Summary: Researchers have uncovered an unexpected phase of circuit remodeling confined to a key memory-storage region in the brain. Using precise mouse models, the team revealed that perineuronal nets (PNNs)—protective extracellular lattices that enwrap neurons to stabilize long-term memory traces—undergo a transient breakdown during late adolescence.
This targeted PNN degradation makes memories formed earlier in life temporarily difficult to access, although those memories later re-emerge in adulthood with reduced specificity.
Key Facts
- PNN disruption discovered: Perineuronal nets are dense extracellular matrices that stabilize mature synapses and protect established memory pathways. The research team found that PNNs in a specific cortical region unexpectedly decline during late adolescence and later rebuild in mature adulthood.
- Regional specificity: The remodeling was tightly restricted to the retrosplenial cortex (RSP). No comparable PNN changes were detected in the nearby hippocampus, indicating the process is a targeted reorganization of cortical storage circuits rather than a widespread brain-wide decline.
- Temporary retrieval deficit: Behavioral tests matched the anatomical changes. Mice trained during early adolescence showed impaired recall weeks later in late adolescence, but those memories reappeared later—sometimes under modified test conditions or in full adulthood—demonstrating temporary inaccessibility rather than erasure.
- TGFβ2 involvement: The PNN decline correlated with reductions in key structural proteins and a marked drop in TGFβ2 signaling, a growth factor that supports PNN maintenance.
- Mechanistic validation: Reinforcing PNNs or restoring TGFβ2 activity during the vulnerable late-adolescent window rescued memory retrieval, providing causal evidence for the molecular mechanism behind the retrieval block.
- Adult generalization and the “reminiscence bump”: When early memories resurfaced in adulthood they were less precise and more generalized—reflecting a loss of contextual detail while preserving emotional content. This pattern resembles the human “reminiscence bump,” in which adults remember the emotional significance of youth events more than exact details.
- Relevance to psychiatric risk: The timing of this adolescent remodeling coincides with the typical emergence window for conditions like schizophrenia and major depression. The authors propose that errors in this sensitive PNN remodeling phase could heighten vulnerability to psychiatric disorders in genetically predisposed individuals.
Source: Albert Einstein College of Medicine
Background: It is well established that the human brain continues to mature beyond the teenage years, with decision-making and emotional regulation evolving into the mid-to-late 20s. This study offers the first direct biological evidence, in mice, of a late-adolescent remodeling process that alters memory circuit stability.
Published in PLOS Biology, the study focused on the retrosplenial cortex, a region critical for organizing and retrieving long-term contextual memories. The researchers observed a transient decline in PNN density during late adolescence followed by restoration in adulthood. This change was not present in the hippocampus, underscoring a selective cortical remodeling process.
“Our findings begin to show what circuit development looks like in a memory system and how it affects recall of earlier experiences,” said senior author Jelena Radulovic, M.D., Ph.D., professor in the Dominick P. Purpura Department of Neuroscience and of psychiatry and behavioral sciences.
The authors suggest that reorganizing PNNs in the RSP may help prioritize the encoding and retrieval of adult experiences at the expense of some access to early-adolescent memories, potentially aiding adaptation to new life challenges.
Key behavioral evidence
To test behavioral impact, mice were trained to associate a specific chamber with a mild foot shock. Immediately after training, mice froze when returned to that chamber, indicating a formed memory. Weeks later, animals trained in early adolescence often showed diminished freezing during the late-adolescent window, while those trained in adulthood retained stable memory. When tested again under altered conditions or later in adulthood, the early-trained mice recovered the fear response, demonstrating that memories were temporarily inaccessible rather than lost.
Molecular analyses linked these changes to reduced levels of PNN components—most notably aggrecan and neurocan—and decreased expression of transforming growth factor beta (TGFβ) family members in the RSP. Infusing TGFβ2 directly into the RSP attenuated PNN loss, supporting a role for TGFβ2 signaling in PNN maintenance. Artificially stabilizing PNNs during the late-adolescent window also restored memory retrieval.
By mid-adulthood many of these memories returned spontaneously but with degraded contextual precision: animals generalized their fear to novel settings rather than responding exclusively to the original environment. This shift from specific to generalized recall mirrors how adults often remember the emotional gist of youthful events but fewer fine-grained details.
The authors note that whether PNN build-up in adulthood is driven by age, experience replay, or other factors remains to be determined. They also highlight the potential clinical relevance: the same developmental window that exposes RSP circuits to major reorganization is when serious psychiatric illnesses commonly appear, raising the possibility that faulty remodeling could contribute to disease risk in susceptible people.
Additional authors include Zorica Petrovic, Elizabeth M. Wood, Ana Cicvaric, Maayan Krispil-Alon, Kendra Parker, Thomas E. Bassett, Anna Carboncino, J. Tiago Goncalves, Vladimir Jovasevic, Anita L. Guedea, Pengfei Yi, and Gal Richter-Levin.
Funding: The study, “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: During late adolescence the brain temporarily removes parts of the PNN “insulation” around retrosplenial neurons. That structural reduction makes the retrieval pathway unstable and noisy, so stored memories become difficult to access until the network is re-stabilized. The memory trace itself remains intact.
A: Lowering access to highly specific early-life memories may be an adaptive trade-off: it reduces the influence of rigid, context-bound childhood learning and prioritizes flexibility for encoding high-stakes adult experiences, improving the ability to adapt to new environments and social demands.
A: The vulnerable late-adolescent window requires dismantling protective scaffolding around neurons. In genetically susceptible individuals, errors or delays in this remodeling could destabilize circuits and increase risk for conditions such as schizophrenia or major depressive disorder, which often first appear in this developmental period.
Editorial Notes
- This article was edited by a Neuroscience News editor.
- The original journal paper was reviewed in full.
- Additional context was provided by editorial staff.
About this research
Author: Elaine Iandoli, Albert Einstein College of Medicine
Source: Albert Einstein College of Medicine
Image: Image credit: Neuroscience News
Original research: Open access. “Retrosplenial Cortical Reorganization During Late Adolescence Introduces Instability of Contextual Memory Circuits,” Ana Cicvaric et al., PLOS Biology. DOI: 10.1371/journal.pbio.3003908
Abstract
Retrosplenial Cortical Reorganization During Late Adolescence Introduces Instability of Contextual Memory Circuits
Hippocampal and cortical circuits that support autobiographical detail are thought to mature by early adolescence. This study demonstrates that the transition to late adolescence involves marked reorganization of the retrosplenial (RSP) cortex accompanied by deficits in the expression of remote memories. PNN and parvalbumin densities established by early adolescence (postnatal day 30) decline by late adolescence (p60–p75), and memories acquired earlier show impaired expression. Stabilizing PNNs rescues these deficits, and memory expression recovers as PNNs rebuild in later life. Molecular findings indicate decreased levels of key PNN constituents (notably aggrecan and neurocan) and lower Tgfβ expression in RSP; local TGFβ2 infusion attenuates PNN loss. Together, results show dynamic RSP extracellular matrix reorganization during adolescence and suggest that, in susceptible individuals, these dynamics could interact with genetic factors to increase risk for late-adolescent psychopathology.