Abstract Objectives Neuroinflammation has been suggested that affects the processing of depression. There is renewed interest in berberine owing to its anti-inflammatory effects. Herein, we investigated whether berberine attenuate depressive-like behaviors via inhibiting NLRP3 inflammasome activation in mice model of depression. Methods Adult male C57BL/6N mice were administrated corticosterone (CORT, 20 mg/kg/day) for 35 days. Two doses (100 mg/kg/day and 200 mg/kg/day) of berberine were orally administrated from day 7 until day 35. Behavioral tests were performed to measure the depression-like behaviors alterations. Differentially expressed gene analysis was performed for RNA-sequencing data in the prefrontal cortex. NLRP3 inflammasome was measured by quantitative reverse transcription polymerase chain reaction, western blotting, and immunofluorescence labeling. The neuroplasticity and synaptic function were measured by immunofluorescence labeling, Golgi–Cox staining, transmission electron microscope, and whole-cell patch-clamp recordings. Results The results of behavioral tests demonstrated that berberine attenuated the depression-like behaviors induced by CORT. RNA-sequencing identified that NLRP3 was markedly upregulated after long-term CORT exposure. Berberine reversed the concentrations of peripheral and brain cytokines, NLRP3 inflammasome elicited by CORT in the prefrontal cortex and hippocampus were decreased by berberine. In addition, the lower frequency of neuronal excitation as well as the dendritic spine reduction were reversed by berberine treatment. Together, berberine increases hippocampal adult neurogenesis and synaptic plasticity induced by CORT. Conclusion The anti-depressants effects of berberine were accompanied by reduced the neuroinflammatory response via inhibiting the activation of NLRP3 inflammasome and rescued the neuronal deterioration via suppression of impairments in synaptic plasticity and neurogenesis. Supplementary Information The online version contains supplementary material available at 10.1186/s12974-023-02744-7. Keywords: Depression, Berberine, NLRP3 inflammasome, Neuroinflammation, Synaptic plasticity Introduction Depression has been identified as a high incidence and severe psychiatric disease [[43]1]. The health burden of depression by using disability-adjusted life-years (DALYs) estimation accounted for 1.85% of all DALYs worldwide, which increased 61.1% from 1990 to 2019 [[44]2]. It is known to significantly increase the risk of suicide for all ages, especially in adolescents. Although the understanding of the pathology of depression has developed considerably. Currently, no single mechanism can satisfactorily explain the pathophysiology of depression [[45]3, [46]4]. Studies have focused on many components of brain including prefrontal cortex (PFC), hippocampus, amygdala, ventral tegmental area (VTA), and nucleus accumbens (NAc), leading to the theories of depression as well as antidepressant response that have been involved in the molecular and cellular signaling mechanisms that mediate synaptic plasticity, contributing to a broader neuroplasticity hypothesis of depression [[47]5, [48]6]. To date, increasing evidence indicated that overexpressed peripheral inflammatory responses could injure the integrity of the blood–brain-barrier (BBB) and result in neuroinflammation in the brain [[49]7]. Consequently, the neuroinflammation-mediated neuroplasticity and neurogenesis defects might be a vital process under the mechanism in neuropsychiatric conditions, including depression [[50]8]. It has been observed that an excess in peripheral acute phase proteins and proinflammatory cytokines production in depression patients, which have been identified to be linked with emotional alterations and severity of psychiatric symptoms [[51]9, [52]10]. Besides, the remission of patients is often occurring after normalization of the inflammatory response, whereas a failure to remission is accompanied by the persistently elevated inflammatory response. This information promotes the hypothesis that the emotional alterations in depression patients might be attributed by an anomalous link between the central nervous system (CNS) and the innate immune response. Moreover, the pooled data from meta-analysis also supported that several anti-inflammatories have significant antidepressant effects [[53]11]. The interactions between the immune system and the CNS are not only involved in shaping behavior, but also in responding to therapeutics [[54]12]. NLRP3 (NLR family, pyrin domain containing 3) inflammasome complex is an intracellular multiprotein complex responsible for several innate immune processes associated with infection, inflammation, and autoimmunity [[55]13]. As a component of the innate immune system that functions as a pattern recognition receptor that recognizes pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs), NLRP3 appears to bridge the gap between immune activation and metabolic danger signals or stress exposure, which might be key factors in the pathogenesis of depression [[56]14, [57]15]. Stimulated by NLRP3, the over-released pro-inflammatory cytokine IL-1β can cross the BBB and alter synaptic plasticity by directly acting on neurons or stimulating the microglia activation [[58]16–[59]18]. In addition, the hypothalamus–pituitary–adrenal (HPA) axis could be stimulated by cytokines and result in glucocorticoids overproduction, exacerbating the stress response [[60]19, [61]20]. On the other hand, the neurotoxic effects of neuroinflammation consequently contribute to the synaptic remodeling, suggesting that neural plasticity also plays a vital role in the pathophysiology of depression and antidepressant function [[62]21]. High levels of inflammatory molecules have been reported to decrease a wide range of neural plasticity markers such as synaptic transmission, membrane excitability, plasticity in pyramidal neurons, as well as neurogenesis. NLRP3 matured IL-1β plays functional roles in the mechanisms of synaptic plasticity and cognitive functions. In the depression mice, the spine density and critical morphologies were significantly decreased, especially in the specific brain regions related to depression, such as the prefrontal cortex and hippocampus. Berberine is a natural isoquinoline alkaloid and there is renewed interest in berberine of its potential role in neurodegenerative and neuropsychiatric disorders because of its effect on neuroinflammation, hormonal regulation, and neurotransmitters [[63]22–[64]24]. In this study, we investigated the differentially expressed genes in corticosterone induced depression mice model (CORT) using a high-throughput microarray. The theory that disruption of neurotrophic factors and synaptic connectivity in the PFC and hippocampus is related to neuroplasticity mechanisms is one of the leading neuroplasticity hypotheses of depression [[65]25]. We found that NLRP3 showed significantly differential expression within the PFC of CORT-induced mice model versus wildtype mice controls and berberine-treated mice. Complementing these findings, the CORT mice result in neuroplasticity deficits and neurogenesis injury and induced depression-like behaviors. Accordingly, these results provide insights into mechanisms involving the functional regulation of corticosterone in depression and specifically, identify berberine as a potential therapy for depression. Materials and methods Animal models and drug treatment Adult male C57BL/6N mice (age 8–10 weeks) were obtained from the Centre for Comparative Medicine Research (CCMR), the University of Hong Kong. All mice were raised in the experimental holding areas (12 h light/dark cycle at 18–22 °C, with lights on at 8:00 A.M., ad libitum access to dry food pellets and water) following the ethics roles of the HKU (CULATR No. 5582-20) in the CCMR. Body weight was daily recorded during the entire experimental period. The mice were divided into 4 groups (n = 18 for each group), including saline-treated (control), corticosterone (20 mg/kg/day) treated (CORT), CORT + berberine (100 mg/kg/day) treated (BBR100), and CORT + berberine (200 mg/kg/day) treated (BBR200). CORT was consecutively administered from day1 to day35. From day7, 100 mg/kg/day or 200 mg/kg/day of berberine were given to mice in BBR100 or BBR200 groups via daily intragastrical administration, respectively. Mice in control and CORT groups received solution without berberine. Mice were given BrdU as daily intraperitoneal injections from day 8 to day 12. From day 28 to day 31, a series of behavioral tests were conducted for mice, CORT and berberine administration were sustained during behavioral tests until to the end of the experiment (day35). The dose of CORT was selected in accordance with a previous study that successfully induced depression in mice from the same laboratory [[66]26]. CORT and berberine were dissolved in a 0.5% aqueous solution of sodium carboxymethyl cellulose and administered via oral gavage. The solutions were freshly prepared before daily use. Figure [67]1a illustrates the experimental design timeline with the time of assays and manipulations. Fig. 1. [68]Fig. 1 [69]Open in a new tab Berberine prevents CORT-induced behavioral changes. a Schematic of experiment paradigm. CORT was consecutively administered from day1 to day35. From day7, 100 mg/kg/day or 200 mg/kg/day of berberine were given to mice in BBR100 or BBR200 groups via daily intragastrical administration, respectively. Mice in control and CORT groups received solution without berberine. Mice were given BrdU as daily intraperitoneal injections from day8 to day12. From day28 to day31, a series of behavioral tests were conducted for mice, CORT and berberine administration were sustained during behavioral tests until to the end of the experiment (day35). b Heatmap of mice exploration during the open field test. c Duration in central zone in the open field test. CORT mice spent less time in the central zone than the control mice (One-way ANOVA, F (3, 32) = 5.448, P = 0.0038; Dunnett’s multiple comparisons test, CORT vs. Control, P = 0.0012, n = 9 in each group). d Total distance in the open field test. CORT mice moved less in the field than the control and high-dose berberine mice (One-way ANOVA, F (3, 32) = 4.203, P = 0.0129; Dunnett’s multiple comparisons test, CORT vs. Control, P = 0.0077, CORT vs. BBR200, P = 0.0212, n = 9 in each group). e Zone transition number in the open field test. CORT administration decreased the number of zone transitions in mice in the open field test compared to the control and high-dose berberine mice (One-way ANOVA, F (3, 32) = 5.711, P = 0.0030; Dunnett’s multiple comparisons test, CORT vs. Control, P = 0.0008, CORT vs. BBR200, P = 0.0429, n = 9 in each group). f Immobile duration in the tail suspension test. CORT mice spent more time in immobile duration (One-way ANOVA, F (3, 28) = 6.435, P = 0.0019; Dunnett’s multiple comparisons test, CORT vs. Control, P = 0.0005, CORT vs. BBR100, P = 0.0425, CORT vs. BBR200, P = 0.0345, n = 8 in each group). g Immobile duration in the forced swim test. CORT mice spent more time in immobile duration (One-way ANOVA, F (3, 32) = 6.316, P = 0.0017; Dunnett’s multiple comparisons test, CORT vs. Control, P = 0.0007, CORT vs. BBR100, P = 0.0145, CORT vs. BBR200, P = 0.0141, n = 9 in each group). h Sucrose consumption in the sucrose preference test. The consumption of sucrose in CORT mice was significantly lower than in the mice in control and high-dose berberine groups (One-way ANOVA, F (3, 32) = 4.638, P = 0.0084; Dunnett’s multiple comparisons test, CORT vs. Control, P = 0.0070, CORT vs. BBR200, P = 0.0090, n = 16 in each group). Bar graphs show the mean ± SEM; *P < 0.05, **P < 0.01, ***P < 0.001. CORT corticosterone, BBR berbberine, ANOVA analysis of variance Behavioral tests Open field test (OFT) For assessment of locomotion and anxiety-like behavior in mice. The OFT was performed in a white plastic apparatus (50 height × 50 widths × 40 cm depth) with a 30 × 30 cm central zone. The total distance and velocity moved and the frequency of transfer between the central and surrounding zones was recorded over a 10-min test period. The 95% ethanol was sprayed to clean the apparatus between each test to avoid odor and waste left by the last mouse. We performed the test for all mice on the first day before the experiment. SMART video tracking software (V.3.0, Panlab, USA) was used to record and analyzed data. Tail suspension test (TST) The TST was performed in a white plastic chamber (55 height × 10 widths × 10 cm depth). Each mouse was suspended from its tail tip with adhesive tape in a head-down position and lasted for 6 min. Immobility time is defined as the cessation of any movements of limbs and the trunk. To avoid the bias affected by the stress response, each mouse was adapted for 2 min after being suspended, only the remaining 4 min was recorded and analyzed. SMART video tracking software (V.3.0, Panlab, USA) was used to record and analyzed data. Forced swimming test (FST) To evaluate a depressive-like behavioral state, the FST was performed in a clear polycarbonate cylinder (30 height × 20 cm diameter). Each mouse was forced to swim in each cylinder filled with water (23 to 25 °C) for 6 min and videotaped. Immobility time is defined as the absence of all movements except the motions required to keep the mice's heads above the surface of the water. To avoid the bias affected by the stress response, each mouse was adapted for 2 min in the water, only the remaining 4 min was recorded and analyzed. Sucrose preference test (SPT) SPT was performed to assess the anhedonia, a core symptom of depression. First, mice were adaptively exposed to two bottles containing 1% sucrose solution (w/v) with ad libitum access for 24 h in groups of 5 per cage. Then, one bottle of 1% sucrose solution and another bottle of tap water were administrated for 24 h. On the last day, the position of the two bottles was switched for 24 h to avoid side preference. At the end of the adaptation period, all mice were deprived of food and water for 12 h before the test. After that, SPT was conducted in an individual mouse housed in a cage with free access to two respective bottles containing 1% sucrose solution and tap water for 2 h. To prevent side preferences in drinking behavior, the position