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

ABSTRACT: Chronic pain induces long-lasting changes in the anterior cingulate cortex (ACC) activity that contribute to the development of comorbid mood disorders. However, how such alterations propagate throughout the ACC connectome remains to be elucidated. Here, we aimed to study the role of the ACC neurons projecting to the lateral habenula (LHb) (ACC-->LHb) in chronic pain induced depression (CPID). CPID was induced using sciatic nerve cuffing in male C57BL/6J mice. Anxiodepressive-like behaviors were evaluated using a battery of behavioral tests. Fiber photometry was used to study the Ca2+ dynamics in the ACC, LHb and AC-->LHb neurons. 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE308643 | GEO | 2026/06/03

REPOSITORIES: GEO

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Project description:Background: As pain persists, it is often accompanied by the development of negative emotional states, such as depression. Approximately 50%-85% of patients with chronic pain experience depressive symptoms. Ventral tegmental area (VTA) γ--aminobutyric acid (GABA) neurons play a crucial role in regulating emotions. VTA GABA neurons can be mainly classified into those expressing somatostatin (SST) and parvalbumin (PV) neurons. The subtypes of VTA GABA neurons exhibit significant heterogeneity, but it remains unclear whether these subtypes mediate different functions in the development of chronic pain and depression. Inward rectifying potassium channel 4.1 (Kir4.1) is an important potassium channel mainly expressed in astrocytes and plays an important role in regulating neural activity. In lipopolysaccharide (LPS)-induced depression, Kir4.1 in lateral habenula (LHb) was upregulated. Lys05 (an inhibitor of Kir4.1) reversed the Kir4.1-driven depression-like phenotype. However, there was no study has reported the changes of Kir4.1 in chronic pain-induced depression or verified the therapeutic effects of Lys05 on it. Methods: We established chronic constriction injury (CCI) model to induce chronic pain in mice, and used the sugar preference test (SPT), tail suspension test (TST), and open field test (OFT) to detect depressive behavior in mice. Lys05 was injected to investigate the effect of Kir4.1 inhibitors on depression caused by chronic neuropathic pain. The adeno-associated virus (AAV) was designed to knockdown or overexpress the expression of Kir4.1 in VTA astrocytes. Using optogenetic manipulations and transgenic mice, specific activation of VTA GABASST neurons or VTA GABAPV neurons was used to explore which types of VTA GABA neurons Kir4.1 has effects on. Patch-clamp recording was applied to explore the effects of Kir4.1 on the excitability of different types of VTA neurons. Results: Lys05 could reverse the depressive behaviors induced by LPS. In detail, mice treated with 10 mg/kg Lys05 showed increased sucrose preference, decreased immobility durations in TST and increased percent center time in OFT. However, Lys05 didn’t show any specific response to depression behavior in CCI-induced depression mice. Then we found Kir4.1 expression decreased in VTA and LHb of CCI-induced depression mice. Next, we found knockdown of Kir4.1 in the VTA resulted mice became depression but with no hyperalgesia. Correspondingly, overexpress Kir4.1 in VTA astrocytes could reverse the chronic pain-induced depression like states. In the patch clamp, when knocked down Kir4.1 in VTA astrocytes, the excitability of dopamine neurons decreased, GABASST neurons increased, but GABAPV neurons did not change significantly. Specifically excitable VTA GABASST neurons could cause depression in mice, while excitable GABAPV neurons did not. Conclusion: Chronic pain decreases the expression of Kir4.1 in VTA astrocytes, which activates GABASST neurons and in turns inhibits DA neurons, then leads depression.

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

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