Translational psychiatryAug 15, 2025

Sleep loss may trigger mania through immune cell inflammation and brain connection changes differently in males and females

Psychedelic Science Weekly Brief ↗PubMed ↗DOI ↗OA ↗

Updated Mar 29, 2026

Abstract

After 4 days of 16-hour daily , mice exhibited mania-like behavior and specific changes in brain inflammation and synaptic activity.

Sleep deprivation triggered reduced cytokine and chemokine production alongside mitochondrial damage in the mice.
Microglial loss and decreased synaptic engulfment by were observed following sleep deprivation.
Single-nucleus RNA sequencing indicated distinct inflammation- and synapse-related gene expression patterns in the brains of sleep-deprived mice.
Significantly more differentially expressed genes were found in female versus male mice after sleep deprivation, particularly in the prefrontal cortex.
Pharmacological depletion of microglia reversed sleep deprivation-induced synapse gain and mania-like behavior in male mice but not in female mice.
Microglial inhibition via minocycline did not affect behaviors induced by sleep deprivation in either sex.

Simplified

Sleep loss is a key trigger for a manic episode of bipolar disorder (BD), but the underlying microglial and molecular mechanisms remain unclear. Sleep loss induces microglial and inflammatory responses. , resident macrophages in the central nervous system, regulate synaptic pruning by engulfing dendritic spines. Here, we introduce a modified paradoxical (SD) paradigm as a BD mouse model. After intermittent 16-h daily SD for 4 days, the mice showed mania-like behavior, reduced cytokine/chemokine production, mitochondrial damage, microglial loss, decreased synaptic engulfment by microglia, and synaptic gain. Single-nucleus RNA sequencing (snRNA-seq) revealed cell-type-specific inflammation- and synapse-related gene expression profiles in the prefrontal cortex (PFC) and hippocampus of SD-treated male mice. Interestingly, much more differentially expressed genes were observed in SD-treated female versus male mouse brain, especially in the PFC. Pharmacological depletion of microglia by colony stimulating factor-1 receptor (CSF1R) inhibitor PLX3397 blocked SD-induced inflammation-related and senescence-associated abnormalities in a sex-specific manner. Microglial elimination reversed SD-induced synapse gain and mania-like behavior in males but not in females. However, microglial inhibition by minocycline had no effect on SD-induced behaviors in a sex-independent manner. These findings demonstrate that microglia-mediated neuroinflammation and synaptic pruning contribute to SD-induced mania-like behavior in a mouse model of BD in a sex-specific manner.

Key numbers

1031

Differentially Expressed Genes (DEGs)

Upregulated genes in the prefrontal cortex of -treated male mice

782

Differentially Expressed Genes (DEGs)

Downregulated genes in the prefrontal cortex of -treated male mice

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Funding

Competing interests

Competing interests: The authors declare no competing interests.

PubMed

Sleep loss may trigger mania through immune cell inflammation and brain connection changes differently in males and females

Abstract

Key numbers

Full Text

Funding

Competing interests

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