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      OPTOGENETIC STIMULATION OF CORTICO-SUBTHALAMIC PROJECTIONS IS SUFFICIENT TO AMELIORATE BRADYKINESIA IN 6-OHDA LESIONED MICE

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          Abstract

          Electrical deep brain stimulation (DBS) of the subthalamic nucleus (STN) is effective for ameliorating the motor symptoms of Parkinson’s disease (PD) including bradykinesia. The STN receives its main excitatory input from cortex; however, the contribution of cortico-subthalamic projection neurons to the effects of DBS remains unclear. To isolate the consequences of stimulating layer 5 primary motor cortex (M1) projections to the STN, we used a dual virus transfection technique to selectively express opsins in these neurons in mice made parkinsonian by unilateral nigrostriatal 6-OHDA lesioning. AAVs containing WGA-Cre constructs were injected in the STN to retrogradely place Cre in STN afferents, while AAVs containing Cre-dependent ultrafast hChR2(E123T/T159C)-EYFP opsin constructs were injected in M1 layer 5, producing specific opsin expression in M1-STN projections. Under unstimulated conditions, lesioned mice showed bradykinesia and hypokinesia (decreased movement), along with electrophysiological changes similar to those observed in PD patients. Specifically, low frequency power (theta, alpha, low beta) was increased and gamma power was decreased, while M1/STN coherence and STN phase-amplitude-coupling (PAC) were increased. Optogenetic stimulation (100–130 Hz) of STN afferents in these mice ameliorated bradykinesia and hypokinesia and brought the neural dynamics closer to the non-parkinsonian state by reducing theta and alpha and increasing gamma power in M1, decreasing STN PAC, and reducing theta band coherence. Histological examination of the EYFP expression revealed that, in addition to orthodromic and antidromic effects, stimulation of cortico-subthalamic neurons may cause wide-spread increased glutamatergic activity due to collaterals that project to areas of the thalamus and other brain regions.

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          Author and article information

          Journal
          9500169
          20475
          Neurobiol Dis
          Neurobiol. Dis.
          Neurobiology of disease
          0969-9961
          1095-953X
          8 August 2016
          21 July 2016
          November 2016
          01 November 2017
          : 95
          : 225-237
          Affiliations
          [1 ]Biology Department, Emory University Atlanta, Georgia, 30322 USA
          Author notes
          Corresponding Author Information. Teresa H. Sanders, PhD, Emory University, Rollins Research Center, Room 2164A, 1510 Clifton Rd. Atlanta, GA 30322, Tele: 770-862-2590/ Fax: 404-727-2880, teresa.hinkle.sanders@ 123456gmail.com , www.biology.emory.edu
          Article
          PMC5010926 PMC5010926 5010926 nihpa808868
          10.1016/j.nbd.2016.07.021
          5010926
          27452483
          9ab2b963-dcad-40b1-8db5-b86bf285e64f
          History
          Categories
          Article

          local field potential,movement analysis,motor cortex,PAC,phase-amplitude coupling,optogenetics,DBS,Deep Brain Stimulation,Parkinson’s disease,subthalamic nucleus

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