The neural circuitry of sensory-evoked awakenings during sleep and anaesthesia

Sleep, wakefulness, and anaesthesia are behavioural states with characteristic differences in brain activity that dramatically affects our sensory perception and behavioural responses. Sleep is accompanied by a significantly reduced responsiveness to the external environment.

However, while some individuals may wake up frequently from weak stimuli, others require intense stimulation to bring about wakefulness.

The neuronal mechanisms that determine sensory-evoked awakenings, and how sleep affects responses along sensory pathways is poorly understood.

Professor Yuval Nir’s research group have recently published two pioneering papers aiding our understanding of sensory disconnection during sleep.

Firstly, they have shown that neurons in the auditory cortex (the primary centre of the brain for processing of auditory information) show little alteration of their activity across sleep and wakefulness in response to auditory stimuli.

In contrast, neurons downstream of the auditory cortex in higher-level perirhinal cortex show decreased responses during sleep compared to wake. Secondly, the locus coeruleus (LC) is a small norepinephrine (NE) releasing nucleus located in the brainstem.

Using electrophysiological, behavioural, pharmacological, and optogenetic techniques alongside auditory stimulation, Professor Nir’s group were able to show that LC-NE activity promotes sensory-evoked awakenings.

The current proposal will feed into an ongoing project to bring these two findings together by studying the sensory responses of neurons in the auditory and perirhinal cortex during LC-NE optogenetic stimulation (which uses light to activate or silence specific neurons).

This work will test the primary hypothesis that LC-NE stimulation is sufficient to elicit a wake-like sensory response in the perirhinal cortex, which would otherwise be attenuated during sleep.

Combining LC-NE optogenetic stimulation with state-of-the-art Neuropixels probes, will allow a novel approach for testing this hypothesis given the step-change in both the breadth of brain area, and number of neurons that can be recorded from with Neuropixels probes. During my proposed stay at Tel Aviv University, I will begin the first stages of this project.

This involves implanting the Neuropixels probes into the auditory and perirhinal cortex and the optogenetic construct into the LC.

We will then test auditory responses of neurons, with and without LC-NE optogenetic stimulation, during light anaesthesia in a small number of head-fixed animals.

Acute surgeries with head-fixation massively reduce the experimental time needed while maximising the number of neurons that can be recorded (which commonly die with chronic set-ups in freely moving animals).

Light anaesthesia will provide an analogue of sleep and these results will collectively guide the future direction of this project moving on to sleep in freely moving animals.

Given my existing experience with Neuropixels and Professor Nir’s expertise with LC-NE optogenetics, this visit has a high chance of success in making a significant contribution to the project within the short time frame, furthering our understanding of sensory disconnection across behavioural states.