ABSTRACT
Lithium has been used to treat major depressive disorder, yet the neural circuit mechanisms underlying this therapeutic effect remain unknown. Here, we demonstrated that the ventral tegmental area (VTA) dopamine (DA) neurons that project to the medial prefrontal cortex (mPFC), but not to nucleus accumbens (NAc), contributed to the antidepressive-like effects of lithium. Projection-specific electrophysiological recordings revealed that high concentrations of lithium increased firing rates in mPFC-, but not NAc-, projecting VTA DA neurons in mice treated with chronic unpredictable mild stress (CMS). In parallel, chronic administration of high-dose lithium in CMS mice restored the firing properties of mPFC-projecting DA neurons, and also rescued CMS-induced depressive-like behaviors. Nevertheless, chronic lithium treatment was insufficient to change the basal firing rates in NAc-projecting VTA DA neurons. Furthermore, chemogenetic activation of mPFC-, but not NAc-, projecting VTA DA neurons mimicked the antidepressive-like effects of lithium in CMS mice. Chemogenetic downregulation of VTA-mPFC DA neurons' firing activity abolished the antidepressive-like effects of lithium in CMS mice. Finally, we found that the antidepressant-like effects induced by high-dose lithium were mediated by BNDF signaling in the mesocortical DA circuit. Together, these results demonstrated the role of mesocortical DA projection in antidepressive-like effects of lithium and established a circuit foundation for lithium-based antidepressive treatment.
Subject(s)
Brain-Derived Neurotrophic Factor , Depressive Disorder, Major , Animals , Antidepressive Agents/pharmacology , Brain-Derived Neurotrophic Factor/metabolism , Lithium , Mice , Nucleus Accumbens/metabolism , Prefrontal Cortex/metabolism , Ventral Tegmental Area/metabolismABSTRACT
Corticotropin-releasing factor (CRF) serves as a neuromodulator in the hypothalamic-pituitary-adrenal axis, playing an essential role in depression, anxiety, and pain regulation. However, its biological role in bone cancer induced pain has not been investigated. In the present study, we aimed to elucidate the expression and distribution of CRF in spinal cord using a rodent model of bone cancer pain. Our study showed that implantation of Walker 256 mammary gland carcinoma cells into the tibia of rats significantly increased CRF expression in the spinal cord in a time-dependent manner. The upregulated expression of CRF mainly expressed in the superficial dorsal horn of spinal cord. Moreover, immunofluorescence double staining showed that CRF was extensively colocalized with neurons, but hardly with astrocytes or microglia. In addition, intrathecal injection of CRF receptor antagonist (α-helical-CRF) significantly inhibited heat hyperalgesia, mechanical allodynia, and the expression of c-Fos in spinal dorsal horn of bone cancer pain rats. In summary, our study demonstrates that CRF plays an important role in the development and maintenance of bone cancer pain via activation of neurons.