PLASTICITY OF INSULAR CORTEX NEURONS IN MICE TREATED WITH THE PSYCHEDELIC 5 MEO-DMT

The insular cortex (insula) is thought to integrate introspective and sensory information. Additionally, the activity of the anterior insula has been shown to positively correlate with anxiety levels, in both humans and mice. As various psychedelics emerge as anxiolytic and antidepressant compounds, the response of this understudied cortical region warrants attention. Among these compounds, 5-MeO-DMT offers a short half-life making it well suited for clinical use. Like many serotonergic psychedelics, 5-MeO-DMT binds serotonin 1A and 2A receptor subtypes, both receptors being highly expressed in the insular. First, we mapped the brain-wide projections of insula 1A+ or 2A+ neurons by injecting Cre-dependent viral vectors expressing fluorescent reporters in the insula of transgenic mice expressing Cre in either 1A+ or 2A+ neurons. Revealing insula circuits likely modulated by psychedelics. Second, to determine the short- and long-term impact of 5-MeO-DMT on insula neurons, we performed whole‑cell patch-clamp recordings of undefined pyramidal neurons, as well as 2A+ and 1A+ neurons. Passive and active electrophysiological properties, as well as synaptic features of anterior and posterior insula neurons were assessed 24 hours and 7 days after a single i.p. injection of 5-MeO-DMT. This work builds on our understanding of the cortical actions of psychedelics and other therapeutic serotonergic compounds, and further advances our knowledge of the neural circuits underlying anxiety.