Brain-Derived Neurotrophic Factor Precursor in the Hippocampus Regulates Both Depressive and Anxiety-Like Behaviors in Rats

Abstract

Depression and anxiety are two affective disorders that greatly threaten the mental health of a large population worldwide. Previous studies have shown that brain-derived neurotrophic factor precursor (proBDNF) is involved in the development of depression. However, it is still elusive whether proBDNF is involved in anxiety, and if so, which brain regions of proBDNF regulate these two affective disorders. The present study aims to investigate the role of proBDNF in the hippocampus in the development of depression and anxiety. Rat models of an anxiety-like phenotype and depression-like phenotype were established by complete Freund's adjuvant intra-plantar injection and chronic restraint stress, respectively. Both rat models developed anxiety-like behaviors as determined by the open field test and elevated plus maze test. However, only rats with depression-like phenotype displayed the lower sucrose consumption in the sucrose preference test and a longer immobility time in the forced swimming test. Sholl analysis showed that the dendritic arborization of granule cells in the hippocampus was decreased in rats with depression-like phenotype but was not changed in rats with anxiety-like phenotype. In addition, synaptophysin was downregulated in the rats with depression-like phenotype but upregulated in the rats with anxiety-like phenotype. In both models, proBDNF was greatly increased in the hippocampus. Intra-hippocampal injection anti-proBDNF antibody greatly ameliorated the anxiety-like and depressive behaviors in the rats. These findings suggest that despite some behavioral and morphological differences between depression and anxiety, hippocampal proBDNF is a common mediator to regulate these two mental disorders.

Reduction in BDNF from Inefficient Precursor Conversion Influences Nest Building and Promotes Depressive-Like Behavior in Mice

“…As BDNF pro/+ mutant mice exhibited reduced mBDNF levels as a result of inefficient cleavage of proBDNF and spent more time immobile in the tail suspension test after being housed in social isolation, the stress of social isolation and impaired proBDNF cleavage may cooperatively promote depressive-like behavior. In line with these findings, it was reported that the ratio of mBDNF to proBDNF increases in mice subjected to chronic unpredicted mild stress that exhibit depressive-like behaviors [43] as well as in a rat model of anxiety induced by intraplantar injections of complete Freund's adjuvant and a model of depression induced by chronic restraint stress [44]. Moreover, a clinical report indicated that the mBDNF/proBDNF ratio in serum is a potential biomarker to discriminate patients with bipolar depression among those with depressive episodes [45].…”

The Relationships Between Stress, Mental Disorders, and Epigenetic Regulation of BDNF

“…Considering the different changes in BDNF in stress-related (decreased BDNF in hippocampus) and reward-related systems (increased BDNF in VTA and NAc), stress-induced anxiety and depression may be associated with the degree of activation of different pathways. Another study also demonstrated that both depressive and anxiety-like behaviors were related with the elevation of proBDNF in the hippocampus, whereas dendritic arborization and synaptophysin in neurons were differently regulated in these two phenotypes [32]. This research suggests the importance of morphological plasticity and supports the "neurotrophic hypothesis" [33], which postulates that stress-induced adverse phenotypes may be due to the loss of cells lacking neurotrophic maintenance.…”

ProBDNF promotes sepsis-associated encephalopathy in mice by dampening the immune activity of meningeal CD4+ T cells

“…injected monoclonal anti-proBDNF antibody (McAb-proB) into mice before LPS treatment. The dose of 100 μg McAb-proB was found to fully block the biological function of the endogenous proBDNF without apparently affecting the behaviors in naïve mice [15,16,18,19]. Systemic administration of McAb-proB did not affect the weight changes induced by LPS injection (Fig.…”

“…For investigating the role of monoclonal anti-proBDNF antibody (McAb-proB), mice were treated with intraperitoneal injection of 100 μg in 0.3 ml McAb-proB at 30 min before the induction of SAE model, or bilateral intracerebroventricular delivery (i.c.v) of 1 μg in 1 μl McAb-proB 3 days before LPS injection. The biological activity and safety of McAb-proB have been characterized by our previous studies [15,16,18,19]. Mouse IgG (CMCTAG, catalog: AT1596) were used for isotype control of related experiments.…”

“…The whole meninges were mounted and washed for 3 times with 0.1 M PBS. After blocking by 5% BSA and 0.2% triton at 37°C for 30 min, slices were stained with humanized monoclonal anti-proBDNF antibody (2 ng ml −1 ) overnight at 4°C as introduced by our previous study [19]. Then, they were washed by 0.1 M PBS for 3 times and incubated with goat anti-human secondary antibody (1:400, USA, catalog: SA00003-12) for 2 h at 37°C .…”