Psilocybin's active metabolite psilocin increases activity in the medial prefrontal cortex (mPFC), a brain region rich in 5-HT2A receptors. A specific population of neurons in the prelimbic/anterior cingulate mPFC that express these receptors becomes more excitable and fires more in response to psilocin and a selective 5-HT2A receptor compound, effects dependent on both the receptor and Gα q signaling. A novel non-hallucinogenic psychedelic compound produced similar effects. These results point to membrane-bound 5-HT2A receptors and intracellular Gα q signaling as potential therapeutic targets for psychedelic-associated plasticity.
Activating norepinephrine-releasing neurons in the locus coeruleus (LC) of the mouse brain alters the default mode network (DMN). Chemogenetic stimulation of these neurons decreased cerebral blood volume and glucose uptake while increasing synchronous low-frequency fMRI activity in the frontal cortices of the DMN. Fiber photometry confirmed that LC-NE activation triggered norepinephrine release, enhanced calcium-weighted neuronal spiking, and reduced cerebral blood volume in the anterior cingulate cortex. These findings indicate that LC-NE changes the typical relationship between neuronal activity and blood volume in the frontal DMN. The activation also strengthened functional connectivity within the frontal DMN, an effect mediated by reduced inputs from retrosplenial and hippocampal regions.