Surprising findings of LSU Health New Orleans research on the brain's response to psychedelic drugs include that psychedelics directly activate only about 5% of brain cells, even in the most highly responding areas of the brain. Led by Charles Nichols, PhD, Associate Professor of Pharmacology and Experimental Therapeutics at LSU Health New Orleans, the research is the first to comprehensively examine the effects of psychedelics at the cellular and molecular level in the intact living brain and describes a level of detail not previously known. The research in rodents, published this month online in the journal EbioMedicine, represents a major step toward understanding how psychedelic drugs alter brain function.
Other findings of the research include that other types of cells, not just neurons, were also activated in the rodents' brains, and the types of cells activated and the genetic response in activated cells, even of the same type, differed between brain regions. Now, instead of thinking that one region or another of the brain is activated by psychedelics, we know that this activation represents a complex interplay between specific subsets of cell types.
"Remarkably, the profound behavioral and perceptual alterations induced by psychedelics involve activation of only a very small fraction of cells in any given brain region," adds Dr. Nichols.
To conduct this research, the Nichols lab developed a powerful new method to sort brain cells using antibodies specific for cells in the nucleus, cytoplasm, or extracellular membranes. Before, cells from the brain could be sorted using antibodies that recognized proteins only in the cell's nucleus, significantly restricting the variety of cell types that could be purified. Once the researchers had the different types of cells highly purified from one another, they were able to catalog the different genes they turned on. Being able to sort cells from one another by the proteins present in their cytoplasm or on their outer membranes, combined with gene profiling, allowed the researchers to perform a detailed analysis of brain tissue that was not previously possible.
"Importantly, these techniques, which we call neurocytometry, can be applied to human brain tissues as well to generate highly purified populations of specific cell types for analysis," notes Dr. Nichols.
In terms of translating these discoveries to therapies, it is a leap forward towards understanding cellular mechanisms in the living brain underlying not only the ability of psychedelics to potentially treat anxiety, depression, and addiction, but of normal cognitive processes as well.
"Future research will involve more detailed examination of differential responses between brain regions, the role of individual cell types in responses and the nature of the initial 5% of neurons that directly respond to psychedelics and their normal role in cognitive processes that we believe are the 'trigger' population whose selective activation is necessary to initiate the observed effects of psychedelics on behavior and brain connectivity," concludes Dr. Nichols. "If activation of this very small and specific subset of neurons can so profoundly change cognition and perception, their role in normal brain function must be very important, and I am very interested in discovering what this is. Ultimately, our results here and in the future towards understanding how psychedelics mechanistically work will potentially lead to more effective therapies for depression and other psychiatric disorders."
This work was partially funded by NIH grants R01MH083689, P30GM106392, and the Heffter Research Institute.
Article: Psychedelics Recruit Multiple Cellular Types and Produce Complex Transcriptional Responses Within the Brain, David A. Martin, Charles D. Nichols, EbioMedicine, doi: 10.1016/j.ebiom.2016.08.049, published online 2 September 2016.