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Parkinsonism and Related Disorders 20 (2014) 468e470

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Parkinsonism and Related Disorders

journal homepage: www.elsevier .com/locate/parkreldis

Letter to the Editor

Possible mechanism of regulating glucose metabolism withsubthalamic nucleus stimulation in parkinson’s disease: A virallymediated trans-synaptic tracing study in transgenic mice

To the editor

The article titled ‘Changes in brain glucose metabolism in sub-thalamic nucleus deep brain stimulation for advanced Parkinson’sdisease’ by Volonté et al. [1], showed mainly an increased glucosemetabolism in subthalamic regions, corresponding to the deepbrain stimulation site, suggesting that the central nervous systemmay regulate glucose homeostasis. It is now widely recognizedthat the central melanocortin system regulates energy expenditureand glucose metabolism. The melanocortin-4 receptor (MC4R) is aG protein-coupled receptor that plays an essential role in regulatingglucose homeostasis. The understanding of neuroanatomical mela-nocortinergic circuitry and neuronal connections from STN to itsconnecting areas in CNS is important for studying the possiblemechanism of regulating glucose metabolism with STN for Parkin-son’s disease by melanocortinergic pathway. We would like tofurther complete the discussion of Volonté and colleagues by intro-ducing a virally mediated transsynaptic tracing study in MC4R-GFPtransgenic mice [2,3].

Volonté et al. revealed a brain metabolic pattern typical ofadvanced Parkinson’s disease by Positron Emission Tomography,and showed that a positive correlation exists between neurosti-mulation clinical effectiveness and metabolic (glucose meta-bolism) differences in ON and OFF state, including the primarysensorimotor, premotor and parietal cortices, anterior cingulatecortex [1]. Batisse-Lignier et al. [4] had reported that endogenousglucose production (EGP) and whole-body glucose disposal rates(GDRs) were higher in PD patients in Stim-OFF conditions thanin the control group by assessing in the postabsorptive state dur-ing a primed continuous iv infusion of D-[6,6-(2)H2]glucose for5 h in 8 STN-DBS-treated patients with PD, without (Stim-OFF)and during STN-DBS (Stim-ON) treatment. Nagaoka et al. foundthat STN-DBS increased the regional cerebral metabolic rate ofglucose (rCMRGlc) in the posterior part of the right middle frontalgyrus, which corresponded to the premotor area, and the rightanterior lobe of the cerebellum by employing [(18) F]fluorodeoxy-glucose (FDG) positron emission tomography (PET) study, suggest-ing STN-DBS either activates the premotor area or normalizes thedeactivation of the premotor area. These findings indicated that

DOI of original article: http://dx.doi.org/10.1016/j.parkreldis.2012.03.016.

1353-8020/$ e see front matter � 2013 Elsevier Ltd. All rights reserved.http://dx.doi.org/10.1016/j.parkreldis.2013.12.008

STN-DBS-induced metabolic changes are tightly linked to glucosemetabolism in CNS.

Despite there exist obvious metabolic changes within brain af-ter STN-DBS, our understanding about the neuroanatomical andneurochemical mechanisms of STN-DBS is still limited. A numberof studies have verified that melanocortin 4 receptors (MC4R) inthe central nervous system are key regulators of glucose meta-bolism, and have also been suggested to regulate the release of in-sulin via the activity of sympathetic neurons We explore thehypothesis that STN-DBS may regulate glucose metabolism inCNS by melanocortinergic pathway. The goal of the present studywas to elucidate the melanocortinergic neuronal circuitry fromSTN to its connecting areas in CNS in MC4R-GFP transgenicmice. The kidney has become a model system in which to studysympathetic function because there is no evidence that betweenmotor nerve and the parasympathetic nervous system providesany innervations to kidneys, so the neurotropic pseudorabies vi-rus (PRV)-614 was injected into the left kidney. We seek to mapthe melanocortin-sympathetic pathway among kidney, subthala-mic and remote connecting regions in MC4R-GFP transgenic miceby using retrograde tracing techniques of PRV-614 [2,3,5].

We found that injection of PRV-614 into the kidney resulted inretrograde infection of neurons in the STN, the primary sensori-motor, premotor and parietal cortices, anterior cingulate cortex. Itwas a strikingly attractive that PRV-614/MC4R-GFP dual labeledneurons were detected in the STN (Fig 1), the primary sensori-motor, premotor and parietal cortices, anterior cingulate cortex,suggesting melanocortinergic and sympathetic neuronal popula-tions present between the STN and remote connecting regions.Therefore, it was presumed that possible mechanism of regulatingglucosemetabolismwith subthalamic nucleus stimulation involvedbetween melanocortinergic and sympathetic signals in STN andremote connecting regions. Because central regulation of sympa-thetic activity is a major component of melanocortinergic action,our data suggest thatMC4R signaling in STN and remote connectingregions may involve in the sympathetic regulation of glucose meta-bolism in CNS.

In conclusion, data presented here provide direct neuroanatom-ical evidences for the central melanocortin-sympathetic circuitsfrom the subthalamic and remote connecting areas (the primarysensorimotor, premotor and parietal cortices, anterior cingulatecortex) to the kidney. Thereby, stimulation of STN may induce theselective increase of MC4R activity in neurons of STN, the primary

Fig. 1. Colocalization of MC4R-GFP (green) and PRV-614 positive neurons (red) within STN areas. (A and B1) MC4R-GFP expressing neurons; (B2) PRV-614 expressing neurons insame section as (B1); (B3) overlap of (B1) and (B2), depicting distribution of MC4R-GFP-IR and PRV-614-bearing neurons in STN areas. Arrows indicate double-labeled neurons. Scalebar: 100 mm for A, B1-3. RMM, retromammillary; SN, substamtia nigra; STN, subthalamic nucleus. Some drawings were taken from HB Xiang (Movement Disorder 2013). (For inter-pretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Fig. 2. Summary diagram showed that the central melanocortin-sympathetic circuitsfrom the subthalamic and remote connecting areas (the primary sensorimotor, premo-tor and parietal cortices, anterior cingulate cortex) to the kidney. Stimulation of STNmay induce the selective increase of MC4R activity in neurons of STN, the primarysensorimotor, premotor and parietal cortices, anterior cingulate cortex, resulting inan increased glucose metabolism in subthalamic and remote connecting regions bythe central melanocortin-sympathetic mechanism.

Letter to the Editor / Parkinsonism and Related Disorders 20 (2014) 468e470 469

sensorimotor, premotor and parietal cortices, anterior cingulatecortex, resulting in an increased glucose metabolism in subthala-mic and remote connecting regions by the central melanocortin-sympathetic mechanism (Fig. 2).

Conflict of interests

The authors have no conflict of interest related to this paper.

Funding

This work was supported by grants from National Natural Sci-ence Foundation of P.R. China (No. 81271766 to H.X, No.30901395 to X.T.), Natural Science Foundation of Hubei Province(No. 2013CFB121 to H.X.), Research Fund for the Doctoral Programof Higher Education of China (No. 20090142120012 to X.T.), SpecialFund of Fundamental Scientific Research Business Expense forHigher School of Central Government (2012 TS060 to H.X) and2010 Clinical Key Disciplines Construction Grant from the Ministryof Health of P.R. China.

Acknowledgments

We gratefully acknowledge Dr. Lynn Enquist for kindlyproviding us with PRV-614 and Dr. Joel Elmquist (UT SouthwesternMedical Center) for providing the MC4R-GFP transgenic mice. Wealso acknowledge Bing Ke for her outstanding work.

References

[1] Volonte MA, Garibotto V, Spagnolo F, Panzacchi A, Picozzi P, Franzin A, et al.Changes in brain glucose metabolism in subthalamic nucleus deep brain stim-ulation for advanced parkinson’s disease. Parkinsonism Relat Disord 2012;18:770e4.

[2] Xiang HB, Zhu WZ, Guan XH, Ye DW. Possible mechanism of deep brain stim-ulation for pedunculopontine nucleus-induced urinary incontinence: a virallymediated transsynaptic tracing study in a transgenic mouse model. Acta Neuro-chir 2013;155:1667e9.

[3] Xiang HB, Liu C, Ye DW, Zhu WZ. Possible mechanism of spinal T9 stimulation-induced acute renal failure: a virally mediatedtranssynaptic tracing study intransgenic mouse model. Pain Physician 2013;16:E47e9.

Letter to the Editor / Parkinsonism and Related Disorders 20 (2014) 468e470470

[4] Batisse-Lignier M, Rieu I, Guillet C, Pujos E, Morio B, Lemaire JJ, et al. Deep brainstimulation of the subthalamic nucleus regulates postabsorptive glucose meta-bolism in patients with parkinson’s disease. J Clin Endocrinol Metab 2013;98:E1050e4.

[5] Xiang HB, Zhu WZ, Guan XH, Ye DW. The cuneiform nucleus may be involved inthe regulation of skeletal muscle tone by motor pathway: A virally mediatedtrans-synaptic tracing study in surgically sympathectomized mice. Brain June13, 2013. http://dx.doi.org/10.1093/brain/awt123.

Qiu Qiu1

Department of Anesthesiology and Pain Medicine, Tongji Hospital ofTongji Medical College, Huazhong University of Science and

Technology, Wuhan, Hubei 430030, PR China

Department of Anaesthesiology, The University of Hong Kong, QueenMary Hospital, Hong Kong, China

Rong-Chun Li1, De-Fang DingDepartment of Pain Management, Wuhan Pu’ai Hospital, Tongji

Medical College, Huazhong University of Science and Technology,Wuhan 430034, PR China

1 These authors contributed equally to this work.

Cheng Liu, Tao-Tao Liu, Xue-Bi Tian, Hong-Bing Xiang*

Department of Anesthesiology and Pain Medicine, Tongji Hospital ofTongji Medical College, Huazhong University of Science and

Technology, Wuhan, Hubei 430030, PR China

Chi-Wai Cheung**

Department of Anaesthesiology, The University of Hong Kong,Queen Mary Hospital, Hong Kong, China

*Corresponding author. Tel.: þ86 27 83663173;fax: þ86 27 83662853.

**Corresponding author.E-mail addresses: xianghongbing0204@163.com,

xhbtj2004@163.com (H.-B. Xiang).E-mail address: cheucw@hku.hk (C.-W. Cheung).

26 August 2013