Husson, Z. | bioRxiv Science

bioRxiv2018

Electrophysiological characterization and MCH/orexin neuronal distribution in the lateral hypothalamus of naked mole-rats (Heterocephalus glaber)

The lateral hypothalamus (LH) controls various homeostatic processes, including sleep-wake cycles, energy balance and thermoregulation in many mammalian species. In the LH, melanin-concentrating hormone (MCH) and hypocretin/orexin (HO) containing neurons differentially regulate these processes. Naked mole-rats (NMR) (Heterocephalus glaber) are eusocial mammals with remarkable physiological peculiarities including extreme longevity without significant weight gain and absence of thermoregulation. Altered hypothalamic function could potentially underlie the unusual NMR phenotypes, but to date electrophysiological characterization of LH NMR neurons and expression of MCH and HO is missing. Here, we performed whole-cell recordings from LH neurons in acute NMR and mouse brain slices and found that NMR and mouse neuronal basic properties and activities were comparable. Additionally, we showed that both MCH-positive and HO-positive neuronal populations exist in the NMR hypothalamus and although the majority of MCH- and HO-positive neurons are located in the LH, as previously described in rodents, significant differences exist in MCH/HO distribution in other NMR hypothalamic areas. These results indicate that NMR LH neurons are comparable to mouse neurons with respect to their electrophysiological properties, but differences in the neuronal MCH and HO populations in hypothalamic regions exist and may contribute to the adaptive changes seen in NMR homeostatic processes.

neuroscience↗

bioRxiv2018

Naked mole-rat brain neurons have reduced ASIC-mediated currents and are resistant to acid-induced cell death

Regulation of brain pH is a critical homeostatic process and changes in brain pH modulate various ion channels and receptors and thus neuronal excitability. Tissue acidosis, resulting from hypoxia or hypercapnia, can activate various proteins and ion channels, among which acid-sensing ion channels (ASICs) a family of primarily Na+ permeable ion channels, which alongside classical excitotoxicity causes neuronal death. Naked mole-rats (NMRs, Heterocephalus glaber) are long-lived, fossorial, eusocial rodents that display remarkable behavioral/cellular hypoxia and hypercapnia resistance. In the central nervous system, ASIC subunit expression is similar between mouse and NMR with the exception of much lower expression of ASIC4 throughout the NMR brain. However, ASIC function and neuronal sensitivity to sustained acidosis has not been examined in the NMR brain. Here, we show with whole-cell patch-clamp electrophysiology of cultured NMR and mouse cortical and hippocampal neurons that NMR neurons have smaller voltage-gated Na+ channel currents and more hyperpolarized resting membrane potentials. We further demonstrate that acid-mediated currents in NMR neurons are of smaller magnitude than in mouse, and that all currents in both species are fully blocked by the ASIC antagonist benzamil. We further demonstrate that NMR neurons show greater resistance to acid-induced cell death than mouse neurons. In summary, NMR neurons show significant cellular resistance to acidotoxicity compared to mouse neurons, contributing factors likely to be smaller ASIC-mediated currents and reduced NaV activity.\n\nAbbreviationsASIC, acid-sensing ion channel; CNS, central nervous system; DRG, dorsal root ganglion; NaV, voltage-gated Na+ channel; NMR, naked mole-rat; TTX, tetrodotoxin

neuroscience↗