The hypothalamus contains neurons that control energy balance and whose activity is sensitive to circulating glucose levels. These neurons control, in part, the body’s response to changes in glucose availability. What is poorly defined, is how glial cells influence glucose-sensing neuron activity and how this is altered in diseases like diabetes.
The hypothalamus contains various neuronal populations controlling aspects of homeostasis, including systemic glucose regulation. One specific region of the hypothalamus known as the ventromedial hypothalamus (VMH) contains neurons that are excited by increasing glucose levels, known as glucose-excited (GE) neurons. Other neurons of the VMH are inhibited by increasing glucose levels, termed glucose-inhibited (GI) neurons. These cells work in concert to orchestrate the whole body response to changing glucose levels, altering release of the main glucose-regulating hormones, insulin and glucagon, which decrease and increase blood glucose levels, respectively. What is not known is whether glial cells, neuromodulatory but non-electrically active cells within the brain, also play a role in detecting changes in glucose and helping GE and GI neurons to function.
Advances in technologies enabling regulation of specific brain cell populations has increased our understanding of glial cell function. It has become increasingly apparent that glial cells do more than just support neurons but also release chemical signals termed gliotransmitters that alter aspects of neuronal activity. For example, glial cells within the hypothalamus have, over the past 3 years, been shown to regulate feeding. What is much less clear is how glial cells regulate blood glucose levels when glucose levels increase or decrease too much. This happens frequently in people with diabetes. The aim of this PhD is to determine how glial cells, specifically astrocytes, may detect changes in glucose levels and contribute to regulation of whole body glucose homeostasis.
To achieve this, the student will utilise a number of cutting edge technologies. Firstly, in rat brain slices, the student will measure neuronal activity across the VMH using a perforated multi-electrode array recordings whilst manipulating astrocytes with pharmacological or genetic approaches. They will examine whether increasing or decreasing astrocyte activity alters responses of GE and GI neurons to changes in glucose concentration.
Secondly, to determine whether neuronal activity alters astrocyte activity, the student will utilise two-photon imaging with calcium-sensitive dyes to monitor changes in astrocyte activity, whilst changing glucose levels or altering neurotransmitter (GABA and glutamate) signalling.
Thirdly, to determine how glial cells alter glucose homeostasis, the student will use advanced microvascular surgery to perform dual carotid artery and jugular vein catheterisation in rats. This allows simultaneous infusion of insulin and glucose to accurately control glucose levels, whilst sampling blood for analysis of glucose and gluco-regulatory hormones. By combining this with chemogenetic viral vector injection into the hypothalamus to express an engineered receptor, the student can manipulate astrocyte activity using a synthetic drug, whilst clamping glucose at a desired level. Thus, they will determine the impact of local glial cell activity on whole body physiology. These experiments will fill an important piece of the glucose homeostasis jigsaw potentially providing new targets for treatment. Moreover, these multidisciplinary approaches will generate high impact publications and provide an excellent training experience for the student.