How Stress Becomes Biology / Glial Dysfunction in Stress

The brain is not a finished structure. Long after development is complete, neural circuits continue to adapt to experience. Synaptic connections are strengthened or weakened, cellular interactions are reshaped, and patterns of activity are refined in ways that allow the brain to learn, remember, and respond to changing environmental needs.

The capacity for adaptation is one of the brain’s greatest strengths. It is also a source of vulnerability.

Stress is among the most powerful experiences capable of altering brain function, particularly within the neural circuits that govern reward, motivation, and decision-making. While the behavioral consequences of stress have been recognized for decades, the cellular mechanisms through which stressful experiences become embedded in brain circuits remain surprisingly unclear.

Our lab investigates the role of glia in this process.

We study how stress alters interactions between microglia and astrocytes within the brain’s reward circuitry, particularly the nucleus accumbens, a region that is involved in motivation, reward valuation, and goal-directed behavior. Although microglia are best known as the brain’s immune cells, they also remain active participants in circuit remodeling throughout life.

Our work has revealed one way this may occur. Following stress, microglia can directly interact with astrocytes and “prune” portions of their cellular processes. This changes the architecture of an astrocyte, altering the way their processes interact with synapses, regulate the chemical environment around neurons, and help control how information is transmitted through the circuit. When microglia remodel astrocytes, they may fundamentally alter the way reward circuits process experience.

We are particularly interested in adolescence, a developmental period when the reward circuitry remains highly plastic and responsive to the environment. Adverse experiences during this critical window, including social isolation, instability, and other forms of chronic stress leave traces that persist long after the experience itself has ended. These traces shape how we evaluate rewards, respond to opportunities, and engage with the world around us. In some individuals, they can increase vulnerability to addiction, depression, and other stress-related disorders. Yet the mechanisms through which these experiences become embedded within neural circuits remain largely unknown.

We believe changes in glial interactions may represent one of those mechanisms.

How does stress change microglial behavior? Why do microglia begin targeting astrocytes? How do these cellular interactions reshape neural circuit activity? And can preventing stress-induced glial remodeling preserve normal reward processing and behavioral function?

To answer these questions, we follow the biology across levels of organization, from glial interactions, to neural circuits, to behavior. We combine viral cell type-specific manipulations, super resolution and 3D confocal imaging, patch clamp electrophysiology, and ex vivo and in vivo calcium signaling with machine learning-driven behavioral analysis to establish causal relationships between stressful early-life experiences and the long-term changes they produce in the brain.

More broadly, we are driven by a fundamental question of resilience. Why do some individuals recover from adversity while others develop persistent alterations in behavior and mental health? Understanding how glia regulate these circuits may reveal mechanisms that help explain this difference and identify opportunities to intervene before vulnerability becomes disease.

Our goal is not simply to understand how stress changes the brain. It is to understand the cellular mechanisms that determine what the brain does with stress.