Summary: Adolescence is a critical period for the brain’s frontal cortex, where executive functions mature and vulnerabilities to psychiatric disorders emerge. A new study shows that microglia, the brain’s immune cells, directly shape dopamine circuits during this time by strengthening axonal connections.
Surprisingly, microglial contact occurs before new boutons form, highlighting their role in circuit plasticity. These findings point to potential treatments for neurodevelopmental and psychiatric disorders by targeting microglia activity during adolescence or even reactivating it in adulthood.
Key Facts
- Microglia’s Role: Brain immune cells strengthen dopamine circuits during adolescence.
- Critical Window: Abnormal frontal cortex development in teens can lead to disorders like schizophrenia and ADHD.
- Therapeutic Potential: Drugs combined with activities like exercise may help restore plasticity in adult brains.
Source: University of Rochester
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.
Funding: This research was supported by the National Institutes of Health and a pilot grant from the Del Monte Institute for Neuroscience.
About this neurodevelopment research news
Author: Kelsie Smith Hayduk
Source: University of Rochester
Contact: Kelsie Smith Hayduk – University of Rochester
Image: The image is credited to Neuroscience News
Original Research: Open access.
“Dopaminergic signaling regulates microglial surveillance and adolescent plasticity in the mouse frontal cortex” by Rianne Stowell et al . Nature Communications
Abstract
Dopaminergic signaling regulates microglial surveillance and adolescent plasticity in the mouse frontal cortex
Adolescence is a sensitive period for frontal cortical development and cognitive maturation, marked by heightened structural plasticity in the dopaminergic (DA) mesofrontal circuit.
However, the cellular and molecular mechanisms underlying this plasticity remain unclear.
Here, we show that microglia, the brain’s innate immune cells, are highly responsive to mesofrontal DA signaling during adolescence.
Longitudinal in vivo two-photon imaging in mice reveals that frontal cortical microglia increase their surveillance of the parenchyma and DA axonal boutons following rewarding experiences or optogenetic stimulation of DA axons.
Microglial contacts with DA axons consistently precede bouton formation, and microglia-bouton interactions are regulated by D1- and D2-type DA receptors in adolescence and adulthood.
Furthermore, microglial purinergic receptor P2RY12 signaling is necessary for enhanced microglial surveillance and DA bouton formation during adolescence.
These results uncover bidirectional interactions between DA signaling and microglial surveillance that drive adolescent frontal plasticity and identify potential targets for restoring plasticity in adulthood.