Post by Flora Moujaes
What's the science?
The brain is not just comprised of neurons: it contains many other types of cells, such as microglia and astrocytes, which play a fundamental role in the brain. Microglia are best known for their role in the immune response, yet they are also involved in a number of other key brain functions including plasticity: the process through which the brain changes and adapts to new experiences. Microglia interact closely with neurons at the synapse: the junction between two neurons. To date, research on microglia has focused on anesthetized animals, leaving open the possibility that microglial dynamics may be different during awake-states. It also remains unknown how neurotransmitters regulate microglial functioning. However, microglia have a higher expression of a specific type of receptor for the neurotransmitter norepinephrine compared to any other type of brain cell, suggesting norepinephrine may be a key modulator. This week in Nature Neuroscience, Stowell et al. use advanced imaging technology to show that microglial dynamics (1) differ between awake and anesthetized mice and (2) are modulated by norepinephrine.
How did they do it?
To determine whether microglial behavior is affected by anesthesia, the researchers first imaged microglial dynamics in healthy adult mice while they were awake and after having been anesthetized with a fentanyl cocktail. Given the role of microglia in the immune response, they also imaged microglial dynamics in awake and anesthetized mice that had suffered an acute brain injury.
In order to uncover the underlying mechanisms responsible for the differences in microglia in awake and anesthetized mice, the researchers explored the role of norepinephrine in microglial functioning. Norepinephrine was of particular interest as (1) it is known to be a powerful mediator of wakefulness, and (2) microglia have a very high number of beta2 adrenergic receptors (which norepinephrine bind to). The researchers modulated the level of noradrenergic signalling in microglia, either by stimulating the microglia’s beta2 adrenergic receptors using the agonist clenbuterol to increase norepinephrine levels or by inhibiting the microglia’s beta2 adrenergic receptors using the antagonist ICI-118,551 to decrease norepinephrine levels. They examined whether this (1) affected microglial functioning in both anesthetized and awake mice, (2) affected microglial response to injury, or (3) impaired synaptic plasticity.
What did they find?
Wakefulness vs. Anaesthesia: The researchers found that microglia in the awake brain differ from those in the anesthetized brain with regards to (1) surveillance monitoring and (2) their injury response. They showed that anesthesia rapidly increased microglial surveillance and increased the microglial response to injury compared to the awake condition. This suggests that wakefulness exerts a primary inhibitory effect on microglial dynamics.
Norepinephrine Modulation: The researchers then replicated the findings from awake vs. anesthetized mice by pharmacologically modulating microglial noradrenergic signalling. They found high levels of norepinephrine in awake mice led to reduced microglial functioning, while low levels of norepinephrine in anesthetized mice led to increased microglial functioning. Increased norepinephrine levels also led to a significant reduction in microglial response to injury. Finally, they found that a chronic increase in microglial noradrenergic signalling impairs experience-dependent plasticity in the developing visual system of mice.
What's the impact?
Overall this study suggests that wakefulness exerts a primarily inhibitory effect on microglial dynamics. It also shows that microglial roles in surveillance and synaptic plasticity in the healthy brain are modulated by norepinephrine. This suggests that the enhanced remodeling of the neural circuits that occurs during sleep may be mediated by the increase in the ability of microglia to dynamically interact with the brain. This is an especially interesting finding as it demonstrates that simply by modulating immune cells, it’s possible to alter synaptic plasticity.
Stowell et al. Noradrenergic signaling in the wakeful state inhibits microglial surveillance and synaptic plasticity in the mouse visual cortex. Nature Neuroscience (2019). Access the original scientific publication here.