Hariom Sharma1, Noel McGrory1, Giovannina Kirby1, Harold A Burgess1

Abstract: Disruptions in sensory gating contribute to several neuropsychiatric disorders, including schizophrenia, yet the neural mechanisms governing short-interval prepulse inhibition (PPI) remain incompletely understood. PPI is a conserved sensorimotor gating mechanism that relies on precise temporal processing of sensory inputs. Here, we identify a hindbrain circuit that selectively regulates PPI at short inter-stimulus intervals (ISIs) using the Gal4 driver lines y242 and y467. Both lines share overlapping expression in rhombomere 3, revealing this region as a critical locus for short-ISI PPI modulation. Functional analyses demonstrate that neurons within rhombomere 3 specifically regulate PPI at brief ISIs without affecting long-ISI PPI. Within this population, a medially located subpopulation of GABAergic neurons was identified, implicating inhibitory control as a key mechanism. Anatomical tracing shows that rhombomere 3 neurons project directly to the Mauthner (M) cell, a command neuron essential for startle responses. Consistently, the M cell expresses GABA receptor 5, and disruption of this receptor impairs PPI. Together, these findings define a rhombomere 3, Mauthner cell inhibitory pathway that gates sensorimotor responses at short ISIs, providing novel insight into the neural substrates of temporal processing and potential mechanisms underlying sensory gating deficits in neuropsychiatric disorders.

1National Institute of Child Health and Human Development, National Institute of Health, Bethesda, USA