A SIRT6-OVOL2 axis governs excitatory neuron resilience to chronic stress.

Excitatory neuron-specific SIRT6 overexpression protects against chronic unpredictable mild stress in mice, preventing anhedonia, despair, anxiety-like behaviors, and circadian disruption.

• Why it matters: Antidepressants that target monoaminergic and glutamatergic systems do not adequately prevent stress-driven neuronal dysfunction, so mechanism-based resilience therapies are needed.
• What they did: In mice, excitatory neuron SIRT6 overexpression (but not astrocytic or inhibitory) was tested in CUMS, while excitatory SIRT6 deletion was assessed under basal conditions; hippocampal single-nucleus transcriptomics and network analysis implicated OVOL2, with SIRT6–OVOL2 interaction affecting OVOL2 stability and downstream Nrg1 transcription.
• The result: CUMS depleted a stress-sensitive excitatory neuronal subtype that was restored by SIRT6 overexpression, and the SIRT6 allosteric agonist MDL-800 produced antidepressant-like effects, supporting SIRT6-targeting strategies for depression.

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