Dysfunction of subthalamic dopaminergic circuitry contributes to anxiety- and depression-like behaviors in 6-OHDA lesion-induced hemiparkinsonian mice.

Abstract

Anxiety and depression are common non-motor symptoms severely affecting the quality of life in patients with Parkinson's disease, but the underlying pathophysiological mechanisms remain elusive. As dopaminergic (DA) system and the subthalamic nucleus (STN) are involved in motor control and emotional processing, we herein investigated the role of DA circuitry in the STN in regulating depression in parkinsonian mice. A hemi-parkinsonian mouse model was established by injection of 6-OHDA into the right medial forebrain bundle (MFB), desipramine (20 mg/kg, i.p.) was injected 30 min before the intracranial injection. Motor function was monitored in open field test and apomorphine-induced contra-lesional rotation and rotarod tests; anxiety- and depression-like behaviors were assessed with the open field test, elevated plus maze, tail suspension test and forced swim test. We found that the hemi-parkinsonian mice displayed motor dysfunction and depression-like behaviors at different time points. Fiber photometry recording revealed that STN neurons were hypersensitive to anxiety- and depression-like stimulation; chemogenetic inhibition of STN neurons mitigated anxiety- and depression-like behaviors. While dopamine release was significantly reduced in the STN of the parkinsonian mice in response to anxiety- and depression-like stimulation, the expression of D1- and D2-like dopamine receptors was time-dependently changed. Intracranial injection of either D1- or D2-like dopamine receptor agonist into the STN mitigated anxiety- and depression-like behaviors in the parkinsonian mice. We conclude that STN DA circuitry may be promising targets to treat anxiety and depression in PD.