Dichotomous cellular properties of mouse orexin/hypocretin neurons

Non-technical summary Orexin/hypocretin neurons are widely projecting, 'multi-tasking' brain cells that promote alertness, reward seeking and feeding. They are vital for stable consciousness in higher mammals. Loss of orexin/hypocretin cells produces narcolepsy. It was originally assumed that orexin/hypocretin neurons are one uniform population of cells, but recent studies hinted that they may be split into subsystems. To explore this, we performed unbiased statistical analysis of electrical properties of orexin/hypocretin cells in combination with 3-D analysis of their shape. Our results pointed to an existence of two subgroups of orexin/hypocretin neurons, that have unique 'electrical fingerprints' and distinct ways of receiving information from other neurons.Hypothalamic hypocretin/orexin (Hcrt/Orx) neurons recently emerged as critical regulators of sleep-wake cycles, reward seeking and body energy balance. However, at the level of cellular and network properties, it remains unclear whether Hcrt/Orx neurons are one homogeneous population, or whether there are several distinct types of Hcrt/Orx cells. Here, we collated diverse structural and functional information about individual Hcrt/Orx neurons in mouse brain slices, by combining patch-clamp analysis of spike firing, membrane currents and synaptic inputs with confocal imaging of cell shape and subsequent 3-dimensional Sholl analysis of dendritic architecture. Statistical cluster analysis of intrinsic firing properties revealed that Hcrt/Orx neurons fall into two distinct types. These two cell types also differ in the complexity of their dendritic arbour, the strength of AMPA and GABA(A) receptor-mediated synaptic drive that they receive, and the density of low-threshold, 4-aminopyridine-sensitive, transient K+ current. Our results provide quantitative evidence that, at the cellular level, the mouse Hcrt/Orx system is composed of two classes of neurons with different firing properties, morphologies and synaptic input organization.