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Liver X receptors (LXRs) have recently been reported to be novel and potential targets for the reversal of depressive‐like behaviors, but the mechanism remains unclear. Hippocampal neuroinflammation and impairment of the normal structure and function of microglia are closely associated with depression. To investigate the effects of LXRs agonist (GW3965) on neuroinflammation and microglia in the hippocampal formation of mice with chronic unpredictable stress (CUS)‐induced depression, depressive‐like behaviors were evaluated by behavioral tests, hippocampal LXRs gene expression were evaluated by qRT‐PCR, the protein expression levels of interleukin‐1β, tumor necrosis factor‐α, inducible nitric oxide synthase, nuclear factor kappa B, and cluster of differentiation 206 were estimated by western blotting, modern stereological methods were used to precisely quantify the total number of microglia in each hippocampal subregion, and immunofluorescence was used to detect the density of activated microglia and the morphology of microglia. We found that GW3965 alleviated the depressive‐like behavior induced by CUS, reversed the decrease in hippocampal LXRα and LXRβ induced by CUS, increased the protein expression of pro‐inflammatory factors, and decreased the protein expression of antiinflammatory factors induced by CUS. Moreover, CUS intervention significantly increased the number of microglia in the CA1 region, CA2/3 region, and dentate gyrus and the density of activated microglia in the CA2/3 region and dentate gyrus and significantly decreased the endpoints of microglial branches and process length of microglia in the dentate gyrus, while 4 weeks of injections with GW3965 reversed these changes. These findings suggest that regulating the number, activated state, and morphology of microglia in hippocampal subregions might be an important basis for the antidepressant effects of LXRs. [ABSTRACT FROM AUTHOR]

According to previous studies, myelin damage may be involved in the occurrence of depression. However, to date, no study has quantitatively investigated the changes in myelinated fibers and myelin sheaths in the hippocampal formation (HF) and hippocampal subfields in the context of depression. Methods: Male Sprague-Dawley (SD) rats (aged 4–5 weeks) were evenly divided into the control group and chronic unpredictable stress (CUS) group. Behavioral tests were performed, and then changes in myelinated fibers and myelin ultrastructure in hippocampal subfields in depression model rats were investigated using modern stereological methods and transmission electron microscopy techniques. Results: After a four-week CUS protocol, CUS rats showed depressive-like and anxiety-like behaviors. The total length and total volume of myelinated fibers were reduced in the CA1 region and DG in the CUS group compared with the control group. The total volumes of myelin sheaths and axons in the CA1 region but not in the DG were significantly lower in the CUS group than in the control group. The decrease in the total length of myelinated nerve fibers in the CA1 region in CUS rats was mainly due to a decrease in the length of myelinated fibers with a myelin sheath thickness of 0.15 μm–0.20 μm. Limitations: The exact relationship between the degeneration of myelin sheaths and depression-like, anxiety-like behaviors needs to be further investigated. Conclusions: CUS induces depression- and anxiety-like behaviors, and the demyelination in the CA1 region induced by 4 weeks of CUS might be an important structural basis for these behaviors. • Unbiased stereological methods were used to assess myelinated fibers and myelin sheaths. • Four weeks of stress did not cause atrophy in the HF or hippocampal subfield regions in young rats. • Demyelination changes in the CA1 region might be a structural basis for depression-like behaviors. [ABSTRACT FROM AUTHOR]

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]

Depression is a complex psychiatric disorder. Previous studies have shown that running exercise reverses depression-like behavior faster and more effectively than fluoxetine therapy. GABAergic interneurons, including the PV+ interneuron subtype, in the medial prefrontal cortex (MPFC) are involved in pathological changes of depression. It was unknown whether running exercise and fluoxetine therapy reverse depression-like behavior via GABAergic interneurons or the PV+ interneurons subtype in MPFC. To address this issue, we subjected mice with chronic unpredictable stress (CUS) to a 4-week running exercise or fluoxetine therapy. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis showed that running exercise enriched GABAergic synaptic pathways in the MPFC of CUS-exposed mice. However, the number of PV+ interneurons but not the total number of GABAergic interneurons in the MPFC of CUS-exposed mice reversed by running exercise, not fluoxetine therapy. Running exercise increased the relative gene expression levels of the PV gene in the MPFC of CUS-exposed mice without altering other subtypes of GABAergic interneurons. Moreover, running exercise and fluoxetine therapy both significantly improved the length, area and volume of dendrites and the spine morphology of PV+ interneurons in the MPFC of mice exposed to CUS. However, running exercise but not fluoxetine therapy improved the dendritic complexity level of PV+ interneurons in the MPFC of CUS-exposed mice. In summary, the number and dendritic complexity level of PV+ interneurons may be important therapeutic targets for the mechanism by which running exercise reverses depression-like behavior faster and more effectively than fluoxetine therapy. • Runing exercise improved depression-like behavior faster and more comprehensively in CUS-exposed mice than fluoxetine therapy. • The number of PV+ interneurons rather than the total number of GABAergic neurons in the MPFC was increased by running exercise but not fluoxetine therapy. • Runing exercise, but not fluoxetine therapy, reversed the complexity levels of PV+ interneuron dendrites in the MPFC of CUS-exposed mice. [ABSTRACT FROM AUTHOR]