Caught up in your thoughts

August 20th, 2024

Written by: Joseph Gallegos

When the first neuroscientists started looking at brain cells under the microscope, one of the things they immediately saw is that many of the cells seemed to be wrapped in some kind of webbing, or net. Many of the early neuroscientists initially dismissed the existence of such a structure, saying it was simply a byproduct of the techniques that were used to observe brain cells over a century ago ¹ . However, those doubtful first observations have stood the test of time, as neuroscientists today recognize that these wrappings do exist, and are fundamentally important for many brain functions.

What are now called perineuronal nets (PNNs for short) are specialized tangles of sticky proteins that assemble into a complex web that surrounds the entire cell^1,2. Why PNNs form, and what their purpose is, could only be speculated initially. However, decades of new research has revealed that PNNs play a major role in regulating brain functions such as memory, and are more than just a flashy outfit for your cells to wear.

Perineuronal nets help keep your thoughts together

One of the initial clues hinting at the function of PNNs comes from when they first appear during brain development. In mammals, the brain is almost fully assembled by the time you are born, in the sense that most of the brain cells that will power you through life are already positioned to do their jobs ³. However, in order to function best, the connections made between brain cells – who talks to who –  need to be constantly updated and refined. The ‘first draft’ of your brain is revised based on your experiences, and like chopping off an un-needed paragraph in an essay, your brain will prune back the connections between cells to streamline the communications it needs to function the best. Scientists have observed that PNNs emerge at the very end of this editing process, when most of this cutting away has been completed and the ‘final draft’ of the brains connections is being written ⁴. The formation of PNNs around brain cells is a critical step in quite literally cementing the connections that brain cells form with one another. The formation of PNNs around the cell creates a physical barrier that blocks new and interfering connections from being made, preserving only the refined connections that were sculpted as the brain developed. Similar to how the spam filter on your email prevents unwanted messages from reaching your inbox, PNNs prevent unnecessary information from distracting your fine-tuned neural connections.

Along these same lines, another key role for PNNs is their involvement in learning and memory. Memories in our brain at the simplest level, are stored by the connections that our brain cells make with each other. Similar to the game ‘connect the dots’ where the picture will only be produced if the dots are connected in the proper order, memory formation requires groups of brain cells to be connected in precise patterns, where tracing through them recaptures the original experience. PNNs form around the cells in these special memory forming groups, helping to stabilize the connections created between them and maintain the patterns of our memory ^6–9.

Altogether, the formation of PNNs seems to be a critical step in fortify the connections made between brain cells. This is important for generating efficient and precise communications during development and memory formation. However, sometimes such rigid thinking may not be a good thing, and some scientists propose that getting trapped in a net may be doing your brain more harm than good.

Too Wrapped to Adapt

Although forming stable memories and associations in the brain is generally a good thing, there are some cases where it might be useful to hit the ‘delete’ button. Since PNNs have such a vital role in memory stabilization, some scientists believe that they might be something that can be targeted for ‘unlearning’ traumatic or harmful thoughts and behaviors.

For instance, substance abuse disorders are driven largely by the formation of ‘drug memories’, where the instinct to seek and administer drugs becomes hardwired into a person’s behavior. Addicts know all too well that no matter how motivated they are to stop drug seeking, the underlying urge to go back to taking drugs never really goes away ¹⁰. This is because those hardwired ‘drug memories’ are not easily unlearned. Scientists have found that after drug intake, PNNs will form around cells in brain regions that drive addictive behavior ¹¹. In fact, some research has found that if you can remove the PNNs that form after drug taking, you can effectively erase the drug memories, and prevent addictive behaviors from taking root ^12,13. These results suggest that the creation of PNNs is likely central for stabilizing these hardwired ‘drug memories’, and reinforcing addictive habits.

Another area of interest for the removal of harmful memories is in cases of childhood trauma, and post-traumatic stress disorder (PTSD). In both instances, past traumatic experiences lead to enduring psychological changes that negatively impact people’s lives. Recent studies have found there are higher numbers of PNNs in the brains of people with a history of childhood abuse compared to those without ¹⁴. Additionally, when scientists have recreated PTSD symptoms in mice, they have found that the creation of PNNs is heavily involved in retaining fearful memories, and removing PNNs helps alleviate improper fear responses ^8,9.

In cases of addiction and trauma, most people struggle to recover no matter how much they wish to ‘move on with their lives’. With indications that the formation of PNNs may be responsible for maintaining these adverse behaviors, some researchers think that clearing them away may be a potential treatment strategy for addiction as well as PTSD and other trauma-related disorders. Removing PNNs may unshackle the rigid patterns that were in place, allowing new ways of thinking to emerge.

What’s the catch?

To put it all together, perineuronal nets are webs of sticky material that wrap around certain brain cells to reinforce the streamlined connections that are made between one another. However, the downside to this is that creating such rigid connections makes it difficult to learn new things, or new ways of thinking. In order to learn (and unlearn), the connections in our brain really do have to be ‘rewired’, and the formation of PNNs are a  physical barrier against this process. This would partially explain why behavioral changes in psychiatric and substance abuse disorders are so resistant to treatment and cognitive therapy.

There is still much to be learned about the role of PNN’s in overall brain health, and in disease. But if it ever feels like your thoughts are trapped in a net, it turns out you aren’t far from the truth.  

References

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2.         van ’t Spijker HM, Kwok JCF. A Sweet Talk: The Molecular Systems of Perineuronal Nets in Controlling Neuronal Communication. Front Integr Neurosci. 2017;11. doi:10.3389/fnint.2017.00033

3.         Johnson MH. Functional brain development in humans. Nat Rev Neurosci. 2001;2(7):475-483. doi:10.1038/35081509

4.         Pizzorusso T, Medini P, Berardi N, Chierzi S, Fawcett JW, Maffei L. Reactivation of Ocular Dominance Plasticity in the Adult Visual Cortex. Science. 2002;298(5596):1248-1251. doi:10.1126/science.1072699

5.         Vo T, Carulli D, Ehlert EME, et al. The chemorepulsive axon guidance protein semaphorin3A is a constituent of perineuronal nets in the adult rodent brain. Mol Cell Neurosci. 2013;56:186-200. doi:10.1016/j.mcn.2013.04.009

6.         Jovasevic V, Wood EM, Cicvaric A, et al. Formation of memory assemblies through the DNA-sensing TLR9 pathway. Nature. 2024;628(8006):145-153. doi:10.1038/s41586-024-07220-7

7.         Fawcett JW, Fyhn M, Jendelova P, Kwok JCF, Ruzicka J, Sorg BA. The extracellular matrix and perineuronal nets in memory. Mol Psychiatry. 2022;27(8):3192-3203. doi:10.1038/s41380-022-01634-3

8.         Gogolla N, Caroni P, Lüthi A, Herry C. Perineuronal Nets Protect Fear Memories from Erasure. Science. 2009;325(5945):1258-1261. doi:10.1126/science.1174146

9.         Banerjee SB, Gutzeit VA, Baman J, et al. Perineuronal Nets in the Adult Sensory Cortex Are Necessary for Fear Learning. Neuron. 2017;95(1):169-179.e3. doi:10.1016/j.neuron.2017.06.007

10.      Hyman SE. Addiction: A Disease of Learning and Memory. Am J Psychiatry. 2005;162(8):1414-1422. doi:10.1176/appi.ajp.162.8.1414

11.       Roura-Martínez D, Díaz-Bejarano P, Ucha M, Paiva RR, Ambrosio E, Higuera-Matas A. Comparative analysis of the modulation of perineuronal nets in the prefrontal cortex of rats during protracted withdrawal from cocaine, heroin and sucrose self-administration. Neuropharmacology. 2020;180:108290. doi:10.1016/j.neuropharm.2020.108290

12.      Xue YX, Xue LF, Liu JF, et al. Depletion of Perineuronal Nets in the Amygdala to Enhance the Erasure of Drug Memories. J Neurosci. 2014;34(19):6647-6658. doi:10.1523/JNEUROSCI.5390-13.2014

13.      Slaker M, Churchill L, Todd RP, et al. Removal of Perineuronal Nets in the Medial Prefrontal Cortex Impairs the Acquisition and Reconsolidation of a Cocaine-Induced Conditioned Place Preference Memory. J Neurosci. 2015;35(10):4190-4202. doi:10.1523/JNEUROSCI.3592-14.2015

14.      Tanti A, Belliveau C, Nagy C, et al. Child abuse associates with increased recruitment of perineuronal nets in the ventromedial prefrontal cortex: a possible implication of oligodendrocyte progenitor cells. Mol Psychiatry. 2022;27(3):1552-1561. doi:10.1038/s41380-021-01372-y

Cover photo: Made with assets by Vadym and eny from Adobe Stock Images. Modified by Joseph Gallegos using Adobe Illustrator.