Lysergic acid diethylamide pretreatment prolongs brain-stimulation induced neural activity changes

A leading theory for how psychedelics are able to produce robust clinical improvement and preclinical behavioral changes is that psychedelics act through neuroplastic mechanisms to induce lasting structural and functional alterations in neural circuits. However, psychedelics produce these effects across wide swaths of the brain. Based on our prior work, we hypothesized that engaging a specific brain circuit with focal brain stimulation during the window of enhanced plasticity produced by psychedelics would lead to more persistent alterations in the activity of that circuit. To test this, we administered either saline (SAL) or lysergic acid diethylamide (LSD) to rats 24 h prior to electrical stimulation targeting the rat infralimbic cortex (IL). Brain activity was recorded before, during, and after stimulation using depth electrodes implanted in four bilateral corticostriatal regions. To assess changes in neural activity, we trained general logistic classifiers to distinguish between time points (e.g., pre-stimulation vs. post-stimulation) and then compared model performances across groups (e.g., LSD vs. SAL). As such, model performance represents the degree of difference between the two neural states (pre vs. post), and a significant difference between groups indicates a larger change in brain activity in one group. We found that LSD pretreatment, compared to SAL, resulted in larger and longer-lasting changes in brain activity following stimulation. Immunohistochemistry revealed that stimulation led to the activation of the mTOR signaling pathway, and the combination of LSD and stimulation was associated with alterations in perineuronal net (PNN) integrity. Regardless of pretreatment, brain activity states recorded during stimulation did not capture the brain state that persisted in the minutes or days that followed. This work has important implications for understanding the general effects of brain stimulation and provides strong support for the development of psychedelic-assisted brain stimulation approaches. By demonstrating that psychedelic pretreatment can extend the durability of brain stimulation-induced changes in activity, these results motivate additional research in psychedelic-assisted brain stimulation to reduce relapse rates, which currently limit the impact of non-invasive stimulation treatments.