Identification of a Novel Neural Circuit for Depressive Symptoms in Chronic Pain

Post by Lincoln Tracy

What's the science?

People with chronic pain (pain that lasts longer than three months) commonly also present with depressive symptoms. The combination of pain and depression can make it complicated for these patients to receive treatment, as depressive symptoms may result in longer-lasting and more intense pain. There are suggestions that the dysfunction of the brain’s serotonin system is related to both pain and depression. However, we lack a good understanding of how chronic pain may affect the functioning of the serotonin system and how this, in turn, might impact depressive symptoms. Previous evidence suggests that the central nucleus of the amygdala (CeA) is a likely convergence point between chronic pain and depression. This week in Nature Neuroscience, Zhou and colleagues aimed to identify the neural circuit underlying the comorbid depressive symptoms in chronic pain by investigating the functional organization of the CeA and the involvement of serotonin using viral tracing, electrophysiological, optogenetic, and chemogenetic methods.

How did they do it?

First, the researchers identified the types of neurons that project into the CeA and their function. Second, they used the spared nerve injury chronic pain model in mice to assess the potential role of the CeA-projecting neurons in comorbid depressive symptoms. The spared nerve injury model involves severing two of the three branches of the sciatic nerve; the nerve running from the back to the lower legs. Whole-cell recordings and in-vivo microdialysis high-performance liquid chromatography were used to record neuronal activity and determine the serotonin concentration, respectively. Third, they tested the functional causality of the DRN-CeA circuit in the development of depressive-like behaviors in mice. Fourth, they investigated which other areas of the brain the CeA neurons project to. Finally, they used resting state functional magnetic resonance imaging to assess whether the neural circuits underlying the depressive symptoms in the mouse model of chronic pain also play a role in the depressive symptoms seen in humans with chronic pain.

What did they find?

First, they found that serotonergic neurons from the dorsal raphe nucleus (DRN) project to somatostatin interneurons in the CeA. The neurons from the DRN inhibit the somatostatin interneurons in the amygdala. Second, they found that inhibiting the somatostatin neurons in the CeA reduced depressive behaviors in mice afflicted by the spared nerve injury. Third, they showed that the DRN-CeA circuit is required for the development of depressive-like behavior specifically in mice with chronic pain, but not in non-pain-related mouse models of depression. Fourth, they identified that the somatostatin neurons of the CeA mainly send glutamatergic projections to neurons within the lateral habenula, a region of the brain that has previously been implicated in the pathophysiology of depression. The authors also identified that the DRN-CeA-lateral habenula circuit connections form part of a disinhibitory circuit that may underlie the depressive symptoms seen in chronic pain. Finally, they found that humans with both chronic pain and depression display decreased brain connectivity between the DRN and the centromedial amygdala, the equivalent of the CeA in mice. The functional connectivity between these two brain regions showed a negative correlation with the Hamilton Depression Rating Scale score (a widely used measure of depression), meaning the lower functional connectivity, the greater the depression experienced.

What's the impact?

This study found that a neural pathway involving serotoninergic neurons in the DRN, somatostatin neurons in the CeA, and the lateral habenula may be the cause of some of the aspects of the commonly occurring depression symptoms that occur in chronic pain. Activating this neural circuit relieved painful symptoms in mice. Pharmacological treatments for comorbid depressive symptoms in chronic pain are limited. Therefore, the findings from this study allow for the possibility of non-pharmacological treatment approaches (such as deep brain or transcranial magnetic stimulation) to target the converging pain and depression pathways.

Zhou et al. A neural circuit for comorbid depressive symptoms in chronic pain. Nature Neuroscience (2019). Access the original scientific publication here.