Cholinergic neurons in the pedunculopontine tegmental nucleus modulate breathing in rats by direct projections to the retrotrapezoid nucleus

Abstract

Key points Cholinergic projections from the pedunculopontine tegmental nucleus (PPTg) to the retrotrapezoid nucleus (RTN) are considered to be important for sleep–wake state‐dependent control of breathing. The RTN also receives cholinergic input from the postinspiratory complex. Stimulation of the PPTg increases respiratory output under control conditions but not when muscarinic receptors in the RTN are blocked. The data obtained in the present study support the possibility that arousal‐dependent modulation of breathing involves recruitment of cholinergic projections from the PPTg to the RTN. Abstract The pedunculopontine tegmental nucleus (PPTg) in the mesopontine region has important physiological functions, including breathing control. The PPTg contains a variety of cell types, including cholinergic neurons that project to the rostral aspect of the ventrolateral medulla. In addition, cholinergic signalling in the retrotrapezoid nucleus (RTN), a region that contains neurons that regulate breathing in response to changes in CO2/H+, has been shown to activate chemosensitive neurons and increase inspiratory activity. The present study aimed to identify the source of cholinergic input to the RTN and determine whether cholinergic signalling in this region influences baseline breathing or the ventilatory response to CO2 in conscious male Wistar rats. Retrograde tracer Fluoro‐Gold injected into the RTN labelled a subset of cholinergic PPTg neurons that presumably project directly to the chemosensitive region of the RTN. In unrestrained awake rats, unilateral injection of the glutamate (10 mm/100 nL) in the PPTg decreased tidal volume (VT) but otherwise increased respiratory rate (fR) and net respiratory output as indicated by an increase in ventilation (VE). All respiratory responses elicited by PPTg stimulation were blunted by prior injection of methyl‐atropine (5 mm/50–75 nL) into the RTN. These results show that stimulation of the PPTg can increase respiratory activity in part by cholinergic activation of chemosensitive elements of the RTN. Based on previous evidence that cholinergic PPTg projections may simultaneously activate expiratory output from the pFRG, we speculate that cholinergic signalling at the level of RTN region could also be involved in breathing regulation.

Pharmacological and Non-pharmacological Treatments of Sleep Disorders in Parkinson's Disease

“…Although PPN-DBS is primarily used to improve gait freezing and postural instability in PD and primary progressive freezing of gait (PPFG), it also shows a modulation effect on some non-motor functions, including REM sleep, mood, attention, arousal, sleep-wake cycle and cognition [ 164 - 167 ]. Recent studies have demonstrated PPN is involved in sleep–wake state-dependent central breathing regulation through cholinergic projections to the retrotrapezoid nucleus, which indicates PPN as a potential target for improving SDB in PD patients [ 168 , 169 ]. However, there are also some studies that suggest PPN-DBS may contribute to REM sleep atonia and aggravate RBD in PD patients [ 165 ].…”

Mapping of the excitatory, inhibitory, and modulatory afferent projections to the anatomically defined active expiratory oscillator in adult male rats

“…Cholinergic neurons in the pedunculopontine tegmental nucleus (PPT), which project widely throughout the reticular formation (RF), and show state‐dependent activity were hypothesized as a likely source for the recruitment of active expiration in REM sleep (Jones, 1990; Topchiy, Waxman, Radulovacki, & Carley, 2010; Woolf, 1991; Woolf & Butcher, 1989; Yeomans, 2012). However, recent tracing studies aiming to identify a further rostral location in the pF L area failed to show any connection between the pF L and PPT (Lima et al, 2019; Silva, Oliveira, Souza, Moreira, & Takakura, 2019).…”

Hypoxic and Hypercapnic Responses in Transgenic Murine Model of Alzheimer’s Disease Overexpressing Human AβPP: The Effects of Pretreatment with Memantine and Rivastigmine

“…The cholinergic system is involved in respiratory control, including central chemosensitivity, state-dependent modulation of breathing, and respiratory motor output [ 34 , 35 , 36 , 37 ]. The retrotrapezoid nucleus (RTN) contributing to chemical respiratory drive (CO 2 /H + ) [ 38 ] receives cholinergic input from the post-inspiratory complex (PiCO) and pedunculopontine tegmental nucleus (PPTg), and stimulation of PPTg has been shown to increase respiratory activity, in part, by cholinergic activation of chemosensitive RTN [ 36 ]. In addition, cholinergic innervation is also present in the parafacial respiratory group (pFRG) where muscarinic transmission contributes to neuronal excitation and promotes recruitment of abdominal muscles and active expiratory flow [ 35 ].…”