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N -methyl- d -aspartate receptor (NMDAR) has been implicated in the pathophysiology of depression. However, as the unique inhibitory subunit of NMDARs, the role of GluN3A in depression is largely unclear. Firstly, expression of GluN3A was examined in a mouse model of depression induced by chronic restraint stress (CRS). Then, rescue experiment with rAAV-Grin3a injection into hippocampus of CRS mice was carried out. Lastly, GluN3A knockout (KO) mouse was generated via CRISPR/Cas9 technique, and the molecular mechanism underlying involvement of GluN3A in depression was initially explored using RNA-seq technique, RT-PCR and western blotting. GluN3A expression in hippocampus was significantly decreased in CRS mice. Depression-like behaviors induced by CRS were ameliorated when the decrease of GluN3A expression in mice exposed to CRS was restored. GluN3A KO mice exhibited symptoms of anhedonia reported as reduced sucrose preference, and symptoms of despair assayed by a longer immobility time in FST. Transcriptome analysis revealed genetic ablation of GluN3A was associated with downregulation of genes implicated in synapse and axon development. Postsynaptic protein PSD95 was decreased in GluN3A KO mice. More importantly, reduction of PSD95 in CRS mice can be rescued by viral mediated Grin3a re-expression. The mechanism underlying GluN3A involvement in depression is not fully determined. Our data suggested that GluN3A dysfunction is involved in depression, which might be mediated by synaptic deficits. These findings will facilitate the understanding of the role of GluN3A in depression, and they might provide a new strategy for the development of subunit-selective NMDAR antagonists as antidepressant drugs. • GluN3A expressionis significantly decreased in the hippocampus of CRS mice, an animal model of depression. • Depression-like behaviors in CRS mice are reversed by viral mediated Grin3a re-expression in the hippocampus. • GluN3A KO mice exhibit depression-like behaviors but not anxiety-related behaviors. • Genetic deletion of GluN3A causes a significant decrease in synaptic proteins. [ABSTRACT FROM AUTHOR]

Depression is one of the most common mental illnesses and seriously affects all aspects of life. Running exercise has been suggested to prevent or alleviate the occurrence and development of depression; however, the underlying mechanisms of these effects remain unclear. Independent studies have indicated that astrocytes play essential roles and that the medial prefrontal cortex (mPFC) is an important brain region involved in the pathology underlying depression. However, it is unknown whether running exercise achieves antidepressant effects by affecting the number of astrocytes and glutamate transport function in the mPFC. Here, animal models of depression were established using chronic unpredictable stress (CUS), and depression‐like behavior was assessed by the sucrose preference test. After successfully establishing the depression model, experimental animals performed running exercise. Glial fibrillary acidic protein‐positive (GFAP+) cell number in the mPFC was precisely quantified using immunohistochemical and stereological methods, and the densities of bromodeoxyuridine‐positive (BrdU+) and BrdU+/GFAP+ cells in the mPFC were measured using a semiquantitative immunofluorescence assay. Changes in glutamate transporter gene expression in mPFC astrocytes were detected by mRNA sequencing and qRT–PCR. We found that running exercise reversed CUS‐induced decreases in sucrose preference, increased astrocyte number and the density of newborn astrocytes, and reversed decreases in gene expression levels of GFAP, S100b, and the glutamate transporters GLT‐1 and GLAST in the mPFC of CUS animals. These results suggested that changes in astrocyte number and glutamate transporter function may be potential meditators of the effects of running exercise in the treatment of depression. [ABSTRACT FROM AUTHOR]

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]

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]

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]

Depression, a common and important cause of morbidity and mortality worldwide, is commonly treated with antidepressants, electric shock and psychotherapy. Recently, increasing evidence has shown that exercise can effectively alleviate depression. To determine the difference in efficacy between exercise and the classic antidepressant fluoxetine in treating depression, we established four groups: the Control, chronic unpredictable stress (CUS/STD), running (CUS/RUN) and fluoxetine (CUS/FLX) groups. The sucrose preference test (SPT), the forced swimming test (FST), the tail suspension test (TST), immunohistochemistry, immunofluorescence and stereological analyses were used to clarify the difference in therapeutic efficacy and mechanism between exercise and fluoxetine in the treatment of depression. In the seventh week, the sucrose preference of the CUS/RUN group was significantly higher than that of the CUS/STD group, while the sucrose preference of the CUS/FLX group did not differ from that of the CUS/STD group until the eighth week. Exercise reduced the immobility time in the FST and TST, while fluoxetine only reduced immobility time in the TST. Hippocampal structure analysis showed that the CUS/STD group exhibited an increase in immature neurons and a decrease in mature neurons. Exercise reduced the number of immature neurons and increased the number of mature neurons, but no increase in the number of mature neurons was observed after fluoxetine treatment. In addition, both running and fluoxetine reversed the decrease in the number of MAP2+ dendrites in depressed mice. Exercise increased the number of spinophilin-positive (Sp+) dendritic spines in the hippocampal CA1, CA3, and dentate gyrus (DG) regions, whereas fluoxetine only increased the number of SP+ spines in the DG. In summary, exercise promoted newborn neuron maturation in the DG and regulated neuronal plasticity in three hippocampal subregions, which might explain why running exerts earlier and more comprehensive antidepressant effects than fluoxetine. • Exercise alleviated some measures of depression faster than fluoxetine. • Only exercise promoted the maturation of new neurons in CUS mice. • Exercise improved synaptic plasticity in more areas of hippocampus than fluoxetine. [ABSTRACT FROM AUTHOR]