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.

Protocol for tissue processing and paraffin embedding of mouse brains following ex vivo MRI.

Combining histology and ex vivo MRI from the same mouse brain is a powerful way to study brain microstructure. Mouse brains prepared for ex vivo MRI are often kept in storage solution for months, potentially becoming brittle and showing reduced antigenicity. Here, we describe a protocol for mouse brain dissection, tissue processing, paraffin embedding, sectioning, and staining. We then detail registration of histology to ex vivo MRI data from the same sample and extraction of quantitative histological measurements.

7,8-dihydroxyflavone enhances long-term spatial memory and alters brain volume in wildtype mice.

Introduction: 7,8-dihydroxyflavone (7,8-DHF) is a low molecular weight compound that can cross the blood brain barrier and has been implicated in numerous functions and behaviours. It is thought to have neuroprotective capability and has been shown to alleviate symptoms in a wide range of diseases. Methods: 7,8-DHF was administered systemically to wildtype mice during Morris water maze training. Long-term spatial memory was assessed 28 days later. Ex-vivo T2-weighted (T2w) imaging was undertaken on a subset of these mice to assess brain-wide changes in volume. Results: We found that systemic 7,8-DHF administration during the training period enhanced spatial memory 28 days later. Volumetric changes were observed in numerous brain regions associated with a broad range of functions including cognition, sensory, and motor processing. Discussion: Our findings give the first whole brain overview of long-term anatomical changes following 7,8-DHF administration providing valuable information for assessing and understanding the widespread effects this drug has been shown to have in behaviour and disease.