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Fear-triggered reactive astrocytes orchestrate selective aversive memory decay via IL-3–CSF2RB2 signaling

ABSTRACT: Forgetting is a fundamental component of the memory system. While existing studies have primarily explored global neural network underlying active forgetting1, the intrinsic pathways impeding selective long-term memory stability remain elusive. Contemporary research has identified multiple decay mechanisms—including adult hippocampal neurogenesis2-6, microglia complement-mediated synaptic pruning7, 8, and protein degradation pathways9-13, yet these predominantly facilitate broad, nonspecific remodeling of neural networks. Whether dedicated mechanisms exist to achieve selective memory decay remains a fundamental unresolved question. Here, we identify a specialized subpopulation of astrocytes, termed Fear-Triggered Reactive Astrocytes (FTRA) in the hippocampal dentate gyrus, which are activated gradually but selectively after contextual fear memory. The FTRA serves as a chronic reducer of fear memory through uniquely release of interleukin-3 (IL-3) and its receptor CSF2RB2 mediated GPCR signaling and mitochondrial‑related energy metabolism in mossy cells. This leads to attenuated mossy cell excitability and behavior-associated calcium signals in granular cell neurons, ultimately driving memory loss. The FTRA operates independently of neurogenesis or microglial pruning, revealing IL-3 as a specific cytokine for spontaneous forgetting and establishing astrocytes as negative mediator of aversive memory maintenance.

ORGANISM(S): Mus musculus

PROVIDER: GSE337197 | GEO | 2026/07/06

REPOSITORIES: GEO

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Project description:The mechanisms underlying age-associated memory impairment are not well understood. We have shown that the onset of memory disturbances in the aging brain is associated with altered hippocampal chromatin plasticity. During learning, aged mice display a specific deregulation of histone H4 lysine 12 (H4K12) acetylation. To analyze if deregulated H4K12 acetylation impacts on learning-induced gene-expression required for memory consolidation we performed a high-density oligonucleotide microarray to compare the entire hippocampal gene-expression profile of 3 and 16-month-old mice during memory consolidation. In order to identify genes differentially regulated between 3- and 16-month old mice upon fear conditioning we subjected 3- and 16-month old mice to fear conditioning (4 mice each group, total 8 mice) . Mice of the same age that were handled but not subjected to any of the employed behavior paradigms served as control (4 mice 3-month old and 4 mice 16-month old, total 8 mice). During fear conditioning mice are subjected to a novel context followed by a mild electric foot-shock (context-shock exposure). In order to identify genes that are differentially regulated upon fear conditioning and are specific to associative learning we also tested the hippocampal gene-expression profile of 3-month old mice subjected to the same context-exposure that is not followed by a foot-shock (Context-exposure) (4 mice) or receive an immediate foot shock once they are placed in the context and only afterwards are allowed to explore the context (shock-context exposure) (4 mice). In order to identify genes that are regulated upon fear conditioning and are specific to associative learning we compared the hippocampal gene-expression profile of mice subjected to fear conditioning (context-shock), context or shock-context exposure regarding to their age-matched control mice (3 month old) mentioned above (control). Hippocampi from each mice were tested resulting to 24 samples which were separately hybridized (OneColor Array Design).

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Fear-triggered reactive astrocytes orchestrate selective aversive memory decay via IL-3–CSF2RB2 signaling

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