Summary: Adolescence is a critical period for the frontal cortex, where executive functions mature and the brain is especially vulnerable to psychiatric disorders. New research from the University of Rochester reveals that microglia—the brain’s resident immune cells—actively shape dopaminergic circuits during this window by promoting the formation and strengthening of axonal connections.
Contrary to expectations, microglial contacts with axons occur before new synaptic boutons appear, suggesting microglia play an instructive role in circuit remodeling. These findings point to opportunities for therapeutic strategies that target microglial activity during adolescence, and possibly reawaken similar forms of plasticity in adulthood.
Key Facts
- Microglial function: Microglia support and strengthen dopamine circuits in the frontal cortex during adolescence.
- Critical developmental window: Disruption of frontal cortex maturation in adolescence can contribute to disorders such as schizophrenia and ADHD.
- Therapeutic implications: Combining pharmacological approaches with behavioral interventions like exercise may help restore circuit plasticity later in life.
Source: University of Rochester
Executive functions—such as planning a snack, taking an evening walk, or showing empathy—depend on the frontal cortex. This brain region undergoes substantial structural and functional refinement during adolescence. When development in these circuits goes off track, the risk for neurodevelopmental and psychiatric disorders rises.
Researchers at the Del Monte Institute for Neuroscience at the University of Rochester have identified a previously underappreciated role for microglia in adolescent frontal cortex maturation. Their work suggests microglia actively respond to dopaminergic activity and directly contribute to the formation of new axonal boutons, thereby enhancing dopamine circuit connectivity during this sensitive period.
“Understanding how we can drive beneficial changes in these circuits opens new avenues for treating disorders that emerge during adolescence,” said Rianne Stowell, PhD, research assistant professor of Neuroscience at the University of Rochester Medical Center and the study’s first author. She noted that the frontal dopamine system is unusually malleable in adolescence: both direct stimulation of those circuits and rewarding experiences can drive structural plasticity at that stage, whereas the adult brain shows far less of this responsiveness.
Microglia actively support circuit connectivity
Dopaminergic networks—composed of neurons that release dopamine—play essential roles in movement, motivation, and cognition. To study how these circuits change during adolescence, the researchers used rewarding behavior (wheel running in mice) and optogenetic stimulation, a method that uses light to control specifically targeted neurons in living animals.
Two-photon imaging in awake mice demonstrated that adolescent microglia increase their surveillance of frontal cortical tissue and are recruited to dopamine axons after these neurons are activated. When dopamine axons were stimulated, microglia extended processes that contacted the axons, and following those contacts new boutons—the presynaptic structures that transmit signals to other neurons—emerged along the axons.
Importantly, microglial contact typically preceded bouton formation, indicating microglia are not merely cleaning up damaged material but may actively trigger or support the structural changes that establish stronger communication within the dopamine circuit.
“We were surprised to observe microglial contact before new boutons formed,” Stowell said. “This sensitivity to dopamine activity and the consistent timing of microglia-axon interactions imply a causal relationship between microglial behavior and axonal remodeling.”
Finding actionable targets in the adult brain
The team also explored how pharmacological manipulation of dopamine receptors affects microglial recruitment and circuit plasticity. In adolescent mice, activating D2-type dopamine receptors with an agonist (quinpirole) blocked plastic changes. In contrast, blocking D2 receptors in adult mice with an antagonist (eticlopride), a drug class used as antipsychotics, restored microglial recruitment to axons and promoted bouton formation.
These results suggest that adult circuits retain latent capacity for microglia-mediated remodeling that can be re-engaged by modifying dopaminergic signaling. Building on that idea, the researchers propose that combining targeted pharmacology with behavioral stimulation—such as exercise or other rewarding experiences that activate dopamine pathways—might help recover adaptive plasticity in adults affected by developmental circuit deficits.
Future work will define the molecular signals microglia use to influence bouton growth. Stowell and colleagues plan to apply pharmacological manipulations of specific microglial signaling pathways and single-cell sequencing to reveal the cellular mechanisms that make the adolescent frontal cortex uniquely malleable.
Kuan Hong Wang, PhD, professor of Neuroscience and Pharmacology and Physiology at the University of Rochester Medical Center, served as lead author on the 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 credit: Neuroscience News
Original Research (open access): “Dopaminergic signaling regulates microglial surveillance and adolescent plasticity in the mouse frontal cortex” by Rianne Stowell et al., published in Nature Communications. DOI: 10.1038/s41467-025-63314-4
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, characterized by elevated structural plasticity in the mesofrontal dopaminergic circuit. The cellular and molecular drivers of that plasticity have remained unclear.
This study shows that microglia are highly responsive to mesofrontal dopamine signaling during adolescence. Longitudinal in vivo two-photon imaging in mice revealed that rewarding experiences or optogenetic stimulation increased microglial surveillance of cortical tissue and dopaminergic axonal boutons. Microglial contacts with dopamine axons consistently preceded bouton formation, and interactions between microglia and boutons were modulated by D1- and D2-type dopamine receptors across development. Additionally, microglial purinergic receptor P2RY12 signaling was necessary for enhanced surveillance and bouton formation during adolescence.
Together, these observations reveal bidirectional interactions between dopamine signaling and microglial behavior that drive adolescent frontal plasticity and identify candidate targets for restoring plasticity in the adult brain.