Spatial lipidomic and neuron-specific transcriptomic signatures in the nucleus accumbens reveal phospholipid dyshomeostasis in depression-related maladaptations.

Lipid systems play a substantial role in the pathophysiological mechanisms underlying several brain disorders. However, the mechanisms underlying the lipid profile in stress-induced maladaptations and how these changes can impact distinct neuronal circuits and behavioral states remain to be fully elucidated. Here, we investigated the effects of p11 deficiency in combination with stress by using p11KO mice and chronic stress mouse models of depression to study spatial lipidomic and transcriptomic signatures in the mouse nucleus accumbens. Our results show that p11 deficiency and stress induce depression-related maladaptive phenotypes and provide novel evidence that these responses are associated with phospholipid dyshomeostasis in the nucleus accumbens. Phospholipid disturbances were predominantly related to phosphatidylethanolamine (PE) and ether PE metabolism, along with targets involved in the PE biosynthetic pathway. Moreover, chelerythrine administration, a compound reported to disrupt phospholipid balance, induces PE changes and depression-like behaviors. Altogether, the present study provides evidence that alterations in phospholipid-related pathways may alter reward/anti-reward circuits and how these changes might be implicated in stress-related disorders.