Kubin Laboratory – Research Overview

Upper Airway Hypotonia

Kubin Lab figure 1In individuals with anatomically predisposed upper airways (small size, often associated with fat deposits around the airway walls), hypoventilations and obstructive apneas occur repeatedly during sleep. They are caused by the characteristic of sleep hypotonia of upper airway muscles.

Sleep-related decrements in activity of upper airway muscles are caused by distinct neurochemical changes upstream from upper airway motor neurons. Our research indicates that these changes are mainly caused by a withdrawal of excitation mediated by norepinephrine and serotonin.

This mechanism operates during all sleep stages. Notably, obstructive episodes are often most severe during Rapid Eye Movement (REM) stage of sleep.

During REM sleep withdrawal from motor neurons of the excitation mediated by norepinephrine and serotonin may be reinforced by active inhibition mediated by neurotransmitters such as gamma-amino butyric acid (GABA), glycine and acetylcholine.

Carbachol Models of REM Sleep

Due to the complex nature of REM sleep, most functional studies need to be performed in vivo. We use chronically instrumented rats in which we can monitor and probe the natural neural mechanisms specific for this behavioral state.

In addition, in order to overcome some of the limitations of the studies in naturally sleeping animals, we have developed and extensively used reduced models of REM sleep.

In particular, in anesthetized rats, we can pharmacologically activate distinct pathways responsible for the generation and maintenance of REM sleep and investigate REM sleep-related changes in the control of breathing and upper airway motoneurons.

Neurochemistry of XII Motoneurons

Kubin Lab figure 2We have extensively used reverse transcription-polymerase chain reaction, neural track tracing, and immunohisto-chemistry to determine which neurotransmitters and neurotransmitter receptors control the output from the central sleep and respiratory networks.

Intermittent Hypoxia

Kubin Lab figure 3In obstructive sleep apnea (OSA), there is a strong association between the severity of the disorder and other cardiorespiratory and metabolic conditions such as insulin resistance, hyperlipidemia, arterial hypertension and stroke.

Sleep deprivation, sleep fragmentation, recurrent nocturnal episodes of mechanical occlusion of the upper airway and recurrent episodes of hypoxemia may all contribute to these different dysregulations in OSA patients.

We investigate whether normal adult rodents exposed for many days to cyclic variations of ambient oxygen in a manner that mimics recurrent hypoxic episodes in OSA patients (chronic-intermittent hypoxia, or IH) have altered central and/or peripheral mechanisms relevant for the of upper airway muscle tone and/or glucose metabolism.

Sensitivity, or Availability, of GABAA Receptors

Kubin Lab Figure 4Through a truly ingenoius analysis of brain lesions in patients with the Encephalitis lethargica, von Economo concluded that the anterior hypothalamus contains neurons that actively induce sleep, whereas cells important for the maintenance of wakefulness are located in the posterior hypothalamus [von Economo, J. Nerv. Ment. Dis., 71:249-259, 1930].

Following up on these and related findings, we found that the sensitivity, or availability, of GABAA receptors in certain wake-related cells of the posterior hypothalamus may gradually increase with the duration of wakefulness, and then decrease during sleep (Volgin et al., PLoS ONE 9(1): e86545, 2014).

Such a state-, or activity-, dependent plasticity of posterior hypothalamic GABAA receptors may represent an important neurochemical substrate of the brain's "sleepiness signal." Identification of the mechanisms one of the fundamental questions in the science of sleep and is highly relevant to OSA, where excessive daytime sleepiness is a major problem.