Lasting dynamic effects of the psychedelic 2,5-dimethoxy-4-iodoamphetamine ((±)-DOI) on cognitive flexibility.

Psychedelic drugs can aid fast and lasting remission from various neuropsychiatric disorders, though the underlying mechanisms remain unclear. Preclinical studies suggest serotonergic psychedelics enhance neuronal plasticity, but whether neuroplastic changes can also be seen at cognitive and behavioural levels is unexplored. Here we show that a single dose of the psychedelic 2,5-dimethoxy-4-iodoamphetamine ((±)-DOI) affects structural brain plasticity and cognitive flexibility in young adult mice beyond the acute drug experience. Using ex vivo magnetic resonance imaging, we show increased volumes of several sensory and association areas one day after systemic administration of 2 mgkg-1 (±)-DOI. We then demonstrate lasting effects of (±)-DOI on cognitive flexibility in a two-step probabilistic reversal learning task where 2 mgkg-1 (±)-DOI improved the rate of adaptation to a novel reversal in task structure occurring one-week post-treatment. Strikingly, (±)-DOI-treated mice started learning from reward omissions, a unique strategy not typically seen in mice in this task, suggesting heightened sensitivity to previously overlooked cues. Crucially, further experiments revealed that (±)-DOI's effects on cognitive flexibility were contingent on the timing between drug treatment and the novel reversal, as well as on the nature of the intervening experience. (±)-DOI's facilitation of both cognitive adaptation and novel thinking strategies may contribute to the clinical benefits of psychedelic-assisted therapy, particularly in cases of perseverative behaviours and a resistance to change seen in depression, anxiety, or addiction. Furthermore, our findings highlight the crucial role of time-dependent neuroplasticity and the influence of experiential factors in shaping the therapeutic potential of psychedelic interventions for impaired cognitive flexibility.

Dopamine-independent effect of rewards on choices through hidden-state inference.

Dopamine is implicated in adaptive behavior through reward prediction error (RPE) signals that update value estimates. There is also accumulating evidence that animals in structured environments can use inference processes to facilitate behavioral flexibility. However, it is unclear how these two accounts of reward-guided decision-making should be integrated. Using a two-step task for mice, we show that dopamine reports RPEs using value information inferred from task structure knowledge, alongside information about reward rate and movement. Nonetheless, although rewards strongly influenced choices and dopamine activity, neither activating nor inhibiting dopamine neurons at trial outcome affected future choice. These data were recapitulated by a neural network model where cortex learned to track hidden task states by predicting observations, while basal ganglia learned values and actions via RPEs. This shows that the influence of rewards on choices can stem from dopamine-independent information they convey about the world's state, not the dopaminergic RPEs they produce.

Lights, fiber, action! A primer on in vivo fiber photometry.

Fiber photometry is a key technique for characterizing brain-behavior relationships in vivo. Initially, it was primarily used to report calcium dynamics as a proxy for neural activity via genetically encoded indicators. This generated new insights into brain functions including movement, memory, and motivation at the level of defined circuits and cell types. Recently, the opportunity for discovery with fiber photometry has exploded with the development of an extensive range of fluorescent sensors for biomolecules including neuromodulators and peptides that were previously inaccessible in vivo. This critical advance, combined with the new availability of affordable "plug-and-play" recording systems, has made monitoring molecules with high spatiotemporal precision during behavior highly accessible. However, while opening exciting new avenues for research, the rapid expansion in fiber photometry applications has occurred without coordination or consensus on best practices. Here, we provide a comprehensive guide to help end-users execute, analyze, and suitably interpret fiber photometry studies.

Publisher Correction: Predictive and reactive reward signals conveyed by climbing fiber inputs to cerebellar Purkinje cells.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Predictive and reactive reward signals conveyed by climbing fiber inputs to cerebellar Purkinje cells.

There is increasing evidence for a cerebellar contribution to cognitive processing, but the specific input pathways conveying this information remain unclear. We probed the role of climbing fiber inputs to Purkinje cells in generating and evaluating predictions about associations between motor actions, sensory stimuli and reward. We trained mice to perform a visuomotor integration task to receive a reward and interleaved cued and random rewards between task trials. Using two-photon calcium imaging and Neuropixels probe recordings of Purkinje cell activity, we show that climbing fibers signal reward expectation, delivery and omission. These signals map onto cerebellar microzones, with reward delivery activating some microzones and suppressing others, and with reward omission activating both reward-activated and reward-suppressed microzones. Moreover, responses to predictable rewards are progressively suppressed during learning. Our findings elucidate a specific input pathway for cerebellar contributions to reward signaling and provide a mechanistic link between cerebellar activity and the creation and evaluation of predictions.