Fiber Distribution and Myelination of Dopaminergic Neurons in the Medial Forebrain Bundle of a Rodent Depression Model

It has been hypothesized that the rapid/long-lasting antidepressant action observed following medial forebrain bundle DBS in clinical trials of Treatment-Resistant Depression patients could partially be driven by modulation of the midbrain-to-forebrain dopaminergic fibers. The study investigated the spatial distribution and myelination status of dopaminergic fibers within the rodent equivalent structure in a preclinical depression model, the Flinders Sensitive Line (FSL). Fixed, sliced brain sections were double stained with anti-tyrosine hydroxylase/anti-dopamine-β-hydroxylase antibodies to distinguish dopaminergic from noradrenergic fibers, and with anti-tyrosine hydroxylase/anti-myelin antibodies to specifically investigate myelination. Quantification was done at six predefined segments. The dopaminergic fibers coursing through the medial forebrain bundle were small diameter, unmyelinated and mainly restricted to the dorsolateral quadrant on the AP axis. Analyses across six predefined planes revealed significantly fewer dopaminergic fibers in FSL males (vs control males, and vs. FSL females) at AP -2.8 mm, the segment corresponding to the medial forebrain bundle DBS target in the rat. No differences were observed elsewhere along the medial forebrain bundle. Previously reported differences in stimulation-evoked dopamine release in the FSLs could be due to differences in the numbers of recruited dopaminergic fibers.