Irvine, Calif., Nov. 14, 2024 — Researchers led by the University of California, Irvine are the first to reveal how two neural circuits located in the brain’s retrosplenial cortex are directly linked to spatial navigation and memory storage. This discovery could lead to more precise medical treatments for Alzheimer’s disease and other cognitive disorders by allowing them to target pathway-specific neural circuits.

The study, recently published online in the journal Molecular Psychiatry, identified two types of RSC pathways, connected to different parts of the brain, each with its own pattern of inputs and functions.

“By demonstrating how specific circuits in the RSC contribute to different aspects of cognition, our findings provide an anatomical foundation for future studies and offer new insights into how we learn and remember the space around us,” said lead and co-corresponding author Xiangmin Xu, UC Irvine Chancellor’s Professor of anatomy and neurobiology and director of the campus’s Center for Neural Circuit Mapping. “This is an important step in understanding how conditions like Alzheimer’s disease and other neurodegenerative disorders affect particular regions of the brain, which will help to inform new approaches and treatments.”

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We’re thrilled to announce the release of our newest newsletter! This edition acknowledges our members’ achievements and highlights what to look forward to this year and beyond. Inside, you’ll find a closer look at our Viral Core updates, upcoming conference and seminar announcements, and more. Dive in to discover what we’ve been up to and how you can get involved!

The full newsletter can be read here.

Irvine, Calif., Aug. 6, 2024 — Researchers led by the University of California, Irvine have discovered how the TREM2 R47H genetic mutation causes certain brain areas to develop abnormal protein clumps, called beta-amyloid plaques, associated with late-onset Alzheimer’s disease. Leveraging single-cell Merfish spatial transcriptomics technology, the team was able to profile the effects of the mutation across multiple cortical and subcortical brain regions, offering first-of-their-kind insights at the single-cell level.

The study, recently published online in the journal Molecular Psychiatry, compared the brains of normal mice and special mouse models that undergo changes like those in humans with Alzheimer’s.

Findings revealed that the TREM2 mutation led to divergent patterns of beta-amyloid plaque accumulation in various parts of the brain involved in higher-level functions such as memory, reasoning and speech. It also affected certain cell types and their gene expression near the plaques.

“Alzheimer’s disease progresses differently in individuals with various genetic risk factors,” said principal investigator Xiangmin Xu, UC Irvine Chancellor’s Professor of anatomy and neurobiology and director of the campus’s Center for Neural Circuit Mapping. “By profiling known mutations, we can develop early, personalized treatments before cognitive decline begins.”

Team members analyzed 19 sections of mouse brains and more than 400,000 cells using a special technique called Merfish to see how they were affected by the Alzheimer’s-related mutations. They were able to examine the expression patterns of genes, providing insight into how they are regulated, contribute to cellular functions and respond to stimuli. Their analysis showed that disparate mutations, like TREM2 R47H, cause changes in the ways microglia and astrocyte cells react to inflammation, as well as how neurons communicate and support brain health.

“Early intervention is key to preventing severe cognitive decline. This is the first study to look at the entire brain at such a detailed level, enabling us to gain a deeper understanding of how the TREM2 R47H mutation impacts gene expression in specific cell types,” Xu said. “These insights can help develop targeted therapies that address these changes and can lead to early intervention strategies that help prevent or slow down the progression of Alzheimer’s disease.”

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The UC Irvine Center for Neural Circuit Mapping has been awarded a five-year, $1.4 million National Institutes of Health T32 grant to establish a training program for Alzheimer’s disease research. The funds will support projects that hold significant promise for clinical translation to the condition, which remains one of our most pressing medical challenges. An interdisciplinary team of 29 faculty members will mentor and support pre- and postdoctoral fellows, employing state-of-the-art approaches to expand the mechanistic understanding of brain disorders through neural circuit mapping. This emerging field is anticipated to drive new therapeutic strategies in the coming decades. “The program will emphasize the development of novel tools and methodologies for early detection, diagnosis and treatment of Alzheimer’s disease and other dementias,” said principal investigator Xiangmin Xu, UCI Chancellor’s Professor of anatomy & neurobiology and director of the CNCM. “Age-related cognitive impairments represent both a major health and socioeconomic concern in the U.S. and globally. The next generation of scientists in this program will lead the charge in understanding and ultimately curing these complex neurological conditions.” Todd Holmes, professor of physiology & biophysics, is co-principal investigator.

Visit the UCI Newsroom Article for more information.

Research on the degu (Octodon degus) by members of the CNCM and Xu lab was recently featured in The Transmitter, a neuroscience-focused online publication. Calli McMurray’s piece recounts the history of degus in the study of Alzheimer’s disease, showcases our publication on degu neurodegenerative features, and comments on future directions for the model.

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