Abstract
Mesolimbic dopamine (DA) system lesion plays a key role in the pathophysiology of depression, and our previous study demonstrated that reduced microtubule (MT) stability aggravated nigrostriatal pathway impairment after intracerebral hemorrhage (ICH). This study aimed to further investigate the occurrence regularity of depression-like behavior after ICH and determine whether maintaining MT stabilization could protect DA neurons in ventral tegmental area (VTA) and alleviate depression-like behavior after ICH. An intrastriatal injection of 20 μl of autologous blood or MT depolymerization reagent nocodazole (Noco) was used to mimic the pathology of ICH model in mice. The concentration of DA, number of DA neurons and acetylated α-tubulin (a marker for stable MT) in VTA were checked, and depression-related behavior tests were performed after ICH. A MT-stabilizing agent, epothilone B (EpoB), was administered to explore the effects of MT stabilization on DA neurons and depression-like behavior after ICH. The results showed that obvious depression-like behavior occurred at 7, 14, and 28 days (P < 0.01) after ICH. These time-points were related to significant decreases in the concentration of DA (P < 0.01) and number of DA neurons (P < 0.01) in VTA. Moreover, The decrease of acetylated α-tubulin expression after ICH and Noco injection contributed to DA neurons’ impairment in VTA, and Noco injecton also aggravate ICH-induced depression-like behaviors and DA neurons’ injury. Furthermore, EpoB treatment significantly ameliorated ICH and Noco-induced depression-like behaviors (P < 0.05) and increased the concentration of DA (P < 0.05) and number of DA neurons (P < 0.05) in VTA by increasing the level of acetylated α-tubulin. The results indicate that EpoB can protect DA neurons by enhancing MT stability, and alleviate post-ICH depressive behaviors. This MT-targeted therapeutic strategy shows promise as a bench-to-bedside translational method for treating depression after ICH.
Highlights
Post-stroke depression is the most frequent psychiatric disorder following stroke, and it is independently associated with increased mortality, morbidity and poorer survival-related functional outcomes[1,2,3]
We employed the forced swimming test (FST), tail suspension test (TST) and sucrose preference test to measure depression-like behaviors after intracerebral hemorrhage (ICH)
We found that ICH group exhibited a significant increase in immobility time (s) in the FST at 7, 14, and 28 days compared with the sham group (Fig. 1B; P < 0.01)
Summary
Post-stroke depression is the most frequent psychiatric disorder following stroke, and it is independently associated with increased mortality, morbidity and poorer survival-related functional outcomes[1,2,3]. Our previous study demonstrated that DA neuronal apoptosis and decreased DA levels contributed to depression-like behavior after traumatic brain injury[12], indicating that protecting DA neurons and increasing DA concentrations could alleviate depression-like behavior after ICH. Our previous research demonstrated that striatal hemorrhage leads to motor dysfunction and DA neuron degeneration in the substantia nigra (SN) as a result of the reduced stability of MT15. These data indicated that ICH-induced MT destabilization might contribute to DA neuronal injury and that MT-targeted therapeutic strategies could alleviate DA neuronal injury. The administration of the MT-stabilizing agent, epothilone B (EpoB), could alleviate DA neuronal impairment, increase DA concentrations and improve depression-like behavior by stabilizing MT
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