The Nonclassic Psychedelic Ibogaine Disrupts Cognitive Maps.

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.

Changes in functional connectivity preserve scale-free neuronal and behavioral dynamics.

Does the brain optimize itself for storage and transmission of information, and if so, how? The critical brain hypothesis is based in statistical physics and posits that the brain self-tunes its dynamics to a critical point or regime to maximize the repertoire of neuronal responses. Yet, the robustness of this regime, especially with respect to changes in the functional connectivity, remains an unsolved fundamental challenge. Here, we show that both scale-free neuronal dynamics and self-similar features of behavioral dynamics persist following significant changes in functional connectivity. Specifically, we find that the psychedelic compound ibogaine that is associated with an altered state of consciousness fundamentally alters the functional connectivity in the retrosplenial cortex of mice. Yet, the scale-free statistics of movement and of neuronal avalanches among behaviorally related neurons remain largely unaltered. This indicates that the propagation of information within biological neural networks is robust to changes in functional organization of subpopulations of neurons, opening up a new perspective on how the adaptive nature of functional networks may lead to optimality of information transmission in the brain.

Using Neuron Spiking Activity to Trigger Closed-Loop Stimuli in Neurophysiological Experiments.

Closed-loop neurophysiological systems use patterns of neuronal activity to trigger stimuli, which in turn affect brain activity. Such closed-loop systems are already found in clinical applications, and are important tools for basic brain research. A particularly interesting recent development is the integration of closed-loop approaches with optogenetics, such that specific patterns of neuronal activity can trigger optical stimulation of selected neuronal groups. However, setting up an electrophysiological system for closed-loop experiments can be difficult. Here, a ready-to-apply Matlab code is provided for triggering stimuli based on the activity of single or multiple neurons. This sample code can be easily modified based on individual needs. For instance, it shows how to trigger sound stimuli and how to change it to trigger an external device connected to a PC serial port. The presented protocol is designed to work with a popular neuronal recording system for animal studies (Neuralynx). The implementation of closed-loop stimulation is demonstrated in an awake rat.

Lose-Shift Responding in Humans Is Promoted by Increased Cognitive Load.

The propensity of animals to shift choices immediately after unexpectedly poor reinforcement outcomes is a pervasive strategy across species and tasks. We report here on the memory supporting such lose-shift responding in humans, assessed using a binary choice task in which random responding is the optimal strategy. Participants exhibited little lose-shift responding when fully attending to the task, but this increased by 30%-40% in participants that performed with additional cognitive load that is known to tax executive systems. Lose-shift responding in the cognitively loaded adults persisted throughout the testing session, despite being a sub-optimal strategy, but was less likely as the time increased between reinforcement and the subsequent choice. Furthermore, children (5-9 years old) without load performed similarly to the cognitively loaded adults. This effect disappeared in older children aged 11-13 years old. These data provide evidence supporting our hypothesis that lose-shift responding is a default and reflexive strategy in the mammalian brain, likely mediated by a decaying memory trace, and is normally suppressed by executive systems. Reducing the efficacy of executive control by cognitive load (adults) or underdevelopment (children) increases its prevalence. It may therefore be an important component to consider when interpreting choice data, and may serve as an objective behavioral assay of executive function in humans that is easy to measure.

Acute Δ-9-tetrahydrocannabinol administration in female rats attenuates immediate responses following losses but not multi-trial reinforcement learning from wins.

Δ-9-Tetrahydrocannabinol (THC) is the main psychoactive component of marijuana and has potent effects on decision-making, including a proposed reduction in cognitive flexibility. We demonstrate here that acute THC administration differentially affects some of the processes that contribute to cognitive flexibility. Specifically, THC reduces lose-shift responding in which female rats tend to immediately shift choice responses away from options that result in reward omission on the previous trial. THC, however, did not impair the ability of rats to flexibly bias responses toward feeders with higher probability of reward in a reversal task. This response adaptation developed over several trials, suggesting that THC did not impair slower forms of reinforcement learning needed to choose among options with unequal utility. This dissociation of THC's effects on innate/rapid and learned/gradual decision-making processes was unexpected, but is supported by emerging evidence that lose-shift responding is mediated by neural mechanisms distinct from those involved in other forms of reinforcement learning. The present data suggest that, at least in some tasks, the apparent reductions in cognitive flexibility by THC may be explained by the immediate effects on loss sensitivity, rather than impairments of all processes used for choice adaptation.