Depression is a prevalent and devastating psychiatric disorder, and there is a great need for a better understanding of the underlying molecular mechanisms to promote new therapeutic approaches. There are well-established sex differences in the risk, symptoms, and response to treatment, with women subjected to a higher risk of developing depression. Long non-coding RNAs (lncRNA) are robustly regulated in postmortem brain tissue of depressed subjects in a sex-specific manner. LINC00473, is a primate-specific, neuronal-enriched lncRNA that is downregulated in the prefrontal cortex (PFC) of depressed females but not males. Viral delivery of LINC00473 to adult mouse PFC neurons mirrors human sex-specific effects by inducing stress resilience solely in female mice and is accompanied by changes in synaptic function and gene expression selectively in females. Moreover, in vitro studies using human neuron progenitor cells derived from healthy controls of both sexes showed a more robust differential gene expression in response to LINC00473 knockdown in females than in male-derived cells.

While previous research identified LINC00473 as a female-specific driver of stress resilience, there are still many open questions regarding its role in stress and its transcriptional regulation. To tackle these questions we will develop a LINC00473 humanized mouse model, which will enable better understanding of both the mechanisms of LINC00473 regulation in the brain in response to stress, as well as its function in stress resilience.

IN COLLABORATION WITH:

Orna Issler, PhD, NYU Langone Health

Maya Farzinpour, PhD, NYU Langone Health