Journal Article

Cell type specificity of neurovascular coupling in cerebral cortex

Vandenberghe, Matthieu, Einevoll, Gaute T, Djurovic, Srdjan, Mateo, Celine, Fainman, Yeshaiahu, Andreassen, Ole A, Thunemann, Martin, Silva, Gabriel A, Sakadžić, Sava, Tian, Peifang, Masliah, Eliezer, Cheng, Qun, Steed, Tyler C, Ferri, Christopher GL, Saisan, Payam A, Kılıç, Kıvılcım, Cremonesi, Jonathan A, Nizar, Krystal, Kleinfeld, David, Uhlirova, Hana, Devor, Anna, Razoux, Florence, Desjardins, Michèle, Dale, Anders M, Weldy, Kimberly L, Sridhar, Vishnu B, Buxton, Richard B, Boas, David A, Ness, Torbjørn V, Abashin, Maxim

2016

Overview

Identification of the cellular players and molecular messengers that communicate neuronal activity to the vasculature driving cerebral hemodynamics is important for (1) the basic understanding of cerebrovascular regulation and (2) interpretation of functional Magnetic Resonance Imaging (fMRI) signals. Using a combination of optogenetic stimulation and 2-photon imaging in mice, we demonstrate that selective activation of cortical excitation and inhibition elicits distinct vascular responses and identify the vasoconstrictive mechanism as Neuropeptide Y (NPY) acting on Y1 receptors. The latter implies that task-related negative Blood Oxygenation Level Dependent (BOLD) fMRI signals in the cerebral cortex under normal physiological conditions may be mainly driven by the NPY-positive inhibitory neurons. Further, the NPY-Y1 pathway may offer a potential therapeutic target in cerebrovascular disease. Unlike other cells in the body, brain cells contain almost no energy reserves and rely on blood vessels for continuous supply of oxygen. A change in the brain’s activity can cause these blood vessels to either dilate or constrict, which alters the supply to match the change in demand. However, it is not known which signals cause these changes in the blood vessels. Previous studies have shown that individual blood vessels in an intact brain tend to dilate when the brain’s activity increases, and constrict when brain activity is inhibited. However, these studies were based on correlations, and there was no direct evidence that the inhibitory cells cause blood vessels to constrict. Uhlirova, Kılıç et al. now provide such evidence. The experiments made use of mice that had been genetically modified such that the excitatory or inhibitory nerve cells in their brains could be selectively activated by shining a blue light on the brain’s surface. The vessels in the outer millimeter of the gray matter of each mouse’s brain were imaged in detail, both before and after the blue light was used to activate the nerve cells. The experiments reveal that both excitatory and inhibitory nerve cells can cause blood vessels in the brain to dilate. However, blood vessels in the brain will only constrict in response to inhibitory nerve cells. Uhlirova, Kılıç et al. went on to identify a molecule called Neuropeptide Y (or NPY short) as a signal that triggers the constriction of the blood vessels. This signaling molecule is released by a specific sub-type of inhibitory nerve cell and it binds to a receptor protein on the brain’s blood vessels to make them constrict. These findings suggest that NPY and its receptor on blood vessels may offer promising targets for drugs to treat diseases of the brain’s blood vessels. Further studies are now needed to identify the signals responsible for the dilation of blood vessels in the brain.

• Publisher: eLife Science Publications, Ltd,eLife Sciences Publications Ltd,eLife Sciences Publications, Ltd
• Subject: 2-photon microscopy / Animals / Cerebral cortex / Cerebral Cortex - blood supply / Cerebral Cortex - drug effects / Cerebral Cortex - metabolism / Cerebral Cortex - physiopathology / Cerebrovascular Disorders - drug therapy / Cerebrovascular Disorders - genetics / Cerebrovascular Disorders - metabolism / Cerebrovascular Disorders - physiopathology / constriction / Diagnostic Imaging / dilation / Functional magnetic resonance imaging / Gene Expression / Health aspects / Hemodynamics / Hypotheses / Magnetic Resonance Imaging / Male / Metabolism / Mice / Mice, Transgenic / Neural circuitry / Neuroimaging / Neurons / Neurons - cytology / Neurons - drug effects / Neurons - metabolism / Neuropeptide Y / Neuropeptide Y - pharmacology / Neuroscience / Neurosciences / Neurovascular Coupling - drug effects / NPY / optogenetic / Optogenetics / Organ Specificity / Oxygen - metabolism / Photic Stimulation / Physics / Protein Binding / Psychosis / Receptors, Neuropeptide Y - genetics / Receptors, Neuropeptide Y - metabolism / Vasoconstriction - drug effects / Vasoconstrictor Agents - pharmacology