Is the organization of serotonergic cell groups in the lower brainstem altered in major depression?

Society for Neuroscience. 2009.


In addition to affective disturbances, major depression is characterized by physical symptoms and is associated with significant medical co-morbidity. Human post-mortem studies (e.g. Watson SJ, et al., SfN 2009 abstract) have documented alterations in the organization of midbrain serotonergic (5-HTergic) cell groups in depression. Neurons within these nuclei send ascending projections and release 5-HT in the forebrain (e.g. cortex, hippocampus, amygdala, etc.), and functional dysregulation of these circuits is thought to contribute to cognitive and affective symptoms of depression. We hypothesize that similar alterations take place within spinally-projecting caudal 5-HTergic cell groups that regulate motor function, autonomic responses, and pain sensation. To test this hypothesis we have collected post-mortem human brainstem samples from subjects with major depression and from psychiatrically-normal comparison individuals. Initial analyses have focused on neurochemical characterization of the lower brainstem to facilitate anatomical precision in gene and protein expression studies. Brainstem samples were serially sectioned in sets of 12 - 10 consecutive sections cut at 10 µm followed by 2 sections cut at 50 µm. Radioactive in situ hybridization (ISH) was used for the detection of tryptophan hydroxylase 2 (TPH2), tyrosine hydroxylase (TH), and choline acetyltransferase (ChAT) on adjacent thin sections. Thin sections were then stained using Klüver-Barrera histological staining to visualize neuroanatomical landmarks. ISH films and histology sections were digitized, pseudocolored, and used to create digital overlays at regular intervals through the brainstem. This approach revealed 5-HT cell groups homologous to those that have been characterized in the rodent brain. These include the midline nuclei: raphe obscurus (ROb), magnus (RMg), and pallidus (RPa); ventrolateral cells located dorsal to pyramidal tracts within the ventral gigantocellular nucleus (GiV) and its pars alpha subdivision (GiA); and a group within ventrolateral medulla-pons (VLMP) that contains 5-HT cells interspersed with the A1/C1 catecholaminergic neurons caudally and that are ventral to the facial nerve nucleus rostrally. We are currently quantifying levels of TPH2 and 5-HT transporter mRNAs in areas that regulate pain sensation (GiA and RMg), sympathetic outflow (VLMP and RPa), and motor function (ROb and GiV).