Off-target Effects of DREADD Actuators Result in Attenuation of BOLD Responses to Optogenetic Stimulation

Motivation: DREADD is becoming more used in combination with fMRI, but its off-target effect in BOLD responses is less understood. Goal(s): Do the DREADD actuators affect BOLD responses in mice which have no specific DREADD receptors? Approach: We used optogenetic fMRI to investigate whether three different DREADD actuators (CNO, JHU37160, and DCZ) caused changes in evoked BOLD responses to optogenetic stimulation of M1 in mice without DREADD receptors. Results: We observed that the injection of DREADD actuators (CNO, JHU37160 and DCZ) caused overall attenuation of both positive and negative BOLD responses induced by optogenetic stimulation of M1. Impact: Our findings suggest that careful consideration for the DREADD actuator selection and control experiments for optimal dose are needed. This will have significant implications for chemogenetic fMRI studies.