Princeton neuroscience researchers Sam Wang, Ph.D., and Esra Sefik, Ph.D., were recently awarded a New Jersey Alliance for Clinical and Translational Science (NJ ACTS) pilot grant to investigate how dendrites, the nerve-cell branches that connect neurons, change over time. Their goal: to better understand neurological disorders like schizophrenia and Alzheimer’s disease, in which these dendritic structures often go awry. 

“Dendritic spines are a fundamental unit of processing, learning and development in the brains of all mammals, whether mouse, human, or any other mammal,” said Wang, a professor of neuroscience at the Princeton Neuroscience Institute. “So, understanding how these spines change is of fundamental importance in learning how brains develop and learn.” 

The pilot grant from NJ ACTS helps bridge basic discoveries like these to clinical interventions, ensuring that fundamental research quickly translates into tangible benefits for neurological disorders.

“This award funds a path which leads from basic research to practical applications,” said Wang. “It is often difficult to navigate this pipeline because basic research and clinical research have different priorities, so it is great to have a source of support that allows us to bridge that gap.” 

Spines are key to brain health

The research project delves into the complex topic of how the brain grows and develops. A sizable portion of the brain is made up of nerve cells called neurons which form connections with each other so that much of the brain’s architecture is a vast network of interconnecting neurons. These connections are the main pathways for information, in the form of electrical and chemical signals, to pass between different areas of the brain, and hence allow an organism to think, move, communicate, and learn. Neurons establish connections at synapses, which are formed when the axon of one neuron approaches the dendrite of another. Axons are long thin fibers that participate in sending messages, while dendrites are branching extensions responsible for receiving information. The actual connections occur when small, microscopic protrusions located on dendrites, called “dendritic spines,” attach to the distal terminations of axons to create most synapses.

Dendritic spines adapt and shift based on brain activity, a phenomenon known as plasticity. This plasticity is essential for learning and memory, but certain spine alterations may contribute to serious health problems, including cognitive decline or psychiatric disorders such as autism spectrum disorder, schizophrenia, and Alzheimer’s disease.

“This suggests that spine plasticity could serve as a shared therapeutic target for multiple disorders,” said Sefik, who has been working in the Wang lab as a C.V. Starr postdoctoral fellow for the past three years. 

Long-term observations of spine changes in intact, functioning brains, however, are rare. Researchers often lack the tools to track large numbers of rodents over extended periods at fine-grained resolution, while also monitoring learning and memory. 

To fill that gap, Wang and Sefik aim to develop a testing platform that uses innovative tools and techniques to address a variety of neuropsychiatric disorders and cognitive dysfunctions. 

Photons and “crystal” skulls 

One of the Wang Lab’s cutting-edge approaches supported by the grant is multiphoton imaging, which uses bursts of photons to create three-dimensional images of neurons in live animals. 

“This technique allows us to track the structural plasticity of the neuronal structures in an intact brain of different mouse models over the period of a month,” said Sefik. “So, every single day, I can use these techniques to locate the same exact neurons, the same exact dendrites and then track any changes that happen to the structure of the dendrite over a thirty-day period.”

To image the brain with minimal invasiveness, the researchers will also employ a novel “crystal episkull” method originally developed by former Wang Lab postdoc, Henk-Jan Boele. Now refined for early developmental stages of postnatal life, the technique renders a mouse’s skull transparent, enabling repeated, high-resolution observations of dendritic spines for weeks without removing or damaging the skull. 

“The ‘crystal episkull’ technique is a novel approach for minimally invasive optical access to the living brain, with few precedents,” said Sefik. “Our lab is at the forefront of pioneering its application in imaging neuropsychiatric and neurodevelopmental disease models, in parallel with studying cognitive function.” 

NJ ACTS advances clinical transformations through translational science

The research is in keeping with the larger goals of NJ ACTS, one of which is to advance clinical and translational science. Translational science generates innovations, approaches or processes that overcome longstanding challenges or bottlenecks and seeks to transform the way research is done for a range of diseases, making it faster, more efficient and more impactful.

Sefik and Wang received the Translational Science Pilot Award in October 2024, which will help them gather preliminary data to build on as they work towards undertaking a larger project. 

“These kinds of grants allow us to gather the preliminary data we need to be able to become more competitive for bigger grants and funding opportunities,” Sefik said. “It is a great opportunity.” 

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Princeton Researchers Interested in Applying for NJ ACTS grants

Dr. Dan Notterman, the Princeton lead and Deputy Director for NJ ACTS, encourages Princeton researchers interested in applying for pilot funding to visit the program’s website and contact the on-campus manager, Bianca Freda, for more information.

The NJ ACTS pilot program is currently supported by a Clinical and Translational Science Award grant (UM1TR004789) from the National Center for Advancing Translational Sciences at the National Institutes of Health.