Chronic pain after nerve damage or inflammatory arthritis is a debilitating condition in which the pain experience persists for long time. Pain is a persistent symptom following injury to nerve or in rheumatoid arthritis (RA) whereby pain remains even after suppression of joint disease with medicines. Chronic pain is difficult to treat, with current drugs being relatively ineffective and often having significant side effects. Therefore, a better understanding of the mechanisms responsible for persistence of pain can bring new ideas on how to prevent or attenuate chronic pain and facilitate the development of new medicines. We use mice in our studies as they also demonstrate pain-related behaviour in their hind paws that persists for several weeks in models of joint arthritis and peripheral neuropathy (PN). Pain is a sign of both RA and PN, where blood cells enter the joint and the injured nerve and produce factors that activate pain nerves: these nerves carry pain signals from the joint or injured nerve to the spinal cord on their way to the brain where pain is felt. We discovered that blood-derived cells are not only in the joint or the injured nerve, but they are also around pain cells outside the joint and injured nerve in a structure that is called dorsal root ganglia (DRG). At this DRG site, far away from the swollen joint and injured nerve, blood-derived cell influence pain nerves and favour pain sensation. In these blood-derived cells we have identified new targets that can be exploited to regulate pain activity and may constitute novel approaches to treating persistent pain. These new targets are small strands of genetic material, produced in the pain cells of the DRG and packaged in small microstructures. Pain cells handover these particles to blood-derived cells to regulate their activity by increasing production of chemicals that increase pain sensitivity. We have identified a new way to target this genetic material within blood-derived cells. In this project, we will use a variety of methods to assess the activity of blood-derived cells in animal models of pain, and determine the effects of this activity on the nerve cells that carry pain signals. We will then measure readouts of pain when specific activity in blood-derived cells has been either blocked. This study will allow us to determine the therapeutic potential of targets in blood-derived cells for the treatment of persistent pain: both chronic pain after nerve damage or inflammatory arthritis will be studied. The ultimate aim of our research is to provide new information that will help in the design of novel pain-relieving medicines, thus allowing chronic pain treatments to be more effective to ultimately improve the quality of life of patients.

Plasticity of nerve cell activity is important for normal brain function. In brain areas that are involved in sensation, including vision, this plasticity includes a process called sensory adaptation. The purpose of the proposed research is to understand how sensory adaptation is affected by neurodegenerative diseases, like Alzheimer's Disease, that are known to affect plasticity in other brain areas that are involved in learning and memory. In humans and animals adaptation normally changes how the world looks - for example, looking out of a moving train's window for a long time causes the world to appear to 'move backwards' when the train stops. This change in how the world looks is due to the effects of adaptation on activity in visual areas of the cerebral cortex, which occur automatically during prolonged exposure to visual scenes. In exciting preliminary experiments we have recently discovered that similar forms of adaptation are impaired in the visual cortex of rodents in the early stages of neurodegeneration. In this project we will use these simple visual tests to understand how degeneration affects the signals of nerve cells in the visual cortex of a rodent model of dementia. We will test the hypothesis that neurodegeneration has a specific impact on the normal processes of adaptation. We will establish 1) how the signals provided by the visual cortex are modified by neurodegeneration, 2) how degeneration affects the plasticity of those signals, and 3) if sensory adaptation may therefore provide a sensitive and early indicator of neurodegeneration. The final outcome will shed light on how degeneration affects nerve cell circuits in the cerebral cortex, in a system likely common to all animals. The project is important, because sensory adaptation can be measured non-invasively in humans as well as other animals, and the mechanisms that provide adaptation are conserved across species and are well understood. As well as providing fundamental knowledge about how neurodegeneration affects sensory adaptation the proposed study therefore also offers the possibility of a novel and sensitive framework for understanding the impact of degeneration on nerve cell circuits in the brain, that may provide new ways to detect and track the impact of degeneration.

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Alzheimer's disease is a devastating illness that causes severe memory loss. Despite the huge social, economic and emotional burden of the condition, there is currently no cure. The development of effective treatments is hindered by the difficulty of accurately identifying the early phase of the disease, years before symptoms become apparent. Recent evidence has come to light of a previously unrecognised waste removal system that clears excess fluid and toxins from the brain. It is thought that impairment of this pathway, known as the glymphatic system, may be a critical causal factor in the development of Alzheimer's disease. However, currently this pathway cannot be measured in humans. We will develop the first non-invasive methods to image the glymphatic system using MRI, enabling assessment in the human brain for the first time. The new techniques will be carefully assessed by: i) comparison to existing invasive methods that require the injection of imaging agents into the fluid that surrounds the brain, ii) imaging mouse models of impaired glymphatic clearance and comparison with healthy mice. Taken together, this proposal may lead to a new method for early detection of Alzheimer's disease and identify a new target for effective treatment.

Our understanding of how chemical signals in the brain produce wakefulness or induce sleep is far from complete. Yet unfortunately, sleep disorders and lack of sleep contribute an estimated £13 billion loss to the UK economy each year. Thus for the pharmaceutical industry, developing effective drugs that act in the brain to specifically induce or maintain sleep is an attractive aim (ref. 4). As anyone who has taken a first-generation antihistamine for allergies such as hay fever can testify, a major neurochemical that promotes wakefulness and arousal is histamine. This molecule, which in the brain is uniquely synthesized in neurons of the hypothalamic tuberomammilary nucleus (TMN) by the enzyme histidine decarboxylase (hdc), acts at widespread neuronal receptor sites (refs. 1 & 6). TMN neurons fire during wakefulness partly because of the excitatory effects of the neuropeptide orexin, but are hypothesised to be actively repressed during sleep by the neurotransmitter gamma-ambinobutyric acid (GABA) and the neuropeptide galanin. Drugs that manipulate aspects of the histaminergic system might be very useful for developing new sleep medicines, and histamine is considered a high priority target in the pharmaceutical industry. For this project, Wisden & Franks have constructed a Cre recombinase diver mouse line, hdc-Cre, that allows genetic manipulations of activity specifically in the histaminergic cells of the TMN without affecting other types of neurons (unpublished). The PhD student would use this Cre mouse line to explore if and how GABA inhibitory transmitter pathways inhibit the TMN neurons to aid sleep induction and maintenance. We will examine the two inhibitory GABA components GABA-A (fast, synaptic, ionotropic) and GABA-B (slow, extrasynaptic, metabotropic). For this, the student will analyse a specific deletion of: (i) the GABA-A receptor gamma2 subunit gene (gabrg2) from TMN cells by a hdc-Cre and lox-gabrg2 cross (ref. 5); (ii) the GABA-B receptor R1 gene (gabrb1) from TMN cells using a hdc-Cre and lox-gabrb1 cross (ref. 2). In a third subproject, the student will use AAV vectors and the hdc-Cre mice to engineer the TMN neurons so that they are selectively sensitive to benzodiazepine hypnotics, with all other neurons remaining insensitive (ref. 5). This will enable us to critically assess our hypothesis that sedatives induce sedation by suppressing the histamine system (refs 3 & 7). The student will acquire a thorough training in systems neuroscience. The student will analyse, by in vivo electrophysiological recordings, how the genetic manipulations of the TMN affect the sleep electrophysiological (EEG) profile. Using Lilly's in-house automated behavioural sleep/activity scoring system, the student will examine how the sleep profile changes in response to the genetic manipulations. During the project, the PhD student would acquire a mixture of laboratory skills including molecular biology (recombinant AAV plasmid and virus construction, transgenic mouse breeding strategies); stereotaxic manipulations; neuroanatomical methods such as immunohistochemistry, in vivo electrophysiological recording techniques and analysis, and behavioural analysis. 1. Haas HL et al (2008). Physiol Rev 88, 1183. 2. Haller C et al (2004). Genesis 40, 125. 3. Nelson LE et al (2002). Nat Neurosci 5, 979. 4. Wafford KA & Ebert B (2008). Nat Rev Drug Discov 7, 530. 5. Wulff, P et al. (2007). Nat Neurosci 10, 923-929. 6. Zecharia AY & Franks NP (2009). Anesthesiology 111, 695. 7. Zecharia AY et al., (2009). J Neurosci 29, 2177.