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Reorganisation of cortical microcircuit activity under anaesthesia

Department of Neuroscience, Psychology and Behaviour

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Dr Michael Okun Applications accepted all year round Self-Funded PhD Students Only

About the Project

How does general anaesthesia work? Although general anaesthetics are in use for over 150 years, the outlines of the answer began to emerge only in the last decades. There is now sufficient evidence that common general anaesthetics, such as propofol or isoflurane, are GABAA receptor agonists, i.e., they act by potentiating inhibitory synapses throughout the central nervous system and in the cortex in particular. This understanding of the fundamental mechanism of general anaesthetics action does not however explain how they produce a stable state of sedation and unconsciousness. Examination of the neurophysiological effect of anaesthetics, using electroencephalography (EEG), functional magnetic resonance imaging (fMRI) and recording of activity of individual neurons shows that under deep anaesthesia cortical activity is dominated by intervals of 1-4 seconds of complete silence (Down states), with active intervals of somewhat shorter duration in between (Up states). It is generally accepted that the reason for loss of consciousness in this condition are the Down states, and even more importantly the fact that Up and Down states happen in different times across the cortex, which means that different parts of the cortex are not active simultaneously and thus are unable to “talk” to each other.

Loss of consciousness, however, occurs also with more superficial level of anaesthesia, which does not produce the Up-and-Down regime of activity. The above explanation cannot therefore account for the loss of consciousness in this case. It is possible that complete cessation of neuronal activity, as observed in the Down states, is not actually necessary, and a reduction of firing rates of cortical neurons, which is achieved even under superficial anaesthesia, is sufficient to produce unconsciousness. An alternative hypothesis, backed by some preliminary data I have recently collected, is that it is not the reduction in firing rates per se that causes the unconsciousness, but reorganisation of the patterns of cortical activity – i.e., the change in identity and order of spiking of neurons under anaesthesia vs wakefulness or sleep.

I propose to address this question by performing recordings of the very same populations of cortical neurons across the three brain states of wakefulness, sleep and anaesthesia. Such experiments can be conducted in mice using high-density multi-electrode arrays chronically implanted into their cortex. Although an abundance of data exists on each of the three brain states individually, very little is known about how the activities of a cortical neuronal population in these three states relate to each other at the single neuron resolution. In addition to testing the basic hypothesis of the existence of population activity reorganisation, we will ask whether this reorganisation is similar in different cortical areas. Based on the way sensory stimuli are processed under anaesthesia in primary sensory and higher association areas of the cortex, I hypothesise that anaesthesia-induced reorganisation of population activity is qualitatively different in primary sensory areas when compared to frontal cortical areas. This hypothesis will be tested by performing the recordings in cortical areas of both kinds.

The project will require the PhD student to learn both advanced experimental methods and computational data analysis approaches which go far beyond textbook statistical tests. If successful, this project will substantially advance our understanding of anaesthesia support further highly competitive applications for external funding of this research direction.
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