Quantifying the neurophysiological effects of 5-HT_2A receptor activation on cortico-limbic and cortico-striatal network dynamics in rats

Abstract

5-Hydroxytryptamine 2A (5-HT_2A) receptor activation may contribute to the psychotomimetic and/or antidepressant effects of psychedelic drugs. 5-HT_2A agonists induce broadband changes in neural population activity, including high frequency oscillations (HFO) spanning diverse brain regions, however, the mechanisms and relevance of these oscillations remain unclear. I therefore quantified the effects of a selective 5-HT_2A agonist 25I-NBOH (25I) on the behaviour and neurophysiology of freely-behaving adult rats.

Local field potentials (LFP) were recorded from rats with electrodes arrays implanted in either cortico-limbic (prefrontal cortex, hippocampus, amygdala; n=5) or cortico-striatal (prefrontal cortex, hippocampus, nucleus accumbens; n=4) circuits. I developed an analysis pipeline encompassing video tracking of behaviour, spectral analysis, functional connectivity, and dynamic causal modelling (DCM).

25I induced visible behavioural changes, though quantification was limited by video resolution and sample size. Spectral analysis confirmed the emergence of HFO throughout cortico-limbic and cortico-striatal circuits, except in hippocampus. Functional connectivity analysis identified increased coupling between the amygdala and prefrontal cortex and implicated the nucleus accumbens as a likely source of HFO. Unexpectedly, changes in undirected (Fourier coherence) and directed (Granger causality) measures of functional connectivity were dissociable, highlighting different facets of these analyses and their interpretation.

DCM was used to model 25I’s effects on the cortico-limbic circuit and identified (1) increases in top-down control of amygdala by prefrontal cortex, which may contribute to the antidepressant and anxiolytic effects of psychedelic drugs, and (2) disrupted top-down cortico-hippocampal connections, which may reflect psychotomimetic effects of 5HT_2A -agonists. DCM also indicated that the effects of 25I on deep pyramidal neurons in the prefrontal cortex contributed to HFO.

This integrated pipeline enabled greater insights into the effects of 5-HT_2A agonism on cortico-limbic and cortico-striatal dynamics than achievable using individual analyses, exemplifying how computational measures and models allow cellular- and synaptic-resolution inferences from translational measures of neural population activity.

Date of Award	23 Mar 2021
Original language	English
Awarding Institution	University of Bristol
Sponsors	Medical Research Council
Supervisor	Matt W Jones (Supervisor) & Matt Hickman (Supervisor)