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

## TL;DR

This study shows that the zona incerta, a brain region with dopamine and GABA neurons, is early affected in ALS, leading to metabolic issues and neuron loss.

## Contribution

The study identifies the zona incerta as an early-affected node in ALS, linking motor and metabolic network dysfunction.

## Key findings

- ZI/DAergic neurons degenerate early in ALS, preceding MCH neuron loss.
- ALS pathology in ZI parallels that in the motor cortex.
- Loss of ZI/DAergic neurons correlates with weight loss in multiple ALS models.

## Abstract

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.

The online version contains supplementary material available at 10.1186/s40478-026-02231-z.