Introduction

Depression has been identified as a high incidence and severe psychiatric disease [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 [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 [3, 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 [5, 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 [7]. Consequently, the neuroinflammation-mediated neuroplasticity and neurogenesis defects might be a vital process under the mechanism in neuropsychiatric conditions, including depression [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 [9, 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 [11].

The interactions between the immune system and the CNS are not only involved in shaping behavior, but also in responding to therapeutics [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 [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 [14, 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 [16,17,18]. In addition, the hypothalamus–pituitary–adrenal (HPA) axis could be stimulated by cytokines and result in glucocorticoids overproduction, exacerbating the stress response [19, 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 [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 [22,23,24]. 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 [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.

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