Transcriptome-Inspired Spiking Simulations Uncover Human-Specific Prefrontal Dynamics and Provide a Mechanistic Platform for Species-Appropriate Disease Modeling.

Researchers have developed a detailed, biophysically realistic Hodgkin-Huxley spiking microcircuit of the human prefrontal cortex. By scaling ion-channel, receptor, and gap-junction conductances according to cell-type-specific gene expression, they were able to parameterize the circuit using single-nucleus RNA-seq data from both human and mouse prefrontal cortex (PFC).

When comparing the human-refined circuit to a mouse-refined circuit and a literature-derived baseline, the human model exhibited distinct differences in high-frequency oscillation (HFO) outputs. The human model generated strongly synchronized parvalbumin-positive (PV) activity and robust ripple- and fast-ripple-band power, while the mouse model remained asynchronous. This difference in oscillatory dynamics was statistically significant across seven different physiological and pathological states.

The human transcriptome was found to drive stronger PV-PV electrical coupling and stronger recurrent pyramidal excitation, which collectively synchronized the fast-spiking PV population into a coherent rhythm. This synchronization was then imposed on the local field potential through perisomatic inhibition. These findings suggest that the human-specific recalibration of PV-mediated coupling and excitation-inhibition balance is a key parameter that needs to be addressed for accurate human brain function modeling.

The study highlights the importance of transcriptome-informed spiking simulations as a powerful tool for uncovering species-specific computational principles and building mechanistically grounded, human-relevant models of prefrontal circuit dysfunction. By moving beyond generic rodent defaults, this approach enables targeted, species-appropriate modeling of neurological and psychiatric disorders, ultimately providing a more accurate platform for disease modeling.