Correlation between neuroanatomical and functional respiratory changes observed in an experimental model of Parkinson's disease

Abstract

We showed previously that 60 days after the induction of Parkinson's disease (PD) in a rat model, there are decreases in baseline breathing and in the number of phox2b-expressing neurons of the retrotrapezoid nucleus (RTN) and nucleus of the solitary tract (NTS), as well as a reduction in the density of the neurokinin-1 receptor (NK1r) in the pre-Bötzinger complex (preBötC) and rostral ventrolateral respiratory group (rVRG). Here, our aim was to evaluate the correlation between neuroanatomical and functional respiratory changes in an experimental model of PD. Male Wistar rats with bilateral injections of 6-hydroxydopamine (6-OHDA, 24 μg μl ) or vehicle into the striatum had respiratory parameters assessed by whole-body plethysmography 1 day before and 30, 40 or 60 days after the ablation. From the 30th day after the ablation, we observed a reduction in the number of phox2b neurons in the RTN and NTS and a reduction in the density of astrocytes in the rVRG. At 40 days after the ablation, we observed decreases in the density of NK1r in the preBötC and rVRG and of astrocytes in the RTN region. At 60 days, we observed a reduction in the density of astrocytes in the NTS and preBötC regions. The functional data showed changes in the resting and hypercapnia-induced respiratory rates and tidal volume from days 40-60 after injury. Our data suggest that the neuroanatomical changes impair respiratory activity and are presumably a major cause of the respiratory problems observed in PD.

Peripheral and central respiratory system pathology in a mouse model of Parkinson's disease: A prodromal signature of clinical relevance?

“…() demonstrate peripheral and central respiratory system pathology in a mouse model of PD revealing aberrant respiratory control and mechanics, outcomes that emerge early in disease progression, before the appearance of overt motor behaviour deficits. The reduction in neurokinin‐1 receptor density in the rhythm‐generating pre‐Bӧtzinger complex is consistent with previous observations by this group in a rat model of PD (Fernandes‐Junior, Carvalho, Moreira, & Takakura, ). The mechanism driving site‐specific remodelling of this crucial microcircuit within the rostrocaudal column of the ventral respiratory group is unclear but will be important to determine.…”

“…The relevance of the findings in PD rodent models (Fernandes‐Junior et al., ; Oliveira et al., ) is that respiratory phenotypes are described in persons with PD, including evidence of respiratory insufficiency in the early stages of disease and observations that CO 2 chemosensitivity is impaired with preserved hypoxic chemosensitivity. There are also reports to the contrary, however, which might relate to considerable heterogeneity in the disease.…”

“…The mechanism driving site‐specific remodelling of this crucial microcircuit within the rostrocaudal column of the ventral respiratory group is unclear but will be important to determine. The resting bradypnoea in PD animals is evident at 10 days in mice, emerging later, between 30 and 40 days, in rats (Fernandes‐Junior et al., ). Somewhat puzzling is the observation that PD mice retain the capacity to increase respiratory frequency considerably during intense hypoxic stimulation, illustrating that the circuitry required to achieve high respiratory rates remains functionally intact, but bradypnoea prevails at rest and during hypercapnic stress.…”

Respiratory disturbances in a mouse model of Parkinson's disease

“…This region is composed of glutamatergic neurons (that do not express tyrosine hydroxylase and choline acetyltransferase) that express the transcription factor Phox2b (Guyenet & Bayliss, 2015;Ruffault et al, 2015;Silva, Tanabe, Moreira, & Takakura, 2016;Takakura et al, 2006Takakura et al, , 2014. In rat models of PD, the impaired respiratory hypercapnic response observed also showed a strong correlation with the reduction of Phox2b + neurons in the RTN (Fernandes-Junior, Carvalho, Moreira, & Takakura, 2018).…”

Brainstem network pathology and impaired respiratory drive as successive signatures in a rat model of Parkinson's disease

“…In this issue of Experimental Physiology , Fernandes‐Junior, Carvalho, Moreira, & Takakura () describe studies using an established experimental model of PD, which aimed to determine the temporal relationship between neuroanatomical changes in the brainstem and functional alterations in breathing. Adult male rats received bilateral injections of 6‐hydroxydopamine (6‐OHDA; a selective neurotoxin) or vehicle (control) into the caudate putamen of the striatum, which was confirmed after 30 days to produce >70% persistent loss of tyrosine hydroxylase‐expressing neurons of the substantia nigra pars compacta of the midbrain.…”