An integrated view of the pedunculopontine nucleus: Anatomy, physiology, and its multifaceted role in Parkinson's disease pathogenesis and neuromodulation therapy.

The pedunculopontine nucleus (PPN) is a heterogeneous cluster within the dorsolateral pontomesencephalic tegmentum, functioning as a critical neuromodulatory hub. A key organizing principle is its rostrocaudal functional gradient rostral glutamatergic Chx10 + neurons mediate global motor arrest, while caudal Vglut2 + neurons drive locomotor initiation and maintenance. This model, emphasizing topographically organized microcircuits, provides a coherent framework for reconciling heterogeneous outcomes of PPN stimulation across experimental and clinical settings. This review comprehensively analyzes the PPN's anatomical organization, neuronal composition, and connectivity, which collectively support its roles in locomotion, arousal, and reward processing. Particular focus is placed on its pathophysiological alterations in Parkinson's disease (PD), wherein selective degeneration of caudal cholinergic and Vglut2 + neurons contributes to treatment-resistant axial symptoms. The nucleus exhibits considerable neurochemical heterogeneity, encompassing cholinergic, glutamatergic, and GABAergic populations; this diversity underpins its broad functional roles and selective vulnerability in PD, with distinct implications for disease subtypes. We further examine disease-associated shifts in oscillatory activity, highlighting abnormal dynamics characteristic of the parkinsonian state. The therapeutic promise of PPN deep brain stimulation for alleviating gait freezing and falls in advanced PD is critically assessed, acknowledging challenges related to target localization, stimulation parameters, and patient selection. By integrating neuroanatomical, electrophysiological, and clinical evidence, this review offers a unified perspective on the PPN's central importance in PD pathophysiology and its growing relevance as a neuromodulation target.