Lysergic acid diethylamide modulates hippocampal and cortical local field potential oscillatory rhythms in male mice

Lysergic acid diethylamide (LSD) acutely reduces the power of electrical signals across multiple frequency bands in the hippocampus and, to a lesser extent, in the somatosensory and medial prefrontal cortices of freely-behaving male mice. The drug also increases variability in signal power between individual animals, suggesting effects that differ from one subject to another. These findings align with clinical neurophysiology data and support the entropic brain theory of psychedelic drug action. The study used intracranial EEG recordings to avoid the stress of physical restraint, providing the first such preclinical evidence of LSD's spectral signatures in freely-behaving mice.

Study at a glance

Abstract

Background and rationaleLysergic acid diethylamide (LSD) is a promising therapeutic for psychiatric disorders, but its physiological profile on the nervous system remains elusive. Rodent electrophysiological data has utilized in vivo single-unit electrophysiology recordings, while clinical neurophysiology studies have focused on spectral signatures using electroencephalography (EEG) and magnetoencephalography (MEG). No study to date has examined these spectral signatures in freely-behaving mice. Studying neural activity when an animal is physically restricted (i.e. head-fixed recordings) is stressful to animals, which informed our decision to avoid this confound of additional physical stress on observed effects. Moreover, how LSD acutely modulates intracranial oscillatory rhythms is not known.Experimental approachHere we present the first in vivo electrophysiological investigation of LSD's cortico-hippocampal effects in freely-behaving male C57BL/6J mice using intracranial EEG (iEEG) recordings. We did not posit a hypothesis concerning the specific effects of LSD on power spectral density (PSD) due to the lack of preclinical literature as well as LSD's promiscuous pharmacological profile. This study was purely exploratory.Key resultsFollowing intraperitoneal (IP) administration of 30 µg/kg LSD, there was a global decrease in PSD signal power in both broadband and discrete narrow band oscillatory rhythms of the ventral hippocampus CA1 and CA3 regions. Similar but less robust effects were observed in the somatosensory and medial prefrontal cortices. These data confer with the existing clinical neurophysiology data. Lastly, LSD increased between-subject PSD signal power variance, suggesting individual-specific effects.Conclusion and implicationsOur data lends further credibility to the entropic brain theory of psychedelic drug actions. We conclude that the preclinical intracranial acute spectral signatures of LSD coincide with their clinical counterparts. Further work is needed to study cross-regional connectivity, such as frequency coupling.