Cortical Correlates of Psychedelic-Induced Shaking Behavior Revealed by Voltage Imaging

Shaking behavior—head twitches in mice and wet dog shakes in rats—is a reliable indicator of psychedelic drug action, thought to involve serotonin 2A receptors on cortical pyramidal cells, though direct evidence in living animals has been limited. Using cell type-specific voltage imaging in awake mice, researchers expressed a voltage indicator in layer 2/3 pyramidal neurons and captured cortical activity while mice displayed psychedelic shaking behavior. Shaking was preceded by high-frequency oscillations and overlapped with low-frequency oscillations in the motor cortex, spectrally mirroring the rhythm of the shakes. These findings reveal a cortical fingerprint of serotonin-2A-receptor-mediated shaking behavior, linking a cross-mammalian psychedelic effect to cell-type specific brain dynamics.

Study at a glance

Abstract

(1) From mouse to man, shaking behavior (head twitches and/or wet dog shakes) is a reliable readout of psychedelic drug action. Shaking behavior like psychedelia is thought to be mediated by serotonin 2A receptors on cortical pyramidal cells. The involvement of pyramidal cells in psychedelic-induced shaking behavior remains hypothetical, though, as experimental in vivo evidence is limited. (2) Here, we use cell type-specific voltage imaging in awake mice to address this issue. We intersectionally express the genetically encoded voltage indicator VSFP Butterfly 1.2 in layer 2/3 pyramidal neurons. We simultaneously capture cortical hemodynamics and cell type-specific voltage activity while mice display psychedelic shaking behavior. (3) Shaking behavior is preceded by high-frequency oscillations and overlaps with low-frequency oscillations in the motor cortex. Oscillations spectrally mirror the rhythmics of shaking behavior and reflect layer 2/3 pyramidal cell activity complemented by hemodynamics. (4) Our results reveal a clear cortical fingerprint of serotonin-2A-receptor-mediated shaking behavior and open a promising methodological avenue relating a cross-mammalian psychedelic effect to cell-type specific brain dynamics.