Hippocampal Neurogenesis and Dendritic Plasticity Support Running-Improved Spatial Learning and Depression-Like Behaviour in Stressed Rats

Abstract

Exercise promotes hippocampal neurogenesis and dendritic plasticity while stress shows the opposite effects, suggesting a possible mechanism for exercise to counteract stress. Changes in hippocampal neurogenesis and dendritic modification occur simultaneously in rats with stress or exercise; however, it is unclear whether neurogenesis or dendritic remodeling has a greater impact on mediating the effect of exercise on stress since they have been separately examined. Here we examined hippocampal cell proliferation in runners treated with different doses (low: 30 mg/kg; moderate: 40 mg/kg; high: 50 mg/kg) of corticosterone (CORT) for 14 days. Water maze task and forced swim tests were applied to assess hippocampal-dependent learning and depression-like behaviour respectively the day after the treatment. Repeated CORT treatment resulted in a graded increase in depression-like behaviour and impaired spatial learning that is associated with decreased hippocampal cell proliferation and BDNF levels. Running reversed these effects in rats treated with low or moderate, but not high doses of CORT. Using 40 mg/kg CORT-treated rats, we further studied the role of neurogenesis and dendritic remodeling in mediating the effects of exercise on stress. Co-labelling with BrdU (thymidine analog) /doublecortin (immature neuronal marker) showed that running increased neuronal differentiation in vehicle- and CORT-treated rats. Running also increased dendritic length and spine density in CA3 pyramidal neurons in 40 mg/kg CORT-treated rats. Ablation of neurogenesis with Ara-c infusion diminished the effect of running on restoring spatial learning and decreasing depression-like behaviour in 40 mg/kg CORT-treated animals in spite of dendritic and spine enhancement. but not normal runners with enhanced dendritic length. The results indicate that both restored hippocampal neurogenesis and dendritic remodelling within the hippocampus are essential for running to counteract stress.

Physical exercise-induced hippocampal neurogenesis and antidepressant effects are mediated by the adipocyte hormone adiponectin

“…n = 4-6 mice per group. physical exercise and antidepressants (5,32). Consistently, we observed a significant negative correlation between the number of newborn cells and depressive severity in mice treated with adiponectin, suggesting that the antidepressant effects of adiponectin may be mediated by enhanced hippocampal neurogenesis.…”

“…The immunostaining was performed as previously described (5,26,27). Immunofluorescent colabeling of BrdU and doublecortin (DCX, immature neuronal marker) was performed as previously reported (5,28). Further details are provided in SI Materials and Methods.…”

“…Previous studies have reported that physical exercise decreases depressive behaviors, improves hippocampal-dependent learning, enhances hippocampal neurogenesis, and increases dendritic plasticity (2)(3)(4)(5). Nevertheless, understanding the mechanisms involved in the functional and structural benefits of exercise has proven to be somewhat of a challenge.…”

Physical Exercise and Antidepressants Enhance BDNF Targeting in Hippocampal CA3 Dendrites: Further Evidence of a Spatial Code for BDNF Splice Variants

“…Similarly, exercise can increase production of both BDNF and synapsin I in CA3 and DG, respectively, and promote an increase in dendritic length and spine density in CA3 pyramidal neurons (Vaynman et al, 2004;Yau et al, 2011). Evidence from studies on stress-induced hippocampal network remodeling also supports this view.…”

Effects of Isx-9 and stress on adult hippocampal neurogenesis: Experimental considerations and future perspectives

“…In addition, considering that Isx-9 is able to increase dendritic complexity in the hippocampus, 11 future studies are also warranted to investigate whether this small synthetic molecule is able to restore other types of stress-related deficits in structural and functional (i.e., synaptic) plasticity such as dendritic atrophy and suppressed hippocampal long-term potentiation (LTP), as well as stress-induced alterations in hippocampal-dependent behaviors. [32][33][34][35] The current work showed that it is also important to consider different vehicles and/or routes of drug administration/delivery and how they may influence results. In both our previous study and the current one, Isx-9 was dissolved in 2-hydroxypropylb-cyclodextrin (HP-b-CD), 11,19 a vehicle commonly used to solubilize and stabilize drugs.…”