Labanca, A. | Search bioRxiv

bioRxiv2026

Cortical astrocytes control stress resilience

BackgroundChronic stress exposure is a risk factor for several psychiatric disorders, including post-traumatic stress disorder (PTSD) and major depression (MDD), with the prefrontal cortex (PFC) playing a key role in mediating this stress susceptibility. However, most individuals who are exposed to chronic stress are resilient and do not develop psychopathology. Recent evidence suggests that glial cells, especially astrocytes, play an important role in controlling stress-induced anxiety- and depression-like behavior, yet their role in contributing to stress resilience is not understood. MethodsUsing fiber photometry, chemogenetics, and RNA-sequencing in male mice, we establish a role for PFC astrocytes in stress resilience. ResultsWe demonstrate that stress-induced increases in astrocytic calcium activity are both necessary and sufficient for resilience. Bioinformatic analysis reveals robust transcriptional responses in PFC astrocytes that differ between susceptible vs. resilient mice and are unique when compared to astrocytic transcriptional changes in other limbic regions. Comparison with human RNA-sequencing data indicates that molecular changes observed in PFC astrocytes from susceptible mice converge with gene expression changes observed in MDD patients. ConclusionsTogether, these data support targeting astrocytes as a potential therapy for negative behavioral consequences following stress exposure and reveal potential molecular mechanisms within PFC astrocytes that could contribute to depressive-like behaviors.

neuroscience↗

bioRxiv2025

Astrocytic CREB regulates transcriptional, neuronal, and behavioral responses to cocaine

Drug addiction is characterized by neuronal adaptations that support a shift from goal-directed behaviors to habitual, compulsive drug-seeking with persistent effects on cognition and decision-making. Emerging evidence increasingly indicates that astrocytes are also involved in nervous system disorders, including addiction, but the cocaine-induced astrocyte-specific transcriptome has not yet been investigated. We utilized whole cell sorting of astrocytes, RNA-sequencing, and bioinformatic approaches to characterize the astrocyte transcriptome in the nucleus accumbens (NAc), a key brain region involved in reward-processing, following cocaine self-administration, prolonged abstinence, and "relapse" in male mice. We found that astrocytes exhibit robust and contextually-specific transcriptional signatures that converge strongly with human cocaine use disorder. Bioinformatic analysis revealed CREB as a highly ranked predicted upstream regulator of cocaine-induced transcriptional regulation in NAc astrocytes, and CUT&RUN-sequencing mapped increased CREB binding across the astrocyte genome in response to cocaine. Viral-mediated manipulation of CREB activity selectively in NAc astrocytes, in combination with several measures of addiction-related behaviors including conditioned place preference and self-administration, revealed that astrocytic CREB increases the rewarding and reinforcing properties of cocaine. This effect is sex-specific, with no change in astrocytic CREB activity or CPP found in females. Subsequent experiments identify potential molecular mechanisms of astrocytic CREBs influence through modulating astrocytic Ca2+ signaling in response to cocaine. Finally, we show that astrocytic CREB selectively modulates D1-type medium spiny neurons in NAc to control cocaine-related behaviors. Together, these data demonstrate that the astrocyte transcriptome responds robustly to cocaine and that CREB mediates cocaines effects on gene expression in astrocytes, with consequent effects on neuronal activity and rewarding responses to the drug.

neuroscience↗