocytes?
01:11:54 - There are Alexander's disease.
01:11:57 - There are some diseases where GFAP has mutations and that causes changes.
01:12:02 - So what are the specific phenotypes you get? They are retarded.
01:12:06 - The children that have a problem with the blood-brain barrier.
01:12:12 - Yes. But are there any diseases that specifically attack the astrocytes later in life?
01:12:18 - It's not known. It's not known because.
01:12:26 - Astrocytes also get older, and probably they are dysfunctional,
01:12:32 - but we don't know, and they are affected by disease.
01:12:36 - The question is whether this is an epiphenomenon, whether it's just the main
01:12:41 - cause of the disease, or it's just a lateral thing.
01:12:45 - That's the question, but absolutely, they don't work that way.
01:12:49 - But you are interested in being therapeutics. Yes, because we have theta,
01:12:53 - and we are very driven by theta.
01:12:57 - Then when we manipulate astrocytes, we manage to recover brain function very effectively.
01:13:02 - And that's in Alzheimer's disease. In traumatic brain injury and Alzheimer's
01:13:06 - disease, we are still trying to understand the molecular makeup of the astrocyte
01:13:11 - change. because the problem is that we cannot suffer.
01:13:16 - We don't have astrocytes isolated from human brains for obvious reasons.
01:13:22 - So we are trying to understand what happens to astrocytes in Alzheimer's disease.
01:13:30 - Happens means all these homeostatic functions, metabolic functions, are they changed?
01:13:34 - And if they are, how does it contribute to disease progression or not?
01:13:40 - Doesn't make any difference whether we treat them more or not.
01:13:44 - So my understanding is that we should go for combination therapies and focusing
01:13:50 - on the neurons is a big mistake.
01:13:52 - Because going back to the vascular system, even if you have the finest treatment
01:13:58 - for neurons in order to help them make these amazing spines, if the blood system,
01:14:06 - the vascular system is not working, the treatment is not going to work.
01:14:09 - So it's a very obvious thing, but the field is not realizing that some very
01:14:17 - obvious things are not being done.
01:14:19 - And for me, recovering the function of astrocytes, it's as important as recovering
01:14:24 - the function of blood vessels, you know, to cure any disease.
01:14:29 - And in addition, perhaps then we can target the neurons more specifically.
01:14:34 - But I think recovering astrocytes will have a major impact on disease recovery
01:14:41 - because of all the many things they do. Right.
01:14:44 - So that's a fantastic outlook, right? So in your career, you have,
01:14:50 - in some sense, you're in this minority field, right?
01:14:53 - That is not necessarily in the limelight of neuroscience, but that also,
01:14:59 - as you show now, there's a long application, as you can all promise.
01:15:02 - And in some sense, it is a scientific field per se, in the sense that there's
01:15:07 - still so much to discover, right?
01:15:10 - It is. And we're really just at the beginning of understanding this whole system.
01:15:14 - So you're, you're now pursuing this for quite a while.
01:15:18 - And so if others would like to follow you, understanding the brain from that
01:15:23 - perspective, what is Elena's law that we shoot at here too, what is.
01:15:28 - Just consider astrocytes and neurons
01:15:32 - and microdegenerative endocytes and vascular cells at the same time.
01:15:36 - So my point is like, yeah, absolutely.
01:15:39 - So getting astrocytes with neurons, absolutely.
01:15:45 - Stop standing cells in isolated systems. Inclusive.
01:15:51 - Always try to be as complex as possible. So we need to have simple models because
01:15:57 - otherwise we cannot really study them.
01:15:59 - But they need to be complicated enough in order to be meaningful for anything.
01:16:04 - So that's the point. So with astrocytes, we need to upgrade astrocytes and study circuits.
01:16:10 - We have to find the minimum circuit that is relevant for astrocyte functions
01:16:18 - and then analyze how they interact with neurons.
01:16:22 - So that's the key idea is stop you're interested in astrocytes stop studying
01:16:28 - astrocytes only get you know collaborate.
01:16:33 - With your own people and get outside and study astrocytes in addition to other
01:16:38 - subtypes stop the xenophobia oh absolutely yeah that's,
01:16:42 - well yeah that's to me otherwise we won't cure diseases absolutely unless we
01:16:48 - have an internal view of the brain that is based upon on circuits,
01:16:52 - for me, that's very important idea.
01:16:55 - Well, that's an interesting point, right, that you make here with,
01:16:57 - you see a lot of also big pharmaceutical companies have actually withdrawn from
01:17:01 - the brain because everything they're through, and in fact- Well,
01:17:04 - the failure, the failure has been- You would say that's because of this neurocentric perspective.
01:17:09 - Well, it's, well, it's neurocentric perspective is the not giving the drug in
01:17:13 - the right moment, depending on the disease, in the case of Alzheimer's disease,
01:17:17 - it's just all the treatments have been very late.
01:17:20 - When the brain is not destroying us, it's not doing that much.
01:17:23 - But yeah, I think we need to understand that the brain are circuits and we need
01:17:27 - to understand that and target and restore circuit function.
01:17:33 - To me, this is the key. It's not just restoring one neuron function or one astrocyte,
01:17:37 - restoring the function circuits and that's going to be more effective on the
01:17:42 - recovery of a given disease or in the prevention of a given disease because
01:17:47 - these circuits are impaired They are very early in disease.
01:17:51 - They're actually an excellent diagnostic marker for early alterations.
01:17:55 - And to me, that's the focus, the therapeutic focus and the focus for the basic
01:18:01 - research from the astrocyte point of view, from the neuron and from microarray
01:18:06 - point of view. And NG2, NG2 cells are fantastic.
01:18:09 - We don't really know. And they do have spikes, actually. So this classification
01:18:13 - of neurons and the spike and cells that don't spike,
01:18:17 - NG2 have spikes because they are like in the middle and they're fantastic too. So we.
01:18:25 - And you mentioned now at the end of our discussion. Right. But because I'm, I'm interested. So the.
01:18:31 - Are they as voluminous as ester sites? How?
01:18:34 - Are they as voluminous as ester sites? They're very big. They're too very big.
01:18:38 - And they share some developmental origin.
01:18:41 - And they talk to the ester sites as well. It's not known. Okay. It's not known.
01:18:45 - But I think we have to have comparison. Why are they not differentiated from
01:18:49 - neurons if they also spike?
01:18:50 - Why were they... Because they don't... They are not as sophisticated as neurons.
01:18:55 - They don't have actions, for instance. They don't transmit information.
01:18:59 - They don't have, like, long distance.
01:19:03 - Okay, but... They don't have spice, I think. Perhaps they do,
01:19:06 - because... Does it form synapses?
01:19:09 - I think there's a paper talking about the NG2 neuronal synapse. I'm not sure about that.
01:19:17 - Okay, that's your next talk. But yeah, the point for me is that we focus on
01:19:22 - our self-type because we need to focus on something.
01:19:25 - But don't lose the perspective that you're looking at a small thing and that
01:19:31 - if perhaps you're missing the connections with other elements,
01:19:34 - you're missing the whole point. That's my point.
01:19:38 - That's a point also well taken. And it's like embrace sort of this inclusive
01:19:44 - perspective. It's not only about all endurance, only exercise,
01:19:47 - also look at this whole variable collection of cells that form circuits that we call the brain.
01:19:53 - Also, moreover, I talked in the talk, the.
01:20:00 - Like, neurons are highly diverse. So even saying, maybe neuron is about work, too.
01:20:06 - Perhaps I'm going too far. But neuron is about work, because if the mouse,
01:20:11 - they discover in the somatosensory cortex 30 types of different neurons.
01:20:16 - Just there. So imagine in the whole brain, I have thousands of different types
01:20:20 - of neurons. So neuron is about turn, too.
01:20:24 - And if we don't understand that they're very different in different circuits,
01:20:27 - they may share some roles.
01:20:29 - But then now the difference may be really very relevant in the way they interact
01:20:34 - with other cells types and the way they encode and the way they store information
01:20:39 - that perhaps that's a problem.
01:20:41 - So let's stop saying neurons.
01:20:45 - So four years from now, I'll come visit you here in Barcelona in your lab.
01:20:50 - And we're going to check whether the prediction you made today was falsified or confirmed.
01:20:55 - What prediction? That's the question. What's the prediction that is most critical
01:20:59 - to your research that you would like to see analyzed?
01:21:03 - That astrocytes encode specific variables in information processing.
01:21:12 - That's my, that they encode. That's the prediction.
01:21:17 - The answer may be that they don't. There may be some variables that are relevant
01:21:22 - to higher brain functions are encoded by estrocytes.
01:21:27 - Okay. Very good. That's my... Galena, thank you very much for this conversation.
01:21:31 - Thank you. Thank you very much.
01:21:35 - The CSN podcast was produced by the Convergent Science Network of Biometrics
01:21:40 - and Biohybrid Systems, a project funded by the European Sevens Research Framework Program.
01:21:48 - For more interviews, recorded lectures, or upcoming conferences in the field
01:21:54 - of biometrics and biohybrid systems, go to csnnetwork.eu.
01:22:00 - Music.

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Elena Galea on astrocytes and glia

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