A new understanding of how certain psychiatric disorders such as bipolar disorder, attention deficit hyperactivity disorder and suicidality manifest and can be treated has been discovered by a group of Northwell Health scientists.
Researchers at Northwell Health’s Feinstein Institute for Medical Research in conjunction with colleagues at Rockefeller University in New York City published a paper Tuesday entitled “Molecular Profiling of Reticular Gigantocellularis Neurons Indicates that eNOS Modulates Environmentally Dependent Levels of Arousal,” focusing on an area deep in the brainstem just above the spinal cord that activates responses to stimuli.
Previously, the enzyme studied, known as endothelial nitric oxide synthase or eNOS, was only known to exist in blood vessels and not in neurons.
“Discovering that eNOS was in neurons was quite unexpected and led to further studying when and how the eNOS within neurons is activated, and how such activation manifests in the body,” said Joel N.H. Stern, co-senior author of the paper and associate professor at the Zucker School of Medicine and the Feinstein Institute for Medical Research, and co-director of the Autoimmune Brain Disorder Center at Lenox Hill Hospital.
Beginning with two key experiments on mice, researchers tested when the enzyme was active in the mice by monitoring the levels of nitric oxide in their cells.
When the mice were in a familiar environment, such as their home cage, the enzyme was not very active, Stern said, but when the mice were exposed to new environments and experiences, such as taken away from their home cage, the enzyme levels increased significantly during and immediately after the change.
From there, Stern said researchers sought to understand what behaviors would occur if the enzyme was blocked or inhibited in some brain cells. A chemical that can inhibit the production of nitric oxide was microinfused into the mice before exposing them to different experiences to explore.
When the mice with an inactivated enzyme were returned to their home cages after exposure to new experiences, they behaved in a hyperactive way long after the return.
“A human analogy might be when a person gets excited by something good that happens and cannot come down from that high, or alternatively, gets stuck in a depressive state after a negative experience,” Stern said.
Prior studies have found genetic mutations in the eNOS gene in humans with various aspects of bipolar disorder and major depressive order, Stern said, suggesting that the mutations could contribute to the development of the psychiatric problems and relief could come from optimizing the production of nitric oxide.
“The discovery of the presence of eNOS in NGC brain cells, and the effect of eNOS on the length of reactions to stimuli, may signal a new understanding and the discovery of a new mechanism for how certain psychiatric diseases that involve a mutation of the NOS-III gene can potentially be treated or controlled,” said Stern.