Genetic interrogation of central circuit regulating blood pressure

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Nearly two-thirds of the UK population is now overweight or obese. This leads to a multitude of related diseases, including high blood pressure, which can increase the chances of suffering a heart attack or stroke. The costs of obesity and its related diseases also put extreme pressure on the NHS.There is a direct relationship between body weight and blood pressure. Thus, the higher your weight the more likely you will suffer from high blood pressure. However, currently, it is unknown what the major factors are which lead to this direct relationship. One suggestion is that obese people produce a lot of a hormone, called leptin, which normally acts on the brain to try and moderate increasing weight. However, in doing this, leptin may also indirectly cause increased blood pressure. We wish to understand where in the brain leptin can have this effect, as we have done previously to show where leptin acts to affect body weight. For example, leptin can increase the number of calories we burn by activating nerve cells (neurones) which lie in a tiny region of the brain called the dorsomedial nucleus of the hypothalamus (or DMH). These neurones contain a messenger called PrRP.We now have evidence from humans for links between PrRP and its receptor, and with obesity. A number of obese patients have been identified who have mutations in the gene that encodes for the PrRP receptor. Interestingly, these patients have lower than expected blood pressure. Furthermore, we have shown that mice that have mutations in their PrRP receptor also have low blood pressure. So, could PrRP neurones in the DMH respond to leptin in obese patients and be responsible for their high blood pressure? To start with we will generate mice that have the same mutations as found in humans, so that we can study the functioning of this gene in an experimental animal. Then we can study the complex circuits in the brain to determine how leptin and PrRP have their effects. We are able to study the extremely complex network of neurones in the brain because we can see the different types, such as the PrRP neurones, in mice because they have been made to shine with fluorescent light. We can record the activity of these neurones while stimulating the other cells that connect with them - all in a petri dish! However, what is also very new is that we can stimulate specific types of neurone in mice while they are behaving perfectly normally. This can be done by either giving the mice an injection of a "designer drug" or by shining light into the mouse's brain using an optic fibre. We can also inhibit the activity of the same neurones and see how the mice respond to us experimentally lowering their blood pressure. By doing this, we can see whether mice without functioning PrRP neurones find it more difficult to counteract low blood pressure when compared with normal mice. This will allow us to study the role of PrRP in the healthy control of blood pressure, as well as the consequences of mutations in both mice and humans. Importantly, it will help us determine how obesity is linked with high blood pressure, which potentially could lead to tailored therapies for obese patients.