Mapping the neurocircuit for the acute effects of psychedelics on anxiety

Psychedelics have been used in indigenous cultures for centuries, with empirical evidence of their mood and perception altering effects. Recently, there has been a renewal of interest in psychedelics given putative therapeutic effects in psychiatric disorders such as anxiety and depression. However, it has remained a mystery as to how psychedelics actually bring about changes in mood-related behavior. A team of researchers led by Prof. Vidita Vaidya from TIFR Mumbai, in collaboration with research groups from Cornell, Columbia and Yale University mapped the precise part of the brain, and the specific class of neurons within this brain region, that drives the decrease in anxiety caused by acute treatment with the psychedelic DOI.

The psychedelic DOI when administered to rats or mice systemically, decreases anxiety behavior on approach-avoidance behavioral tasks, such as the elevated plus maze and open field test. To precisely pinpoint the part of the brain that responds to DOI and drives this decrease in anxiety behavior, local infusions of the drug into targeted brain regions uncovered a critical role of the ventral hippocampus in mediating this effect of the psychedelic DOI. Further, the study uncovered that the psychedelic DOI targets the serotonin_2A receptor in the ventral hippocampus to exert its effects on anxiety. At the same time, the team also ruled out contributions from other brain regions including the prefrontal cortex and amygdala. What was striking is that the ventral hippocampus while vital for the decrease in anxiety evoked by DOI, did not contribute to hallucinations, highlighting that psychedelics target different parts of the brain to drive many behavioral changes.

Electrophysiological studies revealed that the psychedelic DOI increased the firing of parvalbumin-positive, fast-spiking, interneurons in the ventral hippocampus, which express the serotonin_2A receptor. This identified the potential cellular trigger through which the psychedelic DOI may reduce anxiety behavior. To behaviorally test this, chemogenetic strategies were used to activate this particular subclass of neurons within the ventral hippocampus in the absence of the psychedelic DOI, which was sufficient to decrease anxiety behavior in animal models. Further, using a genetic knockout mouse model that lacked any serotonin_2A receptor in the brain and body, selective restoration of the serotonin_2A receptor on parvalbumin neurons was sufficient to reinstate the decline in anxiety that was seen on treatment with the psychedelic DOI in the ventral hippocampus.  Together, using genetic, pharmacological, electrophysiological and behavioral studies, the team identified parvalbumin-positive, fast-spiking, interneurons in the ventral hippocampus as the cellular trigger through which the psychedelic DOI can reduce anxiety.

This provides the first evidence of a clear mapping of the precise neuronal population and brain region targeted by a psychedelic to influence anxiety behavior. Since it also demonstrated that this brain circuit does not evoke altered perception and hallucinations, it opens up the intriguing possibility of using psychedelic-inspired drugs that have therapeutic potential for the treatment of anxiety disorders, whilst not exerting potent hallucinatory effects.