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Letter to the Editor Stimulation of the dorsal portion of subthalamic nucleus may be a viable therapeutic approach in pharmacoresistant epilepsy: A virally mediated transsynaptic tracing study in transgenic mouse model To the Editor During the last decade, the neural bases of deep brain stimulation have been widely investigated. The ability to insert electronic stimula- tion systems into precise locations of brain tissues provides powerful ca- pabilities to activate/deactivate critical cellular signaling and neural systems. In such cases, determining neuronal phenotype and biochem- ically anatomical identity of the exact targets for deep brain stimulation is essential to avoid adverse effects of stimulation on normal physiolog- ical processes. It is well known that accurate localization of the subtha- lamic nucleus (STN) is critical to the success of deep brain stimulation surgery for pharmacoresistant epilepsy [13]. Though recent develop- ments in high-eld-strength magnetic resonance imaging (MRI) had made it possible to visualize the STN in greater detail [4], the important differences of the neuroanatomical and neurochemical structure be- tween STN subregions have not been observed. Accumulating clinic reports highlight the functionally heteroge- neous nature of the STN region, and STN exhibits a wide heterogeneity in terms of neurochemical properties (cholinergic and noncholinergic neurons) and connectivity [5,6]. The regions of STN reported by Parent and Hazrati were collective structures consisting of a dorsal sensorimo- tor region, a ventral associative region, and a medial limbic region [7], and the regions dened by Eitan et al. as the dorsolateral part, corre- sponding to the anatomically dened sensorimotor STN, and the more medial, more anterior, and more ventral parts, corresponding to the an- atomically dened limbic and associative territories of the STN [8], whereas McNeely et al. reported that STN contains the dorsal part, which is involved in motor function, and the ventral part, which regu- lates cognitive function [9], based on anatomical connectivity. Little is known about different parts of the subthalamic nucleus from a virally mediated transsynaptic tracing study. As a marker for synaptic connectivity in CNS by propagating retrogradely through chains of functionally connected neurons, the neurotropic pseudorabies virus (PRV) has provided new insight into neuronal communication and complex brain function [1018]. We had characterized projections from the kidney to the STN of the basal ganglia system in adult male MC4R-green uorescent protein (GFP) transgenic mice by using retrograde tracing techniques of pseudorabies virus (PRV)-614, expressing a novel monomeric red uorescent protein (mRFP1) under control of the cytomegalovirus immediate early pro- moter for direct visualization under uorescence microscope [1924]. We found that injections of PRV-614 into the kidney preferentially re- sulted in retrograde infection of neurons in the ventral STN, which was in agreement with a previous immunohistochemical study [25], suggesting direct neuronal circuit from the ventral STN to the kidney via the sympathetic pathways. Otherwise, we did not detect PRV-614- positive neurons in the dorsal STN (Fig. 1), suggesting that the dorsal STN may not play a major role in the regulation of central sympathetic pathways. Our results also showed that MC4R-GFP-positive neurons were most heavily concentrated in the dorsal STN and rarely distributed in the ventral STN, suggesting that the dorsal STN may play a major role in the regulation of central MC4R signaling. These data were also in line with previous studies in which the distinct subpopula- tions of neurons were detected in the subdivision of the STN region, suggesting that the STN should not be considered as a homogeneous structure [5,6,26,27]. Therefore, it was presumed that deep brain stimulation of the ventral portions of STN involved in sympathetic function whereas stimulation of the dorsal portions of STN involved in nonsympathetic signaling Based on all these ndings, we speculate that the dorsal portion of STN may play a major role in the regulation of central MC4R signaling and motor pathway, suggesting that stimulation for the dorsal, not the ventral, portion of the subthalamic nucleus may be a viable therapeutic approach in pharmacoresistant epilepsy. Acknowledgments The authors would like to gratefully acknowledge Dr. Lynn Enquist for kindly providing us with PRV-614 and Dr. Joel Elmquist (UT South- western Medical Center) for providing the MC4R-GFP transgenic mice. Funding This work was supported by grants from the National Natural Sci- ence Foundation of PR China (No. 81271766 to H.X.), the National Nat- ural Science Foundation of Hubei Province (No. 2013CFB121 to H.X.), Special Fund of Fundamental Scientic Research Business Expense for Higher School of Central Government (2012 TS060 to H.X.), and a 2010 Clinical Key Disciplines Construction Grant from the Ministry of Health of PR China. Conict of interest The authors declare that they have no competing interests. References [1] Tykocki T, Mandat T, Kornakiewicz A, Koziara H, Nauman P. Deep brain stimulation for refractory epilepsy. Arch Med Sci 2012;8:80516. [2] Ge Y, Hu W, Liu C, Zhang JG, Meng FG. Brain stimulation for treatment of refractory epilepsy. Chin Med J (Engl) 2013;126:336470. [3] Handforth A, DeSalles AA, Krahl SE. Deep brain stimulation of the subthalamic nucleus as adjunct treatment for refractory epilepsy. Epilepsia 2006;47:123941. [4] Patil PG, Conrad EC, Aldridge JW, Chenevert TL, Chou KL. The anatomical and electro- physiological subthalamic nucleus visualized by 3-T magnetic resonance imaging. Neurosurgery 2012;71:108995. [5] Campbell MC, Black KJ, Weaver PM, Lugar HM, Videen TO, Tabbal SD, et al. Mood response to deep brain stimulation of the subthalamic nucleus in Parkinson's disease. J Neuropsychiatry Clin Neurosci 2012;24:2836. Epilepsy & Behavior 31 (2014) 114116 1525-5050/$ see front matter © 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.yebeh.2013.11.030 Contents lists available at ScienceDirect Epilepsy & Behavior journal homepage: www.elsevier.com/locate/yebeh

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Epilepsy & Behavior 31 (2014) 114–116

Contents lists available at ScienceDirect

Epilepsy & Behavior

j ourna l homepage: www.e lsev ie r .com/ locate /yebeh

Letter to the Editor

Stimulation of the dorsal portion ofsubthalamic nucleus may be a viable

therapeutic approach in pharmacoresistantepilepsy: A virally mediated transsynaptictracing study in transgenic mouse model

To the Editor

During the last decade, the neural bases of deep brain stimulationhave been widely investigated. The ability to insert electronic stimula-tion systems into precise locations of brain tissues provides powerful ca-pabilities to activate/deactivate critical cellular signaling and neuralsystems. In such cases, determining neuronal phenotype and biochem-ically anatomical identity of the exact targets for deep brain stimulationis essential to avoid adverse effects of stimulation on normal physiolog-ical processes. It is well known that accurate localization of the subtha-lamic nucleus (STN) is critical to the success of deep brain stimulationsurgery for pharmacoresistant epilepsy [1–3]. Though recent develop-ments in high-field-strength magnetic resonance imaging (MRI) hadmade it possible to visualize the STN in greater detail [4], the importantdifferences of the neuroanatomical and neurochemical structure be-tween STN subregions have not been observed.

Accumulating clinic reports highlight the functionally heteroge-neous nature of the STN region, and STN exhibits a wide heterogeneityin terms of neurochemical properties (cholinergic and noncholinergicneurons) and connectivity [5,6]. The regions of STN reported by Parentand Hazrati were collective structures consisting of a dorsal sensorimo-tor region, a ventral associative region, and a medial limbic region [7],and the regions defined by Eitan et al. as the dorsolateral part, corre-sponding to the anatomically defined sensorimotor STN, and the moremedial, more anterior, andmore ventral parts, corresponding to the an-atomically defined limbic and associative territories of the STN [8],whereas McNeely et al. reported that STN contains the dorsal part,which is involved in motor function, and the ventral part, which regu-lates cognitive function [9], based on anatomical connectivity. Little isknown about different parts of the subthalamic nucleus from a virallymediated transsynaptic tracing study.

As a marker for synaptic connectivity in CNS by propagatingretrogradely through chains of functionally connected neurons, theneurotropic pseudorabies virus (PRV) has provided new insight intoneuronal communication and complex brain function [10–18]. Wehad characterized projections from the kidney to the STN of the basalganglia system in adult male MC4R-green fluorescent protein (GFP)transgenic mice by using retrograde tracing techniques of pseudorabiesvirus (PRV)-614, expressing a novel monomeric red fluorescent protein(mRFP1) under control of the cytomegalovirus immediate early pro-moter for direct visualization under fluorescence microscope [19–24].We found that injections of PRV-614 into the kidney preferentially re-sulted in retrograde infection of neurons in the ventral STN, whichwas in agreement with a previous immunohistochemical study [25],suggesting direct neuronal circuit from the ventral STN to the kidney

1525-5050/$ – see front matter © 2013 Elsevier Inc. All rights reserved.http://dx.doi.org/10.1016/j.yebeh.2013.11.030

via the sympathetic pathways. Otherwise, we did not detect PRV-614-positive neurons in the dorsal STN (Fig. 1), suggesting that the dorsalSTN may not play a major role in the regulation of central sympatheticpathways.

Our results also showed that MC4R-GFP-positive neurons weremost heavily concentrated in the dorsal STN and rarely distributedin the ventral STN, suggesting that the dorsal STN may play a majorrole in the regulation of central MC4R signaling. These data werealso in line with previous studies in which the distinct subpopula-tions of neurons were detected in the subdivision of the STN region,suggesting that the STN should not be considered as a homogeneousstructure [5,6,26,27]. Therefore, it was presumed that deep brainstimulation of the ventral portions of STN involved in sympatheticfunction whereas stimulation of the dorsal portions of STN involvedin nonsympathetic signaling

Based on all these findings, we speculate that the dorsal portion ofSTN may play a major role in the regulation of central MC4R signalingand motor pathway, suggesting that stimulation for the dorsal, not theventral, portion of the subthalamic nucleus may be a viable therapeuticapproach in pharmacoresistant epilepsy.

Acknowledgments

The authors would like to gratefully acknowledge Dr. Lynn Enquistfor kindly providing us with PRV-614 and Dr. Joel Elmquist (UT South-western Medical Center) for providing the MC4R-GFP transgenic mice.

Funding

This work was supported by grants from the National Natural Sci-ence Foundation of PR China (No. 81271766 to H.X.), the National Nat-ural Science Foundation of Hubei Province (No. 2013CFB121 to H.X.),Special Fund of Fundamental Scientific Research Business Expense forHigher School of Central Government (2012 TS060 to H.X.), and a2010 Clinical Key Disciplines Construction Grant from the Ministry ofHealth of PR China.

Conflict of interest

The authors declare that they have no competing interests.

References

[1] Tykocki T, Mandat T, Kornakiewicz A, Koziara H, Nauman P. Deep brain stimulationfor refractory epilepsy. Arch Med Sci 2012;8:805–16.

[2] Ge Y, Hu W, Liu C, Zhang JG, Meng FG. Brain stimulation for treatment of refractoryepilepsy. Chin Med J (Engl) 2013;126:3364–70.

[3] Handforth A, DeSalles AA, Krahl SE. Deep brain stimulation of the subthalamicnucleus as adjunct treatment for refractory epilepsy. Epilepsia 2006;47:1239–41.

[4] Patil PG, Conrad EC, Aldridge JW, Chenevert TL, Chou KL. The anatomical and electro-physiological subthalamic nucleus visualized by 3-T magnetic resonance imaging.Neurosurgery 2012;71:1089–95.

[5] Campbell MC, Black KJ, Weaver PM, Lugar HM, Videen TO, Tabbal SD, et al. Moodresponse to deep brain stimulation of the subthalamic nucleus in Parkinson'sdisease. J Neuropsychiatry Clin Neurosci 2012;24:28–36.

Fig. 1. Sympathetic andmelanocortinergic neurons in the STN. The kidney has become amodel system inwhich to study sympathetic function. Because there is no evidence that connec-tions of themotor nerve and the parasympathetic nervous system innervate the kidneys, the neurotropic pseudorabies virus (PRV)-614was injected into the left kidney.We seek tomapthemelanocortin-sympathetic pathway between the kidney and subthalamic region inMC4R-GFP transgenicmice by using retrograde tracing techniques of PRV-614. A shows anatomicalplates taken from Franklin and Paxinos [28]; images B–D were taken from an animal that survived 5 d after injections of PRV-614. B shows overlaid images of B plus C; C shows neuronsinfectedwith PRV-614, which send transsynaptic projections to the kidney; D showsMC4R-GFP-positive neurons in the STN. LH, lateral hypothalamic area; dSTN, dorsal STN; dlSTN, dor-solateral STN; vSTN, ventral STN. Scale bar, 200 μm.

115Letter to the Editor

[6] Brunenberg EJ, Moeskops P, Backes WH, Pollo C, Cammoun L, Vilanova A, et al.Structural and resting state functional connectivity of the subthalamic nucleus:identification of motor STN parts and the hyperdirect pathway. PLoS One2012;7:e39061.

[7] Parent A, Hazrati LN. Functional anatomy of the basal ganglia. II. The place of subtha-lamic nucleus and external pallidum in basal ganglia circuitry. Brain Res Brain ResRev 1995;20:128–54.

[8] Eitan R, Shamir RR, Linetsky E, Rosenbluh O, Moshel S, Ben-Hur T, et al. Asymmetricright/left encoding of emotions in the human subthalamic nucleus. Front SystNeurosci 2013;7:69.

[9] McNeely ME, Hershey T, Campbell MC, Tabbal SD, Karimi M, Hartlein JM, et al. Ef-fects of deep brain stimulation of dorsal versus ventral subthalamic nucleus regionson gait and balance in Parkinson's disease. J Neurol Neurosurg Psychiatry2011;82:1250–5.

[10] Ye D, Guo Q, Feng J, Liu C, Yang H, Gao F, et al. Laterodorsal tegmentum andpedunculopontine tegmental nucleus circuits regulate renal functions: neuroana-tomical evidence in mice models. J Huazhong Univ Sci Technolog Med Sci2012;32:216–20.

[11] Kerman IA, Enquist LW, Watson SJ, Yates BJ. Brainstem substrates of sympatho-motor circuitry identified using trans-synaptic tracing with pseudorabies virusrecombinants. J Neurosci 2003;23:4657–66.

[12] Jovanovic K, Pastor AM, O'DonovanMJ. The use of PRV-Bartha to define premotor in-puts to lumbar motoneurons in the neonatal spinal cord of the mouse. PLoS One2010;5:e11743.

[13] Kerman IA, Akil H, Watson SJ. Rostral elements of sympatho-motor circuitry: a viral-ly mediated transsynaptic tracing study. J Neurosci 2006;26:3423–33.

[14] Lee TK, Lois JH, Troupe JH,Wilson TD, Yates BJ. Transneuronal tracing of neural path-ways that regulate hindlimb muscle blood flow. Am J Physiol Regul Integr CompPhysiol 2007;292:R1532–41.

[15] Stanley S, Pinto S, Segal J, Perez CA, Viale A, DeFalco J, et al. Identification of neuronalsubpopulations that project from hypothalamus to both liver and adipose tissuepolysynaptically. Proc Natl Acad Sci U S A 2010;107:7024–9.

[16] Zhang Y, Kerman IA, Laque A, Nguyen P, Faouzi M, Louis GW, et al. Leptin-receptor-expressing neurons in the dorsomedial hypothalamus and medianpreoptic area regulate sympathetic brown adipose tissue circuits. J Neurosci2011;31:1873–84.

[17] Xiang HB, Liu C, Guo QQ, Li RC, Ye DW. Deep brain stimulation of thepedunculopontine tegmental nucleus may influence renal function. Med Hypothe-ses 2011;77:1135–8.

[18] Ye DW, Li RC, Wu W, Liu C, Ni D, Huang QB, et al. Role of spinal cord in regulatingmouse kidney: a virally mediated trans-synaptic tracing study. Urology2012;79:745e1–4.

[19] Tian XB, Li RC, Bu HL, Liu C, Liu TT, Xiang HB, et al. The mechanism ofelectroacupuncture for predicting the efficacy of deep brain stimulation inpharmacoresistant epilepsy may be involved in the melanocortinergic signal. Epi-lepsy Behav 2013;29:594–6.

[20] Ye DW, Ding DF, Liu TT, Tian XB, Liu C, Li RC, et al. The optimal segment for spinalcord stimulation in intractable epilepsy: a virally mediated transsynaptic tracingstudy in spinally transected transgenic mice. Epilepsy Behav 2013;29(3):599–601.

[21] Xiang HB, ZhuWZ, Guan XH, Ye DW. Possiblemechanism of deep brain stimulation forpedunculopontine nucleus-induced urinary incontinence: a virally mediated trans-synaptic tracing study in a transgenic mouse model. Acta Neurochir 2013;155:1667–9.

[22] Pan XC, Song YT, Liu C, Xiang HB, Lu CJ. Melanocortin-4 receptor expression in therostral ventromedial medulla involved in modulation of nociception in transgenicmice. J Huazhong Univ Sci Technolog Med Sci 2013;33:195–8.

[23] Xiang HB, Liu C, Ye DW, Zhu WZ. Possible mechanism of spinal T9 stimulation-induced acute renal failure: a virally mediated transsynaptic tracing study in trans-genic mouse model. Pain Physician 2013;16:E47–9.

[24] Liu C, Ye DW, Guan XH, Li RC, XiangHB, ZhuWZ. Stimulation of the pedunculopontinetegmental nucleus may affect renal function by melanocortinergic signaling. MedHypotheses 2013;81:114–6.

[25] Xiang HB, Zhu WZ, Bu HL, Liu TT, Liu C. Possible mechanism of subthalamic nucleusstimulation-induced acute renal failure: a virally mediated transsynaptic tracing studyin transgenic mouse model. Mov Disord 2013;28:2037–8.

[26] Piallat B, Polosan M, Fraix V, Goetz L, David O, Fenoy A, et al. Subthalamic neuronalfiring in obsessive–compulsive disorder and Parkinson disease. Ann Neurol2011;69:793–802.

[27] Burbaud P, Clair AH, Langbour N, Fernandez-Vidal S, GoillandeauM,Michelet T, et al.Neuronal activity correlated with checking behaviour in the subthalamic nucleus ofpatients with obsessive–compulsive disorder. Brain 2013;136:304–17.

[28] Franklin KB, Paxinos G. The mouse brain in stereotaxic coordinates. Third edition.San diego, CA: Academic press; 2007.

116 Letter to the Editor

Li FengTao-Tao Liu

Department of Anesthesiology and Pain Medicine,Tongji Hospital of Tongji Medical College,

Huazhong University of Science and Technology, Wuhan,Hubei 430030, PR China

Da-Wei YeCancer Center, Tongji Hospital of Tongji Medical College,Huazhong University of Science and Technology, Wuhan,

Hubei 430030, PR China

Qiu QiuDepartment of Anesthesiology and Pain Medicine,

Tongji Hospital of Tongji Medical College,Huazhong University of Science and Technology, Wuhan,

Hubei 430030, PR ChinaDepartment of Anaesthesiology, The University of Hong Kong,

Queen Mary Hospital, Hong Kong, China

Hong-Bing XiangDepartment of Anesthesiology and Pain Medicine,

Tongji Hospital of Tongji Medical College,Huazhong University of Science and Technology, Wuhan,

Hubei 430030, PR ChinaCorresponding author. Fax: +86 27 83662853.E-mail address: [email protected].

Chi-Wai CheungDepartment of Anaesthesiology, The University of Hong Kong,

Queen Mary Hospital, Hong Kong, ChinaCorresponding author. Fax: +852 22553384.

E-mail address: [email protected].

16 November 2013