Upregulation of serotonin 1b receptor expression in the human lower brainstem in major depression

Tyle A, Amilineni S, Simpson DN, Jones EG, Bunney WE, Akil H, Watson SJ, Kerman IA
Society for Neuroscience. 2012.


In addition to affective disturbances major depressive disorder (MDD) is characterized by physical symptoms, which suggest dysfunction of motor, autonomic, and pain regulatory systems. These functions are modulated by serotonin (5-HT) signaling, and extensive evidence implicates dysfunction in 5-HTergic neurotransmission in the pathophysiology of MDD. We have previously demonstrated an increase in the expression of tryptophan hydroxylase 2 (TPH2), a key synthetic enzyme in the production of 5-HT, in the MDD brain within lower brainstem regions that mediate stress-elicited physiological responses. In the present study we aimed to extend our findings to the expression of serotonin 1B receptor (5HT1B), an inhibitory autoreceptor implicated in the pathophysiology of MDD. We collected post-mortem human brainstem samples from MDD and control subjects, and used a combined neurochemical and histological staining approach to identify 5-HT cell groups in the lower brainstem. Using radioactive in situ hybridization we detected an upregulation in 5HT1B mRNA levels within multiple medullopontine cell groups, including caudal raphe nuclei: obscurus, pallidus, and magnus. Similar upregulation was observed within the ventromedial (ventral gigantocellular and gigantocellular pars alpha nuclei) and ventrolateral medulla. These brainstem regions regulate somatomotor, autonomic, and nociceptive functions via their spinal projections. Taken together with our previous observations of increased TPH2 and tyrosine hydroxylase mRNA levels in related brainstem regions, these findings suggest dysfunction in pre-motor, pre-autonomic, and nociceptive brainstem circuits in MDD. These alterations in gene expression within multiple lower brainstem regions may mediate physical manifestations of MDD, including fatigue, sympathetic activation, and increased pain sensitivity.