by Pat Harriman, University of California, Irvine

Distinct RSC neuronal circuits corresponding to M2- and AD-projection neurons revealed by retrograde adeno-associated (rAAV2-retro) virus and anterograde AAV-SynaptoTAG2 virus. Credit: Molecular Psychiatry (2024). DOI: 10.1038/s41380-024-02819-8

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, published in 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."

The RSC is linked to multiple regions of the brain. The team focused on two main pathways: the M2-projecting, which is connected to the secondary motor cortex, and the AD-projecting, which is connected to the anterior thalamus. M2 neurons are involved in turning spatial thought into action, while the AD neurons are vital for remembering specific locations.

To observe these circuits in action, researchers used advanced viral tools to map and manipulate the connections separately and evaluate the effects. They found that blocking M2-projecting neurons made it more difficult to remember where objects were located and to associate specific places with actions. Inhibiting AD-projecting neurons only diminished memory of objects' location.

"We are expanding on these results to explore additional pathways within the RSC, examining how different types of neurons impact memory and spatial orientation," Xu said.

"Our goal is to build a map of the brain's 'GPS system.' This will not only increase our knowledge of how we navigate our world and form memories of it, but also help identify specific brain cells and their pathways contributing to various disorders such as Alzheimer's disease and develop treatments that target them."

Other team members were Xiaoxiao Lin, Ali Ghafuri, Xiaojun Chen and Musab Kazmi, all current or former members of Xu's lab; and co-corresponding author Douglas A. Nitz, professor and chair of cognitive science at UC San Diego.

More information: Xiaoxiao Lin et al, Projection-specific circuits of retrosplenial cortex with differential contributions to spatial cognition, Molecular Psychiatry (2024). DOI: 10.1038/s41380-024-02819-8

Journal information: Molecular Psychiatry 

Provided by University of California, Irvine