The involvement of the pathway connecting the substantia nigra, the periaqueductal gray matter and the retrotrapezoid nucleus in breathing control in a rat model of Parkinson's disease

Abstract

Parkinson's disease (PD) is characterized by a reduction in the number of dopaminergic neurons of the substantia nigra (SNpc), accompanied by motor and non-motor deficiencies such as respiratory failure. Here, our aim was to investigate possible neuronal communications between the SNpc and chemoreceptor neurons within the retrotrapezoid nucleus (RTN), in order to explain neurodegeneration and the loss of breathing function in the 6-OHDA PD animal model. Male Wistar rats received tracer injections in the SNpc, RTN and periaqueductal gray (PAG) regions to investigate the projections between those regions. The results showed that neurons of the SNpc project to the RTN by an indirect pathway that goes through the PAG region. In different groups of rats, reductions in the density of neuronal markers (NeuN) and the number of catecholaminergic varicosities in PAG, as well as reductions in the number of CO-activated PAG neurons with RTN projections, were observed in a 6-OHDA model of PD. Physiological experiments showed that inhibition of the PAG by bilateral injection of muscimol did not produce resting breathing disturbances but instead reduced genioglossus (GG) and abdominal (Abd) muscle activity amplitude induced by hypercapnia in control rats that were urethane-anesthetized, vagotomized, and artificially ventilated. However, in a model of PD, we found reductions in resting diaphragm muscle activity (Dia) and GG frequencies, as well as in hypercapnia-induced Dia, GG and Abd frequencies and GG and Abd amplitudes. Therefore, we can conclude that there is an indirect pathway between neurons of the SNpc and RTN that goes through the PAG and that there is a defect of this pathway in an animal model of PD.

Respiratory disturbances in a mouse model of Parkinson's disease

“…Previous findings also demonstrated in a rat model of PD that central chemoreception is initially reduced, but then recovers during the course of PD (Oliveira et al, 2017). One explanation for that recovery is the fact (Lima et al, 2018). Other possibilities are the presence of a dysfunctional blood-brain barrier, inflammation or an increase of oxidative stress in this model that could lead to death of brainstem neurons or loss of their markers.…”

“…Although we have observed a reduction in the number of neurons or receptors in crucial regions involved in the neural control of breathing in this mouse model of PD, the underlying mechanisms are still unknown. It is possible that SNpc dopaminergic neurons project indirectly to ventral respiratory column (VRC) through the periaqueductal grey matter, as already demonstrated in rats (Lima et al., ). Other possibilities are the presence of a dysfunctional blood–brain barrier, inflammation or an increase of oxidative stress in this model that could lead to death of brainstem neurons or loss of their markers.…”

“…Then, the neurotoxin is retrogradely transported and selectively kills dopaminergic neurons of the substantia nigra pars compacta (SNpc) by inhibition of mitochondrial complexes I and IV and formation of reactive oxygen species (Glinka, Tipton, & Youdim, 1996;Hernandes et al, 2013). The dose of 6-OHDA used in the present study was selected based on previous reports (Blandini, Armentero, & Martignoni, 2008;Fulceri et al, 2006;Lima, Oliveira, Botelho, Moreira, & Takakura, 2018;Oliveira et al, 2017;Schwarting & Huston, 1996). The 6-OHDA injections were performed bilaterally in the striatum to induce a retrograde neuronal nigrostriatal injury (Blum et al, 2001).…”

Monosynaptic projections to excitatory and inhibitory preBötzinger Complex neurons

“…Both the substantia nigra and the red nucleus participate in motor coordination, but neither has been directly linked to neural pathways affecting breathing. An indirect pathway between the substantia nigra and the retrotrapezoid nucleus through the PAG is impacted in a Parkinson's model of respiratory failure in rats (Lima, Oliveira, Botelho, Moreira, & Takakura, 2018), and red nucleus neurons may play a role in regulating ventilatory response to hypoxia (Ackland, Noble, & Hanson, 1997). As the red nucleus and the substantia nigra are responsible for coordinating and facilitating movement, these regions could be relaying information to the preBötC to synchronize breathing with gait or other movements.…”

Quimiossensibilidade central e ritmicidade respiratória na Doença de Parkinson.

“…A fim de fortalecer os nossos dados, evidenciamos mais uma vez a degeneração de 37% dos neurônios PHOX2B na região do RTN em camundongos submetidos a injeção bilateral de 6-OHDA no estriado. Muito embora diversos estudos na literatura evidenciarem a degeneração de grupos de neurônios que controlam a respiração (Fernandes-Junior et al, 2018;Lima et al, 2018;Oliveira et al, 2017b), o mecanismo de morte neuronal dos mesmos ainda não foi esclarecido.…”