Optogenetic Stimulation and Inhibition in Parkinsonian Rodents Reveal a Therapeutic Mechanism by Indirect Modulation of Motor Cortical Activity

光激活與抑制帕金森動物模型揭示間接調控運動皮層在深部腦刺激治療中的作用

Student thesis: Doctoral Thesis

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Award date12 Feb 2018

Abstract

Parkinson’s disease (PD) is a common neurodegenerative disease that mainly affects the motor function of patients, causing rigidity, tremor and bradykinesia of limbs and postural instability in gait {Rascol, 2002 #478}. Nowadays, high frequency deep brain stimulation (DBS) by pulsed electrical signals within basal ganglia, especially subthalamus (STN), is a widely used treatment for improving motor capability in otherwise-treatment-resistant Parkinson patients {Kringelbach, 2007 #481}. While effective surgical treatment {Kern, 2007 #581}, the exact mechanism of DBS’s therapeutic effect is still elusive{Chiken, 2016 #488}{Ashkan, 2013 #484}{Schlapfer, 2014 #482}. Previous studies reveal that electrical stimulation in STN can induce various activities in local neurons or axons, including release of neurotransmitters{Wang, 1998 #582}{Zucker, 2002 #584}, antidromic activation of afferent axons from GPi neurons {Moran, 2011 #587} or cortico-STN afferent {Gradinaru, 2009 #6}, orthodromic activation of STN output neurons {Hershey, 2003 #589}{Boertien, 2011 #590}{Jech, 2001 #588}, and direct stimulation of bypassing axons {ref}. Based on these findings, several hypotheses have been raised to explain the root reason of DBS’s therapy effects {Chiken, 2016 #488}, which are inhibition of local STN neurons {Filali, 2004 #454}{Welter, 2004 #456}{Shi, 2006 #457}{Tai, 2003 #459}, excitation of GPi/GPe neurons through the excitatory STN-GPi/SNr/GPe projections{Galati, 2006 #595}{Hashimoto, 2003 #593}{Reese, 2011 #594}, disruption of information flow through STN{Chiken, 2016 #488}. Recently, antidromic activation of motor cortex has also been suggested to play important roles in this process {Li, 2012 #4}{Gradinaru, 2009 #6}. Li et al reported that Stochastic antidromic spikes were recorded in the corresponding motor cortex of Parkinson rat under ipsilateral STN-DBS{Li, 2012 #2}. But more specific stimulation of STN neurons by the optogenetic method can not induce any behavioral relief in 6-hydroxydopamine (6-OHDA) lesioned mice {Gradinaru, 2009 #6}. Another study also found that optogenetic inhibition of STN ameliorates motor deficiency in of Parkinson rats {Yoon, 2014 #9}. Clearly, many of these explanations are still controversial or even self-contradicting. In addition, it also hard to explain clinical practice of electrical of STN lesion for treating PD {Patel, 2003 #597}{Vilela Filho, 2002 #596}

In this study, we took a multi-modal brain modulation approach that combines optogenetics and electrophysiology recording to perform a mechanistic study of DBS. We found that high frequency optical inhibition of STN can work similarly as high frequency electrical stimulation to modify the pathologic electrical activity in the motor cortex and restore the motor deficiency in hemi-Parkinsonian rats. The motor cortex even responds to STN inhibition with a shorter latency compared to its response to STN stimulation. We also showed that indirect inhibitory modification of entopeduncular nucleus (EP) within the basal ganglia system, which is induced by either STN inhibition or stimulation, plays a critical role in the STN-DBS induced therapeutic effects. These results provide a first experimental evidence supporting a working principle of STN-DBS by disruption of anterograde signal transmission along the indirect pathway of basal ganglia and could be instructive for future clinical treatment of PD with DBS.