The Nonclassic Psychedelic Ibogaine Disrupts Cognitive Maps

Abstract

Background: The ability of psychedelic compounds to profoundly alter mental function has been long known, but the underlying changes in cellular-level information encoding remain poorly understood.

Methods: We used two-photon microscopy to record from the retrosplenial cortex in head-fixed mice running on a treadmill before and after injection of the nonclassic psychedelic ibogaine (40 mg/kg intraperitoneally).

Results: We found that the cognitive map, formed by the representation of position encoded by ensembles of individual neurons in the retrosplenial cortex, was destabilized by ibogaine when mice had to infer position between tactile landmarks. This corresponded with increased neural activity rates, loss of correlation structure, and increased responses to cues. Ibogaine had surprisingly little effect on the size-frequency distribution of network activity events, suggesting that signal propagation within the retrosplenial cortex was largely unaffected.

Conclusions: Taken together, these data support proposals that compounds with psychedelic properties disrupt representations that are important for constraining neocortical activity, thereby increasing the entropy of neural signaling. Furthermore, the loss of expected position encoding between landmarks recapitulated effects of hippocampal impairment, suggesting that disruption of cognitive maps or other hippocampal processing may be a contributing mechanism of discoordinated neocortical activity in psychedelic states.

Keywords: Neuronal avalanches; Path integration; Psychedelics; Retrosplenial cortex.

Figure 1

Ibogaine disrupts encoding of virtual position. (A) Illustration of experimental setup (bottom) and sample image showing segmented neurons (indicated by colored patches) within the field of view over the retrosplenial cortex (inset). Symbols on the treadmill belt indicate approximate locations of tactile cues. (B) Activity of 1 neuron as a function of position on the belt for several consecutive trials. Vertical lines indicate locations of tactile cues. The neuron selectively activates at one position prior to ibogaine but loses location specificity after injection. The right panel shows the change in session-averaged adjusted MI from baseline for all sessions (n = 17). (C) Session-averaged activity of position-tuned cells before (left panel) and after (center panel) injection of ibogaine for all sessions. Cells in both panels are ordered by a lag to peak activity before injection. The right panel shows the change in decoding error after injection of ibogaine. (D) The same as (C), but for saline injection. ∗p < .001. IBO, ibogaine; MI, mutual information; SAL, saline.

Figure 2

Population covariance. (A) Pairwise correlation of unit activity in 1 representative session prior to injection (left panel) and after saline injection. The middle panel has the same ordering as the left panel, and the right panel shows a reclustering of correlation patterns. (B) Pairwise correlation before and after injection of ibogaine in 1 session, showing that functional connectivity is reorganized and becomes less structured (fewer large blocks of high correlation) after injection. (C) Box plot of the change in clustering coefficient of the correlation matrices from baseline. The reduced clustering after ibogaine reflects a loss of dominant functional connectivity motifs. (D) Cumulative explained variance as a function of principal component factors, showing that signaling among neurons becomes more independent after ibogaine. ∗p < .0001. EV, explained variance; IBO, ibogaine; PCA, principal component analysis; SAL, saline.

Figure 3

Neural avalanches. (A) Diagram showing parametrization of avalanche size, duration, and quiescent period duration from the sum of thresholded activity among simultaneously recorded cells (blue trace). Λ is a scaling factor applied to each recording prior to generating grand averages over recordings. It is the product of the number of neurons and the mean firing rate of the population in the recording. (B) Frequency distributions of normalized avalanche size (left panel), avalanche duration (center panel), and quiet period duration (right panel) for baseline, saline administration, and ibogaine administration. Data in all plots show mean ± 1 SD computed over all sessions of each type. The arrow indicates the cutoff point for baseline. Insets show cumulative densities from large to small values. (C) Correlations among the size of an avalanche and the size of future avalanches. Right-side panel shows mean and standard deviation for successive avalanches in a window including the past 3 and future 3 events. (D) Correlation among duration of an avalanche and the duration of future quiescent periods. (E) Cross-correlation of avalanche size and the duration of past/current quiescent periods. These data show that ibogaine reduced correlation structure among events, but the properties of the events themselves (e.g., power-law slope of size, duration, and quiescent periods) were not affected much. This suggests that ibogaine had little effect on the propagation of network activity within the retrosplenial cortex. #p < .05 (statistical significance of correlation values). ∗∗∗∗p < .0001 (statistical difference of means). acorr, autocorrelation; CDF, cumulative distribution function; Ibo, ibogaine; xcorr, cross-correlation.