Neuroscience

Using c-Src inhibitors to improve opioid analgesia

The prevalence of persistent moderate to severe pain is high, affecting 19% of Europeans. While opioids are among the best analgesics for severe pain their prolonged use is compromised by tolerance, which leads to reduced potency and a requirement for escalating doses to maintain adequate pain control. Pain management is also compromised by the major opioid side effects: constipation and respiratory depression.

The use of a novel in vitro microfluidic model to understand how neurons in a network work together to respond to a local injury.

Acute secondary neuronal cell death, as seen in neurodegenerative disease, cerebral ischemia (stroke) and traumatic brain injury (TBI), drives spreading neurotoxicity into surrounding, undamaged, brain areas. This spreading toxicity occurs via two mechanisms, synaptic toxicity through hyperactivity, and excitotoxicity following the accumulation of extracellular glutamate. To date, there are no fast-acting therapeutic tools capable of terminating secondary spreading toxicity within a time frame relevant to the emergency treatment of stroke or TBI patients.

The use of a novel in vitro microfluidic model to understand how neurons in a network work together to respond to a local injury.

Acute secondary neuronal cell death, as seen in neurodegenerative disease, cerebral ischemia (stroke) and traumatic brain injury (TBI), drives spreading neurotoxicity into surrounding, undamaged, brain areas. This spreading toxicity occurs via two mechanisms, synaptic toxicity through hyperactivity, and excitotoxicity following the accumulation of extracellular glutamate. To date, there are no fast-acting therapeutic tools capable of terminating secondary spreading toxicity within a time frame relevant to the emergency treatment of stroke or TBI patients.

Early-life adversity and depression: nature versus nurture.

Adverse early life experiences, in the form of poor maternal care, are recognized to program an abnormal stress response, which increases the risk of psychiatric disorders e.g. depression in adulthood. Moreover, the impact of adverse early-life experiences has the potential to extend to future generations, suggesting a contribution by genetic and possibly, epigenetic factors. The mechanisms of stress dysfunction are complex, but may involve inhibitory GABAA receptors (GABAARs), as these receptors crucially curtail stress-induced activation of the HPA axis.

Cocaine Addiction and α2-GABAA Receptors

The laboratory is part of an MRC-funded multidisciplinary “addiction cluster”. Understanding the basic neurobiological mechanisms by which drugs of abuse become addictive is essential for the future development of strategies to combat drug addiction. Addictive drugs have in common that they influence the function of the pathways in the brain mediating reward, particularly the nucleus accumbens, a region which consists almost exclusively GABA-ergic neurones. Our collaborators studying cocaine addicts have implicated the α2-GABAA receptor isoform in cocaine abuse.

Mutations in the Garb1 gene promote ethanol consumption: Exploring a genetic and physiological basis for alcoholism.

Alcohol addiction is difficult to study in humans due to genetic and environmental complexities. Two mouse lines have been identified that exhibit a greatly increased voluntary consumption of ethanol and harbour single but distinct nucleotide mutations of the GABAA receptor (GABAAR) β1 subunit gene. Importantly, in the nucleus accumbens, a region associated with reward/addiction, we found GABAAR inhibition to be greatly enhanced in these mice as the mutant receptors now open spontaneously i.e. without the neurotransmitter GABA.

An investigation into cognitive dysfunction in honeybees and bumblebees as models for human neurodegenerative disease

The incidence of neurodegenerative disease is expected to become a major social and economical burden on society as the world’s population ages. There are no animal models that permit an investigation into both higher cognitive function and social interaction. One recently identified model is the use of bee colonies that exist as large (60,000 for honeybees) social communities where decisions are made democratically and bees communicate constantly.

Novel leptin based therapies to treat neurodegenerative disease.

Alzheimer’s disease (AD) is a progressive brain disorder resulting in profound cognitive and memory impairments. Clinical studies indicate that diet and lifestyle are key risk factors for developing neurodegenerative disorders like AD. Metabolic imbalance is also implicated in AD. Recent studies have linked the metabolic hormone, leptin to an increased incidence of AD. Consequently, leptin dysfunction may be a key factor in AD pathogenesis. Thus leptin-based therapies may prove beneficial in treating AD.

Leptin: a novel therapeutic target in Alzheimer’s disease?

Alzheimer’s disease (AD) is a progressive brain disorder that leads to profound cognitive and memory impairments. The prevalence of AD is predicted to rise rapidly in the future, which will pose a huge burden on health care services in the coming years. Evidence is growing that diet and lifestyle are key risk factors for developing AD and clinical studies indicate that metabolic dysfunction is a common trait in AD.

Environmental stress and the brain

The last few decades has seen a marked increase in the incidence of both type 1 and type 2 diabetes in Western Societies resulting in a significant individual and societal health costs. Understanding those mechanisms that contribute to the development of obesity and disorders of glucose homeostasis are therefore critical areas of research. It is increasingly recognized that the brain contributes to the development of both diabetes and obesity.

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