Unraveling the Mechanisms Underlying Irregularities in Inspiratory Rhythm Generation in a Mouse Model of Parkinson's Disease

Abstract

Parkinson's disease (PD) is a neurodegenerative disorder anatomically characterized by a progressive loss of dopaminergic neurons in the substantia nigra compacta (SNpc). Much less known, yet clinically very important, are the detrimental effects on breathing associated with this disease. Consistent with the human pathophysiology, the 6-hydroxydopamine hydrochloride (6-OHDA) rodent model of PD shows reduced respiratory frequency (f R ) and NK1r-immunoreactivity in the pre-Bötzinger complex (preBötC) and PHOX2B 1 neurons in the retrotrapezoid nucleus (RTN). To unravel mechanisms that underlie bradypnea in PD, we employed a transgenic approach to label or stimulate specific neuron populations in various respiratoryrelated brainstem regions. PD mice were characterized by a pronounced decreased number of putatively rhythmically active excitatory neurons in the preBötC and adjacent ventral respiratory column (VRC). Specifically, the number of Dbx1 and Vglut 2 neurons was reduced by 47.6% and 17.3%, respectively. By contrast, inhibitory Vgat 1 neurons in the VRC, as well as neurons in other respiratory-related brainstem regions, showed relatively minimal or no signs of neuronal loss. Consistent with these anatomic observations, optogenetic experiments identified deficits in respiratory function that were specific to manipulations of excitatory (Dbx1/Vglut 2 ) neurons in the preBötC. We conclude that the decreased number of this critical population of respiratory neurons is an important contributor to the development of irregularities in inspiratory rhythm generation in this mouse model of PD.

Respiratory disorders of Parkinson’s disease

“…In addition, optogenetic stimulation of inhibitory neurons present in preBötC was also performed during inspiration and expiration, confirming the absence of the disorders and the effects on the activity of this subpopulation of neurons in the experimental model. During inspiration, fR was increased in both groups but not significantly in the PD model animals (16.1%); and during expiration, the two groups presented reduced fR in similar proportions (126). Thus, the fact that we still have neurons capable of stimulating respiration in this PD experimental model indicates it is possible to study new techniques and therapeutic approaches that, in the future, will help to improve respiratory symptoms and the quality of life of the population with PD.…”

“…After PD induction, a significant reduction in the glutamatergic neurons in the VRG and neurons expressing DBX1 in the preBötC was observed (126) (Figure 3B). However, when evaluating inhibitory neurons (glycinergic and GABAergic) they did not notice differences between the control and experimental groups (126).…”

“…SN dopaminergic neurons degeneration and also neurons that express Phox2b in the RTN, NTSi and NTSc and those that express NK1r in the preBötC and rVRG in Wistar rats and mice that received bilateral injections of 6-OHDA has been demonstrated (50,52,125) (Figure 3B). A recent study by Oliveira et al demonstrated the degeneration of different subpopulations of neurons involved in respiratory activity in PD mice model (126). After PD induction, a significant reduction in the glutamatergic neurons in the VRG and neurons expressing DBX1 in the preBötC was observed (126) (Figure 3B).…”

“…Oliveira et al also promoted selective optogenetic stimulation of different populations of preBötC neurons (126). preBötC glutamatergic neuron stimulation during the inspiration phase promoted a significant reduction in fR in control animals (20.2%) but not in PD model animals (10.1%) (Figure 3E).…”

“…In addition, these same studies performed functional respiratory analyses using whole-body plethysmography, an approach that is capable of analyzing ventilatory activity, providing parameters such as respiratory rate (fR), tidal volume (V T ) and V E , and noted a reduction in fR under basal situations and in response to hypercapnia after 40 days of PD induction, with no ventilatory change under hypoxic conditions (50,52,126) (Figure 3D). Regarding the reduction in basal fR, it is important to emphasize that it occurred mainly during the light phase in which the animals were sleeping (127).…”