MPTP-Induced D1R-Dependent Dysregulation of Ventral Hippocampal Newborn Cell Pools and Associated Alterations in the Hypothalamic–Pituitary–Adrenal Axis

Objective: This study investigated how dopaminergic (DAergic) depletion-induced ventral hippocampal neurogenesis triggers hypothalamic–pituitary–adrenal (HPA) axis hyperactivity. Methods: Three-month-old male C57BL/6 mice were subjected to systemic 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or ventral tegmental area (VTA) injections of 1-methyl-4-phenylpyridinium ion (MPP+). We observed tyrosine hydroxylase (TH)-positive cells in the midbrain VTA and hippocampal DA content. We examined BrdU-positive cells in the ventral hippocampal dentate gyrus (vDG) on day 7 (D7) and day 28 (D28) after the BrdU injection. The expression of GAD67 and c-Fos-positive cells reflected the activation of GABAergic neurons. We assessed HPA-axis activity based on the levels of CORT, ACTH, and CRH mRNA. Results: TH immunoreactivity in VTA DAergic neurons and hippocampal DA were markedly reduced on D7 post-MPTP/MPP+ and recovered on D28. The numbers of BrdU-positive cells on D7 and D28 in the vDG were drastically reduced and were remedied by SKF38393 rather than quinpirole. MPTP significantly elevated levels of CORT, ACTH, and CRH mRNA on D28. A SKF38393 injection in the vDG, an AMPA injection in the amBNST, or a muscimol injection in the PVN effectively reversed HPA-axis hyperactivity. Conclusions: These results indicate that VTA DAergic depletion reduces the number of BrdU-labeled newborn cells within the vDG in a D1R-dependent manner. Given our previous work demonstrating unchanged progenitor cell proliferation but impaired survival of vDG newborn neurons under MPTP insult, we propose that disrupted D1R-dependent maintenance of newborn cell populations impairs vHPC-originated glutamatergic input to the amBNST, with associated alterations in the HPA-axis activity.