Hypoxia and hypercapnia inhibit hypothalamic orexin neurons in rats

Abstract

Evidence of impaired function of orexin neurons has been found in individuals with cardiorespiratory disorders, such as obstructive sleep apnea (OSA) and sudden infant death syndrome (SIDS), but the mechanisms responsible are unknown. Individuals with OSA and SIDS experience repetitive breathing cessations and/or rebreathing of expired air, resulting in hypoxia/hypercapnia (H/H). In this study, we examined the responses of fluorescently identified rat orexin neurons in the lateral hypothalamus to acute H/H to test if and how these neurons alter their activity and function during this challenge. Experiments were conducted in an in vitro slice preparation using voltage-clamp and current-clamp configurations. H/H (10 min) induced hyperpolarization, accompanied by rapid depression, and finally, cessation of firing activity in orexin neurons. Hypoxia alone had similar but less potent effects. H/H did not alter the frequency of inhibitory glycinergic postsynaptic currents. The frequency of GABAergic currents was diminished but only at 8-10 min of H/H. In contrast, the frequency of excitatory glutamatergic postsynaptic events was diminished as early as 2-4 min of H/H. In the presence of glutamatergic receptor blockers, the inhibitory effects of H/H on the firing activity and membrane potential of orexin neurons persisted but to a lesser extent. In conclusion, both direct alteration of postsynaptic membrane properties and diminished glutamatergic neurotransmission likely contribute to the inhibition of orexin neurons by H/H. These mechanisms could be responsible for the decreased function of orexin in individuals at risk for OSA and SIDS.

Definition and Diagnosis of the Trigeminocardiac Reflex: A Grounded Theory Approach for an Update

“…This phenomenon explains the classic clinical manifestation, described in 1999 by the senior author ( 4 ). It seems that a defect interaction of neurons might play a principal role to be prone to the TCR ( 36 ) as it was already suggested in case of the SIDS ( 37 ).…”

Direct projections from hypothalamic orexin neurons to brainstem cardiac vagal neurons

“…The generation of these transgenic animals in which Cre recombinase and green fluorescent protein are exclusively expressed in hypothalamic orexin neurons has been described previously (Dergacheva et al, 2016). Rats were housed in the George Washington University animal care facility.…”

Hypocretin/orexin modulates body weight and the metabolism of glucose and insulin

“…RTIOX‐276 and TCS‐OX2‐29 are selective antagonists for orexin‐1 and orexin‐2 receptors, respectively. Recent studies have shown that hypoxia and hypercapnia inhibit orexin neurons through conformational changes at the level of the postsynaptic membrane . Hypoxia and hypercapnia‐induced changes cause abnormal membrane depolarization resulting in neural depression and failure to send electrical impulses to effector cells.…”