Making a smoothie, going for an evening walk, or having empathy for a loved one are all examples of executive functions that are controlled by the brain's frontal cortex. This area of the brain goes through profound change throughout adolescence, and it is during this time that abnormalities in maturing circuits can set the stage for neurodevelopmental disorders, such as schizophrenia and ADHD. Researchers at the Del Monte Institute for Neuroscience at the University of Rochester have discovered that microglia, the brain's immune cells, play a key role in how the brain adapts to the changes in this area during adolescence, which may transform how neurodevelopmental disorders are treated during this window and, possibly, into adulthood.
"A better understanding of the ways we can drive changes in these circuits offers new targets for disease treatment," said Rianne Stowell, PhD , research assistant professor of Neuroscience at the University of Rochester Medical Center , and first author of the study out today in Nature Communications . "This area is also susceptible to change, both good and bad, during adolescence. Previous work in our lab has found that both direct activation of frontal dopamine circuits and rewarding behavior drive plasticity of dopaminergic connections to the frontal cortex during adolescence, but not adulthood."
Immune Cells Support Circuit Connection
The dopaminergic circuits in the brain are made up of networks of neurons that use dopamine to send information. These circuits are critical for regulating brain functions, including movement, motivation, and cognition. Exercise, or wheel running for mice, is a natural, rewarding experience that activates the frontal dopamine circuit. Using this model and optogenetics, a technique that uses light to control genetically targeted neurons, researchers observed that microglia in the living brain are recruited to the frontal dopaminergic circuit in adolescent mice. The microglia responded to dopaminergic activation by making contact with the axons, the long part of the neuron that acts like a cable relaying signals, and then new boutons formed along those axons. Boutons are the parts of the neuron that transmit signals to other cells. According to Stowell, this shows that microglia have a direct impact on increased dopaminergic circuit connectivity. Basically, the brain's immune cells appear to play a key role in strengthening the brain's communication network.
"We were surprised to see that the microglial contact with the axon happens before the formation of new boutons," Stowell said. "This research suggests that microglia are very sensitive to changes in dopamine activity, and there is a compelling connection between microglial contact and structural changes at the axon."
Finding a Target in the Adult Brain
Research in the Wang lab showed that administering a dopamine D2 receptor agonist, quinpirole, blocked plasticity in adolescence. Conversely, administering a D2 antagonist, eticlopride—an antipsychotic drug—to adult mice reinstated microglia recruitment to axons and promoted the formation of new boutons. Stowell said that future research will explore if combining pharmacological therapies with dopamine stimulation, such as through exercise, could help treat psychiatric disorders impacted by deficits in this area of the brain.
"We now want to determine, at the molecular level, what exactly microglia are doing within the circuit. For example, how they are influencing the growth of boutons," Stowell said. "We will be using pharmacological manipulations of specific microglial signaling systems as well as single-cell sequencing to dig into what makes this circuit malleable during adolescence but not adulthood."
Kuan Hong Wang, PhD , professor of Neuroscience and Pharmacology and Physiology at the University of Rochester Medical Center, was the lead author of this study. This research was supported by the National Institutes of Health and a pilot grant from the Del Monte Institute for Neuroscience .
