Wenjuan Lin

Fluoxetine increases the activity of the ERK-CREB signal system and alleviates the depressive-like behavior in rats exposed to chronic forced swim stress.

Our previous research indicates that the extracellular signal-regulated kinase (ERK)-cyclic AMP-responsive-element-binding protein (CREB) signal system may be involved in the molecular mechanism of depression. The present study further investigated the effect of antidepressant fluoxetine on the ERK-CREB signal system and the depressive-like behaviors in rats. Fluoxetine was administrated to either naive rats or stressed rats for 21 days. The results showed that chronic forced swim stress induced depressive-like behaviors and decreased the levels of P-ERK2, P-CREB, ERK1/2 and CREB in hippocampus and prefrontal cortex. Fluoxetine alleviated the depressive-like behaviors and reversed the disruptions of the P-ERK2 and P-CREB in stressed rats. Fluoxetine also exerted mood-elevating effect and increased the levels of the P-ERK2 and P-CREB in naive rats. These results suggest that the ERK-CREB signal system may be the targets of the antidepressant action of fluoxetine and participate in the neuronal mechanism of depression.

The depressive-like behaviors are correlated with decreased phosphorylation of mitogen-activated protein kinases in rat brain following chronic forced swim stress

In the present study, 40 Sprague-Dawley rats were divided into forced swim stress group and controls, with 20 rats in each group (10 for behavioral tests, 10 for protein detection). The forced swim stress group received swim stress for 14 consecutive days, and the controls were stress-free. After stress, 20 rats were tested for behavioral observation using body weight gain, open field, elevated plus-maze and saccharin preference test, and 20 rats were decapitated for protein detection. The extracellular signal-regulated kinase (Erk) and phospho-Erk (P-Erk) in the hippocampus and prefrontal cortex were determined using western blot. It was found that the body weight gain of stressed animals during the 7 stressed days and the 14 stressed days was significantly decreased compared to that of controls. Stressed animals spent less time in open arms and longer time in closed arms. The stressed animals demonstrated decreased locomotor activity and increased grooming in open field. The saccharin solution intake and the ratio of saccharin solution intake to total liquid intake were both decreased in the stressed group. Stressed animals showed decreased P-Erk2 and decreased ratio of P-Erk2 to total Erk2 in the hippocampus and prefrontal cortex, but their Erk1/2 was increased in the prefrontal cortex with no change in hippocampus. The saccharin solution intake positively correlated with the P-Erk2 in the hippocampus and negatively correlated with the Erk2 in the prefrontal cortex. In conclusion, chronic forced swim stress was a good animal model of depression, and it induced depressive-like behavior and decreased P-Erk2 in the hippocampus and prefrontal cortex in rats. The depressive-like behaviors were correlated with decreased phosphorylation of Erk, which suggested that the dysfunction of Erk activity might be one of biological mechanisms underlying depression induced by stress.

A role for the extracellular signal-regulated kinase signal pathway in depressive-like behavior.

Our recent research demonstrates that the extracellular signal-regulated kinase (ERK) signal pathway is impaired in depressed animals, and such disruption is effectively reversed following antidepressant treatment. These results indicate that the ERK pathway may participate in the molecular mechanism of depression. To provide direct evidence for the potential role of the ERK pathway in depression, the present study using a sub-chronic regimen of ERK inhibition investigated the disparate role for the ERK cascade in two specific brain areas, the dorsal hippocampus (dHP) and the medial prefrontal cortex (mPFC), in the pathophysiology of depressive-like behavior. Rats were bilaterally implanted with cannulas in the dHP or mPFC and were microinjected with U0126, a specific inhibitor of ERK upstream activator, or vehicle for 7 consecutive days. The behavioral effects of the ERK pathway inhibition were examined in the open field, elevated plus maze, and saccharin preference test. The results showed that the inhibition of the ERK pathway in dHP resulted in anhedonia and anxiety-like behavior, and the ERK pathway inhibition in the mPFC induced anhedonia and locomotor impairment in rats. The phosphorylation of the cyclic AMP-responsive-element-binding protein (CREB) was decreased following the ERK pathway inhibition either in dHP or mPFC. These findings demonstrate that the ERK pathway in either the dHP or mPFC participates in the pathophysiology of the depressive-like behavior, and may have pivotal role in human depression.

Pubertal isolation alters latent inhibition and DA in nucleus accumbens of adult rats

Puberty is a critical period for neurodevelopment of schizophrenia. In the present study, we investigated the effects of peri-pubertal social isolation on psychotic behaviors in rats and its relationship to dopamine expression. Wistar male rats were randomly divided into pubertal isolation (ISO; isolate housing, 38-51 days of age) and social (SOC) groups. Latent inhibition (LI) and behavior in open field were tested during adolescence and adulthood. After the behavioral test, dopamine (DA) levels were measured in the medial prefrontal cortex (mPFC), nucleus accumbens (NAC), caudate-putamen (CPU), and the hippocampus (HIP). Pubertal social isolation impaired LI and increased the DA level in the NAC of young adult rats, but not adolescent rats, and enhanced open field locomotor activity in both adolescent and young adult rats. These data suggest that development of an LI deficit can be induced by social isolation during puberty after a developmental delay, and that NAC DA maybe involved in this process, which may mirror some aspects of the ontogency of schizophrenic symptoms.

The effects of central pro-and anti-inflammatory immune challenges on depressive-like behavior induced by chronic forced swim stress in rats

Although increasing evidence demonstrates that both chronic stressors and inflammatory immune activation contribute to pathophysiology and behavioral alterations associated with major depression, little is known about the interaction effect of central inflammatory immune activation and stress on depressive-like behavior. Our previous work has shown that 14-day chronic forced swim stress induces significant depressive-like behavior. The present investigation assessed whether pro-inflammatory cytokine and anti-inflammatory cytokine challenges have differential interaction effect on depressive-like behavior induced by chronic forced swim stress in rats. The pro-inflammatory and anti-inflammatory immune challenges were achieved respectively by central administration of lipopolysaccharide (LPS), a pro-inflammatory cytokine inducer, and interleukin-10 (IL-10), an anti-inflammatory cytokine. It was found that either central LPS treatment alone or chronic forced swim stress alone significantly induced depressive-like behavior, including reduced body weight gain, reduced saccharin preference and reduced locomotor activity. However, there was no significant synergistic or additive effect of central LPS treatment and stress on depressive-like behavior. LPS treatment did not exacerbate the depressive-like behavior induced by forced swim stress. Nevertheless, IL-10 reversed depressive-like behavior induced by forced swim stress, a finding indicating that IL-10 has antidepressant effect on behavioral depression induced by stress. The present findings provide new insight into the complexity of the immunity-inflammation hypothesis of depression.

Enhancement of antibody production and expression of c-Fos in the insular cortex in response to a conditioned stimulus after a single-trial learning paradigm.

Immune responses can be modulated by Pavlovian conditioning techniques. In this study, to evaluate the conditionability of antibody response via a single-trial conditioning paradigm, we used a protein antigen ovalbumin as an unconditioned stimulus (UCS) that was paired with a novel taste of saccharin in a single-trial learning protocol. A significant enhancement of anti-ovalbumin antibody production was observed in the conditioned rats at Days 15, 20 and 25 after re-exposure to the conditioned stimulus. The pattern of conditioned antibody response is similar to that of antigen-induced antibody response. Furthermore, to identify the involvement of a limbic brain structure in the expression of conditioned antibody response, immediate-early gene c-fos expression was used as a marker of neuronal activation to detect the functional activation in the insular cortex (IC) in response to the conditioned stimulus. The re-exposure of conditioned rats to the conditioned stimulus resulted in a significant increase of c-Fos immunoreactivity in all three areas of the IC including the agranular, dysgranular, and granular areas, suggesting that IC is involved in the neural mechanism of expression of conditioned immune response.

Chronic blockade of glucocorticoid receptors by RU486 enhances lipopolysaccharide-induced depressive-like behaviour and cytokine production in rats

Although accumulating evidence supports a role for cytokines in the pathophysiology of depression, the cytokine hypothesis of depression is debatable. It has been suggested that neuroendocrine and immune systems acting in concert may have roles in the development and the maintenance of the disease. Glucocorticoid receptor (GR) is the key element which exerts both anti-inflammatory and cytokine-inhibiting effects. Whether functional changes of GR are involved in the pathophysiology of cytokine-induced depression remains elusive. In the present study, the effects of both acute and chronic GR blockade on depressive-like behaviour and cytokine production induced by lipopolysaccharides (LPS), cytokine inducer, were investigated in rats. Acute or chronic blockade of GR was achieved by a single administration or repeated administrations, respectively, of the GR antagonist RU486 (RU). Behavioural measurements, including saccharin preference, locomotor activity, and immobility time, were assessed. The serum levels of proinflammatory cytokines (TNFα, IL-1β, and IFNγ) were determined by ELISA. The results showed that LPS induced significant but transient depressive-like behaviour. Repeated, but not single, administration of RU significantly enhanced and prolonged LPS-induced depressive-like behaviour and an increase in the serum production of TNFα and IFNγ. These results indicate that the effective blockade of GR enhanced the depressive-like behaviour induced by cytokines. Findings from this study suggest that GR dysfunction may be an important contributing factor to the development of cytokine-related depression. These findings add to the growing evidence of mechanisms by which cytokines influence depression.

Hippocampal neurogenesis dysfunction linked to depressive-like behaviors in a neuroinflammation induced model of depression

Our previous work found that triple central lipopolysaccharide (LPS) administration could induce depressive-like behaviors and increased central pro-inflammatory cytokines mRNA, hippocampal cytokine mRNA in particular. Since several neuroinflammation-associated conditions have been reported to impair neurogenesis, in this study, we further investigated whether the neuroinflammation induced depression would be associated with hippocampal neurogenesis dysfunction. An animal model of depression induced by triple central lipopolysaccharide (LPS) administration was used. In the hippocampus, the neuroinflammatory state evoked by LPS was marked by an increased production of pro-inflammatory cytokines, including interleukin-1β, interleukin-6, and tumor necrosis factor-α. It was found that rats in the neuroinflammatory state exhibited depressive-like behaviors, including reduced saccharin preference and locomotor activity as well as increased immobility time in the tail suspension test and latency to feed in the novelty suppressed feeding test. Adult hippocampal neurogenesis was concomitantly inhibited, including decreased cell proliferation and newborn cell survival. We also demonstrated that the decreased hippocampal neurogenesis in cell proliferation was significantly correlated with the depressive-like phenotypes of decreased saccharine preference and distance travelled, the core and characteristic symptoms of depression, under neuro inflammation state. These findings provide the first evidence that hippocampal neurogenesis dysfunction is correlated with neuroinflammation-induced depression, which suggests that hippocampal neurogenesis might be one of biological mechanisms underlying depression induced by neruoinflammation.

Comparison of stress-induced and LPS-induced depressive-like behaviors and the alterations of central proinflammatory cytokines mRNA in rats

Although proinflammatory cytokine changes in depression have been studied widely, few investigations have searched for specific and common changes in cytokines. In the present study, two animal models of depression were compared: a chronic stress model using forced swim stress and an immune activation model using repeated central lipopolysaccharide (LPS) infusion. The levels of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6 mRNA were examined in the brain regions of the prefrontal cortex, amygdala, and hippocampus using real-time polymerase chain reaction (RT-PCR). It was found that both chronic swim stress and repeated central LPS infusion induced depressive-like behaviors, including decreased body weight, reduced saccharin preference, and increased immobility time or shortened latency of immobility in the tail suspension test. Central TNF-α mRNA expression was elevated in both models and central IL-6 mRNA expression was unchanged in both models. Central IL-1β mRNA expression was increased only in the chronic immune activation model. The findings from this study suggest that TNF-α may be a common risk factor for inflammation in depressive disorders.

Exogenous FGF2 reverses depressive-like behaviors and restores the suppressed FGF2-ERK1/2 signaling and the impaired hippocampal neurogenesis induced by neuroinflammation

Our previous work demonstrated that neuroinflammation evoked by triple repeated central LPS challenges inhibited adult hippocampal neurogenesis that were correlated with the depressive-like behavioral symptoms induced by neuroinflammation. These findings suggest that hippocampal neurogenesis might be one of biological mechanisms underlying depression induced by neuroinflammation and targeting neurogenesis might lead to new therapeutic strategies for the treatment of depression. In this study, we manipulated adult hippocampal neurogenesis using fibroblast growth factor 2 (FGF2), one crucial molecule modulating cell proliferation and survival in central nervous system, and investigate the involvement and the potential therapeutic effects of FGF2 on neuroinflammation-induced depression. Central lipopolysaccharides (LPS) challenges were used as previously to evoke the neuroinflammatory state in the brain of rat. Exogenous FGF2 was infused into lateral ventricle during the neuroinflammatory state. It was found that the protein expression of FGF2 in hippocampus was inhibited by neuroinflammation. The activation of extracellular signal-regulated kinase (ERK), the downstream molecule of FGF2, was also inhibited by neuroinflammation. Exogenous FGF2 infusions prevented the decrease in phosphorylation of ERK1/2 under neuroinflammation state. Exogenous FGF2 reversed depressive-like behaviors and the impaired hippocampal neurogenesis induced by neuroinflammation. These findings provide evidence that the FGF2-ERK1/2 pathway is involved in the pathophysiology of depressive-like behaviors, and manipulating the neurogenesis pathway is a viable therapeutic approach to inflammation-associated depression.