The role of nitric oxide synthase neurons in dorsal raphe nucleus stress circuitry

Anxiety afflicts approximately 20% of the US adult population, making it a prevalent disorder in our society. The serotonergic (5HT) dorsal raphe nucleus (DRN) has been implicated in this illness, and treatments targeting this system and brain structure typically alleviate anxiety symptoms. The DRN also contains neurons which produce a number of other transmitters, including nitric oxide. Cells expressing nitric oxide synthase (NOS) have a unique topographical relationship with 5HT cells of the DRN and contribute to the stress response of the rat, yet have not been extensively characterized. Our general hypothesis is that NOS neurons specifically located in the DRN lateral wing subregion constitute a unique contingent of cells that contribute to the stress response. Anatomical, pharmacological, and electrophysiological properties of NOS cells within the DRN lateral wing region were investigated in the rat. This group of neurons was found to project to brain regions involved in sensory processing, emotional regulation, and arousal/feeding behaviors. In addition, NOS lateral wing cells express the 5HT1A receptor and co-localize the neurotransmitter acetylcholine, associating them with the adjacent lateral dorsal tegmental nucleus (LDT) and not the DRN. Electrophysiological profiling of this group of NOS cells revealed distinguishing features compared to both the midline and rostral lateral wing DRN subregions. These properties were consistent with those expressed by NOS neurons of the LDT. Preliminary investigations of this DRN lateral wing/LDT group of NOS cells in the waking rat suggests a correlation between restraint stress and their pattern of discharge, further implicating a role for these cells during the stress response. Overall, our results indicate that NOS cells within the DRN lateral wing have connections to limbic brain regions, possess functional 5HT1A receptors, and co-localize acetylcholine. Previous studies and preliminary results from these studies indicate activation of this group of neurons as part of the stress response. Further examination into the role of this cell group during acute and chronic stressor exposure may provide insight into the mechanisms of current anxiety treatments and may lead to new targets for the management of this disorder.