Hugel, S. | bioRxiv Science

bioRxiv2022

The basolateral amygdala-anterior cingulate pathway contributes to depression and its comorbidity with chronic pain

While depression and chronic pain are frequently comorbid, underlying neuronal circuits, and their relevance for the understanding of psychopathology, remain poorly defined. Here we show in mice that hyperactivity of the neuronal pathway linking the basolateral amygdala to the anterior cingulate cortex is essential for chronic pain-induced depression. In naive animals, we demonstrate that activation of this pathway is sufficient to trigger depressive-like behaviors, as well as transcriptomic alterations that recapitulate core molecular features of depression in the human brain. These alterations notably impact gene modules related to myelination and the oligodendrocyte lineage. Among these, we show that Sema4a, a hub gene significantly upregulated in both mice and humans in the context of altered mood, is necessary for the emergence of depressive-like behaviors. Overall, these results place the BLA-ACC pathway at the core of pain and depression comorbidity, and unravel the role of impaired myelination and Sema4a in mood control.

neuroscience↗

bioRxiv2022

Dissecting the autism-associated 16p11.2 locus identifies multiple drivers in brain phenotypes and unveils a new role for the major vault protein

Using mouse genetic studies, we set out to identify which of the 30 genes causes brain size and other NeuroAnatomical Phenotypes (NAPs) at the autism-associated 16p11.2 locus. We show that multiple genes mapping to this region interact to regulate brain size in contrast to previous studies, with female significantly less affected. Major Vault Protein (MVP), the main component of the vault organelle, is a highly conserved protein found in higher and lower eukaryotic cells, yet its function is not understood. Here we find MVP expression highly specific to the limbic system and Mvp as the top driver gene of NAPs, regulating the morphology of neurons, postnatally and specifically in male. Finally, we demonstrate that the double hemideletion Mvp::Mapk3 rescues NAPs, increases phosphorylation of ERK and alters behavioral performances, suggesting that MVP and ERK share the same signalling pathway, in vivo. Our results highlight that sex-specific cellular and neuroanatomical mechanisms must be considered in neurological disorders such as autism. Most importantly, it provides the first evidence for the involvement of the vault organelle in the regulation of the mammalian brain size and limbic structures.

genetics↗