For decades, the spotlight in neuroscience has shone predominantly on neurons as the primary architects of memory. Yet, a groundbreaking new study from the RIKEN Center for Brain Science challenges this long-held belief, revealing an unexpected protagonist in the story of memory stabilization: astrocytes. These star-shaped glial cells, traditionally cast as mere supporting actors to neurons, now emerge as central players in the persistence of emotionally charged memories. Published in the journal Nature, this pioneering research led by Jun Nagai elucidates the biological mechanisms by which astrocytes become selectively activated during the recall of emotional experiences, fundamentally transforming our understanding of how memories are preserved over time.
The researchers embarked on an ambitious quest to unravel why only some experiences are etched firmly into our minds, while others fade into oblivion. Their approach revolved around tracking the activation of a protein known as Fos, a hallmark of cellular engagement, within astrocytes during both the formation and recall of memories in mice. Prior studies had revealed that neurons generate Fos when involved in memory encoding, but Nagai’s team introduced an innovative technique that fluorescently labels Fos-positive astrocytes specifically, without marking neurons, within defined time windows. This breakthrough was made possible by administering a compound called 4-hydroxytamoxifen (4-OHT), which finely tunes the timing of astrocytic labeling.
Employing this cutting-edge system, they subjected mice to a classical fear-conditioning paradigm—associating a particular environment with an aversive stimulus. Remarkably, while neurons demonstrated Fos expression during both initial learning and later recall, astrocytes exhibited strong Fos activity exclusively during the recall phase. This temporal specificity suggests that astrocytes are not simply passive participants but become actively engaged when a memory resurfaces. Further disentangling this phenomenon, the team uncovered that Fos activation in astrocytes during recall hinges on dual input: signals emanating from amygdala neurons—where the core fear engram resides—and concurrent input from noradrenergic neurons that release noradrenaline, a neurotransmitter associated with arousal and attention.
The paradox here is profound. Both engram neurons and noradrenaline signaling are active during learning and recall, so why do astrocytes respond with Fos induction only during recall? Single-cell RNA sequencing offered compelling clues. Days after the emotional experience, astrocytes upregulate alpha and beta adrenergic receptors, molecular tags that render them responsive to noradrenaline. This receptor expression essentially primes astrocytes for selective reactivation, serving as a biological “tag” that earmarks these cells to partake in the memory stabilization process during subsequent recall. When this astrocytic marker is disrupted, the stability of fear memories deteriorates, underscoring the functional significance of this mechanism.
The implications of manipulating astrocyte activity extend far beyond basic science. The RIKEN team demonstrated that silencing Fos-positive astrocytes during recall impaired mice’s memory retention, whereas artificially stimulating these cells heightened recall intensity and even generalized the fear response to novel contexts. Such findings raise profound questions about the role astrocytes may play in post-traumatic stress disorder (PTSD), where traumatic memories persist maladaptively and cues trigger excessive fear. Jun Nagai envisions this astrocytic “memory switch” as a promising target for therapeutics capable of selectively dampening pathological memories without erasing benign ones, potentially revolutionizing treatment approaches for trauma-related psychiatric disorders.
This paradigm-shifting discovery also resonates beyond biology, suggesting intriguing intersections with artificial intelligence (AI). Nagai speculates that astrocytes’ ability to selectively tag and filter memories based on emotional salience and recurrence could inspire novel AI architectures. Current AI systems are notoriously data and energy-intensive, lacking nuanced memory filtering. Mimicking astrocyte-like gating mechanisms might enable AI to prioritize relevant information more efficiently, paving the way for energy-conscious, context-sensitive models that emulate human memory dynamics.
At the molecular level, this study refines our grasp of glial-neuronal interactions during memory tasks. While neurons encode experiential traces via engrams, astrocytes provide an essential overlay by stabilizing these traces through astrocyte-specific Fos induction. The integration of neuromodulatory signals, such as noradrenaline, with engram neuron activity highlights a complex, bidirectional communication network essential for lasting memory formation. This refined model challenges the neurocentric dogma, advocating for a holistic perspective that acknowledges astrocytes’ pivotal roles within neural circuitry.
Moreover, the novel fluorescent labeling methodology developed by Nagai and colleagues sets a new standard for temporally precise identification of active astrocytes, offering a powerful tool for future inquiries into glial function across diverse cognitive states. This approach could be adapted to explore astrocytic roles in other emotional experiences, memory types, or neurological disorders, broadening our understanding of brain plasticity and resilience.
With the discovery that astrocytes become “eligible” for memory gating only after an emotional experience primes them, the team is poised to investigate how specificity in astrocyte activation arises. Understanding whether different classes of memories—such as positive versus negative valence, or procedural versus declarative—rely on distinct astrocytic populations could unveil new layers of neural complexity. Such insights are vital for developing targeted interventions to modulate memory strength or selectivity in clinical settings.
At its core, this study reframes memory stabilization as a dynamic interplay between neurons and glial cells, united by molecular tags and neuromodulatory cues. Astrocytes, long relegated to the sidelines, now claim their place as active gatekeepers of memory persistence. This recalibration enriches the neuroscientific narrative and opens pathways for novel therapies enhancing cognitive health.
In a broader cultural context, these revelations prompt reevaluation of how we conceptualize memory, identity, and emotional experience. Recognizing astrocytes’ centrality invites us to appreciate the brain’s cellular symphony in all its complexity. It underscores the profound connection between cellular biology and psychological phenomena, offering new vistas for interdisciplinary exploration spanning psychology, neurology, psychiatry, and computational modeling.
Ultimately, this pioneering work from the RIKEN team heralds a paradigm shift with far-reaching implications. By illuminating the astrocytic contributions to memory stabilization and emotional recall, it challenges entrenched frameworks and inspires fresh lines of inquiry. As neuroscience advances, the story of memory will undoubtedly expand beyond neurons, intertwining with the vibrant tapestry of glial function and neuromodulatory dynamics.
Subject of Research: Memory Stabilization Mechanisms in the Brain
Article Title: Astrocytes as Key Mediators of Emotionally Tagged Long-Term Memory Stabilization
News Publication Date: October 15, 2025
Web References: https://doi.org/10.1038/s41586-025-09619-2
References: Nagai, J., et al. (2025). Nature. DOI: 10.1038/s41586-025-09619-2
Image Credits: RIKEN
Keywords: Astrocytes, Memory Stabilization, Fos Protein, Fear Memory, Noradrenaline, Engram, Glia, Cognitive Neuroscience, Memory Recall, Post-Traumatic Stress Disorder, Neuroimaging, Molecular Neuroscience
