Wednesday, April 2, 2025
4/2/2025
Neural mechanisms of psilocybin action in the frontal cortex - PROJECT SUMMARY Serotonergic psychedelics are best known for altering perception, cognition, and mood. Recently, there has been a resurgence in clinical trials investigating psychedelics for their potential in treating neuropsychiatric illnesses, such as substance use disorder. Psilocybin-assisted therapy, for example, holds promise in treating alcohol, opioid, or stimulant addiction. It has received attention for showing positive, long-lasting effects after only a single treatment. Still, it is unknown how psilocybin acts on the brain immediately after administration to begin altering neuronal processing. This proposal aims to determine psilocybin’s cellular and microcircuit mechanisms of action in the mouse medial frontal cortex, with a specific focus on GABAergic interneurons and soma-dendrite coupling. Interneurons in the frontal cortex express serotonin receptors and likely respond to psilocybin to mediate changes in cortical information processing. Meanwhile, soma-dendrite coupling controls the efficiency of information flow in pyramidal neurons, thereby governing spike output, and it is associated with cognitive processing. In the medial frontal cortex, psilocybin-driven changes in microcircuit activity and soma-dendrite coupling may therefore underlie the cognitive state that accompanies a psychedelic experience. More importantly, these cellular and microcircuit-level changes may be linked to psilocybin’s therapeutic effects. In Aim 1 of this proposal, we will use two-photon calcium imaging to determine how psilocybin influences the activity of three dendrite-modulating interneuron populations in the medial frontal cortex. Additionally, we will examine whether the observed activity changes are mediated by specific serotonin receptors expressed in these interneuron populations. In Aim 2, we will use multi-plane calcium imaging to determine how psilocybin influences soma-dendrite coupling in pyramidal neurons of the medial frontal cortex. We will also perturb the activity of the three dendrite-modulating interneuron populations to determine their role in shaping soma-dendrite coupling during psilocybin action. The proposed experiments are designed to elucidate how psilocybin shapes cortical computations. In doing so, this proposal will advance our understanding of the neurobiology of psychedelics, specifically in the circuits that are important for executive function and impulse control, which will lead to improved treatments for addiction.
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