Cellular Imaging May Link Brain Insulin Resistance to Neurodegeneration

Li Ye, Ph.D.

Scripps Research Institute

Grant Program:

David Mahoney Neuroimaging Program

Funded in:

September 2018, for 3 years

Funding Amount:


Lay Summary

Cellular imaging may link brain insulin resistance to neurodegeneration

This animal model study may help reveal how reduced sensitivity to insulin in the brain in Type 2 diabetes relates to neurodegeneration. Type 2 diabetes is characterized by the body’s reduced sensitivity to the glucose-lowering hormone insulin. This “insulin resistance” affects brain energy metabolism and may directly influence cognitive functions that are associated with changes in structural and functional connections. The changes are correlated with higher risks of developing neurodegeneration.

Identifying how insulin resistance occurs in the brain, therefore, requires mapping brain-wide connectivity while simultaneously gaining information on molecular activities in brain cells. Conventional imaging does not have the capacity to do this, although it has identified several brain areas that are activated when insulin is administered. Related basic studies have identified molecules that are abundant in those activated areas. Now a series of technological innovations makes it possible in laboratory animals to simultaneously image the whole brain with enough resolution to visualize single cells and molecular markers on the cells. With this technique, called CLARITY, the brain becomes a transparent “matrix” where a “light sheet” microscope can provide a 3-D scan of the animal’s entire brain with unprecedented speed and resolution.

The investigators hypothesize that with CLARITY, they can quantitively analyze brain insulin resistance encompassing heterogeneous abnormalities in cells’ molecules and connections across multiple brain regions. The Scripps investigator, who was part of the group that developed CLARITY, will map all brain elements that are activated when insulin is administered in insulin-resistant and healthy animal models. He and his colleagues will compare the maps to establish the neurobiological basis of insulin resistance.

First, they will look for molecular biomarkers of all insulin-responsive neurons. Then they will map all neuronal connections and determine if the connections change when the animals develop insulin resistance. If so, they will be able to link each neuron’s molecular and connectivity features, providing an essential step in establishing a causal relationship between insulin resistance and neurodegeneration.


Cellular imaging may link brain insulin resistance to neurodegeneration

Acute metabolic disruption can severely injure the brain. However, it is less known how chronic, mild metabolic stress affects the structure and function of the brain. Insulin resistance (IR), a hallmark of type 2 diabetes and aging, is strongly associated with dementia and other neurodegenerative diseases. Unlike its peripheral counterpart, brain insulin resistance is poorly understood. There is a large gap between human and pre-clinical studies as it has been very difficult to link brain-wide activity/connectivity to molecular changes at the cellular level (primarily identified from the hypothalamus). This represents a general and long-standing challenge in neuroscience, due to the lack of imaging modality with sufficient scope to map brain-wide connectivity and simultaneously, to access molecular information at the cellular level, which would be essential for establishing the full landscape of central insulin resistance. A series breakthroughs (termed “CLARITY”) have recently been achieved such that an intact mammalian brain can be transformed into a hydrogel-tissue matrix, rapidly imaged with a lightsheet microscope at sub-cellular resolution, and computationally analyzed for the connectivity and molecular features within the same image volume. Here, we will leverage the power of this multi-scale imaging platform, together with a mouse model of IR, to test the hypothesis that brain IR encompasses heterogeneous yet spatially unique molecular and connectivity abnormality across multiple brain regions. The establishment of an unbiased multi-scale, multi-modal brain map of insulin actions will serve as the foundation for early detection of central insulin resistance and associated diseases as well as for better understanding the mechanistic link between metabolic dysfunction and neurodegeneration.

Investigator Biographies

Li Ye, Ph.D.

Dr. Li Ye is an Assistant Professor in the Department of Neuroscience and Molecular Medicine at The Scripps Research Institute in La Jolla, CA. He received his Ph.D. from Harvard University under the guidance of Professor Bruce Spiegelman, where he used chemical biology approaches to understand the molecular basis of insulin resistance and Type 2 Diabetes. Dr. Ye completed his postdoctoral training with Professor Karl Deisseroth at Stanford University, during which he focused on developing and applying whole-brain circuit mapping technologies. He joined the Dorris Neuroscience Center at the Scripps Research Institute in January 2018. Dr. Ye has extensive expertise in both metabolism and neuroscience. His lab is interested in how the brain adapts to both acute and chronic metabolic changes and how such adaptation, in turn, affects the control of organismal physiology and behaviors by the CNS, at the biochemical, cellular, as well as the systems levels. The long-term goal of the lab is to harness the molecular and circuit mechanisms underlying these adaptations to target metabolic disorders and neurodegenerative diseases.