Optogenetic analysis of the neural function of 5-HT-glutamate co-transmission (360G-Wellcome-205968_Z_17_Z)

This research investigates the relationship between 5-HT neurons and two key brain functions: sleep-wake changes and fear learning. Of particular interest is the role in these processes of glutamate co-released from 5-HT neurons. Two approaches will be used. One approach is based on recent evidence that glutamate is preferentially released from 5-HT neurons firing at low frequencies, whereas 5-HT is preferentially released at higher frequencies. The second approach is based on a mouse with glutamate deficient 5-HT neurons.In Oxford the research will have 3 main goals:i) Measurement of firing of identified 5-HT neurons during the sleep-wake cycle. This will be achieved using optotagging to record for the first time, the firing of identified 5-HT neurons during changes in sleep-wake activity.ii) Optogenetic manipulation of 5-HT neurons on sleep-wake activity. These experiments will optogenetically manipulate 5-HT neurons (using different stimulation frequencies) to establish the causal relationship between changes in 5-HT firing and sleep-wake activity.iii) Optogenetic manipulation of 5-HT neurons in mice with glutamate-deficient 5-HT neurons. These experiments will use a mouse with glutamate-deficient 5-HT neurons to further test the role of glutamate co-release.I will follow a similar research strategy to investigate the role of glutamate co-released from 5-HT neurons in emotional learning at NIH.