Summary: Researchers identified an unexpected period of circuit remodeling restricted to a major memory storage zone in the brain. Utilizing precise murine models, the scientists unmasked that specialized, protective lattice structures called perineuronal nets (PNNs), which encapsulate neurons to stabilize long-term memory tracks, temporarily break down during late adolescence.
This targeted degradation causes memories formed earlier in life to become physically inaccessible before they spontaneously resurface in adulthood with altered, less precise parameters.
Key Facts
- The Perineuronal Net Disruption Unmasked: Perineuronal nets are dense, supportive extracellular matrices that wrap around specific neurons like a protective scaffolding, stabilizing mature synaptic connections and preventing unwanted changes to established memory paths. The Einstein team discovered that these nets unexpectedly shrink and diminish during late adolescence before rebuilding their structural density during mature adulthood.
- Anatomical Specificity: This dynamic structural remodeling was strictly confined to the retrosplenial cortex (RSP). The researchers observed zero PNN fluctuations in the nearby hippocampus, proving that this adolescent remodeling is a targeted feature of long-term cortical storage rather than a general brain decline.
- The Biology of Temporary Amnesia: Behavior matched the biology: when mice trained in early adolescence were re-tested weeks later during late adolescence, their ability to recall a previously learned environmental fear response dropped significantly. However, when tested again under modified criteria or allowed to transition into full adulthood, the memories spontaneously resurfaced, proving the data was never erased, but temporarily blocked due to circuit instability.
- The TGFβ2 Growth Factor Vector: The team mapped the root of this matrix degradation to a temporary drop in key structural proteins, coupled with a significant downshift in the activity of TGFβ2, a vital growth factor tasked with maintaining PNN stability.
- Mechanism-Based Proof: To validate this pathway, the researchers used targeted interventions to artificially reinforce the crumbling perineuronal nets or restore normal TGFβ2 levels during late adolescence. The treated models immediately regained full access to their early memories, confirming the exact molecular switch responsible for the retrieval block.
- Explaining the “Reminiscence Bump” & Generalization: When these blocked early memories naturally resurfaced in mature adulthood, they returned with a significant structural twist: they lost their original precision. Rather than remembering the exact setting where an event occurred, adult models generalized their response to entirely new environments. The authors note this mirrors the human “reminiscence bump,” where adults vividly recall the broad emotional meaning of youth events while losing hold of the exact, granular details.
- Vulnerability to Psychiatric Disorders: This extensive adolescent circuit overhaul aligns perfectly with the exact developmental window when conditions like schizophrenia and major depressive disorder typically surface in humans. The researchers suggest that in individuals with a genetic predisposition, a disruption or error during this sensitive PNN remodeling phase could create an acute vulnerability to psychiatric illness.
Source: Albert Einstein College of Medicine
Scientists have long known that the human brain continues developing well beyond the teenage years, with important changes involving decision-making and emotional regulation extending into the mid-to-late 20s.
Now, for the first time, researchers at Albert Einstein College of Medicine have identified a biological process in mice that offers new insight into how memory circuits mature during this extended period of brain development.
Published today in PLOS Biology, the study found that a key memory region of the mouse brain undergoes an unexpected period of remodeling during late adolescence.
As those changes unfold, memories formed earlier in life become temporarily more difficult to retrieve before resurfacing later, often with less precise detail. The findings align with growing evidence that adolescence is a dynamic period of brain maturation and identify a biological mechanism that may help explain how access to memories changes during this stage of development.
Using mouse models, the researchers focused on the retrosplenial cortex (RSP), a brain region that plays an important role in organizing and retrieving long-term memories. They discovered that protective mesh-like structures called perineuronal nets, which help stabilize memory circuits, unexpectedly diminished during late adolescence before rebuilding in adulthood.
The changes were confined to the RSP and were not observed in the nearby hippocampus, another brain region essential for memory.
“We’ve known for years that the brain continues developing through adolescence and young adulthood,” said senior author Jelena Radulovic, M.D., Ph.D. professor in the Dominick P. Purpura Department of Neuroscience and of psychiatry and behavioral sciences at Einstein.
“Our findings begin to explain what that developmental process looks like in one of the brain’s memory circuits and how it can influence the way earlier experiences are recalled.
We do not yet fully understand the consequences of the observed fluctuations of perineuronal nets, but we believe that their reorganization in RSP helps prioritize access to memories formed in adulthood at the expense of those formed in early adolescence. This could help to better adapt to the circumstances and challenges encountered at different life stages.
“Whether remembering early adolescent experiences comes at the cost of adjusting to new ones, is a possibility that we are currently investigating.”
Dr. Radulovic is also director of the Psychiatry Research Institute at Montefiore Einstein (PRIME) and holds the Sylvia and Robert S. Olnick Chair in Neuroscience.
The Teenaged Brain Isn’t Finished Yet
Previous studies suggested that the memory circuits examined in this study reached maturity during early adolescence. Instead, the researchers found that an important stabilizing system temporarily weakened during late adolescence before recovering in adulthood.
The timing is notable because it corresponds to a period now recognized as one of continued brain maturation in humans. While adolescence was once defined as ending around age 19, neuroscientists increasingly acknowledge that important developmental changes continue well into the 20s. According to the National Institutes of Health, the brain continues developing and maturing into the mid-to-late 20s.
“The behavior matched the biology,” said lead author Hui Zhang, Ph.D., a research fellow at Einstein. “The retrosplenial cortex is responsible for older, more established memories. As its stabilizing structures declined, access to memories formed earlier in life became less reliable.”
Restoring Memories
To determine how these brain changes affected behavior, the researchers trained mice to associate a specific environment with an unpleasant experience, a mild foot shock. Shortly afterward, the mice remembered the experience and froze when returned to the same chamber.
Weeks later, however, many of the mice trained during early adolescence no longer showed that fear response, while mice trained during adulthood retained stable memories over the same period.
When the adolescent mice later experienced another test in a different environment, they once again responded to the original setting, demonstrating that the memories had become temporarily inaccessible rather than erased.
The researchers traced these changes to a decline in key structural proteins that help build and maintain perineuronal nets, along with reduced activity of TGFβ2, a growth factor involved in maintaining those structures. When they reinforced the protective network or restored TGFβ2 activity, the mice regained their ability to retrieve memories formed earlier in life.
By mid-adulthood, many of those memories resurfaced spontaneously, although they had become less precise. Rather than responding only to the original environment, the mice generalized their fear to unfamiliar settings.
The researchers note that this pattern resembles the “reminiscence bump,” a well-known phenomenon in which adults disproportionately recall memories from adolescence and early adulthood while often remembering the emotional significance of an experience more readily than its specific details.
Whether this is due to a random increase of perineuronal nets with advancing age, to their increase in response to similar experiences, or to the replay of past experiences, or some other factors, remains to be established.
The findings may also have implications beyond memory. Schizophrenia and major depression often emerge in humans during late adolescence—the same developmental period in which the researchers observed this extensive remodeling of memory circuits in mice.
The authors suggest that, in genetically susceptible individuals, changes in this developmental process could contribute to vulnerability to psychiatric disorders, although additional research will be needed to determine whether similar mechanisms occur in people.
Additional Einstein authors include Zorica Petrovic, M.S., Elizabeth M. Wood, Ph.D., Ana Cicvaric, Ph.D., Maayan Krispil-Alon, Ph.D., Kendra Parker, B.A., Thomas E. Bassett, Ph.D., Anna Carboncino, Ph.D., and J. Tiago Goncalves, Ph.D. Other authors include Vladimir Jovasevic, Ph.D., Anita L. Guedea, M.S., and Pengfei Yi, Ph.D., at the Feinberg School of Medicine at Northwestern University, as well as Gal Richter-Levin, Ph.D., at the Sagol Department of Neurobiology at the University of Haifa.
Funding: The paper, “Retrosplenial Cortical Reorganization During Late Adolescence Introduces Instability of Contextual Memory Circuits” (DOI: 10.1371/journal.pbio.3003908), was supported by NIH grants R01MH108837 and R01MH078064 and the United States-Israel Binational Science Foundation Grant 2019261.
Key Questions Answered:
A: Think of your long-term memory circuit like an advanced electrical grid. In early youth, the brain protects its newly formed connections by building a dense, physical mesh called a perineuronal net around neurons, acting like a layer of thick rubber insulation around an electrical wire. During late adolescence, the brain purposefully strips away this insulation in the retrosplenial cortex to prepare for adult updates. Without that structural casing, the circuit becomes temporarily unstable and noisy, making it incredibly difficult for the brain to cleanly find and retrieve the early memory file. The file is still safely on the hard drive; the brain’s internal retrieval pathway is simply offline while the system undergoes renovations.
A: While losing access to past memories sounds like a system flaw, senior author Dr. Jelena Radulovic notes it is likely a highly sophisticated survival adaptation. As an individual transitions from the dependent bubble of early youth into the complex, independent challenges of adulthood, their environment changes completely. If the brain remained rigidly anchored to the hyper-specific lessons of childhood, it would struggle to adapt to new rules. By temporarily lowering the volume on early memories, the brain prioritizes a clean slate to capture and process high-stakes adult experiences, helping the individual better adapt to the immediate challenges of their current life stage.
A: This study unmasks a double-edged sword of brain development. On the positive side, when these nets naturally rebuild in adulthood, early memories return with a soft, generalized focus, allowing adults to experience the “reminiscence bump,” where they vividly recall the emotional meaning of youth while letting go of unnecessary specific details. However, because this late adolescent window requires the brain to intentionally pull down its protective scaffolding, it leaves the neural network incredibly unprotected. The authors warn that in genetically vulnerable individuals, any error or delay during this sensitive remodeling phase can cause the circuit to crack under stress, helping to explain why major psychiatric conditions like schizophrenia and deep depression so often emerge during this precise period of young adulthood.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- Journal paper reviewed in full.
- Additional context added by our staff.
About this memory and neurodevelopment research news
Author: Elaine Iandoli
Source: Albert Einstein College of Medicine
Contact: Elaine Iandoli – Albert Einstein College of Medicine
Image: The image is credited to Neuroscience News
Original Research: Open access.
“Retrosplenial Cortical Reorganization During Late Adolescence Introduces Instability of Contextual Memory Circuits” by Ana Cicvaric, Anita L. Guedea, Anna Carboncino, Elizabeth M. Wood, Gal Richter-Levin, Hui Zhang, J. Tiago Gonçalves, Jelena Radulovic, Kendra Parker, Maayan Krispil-Alon, Pengfei Yi, Thomas E. Bassett, Vladimir Jovasevic, Zorica Petrovic. PLOS Biology
DOI:10.1371/journal.pbio.3003908
Abstract
Retrosplenial Cortical Reorganization During Late Adolescence Introduces Instability of Contextual Memory Circuits
Hippocampal and cortical memory circuits, which enable the capacity to remember details from one’s past, are believed to reach maturity by early adolescence. Here, we demonstrate that the transition from early to late adolescence involves extensive reorganization of the retrosplenial (RSP) cortex along with significant memory expression deficits.
Specifically, the densities of perineuronal nets (PNNs) and the expression of parvalbumin (PV) established in mice RSP during early adolescence (p30) significantly declined by late adolescence (p60–p75). In parallel, using context fear conditioning, we found that memories acquired during early adolescence were significantly impaired. These cellular and memory changes could be alleviated by PNN stabilization, indicating that they were secondary to PNN loss. Consistent with this, memory expression spontaneously recovered with PNN build-up in later life.
Furthermore, late adolescence mice show a decrease in the level of key PNN constituents (especially aggrecan and neurocan) and the expression of transforming growth factor beta (Tgfβ) in RSP. RSP-targeted infusion of Tgfβ2 attenuated the decrease of PNN and neurocan, supporting a role of Tgfβ2 signaling in PNN build-up. These indicate that the decrease of PNNs during late adolescence was likely due to multiple molecular adaptations.
Together, our findings show that RSP ECM undergoes dynamic reorganization until adulthood and beyond, with particularly strong fluctuations during late adolescence. In addition to affecting the expression of remote memories, in susceptible individuals, the observed dynamics could interact with genetic factors, increasing the risk of late adolescent psychopathologies.
