2023-06-15 07:39:23
Chronic pain is frequently associated with anxiety and depressive disorders. Imaging studies in humans point to a number of similarities in brain structures implicated in chronic pain and mood disorders. In particular, patients suffering from these pathologies show abnormal activation of an anterior region of the brain, the anterior cingulate cortex (ACC). In previous work, the scientists had shown that the lesion or inhibition of the activity of this same structure in mice made it possible to neutralize the negative emotional consequences following chronic pain. Conversely, in a complementary fashion, the sustained activation of the CCA in naive, non-painful mice was sufficient to produce anxiety-like and depressive effects.
In the present study, the scientists were interested in the mechanisms leading to this excessive activation of the CCA. First, they showed that neurons located in the basolateral amygdala (BLA) and projecting to the CCA were hyperactive in a model of depression induced by chronic pain. In addition, the inhibition of the connection between these two structures, called the BLA-CCA pathway, makes it possible to suppress depressive-type behaviors induced by chronic pain in mice. Interestingly, while inhibition of the entire CCA reduces depressive and anxiety-like behaviors, inhibition of the BLA-CCA pathway has no effect on anxiety. This suggests that emotional regulation by the CCA occurs through the recruitment of different brain pathways.
Subsequently, scientists demonstrated that hyperactivity of the BLA-CCA pathway was sufficient to induce the development of depression-like behaviors. To do this, they set up a protocol allowing the repeated activation of the BLA-CCA pathway over a period of 3 weeks. The animals thus stimulated develop behaviors of the depressive type gradually, with a maximum effect after 3 weeks of stimulation. These effects are associated with changes in gene expression in the CCA strongly resembling the transcriptomic changes observed in depressive patients in the same brain structure, during a post-mortem study. Among the most important modifications, a drastic reduction in the expression of genes involved in myelination is particularly conserved between mice and humans.
Myelination is the process by which cells, called oligodendrocytes, will produce a sheath, myelin, around neurons. This sheath allows faster communication between neurons. Alterations in the integrity of this sheath can profoundly impact communication between brain structures. Besides the decrease in the expression of genes related to myelination, an increase in the expression of the gene Sema4a, acting as an inhibitor of myelination, was also observed. In order to test the causal role of this gene in the genesis of depressive behaviors, the scientists blocked its expression in the CCA in mice, before activating the BLA-CCA pathway. This made it possible to prevent the development of depressive-type behaviors, thus showing that Sema4a plays a pivotal role in their implementation. Taken together, these results highlight the critical role of the BLA-CCA pathway in the comorbidity between chronic pain and depression. By combining the data obtained in humans and animals, this study paints a picture of the molecular mechanisms underlying a depressive state and conserved between the two species. In particular, it highlights the importance of the regulation of myelination, in particular via Sema4ain mood control.
Video “My thesis in 180s”: https://youtu.be/BrZu2CMy8QE
Figure: A. Optogenetic activation of the BLA-ACC pathway reproduces part of the molecular signature of depression in humans. B. Decreasing the expression of Sema4a blocks the emotional deficits induced by the activation of the BLA-CCA pathway.
To know more :
The basolateral amygdala-anterior cingulate pathway contributes to depression-like behaviors and comorbidity with chronic pain behaviors in male mice
Léa J Becker, Clémentine Fillinger, Robin Waegaert, Sarah H Journée, Pierre Hener, Beyza Ayazgok, Muris Humo, Meltem Karatas, Maxime Thouaye, Mithil Gaikwad, Laetitia Degiorgis, Marie des Neiges Santin, Mary Mondino, Michel Barrot, El Chérif Ibrahim, Gustavo Turecki, Raoul Belzeaux, Pierre Veinante, Laura A Harsan, Sylvain Hugel, Pierre-Eric Lutz, Ipek Yalcin
Nature Communications (2023) 14(1):2198. DOI: 10.1038/s41467-023-37878-y.
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#neural #pathway #depression #amygdala #cingulate #cortex