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Research Articles, Cellular/Molecular

Leptin activates dopamine and GABA neurons in the substantia nigra via a local pars compacta-pars reticulata circuit

Maria Mancini, Takuya Hikima, Paul Witkovsky, Jyoti C. Patel, Dominic W. Stone, Alison H. Affinati and Margaret E. Rice
Journal of Neuroscience 24 March 2025, e1539242025; https://doi.org/10.1523/JNEUROSCI.1539-24.2025
Maria Mancini
1Department of Neuroscience and Physiology, NYU School of Medicine, New York, NY, USA
2Neuroscience Institute, NYU School of Medicine, New York, NY, USA
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Takuya Hikima
3Department of Neurosurgery, NYU School of Medicine, New York, NY, USA
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Paul Witkovsky
3Department of Neurosurgery, NYU School of Medicine, New York, NY, USA
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Jyoti C. Patel
2Neuroscience Institute, NYU School of Medicine, New York, NY, USA
3Department of Neurosurgery, NYU School of Medicine, New York, NY, USA
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Dominic W. Stone
3Department of Neurosurgery, NYU School of Medicine, New York, NY, USA
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Alison H. Affinati
4Division of Metabolism, Endocrinology, and Diabetes, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
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Margaret E. Rice
1Department of Neuroscience and Physiology, NYU School of Medicine, New York, NY, USA
2Neuroscience Institute, NYU School of Medicine, New York, NY, USA
3Department of Neurosurgery, NYU School of Medicine, New York, NY, USA
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  • For correspondence: margaret.rice@nyu.edu
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Abstract

Adipose-derived leptin contributes to energy homeostasis by balancing food intake and motor output, but how leptin acts in brain motor centers remains poorly understood. We investigated the influence of leptin on neuronal activity in two basal ganglia nuclei involved in motor control: the substantia nigra pars compacta (SNc) and pars reticulata (SNr). Using a mouse reporter line to identify cells expressing leptin receptors (LepRs), we found that in both sexes, a majority of SNc dopamine neurons express a high level of LepR. Whole-cell recording in ex vivo midbrain slices from male wild-type mice showed that leptin activates SNc dopamine neurons directly and increases somatodendritic dopamine release. Although LepR expression in SNr GABA output neurons was low, leptin also activated these cells. Additional experiments showed that the influence of leptin on SNr neurons is indirect and involves D1 dopamine receptors and TRPC3 channels. Administration of leptin to male mice increased locomotor activity, consistent with activation of dopamine neurons in the SNc coupled to previously reported amplification of axonal dopamine release by leptin in striatal slices. These findings indicate that in addition to managing energy homeostasis through its actions as a satiety hormone, leptin also promotes axonal and somatodendritic dopamine release that can influence motor output.

Significance statement Dopamine neurons regulate motivated behaviors, but how they are influenced by metabolic hormones, like leptin, is incompletely understood. We show here that leptin increases the activity of substantia nigra (SN) pars compacta dopamine neurons directly, and that this enhances somatodendritic dopamine release. Leptin also increases the activity of GABAergic neurons in the SN pars reticulata, but does so indirectly via D1 dopamine receptors activated by locally released dopamine. Consistent with increased nigral dopamine neuron activity and previous evidence showing that leptin amplifies striatal dopamine release, systemic leptin increases locomotor behavior. This increase in motor activity complements the well-established inhibitory effect of leptin on food intake and adds an additional dimension to the regulation of energy balance by this hormone.

Footnotes

  • The authors declare no competing financial interests.

  • Funding was provided by the Marlene and Paolo Fresco Institute for Parkinson’s Disease and Movement Disorders, including a postdoctoral fellowship to M.M., and by National Institutes of Health grants DA050165 (M.E.R.) and DK122660 (A.H.A.). We are grateful to Martin G. Myers Jr. at the University of Michigan for providing LepRbEGFP mice utilized in this study, to Adam C. Mar at the NYU Grossman School of Medicine for advice on the locomotor experiments, and to Riccardo Melani for advice on statistical analyses.

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Leptin activates dopamine and GABA neurons in the substantia nigra via a local pars compacta-pars reticulata circuit
Maria Mancini, Takuya Hikima, Paul Witkovsky, Jyoti C. Patel, Dominic W. Stone, Alison H. Affinati, Margaret E. Rice
Journal of Neuroscience 24 March 2025, e1539242025; DOI: 10.1523/JNEUROSCI.1539-24.2025

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Leptin activates dopamine and GABA neurons in the substantia nigra via a local pars compacta-pars reticulata circuit
Maria Mancini, Takuya Hikima, Paul Witkovsky, Jyoti C. Patel, Dominic W. Stone, Alison H. Affinati, Margaret E. Rice
Journal of Neuroscience 24 March 2025, e1539242025; DOI: 10.1523/JNEUROSCI.1539-24.2025
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