The pedunculopontine nucleus (PPN) is a rostral brainstem structure that has extensive connections with basal ganglia nuclei and the thalamus. Through these the PPN contributes to neural circuits that effect cortical and hippocampal activity. The PPN also has descending connections to nuclei of the pontine and medullary reticular formations, deep cerebellar nuclei, and the spinal cord. Interest in the PPN has increased dramatically since it was first suggested to be a novel target for treating patients with Parkinson's disease who are refractory to medication. However, application of frequency-specific electrical stimulation of the PPN has produced inconsistent results. A central reason for this is that the PPN is not a heterogeneous structure. In this article, we review current knowledge of the neurochemical identity and topographical distribution of neurons within the PPN of both humans and experimental animals, focusing on studies that used neuronally selective targeting strategies to ascertain how the neurochemical heterogeneity of the PPN relates to its diverse functions in relation to movement and cognitive processes. If the therapeutic potential of the PPN is to be realized, it is critical to understand the complex structure-function relationships that exist here.

Diabetes increases the risk of Alzheimer’s disease (AD), and mitochondrial dysfunction is implicated in both diseases, however the impact of both diabetes and AD on brain mitochondria is not known. We measured mitochondrial DNA (mtDNA), an indicator of mitochondrial function, in frontal, parietal, and cerebellar regions of post-mortem human brains (n = 74) from non-cognitively impaired controls (NCI), mild-cognitively impaired (MCI) and AD cases. In a subset of parietal cortices, we measured mRNAs corresponding to cell types and mitochondrial function and semi-automated stereological assessment was performed on immune-staining of parietal cortex sections. mtDNA showed significant regional variation, highest in parietal cortex, and lowest in cerebellum. Irrespective of cognitive status, all brain regions had significantly higher mtDNA in diabetic cases. In the absence of diabetes, AD parietal cortices had decreased mtDNA, reduced MAP2 (neuronal) and increased GFAP (astrocyte) mRNA, relative to NCI. However, in the presence of diabetes, we did not observe these AD-related changes, suggesting that the pathology observed in diabetic AD may be different to that seen in non-diabetic AD. The lack of clear functional changes in mitochondrial parameters in diabetic AD suggest different cellular mechanisms contributing to cognitive impairment in diabetes which remain to be fully understood.

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