Neurogenesis is the process by which new neurons be generated by neural stem cells (NSCs), promoting the structural plasticity of the brain (19). Although neurons in the adult brain do not regenerate or replenish in the traditional view, recent decades have seen the publication of numerous studies demonstrating that a large majority of mammalian species retain the capacity for neurogenesis in the CNS into adult life. It is currently understood that the adult mammalian brain has two major reservoirs of neural stem cells (NSCs), called “neurogenic niches” in the SVZ of the lateral wall of the lateral ventricle and the subgranular zone (SGZ) of the DG of the hippocampus (20). Under resting conditions, neurogenesis is restricted in the above two neurogenic niches, while under pathological conditions, neural precursor cells generated in the SGZ and SVZ need to migrate to the olfactory bulb and the subgranular zone of the DG of the hippocampus to compensate for neuronal loss in the brain to maintain hippocampal structural and functional plasticity (21). Although the process of neurogenesis is sophisticated, it can be summarized in four phases: In the first stage, NSCs divide and proliferate to form a pool of NSCs, which can differentiate to produce neuroblasts and further differentiate into immature neurons. In the second stage, neuroblasts and immature neurons located in the subgranular region migrate to the granular cell layer. However, due to the mature neuronal structures not yet being formed, the axons and dendrites of immature neurons are short. In the third stage, in order to establish correct synapses with other neurons, immature neurons differentiate into mature neurons with intact neuronal structures and neurites. Meanwhile, dendrites extend into the molecular layer and axons extend to the CA3 subfield. Finally, the dendrites and axons of mature neurons establish synaptic connections with other neurons, and these synaptic connections integrate with pre-existing circuits to ensure the normal functioning of the CNS (22). Since the hippocampus is an important structure involving humans’ learning, memory, and mood regulation (23, 24), and the DG is one of the core regions for neurogenesis, neurogenesis in the hippocampus has been implicated in the process of cognitive functions and emotion. Indeed, it has been found that adult-born neurons in the DG contribute to learning and memory, including cognitive flexibility, emotional memory, spatial navigation, novelty detection, pattern separation, stress response, and emotion (25). Thus, the regulation of adult neurogenesis has a vital impact on the treatment of some neuropsychiatric diseases.

Abnormalities in different stages of neurogenesis can lead to the development of depression (26). First, in patients with depression, the number and differentiation capacity of NSCs in the hippocampus decrease, which may lead to a decrease in neurons and dysfunction, which affects emotion regulation and cognitive function in patients with depression (27, 28). The antidepressant fluoxetine can increase the proliferative capacity of NSCs and the expression of Bcl-2, thereby preventing apoptosis through the activation of Bcl-2, promoting the development of synapses and the differentiation of serotonin neurons (29). This study reveals a new antidepressant drug treatment mechanism that promotes the development and differentiation of NSCs by stimulating Bcl-2 expression, thereby helping to treat depression. Secondly, when there are problems with the maturity of newborn neurons in the hippocampus, it may negatively affect behavioral functions such as learning, memory, and emotional control (30). Previous studies have shown that antidepressants can promote the increase of new neurons. For instance, many studies have shown that antidepressants including fluoxetine, paroxetine, tranylcypromine, and reboxetine reverse hippocampal volume loss in patients with depression as well as depression in rodents (8, 31, 32). Furthermore, the proliferation rate of newborn neurons, which is promoted by fluoxetine in the hippocampus, is synchronized with the clinically observed delay time of the therapeutic effect (33). It has been shown that newborn cell proliferation in the adult hippocampus decreases when exposed to chronic stress (34). Interestingly, the presence of newborn neurons was sufficient to cause anti-reversal and remission in mouse models of depression (35, 36). In addition, previous studies have shown that in the early neuronal development stage, neurons with deletion of the TLR7 gene show downregulation of gene expression related to neurodevelopment, synaptic organization, and activity, while mice with deletion of the TLR7 gene show significant behavioral changes in anxiety, aggression, smell, and situational fear memory. The electrophysiological analysis further revealed that loss of TLR7 led to impaired hippocampal long-term enhancement (37). What’s more, recent studies showed that if the newborn granule cells are damaged, it causes damage to neurons connected to CA3 in the DG network, which affects the information coding in the downstream hippocampal region, which may lead to the onset and progression of depression (38, 39). The above implies that impaired neuronal maturity can also lead to depression. Therefore, this current research has indicated that diminished adult hippocampal neurogenesis may be associated with the development of depression, and that it might be one of the ways to reverse or prevent diminished hippocampal neurogenesis in adults with antidepressants ( Figure 1 ).

Microglial originate from the embryonic mesoderm, primarily derived from myeloid progenitors within the yolk sac (40). During early embryonic development, these cells persistently proliferate in the brain and are regulated by various molecular factors, including but not limited to transcription factors, growth factors, chemokines, MMPs, and microRNAs (41). The exact numbers or proportions of microglia in the hippocampus can vary, influenced by factors such as age and health (42). Generally, the hippocampus exhibits a relatively high microglial density compared to other brain regions, reflecting its vital role in cognitive function (43). In the hippocampus, microglia constitute a slightly higher proportion, accounting for approximately 10 to 15 percent of the total cell population, whereas in other brain regions, this proportion typically ranges from 5 to 10 percent (43). Microglia are the leading type of immune cells in the CNS and are in charge of modulating inflammation. Originally, microglia were thought to exist in a quiescent or resting state when characterized by small stationary soma, with smaller cell bodies and highly branched protrusions (44). Normally, the highly branched resting state of microglia provides a highly dynamic and efficient monitoring system for the brain (Physiology of Microglia) (45, 46). Conversely, when pathological stimulation occurs, microglia are rapidly activated. There are three main activated microglial morphotypes in current reports: hyper-ramified, phagocytic, and amoeboid types (47–49). When the brain microenvironment changes, the resting microglia react by transitioning into “hyper-ramified” morphotypes, which are often defined by longer, thicker, more abundant processes that attach to larger, lobular, and irregularly shaped cell bodies (50, 51). Once the changes or stimuli intensify, the hyper-ramified microglia shift into phagocytic and even amoeboid types, which show much fewer, albeit thicker and shorter, processes, and much rounder, larger, and more regularly shaped cells with no processes, respectively (52). Alternatively, the activated microglia, similar to peripheral macrophages, have two primary polarization phenotypes: M1 (classical activation) and M2 (alternative activation) (53). M1-phenotype microglia are classically activated microglia that can express surface markers such as cluster of differentiation 86 (CD86) and inducible nitric oxide synthase (iNOS) (54, 55). M1-phenotype microglia mainly play a pro-inflammatory role and promote the synthesis of inflammatory mediators such as tumor necrosis factor-alpha (TNF-α), interleukin-1β (IL-1β), and iNOS, which can promote chronic neuroinflammation, phagocytosis, oxidative stress, and neurodegeneration and inhibit regeneration (56). Therefore, M1 microglia often have obvious neurotoxic effects (57). In contrast, the M2-phenotype microglia are alternatively activated microglia that can express surface markers such as cluster of differentiation 206 (CD206) and cluster of differentiation 163 (CD163), which release neuroprotective and anti-inflammatory cytokines, such as interleukin-10 (IL-10) and transforming growth factor-β (TGF-β), to exert anti-inflammatory effects, promote wound healing, neuroprotection, and tissue repair (58). Therefore, M2 microglia often have neuroprotective effects (59). Furthermore, many studies have reported three main sub-phenotypes (M2a, M2b, and M2c) in M2 microglia, corresponding to different stimulations and functions (42). The M2a phenotype can be activated by interleukin-4 (IL-4) and interleukin-13 (IL-13), resulting in the secretion of IL-10, chemoattractant cytokine ligand 17 (CCL17), and chemoattractant cytokine ligand 18 (CCL18) to clear apoptotic cells, promote cell debris removal, and contribute to neuroprotection (56, 60, 61). The M2b phenotype can be activated by toll-like receptor (TLR) ligands and immune complexes, which secrete TNF-α, interleukin 1 (IL-1), and interleukin 6 (IL-6). These cytokines support immune regulation, inflammation inhibition, B cell conversion and antibody production, and recruitment of regulatory T cells (62, 63). The M2c phenotype can be activated by anti-inflammatory IL-10 and corticosteroids, which in turn release many more anti-inflammatory cytokines, such as IL-4, and increase growth factors, such as TGF-β, to promote nerve regeneration (64, 65). Usually, an imbalance of M1 and M2 polarization occurs in neurodegenerative or neuro-damaged illnesses, such as depression, stroke, and Alzheimer’s disease, and therapeutic candidates that target modulating the activation of M1 and M2 polarization appear promising for these diseases (66).

In many clinical reports, microglial activation in the insula, anterior cingulate cortex, and prefrontal cortex (PFC) have been found in patients with depression and those with suicidal ideation (67). These results suggest that the degree of microglial activation is positively correlated with depression severity (68). In rodents, chronic stress, including chronic unpredictable mild stress (CUMS), chronic social defeat stress (CSDS), and chronic restraint stress (CRS), commonly used to induce depression, results in elevated peripheral cytokines and the activation of microglia in stress-sensitive brain regions, such as the hippocampus, PFC, and amygdala (69). In contrast, minocycline, a potential anti-inflammatory agent, significantly blocks microglial activation and has been shown to contribute to improving depressive-like behaviors (70–72). Similarly, a previous study found that lipopolysaccharide (LPS)-induced inflammation, a classical microglia activation pathway that acts via the TLR4/nuclear factor-k-gene binding signaling pathway, increased the risk of depression in mice, which could be improved by the microglial depletion of PLX5622 or minocycline (70, 73). This indicates that microglial activation is strongly associated with the development of depression ( Figure 2 ).

Many studies have revealed how the activation of microglia leads to the occurrence and development of depression. Firstly, it involves inflammation and polarization of microglia. Reassuringly, some preclinical studies have conducted more in-depth investigations in this area (74). Tang et al. found that CSDS mice showed higher M1 microglia markers, including iNOS, cluster of differentiation 16 (CD16), CD86, and C-X-C motif chemokine ligand 10, and no significant changes in M2 markers such as arginase-1 (Arg-1) and CD206 in the hippocampus at the transcriptional and protein levels, suggesting that M1 polarization plays a vital role in depression pathogenesis (75). Another study revealed that although no change in the total microglia number in CUMS-induced depressive mice was observed, much more activated microglia expressing M1-marker CD68 and less M2-marker CD206 was detected throughout the DG, CA1, and CA2 regions in the hippocampus (76). Taken together, the activation of microglia in susceptible brain regions towards the classical M1 polarization state instead of the M2 polarization state results in an increase in the production of toxic substances that harm neurons, which factors are crucial in the development and progression of depression (77).

Secondly, the phagocytic function of microglia in depression. The phagocytic function of microglia is considered an important factor affecting the occurrence and development of depression. Synapses interconnect neurons into networks that transmit neurotransmitters and mediate neuronal signaling, which contains pre-and postsynaptic separated by the synaptic cleft. Preclinical and clinical evidence suggests activated microglia in depressed animals and humans may aberrantly phagocytose neuronal synapses, resulting in synaptic dysfunction and depressive symptoms (78, 79). Preclinical studies in mouse models of depression have reported increased microglial phagocytosis of synapses in microglia-neuron contact areas (80). For example, there was a notable increase in the presence of phagocytic microglia actively engulfing puncta containing Postsynaptic density protein 95 (PSD95) in the DG of CSDS mice when compared with normal mice (81). Similar findings have been observed in other models, including decreased hippocampal expression of PSD95, synapses, and growth associated protein-43 and enhanced microglial phagocytosis in maternally separated rats. The hippocampus of chronic unpredictable mild stress mice also showed comparable results. Interestingly, intraperitoneal LPS injection in mice at postnatal day 50 to model early-life inflammation resulted in long-term phagocytosis of glutamatergic spines on neurons of the anterior cingulate cortex (82). The H3-receptor inverse agonist JNJ10181457 prevented abnormal LPS-induced microglial phagocytosis, decreased neuronal loss, improved neurotransmitter transmission, and had antidepressant effects in mice (83). Positron emission tomography revealed significantly increased translocator protein, a microglial marker, in the hippocampus, prefrontal cortex, and temporal cortex of depressed patients, suggesting microglial activation may contribute to depression pathophysiology. Functional imaging studies have also shown depressed patients exhibit decreased synaptic connectivity and neuronal circuitry in the prefrontal cortex and hippocampus (84). Together, these findings suggest aberrant phagocytosis of synapses by activated microglia in the hippocampus may underlie decreased synapses observed in depression. Therefore, in addition to modulating neuroinflammation, regulating microglial phagocytosis of synapses may provide novel insights into the mechanisms and therapeutic approaches for depression.

Finally, the trophic support function of microglia and endogenous microglial reduction is closely related to depression. Microglia support neuronal plasticity, neurogenesis, neural circuits and synaptic integrity through neuroimmune mechanisms including phagocytosis and cytokine secretion under baseline physiological conditions (85–87). Microglia also produce and respond to trophic factors like brain derived neurotrophic factor (BDNF) (88). BDNF was first isolated from the porcine brain in 1982 and found to support the survival of cultured embryonic sensory neurons (89). Considerable clinical evidence over subsequent decades has demonstrated BDNF plays an important role in depression (90). Regulating the C-X3-C motif chemokine receptor 1 (CX3CR1) in horses with phytoestrogens such as genistein increases BDNF and TGF-β secretion, promoting neuron-microglia interactions and synaptic remodeling. Endogenous microglial reduction or impairment may deprive neurons of adequate nutrition and energy, disrupting their function and contributing to depression (91). Kreisel et al. first reported the chronic unpredictable stress-induced microglial loss in the hippocampus, which could worsen severe depression (92). Administering innate immune stimulants like LPS and macrophage colony-stimulating factors to increase microglial numbers in the DG has reversed depressive behaviors in chronic stress mice. For instance, a single intraperitoneal 75 or 100 μg/kg dose of LPS reversed depressive behaviors of chronic unpredictable stress mice within 5 hours, as demonstrated by behavioral testing (93). The antidepressant effect of low-dose LPS depends on microglial activation regulating extracellular signal-regulated kinase (ERK) 1/2 signaling to increase BDNF synthesis. These findings suggest restoring endogenous microglial levels and function may benefit severe depression treatment, in addition to modulating microglia directly.

TLRs, expressed on microglia are a subfamily of pattern recognition receptors (PRRs) that identify endogenous noxious stimuli and invading pathogens, thereby inducing induction of innate and adaptive immune responses (109, 110). Experimental results demonstrated that social avoidance and anxiety induced by repeated social defeat stress (R-SDS) were abolished in mice lacking Toll-like receptors 2 and 4 (TLR2/4). Transcriptome analysis further revealed that microglia in the brains of R-SDS mice induced the expression of IL-1α and TNF-α via the TLR2/4 signaling pathway. Treatment capable of blocking microglial-mediated cytokine release was able to attenuate R-SDS-induced social avoidance. These results suggest a crucial role of TLR2/4 in microglial activation and cytokine release in response to R-SDS-induced stress (111). Research has revealed that Toll-like receptor 5 (TLR5) expression in mouse embryonic stem cells promotes neurodifferentiation and enhances it through the nuclear factor-κB and interleukin 6/CREB pathways. Furthermore, TLR5 expression was also observed in the SGZ of the hippocampus in rat, where it governs the proliferation of adult hippocampal NSCs by regulating the cell cycle, and promotes neural differentiation through the JNK pathway. These findings provide evidence of TLR5’s significant modulatory role in neurogenesis from embryonic stem cells and adult hippocampal NSCs, and suggest it is a promising therapeutic target for Brain-related diseases (112). In contrast, promising immunosuppressive drugs, such as icariin, can improve neuroinflammation in the hippocampus by inhibiting the activation of the TLR4-NF-κB signaling pathway to exert protective effects on neurogenesis, thereby improving depressive behavior in mice (113). These results provide a new understanding of depression pathology, wherein inflammation can be triggered by activating TLRs in microglia, resulting in a reduction in neurogenesis, and ultimately playing a crucial role in the development of depression.

Inflammasomes are cytosolic immune signaling complexes that lead to inflammation and pyroptosis. They are composed of pattern recognition receptors, adapter structural domains and enzymatic caspase-1 structural domains. Inflammasome initiation sensors are PRRs, including nucleotide-binding oligomerization domains leucine-rich repeat-containing protein receptors (NLRs), which are not present in melanoma-2-like receptors, and proteins with tripartite motifs (114). NLRs consist of NLRP1, NLRP2, NLRP3, NLRP6, NLRC4, and NLRP12, of which NLRP3 has received the most attention in studies of the pathological mechanism of depression (115, 116). Male C57BL/6 mice were subjected to CUMS for a period of 6 weeks. A comprehensive assessment of negative emotional behaviors was carried out to determine the susceptibility of the mice. Various parameters such as microglial activation, transcription of endogenous retroviral sequences, intrinsic nucleic acid sensing response, and immune inflammation were evaluated in the Basolateral Amygdala. The findings of the study revealed that chronically stressed mice exhibited significant depressive and anxious-like behaviors, accompanied by notable microglial cell morphological activation, transcription of MuERV-L, MusD, and IAP genes, activation of the cGAS-IFI16-STING pathway, initiation of the NF-κB signaling pathway, and activation of the NLRP3 inflammasome in the Basolateral Amygdala (115). However, these abnormal indicators were gradually reversed after antidepressant administration, suggesting a close link between depression and the NLRP3 inflammasome. For example, Du et al. found that fluoxetine, a classical antidepressant, can remarkably suppress the activation of NLRP3 inflammasome, followed by reduced caspase-1 cleavage and IL-1β which were secreted in peripheral macrophages and central microglia (117). Recent studies have demonstrated that they can diminish the expression of NLRP3 inflammasome and lower the levels of inflammatory factors that are regulated by microglia, ultimately providing anti-depressant effects. NLRP3 is also involved in the regulation of neurogenesis. Many studies have shown that microglia triggered by NLRP3 inflammasome activation secrete many more pro-inflammatory cytokines, such as IL-1β, thus resulting in the reduction of hippocampal neurogenesis (118). Conversely, mice were exposed to CMS for three weeks, and the results revealed that CMS exposure altered the morphology of microglia in the hippocampus and increased the number of TUNEL⁺ and GSDMD⁺ microglia in the dentate gyrus (119). Furthermore, the CMS exposure led to a decrease in the number of 5-ethynyl-2-deoxyuridine (BrdU) ⁺, BrdU-DCX⁺, and BrdU-NeuN⁺ cells in the hippocampal dentate gyrus, as well as a reduction in the percentage of NeuN⁺ cells among BrdU⁺ cells. Additionally, the expression of pyroptosis-related molecules, such as NLRP3, caspase-1, GSDMD-N, and IL-1β, was significantly upregulated in the hippocampus of CMS-exposed mice (119). These findings indicate that CMS exposure impairs hippocampal neurogenesis and induces microglial pyroptosis. The study found that porphyran suppressed the NF-κB/NLRP3 signaling pathway in the hippocampus and activated the BDNF/TrkB/ERK/CREB signaling pathway in CUMS mice, thereby inhibiting the activation of microglia and reducing the release of pro-inflammatory cytokines mediated by microglia (120). It also increased the expression of DCX in the hippocampal DG area, promoted neurogenesis, and maintained synaptic plasticity, ultimately exerting an antidepressant effect (120). These data have shown that NLRP3 plays a key role in the regulation of neurogenesis, a key molecular mechanism in the pathogenesis of depression.

The M1 and M2 polarization of microglia differentially regulates neurogenesis in physiological and pathological states (121). M1 polarization of microglia is negatively correlated with neurogenesis (117). The M1 phenotype of microglia secretes excessive inflammatory mediators that lead to impaired neurogenesis and promote the onset and progression of depression. Additionally, pro-inflammatory mediators such as macrophage inflammatory protein-2 (MIP2), IL-1β, iNOS, and TNF-α activate M1 microglia, which then produce many more damaging factors that reduce hippocampal neurogenesis and induce depression (121). The activation of microglia into the M1 state affects neurogenesis by inhibiting the proliferation of NSCs, increasing the apoptosis of neural progenitors, and reducing the survival of newborn neurons and their integration into existing neural circuits (122). In contrast, M2 polarization of microglia, an alternative subtype of microglial activation, is positively correlated with neurogenesis. A recent study found that the alternatively activated microglial phenotype (M2), which is activated by IL-4, enhances neurogenesis and thus ameliorates depression-like behaviors (123). Therefore, modulating the microglial phenotype to regulate neuroinflammation and neurogenesis appears to be a possible mechanism for the development of depression.

The Janus kinase (JAK)/STAT pathway is engaged in the modulation of a number of CNS functions, involving neurogenesis, synaptic plasticity and microglia activation, all of which are implicated in the pathophysiology of depression (124, 125). First, JAK/STAT signaling is important for regulating inflammatory responses and microglial polarization (125). Studies have shown that inhibition of the JAK/STAT1 pathway can block microglial activation and suppress microglia-mediated neuroinflammation. Kwon et al. found that microglia-specific STAT3 KO mice showed antidepressive-like behavior in the animal model of chronic stress procedures, suggesting that suppression of microglia STAT3 may be a new treatment tactic for depression (126). Furthermore, recent studies have indicated that JAKs may have a role in hippocampal neurogenesis. For instance, research has demonstrated that pharmacologically inhibiting JAK3 in cultured neurons can stimulate neurogenesis (127). Other studies have shown that JAK3 is involved in inhibiting neurogenesis and causing depressive symptoms in animal models under stress (128, 129). As a result, JAK3 inhibition has the potential to improve depressive and anxious behavior and restore normal levels of hippocampal neurogenesis in mice subjected to stress (130). However, microglia modulate the mechanisms of microglia as well as neurogenesis in response to depression via the JAK/STAT signaling pathway is unclear. Therefore, it is important to concentrate on the JAK/STAT signaling pathway in microglia and elucidate its relationship with depression. Such research may provide new insights for future studies on depression.

The signaling pathway of Fractalkine-CX3CR1 is essential for regulating of interactions between microglia and neurons (131). Fractalkines, also called CX3CL1, are transmembrane chemokines expressed by neurons in the brain. It reduces migration and increases neuronal adhesion (132). A combination of CX3CR1 and CX3CL1, which is only expressed by microglia, maintains microglia in a quiescent state, and hence inhibits the release of pro-inflammatory cytokines (133). CX3CR1 is significantly upregulated in depression (134). The character of microglia in modulating neurogenesis in depression via the CX3CL1-CX3CR1 signal is complex and controversial. Evidence has shown that CX3CL1-CX3CR1 signaling participates in the control of microglial activation, and thus influences adult neurogenesis. For instance, there are reports indicating that compared with wild-type mice, the number of DCX⁺ positive cells and BrdU⁺ labeled cells in the hippocampus of CXCR1 deficient mice is reduced, indicating that neurogenesis is inhibited due to CX3CR1 deficiency (135). Similarly, studies have shown that the deficiency of the CX3CR1 of microglial damages synaptic integration in hippocampal granule neurons in adult neurogenesis, promotes the activation of microglia in the DG of CXCR1 deficient mice, and induces a pro-inflammatory phenotype in this area of DG (136). These results suggest that microglia regulate adult hippocampal neurogenesis via CX3CL1-CX3CR1 signaling. However, many contradictory reports have been published. For example, Mattison et al. found that the freeing of pro-inflammatory factors such as IL-6 was significantly reduced by LPS administration in CX3CR1 knockout mice, suggesting an obvious suppression of the inflammatory response in CX3CR1 knockout mice (137). Moreover, Liu et al. found that deficiency of CX3CR1 might promote alternative activation of microglia (M2 polarization) and attenuate their ability to synthesize and release inflammatory cytokines, thus benefiting adult neurogenesis (138). Therefore, the role of CX3CL1/CX3CL1 signaling in microglial activation and subsequent regulation of neurogenesis in depression is an intricate and controversial topic of research, which is further complicated as new studies have revealed inconsistent results.

The HPA axis is a complicated combination of interactions concerning the pituitary, hypothalamus gland, and adrenal gland. The HPA axis is an essential component of the neuroendocrine system and is related to the control of stressful responses and the pathophysiology of a lot of neuropsychiatric disorders (139). Inflammation and stress stimulate the hypothalamus to secrete corticotropin-releasing hormone, which further stimulates the pituitary to release corticotropin. The adrenal gland releases glucocorticoids, which can act on the hypothalamus for negative feedback regulation. The HPA axis is hyperactive during depression (140). Abnormalities in the HPA axis are observed in a substantial proportion of patients with depression and are primarily characterized by glucocorticoid dysregulation (141). Studies have shown that excessive glucocorticoids reduce the proliferation of nerve cells, thereby inhibiting adult neurogenesis (142). Moreover, adult hippocampal neurogenesis can mediate negative feedback through the HPA axis. Snyder et al. used the spatial specificity of X-ray irradiation to reduce hippocampal neurogenesis, resulting in excessive secretion of glucocorticoids (135). Taken together, glucocorticoids reduce adult hippocampal neurogenesis, resulting in the failure of negative feedback that is critical for the HPA axis, which leads to a persistent elevation of glucocorticoids and reduces adult hippocampal neurogenesis. This vicious cycle may play an essential character in depression pathophysiology. Interestingly, regulation of the HPA axis is also influenced by cytokines released by microglia. For example, microglia-discharged pro-inflammatory cytokines, such as IL-1 and IL-6, can effectively induce glucocorticoid secretion during chronic and acute stress (143). Therefore, microglia may regulate the HPA axis by releasing pro-inflammatory factors and elevating glucocorticoids to reduce adult hippocampal neurogenesis, thereby playing a crucial role in depression.

TRY metabolism involves two important metabolic pathways: 5-HT synthesis and kynurenine synthesis. The 5-HT synthesis is initiated by tryptophan hydroxylase, which converts TRY to hypoxanthine, which in turn is converted to 5-HT by serotonin synthetase (144). It is currently known that 5-HT strongly correlates with the pathogenesis of depression. Selective serotonin reuptake inhibitors (SSRIs), the most common clinical antidepressants, improve depressive mood by adding the 5-HT levels of the synaptic cleft (145). Studies have reported that 5-HT is synthesized by 5-HT neurons located in the raphe nucleus, and has significant implications in the regulation of neurogenesis. Removal of 5-HT neurons in the dorsal raphe and median raphe has been found to decrease neurogenesis, which is recovered by 5-HT reinnervation. Increased 5-HT levels have been shown to promote neurogenesis, thereby improving depressive behavior (146). Thus, the depletion of 5-HT suppresses neurogenesis in the DG, which is a hypothesis for the pathogenesis of depression. Another catabolic pathway of TRY contains indoleamine 2,3-dioxygenase (IDO) and TRY 2,3-dioxygenase (TDO), which produce by metabolism from TRY to kynurenine (KYN) (147). When the KYN metabolic pathway is enhanced, it deprives TRY of 5-HT synthesis, resulting in reduced serotonin production (148). Increased activation of the KYN pathway has been observed in depressed patients, and the level of activation is relevant to the level of depression (149). KYN can be further metabolized into several neurotoxins such as 3-hydroxykynurenine (3-HK), which is catalyzed by kynurenine monooxygenase (KMO) (150). Numerous studies have shown that pro-inflammatory cytokines stimulate IDO and KMO, which are mainly expressed in microglia, thereby increasing neurotoxins, which is one of the potential mechanisms by which inflammation is mediated by microglia and induces depression (150). However, the mechanism by which microglial activity interacts with KYN metabolites has not been definitively determined, though we can infer that under stress conditions, pro-inflammatory factors released by activated microglia activate the kynurenine pathway, resulting in a decrease in the synthesis of 5-HT and an increase in neurotoxins such as 3-HK, which may inhibit neurogenesis and lead to depression.

Cytokines are redundant secreted proteins with growth, differentiation, and activation functions that regulate and determine the nature of immune responses and control immune cell trafficking and cellular arrangement of immune organs (151). Inflammatory cytokines consist of pro-inflammatory and anti-inflammatory cytokines, the balance of which determines whether the body produces an inflammatory response. The role of cytokines in neurogenesis is reflected in the fact that pro-inflammatory cytokines impair neurogenesis, whereas anti-inflammatory cytokines protect or promote neurogenesis. Excessive pro-inflammatory cytokines induce an inflammatory response, which can induce the expression and release of cathepsin C in microglia to promote an inflammatory response and reduce neurogenesis (152). For example, IL-1β, IL-6, TNF-α, and IFN-α are currently the broadest studied inflammatory cytokines (153). Multiple studies have suggested that TNF-α and IL-6 levels are increased remarkably in the peripheral blood of depressed patients than in healthy controls, suggesting a strong association between inflammatory cytokines and depression (153). This mechanism may be related to the activated M1 microglial phenotype (154, 155). Conversely, anti-inflammatory cytokines, including TGF-β and IL-10, secreted by M2 phenotype microglia, exerted anti-inflammatory effects. Furthermore, existing evidence suggests that inflammatory cytokines are strong relativity of neurogenesis. For instance, CMS exposure in mice was found to upregulate inflammatory factors and inhibit neuronal growth in the dentate gyrus region of the hippocampus, leading to depression-like behavior (156). Surprisingly, drug treatment reprogrammed Arg-1⁺ microglial cell phenotypes in the dentate gyrus region, suppressed neuronal inflammation, increased the quantification of hippocampal newborn neurons (BrdU⁺ - DCX⁺ cells), and improved depression-like behavior in CMS-exposed mice (156). Thus, the balance of cytokines participates in neurogenesis, thus influencing the occurrence of depression.

BDNF, a protein synthesized in the brain and are widespread in the CNS, has critical function in the survival, differentiation, growth, and development of neurons (157). Tyrosine kinase receptor B (TrkB) acts as a BDNF specific receptor. Binding to the TrkB receptor activates intracellular signaling pathways that play an important role in sustaining neural growth, neuronal differentiation, and neuronal survival, as well as in maintaining synaptic plasticity and neuronal structure and function in adults (158). Wen et al. found that BDNF and TrkB were significantly reduced in the brain, especially in the hippocampus of mice, with significantly increased depressive and anxiety-like behaviors, suggesting a strong link between depression and the BDNF-TrkB signaling pathway (159). This mechanism may be related to the function of the BDNF-TrKB signaling pathway in neurogenesis. For example, Sonoyama et al. demonstrated that BDNF variants and variants of the TrkB kinase domain can lead to damaged processing and secretion of mature peptides in the BDNF-TrKB signaling pathway, resulting in impaired neurite growth and inhibition of hippocampal neurogenesis (160). Notably, Li et al. have shown that upregulation of the BDNF-TrkB signaling pathway can promote neuronal plasticity and thus increase the antidepressant response (161). In addition, some studies have found that the BDNF-TrkB signaling pathway is associated with microglia. Bagheri et al. found that high activation of M2 microglia and decreased activation of M1 microglia resulted in increased BDNF secretion (162). Ding found that BDNF can accelerate the activation of microglia to free TNF-α and IL-1β, aggravating the neuroinflammatory response through the BDNF-TrkB signaling pathway (162). The microglial subset with high expression of Arg-1 driven by IL-4 is crucial for maintaining hippocampal neurogenesis and stress resilience. In a mouse model, reducing Arg-1⁺ microglia led to decreased secretion of BDNF from Arg-1⁺ microglia in the DG region of the hippocampus, resulting in reduced survival and maturation of NSPCs and inhibition of hippocampal neurogenesis, as well as increased susceptibility to stress-induced depression. Conversely, enhancing IL-4 signaling to increase Arg-1⁺ microglia restored hippocampal neurogenesis and resistance to stress-induced depression (105). Therefore, microglia can promote neurogenesis and reduce depressive symptoms by acting on the BDNF or BDNF-TrkB signaling pathway.

The gut-brain axis is a two-way relationship between the gut and CNS connected by neurons of the sympathetic and parasympathetic nervous systems, that has been shown to induce stress-related gastrointestinal and mental symptoms. The gut microbiome is strongly connected to the gut, and by extension the brain, thus extending the gut-brain axis to the gut-brain-microbiota axis (163). Recently, dysregulation of the gut-brain-microbiota axis has been emerged as one of the leading hypotheses for explaining the pathogenesis of depression (164). Yu Du. found that mouse treated with antibiotics demonstrated a reduction in saccharin preference due to more than 90% of the gut microbiota being killed by antibiotics, which may indicate the key function of the gut microbiota in depressive-like behaviors (164). The underlying mechanism may be related to the significant role of gut microbiota in regulating the maturation and activation of microglia. Sun et al. found that changes in gut microbiota led to systemic inflammation that differentially activated inflammatory regulatory pathways in the brain, especially those associated with microglia, leading to the occurrence of depression (165). Carlessi et al. found that gut microbes secrete substantial amounts of microglia-activated amyloid and LPS to induce depression (166). Furthermore, several clinical and experimental studies have indicated that gut microbiota may be both a pathogenic determinant of neurogenesis-related diseases and a novel therapeutic target. For example, Sarubbo et al. found that germ-free (GF) and GF-colonized mice exhibited a trend of cell proliferation with elevated expression of BrdU in the dorsal hippocampus (167). Notably, Cerdó et al. found that using a strain-specific combination of probiotics restores neurogenesis defects in adult patients, which further confirms the link between gut microbiota and hippocampal neurogenesis (168). Previously, literature reported that regulating short-chain fatty acids, which are widely present in intestinal endocrine and immune cells and are important mediators for regulating body function through the gut microbiota, can decrease the ratio of Iba-1⁺/CD68⁺ cells in the hippocampal DG area of CUMS mice while increasing Ki67/NeuN, granular cell layer width, and dendritic spine density and quantity of neurons, thereby promoting neurogenesis and exerting an anti-depressant effect (101). In addition, Hanna Karakuła-Juchnowicz et al. found that gut dysbiosis and irritation may dysregulate the immune system near the brain, causing neurodegeneration (169). These results suggest that the microbial gut-brain axis may influence microglial activation and neurogenesis in depression. However, the function of the microbial-gut-brain axis in microglial regulation of neurogenesis requires further study.

MicroRNA (miRNA) is a non-coding RNA (ncRNA) that consists of 18-24 nucleotides, which is highly conserved in species that modulate gene expression, mainly by destabilizing the target mRNA and inhibiting the translation of the target mRNA to regulate target mRNAs (170). Microglia utilize exosomes to transfer microRNAs, specifically miR-146a-5p, to inhibit neurogenesis in cases of depression. Overexpression of miR-146a-5p in the hippocampal DG leads to a suppression of excitatory neuron spontaneous discharge and neurogenesis via direct targeting of Krüppel-like factor 4 (KLF4). Downregulation of miR-146a-5p expression results in improved adult neurogenesis in the DG and alleviates depression-like behaviors in rats. Notably, circular RNA ANKS1B acts as a miRNA sponge for miR-146a-5p and mediates post-transcriptional regulation of KLF4 expression. These findings demonstrate the critical role of miR-146a-5p in regulating neurogenesis during pathological processes related to depression and indicate that exosomes from microglia provide a new communication pathway between glial cells and neurons (171). These data demonstrate that multiple miRNA genes in the human body have different effects on depression and neurogenesis, which will be further clarified. It was also found that different miRNAs also have different effects on the polarization of microglia (172). For example, neuron-derived exosomes with high miR-21-5p expression promote M1 polarization of microglia. In contrast, MiR-124-enriched exosomes promoted M2 polarization of microglia (173). Currently, there are few studies on the roles of miRNAs in the regulation of microglia and neurogenesis, despite the complex link between neurogenesis and microglia in depression. Thus, elucidating the regulatory mechanisms of miRNAs in depression from the perspective of the regulation of microglia in neurogenesis may provide new insights into depression.