Neuronal Network Activity Controls Microglial Process Surveillance in Awake Mice via Norepinephrine Signaling

Nat Neurosci. 2019 Nov;22(11):1771-1781. doi: 10.1038/s41593-019-0511-3. Epub 2019 Oct 21.

Abstract

Microglia dynamically survey the brain parenchyma. Microglial processes interact with neuronal elements; however, what role neuronal network activity plays in regulating microglial dynamics is not entirely clear. Most studies of microglial dynamics use either slice preparations or in vivo imaging in anesthetized mice. Here we demonstrate that microglia in awake mice have a relatively reduced process area and surveillance territory and that reduced neuronal activity under general anesthesia increases microglial process velocity, extension and territory surveillance. Similarly, reductions in local neuronal activity through sensory deprivation or optogenetic inhibition increase microglial process surveillance. Using pharmacological and chemogenetic approaches, we demonstrate that reduced norepinephrine signaling is necessary for these increases in microglial process surveillance. These findings indicate that under basal physiological conditions, noradrenergic tone in awake mice suppresses microglial process surveillance. Our results emphasize the importance of awake imaging for studying microglia-neuron interactions and demonstrate how neuronal activity influences microglial process dynamics.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain / drug effects
  • CX3C Chemokine Receptor 1 / genetics
  • Clozapine / analogs & derivatives
  • Clozapine / pharmacology
  • Isoflurane / pharmacology
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • Microglia / drug effects
  • Microglia / physiology*
  • Microinjections
  • Muscimol / pharmacology
  • Neurons / physiology*
  • Norepinephrine / pharmacology
  • Norepinephrine / physiology*
  • Optogenetics
  • Propanolamines / pharmacology
  • Propranolol / pharmacology
  • Receptors, Purinergic P2Y12 / genetics
  • Sensory Deprivation / physiology
  • Somatosensory Cortex / drug effects
  • Somatosensory Cortex / physiology*
  • Tetrodotoxin / pharmacology
  • Wakefulness

Substances

  • CX3C Chemokine Receptor 1
  • Cx3cr1 protein, mouse
  • P2ry12 protein, mouse
  • Propanolamines
  • Receptors, Purinergic P2Y12
  • Muscimol
  • Tetrodotoxin
  • ICI 118551
  • Propranolol
  • Isoflurane
  • Clozapine
  • clozapine N-oxide
  • Norepinephrine