Correlation between persistent changes in ciliary dynamics in the FrA and depressive-like behavior

Abstract

Long-term stress contributes to depressive disorders, for which monoamine-based treatments are often inadequate. This study identifies neuronal primary cilia as critical regulators of stress-induced depressive-like behavior. In mice, short-term restraint stress (3 days) reduced cilia length and the proportion of cilia-bearing neurons within the frontal association cortex (FrA). These changes were reversible, with ciliary dynamics recovering after 2 weeks of normal housing, and depressive-like behavior being absent. In contrast, long-term stress (3 weeks) caused persistent cilia shortening and reduced prevalence in the FrA, accompanied by depressive-like behavior. Unlike for short-term stress, these changes persisted even after a 2-week recovery period. However, following a 10-week recovery period, both ciliary morphology and prevalence returned to control levels, along with a resolution of depressive-like behaviors. These findings strongly implicate ciliary dynamics as critical determinants of behavioral outcomes. We found that melanin-concentrating hormone receptor 1 (MCHR1) was predominantly expressed in FrA primary cilia, and restraint stress upregulated MCH expression. Ex vivo MCH treatment recapitulated the stress-induced ciliary shortening and reduced cilia prevalence in FrA brain slices. These findings suggest that MCH-MCHR1 signaling mediates ciliary changes under stress and that the failure to restore ciliary structure may be a key factor in the development of depressive-like behavior. Given the non-synaptic pathways of ciliary signaling, this pathway may represent a novel therapeutic target, especially for treatment-resistant depression.