The role of inhibitory interneurons in neurovascular coupling

• Applicant: Dr. Martin Thunemann
• Subject Area: Human Cognitive and Systems Neuroscience ; Molecular Biology and Physiology of Neurons and Glial Cells
• Term: from 2015 to 2017
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 275392440

Neurovascular coupling links neuronal activity with cerebral blood flow (CBF) to meet changes in oxygen and energy consumption of the nervous tissue. This hemodynamic response largely relies on diameter changes of vessels in the affected brain region. Multiple pathways act in parallel to alter CBF upon changes in neuronal activity. These changes are assessed indirectly through imaging methods that measure CBF noninvasively in humans and experimental animals. Interpretation of these imaging signals requires a solid mechanistic understanding of neurovascular coupling. This challenge is often met by analyzing neurovascular coupling in vivo using two-photon laser scanning microscopy (2PLSM). Recently, optogenetic tools for precise manipulation of neuronal activity have been utilized in these studies. Evidence was provided that cortical inhibitory interneurons (INs) are important mediators of the acute hemodynamic response. However, how INs modulate CBF in vivo is not yet understood.In the proposed project, I want to understand the role of INs in neurovascular coupling. The first goal is to untangle the contribution of different IN subtypes to stimulus-induced vasoconstriction/vasodilation in the primary somatosensory cortex of living mice. A Cre/lox-based genetic system will be used to express the light-sensitive ion channel channelrhodopsin in distinct IN subtypes. 2PLSM is then used to measure spatiotemporal profiles of vessel diameter changes in response to optogenetic stimulation. I hypothesize that these profiles are altered when different types of neurons are stimulated. From there, I aim to identify the vasoactive messengers that are released from different neuron subtypes in vivo. For that, I will combine optogenetic stimulation with in vivo pharmacology, as I hypothesize that blocking synthesis or action of putative messengers alters the hemodynamic response. Most 2PLSM studies will be performed in anesthetized animals, but anesthesia can affect neurovascular coupling. Therefore, I plan to validate key findings in non-anesthetized mice by comparing hemodynamic responses in the same animal under anesthetized and awake state.The proposed studies will extend our understanding of mechanisms underlying CBF regulation and will support the interpretation of noninvasive hemodynamic imaging signals. The innovative combination of 2PLSM with novel optogenetic approaches forms the basis for further studies to resolve central questions on neurovascular communication under normal and diseased conditions. This project combines my previous expertise in mouse genetics and vascular physiology with the expertise of the host laboratory in development and application of innovative techniques to study neurovascular communication in vivo. Besides learning these exciting new methods, I want to improve my personal abilities and to develop my scientific career to be able to perform research on neurovascular physiology as an independent scientist in the future.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professorin Anna Devor, Ph.D.