Neuroscience

*BBSRC EASTBIO Programme* Is there a role for GABA-A receptor alpha-5 subunits in cognitive deficits caused by consumption of a high fat diet?

Project Synopsis: This project will use dietary manipulations in mice and look at behavioural effects on memory alongside electrophysiological changes in synaptic plasticity and changes in receptor expression in the brain. It will investigate the question of whether GABA-A receptor alpha-5 subunits, a target for cognitive enhancing drugs, are upregulated by a high fat diet and whether this is linked to inflammatory cytokine activation. It aims to define a mechanistic link between fat consumption and memory loss.

*BBSRC EASTBIO Programme* Age-dependent regulation of hippocampal synaptic function by the estrogen-sensitive receptor, GPER1

In Western societies, life expectancy is steadily increasing and currently around 20% of the UK’s population is over 65. Consequently, more people are suffering from age-related disorders, such as cognitive decline and neurodegeneration. It is known that the hippocampus plays a key role in learning and memory, and hippocampal damage results in cognitive deficits similar to those experienced with aging. The hippocampus is also one of the first areas of the brain to degenerate in age-related brain disorders such as Alzheimer’s disease.

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.

Developmental rodent models for the study of cognitive disorders.

The Langston lab aims to characterise the ontogeny of different types of learning and memory in laboratory rodents, with a particular emphasis on episodic memory which is a key diagnostic in many human cognitive disorders. In humans, learning occurs over an extended time period with different types of memory capability emerging at different stages of development. We have discovered that this is mirrored in rodents.

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.

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