We are interested in the molecular mechanisms and neural circuit changes that underlie behavior. We are taking advantage of the fantastic genetic toolbox available in Drosophila to tackle this problem.
We are studying how dynamic changes in calcium through CaMKII bring about changes in synaptic plasticity underlying memory. Key to this process is CaMKII’s ability to autophosphorylate a mechanism dubbed “the molecular memory switch” which is regulated by a synaptic scaffolding molecule called CASK. Dr Bilal Malik and John Gillespie showed that CASK regulates dynamic changes in calcium and CaMKII autophosphorylation both in negatively and positively reinforced memory in adult and larval Drosophila including long-term memory (Malik et al, 2013; Gillespie and Hodge, 2013). This novel form of CASK mediated regulation of the molecular memory switch is conserved between flies and human. This allows us to model how human CASK mutations and dysregulation of CaMKII autophosphorylation leads to intellectual disability and cognitive impairment in Alzheimer’s and Parkinson’s disease.
We have also shown that CASK and CaMKII can change the excitability of neural circuits by modulating potassium channels such as eag (KCNH, Kv10).
In addition we identified and characterized members of the Shaw (KCNC1, Kv3.1 and KCNC2, Kv3.2) family showing that Shaw regulates resting membrane potential of central neurons and is important for circadian rhythms and sleep (Hodge et al, 2005; Hodge and Stanewsky, 2008). In a BBSRC funded collaborative project with Prof Ralf Stanewsky’s lab, we are studying how light controls the activity and electrical properties of neurons integrating arousal behaviour, circadian rhythms, and sleep. To do this we are using molecular genetics, behaviour, optogenetics and whole cell patch clamp of adult fly clock neurons performed by Dr Edgar Buhl. In collaboration with Dr Krasi Tsaneva we are using dynamic clamp to develop mathematical and computational models of clock neuron electrophysiology and circadian rhythms. While we are working with Prof Hugh Piggins in order to directly compare the electrophysiology of clock neurons in flies and rodents, shedding light on how each is keeping time across evolution.
We have started modeling the function of KCNQ (Kv7) channels, mutation of which cause the most common form of cardiac arrhythmia, long QT syndrome as well as short QT syndrome, atrial fibrillation and sudden death syndrome. Dr Sonia Cavaliere has compared the electrophysiology and pharmacology of the fly and human KCNQ channels showing that they have conserved block by type III cardiac anti-arrhythmic drugs (Cavaliere and Hodge, 2009). Loss of function neuronal KCNQ mutations cause epilepsy and we showed that KCNQ anti-epileptics also act as openers of fly KCNQ. This work allows us to model these important channelopathies in fly and screen for new drug treatments. We have also shown that fly and mammalian KCNQ are acutely blocked by very low concentrations of ethanol with changes in dopamine neuron KCNQ activity controlling ethanol behavior (Cavaliere et al, 2012). In addition ethanol disrupts memory in flies via KCNQ and that KCNQ sets excitability of neural circuits during behavior and is required for memory formation. During aging KCNQ expression goes down resulting in age-dependent cardiac and cognitive impairment. We have rescued age-dependent memory impairment by overexpressing KCNQ in memory neurons (Cavaliere et al, 2013).
We are currently interested in studying the genetic and environmental determinants of age-related memory impairment. Xiohan Li is studying age related memory decline in Alzheimer’s models. Sebastian Green is studying the effect of sleep deprivation and stress on age-related memory impairment. Alan Brindle is studying changes in dopamine neuron mitochondrial function associated with cognitive impairment in Parkinson’s. In collaboration with Dr David Leslie, Hannah Julienne is developing a mathematical model of reinforcement learning in Drosophila and the effect of Parkinson’s disease.
PhD student Simon Lowe is working with Dr Maria Usowicz to develop new genetic models of Down’s syndrome to explore the electrophysiological basis of the motor and cognitive impairments associated with the disease. In collaboration with Prof Mike Mendl and Bill Brown, PhD student Amanda Deakin is using behavioural, neurobiological and mathematical approaches to study affective processes and decision-making usingDrosophila, exploring the evolutionary origins of emotion in learning. We are also collaborating with Dr Frank Hirth (Institute of Psychiatry, Kings) on characterising the Central Complex, a brain region analogous to the Basal Ganglia.
Please contact me if you are interested in research opportunities in the lab.
View complete publications list in the University of Bristol publications system
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