NAc-VTA circuit underlies emotional stress-induced anxiety-like behavior in the three-chamber vicarious social defeat stress mouse model.

Emotional stress is considered a severe pathogenetic factor of psychiatric disorders. However, the circuit mechanisms remain largely unclear. Using a three-chamber vicarious social defeat stress (3C-VSDS) model in mice, we here show that chronic emotional stress (CES) induces anxiety-like behavior and transient social interaction changes. Dopaminergic neurons of ventral tegmental area (VTA) are required to control this behavioral deficit. VTA dopaminergic neuron hyperactivity induced by CES is involved in the anxiety-like behavior in the innate anxiogenic environment. Chemogenetic activation of VTA dopaminergic neurons directly triggers anxiety-like behavior, while chemogenetic inhibition of these neurons promotes resilience to the CES-induced anxiety-like behavior. Moreover, VTA dopaminergic neurons receiving nucleus accumbens (NAc) projections are activated in CES mice. Bidirectional modulation of the NAc-VTA circuit mimics or reverses the CES-induced anxiety-like behavior. In conclusion, we propose that a NAc-VTA circuit critically establishes and regulates the CES-induced anxiety-like behavior. This study not only characterizes a preclinical model that is representative of the nuanced aspect of CES, but also provides insight to the circuit-level neuronal processes that underlie empathy-like behavior.

CDK5-mediated phosphorylation and autophagy of RKIP regulate neuronal death in Parkinson's disease.

Raf kinase inhibitor protein (RKIP) is a major negative mediator of the extracellular signal-related kinase (ERK)/mitogen-activated protein kinase (MAPK) pathway. The downregulation of RKIP is correlated with many cancers, but the mechanisms that underlie this downregulation and its roles in the nervous system remain unclear. Here, we demonstrate that RKIP is a substrate of cyclin-dependent kinase 5 (CDK5) in neurons and that the phosphorylation of RKIP at T42 causes the release of Raf-1. Moreover, T42 phosphorylation promotes the exposure and recognition of the target motif "KLYEQ" in the C-terminus of RKIP by chaperone Hsc70 and the subsequent degradation of RKIP via chaperone-mediated autophagy (CMA). Furthermore, in the brain sample of Parkinson's disease (PD) patients and in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride-induced and transgenic PD models, we demonstrate that CDK5-mediated phosphorylation and autophagy of RKIP are involved in the overactivation of the ERK/MAPK cascade, leading to S-phase reentry and neuronal loss. These findings provide evidence for the role of the CDK5/RKIP/ERK pathway in PD pathogenesis and suggest that this pathway may be a suitable therapeutic target in PD.