Brain-derived Neurotrophic Factor Expression In Hippocampus Research Articles

Diet enriched with high-phenolic cocoa potentiates hippocampal brain-derived neurotrophic factor expression and neurogenesis in healthy adult micewith subtle effects on memory.

Cocoa is widely known for its health benefits, but its neurocognitive impact remains underexplored. This preclinical study aimed to investigate the effects of cocoa and cocoa polyphenols on hippocampal neuroplasticity, cognitive function and emotional behavior. Seventy young-adult C57BL/6JRj male and female mice were fed either a standard diet (CTR) or a diet enriched with 10% high-phenolic content cocoa (HPC) or low-phenolic content cocoa (LPC) for at least four weeks. In a first experiment, behavioral tests assessing exploratory behavior, emotional responses and hippocampal-dependent memory were conducted four weeks into the diet, followed by animal sacrifice a week later. Adult hippocampal neurogenesis and brain-derived neurotrophic factor (BDNF) expression in the hippocampus and prefrontal cortex were evaluated using immunohistochemistry and western blot. In a different experiment, hippocampal synaptic response, long-term potentiation and presynaptic-dependent short-term plasticity were studied by electrophysiology. Cocoa-enriched diets had minimal effects on exploratory activity and anxiety-like behavior, except for reduced locomotion in the LPC group. Only the HPC diet enhanced object recognition memory, while place recognition memory and spatial navigation remained unaffected. The HPC diet also increased adult hippocampal neurogenesis, boosting the proliferation, survival and number of young adult-born neurons. However, both cocoa-enriched diets increased immobility in the forced swimming test and hippocampal BDNF expression. Hippocampal electrophysiology revealed no alterations in neuroplasticity among diets. The results were mostly unaffected by sex. Overall, the HPC diet demonstrated greater potential regarding cognitive and neuroplastic benefits, suggesting a key role of cocoa flavanols in dietary interventions aimed at enhancing brain health.

Adolescent treadmill exercise enhances hippocampal brain-derived neurotrophic factor (BDNF) expression and improves cognition in autism-modeled rats

Autism spectrum disorder (ASD) is a prevalent neurodevelopmental disorder characterized by repetitive behaviors and altered communication abilities. Exercise is a low-cost intervention that could improve cognitive function and improve brain plasticity mechanisms. Here, the valproic acid (VPA) model was utilized to induce ASD-like phenotypes in rodents. Animals were exercised on a treadmill and performance was evaluated on a cognitive flexibility task. Biomarkers related to exercise and plasticity regulation were quantified from the prefrontal cortex, hippocampus, and skeletal muscle. Exercised VPA animals had higher levels of hippocampal BDNF compared to sedentary VPA animals and upregulated antioxidant enzyme expression in skeletal muscle. Cognitive improvements were demonstrated in both sexes, but in different domains of cognitive flexibility. This research demonstrates the benefits of exercise and provides evidence that molecular responses to exercise occur in both the central nervous system and in the periphery. These results suggest that improving regulation of BDNF via exercise, even at low intensity, could provide better synaptic regulation and cognitive benefits for individuals with ASD.

Lactobacillus rhamnosus GG improves cognitive impairments in mice with sepsis.

Survivors of sepsis may encounter cognitive impairment following their recovery from critical condition. At present, there is no standardized treatment for addressing sepsis-associated encephalopathy. Lactobacillus rhamnosus GG (LGG) is a prevalent bacterium found in the gut microbiota and is an active component of probiotic supplements. LGG has demonstrated to be associated with cognitive improvement. This study explored whether LGG administration prior to and following induced sepsis could ameliorate cognitive deficits, and explored potential mechanisms. Female C57BL/6 mice were randomly divided into three groups: sham surgery, cecal ligation and puncture (CLP), and CLP+LGG. Cognitive behavior was assessed longitudinally at 7-9d, 14-16d, and 21-23d after surgery using an open field test and novel object recognition test. The impact of LGG treatment on pathological changes, the expression level of brain-derived neurotrophic factor (BDNF), and the phosphorylation level of the TrkB receptor (p-TrkB) in the hippocampus of mice at two weeks post-CLP (16d) were evaluated using histological, immunofluorescence, immunohistochemistry, and western blot analyses. The CLP surgery induced and sustained cognitive impairment in mice with sepsis for a minimum of three weeks following the surgery. Compared to mice subjected to CLP alone, the administration of LGG improved the survival of mice with sepsis and notably enhanced their cognitive functioning. Moreover, LGG supplementation significantly alleviated the decrease in hippocampal BDNF expression and p-TrkB phosphorylation levels caused by sepsis, preserving neuronal survival and mitigating the pathological changes within the hippocampus of mice with sepsis. LGG supplementation mitigates sepsis-related cognitive impairment in mice and preserves BDNF expression and p-TrkB levels in the hippocampus.

Improving dietary patterns in obese mice: Effects on body weight, adiposity, anhedonia-like behavior, pro-BDNF expression and 5-HT system

IntroductionThe excessive fat accumulation in obesity, resulting from an unbalanced diet, can lead to metabolic and neurological disorders and increase the risk of developing anxiety and depression. AimAssess the impact of dietary intervention (DI) on the serotonergic system, brain-derived neurotrophic factor (BDNF) expression and behaviors of obese mice. MethodsMale C57BL/6 mice, 5 weeks old, received a high-fat diet (HFD) for 10 weeks for the induction of obesity. After this period, for 8 weeks, half of these animals received a control diet (CD), group obese (OB) + control diet (OB + CD, n = 10), and another half continued being fed HFD, group obese + HFD (OB + HFD, n = 10). At the end of the eighth week of intervention, behavioral tests were performed (sucrose preference test, open field, novel object recognition, elevated plus maze and tail suspension). Body weight and food intake were assessed weekly. Visceral adiposity, the hippocampal and hypothalamic protein expression of BDNF, 5-HT1A (5-HT1A serotonin receptor) and TPH2 (key enzyme in serotonin synthesis), were evaluated after euthanasia. ResultsThe dietary intervention involved changing from a HFD to a CD over an 8-week period, effectively reduced body weight gain, adiposity, and anhedonia-like behavior. In the OB + HFD group, we saw a lower sucrose preference and shorter traveled distance in the open field, along with increased pro-BDNF expression in the hypothalamus compared to the OB + CD mice. However, the levels of TPH2 and 5-HT1A remained unchanged. ConclusionThe HFD model induced both obesity and anhedonia, but the dietary intervention successfully improved these conditions.

Chronic REM sleep deprivation leads to manic- and OCD-related behaviors, and decreases hippocampal BDNF expression in female rats.

Rapid-eye movement (REM) sleep deprivation (SD) can induce manic-like behaviors in rodents. On the other hand, lithium, as one of the oldest drugs used in neuropsychiatric disorders, is still one of the best drugs for the treatment and control of bipolar disorder. In this study, we aimed to investigate the role of chronic short-term REM SD in the induction of manic-like behaviors in female rats. The rats were exposed to REM SD for 14 days (6 hours/day). Lithium was intraperitoneally injected at the doses of 10, 50, and 100 mg/kg. REM SD induced hyperactivity and OCD-like behavior, and decreased anxiety, depressive-like behavior, and pain subthreshold. REM SD also impaired passive avoidance memory and decreased hippocampal brain-derived neurotrophic factor (BDNF) expression level. Lithium at the doses of 50 and 100 mg/kg partly and completely abolished these effects, respectively. However, lithium (100 mg/kg) increased BDNF expression level in control and sham REM SD rats with no significant changes in behavior. Chronic short-term REM SD may induce a mania-like model and lead to OCD-like behavior and irritability. In the present study, we demonstrated a putative rodent model of mania induced by chronic REM SD in female rats. We suggest that future studies should examine behavioral and mood changes following chronic REM SD in both sexes. Furthermore, the relationship between manic-like behaviors and chronic REM SD should be investigated.

Fatty acid amides present in Camembert cheese improved cognitive decline after oral administration in mice

Herein, we investigated the effects of Camembert cheese (CC) and its fatty acid contents on cognitive function in mice by employing the object recognition test to evaluate hippocampus-dependent memory. Orally administered CC improved the cognitive decline induced by a high-fat diet. Next, we focused on myristamide (MA), oleamide, and stearamide, which are fatty acid amides produced during the fermentation process of CC. We found that oral administration of MA improved cognitive decline. Notably, an improvement was not observed using myristic acid, a free fatty acid that is not amidated. Thus, fatty acid amidation may contribute to the physiological activity. Moreover, we investigated changes in gene expression related to neurogenesis in the hippocampus. After MA administration, mRNA expression analysis indicated that MA increased hippocampal brain-derived neurotrophic factor expression.

Impact of NMDA receptors block versus GABA-A receptors modulation on synaptic plasticity and brain electrical activity in metabolic syndrome

PurposeMetabolic syndrome (MetS) is a common disorder associated with disturbed neurotransmitter homeostasis. Memantine, an N-methyl-d-aspartate receptor (NMDAR) antagonist, was first used in Alzheimer's disease. Allopregnanolone (Allo), a potent positive allosteric modulator of the Gamma-Amino-Butyric Acid (GABA)-A receptors, decreases in neurodegenerative diseases. The study investigated the impact of Memantine versus Allo administration on the animal model of MetS to clarify whether the mechanism of abnormalities is related more to excitatory or inhibitory neurotransmitter dysfunction. Materials and methodsFifty-six male rats were allocated into 7 groups: 4 control groups, 1 MetS group, and 2 treated MetS groups. They underwent assessment of cognition-related behavior by open field and forced swimming tests, electroencephalogram (EEG) recording, serum markers confirming the establishment of MetS model and hippocampal Glial Fibrillary Acidic Protein (GFAP) and Brain-Derived Neurotrophic Factor (BDNF). ResultsAllo improved anxiety-like behavior and decreased grooming frequency compared to Memantine. Both drugs increased GFAP and BDNF expression, improving synaptic plasticity and cognition-related behaviors. The therapeutic effect of Allo was more beneficial regarding lipid profile and anxiety. We reported progressive slowing of EEG waves in the MetS group with Memantine and Allo treatment with increased relative theta and decreased relative delta rhythms. ConclusionsBoth Allo and Memantine boosted the outcome parameters in the animal model of MetS. Allo markedly improved the anxiety-like behavior in the form of significantly decreased grooming frequency compared to the Memantine-treated groups. Both drugs were associated with increased hippocampal GFAP and BDNF expression, indicating an improvement in synaptic plasticity and so, cognition-related behaviors.

Impact of Exercise Intensity on Cerebral BDNF Levels: Role of FNDC5/Irisin.

The positive effects of physical exercise (EX) are well known to be mediated by cerebral BDNF (brain-derived neurotrophic factor), a neurotrophin involved in learning and memory, the expression of which could be induced by circulating irisin, a peptide derived from Fibronectin type III domain-containing protein 5 (FNDC5) produced by skeletal muscle contraction. While the influence of EX modalities on cerebral BDNF expression was characterized, their effect on muscle FNDC5/Irisin expression and circulating irisin levels remains to be explored. The present study involved Wistar rats divided into four experimental groups: sedentary (SED), low- (40% of maximal aerobic speed, MAS), intermediate- (50% of MAS) and high- (70% of MAS) intensities of treadmill EX (30 min/day, 7 days). Soleus (SOL) versus gastrocnemius (GAS) FNDC5 and hippocampal BDNF expressions were evaluated by Western blotting. Additionally, muscular FNDC5/Irisin localization and serum/hippocampal irisin levels were studied by immunofluorescence and ELISA, respectively. Our findings revealed that (1) serum irisin and hippocampal BDNF levels vary with EX intensity, showing a threshold intensity at 50% of MAS; (2) hippocampal BDNF levels positively correlate with serum irisin but not with hippocampal FNDC5/Irisin; and (3) GAS, in response to EX intensity, overexpresses FNDC5/Irisin in type II muscle fibers. Altogether, peripheral FNDC5/Irisin levels likely explain EX-dependent hippocampal BDNF expression.

Neurobehavioral impairments in ciprofloxacin- treated osteoarthritic adult rats.

<p>Ciprofloxacin (CIP) is a broad-spectrum antibiotic widely used in clinical practice to treat musculoskeletal infections. Fluoroquinolone-induced neurotoxic adverse events have been reported in a few case reports, all the preclinical studies on its neuropsychiatric side effects involved only healthy animals. This study firstly investigated the behavioral effects of CIP in an osteoarthritis rat model with joint destruction and pain, which can simulate inflammation-associated musculoskeletal pain. Furthermore, effects of CIP on regional brain-derived neurotrophic factor (BDNF) expression were examined given its major contributions to the neuromodulation and plasticity underlying behavior and cognition.&nbsp;</p>. <p>Fourteen days after induction of chronic osteoarthritis, animals were administered vehicle, 33 mg/kg or 100 mg/kg CIP for five days intraperitoneally. Motor activity, behavioral motivation, and psychomotor learning were examined in a reward-based behavioral test (Ambitus) on Day 4 and sensorimotor gating by the prepulse inhibition test on Day 5. Thereafter, the prolonged BDNF mRNA and protein expression levels were measured in the hippocampus and the prefrontal cortex.&nbsp;</p>. <p>CIP dose-dependently reduced both locomotion and reward-motivated exploratory activity, accompanied with impaired learning ability. In contrast, there were no significant differences in startle reflex and sensory gating among treatment groups; however, CIP treatment reduced motor activity of the animals in this test, too. These alterations were associated with reduced BDNF mRNA and protein expression levels in the hippocampus but not the prefrontal cortex.&nbsp;</p>. <p>This study revealed the detrimental effects of CIP treatment on locomotor activity and motivation/learning ability during osteoarthritic condition, which might be due to, at least partially, deficient hippocampal BDNF expression and ensuing impairments in neural and synaptic plasticity.</p>.

Activation of mediodorsal thalamic dopamine receptors inhibited nicotine-induced anxiety in rats: A possible role of corticolimbic NMDA neurotransmission and BDNF expression

The present study aimed to evaluate the functional interaction between the dopaminergic and glutamatergic systems of the mediodorsal thalamus (MD), the ventral hippocampus (VH), and the prefrontal cortex (PFC) in nicotine-induced anxiogenic-like behaviors. Brain-derived neurotrophic factor (BDNF) level changes were measured in the targeted brain areas following the drug treatments. The percentage of time spent in the open arm (% OAT) and open arm entry (% OAE) were calculated in the elevated plus maze (EPM) to measure anxiety-related behaviors in adult male Wistar rats. Systemic administration of nicotine at a dose of 0.5 mg/kg induced an anxiogenic-like response associated with decreased BDNF levels in the hippocampus and the PFC. Intra-MD microinjection of apomorphine (0.1–0.3 μg/rat) induced an anxiogenic-like response, while apomorphine inhibited nicotine-induced anxiogenic-like behaviors associated with increased hippocampal and PFC BDNF expression levels. Interestingly, the blockade of the VH or the PFC NMDA receptors via the microinjection of D-AP5 (0.3–0.5 μg/rat) into the targeted sites reversed the inhibitory effect of apomorphine (0.5 μg/rat, intra-MD) on the nicotine response and led to the decrease of BDNF levels in the hippocampus and the PFC. Also, the microinjection of a higher dose of D-AP5 (0.5 μg/rat, intra-PFC) alone produced an anxiogenic effect. These findings suggest that the functional interaction between the MD dopaminergic D1/D2-like and the VH/PFC glutamatergic NMDA receptors may be partially involved in the anxiogenic-like effects of nicotine, likely via the alteration of BDNF levels in the hippocampus and the PFC.

Lactobacillus casei and Its Supplement Alleviate Stress-Induced Depression and Anxiety in Mice by the Regulation of BDNF Expression and NF-κB Activation.

Stress-induced depression and anxiety (DA) are closely connected to gastrointestinal inflammation and dysbiosis, which can suppress brain-derived neurotrophic factor (BDNF) in the brain. Herein, we isolated the BDNF expression-inducing probiotics Lactobacillus casei HY2782 and Bifidobacterium lactis HY8002 in lipopolysaccharide-stimulated SH-SY5Y cells. Then, we investigated the effects of HY2782, HY8002, anti-inflammatory L-theanine, and their supplement (PfS, probiotics-fermented L-theanine-containing supplement) on DA in mice exposed to restraint stress (RS) or the fecal microbiota of patients with inflammatory bowel disease and depression (FMd). Oral administration of HY2782, HY8002, or L-theanine alleviated RS-induced DA-like behaviors. They also decreased RS-induced hippocampal interleukin (IL)-1β and IL-6 levels, as well as NF-κB-positive cell numbers, blood corticosterone level, and colonic IL-1β and IL-6 levels and NF-κB-positive cell numbers. L-theanine more potently suppressed DA-like behaviors and inflammation-related marker levels than probiotics. However, these probiotics more potently increased RS-suppressed hippocampal BDNF level and BDNF+NeuN+ cell numbers than L-theanine. Furthermore, HY2782 and HY8002 suppressed RS-increased Proteobacteria and Verrucomicrobia populations in gut microbiota. In particular, they increased Lachnospiraceae and Lactobacillacease populations, which are closely positively associated with hippocampal BDNF expression, and suppressed Sutterellaceae, Helicobacteriaceae, Akkermansiaceae, and Enterobacteriaceae populations, which are closely positively associated with hippocampal IL-1β expression. HY2782 and HY8002 potently alleviated FMd-induced DA-like behaviors and increased FMd-suppressed BDNF, serotonin levels, and BDNF-positive neuronal cell numbers in the brain. They alleviated blood corticosterone level and colonic IL-1β α and IL-6 levels. However, L-theanine weakly, but not significantly, alleviated FMd-induced DA-like behaviors and gut inflammation. BDNF expression-inducing probiotic (HY2782, HY8002, Streptococcus thermophilus, and Lactobacillus acidophilus)-fermented and anti-inflammatory L-theanine-containing supplement PfS alleviated DA-like behaviors, inflammation-related biomarker levels, and gut dysbiosis more than probiotics or L-theanine. Based on these findings, a combination of BDNF expression-inducing probiotics with anti-inflammatory L-theanine may additively or synergistically alleviate DA and gut dysbiosis by regulating gut microbiota-mediated inflammation and BDNF expression, thereby being beneficial for DA.

Effect of electroacupuncture on the expression of Iba-1 in spinal dorsal horn and hippocampus of chronic pain rats with knee osteoarthritis

To observe the effect of electroacupuncture(EA) on pain-ralated behaviors, morphology of hippocampus, concentrations of inflammatory cytokines and expression of ionized calcium binding adapter molecule 1(Iba-1) in dorsal horn of the spinal cord and the hippocampus, and brain-derived neurotrophic factor (BDNF) in hippocampus of rats with knee osteoarthritis (KOA), so as to explore the mechanism of EA in improving chronic pain of KOA. Forty SD rats were randomly divided into blank group, saline group, model group and EA group, with 10 rats in each group. Monosodium iodoacetate(MIA, 80 mg/mL, 50 μL) was injected into the left knee joint cavity of rats in the model group and EA group to establish the chronic pain model of KOA, while the same volume of normal saline was injected into the left knee joint cavity of rats in the saline group. Rats in the EA group received EA stimulation(2 Hz/100 Hz, 1-2 mA) at left "Yanglingquan"(GB34) and "Neixiyan"(EX-LE4) for 15 min, 14 d after MIA injection. The treatment was given once daily, 5 d as 1 session and 2 sessions of treatment were required. Methanical withdrawl threshold(MWT) and weight-bearing capacity tests on left hind limbs were carried out 1 d before, 7 d，14 d, 20 d and 26 d after MIA injection. At the 27th day, rats were sacrificed and HE staining was used to observe the morphology of hippocampal CA1 area. Concentrations of interleukin(IL)-1β and tumor necrosis factor(TNF)-α in the left L3-L5 spinal dorsal horn and hippocampal CA1 area were detected by ELISA, the expressions of Iba-1 in the spinal dorsal horn and hippo-campal CA1 area were detected by immunofluorescence, and the expression of BDNF in left hippocampal CA1 area was detected by Western blot. The HE staining results of the hippocampal CA1 area showed reduced number of neurons, unclear cell contour and boundary between nucleus and cytoplasm, and nuclear pyknosis in the model group, which was relatively milder in the EA group. Compared with the blank group, MWT and weight-bearing capacity of rats' left hind limbs, and expression of BDNF protein in hippocampal CA1 area were significantly decreased (P<0.01), while the contents of IL-1β and TNF-α, the expression of Iba-1 in spinal dorsal horn and hippocampal CA1 area were significantly increased (P<0.01) in the model group. In comparison with the model group, MWT and weight-bearing capacity of rats' left hind limbs, and protein expression of BDNF in hippocampal CA1 area were significantly increased (P<0.01), while the contents of IL-1β and TNF-α, and the expression of Iba-1 protein in spinal dorsal horn and hippocampal CA1 area were significantly decreased after EA intervention(P<0.01). EA at GB34 and EX-LE4 can alleviate the pain-related behaviors of KOA rats. The mechanism might be related to the inhibition of inflammatory reaction mediated by microglia in spinal dorsal horn and hippocampus, and the up-regulation of BDNF expression in hippocampus.

14-3-3ζ Plays a key role in the modulation of neuroplasticity underlying the antidepressant-like effects of Zhi-Zi-Chi-Tang

BackgroundZhi-Zi-Chi-Tang (ZZCT) is an effective traditional Chinese medicinal formula. ZZCT has been used for the treatment of depression for centuries. Its clinical efficacy in relieving depression has been confirmed. However, the molecular mechanisms of ZZCT regarding neuroplasticity in the pathogenesis of depression have not yet been elucidated. PurposeThe present study aimed to examine the effects of ZZCT on neuroplasticity in mice exposed to chronic unpredictable mild stress (CUMS), and to explore the underlying molecular mechanisms. MethodsFor this purpose, a murine model of depression was established using the CUMS procedure. Following the intragastric administration of ZZCT or fluoxetine, classic behavioral experiments were performed to observe the efficacy of ZZCT as an antidepressant. Immunofluorescence was used to label and quantify microtubule-associated protein (MAP2) and postsynaptic density protein (PSD95) in the hippocampus. Golgi staining was applied to visualize the dendritic spine density of neurons in the hippocampi. Isolated hippocampal slices were prepared to induce long-term potentiation (LTP) in the CA1 area. The hippocampal protein expression levels of glycogen synthase kinase-3β (GSK-3β), p-GSK-3β (Ser9), cAMP response element binding protein (CREB), p-CREB (Ser133), brain-derived neurotrophic factor (BDNF) and 14–3–3ζ were detected using western blot analysis. The interaction of 14–3–3ζ and p-GSK-3β (Ser9) was examined using co-immunoprecipitation. LV-shRNA was used to knockdown 14–3–3ζ by an intracerebroventricular injection. ResultsZZCT (6 g/kg) and fluoxetine (20 mg/kg) alleviated depressive-like behavior, restored hippocampal MAP2+ PSD95+ intensity, and reversed the dendritic spine density of hippocampal neurons and LTP in the CA1 region of mice exposed to CUMS. Both low and high doses of ZZCT (3 and 6 g/kg) significantly promoted the binding of 14–3–3ζ to p-GSK-3β (Ser9) in the hippocampus, and ZZCT (6 g/kg) significantly promoted the phosphorylation of GSK-3β Ser9 and CREB Ser133 in the hippocampus. ZZCT (3 and 6 g/kg) upregulated hippocampal BDNF expression in mice exposed to CUMS. LV-sh14–3–3ξ reduced the antidepressant effects of ZZCT. ConclusionZZCT exerted antidepressant effects against CUMS-stimulated depressive-like behavior mice. The knockdown of 14–3–3ζ using lentivirus confirmed that 14–3–3ζ was involved in the ZZCT-mediated antidepressant effects through GSK-3β/CREB/BDNF signaling. On the whole, these results suggest that the antidepressant effects of ZZCT are attributed to restoring damage by neuroplasticity enhancement via the 14–3–3ζ/GSK-3β/CREB/BDNF signaling pathway.

Memory-Improving Activity of the Flower Extract from Chrysanthemum boreale (Makino) Maskino in Scopolamine-Treated Rodents

One of the factors related to the pathogenesis of Alzheimer’s disease, a disease characterized by gradual cognitive and memory impairment, is an inflammatory process induced by the amyloid-β-mediated activation of microglia. In the present study, an extract of the Chrysanthemum boreale (Makino) Makino (CB) flower, which has inhibitory effects on inflammation and the production of phosphorylated tau in cells, was investigated for its ameliorative effect on memory dysfunction in scopolamine-treated Alzheimer’s disease models. The CB-extract-diet-administered groups, which were treated chronically with scopolamine (intraperitoneal), showed increased spontaneous alterations (12.5–15.5% increase) in the Y-maze test and latency to escape (3.7–6.7-fold increase) in the passive avoidance test, compared to the negative control (NC) group. Rats administered the CB extract also showed a higher tendency (66–86% increase) of hippocampal brain-derived neurotrophic factor expression than NC rats. Moreover, the ratio of phosphorylated extracellular signal-regulated kinase/extracellular signal-regulated kinase in the CB-extract-administered group was lower (48.0–52.2%) than that (100%) in the NC group. In the Morris water maze test conducted on the fifth day, the free-swimming times of the CB-extract-administered mice that were also treated with scopolamine for a short time (5 d) increased (51.7–56.1%) significantly compared to those of the NC mice. Finally, high-performance liquid chromatography analysis confirmed that isochlorogenic acid A, linarin, and chlorogenic acid are the major phenolic components of the CB extract. These results suggest that the extract of CB flowers might be useful as a functional material with memory-enhancing effects.

Suppressive effects of bilobalide on depression-like behaviors induced by chronic unpredictable mild stress in mice.

Background: Depression is a psychiatric disorder with depressed mood and even suicide attempts as the main clinical symptoms, and its pathogenesis has not yet been fully elucidated. Brain derived neurotrophic factor (BDNF) plays an important role in the pathogenesis of depression. Purpose: The main aim of the present study was to evaluate the effectiveness and reveal the potential mechanisms of bilobalide (BB) intervention in alleviating depression-like behaviors by using chronic unpredictable mild stress (CUMS) mice via mediating the BDNF pathway. Methods: Behavioral assessments were carried out by using the sucrose preference test (SPT), tail suspension test (TST), and forced swimming test (FST). CUMS mice were randomly divided into 5 groups: CUMS + solvent, CUMS + BB low, CUMS + BB medium, CUMS + BB high and CUMS + fluoxetine. Total serum levels of tumor necrosis factor (TNF-α) and interleukin-6 (IL-6) were measured by ELISA. Expression of TNF-α, IL-6, AKT, GSK3β, β-catenin, Trk-B and BDNF in the mouse hippocampus was assessed by western blotting. Results: BB treatment reduced the levels of pro-inflammatory cytokines (IL-6 and TNF-α) and increased the protein expression of BDNF in the hippocampus region of the CUMS mice. Moreover, BB treatment enhanced the AKT/GSK3β/β-catenin signaling pathway which is downstream of the BDNF receptor Trk-B in the hippocampus of these mice. Conclusions: Overall, the experimental results indicated that BB reverses CUMS-induced depression-like behavior. BB exerts antidepressant-like effects by inhibiting neuroinflammation and enhancing the function of neurotrophic factors.

Effect of consumption of blue maize tortilla on anxiety-like behaviour, learning, memory and hippocampal BDNF expression in a chronic stress model in rats

ABSTRACT Background Pigmented maize consumption is of much interest because of its high anthocyanin content and multiple health benefits. Objetives: This study was aimed to assess the effect of consuming blue maize tortillas on the anxiolytic capacity, preserve emotional memory, and the expression of brain-derived neurotrophic factor (BDNF) in rats subjected to chronic stress. Methods: Sixty-four 3-month-old male Wistar rats were used, divided into eight groups (n = 8). Four groups were subjected to chronic stress by movement restriction (7 h/daily/7 consecutive days) and the remaining four groups were subjected to standard management. The treatments were commercial food, blue tortilla, anthocyanin extract, or white tortilla, administered for nine weeks to stressed or unstressed animals. In the eighth week, the animals were subjected to the restraint stress model. Subsequently, anxiety-like behaviour was assessed using the elevated plus-maze, and memory and emotional learning were evaluated by the step-down passive avoidance test. The animals were then sacrificed to quantify the relative expression of hippocampal BDNF by RT-qPCR. Results: The consumption of anthocyanin extract or tortilla made with blue corn decreased anxiety-like behaviours, additionally, it improved the ability to retain emotionally relevant information, and it upregulated BDNF mRNA expression. Perspective: Thus, the analyse of the impact of blue tortilla consumption on the nervous system is now necessary to guarantee the nutraceutical value of this food.

Obesity aggravated hippocampal-dependent cognitive impairment after sleeve gastrectomy in C57/BL6J mice via SIRT1/CREB/BDNF pathway.

Postoperative cognitive dysfunction (POCD) is characterized by cognitive impairments following anesthesia/surgery, but the role of obesity and the underlying mechanisms are not known. We investigated the impact of obesity on POCD. Eighty male C57BL/6J mice were assigned randomly to two groups fed a normal chow diet (ND, n = 40) or a high-fat diet (HD, n = 40) for 20weeks. Then, they were divided randomly into eight subgroups of 10: ND control (NDC), ND with surgery (NDS), HD control (HDC), HD with surgery (HDS); NDS + DMSO (NDS + DS), NDS + SRT1720 (NDS + SRT), HDS + DMSO (HDS + DS), and HDS + SRT1720 (HDS + SRT). Body weight, blood glucose level, and serum lipid levels were measured. Staining methods on liver tissues were used to determine hepatic steatosis. A POCD model was established by sleeve gastrectomy (SG) under isoflurane anesthesia. Cognitive function was assessed using the Morris water maze test (MWMT). Expression of sirtuin1 (SIRT1), phosphorylated cAMP-responsive element binding protein (p-CREB), CREB and brain-derived neurotrophic factor (BDNF) in the hippocampus were measured. High-fat diet-fed mice for 20weeks could establish an obesity model with hyperlipidemia and hepatic steatosis. Cognitive impairment was significantly worse in the HDC and HDS groups than that in the NDC and NDS groups, respectively. Hippocampal expression of SIRT1, p-CREB, and BDNF in the HDS group was significantly lower than that of the HDC group. SRT1720 (SIRT1 activator) pretreatment could attenuate cognitive impairment by upregulating SIRT1 expression.These data suggest that obesity exacerbated postoperative hippocampal-dependent cognitive impairment via a SIRT1 pathway, and SRT1720 pretreatment could alleviate it.

Stress Affects Central Compensation of Neural Responses to Cochlear Synaptopathy in a cGMP-Dependent Way.

In light of the increasing evidence supporting a link between hearing loss and dementia, it is critical to gain a better understanding of the nature of this relationship. We have previously observed that following cochlear synaptopathy, the temporal auditory processing (e.g., auditory steady state responses, ASSRs), is sustained when reduced auditory input is centrally compensated. This central compensation process was linked to elevated hippocampal long-term potentiation (LTP). We further observed that, independently of age, central responsiveness to cochlear synaptopathy can differ, resulting in either a low or high capacity to compensate for the reduced auditory input. Lower central compensation resulted in poorer temporal auditory processing, reduced hippocampal LTP, and decreased recruitment of activity-dependent brain-derived neurotrophic factor (BDNF) expression in hippocampal regions (low compensators). Higher central compensation capacity resulted in better temporal auditory processing, higher LTP responses, and increased activity-dependent BDNF expression in hippocampal regions. Here, we aimed to identify modifying factors that are potentially responsible for these different central responses. Strikingly, a poorer central compensation capacity was linked to lower corticosterone levels in comparison to those of high compensators. High compensators responded to repeated placebo injections with elevated blood corticosterone levels, reduced auditory brainstem response (ABR) wave I amplitude, reduced inner hair cell (IHC) ribbon number, diminished temporal processing, reduced LTP responses, and decreased activity-dependent hippocampal BDNF expression. In contrast, the same stress exposure through injection did not elevate blood corticosterone levels in low compensators, nor did it reduce IHC ribbons, ABR wave I amplitude, ASSR, LTP, or BDNF expression as seen in high compensators. Interestingly, in high compensators, the stress-induced responses, such as a decline in ABR wave I amplitude, ASSR, LTP, and BDNF could be restored through the “memory-enhancing” drug phosphodiesterase 9A inhibitor (PDE9i). In contrast, the same treatment did not improve these aspects in low compensators. Thus, central compensation of age-dependent cochlear synaptopathy is a glucocorticoid and cyclic guanosine-monophosphate (cGMP)-dependent neuronal mechanism that fails upon a blunted stress response.

Sex dimorphism in isoproterenol-induced cardiac damage associated neuroinflammation and behavior in old rats.

Acute cardiac damage can be induced by isoproterenol injections in animals. The associated inflammatory response could be reflected in the brain as neuroinflammation, with potential consequences for brain function and behavior. Although cardiac responses are reported age and sex-related, for neuroinflammation and brain function this is virtually unknown. Therefore, cardiac damage and its consequences for neuroinflammation, brain function and behavior were compared in aged male and female rats. Wistar rats of 24 months of age were treated with isoproterenol (ISO, twice s.c.) or saline. Four weeks after injections, exploratory behavior and short-term memory were tested. Then, rats were sacrificed. Hearts were collected to measure cardiac damage. Brain tissue was collected to obtain measures of neuroinflammation and brain function. In male-, but not in female rats, ISO induced significant cardiac damage. Accordingly, mortality was higher in males than in females. Baseline hippocampal microglia activity was lower in females, while ISO induced neuroinflammation in both sexes, Hippocampal brain-derived neurotrophic factor expression appeared lower in females, without effects of ISO. In the open field test, ISO-treated males, but not females, displayed anxiety-like behavior. No effects of ISO were observed on short-term memory in either sex. In conclusion, sex dimorphism in effects of ISO was observed for cardiac damage and open field behavior. However, these effects could not be related to differences in hippocampal neuroinflammation or neuronal function.

Resveratrol ameliorates learning and memory impairments induced by bilateral hippocampal injection of streptozotocin in mice

Resveratrol (RES) is a polyphenol with diverse beneficial pharmacological activities, and our previous results have demonstrated its neuroprotective potential. The purpose of this study was to investigate the therapeutic effect of RES in Alzheimer's disease (AD)-like behavioral dysfunction induced by streptozotocin (STZ) and explore it's potential mechanism of action. STZ was microinjected bilaterally into the dorsal hippocampus of C57BL/6J mice at a dose of 3 mg/kg, and RES was administered intragastrically at a dose of 25 mg/kg for 5 weeks. Neurobehavioral performance was observed, and serum concentrations of insulin and Nesfatin-1 were measured. Moreover, the protein expression of amyloid beta 1–42 (Aβ1-42), Tau, phosphorylated Tau (p-Tau) (Ser396), synaptic ras GTPase activation protein (SynGAP), postsynaptic density protein 95 (PSD95), synapsin-1, synaptogomin-1, and key molecules of the Wnt/β-catenin signaling pathway in the hippocampus and prefrontal cortex (PFC) were assessed. Finally, pathological damage to hippocampal tissue was examined by Nissl and immunofluorescence staining. The results showed that compared with the controls, bilateral hippocampal microinjections of STZ induced task-specific learning and memory impairments, as indicated by the disadvantaged performances in the novel object recognition test (NOR) and Morris water maze (MWM), but not the contextual fear conditioning test (CFC). Treatment with RES could improve these behavioral disadvantages. The serum concentrations of insulin and Nesfatin-1 in the model group were remarkably higher than those of the control group. In addition, protein expression of Aβ1-42, Tau, and p-Tau (Ser396) was increased but expression of SynGAP, PSD95, brain-derived neurotrophic factor (BDNF), and p-GSK-3β/GSK-3β were decreased in the hippocampus. Although the protein expression of BDNF and SynGAP was also markedly decreased in the PFC of the model mice, there was no significant difference among groups in the protein expression of PSD95, BDNF, synapsin-1, synaptogomin-1, and p-GSK-3β/GSK-3β. RES (25 mg/kg) reversed the enhanced insulin level, the abnormal protein expression of Aβ1-42, Tau, and p-Tau (Ser396) in the hippocampus and PFC, and the hippocampal protein expression of SynGAP, PSD95 and BDNF. In addition, RES reversed the STZ-induced decrease in the number of Nissl bodies and the increase in fluorescence intensity of IBA1 in the hippocampal CA1 region. These findings indicate that RES could ameliorate STZ-induced AD-like neuropathological injuries, the mechanism of which could be partly related to its regulation of BDNF expression and synaptic plasticity-associated proteins in the hippocampus.