Decreased Brain-derived Neurotrophic Factor mRNA Research Articles

Glutathione Deficiency during Early Postnatal Development Causes Schizophrenia-Like Symptoms and a Reduction in BDNF Levels in the Cortex and Hippocampus of Adult Sprague-Dawley Rats.

Growing body of evidence points to dysregulation of redox status in the brain as an important factor in the pathogenesis of schizophrenia. The aim of our study was to evaluate the effects of l-buthionine-(S,R)-sulfoximine (BSO), a glutathione (GSH) synthesis inhibitor, and 1-[2-Bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine dihydrochloride (GBR 12909), a dopamine reuptake inhibitor, given alone or in combination, to Sprague–Dawley pups during early postnatal development (p5–p16), on the time course of the onset of schizophrenia-like behaviors, and on the expression of brain-derived neurotrophic factor (BDNF) mRNA and its protein in the prefrontal cortex (PFC) and hippocampus (HIP) during adulthood. BSO administered alone decreased the levels of BDNF mRNA and its protein both in the PFC and HIP. Treatment with the combination of BSO + GBR 12909 also decreased BDNF mRNA and its protein in the PFC, but in the HIP, only the level of BDNF protein was decreased. Schizophrenia-like behaviors in rats were assessed at three time points of adolescence (p30, p42–p44, p60–p62) and in early adulthood (p90–p92) using the social interaction test, novel object recognition test, and open field test. Social and cognitive deficits first appeared in the middle adolescence stage and continued to occur into adulthood, both in rats treated with BSO alone or with the BSO + GBR 12909 combination. Behavior corresponding to positive symptoms in humans occurred in the middle adolescence period, only in rats treated with BSO + GBR 12909. Only in the latter group, amphetamine exacerbated the existing positive symptoms in adulthood. Our data show that rats receiving the BSO + GBR 12909 combination in the early postnatal life reproduced virtually all symptoms observed in patients with schizophrenia and, therefore, can be considered a valuable neurodevelopmental model of this disease.

Maternal Iron Deficiency Programs Offspring Cognition and Its Relationship with Gastrointestinal Microbiota and Metabolites.

Iron is an essential micronutrient for the brain development of the fetus. Altered intestinal microbiota might affect behavior and cognition through the so-called microbiota-gut-brain axis. We used a Sprague-Dawley rat model of a maternal low-iron diet to explore the changes in cognition, dorsal hippocampal brain-derived neurotrophic factor (BDNF) and related pathways, gut microbiota, and related metabolites in adult male offspring. We established maternal iron-deficient rats by feeding them a low-iron diet (2.9 mg/kg), while the control rats were fed a standard diet (52.3 mg/kg). We used a Morris water maze test to assess spatial learning and long-term memory. Western blot (WB) assays and a quantitative reverse-transcription polymerase chain reaction (qRT-PCR) were used to detect the BDNF concentration and related signaling pathways. We collected fecal samples for microbiota profiling and measured the concentrations of plasma short-chain fatty acids. The adult male offspring of maternal rats fed low-iron diets before pregnancy, during pregnancy and throughout the lactation period had (1) spatial deficits, (2) a decreased BDNF mRNA expression and protein concentrations, accompanied by a decreased TrkB protein abundance, (3) a decreased plasma acetate concentration, and (4) an enrichment of the Bacteroidaceae genus Bacteroides and Lachnospiraceae genus Marvinbryantia. Maternal iron deficiency leads to an offspring spatial deficit and is associated with alternations in gastrointestinal microbiota and metabolites.

The vagus nerve modulates BDNF expression and neurogenesis in the hippocampus

Accumulating evidence suggests that certain gut microbiota have antidepressant-like behavioural effects and that the microbiota can regulate neurogenesis and the expression of brain-derived neurotrophic factor (BDNF) in the hippocampus. The precise mechanisms underlying these effects are not yet clear. However, the vagus nerve is one of the primary bidirectional routes of communication between the gut and the brain and thus may represent a candidate mechanism. Yet, relatively little is known about the direct influence of vagus nerve activity on hippocampal function and plasticity. Thus, the aim of the present study was to determine whether constitutive vagus nerve activity contributes to the regulation of neurogenesis and BDNF mRNA expression in the hippocampus. To this end, we examined the impact of subdiaphragmatic vagotomy in adult mice on these parameters. We found that vagotomy decreased BDNF mRNA in all areas of the hippocampus. Vagotomy also reduced the proliferation and survival of newly born cells and decreased the number of immature neurons, particularly those with a more complex dendritic morphology. Taken together, these findings suggest that vagal nerve activity influences neurogenesis and BDNF mRNA expression in the adult hippocampus.

Reoxygenation with 100% Oxygen Following Hypoxia in Mice Causes Apoptosis.

After hypoxia, reoxygenation with air is the consensus treatment for full-term neonates; however, the effect of hyperoxic reoxygenation of adults is unknown. The present study was designed to investigate the effects of reoxygenation with 100% oxygen after hypoxia on inflammation and apoptosis in mice. Eight-week-old mice were either subjected to hypoxia in 8% oxygen for 30 min or air served as controls. Following hypoxia, mice underwent reoxygenation for 30 min with 21% or 100% oxygen. Tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), caspase-3 and brain derived neurotrophic factor (BDNF) mRNA study and histopathological study were performed. Reoxygenation with 100% oxygen significantly increased TNF-α (2.5 h after hypoxia), IL-1β (5 h after hypoxia), caspase-3 (8 h after hypoxia) mRNA levels in the whole brain compared with 21% oxygen, and significantly decreased erythropoietin mRNA expression compared with 21% oxygen 9 h after reoxygenation. However, reoxygenation with 100% oxygen and 21% oxygen significantly decreased BDNF mRNA levels compared with control air group. There were no clear abnormal findings showing neuronal death among the three groups. Reoxygenation with 100% oxygen after hypoxia induced inflammation and apoptosis in adult mice. Therefore, these results suggest that the reoxygenation with 100% oxygen after hypoxia has harmful effects on adult brain as well as on neonatal brain.

Maternal obesity alters brain derived neurotrophic factor (BDNF) signaling in the placenta in a sexually dimorphic manner

IntroductionObesity is a major clinical problem in obstetrics being associated with adverse pregnancy outcomes and fetal programming. Brain derived neurotrophic factor (BDNF), a validated miR-210 target, is necessary for placental development, fetal growth, glucose metabolism, and energy homeostasis. Plasma BDNF levels are reduced in obese individuals; however, placental BDNF has yet to be studied in the context of maternal obesity. In this study, we investigated the effect of maternal obesity and sexual dimorphism on placental BDNF signaling. MethodsBDNF signaling was measured in placentas from lean (pre-pregnancy BMI < 25) and obese (pre-pregnancy BMI>30) women at term without medical complications that delivered via cesarean section without labor. MiRNA-210, BDNF mRNA, proBDNF, and mature BDNF were measured by RT – PCR, ELISA, and Western blot. Downstream signaling via TRKB (BDNF receptor) was measured using Western blot. ResultsMaternal obesity was associated with increased miRNA-210 and decreased BDNF mRNA in placentas from female fetuses, and decreased proBDNF in placentas from male fetuses. We also identified decreased mature BDNF in placentas from male fetuses when compared to female fetuses. Mir-210 expression was negatively correlated with mature BDNF protein. TRKB phosphorylated at tyrosine 817, not tyrosine 515, was increased in placentas from obese women. Maternal obesity was associated with increased phosphorylation of MAPK p38 in placentas from male fetuses, but not phosphorylation of ERK p42/44. DiscussionBDNF regulation is complex and highly regulated. Pre-pregnancy/early maternal obesity adversely affects BDNF/TRKB signaling in the placenta in a sexually dimorphic manner. These data collectively suggest that induction of placental TRKB signaling could ameliorate the placental OB phenotype, thus improving perinatal outcome.

Activity-Based Anorexia Alters the Expression of BDNF Transcripts in the Mesocorticolimbic Reward Circuit.

Anorexia nervosa (AN) is a complex eating disorder with severe dysregulation of appetitive behavior. The activity-based anorexia (ABA) paradigm is an animal model in which rodents exposed to both running wheels and scheduled feeding develop aspects of AN including paradoxical hypophagia, dramatic weight loss, and hyperactivity, while animals exposed to only one condition maintain normal body weight. Brain-derived neurotrophic factor (BDNF), an activity-dependent modulator of neuronal plasticity, is reduced in the serum of AN patients, and is a known regulator of feeding and weight maintenance. We assessed the effects of scheduled feeding, running wheel access, or both on the expression of BDNF transcripts within the mesocorticolimbic pathway. We also assessed the expression of neuronal cell adhesion molecule 1 (NCAM1) to explore the specificity of effects on BDNF within the mesocorticolimbic pathway. Scheduled feeding increased the levels of both transcripts in the hippocampus (HPC), increased NCAM1 mRNA expression in the ventral tegmental area (VTA), and decreased BDNF mRNA levels in the medial prefrontal cortex (mPFC). In addition, wheel running increased BDNF mRNA expression in the VTA. No changes in either transcript were observed in the nucleus accumbens (NAc). Furthermore, no changes in either transcript were induced by the combined scheduled feeding and wheel access condition. These data indicate that scheduled feeding or wheel running alter BDNF and NCAM1 expression levels in specific regions of the mesocorticolimbic pathway. These findings contribute to our current knowledge of the molecular alterations induced by ABA and may help elucidate possible mechanisms of AN pathology.

Human Obesity Associated with an Intronic SNP in the Brain-Derived Neurotrophic Factor Locus.

Brain-derived neurotrophic factor (BDNF) plays a key role in energy balance. In population studies, SNPs of the BDNF locus have been linked to obesity, but the mechanism by which these variants cause weight gain is unknown. Here, we examined human hypothalamic BDNF expression in association with 44 BDNF SNPs. We observed that the minor C allele of rs12291063 is associated with lower human ventromedial hypothalamic BDNF expression (p < 0.001) and greater adiposity in both adult and pediatric cohorts (p values < 0.05). We further demonstrated that the major T allele for rs12291063 possesses a binding capacity for the transcriptional regulator, heterogeneous nuclear ribonucleoprotein D0B, knockdown of which disrupts transactivation by the T allele. Binding and transactivation functions are both disrupted by substituting C for T. These findings provide a rationale for BDNF augmentation as a targeted treatment for obesity in individuals who have the rs12291063 CC genotype.

Prolonged hyperglycemia & hyperinsulinemia increases BDNF mRNA expression in the posterior ventromedial hypothalamus and the dorsomedial hypothalamus of fed female rats.

Brain-derived neurotrophic factor (BDNF) plays a key role in neuronal development, synaptic plasticity, and the central control of energy homeostasis. Peripheral metabolic signals such as leptin and glucose regulate hypothalamic BDNF gene expression. However, the effects of long-term hyperglycemia and/or hyperinsulinemia on BDNF mRNA levels in the hypothalamus and other brain regions where BDNF regulates physiological functions have not been investigated. Therefore, using in situ hybridization we examined whether high glucose, high insulin, or both affected BDNF gene expression in vivo. Ovariectomized, estrogen-replaced adult rats were fitted with indwelling jugular catheters and infused for 48 h with: saline (control), glucose (hyperglycemia-hyperinsulinemia), glucose with insulin (hyperinsulinemia only), diazoxide (Dzx) (control), or glucose with Dzx (hyperglycemia only). Glucose infusion (Hyperglycemia and hyperinsulinemia) significantly increased BDNF mRNA expression in the posterior ventromedial nucleus of the hypothalamus (pVMH) and in the dorsomedial nucleus of the hypothalamus (DMH). Unexpectedly, infusion of the KATP channel opener Dzx also increased BDNF mRNA expression in the pVMH and DMH. In contrast, no significant changes in BDNF mRNA expression were observed in the groups that were hyperinsulinemic only or hyperglycemic only. BDNF mRNA expression did not differ as a function of treatment in the anterior VMH, paraventricular nucleus of the hypothalamus, the hippocampus, or the amygdala. Hyperglycemia with and without hyperinsulinemia decreased BDNF mRNA levels in the pituitary. Plasma BDNF concentrations were not changed by any of the treatments. Our results suggest that hyperinsulinemia alone does not affect BDNF mRNA expression in the hypothalamus, hippocampus, or pituitary. Our study is the first to distinguish that within the hypothalamus, prolonged high glucose levels in non-fasted rats regulates BDNF gene expression in a brain nuclei-specific fashion.

Time Course of Behavioral Alteration and mRNA Levels of Neurotrophic Factor Following Stress Exposure in Mouse.

Stress is known to affect neurotrophic factor expression, which induces depression-like behavior. However, whether there are time-dependent changes in neurotrophic factor mRNA expression following stress remains unclear. In the present study, we tested whether chronic stress exposure induces long-term changes in depression-related behavior, serum corticosterone, and hippocampal proliferation as well as neurotrophic factor family mRNA levels, such as brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), neurotrophin-3 (NT-3), and ciliary neurotrophic factor (CNTF), in the mouse hippocampus. The mRNA level of neurotrophic factors (BDNF, NGF, NT-3, and CNTF) was measured using the real-time PCR. The serum corticosterone level was evaluated by enzyme-linked immunosorbent assay, and, for each subject, the hippocampal proliferation was examined by 5-bromo-2-deoxyuridine immunostaining. Mice exhibited depression-like behavior in the forced-swim test (FST) and decreased BDNF mRNA and hippocampal proliferation in the middle of the stress exposure. After 15days of stress exposure, we observed increased immobility in the FST, serum corticosterone levels, and BDNF mRNA levels and degenerated hippocampal proliferation, maintained for at least 2weeks. Anhedonia-like behavior in the sucrose preference test and NGF mRNA levels were decreased following 15days of stress. NGF mRNA levels were significantly higher 1week after stress exposure. The current data demonstrate that chronic stress exposure induces prolonged BDNF and NGF mRNA changes and increases corticosterone levels and depression-like behavior in the FST, but does not alter other neurotrophic factors or performance in the sucrose preference test.

Chronic social instability stress enhances vulnerability of BDNF response to LPS in the limbic structures of female rats: A protective role of antidepressants

The aim of the present study was to estimate the influence of antidepressants given chronically on brain-derived neurotrophic factor (BDNF) alterations induced by lipopolysaccharide (LPS) in the amygdala and hippocampus of female rats subjected to chronic social instability stress (CSIS) for 29–30 days. CSIS was used as a paradigm known to be more stressful for females because stress induces affective disorders more frequently in women than men. An increased relative adrenal weight and a tendency towards the enhanced plasma corticosterone concentration were found in the stressed rats. Sucrose preference was not changed. On the last experimental day, the rats in the estrus phase were injected ip with LPS (1mg/kg). In the stressed rats, LPS administration decreased BDNF mRNA levels in both limbic structures. Desipramine (10mg/kg), fluoxetine (5mg/kg) or tianeptine (10mg/kg) given ip once daily reversed the effect of the combined stress and LPS, and tianeptine induced the strongest effects. These results indicate that chronic stress enhances vulnerability of BDNF response to deleterious influence of neuroinflammation in the examined limbic structures, what may account for its role in triggering neuropsychiatric diseases. The observed effect of antidepressants may be of significance for their therapeutic effects in the stress-induced affective disorders in females.

Intranigral lipopolysaccharide induced anxiety and depression by altered BDNF mRNA expression in rat hippocampus

It is known that lipopolysaccharide (LPS) treatment induces neuroinflammation and memory deterioration. One of the mechanisms may be the interference with brain-derived neurotrophic factor (BDNF) gene expression and function. Lipopolysaccharide (3 μg/kg and 10 μg/kg) was unilaterally injected into the substantia nigra of adult male Wistar rats. Pergolide-induced rotational behavior test was employed to validate unilateral damage to the dopamine nigrostriatal neurons. Anxiety-depression-like behaviors were studied by means of elevated plus-maze task and forced swimming test, as animal models of anxiety and depression. Rats given LPS exhibited the following: decrease of the percentage of the time spent and the number of entries in the open arm within elevated plus-maze test and decrease of swimming and increase of immobility times within forced swimming test. In addition, these behaviors are associated with decreased BDNF mRNA expression in rat hippocampus. Taken together, these data indicate that intranigral LPS infusion influences the induction of BDNF mRNA expression within hippocampus which contributes to observed behavioral responses in rats, with relevance for Parkinson's disease conditions.

Upregulated expression of brain enzymatic markers of arachidonic and docosahexaenoic acid metabolism in a rat model of the metabolic syndrome

BackgroundIn animal models, the metabolic syndrome elicits a cerebral response characterized by altered phospholipid and unesterified fatty acid concentrations and increases in pro-apoptotic inflammatory mediators that may cause synaptic loss and cognitive impairment. We hypothesized that these changes are associated with phospholipase (PLA2) enzymes that regulate arachidonic (AA, 20:4n-6) and docosahexaenoic (DHA, 22:6n-6) acid metabolism, major polyunsaturated fatty acids in brain. Male Wistar rats were fed a control or high-sucrose diet for 8 weeks. Brains were assayed for markers of AA metabolism (calcium-dependent cytosolic cPLA2 IVA and cyclooxygenases), DHA metabolism (calcium-independent iPLA2 VIA and lipoxygenases), brain-derived neurotrophic factor (BDNF), and synaptic integrity (drebrin and synaptophysin). Lipid concentrations were measured in brains subjected to high-energy microwave fixation.ResultsThe high-sucrose compared with control diet induced insulin resistance, and increased phosphorylated-cPLA2 protein, cPLA2 and iPLA2 activity and 12-lipoxygenase mRNA, but decreased BDNF mRNA and protein, and drebrin mRNA. The concentration of several n-6 fatty acids in ethanolamine glycerophospholipids and lysophosphatidylcholine was increased, as was unesterified AA concentration. Eicosanoid concentrations (prostaglandin E2, thromboxane B2 and leukotriene B4) did not change.ConclusionThese findings show upregulated brain AA and DHA metabolism and reduced BDNF and drebrin, but no changes in eicosanoids, in an animal model of the metabolic syndrome. These changes might contribute to altered synaptic plasticity and cognitive impairment in rats and humans with the metabolic syndrome.

Brain-derived neurotrophic factor expression after acute administration of ethanol

Earlier findings suggest that, in addition to its well-known neurotrophic role, brain-derived neurotrophic factor (BDNF) is also involved in the rewarding and reinforcing effects of drugs of abuse. The purpose of the present study was to examine the effects of acute administration of ethanol (1.25 or 2.5g/kg i.p.) on the expression profile of BDNF in the rat brain by determining the BDNF mRNA expression in the frontal cortex, nucleus accumbens, amygdala, hippocampus, and ventral tegmental area. Ethanol decreased BDNF mRNA levels dose-dependently in the hippocampus, and after the higher ethanol dose in the frontal cortex, nucleus accumbens and amygdala, while increasing them in the ventral tegmental area. Furthermore, BDNF mRNA expression was found to be regulated in a temporally different manner in all investigated brain areas. These data suggest that BDNF is involved in the acute effects of ethanol, but separate brain areas may be differentially engaged in the mediation of these effects.

Decreased response to social defeat stress in μ-opioid-receptor knockout mice

Substantial evidence exists that opioid systems are involved in stress response and that changes in opioid systems in response to stressors affect both reward and analgesia. Reportedly, mice suffering chronic social defeat stress subsequently show aversion to social contact with unfamiliar mice. To further examine the role of opioid systems in stress response, the behavioral and neurochemical effects of chronic social defeat stress (psychosocial stress) were evaluated in μ-opioid-receptor knockout (MOR-KO) mice. Aversion to social contact was induced by chronic social defeat stress in wild-type mice but was reduced in MOR-KO mice. Moreover, basal expression of brain-derived neurotrophic factor (BDNF) mRNA in MOR-KO mice hippocampi was significantly lower than in wild-type mice. Psychosocial stress significantly decreased BDNF mRNA expression in wild-type mice but did not affect BDNF expression in MOR-KO mice; no difference in basal levels of plasma corticosterone was observed. These results suggest that the μ-opioid receptor is involved in the behavioral sequelae of psychosocial stress and consequent regulation of BDNF expression in the hippocampus, and may play an important role in psychiatric disorders for which stress is an important predisposing or precipitating factor, such as depression, posttraumatic stress disorder, and social anxiety disorder.

Intervention effects of enriched environment on brain damage of MPTP-induced senescence-accelerated prone mice

Objective To observe the effects of enriched environmen(EE) on brain-derived neurotrophic factor(BDNF) in substantia nigra(SN) of senescence-accelerated prone mice,so as to explore the possible mechanism of EE in alleviating MPTP induced damage and in protecting dopaminergic neurons in the SN.Methods Totally 80 3-month old female SAMP8 mice were averagely assigned to EE and standard environment(SE) groups at random.After three months,the mice in each group were further divided into 2 subgroups at random:MPTP group and NS group(n = 20).The MPTP groups received subcutaneous injection of MPTP,and the NS mice were treated with an equal volume of NS.At the seventh day,the mice were sacrificed for RT-PCR and immunohistochemistry staining.RT-PCR was used to examine BDNF mRNA expression and immunohistochemistry staining was used to examine BDNF-ir expression.Results Compared with SE + NS mice,EE + NS mice had significantly increased BDNF mRNA expression(P 0.01),and the number of BDNF-ir cell and COD values in SN were also significantly increased(P 0.01).Compared with SE + NS mice,SE + MPTP mice showed significantly decreased BDNF mRNA expression(P 0.001),and the number of BDNF-ir cells and the COD values in SN of mice were significantly decreased(P 0.01).Compared with SE + MPTP mice,EE + MPTP mice showed increased BDNF mRNA expression(P 0.01),and the number of BDNF-ir cells and the COD values in SN were significantly increased(P 0.01).Conclusion EE can increase BDNF mRNA expression and BDNF-ir cell number in SN of SAMP8 mice,alleviating MPTP-induced SN damage.

Allowing animals to bite reverses the effects of immobilization stress on hippocampal neurotrophin expression

Acute immobilization stress alters the expression of neurotrophins, including brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3), in rat hippocampus. We found that biting may be associated with reduction of systemic stress responses. The purpose of this study was to examine whether neurotrophin expression in rat hippocampus is influenced by biting. Rats were exposed to immobilization stress for 2 h (stress group without biting) or biting for the latter half of 2-hour immobilization stress (biting group). Adrenocorticotropic hormone (ACTH) and corticosterone levels were markedly elevated in the stress group, while the increases in ACHT and corticosterone were suppressed in the biting group. Decreased BDNF mRNA and increased NT-3 mRNA expression in hippocampus were detected on real-time polymerase chain reaction (PCR) in the stress group. The decrease in BDNF mRNA under acute immobilization stress was recovered by biting. In addition, the magnitude of increase in NT-3 mRNA was decreased. No changes in expression of tyrosine receptor kinase B or C, the receptors for BDNF and NT-3, respectively, were observed in this model. These findings suggest that biting influences the alterations in neurotrophin levels induced by acute immobilization stress in rat hippocampus.

Early-life infection leads to altered BDNF and IL-1β mRNA expression in rat hippocampus following learning in adulthood

Neonatal bacterial infection in rats leads to profound hippocampal-dependent memory impairments following a peripheral immune challenge in adulthood. Here, we determined whether neonatal infection plus an immune challenge in adult rats is associated with impaired induction of brain-derived neurotrophic factor (BDNF) within the hippocampus (CA1, CA3, and dentate gyrus) following fear conditioning. BDNF is well characterized for its critical role in learning and memory. Rats injected on postnatal day 4 with PBS (vehicle) or Escherichia coli received as adults either no conditioning or a single 2min trial of fear conditioning. Half of the rats in the conditioned group then received a peripheral injection of 25μg/kg lipopolysaccharide (LPS) and all were sacrificed 1 or 4h later. Basal (unconditioned) BDNF mRNA did not differ between groups. However, following conditioning, neonatal infection with E. coli led to decreased BDNF mRNA induction in all regions compared to PBS-treated rats. This decrease in E. coli-treated rats was accompanied by a large increase in IL-1β mRNA in CA1. Taken together, these data indicate that early infection strongly influences the induction of IL-1β and BDNF within distinct regions of the hippocampus, which likely contribute to observed memory impairments in adulthood.

Expression of fibroblast growth factor-2 and brain-derived neurotrophic factor mRNA in the medial prefrontal cortex and hippocampus after uncontrollable or controllable stress

Neurotrophic factors, including basic fibroblast growth factor (FGF-2) and brain-derived neurotrophic factor (BDNF) are known to be affected by exposure to stressful experiences. Here, we examine the effects of behaviorally controllable (escapable tailshock, ES) or uncontrollable (inescapable tailshock, IS) stress on the expression of FGF-2 and BDNF mRNA in subregions of the medial prefrontal cortex (mPFC) and the hippocampal formation (HF) of male Sprague–Dawley rats. ES rats were placed in Plexiglas boxes equipped with a free spinning wheel and IS rats were placed in identical boxes with the wheels fixed. ES and IS rats were yoked such that they received the same tailshocks, but the ES rat could terminate each shock for both rats. No stress controls (NS) remained in their home cages. Rats were killed 0, 2, 24, or 72 h after termination of the stress session. In situ hybridization was performed to measure FGF-2 and BDNF mRNA in the mPFC and HF. In the mPFC, ES produced a significant increase in FGF-2 mRNA expression at 0 and 2 h post-stress. In the HF, ES produced a greater increase in FGF-2 mRNA expression than IS and NS only in CA2. ES also produced an increase in BDNF mRNA expression in the anterior cingulate at 0 h post-stress. No effects of stressor controllability on BDNF were observed in the HF, although both ES and IS decreased BDNF mRNA in the DG. FGF-2 in the mPFC may be involved in emotional regulation (“coping”) during stressful experiences.

Learned helplessness is independent of levels of brain-derived neurotrophic factor in the hippocampus

Reduced levels of brain-derived neurotrophic factor (BDNF) in the hippocampus have been implicated in human affective disorders and behavioral stress responses. The current studies examined the role of BDNF in the behavioral consequences of inescapable stress, or learned helplessness. Inescapable stress decreased BDNF mRNA and protein in the hippocampus of sedentary rats. Rats allowed voluntary access to running wheels for either 3 or 6 weeks prior to exposure to stress were protected against stress-induced reductions of hippocampal BDNF protein. The observed prevention of stress-induced deceases in BDNF, however, occurred in a time course inconsistent with the prevention of learned helplessness by wheel running, which is evident following 6 weeks, but not 3 weeks, of wheel running. BDNF suppression in physically active rats was produced by administering a single injection of the selective serotonin reuptake inhibitor fluoxetine (10 mg/kg) just prior to stress. Despite reduced levels of hippocampal BDNF mRNA following stress, physically active rats given the combination of fluoxetine and stress remained resistant against learned helplessness. Sedentary rats given both fluoxetine and stress still demonstrated typical learned helplessness behaviors. Fluoxetine by itself reduced BDNF mRNA in sedentary rats only, but did not affect freezing or escape learning 24 h later. Finally, bilateral injections of BDNF (1 μg) into the dentate gyrus prior to stress prevented stress-induced reductions of hippocampal BDNF but did not prevent learned helplessness in sedentary rats. These data indicate that learned helplessness behaviors are independent of the presence or absence of hippocampal BDNF because blocking inescapable stress-induced BDNF suppression does not always prevent learned helplessness, and learned helplessness does not always occur in the presence of reduced BDNF. Results also suggest that the prevention of stress-induced hippocampal BDNF suppression is not necessary for the protective effect of wheel running against learned helplessness.

Brain distribution of cytokine mRNA induced by systemic administration of interleukin-1β or tumor necrosis factor α

Brain cytokine mRNA levels are impacted by systemic cytokines. For example, systemic interleukin-1β (IL1β) increases brain IL1β mRNA; subdiaphragmatic vagotomy blocks this effect. To localize which brain regions respond to intraperitoneal cytokines, we measured mRNA levels in selected brain regions for a variety of cytokines and growth factors, IL1β, TNFα, interleukin-6 (IL-6), interleukin-10 (IL10), nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF). Relative to saline administration, IL1β increased IL1β, TNFα and IL6 mRNAs in the nucleus tractus solitarius (NTS), hypothalamus, hippocampus and somatosensory cortex (SSctx), but did not induce any changes in IL10. TNFα also increased TNFα and IL1β mRNAs in the hypothalamus, hippocampus and SSctx. TNFα increased TNFα, IL1β and IL10 mRNAs in the NTS, but did not induce any changes in IL-6 mRNA. In the amygdala, IL1β enhanced IL6 mRNA and TNFα increased IL1β mRNAs. In the insular cortex, IL1β enhanced IL6 mRNA and TNFα increased IL1β mRNA. TNFα administration increased NGF mRNA in the SSctx but decreased NGF and BDNF mRNA levels in the insular cortex. Both IL1β and TNFα decreased BDNF mRNA in the amygdala. We also verified the IL1β-induced increases in TNFα mRNA within the NTS using in situ hybridization. These results support the hypothesis that somnogenic doses of IL1β and TNFα enhance their own mRNA levels as well as affect mRNA levels for other sleep-promoting substances.