Hippocampal Brain-derived Neurotrophic Factor Levels Research Articles

Small litter size impairs spatial memory and increases anxiety- like behavior in a strain-dependent manner in male mice

Early life overfeeding is associated with cognitive decline and anxiety-like behaviors in later life. It is not clear whether there are individual differences in the effects of early life overfeeding and what the underlying mechanistic pathways are. We investigated the long-lasting effects of small litter size, an experimental manipulation to induce neonatal overfeeding, in two strains of mice, C57BL/6 and NMRI. We measured body weight, learning and memory, anxiety-related behaviors, interleukin-(IL)-1β and brain-derived-neurotrophic-factor (BDNF) levels in the hippocampus, and both basal and stress corticosterone levels in adult mice which have been nursed in small litters compared with those from control litters. Our findings showed that small litter size led to increased body weight in both strains of mice. Small litter size significantly decreased spatial memory and hippocampal BDNF levels, and increased hippocampal IL-1β, in NMRI mice, but not C57BL/6 mice. Interestingly, we found that small litter size resulted in a significant increase in anxiety-like behaviors and stress-induced corticosterone in NMRI mice, whereas small litter size reduced anxiety-like symptoms and stress-induced corticosterone levels in C57BL/6 mice. These data show that small litter size, which is life-long associated with increased body weight, affects memory and anxiety-related behaviors in a strain-dependent manner in male mice. This suggests that there are individual differences in the developmental consequences of early life overfeeding.

The effect of NAD-299 and TCB-2 on learning and memory, hippocampal BDNF levels and amyloid plaques in Streptozotocin-induced memory deficits in male rats.

Alzheimer's disease (AD) is the most common form of dementia characterized by a progressive decline in cognitive function. The serotonergic system via the 5-HT1A receptor and 5-HT2A receptor is proposed to affect the cognitive process. In the present study, the effects of NAD-299 (5-HT1AR antagonist) and TCB-2 (5-HT2AR agonist) on learning and memory processes, hippocampal brain-derived neurotrophic factor (BDNF) levels, neuronal necrosis, and Aβ plaque production have been investigated on the intracerebroventricular (icv) injection of streptozotocin (STZ)-induced memory deficits in rats. Fifty-four adult male Wistar rats (250-300g) were divided into six groups (n = 9 in each group): control, sham-operated, AD (icv-STZ (3mg/kg, 10μl)), AD+NAD-299 (5μg/1μl icv for 30days), AD+TCB-2 (5μg/1μl icv for 30days), and AD+NAD-299 + TCB-2 (NAD-299 (5μg/0.5μl icv) and TCB-2 (5μg/0.5μl icv) for 30days). Following the treatment period, rats were subjected to behavioral tests of learning and memory. Then, hippocampal BDNF, amyloid-beta (Aβ) plaque, and neuronal loss were determined by ELISA Kit, Congo red staining, and Nissl staining, respectively. The results of behavioral tests showed that icv-STZ injection decreased the discrimination index in the novel object recognition (NOR) test. In the passive avoidance learning (PAL) task, icv-STZ injection significantly decreased step-through latency (STLr) and increased time spent in dark compartment (TDC). Treatment with NAD-299, TCB-2, and NAD-299 + TCB-2 attenuated the STZ-induced memory impairment in both NOR and PAL tasks. icv-STZ induced a decrease in hippocampal BDNF levels and increased Aβ plaques production in the brain, whereas treatment with NAD-299, TCB-2, and NAD-299 + TCB-2 reduced Aβ plaques in the brain and increased the hippocampal BDNF level. Results of Nissl staining showed that icv-STZ injection increased neuronal loss in the hippocampus, while treatment with NAD-299, TCB-2, and NAD-299 + TCB-2 reduced hippocampal neurodegeneration. These findings suggest that 5-HT1AR blockade by NAD-299 and 5-HT2AR activation by TCB-2 improve cognitive dysfunction in icv-STZ-treated rats, and these drugs may potentially prevent the progression of AD.

Monoamine Involvement in the Antidepressant-Like Effect of β-Caryophyllene.

Major depressive disorder is a psychiatric disorder that affects 4.4% of the population worldwide. Although the majority of antidepressant drugs ameliorate depressive symptoms, there is still a need for safer and more effective antidepressant. Evaluate the antidepressant-like activity of sesquiterpene compound β-caryophyllene (BCP) for the possible contribution of the monoamine and hippocampal levels of brain-derived neurotrophic factor (BDNF). Male albino Swiss mice were subjected to the forced swimming test after acute treatment and to the tail suspension test after repeated treatment. Hippocampal levels of BDNF were assayed by enzyme-linked immunosorbent assay. The anti-immobility effect of BCP was reverted by pretreatment with an inhibitor of catecholamine synthesis α-methyl-p-tyrosine (100 mg/kg, i.p.), α2-adrenergic antagonist yohimbine (1 mg/kg, i.p.), and β-adrenergic antagonist propranolol (2 mg/kg, i.p.), but not by pretreatment with either α1-adrenergic antagonist prazosin (1 mg/kg, i.p.) or 5-HT1A antagonist NAN-190 (0.5 mg/kg, i.p.), thereby suggesting the involvement of α2 and β-adrenergic receptors, but not of the α1-adrenergic and 5-HT1A serotonergic receptors, in BCP's antidepressive-like activity. Furthermore, BCP increased BDNF levels in the hippocampus after 14 days of treatment. No treatments in this study altered locomotor activity in the open field test. This study provides a new mechanism of BCP-induced antidepressant-like effect mediated by some sub-types of catecholaminergic neurotransmitter system that could be a candidate for clinical tests of new treatments for depressive disorders.

Aerobic exercise upregulates the BDNF-Serotonin systems and improves the cognitive function in rats.

Aerobic exercise (AE) benefits brain health and behavior. Serotonin (5-HT) and brain-derived neurotrophic factor (BDNF) are known to mediate and shape cognitive processes. Both systems share some actions: BDNF is involved in the maturation and function of 5-HT neurons. In turn, 5-HT is involved in neuroplasticity phenomena mediated by BDNF and stimulated by exercise. The aim of this work was to study the long-term effects of AE on BDNF- 5-HT systems and cognitive function in rats at different ages. A lifelong moderate-intensity aerobic training program was designed, in which aerobically exercised (E) and sedentary control (C) rats were studied at middle (8 months) and old age (18 months) by means of biochemical, immunohistochemical and behavioral assays. The levels and expression of BDNF, 5-HT, serotonin transporter (SERT) and 5-HT1A receptor were determined in selected brain areas involved in memory and learning. Immunopositive cells to neuronal nuclear protein (NeuN) in the hippocampus CA1 area were also quantified. The cognitive function was evaluated by the object recognition test (ORT). Results indicate that AE enhanced spatial and non-spatial memory systems, modulated by age. This outcome temporarily correlated with a significant upregulation of cortical, hippocampal and striatal BDNF levels in parallel with an increase in the number of hippocampal CA1-mature neurons. AE also increased brain and raphe 5-HT levels, as well as the expression of SERT and 5-HT1A receptor in the cortex and hippocampus. Old AE rats showed a highly conserved response, indicating a remarkable protective effect of exercise on both systems. In summary, lifelong AE positively affects BDNF-5-HT systems, improves cognitive function and protects the brain against the deleterious effects of sedentary life and aging.

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.

Spermine protects from LPS-induced memory deficit via BDNF and TrkB activation.

Lipopolysaccharide (LPS) has been long known to promote neuroinflammation and learning and memory deficits. Since spermine, one of the main natural polyamines in the central nervous system, protects from LPS-induced memory deficit by a mechanism that comprises GluN2B receptors, the aim of the present study was to determine whether brain-derived neurotrophic factor (BDNF), tropomyosin-related kinase B (TrkB) receptor and cAMP response element binding (CREB) are involved in this protective effect of spermine. Adult male Swiss albino mice received, immediately after training in the novel object recognition task, saline or LPS (250 μg/kg, i.p.); 5 min later they received saline or spermine (0.3 mg/kg, i.p.) and, when specified, 5 min thereafter saline or the TrkB receptor antagonist ANA-12 (0.5 mg/kg, i.p.) in different flanks. Animals were tested 24 h after training. Spermine protected from LPS-induced memory deficit and this protective effect was reversed by ANA-12. In a subset of animals BDNF, CREB and phospho-CREB immunoreactivity was determined in the hippocampi and cerebral cortex 4 h after spermine injection. Spermine reversed the decrease of mature BDNF levels induced by LPS in both hippocampus and cerebral cortex. Spermine increased phospho-CREB content and phospho-CREB/total CREB ratio in the cerebral cortex of LPS-treated mice. The results support that the protective effect of spermine on LPS-induced memory deficits depends on TrkB receptor activation and is accompanied by restoration of mature BDNF levels in hippocampus and cerebral cortex, as well as increased CREB phosphorylation in the cerebral cortex.

Apocynum venetum leaf extract reverses depressive-like behaviors in chronically stressed rats by inhibiting oxidative stress and apoptosis

BackgroundMajor depressive disorder (MDD) is a common but serious psychiatric disorder, but current treatments are inadequate for approximately half of the patients with MDD. Thus, better methods of treatment are urgently needed. This study aimed to investigate the antidepressant-like effects and potential mechanism of Apocynum venetum leaf extract (AVLE) in chronic unpredictable mild stress (CUMS) rat model of depression. Materials and methodsThe CUMS rat model of depression was used to investigate the antidepressant-like activity and relevant mechanism of AVLE (30, 60, and 125 mg/kg, i.g.). Behavioral tests, including sucrose preference test (SPT), open field test (OFT), and forced swimming test (FST) were conducted to assess anhedonic, despairing, and spontaneous behaviors, respectively. The activity of the hypothalamic-pituitary-adrenal (HPA) axis was evaluated by measuring the serum adrenocorticotrophic hormone (ACTH) and corticosterone (CORT) concentrations. The underlying mechanism was further explored by assessing oxidative stress parameters, cell apoptosis, and brain-derived neurotrophic factor (BDNF) expression in the rat hippocampus exposed to CUMS. ResultsThe AVLE (36, 60, 125 mg/kg) treatment exerted antidepressant-like effects in CUMS-exposed rats similar to fluoxetine (10 mg/kg). The AVLE treatment reduced the serum CORT and ACTH levels in CUMS rats. It also increased the activities and gene expression of antioxidant enzymes (SOD, CAT, and GPx) and decreased the ROS generation levels and the lipid peroxidation marker MDA in the rat hippocampus subjected to CUMS. Additionally, it suppressed the apoptosis of hippocampus cells by modulating Bcl-2/Bax pathways and improved the hippocampal BDNF expressions of CUMS rats. ConclusionOur findings suggested that AVLE exerted antidepressant-like effects in CUMS rats, which was possibly mediated by the prevention of oxidative stress, the inhibition of hippocampal neuronal apoptosis, and the upregulation of the hippocampal BDNF level.

Nasal obstruction during adolescence induces memory/learning impairments associated with BDNF/TrkB signaling pathway hypofunction and high corticosterone levels.

The hippocampus is an important brain region involved in memory and learning. Brain-derived neurotrophic factor (BDNF), tyrosine kinase receptor B (TrkB), and phospho-p44/p42 mitogen-activated protein kinase (MAPK) are known to contribute to hippocampal memory/learning. The present study aimed to clarify the effects of nasal obstruction during the growth period on memory/learning in an animal model, using combined behavioral, biochemical, and histological approaches. Male BALB/C mice underwent unilateral nasal obstruction (UNO) by cauterization at 8 days of age and were subjected to Y-maze and passive avoidance tests at 15 weeks of age. The serum corticosterone levels were measured using an enzyme-linked immunosorbent assay, and brain tissues were subjected to hematoxylin-eosin staining and histological analysis or homogenization and Western blot analysis. Compared with control mice, UNO mice had lower blood oxygen saturation levels and exhibited apparent memory/learning impairments during behavioral testing. Additionally, the UNO group had higher hippocampal BDNF levels and serum corticosterone levels, lower hippocampal TrkB and phospho-p44/p42 MAPK levels, and reduced neuron numbers relative to controls. Our findings suggest that UNO during adolescence affects the hippocampus and causes memory/learning impairments.

The role of hippocampal brain-derived neurotrophic factor in age-related differences in neuropathic pain behavior in rats

AimsThis study was aimed to explore the contribution of central brain-derived neurotrophic factor (BDNF) in the neuropathic pain pathogenesis using an aged rodent model. Main methodsAdult and aged rats were randomly assigned to either a sciatic nerve ligation (SNL) group or a control skin sham surgery group. Sensory behavioral testing were performed on the day before surgery and on the 3rd, 7th, 14th, and 21st days after surgery, followed by measurement of BDNF protein levels in different brain regions. In another experiment, the hippocampal BDNF gene expression after SNL surgery was assessed at different time-points. Furthermore, the analgesic effects of intranasal BDNF administration were tested in SNL animals. Key findingsOur behavioral results demonstrated that the hyperalgesia-like behavior after painful nerve injury has a higher incidence in aged rats compared with in adult animals. In particular, the hippocampal BDNF levels were inversely correlated with the probability of hyperalgesia-type behavior, in both brain-region specific and age-dependent manner. Time-course analysis showed that the hippocampal levels of BDNF mRNA in aged and adult rats started to decrease 7 and 14 days after surgery, respectively. However, the decrease was more pronounced in aged animals. Moreover, the repeated intranasal BDNF treatment could restore the central BDNF signaling, counteracting the age-related exacerbation of hyperalgesic behavior. SignificanceOur findings imply that hippocampal BDNF may be related with the pathogenesis of elderly neuropathic pain. Pharmacological data further suggest that brain BDNF may be modifiable in aged neuropathic animals, and therefore, represent a promising target for intervention.

Moderate treadmill exercise ameliorates amyloid-β-induced learning and memory impairment, possibly via increasing AMPK activity and up-regulation of the PGC-1α/FNDC5/BDNF pathway

Alzheimer’s disease (AD) is a neurodegenerative disorder associated with loss of memory and cognitive abilities. Previous evidence suggested that exercise ameliorates learning and memory deficits by increasing brain derived neurotrophic factor (BDNF) and activating downstream pathways in AD animal models. However, upstream pathways related to increase BDNF induced by exercise in AD animal models are not well known. We investigated the effects of moderate treadmill exercise on Aβ-induced learning and memory impairment as well as the upstream pathway responsible for increasing hippocampal BDNF in an animal model of AD. Animals were divided into five groups: Intact, Sham, Aβ1−42, Sham-exercise (Sham-exe) and Aβ1−42-exercise (Aβ-exe). Aβ was microinjected into the CA1 area of the hippocampus and then animals in the exercise groups were subjected to moderate treadmill exercise (for 4 weeks with 5 sessions per week) 7 days after microinjection. In the present study the Morris water maze (MWM) test was used to assess spatial learning and memory. Hippocampal mRNA levels of BDNF, peroxisome proliferator-activated receptor gamma co-activator 1 alpha (PGC-1α), fibronectin type III domain-containing 5 (FNDC5) as well as protein levels of AMPK-activated protein kinase (AMPK), PGC-1α, BDNF, phosphorylation of AMPK were measured. Our results showed that intra-hippocampal injection of Aβ1−42 impaired spatial learning and memory which was accompanied by reduced AMPK activity (p-AMPK/total-AMPK ratio) and suppression of the PGC-1α/FNDC5/BDNF pathway in the hippocampus of rats. In contrast, moderate treadmill exercise ameliorated the Aβ1−42-induced spatial learning and memory deficit, which was accompanied by restored AMPK activity and PGC-1α/FNDC5/BDNF levels. Our results suggest that the increased AMPK activity and up-regulation of the PGC-1α/FNDC5/BDNF pathway by exercise are likely involved in mediating the beneficial effects of exercise on Aβ-induced learning and memory impairment.

A noradrenergic lesion aggravates the effects of systemic inflammation on the hippocampus of aged rats.

Neuroinflammation is potentiated by early degeneration of the locus coeruleus noradrenergic pathway (LC-NE) commonly seen in aging-related neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease. In animal models, lipopolysaccharide (LPS) induces strong peripheral immune responses that can cause cognitive changes secondary to neuroinflammation. The influence of the peripheral immune response on cognition might be exacerbated by LC-NE degeneration, but this has not been well characterized previously. In this study, we investigated how systemic inflammation affects neuroinflammation and cognition in aged rats that have had either normal or damaged LC-NE transmitter systems. Rats were first exposed to the selective noradrenergic (NE) neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP4) to induce degeneration of central NE pathways. Two weeks later, the rats received a low dose of LPS. This resulted in 3 treatment groups (Control, LPS-, and DSP4+LPS-treated rats) studied at 4 hours (short-term subgroup) and 7 days (long-term subgroup) following the LPS injection. DSP4+LPS-treated rats exhibited increased serum levels of several pro-inflammatory cytokines, increased astroglial and microglial activation in the hippocampus, and poorer performance in the novel object recognition task (NORT) compared to controls and LPS-treated rats. Additionally, serum and brain tissue levels of brain-derived neurotrophic factor (BDNF) were modulated over time in the DSP4+LPS group compared to the other two groups. Specifically, DSP4+LPS-treated rats in the short-term subgroup had lower hippocampal BDNF levels (~25%) than controls and LPS-treated rats, which negatively correlated with hippocampal astrogliosis and positively correlated with hippocampal IL-1β levels. Serum and hippocampal BDNF levels in the DSP4+LPS-treated rats in the long-term subgroup returned to levels similar to the control group. These results show that systemic inflammation in LC-NE-lesioned aged rats promotes an exacerbated systemic and central inflammatory response compared to LC-NE-intact rats and alters BDNF levels, indicating the important role of this neurotransmitter system in response to neuroinflammation.

Deleterious effects of prenatal exposure to morphine on the spatial learning and hippocampal BDNF and long-term potentiation in juvenile rats: Beneficial influences of postnatal treadmill exercise and enriched environment

Prenatal morphine exposure causes a variety of neurobehavioral alterations observed in later life. The present study investigated the effects of postnatal exercise and enriched environment (EE) on alterations in water maze learning and hippocampal long-term potentiation (LTP) and brain derived neurotrophic factor (BDNF) levels induced by exposure to morphine during prenatal period in rats. On gestation days 11–18, pregnant rats were injected twice daily with saline or morphine. Offspring were subjected to postnatal exercise and EE for 30 days and afterward, spatial learning and hippocampal LTP and BDNF levels were investigated. Prenatal morphine-exposure impaired the spatial learning and hippocampal LTP in both male and female offspring. Interestingly, postnatal exercise and EE increased performance in the water maze and improved LTP in both prenatally saline and morphine-exposed male and female rats. Prenatal morphine exposure also caused a reduction in the hippocampal BDNF levels in the female, but not male rats, and postnatal exercise and EE alleviated this deficit. Our results demonstrate that postnatal exercise and EE can improve deficits in water maze learning and hippocampal LTP and BDNF levels caused by prenatal morphine exposure.

Repeated treatment with nitric oxide synthase inhibitor attenuates learned helplessness development in rats and increases hippocampal BDNF expression.

Nitric oxide synthase (NOS) inhibitors induce antidepressant-like effects in animal models sensitive to acute drug treatment such as the forced swimming test. However, it is not yet clear if repeated treatment with these drugs is required to induce antidepressant-like effects in preclinical models. The aim of this study was to test the effect induced by acute or repeated (7 days) treatment with 7-nitroindazole (7-NI), a preferential inhibitor of neuronal NOS, in rats submitted to the learned helplessness (LH) model. In addition, we aimed at investigating if 7-NI treatment would increase brain-derived neurotrophic factor (BDNF) protein levels in the hippocampus, similarly to the effect of prototype antidepressants. Animals were submitted to a pre-test (PT) session with inescapable footshocks or habituation (no shocks) to the experimental shuttle box. Six days later they were exposed to a test with escapable footshocks. Independent groups received acute (a single injection after PT or before test) or repeated (once a day for 7 days) treatment with vehicle or 7-NI (30 mg/kg). Repeated, but not acute, treatment with 7-NI attenuated LH development. The effect was similar to repeated imipramine treatment. Moreover, in an independent experimental group, only repeated treatment with 7-NI and imipramine increased BDNF protein levels in the hippocampus. The results suggest the nitrergic system could be a target for the treatment of depressive-like conditions. They also indicate that, similar to the positive control imipramine, the antidepressant-like effects of NOS inhibition could involve an increase in hippocampal BDNF levels.

Escitalopram and NHT normalized stress-induced anhedonia and molecular neuroadaptations in a mouse model of depression.

Anhedonia is defined as a diminished ability to obtain pleasure from otherwise positive stimuli. Anxiety and mood disorders have been previously associated with dysregulation of the reward system, with anhedonia as a core element of major depressive disorder (MDD). The aim of the present study was to investigate whether stress-induced anhedonia could be prevented by treatments with escitalopram or novel herbal treatment (NHT) in an animal model of depression. Unpredictable chronic mild stress (UCMS) was administered for 4 weeks on ICR outbred mice. Following stress exposure, animals were randomly assigned to pharmacological treatment groups (i.e., saline, escitalopram or NHT). Treatments were delivered for 3 weeks. Hedonic tone was examined via ethanol and sucrose preferences. Biological indices pertinent to MDD and anhedonia were assessed: namely, hippocampal brain-derived neurotrophic factor (BDNF) and striatal dopamine receptor D2 (Drd2) mRNA expression levels. The results indicate that the UCMS-induced reductions in ethanol or sucrose preferences were normalized by escitalopram or NHT. This implies a resemblance between sucrose and ethanol in their hedonic-eliciting property. On a neurobiological aspect, UCMS-induced reduction in hippocampal BDNF levels was normalized by escitalopram or NHT, while UCMS-induced reduction in striatal Drd2 mRNA levels was normalized solely by NHT. The results accentuate the association of stress and anhedonia, and pinpoint a distinct effect for NHT on striatal Drd2 expression.

The antidepressant-like activity of ellagic acid and its effect on hippocampal brain derived neurotrophic factor levels in mouse depression models

The aim of present study was to evaluate the antidepressant-like activity of ellagic acid (EA) in mice-forced swim test (FST) and tail suspension test (TST) and the possible role of brain-derived neurotrophic factor (BDNF) in EA’s antidepressant-like effect. We found that EA and sertraline did not affect the spontaneous locomotor activity of mice. EA produced statistically significant decrease in immobility time as compared to vehicle group in TST. EA at 1 and 5 mg/kg doses did not produce any significant effect in immobility time as compared to vehicle group in FST. But EA produced significantly reduced immobility time at 2.5 mg/kg dose. EA treatment increased hippocampal BDNF level. This study demonstrates that EA is able to produce antidepressant-like effect in both TST and FST in mice. Moreover, the antidepressant-like effects of EA seems to be mediated by increased BDNF level in mice hippocampus.

Resveratrol ameliorates chronic unpredictable mild stress-induced depression-like behavior: involvement of the HPA axis, inflammatory markers, BDNF, and Wnt/β-catenin pathway in rats.

Classic antidepressant drugs are modestly effective across the population and most are associated with intolerable side effects. Recently, numerous lines of evidence suggest that resveratrol (RES), a natural polyphenol, possesses beneficial therapeutic activity for depression. The aim of the present study was to explore whether RES exhibits an antidepressant-like effect in a depression model and to explore the possible mechanism. A depression model was established via chronic unpredictable mild stress (CUMS), after which the model rats in the RES and fluoxetine groups received a daily injection of RES or fluoxetine, respectively. The sucrose preference test, open field test, and forced swimming test were used to explore the antidepressant-like effects of RES. The activity of the hypothalamic–pituitary–adrenal (HPA) axis was evaluated by detecting the plasma corticosterone concentration and hypothalamic mRNA expression of corticotrophin-releasing hormone. The plasma interleukin-6 (IL-6), C-reactive protein (CRP), and tumor necrosis factor-α (TNF-α) concentrations were measured by enzyme-linked immunosorbent assay. Hippocampal protein expression of brain-derived neurotrophic factor (BDNF) and the Wnt/β-catenin pathway were analyzed by western blot. The results showed that RES relieved depression-like behavior of CUMS rats, as indicated by the increased sucrose preference and the decreased immobile time. Rats that received RES treatment exhibited reduced plasma corticosterone levels and corticotrophin-releasing hormone mRNA expression in the hypothalamus, suggesting that the hyperactivity of the HPA axis in CUMS rats was reversed by RES. Moreover, after RES treatment, the rats exhibited increased plasma IL-6, CRP, and TNF-α concentrations. Furthermore, RES treatment upregulated the hippocampal protein levels of BDNF and the relative ratio of p-β-catenin/β-catenin while downregulating the relative ratio of p-GSK-3β/GSK-3β. Our findings suggest that RES improved depressive behavior in CUMS rats by downregulating HPA axis hyperactivity, increasing BDNF expression and plasma IL-6, CRP, and TNF-α concentrations, and regulating the hippocampal Wnt/β-catenin pathway.

Salivary Gland Derived BDNF Overexpression in Mice Exerts an Anxiolytic Effect.

Brain-derived neurotrophic factor (BDNF) is abundant in the hippocampus and plays critical roles in memory and synapse formation, as well as exerting antidepressant-like effects in psychiatric disorders. We previously reported that BDNF is expressed in salivary glands and affects blood BDNF content. However, the function of salivary BDNF remains unclear. The aim of this study was to generate transgenic mice overexpressing BDNF in the salivary glands. Hence, we used the Lama construct (hemagglutinin (HA)-tagged mouse Bdnf cDNA) to specifically express BDNF in mouse salivary glands. Compared with control mice, Bdnf-HA transgenic mice showed increased blood BDNF and expressed salivary BDNF-HA. Molecular analysis revealed enhanced hippocampal BDNF levels and activation of the BDNF receptor, tyrosine kinase B (TrkB), in transgenic mice. In both the open field and elevated-plus maze tests, transgenic mice showed anxiolytic-like behavioral effects compared with control or sialoadenectomized mice. Among downstream components of the BDNF-TrkB signaling pathway, metabolic activation of the γ-aminobutyric acid (GABA) synthetic pathway was found, including higher levels of the GABA synthetic enzyme, glutamate decarboxylase 1 (GAD1). Thus, we have established a transgenic mouse expressing BDNF in the parotid gland that may be useful to examine the hippocampal effects of salivary BDNF.

Timosaponin B-III exhibits antidepressive activity in a mouse model of postpartum depression by the regulation of inflammatory cytokines, BNDF signaling and synaptic plasticity.

The aim of this study was to investigate the antidepressive effects of timosaponin B-III (TB-III) and the underlying mechanism. A postpartum depression (PPD) mouse model was established by the administration of dexamethasone sodium phosphate during pregnancy. Mice with PPD were assigned to the following groups: Model, fluoxetine and high, medium and low doses of TB-III. Post-parturient mice without PPD served as a normal control group. To examine the effect of TB-III, mice were treated with TB-III, then forced swimming tests (FSTs) and tail suspension tests (TSTs) were performed to evaluate depression. Serum and hippocampal cytokines, namely tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6 and IL-10, were quantified using ELISAs and protein levels of hippocampal brain-derived neurotrophic factor (BDNF), glucagon synthase kinase (GSK)-3β, glutamate receptor subunit 1 (GluR1), postsynaptic density protein 95 (PSD95) and synapsin I were quantified using western blot analysis. Compared with those in the control group, immobility time in the FST and TST, serum and hippocampal TNF-α, IL-1β and IL-6 levels and hippocampal IL-10 levels were increased significantly in the model group (P<0.01). Serum IL-10 levels and hippocampal levels of BDNF, GSK-3β, GluR1, PSD95 and synapsin I decreased significantly in the model group compared with the control group (P<0.01). Fluoxetine or TB-III (10, 20 or 40 mg/kg) treatment significantly decreased immobility times in the FST and TST (P<0.01) and significantly reversed the aforementioned alterations in cytokine and protein levels (P<0.01). Thus, TB-III exhibited a protective effect against depression in PPD and such effects may have been mediated via the regulation of inflammatory cytokines, the BNDF signaling pathway and synaptic plasticity-related proteins.

Antidepressant-like effects and cognitive enhancement of Schisandra chinensis in chronic unpredictable mild stress mice and its related mechanism

The aim of this study was to evaluate whether Schisandra chinensis extract (SCE) administration influences chronic unpredictable mild stress (CUMS)-induced depression and cognitive impairment, and explores underlying mechanisms. Sucrose preference test (SPT) and forced swimming test (FST) were used for assessing depressive symptoms, and Y-maze, Morris water maze were used for evaluating cognition processes. The results showed that CUMS (4 weeks) was effective in producing both depression and memory deficits in mice. Additionally, CUMS exposure significantly decreased brain derived neurotrophic factor (BDNF) levels in hippocampus as indicated by ELISA, immunohistochemistry and immunofluorescence assays, accompanied by down-regulated tyrosine kinase receptor B (TrkB)/cAMP-response element binding protein (CREB)/extracellular signal-regulated kinase (ERK) and phosphatidylinositol 3 kinase (PI3K)/ protein kinase B (AKT)/ glycogen synthase kinase-3β (GSK-3β) signaling pathways. Chronic administration of SCE (600 or 1200 mg/kg, i.g.) significantly prevented all these CUMS-induced behavioral and biochemical alterations. It suggested that SCE could improve the depression-like emotional status and associated cognitive deficits in CUMS mice, which might be mediated by regulation of BDNF levels in hippocampus, as well as up-regulating of TrkB/CREB/ERK and PI3K/AKT/GSK-3β pathways.

Clozapine blockade of MK-801-induced learning/memory impairment in the mEPM: Role of 5-HT1A receptors and hippocampal BDNF levels

Cognitive impairment associated with schizophrenia (CIAS) is highly prevalent and affects the overall functioning of patients. Clozapine (Clz), an atypical antipsychotic drug, significantly improves CIAS although the underlying mechanisms remain under study. The role of the 5-HT1A receptor (5-HT1A-R) in the ability of Clz to prevent the learning/memory impairment induced by MK-801 was investigated using the modified elevated plus-maze (mEPM) considering the Transfer latency (TL) as an index of spatial memory. We also investigated if changes in hippocampal brain-derived neurotrophic factor (BDNF) levels underlie the behavioral prevention induced by Clz.Clz (0.5 and 1mg/kg)- or vehicle-pretreated Wistar rats were injected with MK-801 (0.05mg/kg) or saline. TL was evaluated 35min later (TL1, acquisition session) while learning/memory performance was measured 24h (TL2, retention session) and 48h later (TL3, long-lasting effect). WAY-100635, a 5-HT1A-R antagonist, was pre-injected (0.3mg/kg) to examine the presumed 5-HT1A-R involvement in Clz action. At TL2, another experimental group treated with Clz and MK-801 and its respective control groups were added to measure BDNF protein levels by ELISA.TL1 and TL3 were not significantly modified by the different treatments. MK-801 increased TL2 compared to control group leading a disruption of spatial memory processing which was markedly attenuated by Clz. WAY-100635 suppressed this action supporting a relevant role of 5-HT1A-R in the Clz mechanism of action to improve spatial memory dysfunction. Although a significant decrease of hippocampal BDNF levels underlies the learning/memory impairment induced by MK-801, this effect was not significantly prevented by Clz.