Duncan NRI Melanie Samuel, Ph.D.

Recent breakthroughs in understanding brain disorders have highlighted surprising roles for non-neuronal cells—such as glial cells and blood vessels—in neuron health and resilience. In the Samuel Lab, we investigate how interactions between neurons and these other brain cell types affect development and disease outcomes. Our research combines genetic, molecular, and cellular approaches using human-derived brain models and in vivo systems. By uncovering shared mechanisms across neurodegenerative conditions like Alzheimer’s disease and epilepsy, we aim to identify conserved therapeutic targets for broad-impact interventions

One of our key research areas involves microglia, a type of glial cell that plays a crucial role in the brain's immune defense. While microglia protect the brain, they can also contribute to damage in some disease conditions. We have identified a neuron-derived signal that instructs microglia on whether to preserve or target neurons and their connections. Our research is exploring how to harness this signaling pathway to prevent disease progression. Ultimately, we aim to develop treatments that target microglial activity to safeguard neurons.

Another key aspect of our work focuses on understanding how the brain’s need for constant energy is supported by communication between blood vessels and neurons. This relationship is known as neurovascular coupling, and it is essential for brain health. We study how disruptions in vessel coupling are linked to aging and diseases like Alzheimer’s, where reduced blood flow and impaired clearance of harmful proteins promotes disease progression. Our discoveries have also highlighted unexpected roles for neuromodulators, such as dopamine, in regulating blood vessel function, which could impact a broad range of brain disorders.

Finally, we investigate how neurons form precise connections with one another, a process essential for thinking, learning, and memory. Disruptions in these connections, or synapses, often serve as early indicators of brain disease. Using advanced techniques like nanoscopic imaging, we explore how neurons establish the right connections within various brain circuits involved in vision, feeding, and dopamine production. Additionally, we aim to uncover pathways that enhance neuronal resilience in critical neural circuits, with the goal of improving the survival of both vulnerable endogenous neurons and transplanted neurons in preclinical therapeutic approaches.