Insight & IntelligenceJuly 10, 2018Blood Protein Linked to Mental DisordersConsciousness-Aiding Protein Produced by Cells Deep in the BrainstemJulianna LeMieux, Ph.DResearchers from several New York institutions have uncovered a key molecular component of mental health disorders involving uncontrollable reactions to stimuli (i.e., bi-polar disorder, attention deficit hyperactivity disorder [ADHD], and major depression). The paper, published in the Proceedings of the National Academy of Sciences, is entitled “Molecular profiling of reticular gigantocellularis neurons indicates that eNOS modulates environmentally dependent levels of arousal.”The research team, led by Joel Stern, Ph.D., an associate professor of Neurology at Zucker School of Medicine at Hofstra/Northwell and an associate professor of Molecular Medicine at the Feinstein Institute for Medical Research, focused on a subset of neurons located deep in the brainstem, in the area just above the spinal cord, known as the nucleus gigantocellularis (NGC). Some of the neurons in the NGC project to the thalamus, which is responsible for maintaining wakefulness and consciousness. When the NGC is damaged or the projections to the thalamus are interrupted, consciousness can be lost. In addition, these neurons are critical for the initiation of conscious movements and waking the brain from certain stages such as deep sleep, anesthesia, or injury. When this process, called “generalized CNS arousal” (GA) does not work properly, disorders may result.When asked why he focused on the neurons of the NGC, Dr. Stern responded, “We wanted to figure out the role that these NGCs play in consciousness. Because NGCs are involved in arousal, it puts them in the center of brain functioning.”A Blood Gene Found in the BrainAlthough the NGC has been recognized as a key player in proper brain function, information regarding its gene expression has remained limited. The underlying reason for this was, in large part, the inability to isolate the NGC cells. Dr. Stern and colleagues utilized the retro-TRAP (translating ribosome affinity purification from retrogradely labeled neurons) technique, developed by the Freidman lab at The Rockefeller University in 2013, which allowed for the successful isolation of the NGC neurons.Using this technique, the researchers were able to detect mRNA specifically from the NGC neurons, resulting in the first transcriptome from these cells. After sequencing and analyzing the transcripts, the enzyme endothelial nitric oxide synthase (eNOS,) which leads to the production of nitric oxide (NO), was found to be uniquely expressed. This novel finding led them to probe the role of eNOS in brain functioning.Both humans and mice have three distinct NO synthase enzymes: neuronal nNOS, endothelial eNOS, and inducible iNOS (induced by cytokines of the immune system.) Because eNOS is generally found in blood vessels, its expression in neurons was an unexpected finding. Dr. Stern says the team was “surprised at the finding that the eNOS pathway was in the neurons.” The group then established a close relationship between the eNOS-positive neurons and the blood supply.