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Decreased hippocampal synaptic plasticity is an important pathological change in stress-related mood disorders, including major depressive disorder. However, the underlying mechanism is unclear. PGC-1α, a transcriptional coactivator, is a key factor in synaptic plasticity. We investigated the relationships between changes in hippocampal PGC-1α expression and depressive-like and stress-coping behaviours, and whether they are related to hippocampal synapses. Adeno-associated virus was used to alter hippocampal PGC-1α expression in male C57BL/6 mice. The sucrose preference test and forced swimming test were used to assess their depressive-like and stress-coping behaviours, respectively. Immunohistochemistry and stereology were used to calculate the total number of excitatory synapses in each hippocampal subregion (the cornu ammonis (CA) 1, CA3, and dentate gyrus). Immunofluorescence was used to visualize the changes in dendritic structure. Western blotting was used to detect the expression of hippocampal PGC-1α and mitochondrial-associated proteins, such as UCP2, NRF1 and mtTFAs. Our results showed that mice with downregulated PGC-1α expression in the hippocampus exhibited depressive-like and passive stress-coping behaviours, while mice with upregulated PGC-1α in the hippocampus exhibited increased stress-coping behaviours. Moreover, the downregulation of hippocampal PGC-1α expression resulted in a decrease in the number of excitatory synapses in the DG and in the protein expression of UCP2 in the hippocampus. Alternatively, upregulation of hippocampal PGC-1α yielded the opposite results. This suggests that hippocampal PGC-1α is involved in regulating depressive-like and stress-coping behaviours and modulating the number of excitatory synapses in the DG. This provides new insight for the development of antidepressants. • PGC-1α in the hippocampus mediates depressive-like and stress-coping behaviours. • PGC-1α in the hippocampus is involved in regulating the number of excitatory synapses in the dentate gyrus. • The regulation of excitatory synapse numbers is the key structural basis in which hippocampal PGC-1α regulates depressive-like and stress-coping behaviours. [ABSTRACT FROM AUTHOR]

Although the antidepressant effects of running exercise have been widely reported, further research is still needed to determine the structural bases for these effects. Astrocyte processes physically contact many synapses and directly regulate the numbers of synapses, but it remains unclear whether running exercise can modulate astrocyte morphological complexity and astrocyte-contacted synapses in the hippocampus of the mice with depressive-like behavior. Male C57BL/6 J mice underwent four weeks of running exercise after four weeks of chronic unpredictable stress (CUS). The sucrose preference test (SPT), tail suspension test (TST) and forced swim test (FST) were used to assess anhedonia in mice. Western blotting was used to measure the expression of astrocyte- and synapse-related proteins. Immunofluorescence and 3D reconstruction were used to quantify the density and morphology of astrocytes, and astrocyte-contacted synapses in each hippocampal subregion. Four weeks of running exercise alleviated depressive-like symptoms in mice. The expression of astrocyte- and synapse-related proteins in the hippocampus; astrocyte process lengths, process numbers, and dendritic arborization; and the number of astrocyte-contacted PSD95 positive synapses in the CA2–3 and DG regions were significantly decreased in the mice with depressive-like behavior, and running exercise successfully reserved these changes. Running exercise improved the decreases in astrocyte morphological complexity and astrocyte-contacted PSD95 positive synapses in the CA2–3 and DG regions of the mice with depressive-like behavior, suggesting that the physical interactions between astrocytes and synapses can be increased by running exercise, which might be an important structural basis for the antidepressant effects of running exercise. • Running exercise increased the expression of astrocyte- and synapse-related proteins in the hippocampus of depressed mice. • Running exercise improved astrocyte morphological complexity in the CA2–3 and DG regions of depressed mice. • Running exercise increased the number of astrocyte-contacted synapses in the CA2–3 and DG regions of depressed mice. [ABSTRACT FROM AUTHOR]

• AD mice has more postsynaptic terminal colocalized with microglia in the hippocampi. • Anti-LINGO-1 antibody rescues the loss of postsynaptic terminal in AD hippocampi. • Microglia might participate in the effect of Anti-LINGO-1 antibody in AD. In Alzheimer's disease (AD), microglia are involved in synaptic pruning and mediate synapse loss. LINGO-1 is a negative regulator of nerve growth, and whether antagonizing LINGO-1 can attenuate synaptic pruning by microglia and rescue dendritic spines in the hippocampus in AD is still unclear. On this basis, the anti-LINGO-1 antibody, which binds to LINGO-1 protein and antagonizes the effects of LINGO-1, was administered to 10-month-old APP/PS1 transgenic mice for 2 months. The Morris water maze test, immunohistochemical and stereological methods, immunofluorescence and 3D reconstruction were used. Compared to wild-type mice, APP/PS1 transgenic mice had worse performance on behavioral tests, fewer dendritic spines but more microglia in the hippocampus. Meanwhile, the microglia in APP/PS1 transgenic mice had more branches of medium length (4–6 µm) and a cell body area with greater variability. Moreover, APP/PS1 transgenic mice had more postsynaptic termini colocalized with microglia in the hippocampus than wild-type mice. The anti-LINGO-1 antibody significantly reversed these changes in AD, indicating that the anti-LINGO-1 antibody can improve hippocampus-dependent learning and memory abilities and effectively rescue dendritic spines in the hippocampus of AD mice and that microglia might participate in this progression in AD. These results provide a scientific basis for further studying the mechanism of the anti-LINGO-1 antibody in AD and help to elucidate the role of LINGO-1 in the treatment of AD. [ABSTRACT FROM AUTHOR]

• Running exercise significantly improves the behavior results in depression model rats. • The number of oligodendrocyte of the CA3 and DG is decreased in depression model rats. • Running exercise has positive effect on the oligodendrocytes in depression model rats. Running exercise has been shown to be associated with decreased symptoms of depression. However, the mechanisms underlying these antidepressant effects of running exercise remain relatively unclear. In the current study, we investigated the relationship between depressive symptoms in chronic unpredictable stress (CUS) model rats treated with running exercise and changes in oligodendrocytes in the hippocampus. After 4 weeks of CUS, the model group was randomly divided into a CUS standard group (18 rats) and a CUS running group (15 rats). Then, a 4-week treadmill running trial was performed with the CUS running group. In addition, the behavioral effects of exercise were investigated by means of a sucrose preference test (SPT) and an at the end of the 8th week. Immunohistochemical methods and modern stereological methods were used to precisely quantify the total number of 2′,3′-cyclic nucleotide 3′-phosphodiesterase (CNPase)-positive (CNPase+) oligodendrocytes in each hippocampal subregion. At the behavioral level, after four weeks of running, the CUS running group displayed significantly higher consumption of sucrose water in the SPT than the CUS standard group. Unbiased stereological analyses revealed significantly higher total numbers of CNPase+ cells in the hippocampal CA3 and dentate gyrus regions in the CUS running group than in the CUS standard group, whereas there was no significant difference between the groups in the number of CNPase+ cells in the hippocampal CA1 region. The present results further confirm that exercise can alleviate symptoms and protect hippocampal oligodendrocytes in depressed rats. [ABSTRACT FROM AUTHOR]

Estrogen replacement therapy (ERT) improves hippocampus-dependent cognition. This study investigated the impact of estrogen on hippocampal volume, CA1 subfield volume and myelinated fibers in the CA1 subfield of middle-aged ovariectomized rats. Ten-month-old bilaterally ovariectomized (OVX) female rats were randomly divided into OVX + E2 and OVX + Veh groups. After four weeks of subcutaneous injection with 17β-estradiol or a placebo, the OVX + E2 rats exhibited significantly short mean escape latency in a spatial learning task than that in the OVX + Veh rats. Using stereological methods, we did not observe significant differences in the volumes of the hippocampus and CA1 subfields between the two groups. However, using stereological methods and electron microscopy techniques, the total length of myelinated fibers and the total volumes of myelinated fibers, myelin sheaths and myelinated axons in the CA1 subfields of OVX + E2 rats were significantly 38.1%, 34.2%, 36.1% and 32.5%, respectively, higher than those in the OVX + Veh rats. After the parameters were calculated according to different diameter ranges, the estrogen replacement-induced remodeling of myelinated fibers in CA1 was mainly manifested in the myelinated fibers with a diameter of <1.0 μm. Therefore, four weeks of continuous E2 replacement improved the spatial learning capabilities of middle-aged ovariectomized rats. The E2 replacement-induced protection of spatial learning abilities might be associated with the beneficial effects of estrogen on myelinated fibers, particularly those with the diameters less than 1.0 μm, in the hippocampal CA1 region of middle-aged ovariectomized rats. [ABSTRACT FROM AUTHOR]

To investigate the effect of running exercise on the number of the neurons in the hippocampus of young APP/PS1 mice, twenty 6-month-old male APP/ PS1 transgenic mice were randomly divided into the APP/PS1 control (AD control) group and the APP/PS1 running (AD running) group (10 mice per group), and ten wild-type mice of the littermate were regarded as the wild-type (WT) group. The AD running mice ran on motorized treadmill machiene for 4 months, while the WT mice and AD control mice were housed in standard condition without running. Then, Morris water maze tests (MWM) were used to assess the special learning and memory abilities of mice in three groups. The stereological methods were used to quantitatively evaluate the volume of the hippocampus, CA1/2, CA3 and the dentate gyrus (DG) and count the number of the neurons in CA1/2, CA3 and DG. We found that 4-month running effectively shortened the escape latency of young APP/PS1 control mice in MWM. More importantly, 4-month running effectively increased the volumes of the hippocampus, CA1/2, CA3 and DG and increased the number of neurons in CA1/2, CA3 and DG in young APP/PS1 mice. The present results suggested that 4-month running has significant beneficial effects on the spatial learning and memory capacities of young APP/PS1 mice and could delay the progress of atrophy of hippocampus and the neuron death in CA1/2, CA3 and DG in young APP/PS1 mice. [ABSTRACT FROM AUTHOR]

Neurogenesis might influence oligodendrogenesis and selectively instruct myelination in the mammalian brain. Running exercise could induce neurogenesis and protect the myelin sheaths in the dentate gyrus of AD mice. It is unclear whether running exercise can protect myelin sheaths in the absence of neurogenesis in the hippocampus of AD mice. Six-month-old male APP/PS1 transgenic mice were randomly assigned to a control group (Tg control) or a running group (Tg runner), and age-matched non-transgenic littermates were used as a wild-type group (WT control). The Tg runner mice were subjected to a running protocol for four months. The behaviors of the mice in the three groups were then assessed using the Morris water maze, and related quantitative parameters of the myelin sheaths within the CA1 field were investigated using unbiased stereological and electron microscopy techniques. Learning and spatial memory performance, CA1 volume, the volumes of the myelinated fibers, and myelin sheaths in the CA1 field were all significantly worse in the Tg control mice than in the WT control mice. Learning and spatial memory performance, CA1 volume and the volume of the myelin sheaths in the CA1 field were all significantly greater in the Tg runner mice than in the Tg control mice. These results reveal demyelinating lesions in the CA1 field of Alzheimer’s disease (AD) mice and indicate that running exercise could protect against myelin sheath degeneration in the absence of neurogenesis, thereby reducing CA1 atrophy and delaying the onset and progression of AD. [ABSTRACT FROM AUTHOR]

• Chronic stress induces spatial memory impairment. • Loss of oligodendrocytes may be associated with the spatial memory impairment induced by chronic stress. • Anti-Lingo-1 treatment protects against chronic stress-induced oligodendrocyte loss. Chronic exposure to stressful conditions may affect spatial learning and memory abilities and the brain structure, and disruptions in oligodendrocyte function may cause cognitive dysfunction. Leucine-rich repeat and immunoglobulin-like domain-containing protein 1 (LINGO-1) is a potent negative regulator of oligodendrocytes and axon myelination. However, the questions we sought to answer in this study are whether hippocampal oligodendrocytes are involved in the pathological process of spatial learning and memory impairments induced by chronic stress (CS) and whether antibodies targeting LINGO-1 improve stress-induced spatial learning and memory impairments by protecting the hippocampal oligodendrocytes in stressed rats. After 4 weeks of CS, rats were randomly divided into either the CS standard group or anti-LINGO-1 group. The anti-LINGO-1 group was treated with an anti-LINGO-1 antibody (8 mg/kg) for 3 weeks; all rats were assessed in the Morris water maze. Immunohistochemical staining and modern stereological methods were used to precisely quantify the total number of 2′,3′-cyclic nucleotide 3′-phosphodiesterase-positive (CNPase+) oligodendrocytes in each subregion of the hippocampus. At the behavioural level, after three weeks of treatment, the anti-LINGO-1 group displayed significantly more platform crossings in the Morris water maze test than the CS standard group. The total swimming distance and swimming speed were not significantly different. In the open field test, the percentage of distance travelled in the central region did not differ between the CS standard group and control group or between the anti-LINGO-1 group and the CS standard group. Unbiased stereological analyses revealed significantly greater total numbers of CNPase+ cells in the CA3 and dentate gyrus (DG) areas of the hippocampus in the anti-LINGO-1 group than in the CS standard group. A significant difference in the total number of CNPase+ cells was not observed in the hippocampal CA1 region between the anti-LINGO-1 and CS standard groups. Based on the results of the present study, the anti-LINGO-1 antibody alleviated spatial memory impairments and protected oligodendrocytes in the hippocampus of chronically stressed rats. [ABSTRACT FROM AUTHOR]