VGluT2 neuron subtypes in the paraventricular thalamic nucleus regulate depression in paraquat-induced Parkinson’s disease.

Parkinson's disease (PD) is a prevalent neurodegenerative disease and approximately one third of patients with PD are estimated to experience depression. Paraquat (PQ) is the most widely used herbicide worldwide and PQ exposure is reported to induce PD with depression. However, the specific brain region and neural networks underlying the etiology of depression in PD, especially in the PQ-induced model, have not yet been elucidated. Here, we report that the VGluT2-positive glutamatergic neurons in the paraventricular thalamic nucleus (PVT) promote depression in the PQ-induced PD mouse model. Our results show that PVTVGluT2 neurons are activated by PQ and their activation increases the susceptibility to depression in PD mice. Conversely, inhibition of PVTVGluT2 neurons reversed the depressive-behavioral changes induced by PQ. Similar to the effects of intervention the soma of PVTVGluT2 neurons, stimulation of their projections into the central amygdaloid nucleus (CeA) also strongly influenced depression in PD mice. PQ induced malfunctioning of the glutamate system and changes in the dendritic and synaptic morphology in the CeA through its role on PVTVGluT2 neuronal activation. In summary, our results demonstrate that PVTVGluT2 neurons are key neuronal subtypes for depression in PQ-induced PD and promote depression processes through the PVTVGluT2-CeA pathway. Environmental Implication Paraquat is the most widely used herbicide. Millions of populations are occupationally or environmentally exposed to it. Studies assure paraquat as an important hazardous material to trigger depression with Parkinson's disease (PD) in vivo and in vitro. However, mechanisms underlying paraquat-induced depression with PD remains unknown, especially for the pathological brain region and neural projections.Here, we demonstrate the role of a specific brain region “PVT” and a core “PVT-CeA” neural projection in paraquat-induced PD with depression. These results reveal paraquat is a hazardous material by targeting “PVT-CeA” neural pathway and provide a new target for treatment in paraquat-exposed neuropsychiatric-disorders.