Perineuronal nets or how to restrain a neuron if you not a neuron

hello this is brain can channel the channel about brain research thank you for watching us don't forget to subscribe and don't forget to like this video so if you will ask me to describe the brain activity the urinal activity in one sentence I would tell you something that it is strictly organized chaos also it's quite similar to music so when music mus you have sounds and you have poses and uh if we come back to neurons neurons also have periods of their firing of their very active neuronal activity and they also have periods of sence and the silence is very critical to encode information and there are different mechanisms how to modulate this silence in neurons and one of them is based on other neurons so in the brain uh the majority of neurons are exiter but there are also proportion of inhibitory neurons that actually suppress activity of other neurons but what if you are not a neuron is it possible to modulate the neuronal activity not so long ago it was found that it's possible to modulate neuronal activity uh with P neuronal Nets and today we have a special guest from Char uh hospital and uh correct me okay uh the from Berlin from Institute of neurophysiology uh Luna shash dakovich she's doing her PhD and uh she studies per neuronal Nets microa and much more and today we will talk with her what perineuronal Nets [Music] [Music] are so Luna could you please tell about history of these nets what is it and so on sure sure uh so it's it's one of the aspects of my research that I that I focus on so these perineuronal nets as the name suggests they're a type of netlike structure and uh they basically uh they exist around certain neurons in the brain um they were actually known for a long time as just a structure uh that was described even in the end of 19th century so the well-known Italian uh biologist Camilo GOI uh has seen them first time and described as a sort of a net like spiderweb like structure around the cell bodies of certain neurons but what is really interesting I think is that uh the function of these structures was was only started to get elucidated end of '90s so 20th century basically only three decades ago um so what these structures are are basically they're a component of what we call the extracellular Matrix this is just the environment of these proteins and various molecules that float around neurons in the brain uh and surround them and give them support and structure and so these perineuronal nets uh basically they enwrap around the bodies which we called somata of neurons and around their some of their proximal dendroides which are basically the input regions where the neuron receives information um as well as part of the axone which is their output where they send off information further so it's not just a mechanical support of the cell exactly so although it's still like a bit of a black box of a structure so do we have several ideas and in the research field there are several ideas of what these structures really do so the most fundamental IDE idea is sure they do provide a structural support and a bit of a shield so it's always good to look at where these structures are and is there a specificity of a type of neuron that they surround and and finnally enough there is so they tend to surround these uh special type of neurons they're inhibitory neurons which you already mentioned um and they are what we call paraluman positive fast spiking interneurons so very active guys reactive so these are so let's let's break down that name so the parum in positive this means this is like a special protein that is only characteristic to these neurons you cannot find it anywhere else it's a uh for for those of you who are more interested it's a calcium buffer and calcium is very important for activity for communication between cells yeah exactly so it's so they parum in positive that's their marker that's the marker Protein that's how we find them when we want to stain them we use albumin and then they're fast spiking which means they uh have this ability to produce Action potentials U so to change their membr Potential from um from their resting and to send a signal off as of in action potential so they have the ability to to do this 3 to 600 times a second so wow it's a very very high frequency of of U of activity so that's why we call them the fast spikers um and apart from that they are functionally very significant they they act as a master controller of broader network activity in the brain uh even though they are in numbers funnily enough much less common than excitatory neurons so as I said it's very important to look at where these perineuronal nets are and they happen to be around the bodies of these neurons and um so the structural support they give at least this is the hypothesis is since these neurons are are so active and therefore require so much energy and sugar and oxygen exactly to create all these spikes so the Nets are there to keep their tiny little environment around the neurons constant because these neurons have to they they have to have a constant inflow of oxygen of sugar and to support this activity so they they are very sensitive they need this little like a like a sheet around them so that's the function one of peral Nets like a structural support the functional U aspect of peral Nets is very interesting as well and this is the part that got sort of elucidated end of '90s uh early 2000s do neuronal plasticity exactly exactly so they are uh they're basically we call the per neuronal Nets the Guardians of plasticity uh so why what what does this mean so when when you develop when for example when a child develops there are these critical periods of time which we call critical plasticity periods and these are the times where the brain is very malleable so it's very malleable to the influence it receives from outside the neurons the connections between the neurons are very we call it plastic so they can remodel quickly all the synapses correct and spines that we can find correct in neurons correct and and so it's so the brain is kind of like a sponge it really uh takes in all the input and based on this input it wires and rewires and slightly adjusts itself um so what is very interesting you have this timeline uh let's say let's say for a human child up to about two years of age the brain is highly highly plastic and it really relies specifically let's give an example specifically for visual inputs it really relies on visual cues um and then from the age of two to approximately 8 years old this plasticity sort of starts to die down a bit gradually and this coincides with the emergence of perineuronal Nets around the neurons that that I mentioned already so the emergence of these nets starts about one to two years of age I have a question about this since uh they provide um mechanical support and they Shield neurons is it possible that they restrain actually neurons so they they prevent this quick remodeling of synapses it could be it may well could May well be because uh you mentioned at the beginning we're talking also about the interactions of neurons and non neuronal stuff in the brain yes so there happen to which about half of other cells in the brain it's not even half it's actually three times more than the neurons it's dependent on the metas yes how you how you look at this so these are there are these non- neuronal types of cells like for example microglia like asides and they all come into contact with neurons and there is a hypothesis indeed that since these nets are around these s of the cells the cell bodies and the proximal parts of the dendrites where also the copses are uh that they maybe prevent excessive influence from other types of cells in the brain and also from other neurons forming copses onto these cells thus making the cells that have the net around them more stable and so this is like when I mentioned this visual input paradig and how the how the child develops and how the Nets develop in the the child as it receives visual inputs from ages 2 to8 you have a progressive development and complexity increase in the perineuronal Nets and this stops the wild neurons from being plastic and uncontrollable yes so very important point if you want to uh work efficiently then you have to have some periods of nonworking you know exactly and and you need to actually have a focus basically this is what I see per on that's as they they sort of they don't necessarily only limit the neuron but they focus it because that you kind of as you develop you go through go towards specialization and this brings more efficiency to the entire system so um yes so this is another function of peronal Nets the most important with regards to plasticity um I mean there's there's a fine example like for example children who have a lazy eye for example um what they do is they put a patch around patch over the the stronger eye so that the lazy eye can get more input while the brain is still plastic and train and train and so this can happen only in this critical period between the ages of two and eight after that for example you could not easily do this as the peronal Nets have set in they have in sheathed the neurons and there is basically no change but when you think about that then you know there's potential there's a there's a thing in the field at the moment of peral Nets where people are thinking can we somehow change or remodel the Nets yes so that we can reawaken this potential this plasticity that we have as as a young child for example the potential to learn languages so easily which is another thing tied to critical perod yes I know it's know can we reawaken this in the adults and then you know there's also a hypothesis that it could have a beneficial effect for for things like disorders like PTSD for example exactly so it's it's very interesting I think topic what is the source of perineuronal Nets and uh as I remember but I can confuse uh that this is polyes right um so this is one of their components uh indeed um so the Nets maybe this was an important thing that I missed missed uh in the beginning uh but uh what they are composed of is so they have a core which is like a scaffold of a protein M uh typical proteins are um agrian uh crotin so these are all the proteins that are also found in this extracellular environment of the neurx and then um these to these proteins what you have connected is these sugar based molecules but basically oligosaccharide residues we call them and they attach to various parts of these proteins um and form this uh polymers because because they polysaccharides they can form Nets these lines and it looks exactly like a net so imagine a neuron in a net exactly like a fish for example like like when you have the you know the the um how do you call it like a net and in it you have oranges this is how it looks like it's like exactly net like this back you know exactly um so uh yeah so it's mostly like a mixture of these uh proteins there's specific groups of proteins to get maybe more technical they're called cspgs which stands for quro and sulfate protein stop saying this yes sorry m 300 subscribers now on my channel but that's that's what they're composed of basically so a bit of proteins a bit of sugars and um this based on this uh actually we also uh try to identify them by finding whatever chemicals bind to either the sugar parts or the protein parts and this is how the labeling of perineuronal Nets is managed basically you either find lectins which are proteins binds to sugars so you have a labeling of this sugar part or you find proteins which is antibodies that bind to the core proteins of the Nets um and you have again another net labeling so so there are different Nets in the brain but they're mostly formed around parin positive neurons basically or exclusively it's it's very rare to find them around any other type of cells it's um in my experience it's something like 10% maybe at maximum of any other cells that have these nets um and for that tiny percentage of cells it's not even really known why they need them because as we discussed for the probab in positive neurons function wise it makes sense so umly but for these other types of cells it's a bit of a an unknown for now and I think now we will step into a very dark side of This research uh all compounds are synthesized somewhere in the body and what is the source of perineuronal Nets and this is really a good question proteins and these polysaccharides uh can for example any cell Express the protein that is a part of this net or it's it cell specific somehow this is a really good question uh especially since the peronal Nets emerge during development which is also another under research part of you know the developing of the brain um we know a few things we have a few breadcrumbs that can kind of lead us to somewhat of a picture of how this happens so um the neuron itself that wants to let's say have a net around it needs to have a few enzymes that synthetize at least the core proteins it seems but then there has to be apparently a contribution by olgod dendrites which are the cells that form the milein sheeld um around neurons helping them conduct action potentials quicker and more efficiently um so one component would be Al dendrites and another would be asites which is another non- neuronal cell type in the brain very versatile very in much involved in trans synaptive transmission and many many processes that support the neuron nourish the neuron help it recover from injury so um EST ites and olender sites are mostly implicated it seems like microa another adorable microa another G cell type is we working on exactly so I full disclosure I'm a microa researcher so they're my favorite um but uh so they are also seem to be implicated uh in generating the perineural Nets although rather in this element of remodeling them because per neuronal Nets are also plastic system so they can be formed but they also can be digested from some side and microa is a typical mro microage y yep can come digest part then we have a a free signups and it works exactly so micro are are sort of perfect for this since they are basically the brain's immune cells so have they have this ability to Chomp off parts of structures like copses and it seems like as the neuro research shows they can also influence the remodeling of perineuronal Nets um and the peronal net itself as you mentioned is it's very cool I think that it's a plastic structure it's like when we think of the body's skeleton we always think of it as a static structure but even the skeleton constantly gets remodeled it's constantly degraded built up by various types of cells that kind of chip it off and then give it more bone back and so the perinal Nets are much in the same way so they're very very mobile let's say structure in motion um and what is also very interesting is I think that they are they seem to be very much influenced by the environment that they're in and for example since I work with brain slices usually so acute tissue they seem to be influenced by the quality of the tissue so so this is and I guess region of the brain exactly exact so in different regions yes in different regions they they can look very differently and also in different stages of life um when they start to emerge and when they're still forming and piling up all these condroitin all these sugars that uh that make up the perinal net they can look strikingly different than when you have an an older um let's say an older sample um so there's that and there's also the aspect of PA ology which is of course very relevant to everybody uh in science it's a it's always the Hot Topic so in with aging for example with aging um with aging paranal Nets seem to they don't change too much so one Trend that can be seen is they just become more dense there it it seems like it so more stable um but it's difficult yet to make any conclusions right this is still a very young very young field I would say sure 30 years but it's it's still um especially this pathology aspect has only now started to be really explored with this context of per neuronal Nets and neuronal plasticity exactly so because plasticity was I I think at least this is my theory why perineural Nets were got so much in the spotlight in the late '90s was because plasticity was all the rage in neuroscience at the time yes it was Hot Topic and this was kind of adjacent somebody probably did some stainings to you know complement functional data and saw this Dynamic of perineural Nets uh do we have some uh contradictory questions in this field for example contradictory questions um well let's pick up one yes uh contradictory questions so H so there's a few things things maybe uh maybe the question of uh localization in certain in certain places in the brain um so it's not that all PV positive interneurons have the Nets wow so so some of them a lot of them have it but um not all of them and it seems to be like for example in neocortical layers so in this newest part of the brain the the kind of the peel of the brain um you can actually see that there is a discrete distribution in fact of perineural Nets uh only around certain PV interneurons and certain locations which are layer specific and I think the reasons why it is certain are not known yet it's not known it's absolutely not known um so this is just something that that has been very recently described so you have you know the neocortex has six layers different layers basically are different inputs or output zones that then carry on towards other parts of the brain um and so you have like a different arrangement of cell types not just neurons also gleo cells and then you have different types of neurons as well by by layer and it seems like that these probab positive interneurons that are in the deeper deeper cortical layers they tend to to mostly have the Nets very welldeveloped um and they their axon are also very branched so there's a lot of innovation going on there but in the higher layers like layer 2 three they don't seem to have either they either don't have a net or they have a very thin like a veil like a net so there's this is also a gradation that that is very interesting to see perinal Nets are not always like this Strong net build around like a fortress the neur so they can also be very thin and Veil like and it seems like there is a correlation between the complexity of the net around the neuron and the neuron's physiology and function um so this is very interesting this this this was already uh studied there is one very cool paper I actually really like it uh usually if you want to study something in science generally you either have to look in the at the baseline or you have to perturb the system and completely turn it upside down somehow either knock something out or take something away one factor yes exactly check what happened and there is this really it's a bit of a rough approach so there is a way to completely remove perineural Nets there is an enzyme it's called condinas Uh it it degrades all the Nets really like strips them away fully um and basically what happens then to the neurons themselves the PV inter neurons is when you check their electrical properties which is what we do in electrophysiology um you can tell that the properties have completely changed the kinetics of their Action potentials are different slower um they're more excitable so these are all the things that it seems like it's kind of a hint that the perineural Nets might be involved also in these functions and giving conferring these functions to these Pig inter neurons so thank you very much Luna y good luck with your research thank you thank you for having me