Abstract
Parkinson’s disease (PD) is a neurodegenerative disorder characterized by hypokinetic motor features; however, patients also display non-motor symptoms like sleep disorders. The standard treatment for PD is dopamine replacement with L-DOPA; however, symptoms including gait deficits and sleep disorders are unresponsive to L-DOPA. Notably, these symptoms have been linked to aberrant activity in the pedunculopontine nucleus (PPN). Of late, clinical trials involving PPN deep brain stimulation (DBS) have been employed to alleviate gait deficits. Although preclinical evidence implicating PPN cholinergic neurons in gait dysfunction was initially promising, DBS trials fell short of expected outcomes. One reason for the failure of DBS may be that the PPN is a heterogenous nucleus that consists of GABAergic, cholinergic, and glutamatergic neurons that project to a diverse array of brain structures. Second, DBS trials may have been unsuccessful because PPN neurons are susceptible to mitochondrial dysfunction, Lewy body pathology, and degeneration in PD. Therefore, pharmaceutical or gene-therapy strategies targeting specific PPN neuronal populations or projections could better alleviate intractable PD symptoms. Unfortunately, how PPN neuronal populations and their respective projections influence PD motor and non-motor symptoms remains enigmatic. Herein, we discuss normal cellular and neuroanatomical features of the PPN, the differential susceptibility of PPN neurons to PD-related insults, and we give an overview of literature suggesting a role for PPN neurons in motor and sleep deficits in PD. Finally, we identify future approaches directed towards the PPN for the treatment of PD motor and sleep symptoms.
Highlights
The pedunculopontine nucleus (PPN) is functionally divided into two components, a rostral portion containing GABAergic, glutamatergic, and sparse cholinergic neurons sending projections primarily to motor structures including the substantia nigra and thalamus, and a caudal portion consisting mainly of cholinergic and glutamatergic neurons projecting to structures involved in reward such as the nucleus accumbens (Dautan et al, 2016; Xiao et al, 2016)
Visual Sensorimotor Integration/ Oscillopsia resulting from PPNDBS Motor Symptoms LDOPA-induced dyskinesia L-DOPA-induced Dyskinesia REM Sleep Behavior Disorder Postural Instability (Bohnen et al, 2009; Hallanger et al, 1987; Bohnen and Albin, 2011; Brazhnik et al, 2016; Bohnen et al, 2019; Kezunovic et al, 2011; Steriade et al, 1990; Mena-Segovia et al, 2008) (Nandi et al, 2002; Zhang et al, 2012) (Garcia-Rill et al, 1987; Garcia-Rill and Skinner, 1988; Roseberry et al, 2016; Josset et al, 2018) (Redgrave et al, 1987; Wallace and Fredens, 1988; Okada and Kobayashi, 2009)
To develop effective PPN-centered treatment strategies, there is a need for cellspecific manipulations in the PPN
Summary
Molecular, and Neuroanatomical Properties of Pedunculopontine Tegmental NucleusThe pedunculopontine tegmental nucleus (PPN), a heterogeneous brainstem structure, consists of glutamatergic, cholinergic, GABAergic, and glycinergic neurons (Mineff et al, 1998; Wang and Morales, 2009; Pienaar and van de Berg, 2013), which co-express neuropeptides including nitric oxide, substance P, atriopeptin, NADPH diaphorase, calcium binding proteins, and corticotropin-releasing factorPPN Degeneration Contributes to PD (Vincent et al, 1983; Standaert et al, 1986; Austin et al, 1995; Martinez-Gonzalez et al, 2012; D’Onofrio et al, 2015). Research shows that the PPN and cuneiform nucleus make up the mesencephalic locomotor region (MLR), a functional neurocircuit modulating movement, rhythm, and speed upon electrical stimulation (Garcia-Rill et al, 1987; Garcia-Rill and Skinner, 1988; see Figure 1A for PPN projections related to PD motor symptoms). Both PPN glutamatergic and cholinergic neurons may exert effects through LGPi efferents, recent data from preclinical models show that these neurons play different roles in locomotion.
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
