Differential remodeling of subthalamic projections to basal ganglia output nuclei and locomotor deficits in 6-OHDA-induced hemiparkinsonian mice.

The subthalamic nucleus (STN) controls basal ganglia outputs via the substantia nigra pars reticulata (SNr) and the globus pallidus internus (GPi). However, the synaptic properties of these projections and their roles in motor control remain unclear. We show that the STN-SNr and STN-GPi projections differ markedly in magnitude and activity-dependent plasticity despite the existence of collateral STN neurons projecting to both the SNr and GPi. Stimulation of either STN projection reduces locomotion; in contrast, inhibition of either the STN-SNr projection or collateral STN neurons facilitates locomotion. In 6-OHDA-hemiparkinsonian mice, the STN-SNr projection is dramatically attenuated, but the STN-GPi projection is robustly enhanced; apomorphine inhibition of the STN-GPi projection through D2 receptors is significantly augmented and improves locomotion. Optogenetic inhibition of either the STN-SNr or STN-GPi projection improves parkinsonian bradykinesia. These results suggest that the STN-GPi and STN-SNr projections are differentially involved in motor control in physiological and parkinsonian conditions.

Subthalamic neurons interact with nigral dopaminergic neurons to regulate movement in mice.

AIM: This study aims to address the role of the interaction between subthalamic (STN) neurons and substantia nigra pars compacta (SNc) dopaminergic (DA) neurons in movement control. METHODS: Fiber photometry and optogenetic/chemogenetic techniques were utilized to monitor and manipulate neuronal activity, respectively. Locomotion in mice was recorded in an open field arena and on a head-fixed apparatus. A hemiparkinsonian mouse model was established by unilateral injection of 6-OHDA in the medial forebrain bundle. Whole-cell patch-clamp techniques were applied to record electrophysiological signals in STN neurons and SNc DA neurons. c-Fos-immunostaining was used to label activated neurons. A rabies virus-based retrograde tracing system was used to visualize STN neurons projecting to SNc DA neurons. RESULTS: The activity of STN neurons was enhanced upon locomotion in an open field arena and on a head-fixed apparatus, and the enhancement was significantly attenuated in parkinsonian mice. Optogenetic stimulation of STN neurons enhanced locomotion, increased activity of SNc DA neurons, meanwhile, reduced latency to movement initiation. Combining optogenetics with patch-clamp recordings, we confirmed that STN neurons innervated SNc DA neurons through glutamatergic monosynaptic connections. Moreover, STN neurons projecting to SNc DA neurons were evenly distributed in the STN. Either 6-OHDA-lesion or chemogenetic inhibition of SNc DA neurons attenuated the enhancement of locomotion by STN stimulation. CONCLUSION: SNc DA neurons not only affect the response of STN neurons to movement, but also contribute to the enhancement of movement by STN stimulation. This study demonstrates the role of STN-SNc interaction in movement control.

Age-dependent alterations in key components of the nigrostriatal dopaminergic system and distinct motor phenotypes.

The nigrostriatal dopaminergic (DA) system, which includes DA neurons in the ventral and dorsal tiers of the substantia nigra pars compacta (vSNc, dSNc) and DA terminals in the dorsal striatum, is critically implicated in motor control. Accumulating studies demonstrate that both the nigrostriatal DA system and motor function are impaired in aged subjects. However, it is unknown whether dSNc and vSNc DA neurons and striatal DA terminals age in similar patterns, and whether these changes parallel motor deficits. To address this, we performed ex vivo patch-clamp recordings in dSNc and vSNc DA neurons, measured striatal dopamine release, and analyzed motor behaviors in rodents. Spontaneous firing in dSNc and vSNc DA neurons and depolarization-evoked firing in dSNc DA neurons showed inverse V-shaped changes with age. But depolarization-evoked firing in vSNc DA neurons increased with age. In the dorsal striatum, dopamine release declined with age. In locomotor tests, 12-month-old rodents showed hyperactive exploration, relative to 6- and 24-month-old rodents. Additionally, aged rodents showed significant deficits in coordination. Elevating dopamine levels with a dopamine transporter inhibitor improved both locomotion and coordination. Therefore, key components in the nigrostriatal DA system exhibit distinct aging patterns and may contribute to age-related alterations in locomotion and coordination.