Regulation of stress susceptibility by chromatin-binding protein PHF6 in the pituitary intermediate lobe

The pituitary intermediate lobe (IL) is a surprisingly understudied pituitary region. Here, we find that chromatin-binding protein PHF6 is enriched in the pituitary IL and plays a crucial role in regulating stress susceptibility in mice. Conditional knockout of Phf6 in PHF6-positive IL cells (^ILPHF6 cells) significantly reduces acute stress-induced anxiety-like behaviors and chronic stress-induced depression-like behaviors by impairing cellular activation and the release of stress-related hormones. Mechanistically, conditional knockout of Phf6 in the pituitary IL cells downregulates the calcium channel β3 subunit and suppresses transcription of stress-responsive genes. Chemogenetic inhibition of ^ILPHF6 cells reduces stress susceptibility, whereas activation of these cells increases anxiety-like behaviors. Circuit tracing demonstrates that ^ILPHF6 cells receive direct synaptic inputs from CRH-expressing neurons in the hypothalamus paraventricular nucleus (PVN), positioning ^ILPHF6 cells as a crucial interface between neural stress signals and endocrine output. These findings reveal a previously unknown mechanism in the regulation of stress susceptibility that operates through anxiogenic ^ILPHF6 cells, providing a perspective for understanding how stress susceptibility is molecularly tuned.