Reversal of hyperactive subthalamic circuits differentially mitigates pain hypersensitivity phenotypes in parkinsonian mice

Abstract

Although pain is a prevalent nonmotor symptom in Parkinson’s disease (PD), it is undertreated, in part because of our limited understanding of the underlying mechanisms. Considering that the basal ganglia are implicated in pain sensation, and that their synaptic outputs are controlled by the subthalamic nucleus (STN), we hypothesized that the STN might play a critical role in parkinsonian pain hypersensitivity. To test this hypothesis, we established a unilateral parkinsonian mouse model with moderate lesions of dopaminergic neurons in the substantia nigra. The mice displayed pain hypersensitivity and neuronal hyperactivity in the ipsilesional STN and in central pain-processing nuclei. Optogenetic inhibition of STN neurons reversed pain hypersensitivity phenotypes in parkinsonian mice, while hyperactivity in the STN was sufficient to induce pain hypersensitivity in control mice. We further demonstrated that the STN differentially regulates thermal and mechanical pain thresholds through its projections to the substantia nigra pars reticulata (SNr) and the internal segment of the globus pallidus (GPi)/ventral pallidum (VP), respectively. Interestingly, optogenetic inhibition of STN-GPi/STN-VP and STN-SNr projections differentially elevated mechanical and thermal pain thresholds in parkinsonian mice. In summary, our results support the hypothesis that the STN and its divergent projections play critical roles in modulating pain processing under both physiological and parkinsonian conditions, and suggest that inhibition of individual STN projections may be a therapeutic strategy to relieve distinct pain phenotypes in PD.

IL‐1β/IL‐1R1 signaling induced by intranasal lipopolysaccharide infusion regulates alpha‐Synuclein pathology in the olfactory bulb, substantia nigra and striatum

“…Aggregated α-Syn is also known to be metabolized by various lysosomal enzymes by the autophagy processes in the mitral cell (7). In periphery, it is well established that Th1 cytokines, including IFN-γ, TNF-α, IL-1, IL-2, IL-6 and TGF-β, induce the effects of autophagy, while classical Th2 cytokines including IL-4, IL-10 and IL-13, inhibit the autophagy effects (31,60). We therefore investigated the role of IL-1R1 on autophagy of neurons after the LPS treatment.…”

Piezoelectric Nanomaterials Activated by Ultrasound: The Pathway from Discovery to Future Clinical Adoption

“…A similar approach has been previously demonstrated in mice using optogenetic tools. 135 Other relevant nonmotor symptoms in Parkinson’s disease, such as pain hypersensitivity, 136 might also be attenuated through the piezostimulation of basal ganglia circuitry.…”

Deep Brain Stimulation of the Subthalamic Nucleus Modulates Reward-Related Behavior: A Systematic Review

“…Because of the small size of the STN in rodents such a spatial resolution could be achieved by targeting pathway-specific output structures. For example, a recent study investigated PDrelated pain, by injecting ChR2 within the STN and placing optic fibers in different STN output structures, such as substantia nigra reticulata or ventral pallidum to target the motor and limbic STN subterritories, respectively (Luan et al, 2020). Or, akin to the work by Gradinaru et al (2009), antidromic activation of afferents can be modeled by expressing excitatory opsin in STN-projecting structures and placing fibers above the STN (Sanders and Jaeger, 2016;Sanders, 2017).…”