Researchers Unveil New Insights into Human Forebrain Development
A team of scientists from the University of California San Diego School of Medicine conducted a study that provides a new understanding of how the human forebrain develops.
The study, led by Changuk Chung, Ph.D., and Xiaoxu Yang, Ph.D., both from the laboratory of Joseph G. Gleeson, M.D., Department of Neurosciences at the School of Medicine and the Rady Children’s Institute for Genomic Medicine, provides a greater understanding of how the human brain develops at the cellular level.
The study also presents evidence for the existence of inhibitory neurons called dInNs in the human brain, which have distinct origins compared to other species like mice. These findings have significant implications for understanding brain diseases and improving models of brain function and disease. The research findings were recently published in the journal Nature.
Functionality and Importance of the Forebrain
The forebrain, also known as the cerebral cortex, is the largest part of the brain and plays a crucial role in a wide range of functions, including cognitive thought, vision, attention, and memory. Neurons, the individual circuits of the brain, can either be excitatory or inhibitory. While excitatory neurons function as “on” switches, inhibitory neurons typically function as “off” switches.
According to Joseph G. Gleeson, M.D., mice, commonly used in brain studies, have inhibitory neurons that originate deep within the developing brain. The study challenges this model by evaluating cellular lineage and reveals the existence of dInNs, which are absent in mice. Understanding the specific type of inhibitory neuron found in humans can provide valuable insights into how the human brain is unique.
Gleeson further explains, “We expect dInNs to support new, more accurate models of human brains. This updated brain model may help explain the origins of certain conditions like epilepsy, schizophrenia, or autism.”
Cellular Lineage and Brain Structure
The research team was particularly interested in investigating the cellular lineage of mosaic variants of brain cells. When two cells share the same mother cell, they are considered to have the same lineage, similar to how family names function in people.
By directly analyzing brains from two neurotypical donors, the team traced the origin of cells using mosaic variants and identified sister cells born in the same brain region. They discovered that some inhibitory and excitatory neurons share the same lineage, indicating that the two neuron types branched during late embryonic cerebral development. This cellular relationship is distinctive to humans and is not present in other species.
These research findings are expected to help other scientists generate improved models of neurological diseases and deepen the understanding of impaired brain development and its association with certain types of brain diseases.
Reference: “Cell-type-resolved mosaicism reveals clonal dynamics of the human forebrain” by Changuk Chung, Xiaoxu Yang, Robert F. Hevner, Katie Kennedy, Keng Ioi Vong, Yang Liu, Arzoo Patel, Rahul Nedunuri, Scott T. Barton, Geoffroy Noel, Chelsea Barrows, Valentina Stanley, Swapnil Mittal, Martin W. Breuss, Johannes C. M. Schlachetzki, Stephen F. Kingsmore, and Joseph G. Gleeson, published on April 10, 2024, in the journal Nature. DOI: 10.1038/s41586-024-07292-5.
This work was supported by National Institute of Mental Health (NIMH) grants U01MH108898, R01MH124890, and R21MH134401; a Larry L. Hillblom Foundation Grant; a Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) grant K99HD111686; a 2021 NARSAD Young Investigator Grant from the Brain & Behavior Research Foundation; and the Rady Children’s Institute for Genomic Medicine.
