A pathway from the anterior cingulate cortex to the lateral habenula controls chronic pain induced depression in male mice

We combined viral Translating Ribosome Affinity Purification (vTRAP) and RNA sequencing to study the molecular alterations in the ACC-->LHb neurons. Finally, we used an optogenetic approach to study the functional role of this pathway in CPID. Our results confirmed a functional connectivity between the ACC and LHb and demonstrated that this connection plays a critical role in emotional processing.

Activation of ACCLHb neurons elicited Ca2+ responses in the LHb and induced anxiodepressive-like behaviors in naive mice. Cell-type specific transcriptomic analysis revealed that CPID altered the expression of genes involved in neuronal excitability such as genes related to sphingolipid metabolism, glycophospholipids and Ca2+ channels in ACCLHb neurons. Interestingly, inhibition of this hyperactivity alleviated chronic pain- but not stress-induced anxiodepressive-like behaviors, demonstrating that the ACCLHb pathway selectively contributed to pain-induced emotional dysregulation.

These results reveal that hyperactivity of the neuronal pathway linking the ACC to the LHb is essential for CPID in male mice.