A Stanford Medicine‑led study shows the human brain has two independent, ancient nervous systems—the forebrain/midbrain and the hindbrain—that originate from separate progenitor cells during development.

Researchers traced two distinct progenitor populations during gastrulation—Otx2‑expressing cells for the forebrain/midbrain and Gbx2‑expressing cells for the hindbrain—each following separate chromatin configurations with no overlap.

The hindbrain, or brain stem, controls automatic functions like breathing, heartbeat, and swallowing, while the forebrain/midbrain is responsible for higher‑level tasks such as language and abstract reasoning.

Evolutionary analysis suggests this dual-origin pattern is conserved across species, from chickens and zebrafish to acorn worms and even ancient links to jellyfish, indicating two neural systems that have remained spatially united for hundreds of millions of years.

The findings offer a new framework for brain‑stem–related disease research and open avenues for regenerative therapies, including potential connections to appetite regulation via hindbrain circuits relevant to obesity treatments.

Understanding the two‑origin model explains why producing hindbrain neurons in the lab has been difficult and enables the growth of functional hindbrain neurons from pluripotent stem cells for study and therapeutic exploration.

The work, published in Nature Neuroscience on September 18, was led by senior author Kyle Loh with Jokhai and Dundes as co‑first authors, based on embryonic development and chromatin studies in mouse models.

The study demonstrates that hindbrain neurons can be produced in vitro, displaying action potentials and hindbrain‑specific protein markers, a breakthrough for research into diseases affecting brain‑stem neurons such as SMA and ALS.