An analog of psychedelics restores functional neural circuits disrupted by unpredictable stress

Introduction

Stress caused by unpredictable adverse events can produce widespread synaptic, circuit, and behavioural disturbances and is implicated in many psychiatric disorders. Previous rodent work has shown region-specific dendritic atrophy and spine loss (for example in hippocampus, medial prefrontal and somatosensory cortices), disruption of excitation–inhibition balance, and resultant impairments in anxiety regulation, sensory processing, and cognitive flexibility. Although classical psychedelics (LSD, psilocybin, DMT and related compounds) have returned to clinical research because of promising efficacy in depression, anxiety and addiction, their hallucinogenic properties limit therapeutic use. Tabernanthalog (TBG), a synthetic analogue of 5-MeO-DMT, was reported to have antidepressant and anti-addictive potential without producing the mouse head-twitch response, but its ability to reverse stress-induced structural and functional brain changes was not known. Lu and colleagues set out to test whether a single post-stress dose of TBG could reverse behavioural deficits produced by an unpredictable mild stress (UMS) protocol in mice, and to determine the underlying neural circuit mechanisms. Specifically, the study examined anxiety-like behaviour, sensory discrimination and cognitive flexibility, dendritic spine dynamics on cortical pyramidal neurons, mesoscopic and cellular calcium activity in barrel cortex during whisking and texture discrimination, and intrinsic excitability of parvalbumin-expressing inhibitory interneurons (PV+ INs). The goal was to link behavioural rescue with synaptic and network-level changes induced by TBG in the stressed brain.