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ABSTRACT: As an adverse early life experience, maternal separation (MS) induces profound neurochemical, cognitive and emotional dysfunction. Although previous studies have reported that MS affected prepulse inhibition (PPI), anxiety-related behaviors, dopaminergic and serotonergic activity in adult rats, and in the present study, we investigated the effects of repeated (4h/day) maternal separation during postnatal days 1-21 on PPI and anxiety-related behaviors in an elevated plus maze, as well as dopamine D2 receptor (DRD2) and 5-HT1A receptor expression in the medial prefrontal cortex (mPFC), nucleus accumbens (NAc) and hippocampus in adolescent rats. Our findings show that repeated MS results in reduced PPI, increased anxiety-related behaviors, decreased DRD2 protein expression in the NAc and hippocampus, and decreased 5-HT1A protein expression in the mPFC and hippocampus in adolescent rats. These data further demonstrate that MS can be used as an animal model of neuropsychiatric disease.
Brain research 04/2013; · 2.46 Impact Factor
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ABSTRACT: 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.
Behavioural brain research 03/2013; · 3.22 Impact Factor
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ABSTRACT: Maternal separation (MS) induces profound behavioral and neurochemical dysregulations in adult rodents. In the present longitudinal study, we investigated the effects of repeated (4h/day) maternal separation during postnatal days 1-21 on serotonergic synthesis and activity in the prefrontal cortex (PFC), nucleus accumbens (NAc) and hippocampus of juvenile (post-natal day 21, PND 21), adolescent (PND 35) and early adult (PND 56) male Wistar rats. We found that MS increased 5-HT levels in the PFC of juvenile rats, and although MS increased 5-HT and 5-HIAA levels in the NAc of adolescent rats, the ratio between 5-HIAA and 5-HT decreased in the PFC. In addition, MS-treated adult rats showed increased levels of 5-HT in the PFC as well as 5-HT and 5-HIAA in the NAc. These data provided evidence that MS leads to profound and age-specific changes in serotonergic synthesis and activity in rodents. Our study also found that there are U-shaped and inverted U-shaped patterns for serotonergic synthesis and serotonergic activity from younger rats to adults, respectively. Together, our findings support the use of maternal separation as an animal model for studying the neurobiological pathogenesis of neurodevelopmental diseases.
Brain research bulletin 03/2013; · 2.18 Impact Factor
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ABSTRACT: This report describes a new model of emotional stress, which was induced by randomly giving an empty water bottle to rats
during watering periods per day for 14 consecutive days. The behavioral, endocrinological and immunological consequences were
investigated. The data showed that the emotional stress activated both the hypothalamic-pituitary-adrenal axis and the sympathetic
nervous system, leading to the increased blood levels of corticosterone and catecholamine. It also elicited attacking and
exploring behavior, suppressed the immune function of the rats, including leukocyte counts, weight of the spleen, and the
level of specific anti-ovalbumin IgG antibody production. Presenting no water and no empty bottle to rats only evoked the
exploring behavior, increased the corticosterone level and decreased the leukocyte counts. These findings demonstrate a role
of psychological factors on behavioral, endocrinological and immunological functioning. The animal model described in the
present study may serve as an analogue mimicking emotional stress experienced in humans (e.g. anger and/or anxiety), and may
be useful for further studying the complex relationships among emotional stress, behavior, and immune function.
Keywordsemotional stress model-attacking-corticosterone-catecholamine-immune function
Chinese Science Bulletin 04/2012; 48(15):1565-1568. · 1.32 Impact Factor
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ABSTRACT: Adolescence is a critical period for neurodevelopment. In the present study, we investigated the effects of peri-adolescent social isolation on latent inhibition (LI) and dopamine D2 receptor expression in the medial prefrontal cortex (mPFC) and nucleus accumbens (NAc) of young adult rats. Male Sprague-Dawley rats were randomly divided into adolescent isolation (ISO; isolated housing, 21-34 days of age) and social housing (SOC) groups. LI was tested at postnatal day 56. After behavioral testing, the number of dopamine D2 receptor-expressing cells was determined using immunohistochemistry. Adolescent social isolation impaired LI and increased the number of cells expressing the D2 receptor in the mPFC and NAc. The results suggest that adolescent social isolation produces profound effects on cognitive and dopaminergic function in adult rats, and could be used as an animal model of various neurodevelopmental disorders.
Brain research 01/2012; 1447:38-43. · 2.46 Impact Factor
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ABSTRACT: Isolation rearing produces significant behavioral and neurochemical dysregulations in rodents. However, few studies have examined the effects of short-term isolation rearing during puberty compared to chronic social isolation from weaning to adulthood. In this study, we subjected weaning rats to a brief two-week social isolation and then re-socialized them until adulthood. We found that early isolation rearing affected reversal learning without interfering with spatial learning in the Morris water maze. We also found that brain-derived neurotrophic factor (BDNF) protein expression was increased in the medial prefrontal cortex (mPFC) but was decreased in the nucleus accumbens (NAc), CA1 and dentate gyrus of the hippocampus in isolation-reared rats. Together, our findings support the use of adolescent social isolation as a rodent model to study brain and behavior abnormalities induced by early environmental interruptions.
Brain research bulletin 07/2011; 86(3-4):173-8. · 2.18 Impact Factor
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ABSTRACT: Isolation rearing induces profound behavioral and neurochemical abnormalities in rodents. However, there is some controversy regarding the effect of isolation rearing on social behaviors and monoamine neurotransmission in mesolimbic and mesocortical areas. In the current study, we aimed to address these issues and demonstrated that isolation rearing from weaning to adulthood resulted in increased playful fighting and social contact behaviors. Isolation-reared rats also manifested increased dopamine and serotonin levels in the medial prefrontal cortex (mPFC) and nucleus accumbens (NAc) as well as an increase in serotonin turnover in the NAc. This study provides additional evidence that social isolation induces alterations in behavior and in the brain.
Brain research 02/2011; 1385:175-81. · 2.46 Impact Factor
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ABSTRACT: Maternal immune activation (MIA) produces a variety of behavioral and brain abnormalities in rodent models of several neuropsychiatric disorders. However, it remains controversial whether MIA impairs reversal learning, a basic function of flexibility relevant to those diseases, in offspring. In the present study, we used the Morris water maze to investigate the effects of middle to late gestation stage poly(I:C) challenges on spatial learning and subsequent reversal learning performance in adolescent rats. Maternal poly(I:C) treatment induced deficits in reversal learning without affecting spatial acquisition abilities. In addition, the serum level of the proinflammatory cytokine tumor necrosis factor-α was increased in MIA rats. This study advances our understanding of how MIA affects adolescent behavior and brain function.
Neuropsychobiology 01/2011; 64(1):9-14. · 2.67 Impact Factor
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ABSTRACT: Adolescence is a critical period for neurodevelopment. Disturbances during adolescence have significant deleterious effects on brain function and animal behavior. Latent inhibition refers to the process in which pre-exposure to a stimulus retards subsequent conditioning of this stimulus. Previous studies demonstrate that adolescent social isolation significantly impairs latent inhibition and disrupts cortical dopamine and glutamate neurotransmission. However, it remains elusive whether dopamine agonism during adolescence has any effect on latent inhibition or cortical glutamate activity. In the current study, adolescent Wistar rats were subjected to chronic dopamine agonist apomorphine treatment (1 mg/kg for 14 days). Latent inhibition and metabotropic glutamate receptor 5 (mGluR5) expression levels were examined at adulthood. The results demonstrate that adolescent chronic apomorphine treatment severely impairs latent inhibition and decreases mGluR5 receptor expression in the prefrontal cortex. This study provides further evidence that pubertal dopaminergic deviation could result in schizophrenic-like behavioral and neurochemical abnormalities.
European journal of pharmacology 12/2010; 649(1-3):202-5. · 2.59 Impact Factor
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ABSTRACT: Adolescence is a critical period for the development of neural plasticity. Social isolation is an important animal model for various neurodevelopmental disorders. Brain derived neurotrophic factor (BDNF) mediates many important brain functions such as neural plasticity, and aberrations in its expression have been implicated in many brain disorders. However, to date there have been few reports of effects of adolescent social isolation on BDNF expression in adult animals. In the present study, we subjected weaning Sprague Dawley rats to a four-week early adolescence social isolation procedure followed by four-week standard housing until adulthood for molecular assays. BDNF protein levels in several key forebrain regions relevant to brain development were investigated using immunohistochemistry, including frontal and cingulate cortex as well as hippocampus. Our results show that adolescent social isolation significantly increased BDNF protein expression in the medial prefrontal cortex and all three sub-fields of the hippocampus, including CA1, CA2/3 and dentate gyrus. This study advances the use of adolescent social isolation as an animal model for studying neurobiological underpinnings of various neurodevelopmental disorders.
European journal of pharmacology 10/2010; 650(1):229-32. · 2.59 Impact Factor
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ABSTRACT: Social isolation results in fundamental behavioral abnormalities in rodents which models certain neuropsychiatric disorders such as schizophrenia. However, the developmental stage that is most vulnerable to social isolation is largely unknown. In the present study, we subjected weaning rats to a four-week peri-adolescence isolation rearing (PAIR) and then returned them to social rearing for an additional four weeks until adulthood. Open field locomotion, social interaction behavior, and acute pain sensitivity were examined at different time points. PAIR rats showed moderate hyperactivity towards a novel environment, an anxiogenic-like behavioral profile, and increased aggression and social interaction behavior, the last three of which could be restored by re-socialization procedure. In addition, PAIR animals showed significantly reduced pain sensitivity even after the re-socialization period. In summary, this study advances the use of peri-adolescent isolation rearing as an animal model to study neurodevelopmental manipulation induced behavioral abnormalities.
Neuroscience Letters 08/2010; 480(1):25-9. · 2.11 Impact Factor
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ABSTRACT: 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.
Physiology & Behavior 07/2009; 98(3):251-7. · 2.87 Impact Factor
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ABSTRACT: 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.
Neurobiology of Disease 09/2008; 31(2):278-85. · 5.40 Impact Factor
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ABSTRACT: 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.
Behavioural Brain Research 01/2007; 175(2):233-40. · 3.42 Impact Factor
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ABSTRACT: 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.
Behavioural Brain Research 11/2004; 154(2):557-65. · 3.42 Impact Factor
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ABSTRACT: The effect of exposure to emotional stress on humoral immune function after injection with ovalbumin, a novel antigen, was studied in adult male Wistar rats. Emotional stress was induced by randomly giving empty water bottles to rats trained to drink water at set times. The results showed that emotional stress induced the decrease in spleen weight and specific immunoglobulin G antibody level to ovalbumin, and increased levels of epinephrine, norepinephrine and corticosterone. A decrease of antibody levels correlated negatively with an increase in plasma norepinephrine levels. These findings suggest that emotional stress can modulate immune function, and that sympathetic nervous system may be involved in this immunomodulation.
Journal of Psychopharmacology 07/2003; 17(2):179-83. · 3.04 Impact Factor
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ABSTRACT: 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.
Behavioural Brain Research.
