Upregulation in the expression of tryptophan hydroxylase 2 (TPH2) and tyrosine hydroxylase (TH) in the lower brainstem in major depression.

N. Amilineni; D.N. Simpson; I.A. Kerman; E.G. Jones; W.E. Bunney; H. Akil; S.J. Watson
Society for Neuroscience. 2010.


In addition to affective disturbances depression is characterized by physical symptoms, which suggest dysfunction of motor, autonomic, and pain regulatory systems. These functions are modulated by serotonin (5-HT) and catecholamine compounds, and extensive evidence implicates dysfunction in their neurotransmission in the pathophysiology of depression. In the current study we examined gene expression of TPH2, a key enzyme in 5-HT synthesis, and TH, the rate-limiting enzyme in the catecholamine synthetic pathway, within brainstem regions that contain 5-HTergic and noradrenergic neurons that mediate stress-elicited physiological responses. We collected post-mortem human brainstem samples from depressed and control subjects, and used a combined neurochemical and histological staining approach to identify 5-HT and noradrenergic cell groups in the lower brainstem that are homologous with those in other species. Using radioactive in situ hybridization we detected an upregulation in TPH2 expression in depressed subjects was detected within: rostral ventrolateral medulla, raphe magnus, raphe interpositus, and paramedian raphe nucleus. No group differences were detected in 9 other 5-HT cell groups that were examined. TH gene expression was also increased in the depressed brain within: A1/C1 and A2/C2 cell, but not within A5 and A6, cell groups. These brainstem regions regulate somatomotor, autonomic, and nociceptive functions via spinal projections, as well as stress-induced endocrine responses via ascending projections to the hypothalamus. Similar gene expression alterations have been reported within more rostral monoaminergic cell groups, suggesting shared molecular alterations within distinct 5-HT and noradrenergic circuits that mediate affective and physical manifestations of depression.