Hippocampal BDNF Levels Research Articles

Neonatal hypoxia-ischemia alters the events governing the hippocampal critical period of postnatal synaptic plasticity leading to deficits in working memory in mice

The postnatal critical period of synaptic plasticity (CPsp) is characterized by profound neural network refinement, which is shaped by synaptic activity and sculpted by maturation of the GABAergic network. Even after therapeutic hypothermia (TH), neonatal hypoxia-ischemia (HI) impairs two triggers for the initiation of the CPsp in the hippocampus: i) PSA-NCAM developmental decline and ii) parvalbumin (PV) + interneuron (IN) maturation. Thus, we investigated whether neonatal HI despite TH disturbs other events governing the onset, consolidation and closure of the postnatal CPsp in the hippocampus. We induced cerebral HI in P10 C57BL6 mice with right carotid ligation and 45 m of hypoxia (FiO2 = 0.08), followed by normothermia (36 °C, NT) or TH (31 °C) for 4 h with anesthesia-exposed shams as controls. ELISA, immunoblotting and immunohistochemistry were performed at 24 h (P11), 5 days (P15), 8 days (P18) and 30 days (P40) after HI injury. We specifically assessed: i) BDNF levels and TrkB activation, controlling the CPsp, ii) Otx2 and NPTX2 immunoreactivity (IR), engaging CPsp onset and iii) NogoR1, Lynx1 IR, PNN formation and myelination (MBP) mediating CPsp closure. Pups aged to P40 also received a battery of tests assessing working memory. Here, we documented deficits in hippocampal BDNF levels and TrkB activation at P18 in response to neonatal HI even with TH. Neonatal HI impaired in the CA1 the developmental increase in PV, Otx2, and NPTX2 between P11 and P18, the colocalization of Otx2 and PV at P18 and P40, the accumulation of NPTX2 in PV+ dendrites at P18 and P40, and the expression of NogoR and Lynx1 at P40. Furthermore, neonatal HI decreased BDNF and impaired PNN development and myelination (MBP) at P40. Most of these abnormalities were insensitive to TH and correlated with memory deficits. Neonatal HI appears to disrupt many of the molecular and structural events initiating and consolidating the postnatal hippocampal CPsp, perhaps due to the early and delayed deficits in TrkB activation leading to memory deficits.

Antidepressant-like and antistress effects of the ACTH(4–10) synthetic analogs Semax and Melanotan II on male rats in a model of chronic unpredictable stress

Current antidepressant therapy shows substantial limitations, and there is an urgent need for the development of new treatment strategies for depression. Stressful events and hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis play an important role in the pathogenesis of depression. HPA axis activity is self-regulated by negative feedback at several levels including adrenocorticotropic hormone (ACTH)-mediated feedback. Here, we investigated whether noncorticotropic synthetic analogs of the ACTH(4–10) fragment, ACTH(4–7)-Pro-Gly-Pro (Semax) and Ac-Nle4-cyclo[Asp5-His6-D-Phe7-Arg8-Trp9-Lys10]ACTH(4–10)-NH2 (Melanotan II (MTII), a potent agonist of melanocortin receptors), have potential antidepressant activity in a chronic unpredictable stress (CUS) rat model of depression. Stressed and control male adult Sprague-Dawley rats received daily intraperitoneal injections of saline or a low dose (60 nmol/kg of body weight (BW)) of Semax or MTII. Rats were monitored for BW and hedonic status, as measured in the sucrose preference test. We found that chronic treatment with Semax and MTII reversed or substantially attenuated CUS-induced anhedonia, BW gain suppression, adrenal hypertrophy and a decrease in the hippocampal levels of BDNF. In the forced swim test, no effects of the CUS procedure or peptides on the duration of rat immobility were detected. Our findings show that in the CUS paradigm, systemically administered ACTH(4–10) analogs Semax and MTII exert antidepressant-like effects on anhedonia and hippocampal BDNF levels, and attenuate markers of chronic stress load, at least in male rats. The results support the argument that ACTH(4–10) analogs and other noncorticotropic melanocortins may have promising therapeutic potential for the treatment and prevention of depression and other stress-related pathologies.

Long‐lasting behavioral and neurochemical effects of early‐life environmental enrichment in rats submitted to neonatal morphine administration

AbstractThe present study examined the medium‐ and long‐term effects of early environmental enrichment (EE) on neuromotor, nociceptive, cognitive, behavioral, and neurochemical parameters in newborn rats repeatedly exposed to morphine. The study employed 90 Wistar rats: 10 adult nulliparous females and 80 male pups. Litter was split into standard and EE housing. Following, half of each litter received saline (S) or morphine (M) injections, resulting in four groups: SC + S, EE + S, SC + M, and EE + M. EE was applied from PND1 to PND21, while morphine or saline was given daily (5 μg/s.c.) from PND8 to PND14. Neuromotor development was similar between groups. In the OF test, morphine reduced outer and total crossings, whereas EE increased inner crossings and rearings. Adult rats showed a decrease in outer and total crossings and grooming and an increase in rearing. EE increased the number of protected and unprotected head dipping. Adult rats showed an increase in protected head dipping. Adult rats showed a lower recognition index, and, when exposed to EE, a lower anxiety index and analgesia. EE increased brainstem and hippocampal BDNF levels. Adult rats had increased hypothalamus, spinal cord, and brainstem BDNF levels, an increase in the spinal cord, and decreased hypothalamus TNF‐α levels. This study demonstrated that early‐life EE raises BDNF levels in the brainstem and hippocampus of rats and modifies their behaviors (such as nociception, exploration, and anxiety) in a state‐dependent manner (morphine and age).

Preventing social defeat stress-induced behavioural and neurochemical alterations by repeated treatment with a mix of Centella asiatica, Echinacea purpurea and Zingiber officinale standardized extracts.

Background: Prolonged exposure to stress is a risk factor for the onset of several disorders. Modern life is burdened by a pervasive prevalence of stress, which represents a major societal challenge requiring new therapeutic strategies. In this context, botanical drug-based therapies can have a paramount importance. Methods: Here we studied the preventive effects of a repeated treatment (p.o. daily, 3weeks) with a combination of Centella asiatica (200mg/kg), Echinacea purpurea (20mg/kg) and Zingiber officinale (150mg/kg) standardized extracts, on the chronic social defeat stress (CSDS) deleterious outcomes. After 10days of CSDS exposure, male mice' performances were evaluated in paradigms relevant for social (social interaction test), emotional (tail suspension test), cognitive (novel object recognition) domains as well as for pain perception (cold plate and von Frey tests) and motor skills (rotarod). Mice were then sacrificed, the spinal cords, hippocampi and frontal cortices dissected and processed for RT-PCR analysis. Results: Extracts mix treatment prevented stress-induced social aversion, memory impairment, mechanical and thermal allodynia and reduced behavioural despair independently of stress exposure. The treatment stimulated hippocampal and cortical BDNF and TrkB mRNA levels and counteracted stress-induced alterations in pro- (TNF-α, IL-1β and IL-6) and anti-inflammatory (IL4, IL10) cytokines expression in the same areas. It also modulated expression of pain related genes (GFAP and Slc1a3) in the spinal cord. Conclusion: The treatment with the extracts mix obtained from C. asiatica, E. purpurea and Z. officinale may represent a promising strategy to promote resilience and prevent the deleterious effects induced by extended exposure to psychosocial stress.

Synergistic effects of melatonin and hydrogen sulfide in alleviating cognitive decline and BDNF dysregulation in a rat model of depression

ABSTRACT This research aimed to investigate the possible anti-amnesic effects of a combined therapy involving melatonin and H2S in a rat model displaying Depressive-Like Behaviors caused by Chronic Unpredictable Mild Stress (CUMS). Our study aims to assess the efficacy of this treatment in mitigating oxidative stress and neuroinflammation in the striatum and hippocampus. Furthermore, we seek to investigate its ability to restore BDNF levels within this specific rat model. The rats underwent a 4-week CUMS protocol and were administered sodium hydrosulfide (a H2S donor) at a dose of 5.6 μmol/100 g/day, as well as melatonin at a dose of 1 mg/100 g/day from the first day of the CUMS protocol. Following the CUMS exposure, the rats were assessed through various behavioral tests. Subsequently, the rats were euthanized after the behavioral tests, and blood samples were collected for corticosterone analysis. Oxidative stress (OS) markers, BDNF and TNF-α levels were analyzed in both the striatum and HP. Concurrently administering H2S and melatonin in a rat model of CUMS-induced depression demonstrates antidepressant-like effects. Furthermore, this combined treatment effectively prevents the development of learning and memory impairments associated with CUMS. Additionally, it reduces Malondialdehyde and nitric oxide levels, enhances glutathione peroxidase and superoxide dismutase activity in the striatum and HP, and mitigates CUMS-induced elevations in TNF-α levels in both brain regions. Significantly, long-term administration of this combination reverses the chronic stress-induced reduction of hippocampal BDNF levels. These findings suggest that the synergy between H2S and melatonin holds promise in alleviating cognitive impairments.

A TNF-α inhibitor abolishes sepsis-induced cognitive impairment in mice by modulating acetylcholine and nitric oxide homeostasis, BDNF release, and neuroinflammation

Neurodegenerative disorders have a pathophysiology that heavily involves neuroinflammation. In this study, we used lipopolysaccharide (LPS) to create a model of cognitive impairment by inducing systemic and neuroinflammation in experimental animals. LPS was injected intraperitoneally at a dose of 0.5 mg/kg during the last seven days of the study. Adalimumab (ADA), a TNF-α inhibitor, was injected at a dose of 10 mg/kg a total of 3 times throughout the study. On the last two days of the experiment, 50 mg/kg of curcumin was administered orally as a positive control group. Open field (OF) and elevated plus maze tests (EPM) were used to measure anxiety-like behaviors. The tail suspension test (TST) was used to measure depression-like behaviors, while the novel object recognition test (NOR) was used to measure learning and memory activities. Blood and hippocampal TNF α and nitric oxide (NO) levels, hippocampal BDNF, CREB, and ACh levels, and AChE activity were measured by ELISA. LPS increased anxiety and depression-like behaviors while decreasing the activity of the learning-memory system. LPS exerted this effect by causing systemic and neuroinflammation, cholinergic dysfunction, and impaired BDNF release. ADA controlled LPS-induced behavioral changes and improved biochemical markers. ADA prevented cognitive impairment induced by LPS by inhibiting inflammation and regulating the release of BDNF and the cholinergic pathway.

Cannabinoid type 2 receptor inhibition enhances the antidepressant and proneurogenic effects of physical exercise after chronic stress

Chronic stress is a major risk factor for neuropsychiatric conditions such as depression. Adult hippocampal neurogenesis (AHN) has emerged as a promising target to counteract stress-related disorders given the ability of newborn neurons to facilitate endogenous plasticity. Recent data sheds light on the interaction between cannabinoids and neurotrophic factors underlying the regulation of AHN, with important effects on cognitive plasticity and emotional flexibility. Since physical exercise (PE) is known to enhance neurotrophic factor levels, we hypothesised that PE could engage with cannabinoids to influence AHN and that this would result in beneficial effects under stressful conditions. We therefore investigated the actions of modulating cannabinoid type 2 receptors (CB2R), which are devoid of psychotropic effects, in combination with PE in chronically stressed animals. We found that CB2R inhibition, but not CB2R activation, in combination with PE significantly ameliorated stress-evoked emotional changes and cognitive deficits. Importantly, this combined strategy critically shaped stress-induced changes in AHN dynamics, leading to a significant increase in the rates of cell proliferation and differentiation of newborn neurons, overall reduction in neuroinflammation, and increased hippocampal levels of BDNF. Together, these results show that CB2Rs are crucial regulators of the beneficial effects of PE in countering the effects of chronic stress. Our work emphasises the importance of understanding the mechanisms behind the actions of cannabinoids and PE and provides a framework for future therapeutic strategies to treat stress-related disorders that capitalise on lifestyle interventions complemented with endocannabinoid pharmacomodulation.

Effects of Gestational Exercise on Nociception, BDNF, and Irisin Levels in an Animal Model of ADHD

Abnormal cognitive and sensorial properties have been reported in patients with psychiatric and neurodevelopmental conditions, such as attention deficit hyperactivity disorder (ADHD). ADHD patients exhibit impaired dopaminergic signaling and plasticity in brain areas related to cognitive and sensory processing. The spontaneous hypertensive rat (SHR), in comparison to the Wistar Kyoto rat (WKY), is the most used genetic animal model to study ADHD. Brain neurotrophic factor (BDNF), critical for midbrain and hippocampal dopaminergic neuron survival and differentiation, is reduced in both ADHD subjects and SHR. Physical exercise (e.g. swimming) promotes neuroplasticity and improves cognition by increasing BDNF and irisin. Here we investigate the effects of gestational swimming on sensorial and behavioral phenotypes, striatal dopaminergic parameters, and hippocampal FNDC5/irisin and BDNF levels observed in WKY and SHR. Gestational swimming improved nociception in SHR rats (p = 0.006) and increased hippocampal BDNF levels (p = 0.02) in a sex-dependent manner in adolescent offspring. Sex differences were observed in hippocampal FNDC5/irisin levels (p = 0.002), with females presenting lower levels than males. Our results contribute to the notion that swimming during pregnancy is a promising alternative to improve ADHD phenotypes in the offspring.

High-intensity interval training improves long-term memory and increases hippocampal antioxidant activity and BDNF levels in ovariectomized Wistar rats

Menopause is the period in which women cease to produce the hormone estrogen, which can trigger physiological, cognitive, and behavioral changes. In this context, alternatives are needed that can reduce the effects provided by menopause, specifically in terms of cognitive and behavioral aspects. High-intensity interval training (HIIT) is an exercise protocol that has shown the potential to improve cognition by promoting an increase in antioxidant defenses and BDNF levels. Therefore, the aim of this study was to evaluate the effects of HIIT on behavior and hippocampal neurochemistry in ovariectomized adult rats. Four groups of rats were divided into: females without ovariectomy surgery and sedentary (SHAM-SED); females with ovariectomy surgery and sedentary (OVX-SED); females without ovariectomy surgery and trained (SHAM-HIIT); females with ovariectomy surgery and trained (OVX-HIIT). After the surgical procedure and the HIIT protocol, the animals underwent anxiety (elevated plus maze and open field) and memory (novel object recognition) tests. Corticosterone was measured in blood and BDNF levels and redox status were evaluated in the hippocampus. The OVX-SED group showed low BDNF levels and antioxidant enzymes, which may be linked to the observed memory impairments. The HIIT protocol (SHAM-HIIT and OVX-HIIT groups) increased the BDNF levels and antioxidant enzymes in the hippocampus, improving the animals' memory. However, HIIT also led to increased plasma corticosterone and anxiety-like behaviors. The ovariectomy procedure induced memory impairment probably due to reductions in hippocampal BDNF levels and redox imbalance. The HIIT protocol demonstrates promising results as an alternative to improve memory in ovariectomized rats.

Vitamin K2 protects against aluminium chloride-mediated neurodegeneration.

Recent studies have shown that, coupled with other environmental factors, aluminium exposure may lead to neurodegeneration resulting in cognitive impairment resembling Alzheimer's disease. Menaquinone, a form of vitamin K2, aids in maintaining healthy bones and avoids coronary calcification. It also has anti-inflammatory and antioxidant properties. Here, we study the neuroprotective effects of vitamin K2 (MK-7) using the animal model of Alzheimer's disease (AD). Aluminium chloride (AlCl3; 100mg/kg for 3weeks orally) was administered to Swiss albino mice to induce neurodegeneration and Vitamin K2 (100g/kg for 3weeks orally) was applied as treatment. This was followed by behavioural studies to determine memory changes. The behavioural observations correlated with proinflammatory, oxidative, and brain histopathological changes in AlCl3-treated animals with or without vitamin K2 treatment. AlCl3 administration led to memory decline which was partially restored in Vitamin K2 treated animals. Myeloperoxidase levels in the brain increased due to AlCl3-mediated inflammation, which Vitamin K2 prevented. The acetylcholine esterase and oxidative stress markers induced by AlCl3 were reversed by Vitamin K2. Also, Vitamin K2 helps to restore hippocampal BDNF levels and reduced the amyloid β accumulation in AlCl3-administered animals. Additionally, Vitamin K2 protected the hippocampal neurons against AlCl3-mediated damage as observed in histopathological studies. We conclude that Vitamin K2 could partially reverse AlCl3-mediated cognitive decline. It increases acetylcholine and BDNF levels while reducing oxidative stress, neuroinflammation, and β-amyloid deposition, thus protecting the hippocampal neurons from AlCl3-mediated damage.

Roflumilast ameliorates ovariectomy-induced depressive-like behavior in rats via activation of AMPK/mTOR/ULK1-dependent autophagy pathway

AimsRoflumilast, a well-known phosphodiesterase-4 (PDE-4) inhibitor, possess an anti-inflammatory activity with approved indications in chronic obstructive pulmonary disease. This study aimed to evaluate the neuroprotective role of roflumilast in ovariectomy (OVX)-induced depressive-like behavior in female rats and to shed light on a potential autophagy enhancing effect. Main methodsRats were randomly divided into four groups: sham, OVX, OVX + roflumilast (1 mg/kg, p.o), and OVX + roflumilast + chloroquine (CQ) (50 mg/kg, i.p). Drugs were administered for 4 weeks starting 2 weeks after OVX. Key findingsRoflumilast improved the depressive-like behaviors observed in OVX rats as evidenced by decreasing both forced swimming and open field immobility times while, increasing % sucrose preference and number of open field crossed squares. Histopathological analysis provides further evidence of roflumilast's beneficial effects, demonstrating that roflumilast ameliorated the neuronal damage caused by OVX. Roflumilast antidepressant potential was mediated via restoring hippocampal cAMP and BDNF levels as well as down-regulating PDE4 expression. Moreover, roflumilast revealed anti-inflammatory and anti-apoptotic effects via hindering TNF-α level and diminishing Bax/Bcl2 ratio. Roflumilast restored the autophagic function via up-regulation of p-AMPK, p-ULK1, Beclin-1 and LC3II/I expression, along with downregulation of P62 level and p-mTOR protein expression. The autophagy inhibitor CQ was used to demonstrate the suggested pathway. SignificanceThe present study revealed that roflumilast showed an anti-depressant activity in OVX female rats via turning on AMPK/mTOR/ULK1-dependent autophagy pathway; and neurotrophic, anti-inflammatory, and anti-apoptotic activities. Roflumilast could offer a more secure alternative to hormone replacement therapy for postmenopausal depression treatment.

Activation of ventral hippocampal CB1 receptors inhibits ketamine-induced anxiogenic-like behavior: Alteration of BDNF/c-Fos levels in the mouse hippocampus

Considering the increasing usage of ketamine as a recreational drug with hallucinogenic properties and also scarce studies about receptor systems responsible for its effects, in the present study we aimed to investigate whether the activation of the ventral hippocampal (VH) CB1 cannabinoid receptors affects the anxiety-like behaviors induced by ketamine. Also, the levels of BDNF and c-Fos proteins in the mouse hippocampus were measured following the treatments. For this purpose, male NMRI mice were cannulated bilaterally in the VH with a stereotaxic apparatus. Anxiety properties and protein changes were measured using elevated plus-maze (EPM) and western blotting respectively. The results revealed that intraperitoneal (i.p.) administration of ketamine (5–20 mg/kg) significantly decreased the percentage of open arm time (%OAT) and open arm entry (%OAE) in the EPM with no alteration in the locomotor activity suggesting an anxiogenic-like behavior to ketamine. Furthermore, ketamine administration (10 mg/kg, i.p.) increased BDNF and c-Fos levels in the hippocampus. Interestingly, activation of the VH CB1 receptors by ACPA (0.5–4 ng/mouse) inhibited the anxiogenic-like behaviors produced by ketamine, whereas the microinjection of the same doses of ACPA into VH by itself had no effect on the EPM parameters. Hippocampal levels of BDNF and c-Fos decreased after treatment with combined ketamine with ACPA. These results suggest the therapeutic potency of cannabinoid receptor agonists for ketamine-induced anxiogenic-related responses. This effect might be at least partially mediated by the alteration of BDNF and c-Fos signaling in the hippocampus.

Agomelatine attenuates cisplatin-induced cognitive impairment via modulation of BDNF/TrkB signaling in rat hippocampus

Cisplatin is a drug used effectively in the treatment of malignant tumors. However, cisplatin has many side effects, including cognitive impairment. Agomelatine, a synthetic melatonin analogue, is an important antidepressant. Increasing evidence has shown that agomelatine may be a potential neuroprotective agent. The aim of this study was to investigate the effect of agomelatine on learning and memory functions in cisplatin-induced cognitive impairment in a rat model. Male rats were administered agomelatine and cisplatin for 4 weeks. Neurobehavioral tests were performed at the end of the 4th week. After behavioral tests, rats were euthanized and BDNF, TNF, IL-1β, MDA and GSH levels were measured in hippocampal homegenates by ELISA. In addition, nNOS and TrkB receptor activity were measured immunohistochemically. The results showed that agomelatine significantly improved cognitive functions in spatial memory tests in rats with cisplatin-induced cognitive impairment. In addition, agomelatine treatment positively affected the discrimination index (DI). On the other hand, agomelatine treatment elevated cisplatin-suppressed hippocampal BDNF levels. Agomelatine treatment reduced cisplatin-induced neuroinflammation by suppressing TNF and IL-1β levels. Similarly, agomelatine reduced oxidative stress in the hippocampus. Histological findings showed that agomelatine treatment reduced pyramidal neuron damage in hippocampal DG, CA1 and CA3. Cisplatin increased nNOS and TrkB positivity in DG, CA1 and CA3 neurons compared to control. In contrast, agomelatine treatment decreased both nNOS and TrkB positive scores. These findings indicate that agomelatine reduces cisplatin-related cognitive impairment by exerting anti-inflammatory action and possibly by the modulation of the BDNF/TrkB/nNOS pathways in the hippocampus.

Low-dose curcumin enhances hippocampal neurogenesis and memory retention in young mice.

Adult neurogenesis generates new functional neurons from adult neural stem cells in various regions, including the subventricular zone (SVZ) of the lateral ventricles and subgranular zone (SGZ) of hippocampal dentate gyrus (DG). Available evidence shows hippocampal neurogenesis can be negatively or positively regulated by dietary components. In a previous study, we reported that curcumin (diferuloylmethane; a polyphenolic found in curry spice) stimulates the proliferation of embryonic neural stem cells (NSCs) by activating adaptive cellular stress responses. Here, we investigated whether subchronic administration of curcumin (once daily at 0.4, 2, or 10mg/kg for 14 days) promotes hippocampal neurogenesis and neurocognitive function in young (5-week-old) mice. Oral administration of low-dose curcumin (0.4mg/kg) increased the proliferation and survival of newly generated cells in hippocampus, but surprisingly, high-dose curcumin (10mg/kg) did not effectively upregulate the proliferation or survival of newborn cells. Furthermore, hippocampal BDNF levels and phosphorylated CREB activity were elevated in only low-dose curcumin-treated mice. Passive avoidance testing revealed that low-dose curcumin increased cross-over latency times, indicating enhanced memory retention, and an in vitro study showed that low-concentration curcumin increased the proliferative activity of neural progenitor cells (NPCs) by upregulating NF1X levels. Collectively, our findings suggest that low-dose curcumin has neurogenic effects and that it may prevent age and neurodegenerative disease-related cognitive deficits.

Aging Promotes Chronic Stress-Induced Depressive-Like Behavior by Activating NLRP1 Inflammasome-Driven Inflammatory Signaling in Mice.

NLRP1 inflammasome has been reported to participate in many neurological disorders. Our previous study has demonstrated that NLRP1 inflammasome is implicated in chronic stress-induced depressive-like behaviors in mice. Age has been reported to be related to depression. Here we examine whether NLRP1 inflammasome is involved in the effect of age on depressive disorder. Two chronic stress stimuli, chronic social defeat stress (CSDS) and repeat social defeat stress (RSDS), were used to establish a depression model in mice of different ages. We found that aged mice exhibited worse depressive-like behaviors and locomotor activity compared to young mice. Interestingly, the expression of hippocampal NLRP1 inflammasome complexes and the levels of the inflammatory cytokines were increased in an age-dependent manner. Also, chronic stress-induced increase in the expression of the hippocampal chemokine C-X-C motif ligand 1 (CXCL1), and its cognate receptor, CXC-motif receptor 2 (CXCR2), was more remarkable in aged mice than that in young mice. Moreover, aged mice exhibited lower hippocampal BDNF levels compared to young mice. Hippocampal Nlrp1a knockdown reduced the levels of pro-inflammatory cytokines and the expression of CXCL1/CXCR2, restored BDNF levels, and alleviated chronic stress-induced depressive-like behaviors in aged mice. Our results suggest that NLRP1 inflammasome-CXCL1/CXCR2-BDNF signaling contributes to the effect of age on chronic stress-induced depressive-like behavior in mice.

Resistance training and Urtica dioica increase neurotrophin levels and improve cognitive function by increasing age in the hippocampus of rats

IntroductionInflammation and oxidative stress are two major factors in accelerating brain aging. Consumption of some traditional herbs with antioxidant and anti-inflammatory properties such as Urtica dioica extract (Ud) and resistance training (RT) may be effective in controlling premature aging and memory impairment. Therefore, we hypothesized that the combined effect of RT and Ud might play an essential role in preventing memory disorders and hippocampal tissue changes caused by increasing age in rats. Methods28 male Wistar rats (24-week) were divided into 4-groups (n = 7): control (C), Ud, RT, and Ud+RT. RT groups were trained for five weeks, and Ud extract in the 0.0166 w/v concentration (50 mg/kg, oral/daily) was administered. We also examined the effects of RT and Ud on the behavioral (memory and learning), histological (the morphological changes in the dentate gyrus), and transcript aspects of hippocampal tissue. ResultsAging led to karyopyknosis in the hippocampal tissue, which was alleviated by RT and Ud supplementation. RT and Ud were accompanied by increased GPx, GSH, GAP-43, and decreased CAP-1 levels in the hippocampus. Moreover, RT and Ud led to increased NGF, BDNF, and GAP-43 levels, decreased MDA, and protection of hippocampal tissue from karyopyknosis, which was associated with cognitive improvement. However, these interventions had no significant effect on the hippocampal levels of IL-1β, SOD, and CAT. ConclusionsThese findings suggest that increasing age decreases hippocampal NGF, BDNF, and GAP-43 levels and impairs cognition, which may be reversed by regular RT and Ud extract.

Swimming Suppresses Cognitive Decline of HFD-Induced Obese Mice through Reversing Hippocampal Inflammation, Insulin Resistance, and BDNF Level.

Obesity is an important public health problem nowadays. Long-term obesity can trigger a series of chronic diseases and impair the learning and memory function of the brain. Current studies show that scientific exercise can effectively improve learning and memory capacity, which also can provide benefits for obese people. However, the underlying mechanisms for the improvement of cognitive capacity under the status of obesity still need to be further explored. In the present study, the obesity-induced cognition-declined model was established using 4-week-old mice continuously fed with a high-fat diet (HFD) for 12 weeks, and then the model mice were subjected to an 8-week swimming intervention and corresponding evaluation of relevant indicators, including cognitive capacity, inflammation, insulin signal pathway, brain-derived neurotrophic factor (BNDF), and apoptosis, for exploring potential regulatory mechanisms. Compared with the mice fed with regular diets, the obese mice revealed the impairment of cognitive capacity; in contrast, swimming intervention ameliorated the decline in cognitive capacity of obese mice by reducing inflammatory factors, inhibiting the JNK/IRS-1/PI3K/Akt signal pathway, and activating the PGC-1α/BDNF signal pathway, thereby suppressing the apoptosis of neurons. Therefore, swimming may be an important interventional strategy to compensate for obesity-induced cognitive impairment.

Post-Weaning Treatment with Probiotic Inhibited Stress-Induced Amnesia in Adulthood Rats: The Mediation of GABAergic System and BDNF/c-Fos Signaling Pathways.

The current study aimed to examine the effect of post-weaning treatment with probiotics on memory formation under stress during the adult period in male Wistar rats. Considering GABA is a potential mediator between probiotics and the host, the present study also investigated the involvement of the GABAergic system in the probiotic response. The hippocampal and prefrontal cortical (PFC) expression levels of BDNF and c-Fos were also assessed to show whether the treatments affect the memory-related signaling pathway. Three weeks after birth, the post-weaning rats were fed with probiotic water (PW) or tap water (TW) for 2, 3, 4, or 5weeks. Exposure to acute stress impaired memory formation in a passive avoidance learning task. Feeding the post-weaning animals with probiotic strains (3, 4, or 5weeks) inhibited stress-induced amnesia of the adult period. Post-training intracerebroventricular (ICV) microinjection of muscimol improved stress-induced amnesia in the animals fed with TW. ICV microinjection of muscimol inhibited probiotic treatment's significant effect on the stress response in the memory task. The expression levels of BDNF and c-Fos in the PFC and the hippocampus were significantly decreased in the stress animal group. The levels of BDNF and c-Fos were increased in the PW/stress animal group. The muscimol response was compounded with the decreased levels of BDNF and c-Fos in the PFC and the hippocampus. Thus, the GABA-A receptor mechanism may mediate the inhibitory effect of this probiotic mixture on stress-induced amnesia, which may be associated with the PFC and hippocampal BDNF/c-Fos signaling changes.

Prior short-term exercise prevents behavioral and biochemical abnormalities induced by single prolonged stress in a rat model of posttraumatic stress disorder

Posttraumatic stress disorder (PTSD) is an anxiety disorder that occurs following exposure to somatic or psychotic trauma. Physical activity is known to improve symptoms of certain neuropsychiatric disorders. However, the role of exercise on acquired PTSD-like phenotype was not examined. The present study investigated the effects of prior moderate treadmill exercise on anxiety-like behaviors, serum corticosterone and BDNF levels, hippocampal BDNF and mRNA expression of apoptotic - related proteins in the single prolonged stress (SPS) as an animal model of PTSD in rats. Male and female rats underwent a regular treadmill exercise regimen (4 weeks, 5 days per week). Following the exercise, rats were exposed to SPS (restraint for 2 h, forced swimming for 20 min and ether anesthesia), and then they were kept undisturbed for 14 days. After testing anxiety-like behaviours in the elevated plus maze, the levels of corticosterone and BDNF in serum and BDNF and apoptosis markers (Bax, Bcl-2, and Caspase) in hippocampus were measured. Sedentary male and female SPS rats significantly (Ps ranging <0.05 to <0.0001) exhibited increased anxiety levels in the elevated plus maze, enhanced serum corticosterone, reduced serum and hippocampal BDNF and enhanced hippocampal apoptosis than the corresponding control group. Prior exercise significantly (Ps ranging <0.05 to <0.001) alleviated all SPS-induced behavioral and biochemical alterations as compared with the sedentary SPS rats. There were no significant differences in serum and hippocampal BDNF and serum corticosterone levels and hippocampal apoptotic markers between male and female rats in all of groups. Our findings strongly support that short term prior exercise training can prevent the harmful effects of traumatic events, and the resulting trauma-related disorders in both sexes.

Interesterified fat maternal consumption before conception programms memory and learning of adulthood offspring: How big is this deleterious repercussion?

In recent years, interesterified fat (IF) has largely replaced trans fat in industrialized food. Studies of our research group showed that IF consumption may not be safe for central nervous system (CNS) functions. Our current aim was to evaluate IF maternal consumption before conception on cognitive performance of adult rat offspring. Female Wistar rats were fed with standard chow plus 20% soybean and fish oil mix (control group) or plus 20% IF from weaning until adulthood (before mating), when the diets were replaced by standard chow only. Following the gestation and pups’ development, locomotion and memory performance followed by neurotrophin immunocontent and fatty acids (FA) profile in the hippocampus of the adulthood male offspring were quantified. Maternal IF consumption before conception decreased hippocampal palmitoleic acid incorporation, proBDNF and BDNF levels, decreasing both exploratory activity and memory performance in adult offspring. Considering that, the adult male offspring did not consume IF directly, further studies are needed to understand the molecular mechanisms and if the IF maternal preconception consumption could induce the epigenetic changes observed here. Our outcomes reinforce an immediate necessity to monitor and / or question the replacement of trans fat by IF with further studies involving CNS functions.