Role of Paraventricular NK1 Receptor Expressing Spinally-Projecting Neurons in Cardiovascular Control

Lay Summary

How The Head Rules the Heart
Although the heart beats in the absence of any conscious effort, the entire cardiovascular system is controlled by the brain. Sit and relax; your heart rate will come down. Worry, or even just think seriously about exercise and your heart rate will increase in advance of you actually moving. This is the same for other species too. We have recorded the heart rates of horses as they move into the stalls and their heart rate rises to somewhere near maximum before they actually run the first metre. This is often called the "fight or flight" reaction; a term first coined by Walter Cannon about 100yrs ago. In healthy animals, such "higher control" allows for anticipation of cardiovascular demand and is a good thing, since an animal that can anticipate an increased oxygen demand is at an evolutionary advantage. For example, it allows animals to escape predators more efficiently than if they only increase cardiac output just *after* they started running or fighting. An athlete that could not increase heart rate prior to a race would almost certainly loose to one who could. However inappropriate or excessive excitation of the cardiovascular system by emotional stress, shock or other stimulus can have disastrous consequences. In the case of people sudden emergency situations can cause people to die from a cardiovascular incident; a phenomenon using the same neurological pathways as the healthy fight or flight reaction. The same occurs with animals, for example there is an increase in dogs dying from "fright" over the firework period.
Similar brain circuitry to that controlling these stress responses is also involved with blood pressure control in a variety of other situations to. Eg, in humans with malfunctioning cardiovascular control neurons, drinking half a litre of water can push up blood pressure by 100mmHg, most elderly people suffer from this phenomenon, to some degree. Whilst experiments over the past century have shown that this level of cardiovascular control involves the hypothalamus the exact neurons responsible are not known. Our laboratory and others have identified a particular group of neurons that may be responsible. Another famous American physiologist, Loewy, once referred to these as the "central command neurons" of the stress response. The full picture turns out to be much more complex and even the idea that these neurons are involved with the stress response has become controversial. The neurons unarguably modulate the cardiovascular system and kidney, but we do not know whether they contribute to cardiovascular stress responses in only some situations, but not others or whether they exclusively play a roll in more subtle, but equally important aspects of cardiovascular control, such as regulation of the volume or electrolyte content of blood. This is particularly interesting, because these aspects of cardiovascular control are known to fail in many older people and contribute to cardiovascular disease. Data also suggests that these neurons also contribute to the daily "circadian" cycle of blood pressure that is seen in humans and other species, where blood pressure increases as we wake and drops (sometimes dangerously) when we sleep. Perhaps these neurons are "polymodal", ie, mediating subtle regulation of the cardiovascular system in response to a wide range of environmental and emotional stimuli. This project will therefore use a range of experimental approaches to investigate the role of a particular subset of these control neurons. Our group has an almost unique combination of skills and experience to enable us to answer these specific questions about the function of these fascinating neurons in animals. Understanding this is not just biologically fascinating, but may pave the way for future development of drugs that can prevent sudden excessive elevations of blood pressure in elderly people and ageing domestic animals.

Several layers of hierarchical control regulate the animal cardiovascular system. One of the highest lies in the hypothalamic area of the forebrain. This is conserved between mammals and allows them to adapt to dynamic environmental changes with sophisticated patterns of behavioural response. Elements of this control become deregulated during ageing and contribute to metabolic and cardiovascular disease, but the fundamental biology of this system is not well understood. The hypothalamus itself is a complex structure, consisting of several "areas", nuclei and sub-nuclei. One of these nuclei is the paraventricular nucleus (PVN). The PVN contains a "parvocellular" sub-nucleus that, in turn, contains a population of neurons that project directly to sympathetic control "centres" of the spinal cord and modulate heart rate (HR), blood pressure (BP) and kidney. Despite detailed knowledge of their anatomical connections, there is no consensus as to their specific role in autonomic control. Theories include mediation of the cardiovascular adaptation to stress, temperature, control of plasma osmolality, blood volume or circadian cycle. We have shown that some of these neurons are controlled by substance P (SP) and will use integrative methodology to determine their contribution to cardiovascular control. We will lesion PVN neurons with saporin-SP conjugate and measure changes in response to different stress stimuli and control of blood volume, body temperature and diurnal cardiovascular rhythm. Our published retrograde labelling methodology will allow us to determine if the in vitro mechanisms of osmotic and temperature sensing in PVN neurons (already established in our labs) occur specifically in identified pre-autonomic neurons. These experiments will advance our knowledge of a core homeostatic control centre in mammals and inform a range of biological problems, such as stress response in animals and cardiovascular diseases associated with ageing.

Impact on Biology of Ageing: As the UK population ages, cardiovascular disease is an ever-increasing socioeconomic problem. For example, 79% of the over 70's suffer from high blood pressure, either treated or otherwise (Source: European Cardiovascular Disease Statistics. European Heart Network, Brussels, European Society of Cardiology, 2012). There are 181,000 deaths per year from cardiovascular disease; this corresponds to 32% of total deaths. For the UK's over 75s the figure rises to 37% of total annual deaths arising from cardiovascular disease (Source: WHO Global Mortality Database). The morbidity and economic impact are also immense with cardiovascular diseases being the largest cause of "Disability-adjusted life years" (DALYs) lost per year in Europe; 23% of the total days lost (source: World Health Organization (2004) The World Health Report 2004. WHO: Geneva). £9bn/yr is spent attempting to treat cardiovascular disease. Naturally there is and has been a considerable amount of research input to developing the improving treatments, but there are still areas of the fundamental biology of cardiovascular control which are not understood. Treatments currently focus on the peripheral effector organs (heart, blood vessels and kidney), but in the future, direct intervention with the CNS is a realistic possibility. It is well known that atherosclerosis is a contributor to coronary heart disease, but frequently overlooked data also shows that there are changes in the CNS cardiovascular control activity of older people too. This project will address the biology of an important component of CNS autonomic control in animals and our data will prove invaluable for those conducting autonomic control research, including cardiovascular disease in the elderly. Our laboratory has the necessary tools and models to make a significant contribution to our understanding of CNS cardiovascular control and to investigate, in the future, how this changes with age.
Impact on BBSRC Strategic Skills training: Our particular strength is our ability to study this system from the level of individual cellular proteins (ion channels and membrane receptors) through mathematical models of cellular function right through to whole-animal telemetric recording. This integrative approach is an important goal of the BBSRC and the PI has previously trained several young researchers in these skills and gained a BBSRC Strategic Skills Award as a part of this continued training program. The PI has also participated in the renowned Manchester /Liverpool Universities Centre for Integrative Mammalian Biology (IMB), supervised several Integrative students and he lectures on the post-graduate Integrative Mammalian Biology programme. This project will not only train a further young PDRA to a very high level, it is intended also to facilitate the training of further "IMB" students and at the conclusion it is hoped that the PDRA will be able to gain independence and further seed the IMB approach.
Dissemination: Our early findings will be disseminated at international conferences and by continued publication in high impact international journals. Costings for important travel to international conferences is included.
Outreach and Public Engagement: The University of Liverpool IACD is a committed participant in Public Engagement and Outreach with proven track record, and the PI is currently the academic lead. Events include hosting a major Science Festival (Meet the Scientists) last year and regular visits to and from local schools. The PI has placed about 5 CREST award school children within the Faculty over the past year. The PDRA, along with other members of IACD will be encouraged to gain STEM ambassador status and participate in organisation of events. The PI is an invited speaker at the public Edinburgh Science Festival (April 2015) debate on Drugs to Treat Ageing by the Physiological and British Pharmacological Societies.