Human neuromodulatory assembloids to study serotonin signaling and disease

Dysfunction of these systems is often involved in neuropsychiatric disease and many drugs for these conditions act on these signaling pathways. Recent advances in stem cell biology have made it possible to derive a wide range of cells across the developing human nervous system in organoids and to functionally integrate them into assembloids, however they currently do not systematically incorporate neuromodulation.

Here, we generate a midbrain-hindbrain organoid (hMHO) from human induced pluripotent (hiPS) cells and fuse them with cortical organoids (hCO) to form neuromodulatory assembloids (hNMA). We focus on serotonin (5-hydroxytryptamine, 5-HT) as one key neuromodulator and find characteristic gene expression patterns and properties of the 5-HT neurons in the hMHO. In hNMA, 5-HT neurons project into hCO, release 5-HT and change cortical network activity.