The Complexly Parcellated, Yet Quantitatively Reduced, Orexinergic/Hypocretinergic System of Humans

The phylogenetic contextualization of human neuroanatomy is crucial for understanding the positive, neutral, and/or negative effects of therapeutic interventions derived from animal models. Here we determined the parcellation of, and quantified, orexinergic (or hypocretinergic) neurons in the hypothalami of humans and several species of primates, including strepsirrhines (two species), platyrrhines (two species), cercopithecoids (three species), and hominoids (three species, including humans). The strepsirrhines, platyrrhines, and cercopithecoids presented with three distinct clusters of orexinergic neurons, revealing an organization like that observed in most mammals. In the three hominoids, an additional orexinergic cluster was found in the tuberal region of the hypothalamus, termed the optic tract cluster extension. In humans only, an additional parvocellular cluster of orexinergic neurons was observed in the dorsomedial hypothalamus. The human presented with the most complex parcellation of orexinergic neurons of the primates studied. Total numbers of orexinergic neurons in nonhuman primates were strongly correlated to brain mass (P_uncorr = 1.2 × 10⁻⁶), with every doubling in brain mass leading to an ∼1.5-times increase in neuron number. In contrast, humans have approximately 74,300 orexinergic neurons, which is significantly less than the 205,000 predicted using the nonhuman primate regression for a brain mass of ∼1363 g. We conclude that although the human orexinergic system is the most complex of primates in terms of parcellation, with potential associated functional specializations, this system is quantitatively paradoxical in having a significantly lower neuronal number than expected for a primate with an ∼1363-g brain.