Structure of neuronal log firing rate reorganisation in psychedelic and intrinsic brain state transitions

How psychedelic drugs modulate the activity of neuronal populations is not well understood. Such compounds have been highly restricted for several decades leaving a considerable gap in knowledge. In order to understand the effects of psychedelics at microcircuit level, we used Neuropixels probes to record from large populations of neurons in medial prefrontal cortex (mPFC), primary visual cortex (V1), hippocampus (HPC) and thalamus of mice given the psychedelic TCB-2. We examined the diversity of neuronal firing via the distribution of log firing rates. TCB-2 ingestion significantly stretched the distribution of log firing rates of neurons in mPFC and HPC but not in V1 or thalamus. Repeated administration on consecutive days attenuated the stretching effect of TCB-2 in mPFC. We then asked if features of the stretching were shared across different brain state transitions. We found that modulation of the width of the log-rate distribution occurred in multiple areas of the cortex and in the hippocampus even in awake drug-free mice, driven by intrinsic fluctuations in their arousal level and by sleep to wakefulness transitions in rat frontal cortex. In both psychedelic and naturally occurring brain state transitions, stretching or squeezing of the log-rate distribution of an entire neuronal population reflected concomitant changes in two subpopulations, with one subpopulation undergoing downregulation and often also stretching of its neurons’ log-rate distribution, while the other subpopulation undergoes upregulation and often also a squeeze of its log-rate distribution. In both subpopulations, the stretching and squeezing were a signature of a greater relative impact of the brain state transition on the rates of the slow-firing neurons. These findings reveal that intrinsic and induced brain state changes share a generic pattern of reorganisation of neuronal log firing rates.