Brain-derived Neurotrophic Factor Protein Levels In Hippocampus Research Articles

Accelerated Fear Extinction by Regular Light-Intensity Exercise: A Possible Role of Hippocampal BDNF-TrkB Signaling.

Growing concern exists worldwide about stress-related mental disorders, such as posttraumatic stress disorder (PTSD), often linked to hippocampal dysfunctions. Recognizing this connection, regular light-intensity exercise (LIE)-such as yoga, walking, or slow jogging-may offer a solution. Easily accessible even to vulnerable individuals, LIE has been found to enhance hippocampus-based cognitive functions through the stimulation of neurotrophic factors like brain-derived neurotrophic factor (BDNF). A prior study that demonstrated BDNF's role in extinguishing original fear memory further leads us to propose that a consistent LIE training might drive fear extinction learning, offering potential therapeutic benefits through BDNF signaling. Eleven-week-old Wistar rats underwent 4 wk of training under conditions of sedentary, LIE, or moderate-intensity exercise (MOE) after contextual or auditory fear conditioning. Subsequently, fear extinction tests were performed. We then administered intraperitoneal (i.p.) ANA-12, a selective antagonist of tropomyosin receptor kinase B (TrkB), or a vehicle to explore the role of BDNF signaling in exercise-induced fear extinction among the LIE rats. Following the regular exercise training, further fear extinction tests were conducted, and hippocampal protein analysis was performed using Western blotting. Both LIE and MOE over 4 wk accelerated hippocampus-associated contextual fear extinction compared with sedentary. In addition, 4 wk of LIE with i.p. administered vehicle increased hippocampal BDNF and TrkB protein levels. In contrast, i.p. ANA-12 administration fully blocked the LIE-enhanced protein levels and its effect on contextual fear extinction. Our findings reveal that LIE regimen promotes fear extinction learning, at least partially tied to hippocampal BDNF-TrkB signaling. This suggests that even regular light exercise could alleviate the excessive fear response in anxiety disorders and PTSD, providing hope for those affected.

Efficacy of electroacupuncture stimulating Shenmen (HT7), Baihui (GV20), Sanyinjiao (SP6) on spatial learning and memory deficits in rats with insomnia induced by para-chlorophenylalanine: a single acupoint combined acupoints.

To investiage the effect of electroacupuncture (EA) at a single acupoint of Shenmen (HT7), Baihui (GV20), Sanyinjiao (SP6) and at combined acupoints of Shenmen (HT7) and Baihui (GV20) and Sanyinjiao (SP6) on the PKA/CREB and BDNF/TrkB signaling, as well as neuroapoptosis and neurogenesis in hippocampus and elucidate the underlying mechanism of single and combined acupoints on ameliorating spatial learning and memory deficits in a rat model of primary insomnia. Primary insomnia was modeled by intraperitoneal injection of para-chlorophenylalanine (PCPA) once daily for 2 d. EA was applied at Shenmen (HT7), Baihui (GV20), Sanyinjiao (SP6), or Shenmen (HT7) + Baihui (GV20) + Sanyinjiao (SP6) (combined) for 30 min daily for 4 d. Spatial learning and memory function was evaluated by the Morris water maze (MWM) test. Protein expressions of hippocampal cAMP-dependent protein kinase (PKA)-Cβ, phosphorylated cAMP-responsive element-binding protein (p-CREB), brain-derived neurotrophic factor (BDNF), and tyrosine kinase receptor B (TrkB) were evaluated by Western blotting. Neuronal apoptosis in the hippocampus was detected with the transferase-mediated dUTP-X nick end labeling assay. Endogenous neurogenesis was examined with bromodeoxyuridine staining. The MWM test and hippocampal p-CREB, BDNF, and TrkB protein levels in the combined acupoints group were evaluated after the administration of a PKA-selective inhibitor (H89). Spatial learning and memory were significantly impaired in rats with insomnia. The spatial learning deficits were ameliorated in the Shenmen (HT7), Baihui (GV20), Sanyinjiao (SP6), and combined groups; this improvement was significantly greater in the combined group than the single acupoint groups. The spatial memory impairment was improved in the combined, Baihui (GV20), and Shenmen (HT7) groups, but not the Sanyinjiao (SP6) group. The expressions of PKA-Cβ, p-CREB, BDNF, and TrkB were decreased in rats with insomnia. All these proteins were significantly upregulated in the combined group. PKA/p-CREB protein levels were elevated in the Baihui (GV20) and Shenmen (HT7) groups, whereas BDNF/TrkB expression was upregulated in the Sanyinjiao (SP6) group. The staining results showed significant attenuation of hippocampal cell apoptosis and increased numbers of proliferating cells in the combined group, whereas the single acupoint groups only showed decreased numbers of apoptotic cells. In the combined group, the PKA inhibitor reversed the improvement of spatial memory and upregulation of p-CREB expression caused by EA, but did not affect its activation of BDNF/TrkB signaling. EA at the single acupoints Baihui (GV20), Shenmen (HT7), or Sanyinjiao (SP6) had an ameliorating effect on the spatial learning and memory deficits induced by insomnia. EA at combined acupoints exerted a synergistic effect on the improvements in spatial learning and memory impairment in rats with insomnia by upregulating the hippocampal PKA/CREB and BDNF/TrkB signaling, facilitating neurogenesis, and inhibiting neuronal apoptosis. These findings indicate that EA at combined acupoints [(Baihui (GV20), Shenmen (HT7), and Sanyinjiao (SP6)] achieves a more pronounced regulation of hippocampal neuroplasticity than EA at single acupoints, which may partly explain the underlying mechanisms by which EA at combined acupoints exerts a better ameliorative effect on the cognitive dysfunction caused by insomnia.

Metrnl regulates cognitive dysfunction and hippocampal BDNF levels in D-galactose-induced aging mice.

Aging is one of the main risk factors for cognitive dysfunction. During aging process, the decrease of brain-derived neurotrophic factor (BDNF) and the impairment of astrocyte function contribute to the cognitive impairment. Metrnl, a neurotrophic factor, promotes neural growth, migration and survival, and supports neural function. In this study, we investigated the role of Metrnl in cognitive functions. D-galactose (D-gal)-induced aging model was used to simulate the process of aging. Cognitive impairment was assessed by the Morris water maze test. We showed that Metrnl expression levels were significantly increased in the hippocampus of D-gal-induced aging mice. Metrnl knockout did not affect the cognitive functions in the baseline state, but aggravated the cognitive impairment in the D-gal-induced aging mice. Furthermore, Metrnl knockout significantly reduced hippocampal BDNF, TrkB, and glial fibrillary acidic protein (GFAP) levels in the D-gal-induced aging mice. In the D-gal-induced aging cell model in vitro, Metrnl levels in the hippocampal astrocytes were significantly increased, and Metrnl knockdown and overexpression regulated the BDNF levels in primary hippocampal astrocytes rather than in neurons. We conclude that Metrnl regulates cognitive functions and hippocampal BDNF levels during aging process. As a neurotrophic factor and an endogenous protein, Metrnl is expected to become a new candidate for the treatment or alleviation of aging-related cognitive dysfunction.

Creatine and Alpha-Lipoic Acid Antidepressant-Like Effect Following Cyclosporine A Administration

Cyclosporine A (CYA), is an immunosuppressant drug used to prevent graft rejection, but it may initiate neuropsychological problems such as depression. The aim was to evaluate the antidepressant-like effects of creatine (Crt), a mediator of oxidative phosphorylation, and alpha-lipoic acid (ALA), a cofactor for the mitochondrial respiratory chain following CYA administration. Female mice (27 ± 2 g) were used, immobility time during the forced swimming test (FST) was measured, and hippocampal brain-derived neurotrophic factor (BDNF) level was evaluated. CYA 20 mg/kg, ALA 40 mg/kg, fluoxetine 20 mg/kg, and Crt 10 mg/kg (oral) were administered for 6 consecutive days, and the tests were performed on day 7. ALA, but not Crt, treatment alone decreased immobility in the FST (i.e., decreases depression-like behavior). CYA administration increased immobility in the FST (175.1 ± 13.16 s, vs. vehicle 130.9 ± 13.5 s, p= 0.0364), and this depression-like behavior was prevented by co-administrating, ALA (100 ± 15.9 s, p= 0.020) or Crt (93.5 ± 16.6, p= 0.009) and the positive control, fluoxetine. Notably, there was a synergistic effect of Crt-ALA co-administration since CYA-induced immobility was lower in this group than in the groups pretreated with Crt or ALA. These behavioral changes were observed without treatment effects on locomotor activity in an open field. CYA treatment increased hippocampal BDNF protein levels prevented by co-administration of ALA (with or without Crt) or fluoxetine. CYA-induced depression-like behavior might be related to hippocampal mitochondrial dysfunction as ALA and Crt prevented the development of this behavioral phenotype. ALA, similar to fluoxetine, prevented BDNF alteration and its possible neurological changes.

Coping with Exercise Induced Spatial Memory Improvement in Morphine Dependent Rats by Inhibiting Brain Derived Neurotrophic Factor (BDNF)

Background: Addiction as a chronic disorder that requires long treatment. One way to treating this chronic disease is exercise. Chronic exposure to opiates impairs spatial learning and memory. Given the well-known beneficial effects of voluntary exercise on cognitive functions, we investigated whether voluntary exercise would ameliorate the cognitive deficits that are induced by morphine dependence. If an effect of exercise was observed, we aimed to investigate the possible role of hippocampal brain-derived neurotropic factor (BDNF) in the exercise-induced enhancement of learning and memory in morphine-dependent rats. Methods: The rats were injected with bi-daily doses (10 mg/kg, at 12 hr. intervals) of morphine over a period of 10 days of voluntary exercise. Following these injections, a water maze task was performed twice a day for 5 consecutive days, followed by a probe trial 2 days later. A specific BDNF inhibitor (TrkB-IgG chimera) was used to block the hippocampal BDNF action during the 10 days of voluntary exercise. Results: The voluntary exercise diminished the severity of the rats’ dependency on morphine. A blockade of the BDNF action blunted the exercise-induced improvement of spatial memory, hippocampal neuron counting and BDNF protein levels in the dependent rats. Our results indicate that voluntary exercise could be increase the expression of LTP by lowering the induction threshold for LTP in the DG of morphine-dependent rats. Conclusion: Thus, voluntary exercise might be considered as a potential method to ameliorate some of the deleterious behavioral consequences of the abuse of morphine and other opiates.

Vitamin D Regulatory Effect on Restraint Stress-Induced Changes in Serum Corticosterone and Hippocampus BDNF Levels in the Male Rats

Background: Chronic stress exerts negative effects on cognitive functions through inducing changes in the hippocampus. Brain-derived neurotrophic factor (BDNF) is an essential factor in cognitive functions, which is considerably reduced under chronic stress. 1,25(OH)2 vitamin D plays neuroprotective roles partially by regulating the expression of various neurotrophic factors. Objectives: Since few studies have studied the impact of vitamin D on BDNF levels, we conducted this brief experiment to understand the role of vitamin D in maintaining hippocampal BDNF protein levels by using restraining as a model of chronic stress in rats. Methods: Rats underwent restraint stress 3 h/day for 28 days, during which they received vitamin D (5, 10 μg/kg) or its vehicle (IP, twice weekly). After the stress period, serum corticosterone (CORT) and hippocampus BDNF protein levels were measured. Results: Restraint stress increased serum CORT (P < 0.001) and reduced BDNF protein levels (P < 0.001) as compared to the non-stress group. Vitamin D markedly maintained BDNF levels close to normal (P < 0.001), but did not change CORT levels significantly. Conclusions: This study demonstrated that 3h/day of chronic restraint stress for 28 days boosted serum CORT and declined hippocampal BDNF levels, similar to stronger restraint stress models. Vitamin D maintained BDNF level close to normal in the hippocampus, but it did not affect CORT level significantly.

Transcranial direct current stimulation alleviates seizure severity in kainic acid-induced status epilepticus rats

Status epilepticus (SE) is a state of prolonged and repeated seizures that can lead to permanent brain damage or life-threatening conditions. Transcranial direct current stimulation (tDCS) non-invasively provides a polarity-specific electric current to modulate brain excitability. Little is known about the therapeutic potential of tDCS in SE. Here, we aim to determine the tDCS effects on seizure severity, EEG and post-SE consequences in rats with kainic acid (KA)-induced SE. Rats were subjected to cathodal tDCS or sham stimulation over the dorsal hippocampus for 5 days. KA was intraperitoneally injected to induce SE. We used continuous video-EEG recording to monitor seizure activity, immunostaining and Timm staining to evaluate neuron counts and mossy fiber sprouting, and ELISA for Brain-derived neurotrophic factor (BDNF) protein measurement. Two featured EEG patterns, gamma ranged high-frequency polyspikes and low-frequency spike-and-wave complexes, were identified in the hippocampal CA1 of KA-induced SE rats. tDCS elicited a significant decrease in severe seizures of Racine stages 4–5 in KA-induced SE rats. tDCS-treated rats manifested diminished high-frequency oscillation during SE, decreased chronic spontaneous spike activities and mossy fiber sproutings compared to sham. tDCS-treated rats also exhibited significantly lower hippocampal BDNF protein levels than sham immediately and 4 weeks after SE. A positive correlation between the hippocampal BDNF level and the seizure severity of SE was found. Altogether, our results show that repeated cathodal tDCS can mitigate seizure severity, alter ictal EEG pattern and reduce the chronic adverse consequences in KA-induced SE rats, supporting the therapeutic potential of tDCS in severe prolonged epileptic seizures.

Concomitant abuse of methadone and methamphetamine could impair spatial learning and memory in male rats

Methadone maintenance therapy (MMT) has been considered as an effective medication for opioid dependence. However there are reports of methamphetamine abuse among MMT patients due to greater desired effects and fewer side effects than either substance alone. Little research has been done on the effects of methamphetamine abuse on cognitive behaviors during MMT. In the current study, we investigated spatial learning and memory along with the brain derived neurotrophic factor (BDNF) as important factors in neural plasticity under concomitant use of methadone and methamphetamine in male rats. The animals received administration of methadone (2.5 mg/Kg, SC, twice a day) and methamphetamine (0.5 mg/Kg, SC, once a day) concomitantly or either alone for 21 days. Three hours after each treatment, the rats were trained in eight-arm radial maze for 7 days, and their learning and working memory were evaluated. Moreover, western blotting was performed to evaluate hippocampal BDNF protein levels. The results showed that administration of methadone and methamphetamine concomitantly impaired spatial learning and memory more than methadone alone (P < 0.05). Additional western blotting analysis revealed that BDNF protein levels of hippocampus in the control group was more than the methadone group, while it was less than methamphetamine treated animals (P < 0.05). Our findings suggest that exposure to methamphetamine during methadone maintenance therapy could lead to spatial learning and memory impairments more than mere methadone.

Gestational stress in mouse dams negatively affects gestation and postpartum hippocampal BDNF and P11 protein levels

Stress during pregnancy increases the risk to develop psychological disorders such as depression during pregnancy or in the postpartum period. According to the neurotrophin hypothesis of depression, the pathophysiology of depression is caused by reduced neurotrophic activity in the brain. However, most studies only focus on the molecular changes happening to the offspring upon gestational stress. To gain insight into the potential molecular changes happening in the stressed dams, C57Bl6/J mice were stressed during their first week of gestation. At 28 days postpartum, the hippocampus and nucleus accumbens core of the dams, two brain regions heavily implicated in depression, were evaluated using immunohistochemistry to detect changes in the neurotrophin system. Gestational stress decreased the weight of the dams, increased the chance for spontaneous abortion and increased the weight of offspring. Litter size, survival rates and sex distribution were not altered as a consequence of gestational stress. Hippocampal brain-derived neurotrophic factor (BDNF) decreased following exposure to stress during pregnancy. Hippocampal protein levels of p75NTR, a low-affinity receptor for BDNF which can induce apoptosis, were increased following exposure to stress. Protein levels of p11, of which the expression is regulated by BDNF, were decreased in the hippocampus. No changes were found for TrkB immunostaining or apoptosis. Taken together, this shows that stress during pregnancy negatively affects the neurotrophin system in the hippocampus of the dams, thereby reducing hippocampal plasticity. These data confirm that gestational stress has a negative impact on pregnancy.

Essential oils from two Allium species exert effects on cell proliferation and neuroblast differentiation in the mouse dentate gyrus by modulating brain-derived neurotrophic factor and acetylcholinesterase.

BackgroundIn the present study, we investigated the effects of oil products from two Allium species: Allium sativum (garlic) and Allium hookeri (Chinese chives) on cell proliferation and neuroblast differentiation in the mouse dentate gyrus.MethodsUsing corn oil as a vehicle, the essential oil from garlic (10 ml/kg), or Chinese chives (10 ml/kg) was administered orally to 9-week-old mice once a day for 3 weeks. One hour following the last treatment, a novel object recognition test was conducted and the animals were killed 2 h after the test.ResultsIn comparison to the vehicle-treated group, garlic essential oil (GO) treatment resulted in significantly increased exploration time and discrimination index during the novel object recognition test, while Chinese chives essential oil (CO) reduced the exploration time and discrimination index in the same test. In addition, the number of Ki67-immunoreactive proliferating cells and doublecortin-immunoreactive neuroblasts significantly increased in the dentate gyrus of GO-treated animals. However, administration of CO significantly decreased cell proliferation and neuroblast differentiation. Administration of GO significantly increased brain-derived neurotrophic factor (BDNF) levels and decreased acetylcholinesterase (AChE) activity in the hippocampal homogenates. In contrast, administration of CO decreased BDNF protein levels and had no significant effect on AChE activity, compared to that in the vehicle-treated group.ConclusionsThese results suggest that GO significantly improves novel object recognition as well as increases cell proliferation and neuroblast differentiation, by modulating hippocampal BDNF protein levels and AChE activity, while CO impairs novel object recognition and decreases cell proliferation and neuroblast differentiation, by reducing BDNF protein levels in the hippocampus.

Rolipram-induced improvement of cognitive function correlates with changes in hippocampal CREB phosphorylation, BDNF and Arc protein levels

Diabetics suffer from a higher risk of cognitive decline. cAMP response element-binding protein (CREB) is a transcription factor associated with memory and synaptic plasticity. Here, we investigated the molecular changes in the hippocampus correlated with diabetes associated cognitive decline (DACD) from a CREB-centered perspective in a rat model of type 2 diabetes. Furthermore, we tested the therapeutic effect of rolipram on DACD. High-fat diet and low-dose streptozocin were adopted to induce diabetes in SD rats. Results show that supplementation with rolipram for 23 days (0.5mg/kg, once a day) improved the performance of diabetic rats in Morris water navigation task with increased level of CREB, brain-derived neurotrophic factor (BDNF), and Arc protein in the hippocampus. Rolipram, acting as an inhibitor of PDE4, was found to repair the imbalance in the CREB/BDNF/Arc pathway. This study may provide important insights into the mechanisms underlying DACD and provide new therapeutic targets for clinical treatment.

Chronic BDNF deficiency leads to an age-dependent impairment in spatial learning

Brain-derived neurotrophic factor (BDNF) is a crucial mediator of neural plasticity and, consequently, of memory formation. In hippocampus-dependent learning tasks BDNF also seems to play an essential role. However, there are conflicting results concerning the spatial learning ability of aging BDNF+/− mice in the Morris water maze paradigm. To evaluate the effect of chronic BDNF deficiency in the hippocampus on spatial learning throughout life, we conducted a comprehensive study to test differently aged BDNF+/− mice and their wild type littermates in the Morris water maze and to subsequently quantify their hippocampal BDNF protein levels as well as expression levels of TrkB receptors. We observed an age-dependent learning deficit in BDNF+/− animals, starting at seven months of age, despite stable hippocampal BDNF protein expression and continual decline of TrkB receptor expression throughout aging. Furthermore, we detected a positive correlation between hippocampal BDNF protein levels and learning performance during the probe trial in animals that showed a good learning performance during the long-term memory test.

BDNF Val66Met Impairs Fluoxetine-Induced Enhancement of Adult Hippocampus Plasticity

Recently, a single-nucleotide polymorphism (SNP) in the brain-derived neurotrophic factor (BDNF) gene (BDNF Val66Met) has been linked to the development of multiple forms of neuropsychiatric illness. This SNP, when genetically introduced into mice, recapitulates core phenotypes identified in human BDNF Val66Met carriers. In mice, this SNP also leads to elevated expression of anxiety-like behaviors that are not rescued with the prototypic selective serotonin reuptake inhibitor (SSRI), fluoxetine. A prominent hypothesis is that SSRI-induced augmentation of BDNF protein expression and the beneficial trophic effects of BDNF on neural plasticity are critical components for drug response. Thus, these mice represent a potential model to study the biological mechanism underlying treatment-resistant forms of affective disorders. To test whether the BDNF Val66Met SNP alters SSRI-induced changes in neural plasticity, we used wild-type (BDNF(Val/Val)) mice, and mice homozygous for the BDNF Val66Met SNP (BDNF(Met/Met)). We assessed hippocampal BDNF protein levels, survival rates of adult born cells, and synaptic plasticity (long-term potentiation, LTP) in the dentate gyrus either with or without chronic (28-day) fluoxetine treatment. BDNF(Met/Met) mice had decreased basal BDNF protein levels in the hippocampus that did not significantly increase following fluoxetine treatment. BDNF(Met/Met) mice had impaired survival of newly born cells and LTP in the dentate gyrus; the LTP effects remained blunted following fluoxetine treatment. The observed effects of the BDNF Val66Met SNP on hippocampal BDNF expression and synaptic plasticity provide a possible mechanistic basis by which this common BDNF SNP may impair efficacy of SSRI drug treatment.

The antidepressive effect of the physical exercise correlates with increased levels of mature BDNF, and proBDNF proteolytic cleavage-related genes, p11 and tPA

Clinical studies show an evident antidepressive effect of physical exercise and animal research corroborate such evidence. However, the neurobiological mechanisms underlying the antidepressive effect of exercise are not completely understood. Notwithstanding, it is known that exercise increases brain-derived neurotrophic factor (BDNF) expression in the hippocampus similarly to antidepressant drugs. BDNF is synthesized as a precursor molecule that undergoes a proteolytic cleavage to generate either a mature or a truncated isoform. Precursor and mature BDNF are assumed to elicit opposing biological effects in neuroplasticity. In the present study we investigated the effect of voluntary physical activity on precursor and mature brain-derived neurotrophic factor levels and on proBDNF cleavage related genes, p11 and tissue plasminogen activator (tPA), as well as the antidepressive and cognitive effects of voluntary physical activity. Mice had access to mobile or locked running wheels for 28 days and were submitted to forced-swim, tail suspension and water maze tests. Their hippocampi were dissected and analyzed by Western blot and real time RT-PCR. Voluntary physical activity, but not locked wheel exposure, induced a robust increase in hippocampal mature BDNF protein levels, as well as in p11 and tPA mRNA expression; and also promoted antidepressive effects and improved learning, when compared with sedentary mice. On the other hand, there were no significant differences between any groups in the expression of precursor or truncated isoforms of BDNF. Our data suggest that the antidepressive effect of the physical exercise may depend, at least in part, on changes in BDNF post-translational processing.

BDNF upregulation rescues synaptic plasticity in middle-aged ovariectomized rats

Brain-derived neurotrophic factor (BDNF) has emerged as a possible broad-spectrum treatment for the plasticity losses found in rodent models of human conditions associated with memory and cognitive deficits. We have tested this strategy in the particular case of ovariectomy. The actin polymerization in spines normally found after patterned afferent stimulation was greatly reduced, along with the stabilization of long-term potentiation, in hippocampal slices prepared from middle-aged ovariectomized rats. Both effects were fully restored by a 60-minute infusion of 2 nM BDNF. Comparable rescue results were obtained after elevating endogenous BDNF protein levels in hippocampus with 4 daily injections of a short half-life ampakine (positive modulator of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate [AMPA]-type glutamate receptors). These results provide the first evidence that minimally invasive, mechanism-based drug treatments can ameliorate defects in spine plasticity caused by depressed estrogen levels.

Aging and depression vulnerability interaction results in decreased serotonin innervation associated with reduced BDNF levels in hippocampus of rats bred for learned helplessness

Epidemiological studies have revealed a strong genetic contribution to the risk for depression. Both reduced hippocampal serotonin neurotransmission and brain-derived neurotrophic factor (BDNF) levels have been associated with increased depression vulnerability and are also regulated during aging. Brains from young (5 months old) and old (13 months old) congenital Learned Helplessness rats (cLH), and congenital Non Learned Helplessness rats (cNLH) were immunohistochemically stained for the serotonin transporter and subsequently stereologically quantified for estimating hippocampal serotonin fiber density. Hippocampal BDNF protein levels were measured by ELISA. An exacerbated age-related loss of serotonin fiber density specific for the CA1 area was observed in the cLH animals, whereas reduced hippocampal BDNF levels were seen in young and old cLH when compared with age-matched cNLH controls. These observations indicate that aging should be taken into account when studying the neurobiological factors behind the vulnerability for depression and that understanding the effect of aging on genetically predisposed individuals may contribute to a better understanding of the pathophysiology behind depression, particularly in the elderly.

Postnatal BDNF Expression Profiles in Prefrontal Cortex and Hippocampus of a Rat Schizophrenia Model Induced by MK-801 Administration

Neonatal blockade of N-methyl-D-aspartic acid (NMDA) receptors represents one of experimental animal models for schizophrenia. This study is to investigate the long-term brain-derived neurotrophic factor (BDNF) expression profiles in different regions and correlation with “schizophrenia-like” behaviors in the adolescence and adult of this rat model. The NMDA receptor antagonist MK801 was administered to female Sprague-Dawley rats on postnatal days (PND) 5 through 14. Open-field test was performed on PND 42, and PND 77 to examine the validity of the current model. BDNF protein levels in hippocampus and prefrontal cortex (PFC) were analyzed on PND 15, PND 42, and PND 77. Results showed that neonatal challenge with MK-801 persistently elevated locomotor activity as well as BDNF expression; the alterations in BDNF expression varied at different developing stages and among brain regions. However, these findings provide neurochemical evidence that the blockade of NMDA receptors during brain development results in long-lasting alterations in BDNF expression and might contribute to neurobehavioral pathology of the present animal model for schizophrenia. Further study in the mechanisms and roles of the BDNF may lead to better understanding of the pathophysiology of schizophrenia.

5‐Fluorouracil chemotherapy affects spatial working memory and newborn neurons in the adult rat hippocampus

Chemotherapy-associated memory deficits in adults are prevalent with systemic treatment utilizing 5-fluorouracil (5-Fu). 5-Fu disrupts cell proliferation and readily crosses the blood-brain barrier. Proliferating cells within the adult dentate gyrus of the hippocampus give rise to new neurons involved in memory and learning and require neurotrophic factors such as brain-derived neurotrophic factor (BDNF) to nurture this process of adult neurogenesis. Some of these proliferating cells are anatomically and functionally supported by vascular endothelial cells. We propose that systemically administered 5-Fu chemotherapy will cause deficits in hippocampal memory that are associated with altered BDNF levels and proliferating cells (particularly vascular-associated cells) in the dentate gyrus. This was tested by determining the effect of 5-Fu on spatial working memory as modelled by the object location recognition test. Numbers of vascular-associated (VA) and non-vascular-associated (NVA) proliferating cells in the dentate gyrus were measured using double-labelling immunohistochemistry with markers of proliferation (Ki67) and endothelial cells (RECA-1). 5-Fu-induced changes in hippocampal BDNF and doublecortin (DCX) protein levels were quantified using Western immunoblotting. 5-Fu chemotherapy caused a marginal disruption in spatial working memory and did not alter the total proliferating cell counts or the percentage of VA and NVA proliferating cells in the dentate gyrus. In contrast, 5-Fu significantly reduced BDNF and DCX levels in the hippocampus, indicating alterations in neurotrophin levels and neurogenesis. These findings highlight the usefulness of animal models of 'chemobrain' for understanding the mechanisms that underlie chemotherapy-associated declines in cognitive performance and memory.

Chronic treatment with a selective ligand for the sigma-1 receptor chaperone, SA4503, up-regulates BDNF protein levels in the rat hippocampus

Numerous studies have shown the sigma-1 receptor chaperone (previously designated as the sigma-1 receptor) to play an important role in various neuronal functions, and selective ligands for sigma-1 receptor chaperone have been found to have therapeutic potential in certain psychiatric disorders and some forms of neuronal damage. Brain-derived neurotrophic factor (BDNF) is postulated to be related to the pharmacological action of sigma ligands, though the functional interaction between sigma-1 receptor chaperone ligands and BDNF remains to be clarified. This study was undertaken to investigate whether or not administration of SA4503, a selective ligand for sigma-1 receptor chaperone, affects BDNF levels in several regions of the rat brain. Rats were injected with SA4503 (0.3, 1 and 3 mg/(kg day), i.p.) once or repeatedly for 2 or 4 weeks. BDNF protein levels were estimated by Western blot analysis in the striatum, midbrain, frontal cortex, hippocampus and thalamus. A single injection of SA4503 did not change BDNF protein levels, while chronic injection for 2 or 4 weeks tended to increase BDNF levels in the hippocampus. In particular, 1 mg/kg of SA4503 daily for 2 weeks led to a statistically significant, i.e. twofold, increase in the BDNF protein level in the hippocampus. On the other hand, the TrkB receptor, a primary receptor for BDNF, exists in truncated and full-length isoforms, hippocampal levels of which were unaffected by SA4503 treatments. Our findings indicate that chronic administration of SA4503 may regulate region-specific BDNF functions in the rat brain.

治療抵抗性うつ病に奏効する薬剤の創薬を目指して&lt;/br&gt;&amp;mdash;電気けいれん療法の有用性と脳由来神経栄養因子（BDNF）の関与&amp;mdash;

In recent years, depression studies have focused on morphological changes associated with depression. Brain-derived neurotrophic factor (BDNF) is a neurotrophic factor that plays an important role in the morphological changes associated with depression and the mechanisms of antidepressants. On the other hand, hyperfunction of the hypothalamic-pituitary-adrenal axis has been link to pathophysiology of depression. In our previous studies, ACTH-treated rats served as a valuable animal model of tricyclic antidepressant-resistant depressive conditions. However, few neuroanatomic studies have been done. In the present study, we investigated mechanisms underling ACTH-treated rat serving an imipramine treatment-resistant depression model using c-Fos as a marker. The c-Fos immunohistochemical study indicated that the medial prefrontal cortex is an action site of imipramine in ACTH-treated rats. Electroconvulsive therapy is considered an effective treatment for treatment-resistant depression. However, the mechanisms causing treatment-resistant depressive conditions are unknown. We investigated the effect of repeated electrical convulsive shock (ECS)-treatment using the forced swim test, a screening method for antidepressant-like activity, and hippocampal BDNF protein levels in ACTH-treated rats. Findings showed that repeated ECS treatment decreased the immobility time during forced swim test. Furthermore, the ECS treatment also markedly increased the hippocampal BDNF levels in the rat tricyclic antidepressant-resistant depression model. In addition, the repeated ECS treatment showed long-lasting effects on forced swim test and increased of hippocampal BDNF levels in normal rats. These findings suggest that BDNF plays a key role in the antidepressant-like effect of ECS and that increased BDNF may be involved in promoting the long-lasting effect.