Chronic Unpredictable Stress-induced Depressive-like Behaviors Research Articles

CX3CR1 (fractalkine receptor)-deficient mice exhibit resilience to chronic unpredictable stress-induced depressive-like behavior and suppressed neurogenesis

We recently demonstrated that microglia undergo dynamic alterations in activation state during the development of chronic unpredictable stress (CUS)-induced depressive-like behavior in mice. Moreover, manipulations of microglial activation, which counteracted these dynamic alternations, reversed the depressive-like behavioral symptoms. Here, we sought to determine whether CX3CR1-deficient mice, which display a mildly activated microglial phenotype, show increased or decreased sensitivity to CUS-induced depressive-like behavior. Experiments were conducted on homozygous mice with microglia-specific transgenic expression of GFP under the CX3CR1 promoter, in which the CX3CR1 gene was functionally deleted, and their C57BL wild-type (WT) controls. We found that following five weeks of CUS exposure, microglia numbers were significantly reduced in the hippocampal dentate gyrus (DG), but not CA3 region, in both WT and CX3CR1-deficient mice. However, only CUS-exposed WT mice showed a significant reduction in microglia soma size compared to controls, indicating resistance of CX3CR1-deficient microglia to stress-induced morphological changes. In addition, only CUS-exposed WT mice showed reduced sucrose preference and impaired novel object recognition memory, suggesting that CX3CR1-deficient mice do not exhibit CUS-induced depressive-like behavior, and show superior memory functioning under stress. Finally, doublecortin immunostaining of the DG revealed that exposure to CUS decreased neurogenesis in WT but not in CX3CR1-deficient mice. We conclude that CX3CR1 deficiency, which is associated with a mildly activated microglial phenotype, confers resilience to CUS-induced microglial alterations, depressive-like behavior, a nd suppressed neurogenesis.

Phosphodiesterase-4D Knock-down in the Prefrontal Cortex Alleviates Chronic Unpredictable Stress-Induced Depressive-Like Behaviors and Memory Deficits in Mice.

Phosphodiesterase 4 (PDE4) has four isoforms (PDE4A-D) with at least 25 splice variants. PDE4 subtype nonselective inhibitors produce potent antidepressant-like and cognition-enhancing effects via increased intracellular cyclic AMP (cAMP) signaling in the brain. Our previous data have demonstrated that long-form PDE4Ds appear to be involved in these pharmacological properties of PDE4 inhibitors in the normal animals. However, it is not clear whether long-form PDE4Ds are critical for the behaviors and related cellular signaling/neuronal plasticity/neuroendocrine alterations in the depressed animals. In the present study, animals exposed to the chronic unpredictable stress (CUS), a rodent model of depression, exhibited elevated corticosterone, depressive-like behavior, memory deficits, accompanied with decreased cAMP-PKA-CREB and cAMP-ERK1/2-CREB signaling and neuroplasticity. These alterations induced by CUS were reversed by RNA interference (RNAi)-mediated prefrontal cortex long-form PDE4Ds (especially PDE4D4 and PDE4D5) knock-down, similar to the effects of the PDE4 subtype nonselective inhibitor rolipram. Furthermore, these effects of RNAi were not enhanced by rolipram. These data indicate a predominant role of long-form PDE4Ds in the pharmacotherapies of PDE4 inhibitors for depression and concomitant memory deficits. Long-form PDE4Ds, especially PDE4D4 and PDE4D5, appear to be the promising targets for the development of antidepressants with high therapeutic indices.

Protective effect of gan mai da zao decoction in unpredictable chronic mild stress-induced behavioral and biochemical alterations

Aim: Growing evidence indicates that the glutamatergic system, especially the abnormalities of glutamate and N-methyl-D-aspartate (NMDA) receptors contribute to the pathophysiology and possibly the pathogenesis of major depressive disorders. This study is to evaluate the effect of gan mai da zao (GMDZ) decoction on glutamate and NMDA receptor in unpredictable chronic mild stress (UCMS) rats.Materials and methods: Sucrose preference test and open field test were used to estimate the depressive-like behaviors of UCMS rats. Glutamate levels and NMDA receptor subunits (NR1, NR2A and NR2B) in the frontal cortex and hippocampus were determined by HPLC-FLD and by western-blot respectively.Results: 32 days UCMS induced depressive-like behaviors, increased glutamate concentration and decreased NMDA receptor subunits NR2A and NR2B in the frontal cortex and hippocampus of rats. However, NR1 expression remained constant in stressed rats compared with normal. The GMDZ decoction alleviated the depressive-like behavior, decreased glutamate level, and increased expression of NMDA receptor subunit NR2A and NR2B in the frontal cortex and hippocampus of stressed rats.Conclusions: These results suggest that GMDZ treatment reversed chronic unpredictable stress-induced depressive-like behaviors in UCMS rats, possibly via reducing glutamate levels and increasing the NMDA receptor subunits NR2A and NR2B in frontal cortex and hippocampus.

Chronic treatment with celecoxib reverses chronic unpredictable stress-induced depressive-like behavior via reducing cyclooxygenase-2 expression in rat brain

Recent clinical trails reported that adjunctive cyclooxygenase (COX)-2 inhibition with celecoxib is beneficial in treating depression. However, another clinical study showed celecoxib did not have inhibitory effect of COX-2 in human brain when given at a therapeutic dose. Therefore, whether celecoxib is exerting its influence through COX inhibition or by some other mechanism remains unclear. The present study further investigated the effect of celecoxib on COX-2 expression, prostaglandin E 2 (PGE 2, a major COX-2-mediated inflammatory mediator) concentration and the depressive-like behaviors in rats. Celecoxib was administrated by oral gavage to naive rats (16 mg/kg) or stressed rats (2, 8, 16 mg/kg, respectively) for 21 days, or to stressed rats for a single dose (16 mg/kg). The results showed that 21 days chronic unpredictable stress induced depressive-like behaviors and increased the COX-2 expression and PGE 2 concentration in rat brain. Chronic treatments with celecoxib alleviated the depressive-like behavior and reversed the levels of COX-2 expression and PGE 2 concentration in stressed rat in a dose-dependent manner. Celecoxib also improved the emotional state and decreased COX-2 expression and PGE 2 concentration in naive rats. In addition, a single dose of celecoxib treatment reversed COX-2 expression and PGE 2 concentration, but didn't alter the depressive-like behavior in stressed rat. These results suggest that COX-2 enzyme might play a key role in pathophysiology of depression. Furthermore, these data indicate that chronic celecoxib treatment reverse chronic unpredictable stress-induced depressive-like behavior might via reducing COX-2 enzyme in brain, and the selective COX-2 inhibitors could be developed as potential remedies for the management of depression.