Research articleImpaired adult hippocampal neurogenesis and cognitive ability in a mouse model of intrastriatal hemorrhage
Introduction
Cognitive impairment has been reported in up to 50% survivors of intracerebral hemorrhage (ICH), which is related to poor life quality [1]. To date, no effective therapeutic achievements have been developed for the treatment of cognitive impairment [2]. Cognitive ability, usually represented by spatial learning and memory in mice, is related to the neurogenesis at subgranular zone (SGZ) of hippocampus [3]. The decline of the adult neurogenesis is correlated with a significant reduction in Morris water maze performance [4].
ICH induced brain injury is composed of primary and secondary mechanisms [5]. The primary mechanism, such as space-occupying effect of hematomas, does not constitute the whole injury [2]. The secondary injuries, which are mainly mediated by the enzymes or cytokines released by hematoma, are largely responsible for the injuries in ICH, and can't be stopped or reversed by current available medications.
Much evidence shows that thrombin is one of the main detrimental molecules in ICH-induced secondary injury [5]. Thrombin injection into the brain tissues causes lysis of vascular basement membrane, injury of neurons and astrocytes, disruption of BBB [6], and brain edema [5] in animal models. Hirudin can inhibit thrombin activity after ICH and effectively reduce the damage mentioned above [6], [7].
The striatum is the most common site of ICH in patients. Striatum injury has also been produced and examined in animal ICH models [8]. However, the range of injury induced by intrastriatal thrombin injection is still unclear. SGZ is the region in the adult brain that maintains the neurogenesis ability throughout life [9]. The effects of intrastriatal thrombin injection on the adult neurogenesis in the SGZ and therefor the cognitive ability are still unknown.
One in vivo study demonstrates that intrastriatal thrombin injection can activate microglial cells in the midbrain and cause dopaminergic neuronal death [10]. Along the rostral to caudal axis of the brain, the substantial nigra is located further away from the thrombin injection site than hippocampus. So we can only speculate that intrastriatal thrombin injection may have impact on the adult neurogenesis at the SGZ.
In this study, we investigated the effect of striatal thrombin injection on the adult neurogenesis at SGZ, as well as hippocampal dependent learning and memory. We found that thrombin injection posed dose-dependent effects on the adult neurogenesis at the SGZ. Higher dose of thrombin is detrimental to the spatial learning and memory ability.
Section snippets
Materials and methods
All animal experiments were performed in accordance with the guidelines approved by the ethics committee of Chinese PLA General Hospital.
To measure the neurogenesis and cognitive ability after thrombin injection, a total of 56 male C57BL/6 mice, 6 weeks of age and weighting 20–22 g, were divided into 7 groups. Each group contained 8 mice.
Sham (group 1): saline was injected into the striatum.
ICH (group 2–6): injection of 0.05, 0.1, 1, 2 or 5 U of thrombin respectively into the striatum.
ICH and
Thrombin caused tissue damage near lateral ventricles
The experiment paradigm was schematically represented in Fig. 1A. The needle tract was identified by the presence of blood, tissue rarefaction, and hematoma (Fig. 1B). On the coronal section containing lateral ventricle, the right lateral ventricles was located in the vicinity of the thrombin infusion site (Fig. 1C). Along the rostral to caudal axis, the SGZ is far away from the injection tract. No coronal sections containing both DG and injection tract was found in our experiments.
Effect of thrombin injection on BrdU and DCX double labeled newborn neurons
In our
Discussion
The role of thrombin in ICH remains controversial. It has been reported that high concentrations of thrombin induce neuronal damage in vitro; however, low concentrations of thrombin are neuroprotective in ischemia or oxidative stress [16]. Injury-induced neurogenesis should be taken into consideration when investigating the effect of thrombin on cerebral injury [17].
In this study, we focused on the effect of intrastriatal injection of thrombin on the neurogenesis at SGZ. We found that 0.05 U
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