Researchers have investigated how psychedelics can treat neuropsychiatric disorders by identifying the neurons activated by these substances in the medial prefrontal cortex (mPFC) of mice. After administering the psychedelic DOI, they observed a reduction in anxiety as measured by behavioral tests.
Psychedelics, such as LSD, psilocybin, and 2,5-dimethoxy-4-iodoamphetamine (DOI), are emerging as promising options for treating neuropsychiatric disorders, including anxiety, due to their ability to modulate neural networks.
Studies suggest that these substances act on serotonin receptors, especially 5-HT2A, promoting brain plasticity and reorganization of circuits in the prefrontal cortex, a region associated with emotional regulation and decision-making.
These effects not only reduce anxious behaviors in animal models but have also been shown to be effective in humans, even weeks after a single dose. Furthermore, psychedelics activate specific neurons in cortical networks, allowing for more targeted interventions.
Researchers are unraveling how psychedelics, often seen as promising alternatives for treating neuropsychiatric disorders, influence adaptive behaviors through specific neural mechanisms.
While the therapeutic impact is clear, the underlying biological processes remain poorly understood.
To investigate this, a team of scientists from the University of California, Berkeley’s Department of Neurology used a novel approach that combines genetic and optogenetic techniques to identify and manipulate psychedelic-activated neurons in the medial prefrontal cortex (mPFC) of mice.
The researchers administered the psychedelic 2,5-dimethoxy-4-iodoamphetamine (DOI) and observed the effects in mouse models of anxiety using two main tests:
1) Elevated Plus Maze
A test that assesses anxiety based on exploratory behavior. Anxious mice avoid the open arms of the maze, preferring the closed, protected arms.
2) Marble Burying Test
Here, anxious mice exhibit compulsive behavior by repeatedly burying marbles.
After administration of DOI, the mice showed a significant increase in the time spent in the open arms and a reduction in compulsive burying behavior, indicating an anxiolytic effect.
Interestingly, these benefits persisted for hours after dosing, even when the hallucinogenic effects (measured by head twitches) had already disappeared. To understand which neurons were involved in these effects, the team used a method called scFLARE2, which allows the genetic marking of brain cells activated by DOI with fluorescence.
With this neuronal map, they used optogenetics to reactivate these neurons later, verifying that it was possible to induce the anxiolytic effects again, even without continuous administration of the psychedelic.
How Psychedelics Activate Neurons. Dendrites (green) branch from a rat neuron in a cell culture dish after exposure to the psychedelic ibogaine. Two proteins in the neuron’s cytoskeleton are labeled in blue and magenta. Image credit: Andras Domokos (Olson Lab, University of California, Davis, California). Source: https://www.pnas.org/doi/10.1073/pnas.2321906121
This advance demonstrates that the cells activated by DOI are crucial for anxiolytic effects and that their isolated reactivation can reproduce these benefits without generating side effects such as hallucinations.
Using single-nuclear RNA sequencing, the researchers genetically profiled the neurons activated by DOI, identifying nine distinct cell types in the mPFC, three of which demonstrated high activation.
This included but was not limited to, neurons expressing 5-hydroxytryptamine 2A receptors, known to mediate the response to psychedelics.
By manipulating these genetically tagged cells, the team showed that it is possible to dissociate therapeutic effects (such as reduced anxiety) from psychedelic effects (such as hallucinations).
This discovery is a milestone in understanding the cellular mechanisms that underlie psychedelic-induced behavioral states.
Neurons are activated by psychedelics. https://www.nature.com/articles/s41592-024-02375-7
The results provide critical insights into how psychedelics can be refined to treat conditions such as anxiety and depression, maintaining their therapeutic benefits while minimizing unwanted effects.
This innovative approach also suggests new strategies for developing neuropsychiatric therapies based on brain circuits, paving the way for more targeted and effective treatments.
This work offers a significant advance in the field of neuroscience by linking the action of psychedelic drugs with specific neural networks, becoming an important step towards personalized medicine in mental health.
READ MORE:
Isolation of psychedelic-responsive neurons underlying anxiolytic behavioral states
J. MUIR , S. LIN , IK AARRESTAD , HR DANIELS, J MA, L TIAN, DE OLSON, and CK KIM
SCIENCE, 14 Nov 2024. Vol 386, Issue 6723. pp. 802-810
Abstract:
Psychedelics hold promise as alternate treatments for neuropsychiatric disorders. However, the neural mechanisms by which they drive adaptive behavioral effects remain unclear. We isolated the specific neurons modulated by a psychedelic to determine their role in driving behavior. Using a light- and calcium-dependent activity integrator, we genetically tagged psychedelic-responsive neurons in the medial prefrontal cortex (mPFC) of mice. Single-nucleus RNA sequencing revealed that the psychedelic drove network-level activation of multiple cell types beyond just those expressing 5-hydroxytryptamine 2A receptors. We labeled psychedelic-responsive mPFC neurons with an excitatory channelrhodopsin to enable their targeted manipulation. We found that reactivation of these cells recapitulated the anxiolytic effects of the psychedelic without driving its hallucinogenic-like effects. These findings reveal essential insight into the cell-type–specific mechanisms underlying psychedelic-induced behavioral states.
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