Detailed mapping of connectivity and cell characteristics reveals specific input pathways and distinct cell types in the subthalamic nucleus|RISS 상세보기

국문 초록 (Abstract)

시상하핵(STN)은 운동 제어에 중요한 역할을 하며, 파킨슨병(PD) 심부뇌자극술(DBS) 치료의 주요 표적이다. 하지만 STN의 주요 입력 경로인 외측 담창구(GPe)에서 오는 Indrect pathway (IP)와 대뇌 피질에서 오는 hyperdirect pathway (HP) 의 정확한 구조는 알려져 있지 않다. 이 논문에서는 바이러스를 이용한 경로 추적, 컴퓨터 재구성 및 연결정보 분석을 사용하여 마우스에서 이 경로를 포괄적으로 지도화 하였다. 경로 모두 STN의 구조적인 축을 따라 연속적이고 중첩된 구조를 보였으며, 기능적으로 분리된 영역은 없었다. 단일 신경세포 재구성을 통해 STN과 GPe를 따로 또는 이 둘과 동시에 연결을 형성하는 가지 유형의 피질 신경세포를 발견했다. 이는 IP 및 HP 경로 신호의 복잡한 통합을 시사한다. STN 내에서 우리는 독특한 발화 패턴과 중간/배외측 STN에 있는 글루탐산성 파발부민 양성(PV+) 신경세포를 확인했다. 흥분성/억제성 수용체 분포를 측정한 결과 복부내측 STN 신경세포에서 글루탐산/GABA 수용체 비율이 더 높은 패턴을 관찰하였다. 세포 유형별 시냅스 매핑에 따르면 PV+ 및 PV- STN 신경세포 모두에 IP 및 HP 회로가 수렴하는 구조를 가지고 있었다. 사람에서는 7T 초고해상도 신경 섬유다발 추적으로 STN의 연속적인 HP 구조를 확인했다. 또한 DBS에 의한 운동 개선 정도는 중간/배외측 STN의 PV+ 신경세포가 있는 전극 위치와 상관관계가 있었다. 이러한 다중 스케일 데이터는 STN의 입력과 세포 기반을 재정의하여 연속적이고 수렴적인 연결 패턴과 생리적 이질성을 보여주었다. 이는 기저핵의 운동 제어 및 DBS 메커니즘을 이해하기 위한 업데이트된 해부학적 프레임워크를 제공한다.

주요단어(Key words) : 기저핵, 시상하핵, 외측 담창구, 피질, 파킨슨 병, 뇌심부자극술

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시상하핵(STN)은 운동 제어에 중요한 역할을 하며, 파킨슨병(PD) 심부뇌자극술(DBS) 치료의 주요 표적이다. 하지만 STN의 주요 입력 경로인 외측 담창구(GPe)에서 오는 Indrect pathway (IP)와 대뇌 피질...

다국어 초록 (Multilingual Abstract)

The subthalamic nucleus (STN) plays a crucial role in motor control and is a key target for deep brain stimulation (DBS) therapy for Parkinson's disease (PD). However, the organization of major inputs to the STN, the indirect pathway from the external globus pallidus (GPe) and the hyperdirect pathway from the cortex, has been unclear. We comprehensively mapped these pathways in mice using viral tracing, computational reconstruction, and connecto-informatic analyses. Both pathways exhibited graded, overlapping topographic organization along the geometric axes of the STN, without segregated functional territories. Single-neuron reconstructions revealed three types of cortical neurons innervating the STN directly, GPe directly, or both in a collateral manner, suggesting complex integration of indirect and hyperdirect pathway signals. Within the STN, we identified glutamatergic parvalbumin-positive (PV+) neurons exhibiting distinct burst firing patterns and preferential localization in the middle/dorsolateral STN. Mapping excitatory/inhibitory receptor distributions revealed distinct topographic patterns, including higher glutamate/GABA receptor ratios in ventromedial STN neurons. Cell type-specific synaptic mapping demonstrated convergence of indirect and hyperdirect inputs onto both PV+ and PV- STN neurons. In humans, ultra-high resolution tractography at 7T confirmed graded hyperdirect pathway organization in the STN. Moreover, the degree of motor improvement from DBS correlated with electrode positions in the middle/dorsolateral STN, where PV+ neurons reside. These multiscale data redefine the inputs and cellular bases of the STN, revealing graded, convergent connectivity patterns and physiological heterogeneity, which provides an updated anatomical framework for understanding motor control and DBS mechanisms in the basal ganglia.

Key words : Basal ganglia, subthalamic nucleus, external globus pallidus, cortex, Parkinson’s disease (PD), deep brain stimulation (DBS)

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목차 (Table of Contents)

Contents
Abstract (English)
Abstract (Korean)
Contents
List of Figures

Contents
Abstract (English)
Abstract (Korean)
Contents
List of Figures
List of Tables
Abbreviation
1. Introduction ··························································· 1
1.1 Subthalamic nucleus and basal ganglia connectivity························· 1
1.2 Subthalamic nucleus and Parkinson’s disease································· 3
1.3 Subdivision of the subthalamic nucleus········································ 5
1.4 Evolutionary conserved subthalamic nucleus·································· 7
1.5 Molecular characteristics of the subthalamic nucleus························ 9
2. Materials and method································································· 13
2.1 Mice················································································· 13
2.2 Human 13
2.3 Stereotaxic injection ······························································ 14
2.4 Tissue preparation ································································ 15
2.5 Microscopy········································································· 16
2.6 Indirect projection mapping pipeline··········································· 17
2.7 Hyperdirect projection data from AMBCA···································· 19
2.8 Single neuron reconstruction data from MouseLight database·············· 20
2.9 Analysis of mouse hyper/indirect pathway topographic organization······ 21
2.10 Serial single-molecule fluorescence in situ hybridization···················· 22
2.11 Electrophysiological recording·················································· 23
2.12 Human 7T-DTI tractography···················································· 26
2.13 Human deep brain stimulation··················································· 27
3. Results ··················································································· 29
3.1 Indirect pathway in the STN ···················································· 29
3.2 Hyperdirect pathway in the STN················································ 31
3.3 Hyperdirect pathway in the GPe················································ 34
3.4 Complex integration of the indirect and hyperdirect pathway··············· 36
3.5 Cellular composition of the STN················································ 38
3.6 Cell type specific synaptic connectivity········································ 40
3.7 Hyperdirect pathway in the human STN and STN DBS····················· 42
4. Discussion ··············································································· 45
5. Acknowledgement
6. Figures and Legends ··································································
7. Tables·····················································································
8. Bibliography·············································································

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