The role of psilocybin in the emergence of new brain cells and the treatment of depression-like symptoms

Major Depressive Disorder (MDD) affects men and women differently, yet the mechanisms underlying this sex disparity remain poorly understood. In rodents, MDD impairs the formation of new brain cells in the hippocampal dentate gyrus, disrupting both cognitive and emotional functions — but whether this process, and its contribution to disease, differs between sexes has been largely overlooked. With current treatments failing many patients, understanding sex-specific mechanisms of depression is essential for developing more effective, tailored therapies.

Using optogenetic techniques, we investigated how controlling newly formed hippocampal neurons affects depression-like behaviour in both male and female rats, directly comparing the two sexes rather than studying either in isolation. We further examined whether these neurons shape the therapeutic effects of psilocybin, a promising compound for treatment-resistant depression.

Our results show that manipulating new brain cell formation influences depression-like symptoms, including emotional and cognitive deficits, in a sex-specific manner, revealing distinct vulnerability profiles in males and females. Notably, psilocybin reversed these symptoms through a mechanism dependent on new hippocampal neurons. These findings identify sex as a critical variable in the neurobiology of depression and its treatment, with direct implications for the design of sex-informed therapeutic approaches to MDD.