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<p>Weight loss and hypermetabolism are early and prognostically significant features of amyotrophic lateral sclerosis (ALS) and are associated with hypothalamic atrophy and degeneration of melanin-concentrating hormone (MCH) neurons that regulate energy balance. To investigate whether MCH vulnerability arises from upstream network dysfunction, we performed whole-brain retrograde rabies tracing in <i>SOD1</i><sup><i>G93A</i></sup> mice. We identified an early, selective loss of monosynaptic inputs from the zona incerta (ZI), a dopaminergic (DA)/gamma-aminobutyric acid (GABA)ergic nucleus that preceded MCH neuron degeneration. Neurochemical profiling confirmed the DA/GABAergic identity of these ZI input neurons, and ZI/DAergic neurons later degenerated. ALS-related pathology emerged early in the ZI, paralleling pathology in the motor cortex, while anterograde mapping revealed that motor cortical projections preferentially targeted the ZI, linking vulnerable motor and metabolic networks. Loss of ZI/DAergic neurons was observed in conjunction with weight loss in non-SOD1 ALS models. These findings identify the ZI as an early-affected node within hypothalamic networks and suggest that disruption of DA/GABAergic inputs to MCH neurons is associated with subsequent MCH and DA neuronal vulnerability, degeneration and metabolic imbalance in ALS.</p>

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Large-scale mapping of the MCH network in ALS mice reveals the vulnerability of dopaminergic and GABAergic neurons in zona incerta

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月6日

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  • Jelena Scekic-Zahirovic,
  • Stefano Antonucci,
  • Diana Wiesner,
  • Chiara Ebner,
  • Hussein El Hajj,
  • Oumayma Aousji,
  • Kareen Halablab,
  • Yiting Fan,
  • Anneka Zelaya,
  • Gizem Yartas,
  • Karthik Baskar,
  • E. Anastasia Çakmak,
  • David Bayer,
  • Hoon-Ki Sung,
  • Luc Dupuis,
  • Jeehye Park,
  • Francesco Roselli

摘要

Weight loss and hypermetabolism are early and prognostically significant features of amyotrophic lateral sclerosis (ALS) and are associated with hypothalamic atrophy and degeneration of melanin-concentrating hormone (MCH) neurons that regulate energy balance. To investigate whether MCH vulnerability arises from upstream network dysfunction, we performed whole-brain retrograde rabies tracing in SOD1G93A mice. We identified an early, selective loss of monosynaptic inputs from the zona incerta (ZI), a dopaminergic (DA)/gamma-aminobutyric acid (GABA)ergic nucleus that preceded MCH neuron degeneration. Neurochemical profiling confirmed the DA/GABAergic identity of these ZI input neurons, and ZI/DAergic neurons later degenerated. ALS-related pathology emerged early in the ZI, paralleling pathology in the motor cortex, while anterograde mapping revealed that motor cortical projections preferentially targeted the ZI, linking vulnerable motor and metabolic networks. Loss of ZI/DAergic neurons was observed in conjunction with weight loss in non-SOD1 ALS models. These findings identify the ZI as an early-affected node within hypothalamic networks and suggest that disruption of DA/GABAergic inputs to MCH neurons is associated with subsequent MCH and DA neuronal vulnerability, degeneration and metabolic imbalance in ALS.