Role of substantia Nigra dopaminergic neurons in respiratory modulation and limitations of levodopa in Parkinson's disease

Author(s)

Miranda, Nicole C. ; Aquino, Yasmin C. ; Macedo, Taina O. ; Oliveira, Luiz M. ; Albernaz-Mariano, Kairo A. ; Munhoz, Carolina D. ; Ramirez, Jan-Marino ; Moreira, Thiago S. ; Takakura, Ana C.

• Document type: Journal article
• Source: Experimental Neurology; v. 387, p. 13-pg., 2025-02-28.

Abstract

The substantia nigra pars compacta (SNpc), a midbrain region enriched with dopaminergic neurons projecting to the dorsal striatum, is essential for motor control and has been implicated in respiratory modulation. In Parkinson's disease (PD) models, the loss of SNpc dopaminergic neurons correlates with baseline respiratory deficits, suggesting a potential link between dopaminergic dysfunction and respiratory impairments. To explore this, we used adult transgenic mice (Vglut2cre Ai6 and Vgatcre Ai6) to map neurotransmitter phenotypes, as well as DATcre mice for pharmacogenetic modulation of SNpc dopaminergic neurons using excitatory (Gq) or inhibitory (Gi) designer receptors exclusively activated by designer drugs (DREADDs). Neuroanatomical tracing revealed SNpc projections to key respiratory nuclei, including the caudal and rostral ventral respiratory groups (cVRG and rVRG), Bo<spacing diaeresis>tzinger complex (Bo<spacing diaeresis>tC), nucleus of the solitary tract (NTS), raphe magnus (RMg), and dorsal raphe (DR). While SNpc neurons were not activated by hypercapnia (7 % CO2) or hypoxia (8 % O2), pharmacogenetic stimulation of SNpc neurons altered respiratory parameters under both baseline and chemosensory challenge conditions. However, dopamine precursor treatment in PD models did not reverse respiratory deficits. These findings suggest that SNpc dopaminergic neurons can modulate respiration when selectively stimulated, but we did not find evidence for an endogenous role in respiratory chemosensitivity. This study reinforces the complexity of dopaminergic contributions to respiratory control in PD and suggests that targeting these neurons may not be sufficient to restore respiratory function, emphasizing the need for broader therapeutic strategies. (AU)

• FAPESP's process: 20/16320-8 - Investigation of the existence of anatomical projections from substantia nigra to pre-Bötzinger complex
• Grantee: Yasmin Cestari Aquino
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• FAPESP's process: 21/05299-0 - Control of the respiratory rhythm and chemosensitivity by the brainstem: role of molecular, cellular and physiopathology aspects
• Grantee: Thiago dos Santos Moreira
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 21/05647-9 - The involvement of pedunculopontine and laterodorsal tegmental nuclei in sleep and respiratory alterations observed in murine model of Parkinsons Disease
• Grantee: Nicole Castro de Souza Miranda
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• FAPESP's process: 21/15211-3 - Doença de Parkinson Effects of omega-3 in the treatment of functional respiratory and neuroanatomical disorders in a murine model of Parkinson's Disease
• Grantee: Tainá Oliveira Macedo
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• FAPESP's process: 21/09768-5 - Influences of sexual dimorphism, inflammation and sleep on respiratory changes observed in Parkinson’s Disease
• Grantee: Ana Carolina Takakura Moreira
• Support Opportunities: Research Projects - Thematic Grants