Connexin 26-mediated breathing control by the healthy and obese brain

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Humans produce about 1 kg of CO2 every day. CO2 dissolves in blood and will cause fatal changes in blood acidity unless its levels are precisely controlled. CO2-sensitive cells, present in the brain, control the depth of breathing to precisely regulate the level of CO2 in the blood and body.Many human illnesses seriously affect to regulate breathing in response to levels of CO2. One of these conditions is obesity. 40% of obese patients have Obesity Hypoventilation Syndrome. These patients cannot breathe deeply enough to expel sufficient CO2, and have impaired CO2-sensitive regulation of breathing. Their blood is therefore more acidic, they feel sleepy, drowsy during daytime, exhaust easily and they have impaired sleep patterns, which result in reduced ability to work, a vicious cycle. Other human conditions, for example Chiari Syndrome, which affects around 1% of people in middle age, leads to severe debilitating problems, ranging from headaches to inabilities to swallow, sleep and breathe, patients suffer from apneas, shallow and irregular breathing during sleep at night. We have recently discovered key cells responsible for sensing of CO2 on the brain's surface, which sheds unexpected new light onto the fundamental question how everybody's brain senses CO2 and provides new avenues to understand the medical conditions mentioned above. An essential molecule inside these cells, a membrane channel called Connexin26, helps these cells to sense CO2 levels. When only a small group of specific cells, no more than 25, are made to lose the Connexin26 gene by a novel genetic method, the ability of the body to regulate breathing in response to higher CO2 levels (comparable to the CO2 levels inside someone's breath) is reduced by 40%. These 25 critical cells develop around puberty in rodents, are retained into late middle age and then lost in old age, thus act in a specific time window during life.Connexin 26 is also active in other cells around the brainstem, however their function in relation to breathing is unknown. We propose to inactivate this gene in further specific groups of cells in transgenic rodents to test whether and how these cells regulate the sensitivity of breathing to CO2. We have discovered that these CO2-sensing cells carry receptors for an important pathway that controls body weight (the leptin pathway). In obese patients, the leptin pathway is impaired. This means that we may have found a missing link between the mechanisms underlying obesity, and the defective regulation of breathing in these patients: the CO2-sensing cells may not be able to sense CO2 well enough as a consequence of impaired leptin signalling. As we can now observe and characterize the properties of these very important cells in animals directly, we can ask whether obesity, induced by high fat/calorie diet during young age, affects the development and properties of these critical CO2-sensory cells. We propose to test further this hypothesis experimentally by altering leptin signalling specifically in the CO2-sensing cells that we have discovered, to see whether we can recapitulate the human Obesity Hypoventilation Syndrome in rodents. With such animal model one can develop and test new drugs that help patients breathe. Our work bears the promise of great relevance to humans. Do those important sensor cells die if we eat too much sugar during adolescence? How are they affected, is that permanent? Can it be reversed by diet or medicines? Which genes do they turn on? If we know how these essential CO2 sensory cells are affected by diet, we can be much more precise on recommending the right types of food to be eaten during adolescence and puberty in humans. Breathing is essential for all we do, whether we are awake or sleep and obesity is a growing global health epidemic. By linking developmental genetics and physiology this project promises to provide long-term benefit to the physical and mental well-being of the wider community.