Specific Reduction of Dopaminergic Fiber Input to Ventrobasal Forebrain Targets in Neonatal Mice Following Prenatal Exposure to Valproate

<b>Background/Objectives</b>: The neuromorphological effects of prenatal administration of valproic acid (VPA) on the dopaminergic system has been studied by our groups for some time. Previously, we found a marked defasciculation of the mesotelencephalic pathway, and a reduction of dopaminergic ventrotegmental output, with diminished dopamine in the nucleus accumbens (NAc) but not in the caudatoputamen (CPu), in VPA exposed P7 mice. Further, we reported a marked decrease in the juxtapositions between tyrosine hydroxylase positive (TH+) axon terminals and calretinin or calbindin containing neurons in the NAc and tuberculum olfactorium (OT). Our aim was to test the existing findings, indicating diminished input of TH+ structures to dopamine recipient forebrain, by another robust and unbiased quantitative approach. <b>Methods</b>: Here, the intensity of TH immunolabel was quantified by 3D image analysis of whole-mount, tissue-cleared (by the iDISCO method) brain specimens of P7 mice born to VPA-exposed or control mothers. <b>Results</b>: We observed a robust reduction in TH+ immunostaining (expressed as mean voxel intensity within the ROI) in the OT, and a less prominent but significant reduction of this parameter in the NAc, in VPA exposed vs control mice. No such effect was observed in the CPu, indicating that the decrease of DA input affected predominantly the limbic component of dopamine recipient forebrain regions. <b>Conclusions</b>: Together with previous observations, the current results seem to converge upon a consistent interpretation, i.e., reduced DAergic fiber input to ventral forebrain regions, following VPA exposure of neonatal mice. Weaker supply of DA at a critical time of embryonic development may result in impaired pattern formation of ventrobasal forebrain regions involved in reward and sociability.