Phosphorylation In Hippocampus Research Articles

Juglanin ameliorates depression-like behavior in chronic unpredictable mild stress-induced mice by improving AMPK signaling

• Juglanin improves anxiety/depression-like behaviors in CUMS-treated mice. • Juglanin restrains depression-related hormones in CUMS-challenged mice. • Juglanin improves neuronal survival in hippocampus of CUMS-treated mice. • Juglanin suppresses glial activation and hippocampal neuroinflammation in hippocampus of CUMS-treated mice. • Juglanin rescues AMPK activation in hippocampus of CUMS-treated mice. • AMPK activation is required for Juglanin to meliorate neuronal death. Depression is a widespread mental disorder with extremely complex pathogenesis, and its effective treatment still requires to be solved. Juglanin (Jug) is a natural compound with anti-inflammatory, antioxidant and anti-tumor effects, but whether it shows neuroprotective effects for depression treatment is largely unknown. In the present study, the chronic unpredictable mild stress (CUMS) mouse model and lipopolysaccharide (LPS)-stimulated cells were constructed to explore the regulatory potential of Jug on depression in vivo and in vitro , respectively. Numerous behavioral tests at first revealed that Jug supplementation significantly ameliorated anxiety/depression-like behavior and cognitive impairment in CUMS mice. CUMS-induced abnormal releases of stress-related markers in serum or hippocampus were strongly reversed in mice co-treated with Jug. Furthermore, neuronal death in hippocampus triggered by CUMS was highly abolished by Jug administration through increasing protein kinase B (AKT) activation and Caspase-3 blockage. We also found that glial activation due to CUMS was evidently ameliorated by Jug, as evidenced by the decreased CD11b and glial fibrillary acidic protein (GFAP) expression. Consistently, hippocampal neuroinflammation caused by CUMS was also considerably mitigated upon Jug consumption by prohibiting nuclear factor-kappa B (NF-κB) signaling. These neuroprotective and anti-inflammatory effects of Jug were confirmed in LPS-stimulated mouse hippocampal neurons and microglial cells via the same mechanisms. Importantly, we found that Jug treatment remarkably rescued AMP-activated protein kinase (AMPK) phosphorylation in hippocampus of CUMS mice, which was also observed in neurons and microglial cells under inflammatory conditions. Surprisingly, our in vitro experiments showed that AMPK deletion almost diminished the function of Jug to improve neuron survival and restrain neuroinflammation in LPS-exposed neurons and microglial cells, respectively, which were accompanied by AKT blockage and NF-κB activation recovery. These data suggested that the neuroprotective and anti-inflammatory capacity of Jug was AMPK-dependent. Collectively, we provided evidence that Jug might be a novel therapeutic strategy for depression treatment by improving AMPK activation.

Astragalin alleviates cognitive deficits and neuronal damage in SAMP8 mice through upregulating estrogen receptor expression.

Senile plaques composed of β-amyloid protein (Aβ) and neurofibrillary tangles (NFTs) composed of intracellular hyper-phosphorylated tau are major causes of cognitive impairment and neuronal damage in Alzheimer disease (AD). Astragalin (AST), a naturally-occurring flavonoid compound, was reported to have neuroprotective effects in the brain, but its effects in AD remain unknown. Herein, the learning and memory deficits were alleviated and neuronal damage in the hippocampus were inhibited after the senescence-accelerated mouse prone 8 (SAMP8) mouse were given AST (5mg/kg or 10mg/kg) daily by gavage for 2 months. Furthermore, AST reduced Aβ1-40 and Aβ1-42 deposition, decreased β-carboxyl-terminal fragment (β-CTF) protein level and tau hyper-phosphorylation, but increased α-CTF protein level and glycogen synthase kinase-3beta (GSK-3β) phosphorylation in hippocampus of SAMP8 mice. Meanwhile, the effects of AST on AD were also explored in vitro by treating primary neurons with amyloid-β1-42 oligomers (Aβ1-42O). Consistently, AST also alleviated amyloid-β1-42 oligomers (Aβ1-42O)-induced neuronal damage, amyloid plaques, and tau phosphorylation in vitro model. Of note, estrogen receptor (ER)α and ERβ expression in the hippocampus of SAMP8 mice and Aβ1-42O-treated neurons was significantly decreased but their levels were increased by AST. Moreover, in vivo and in vitro experiments revealed that ER antagonist, Fulvestrant, reversed the effects caused by AST. Altogether, our investigation indicates that AST may ameliorate cognitive deficits and AD-type pathologies in SAMP8 mice and Aβ1-42O-treated neurons through upregulating ERα and ERβ expression. Our findings indicate the value of AST as a potential reagent for AD treatment.

Antidepressant-like effect of male mating behavior through oxytocin-induced CREB signaling

Male sexual activity reduces the level of depression through oxytocin (OT) release within the brain. In this study, we showed that male mating behavior reduces depression-like behavior through OT-induced cAMP response element binding protein (CREB) signaling in the hippocampus. Moreover, we showed that mating behavior in wild-type (WT) male mice increased CREB phosphorylation in hippocampus, whereas that OT receptor knockout (OTR KO) male mice had no effect on CREB phosphorylation. CREB phosphorylation in hippocampus was also increased after OT induction in hippocampal slices prepared from WT mice. In addition, male mating behavior induced the expression of brain-derived neurotrophic factor (BDNF), which was not observed in OTR KO mice. Antidepressant-like effect of mating behavior had no effect in OTR KO mice. These findings suggest that male sexual activity has antidepressant effects through OT-induced CREB signaling in the hippocampus.

Combined exposure of lead and high-fat diet enhanced cognitive decline via interacting with CREB-BDNF signaling in male rats

The health risks to populations induced by lead (Pb) and high-fat diets (HFD) have become a global public health problem. Pb and HFD often co-exist and are co-occurring risk factors for cognitive impairment. This study investigates effect of combined Pb and HFD on cognitive function, and explores the underlying mechanisms in terms of regulatory components of synaptic plasticity and insulin signaling pathway. We showed that the co-exposure of Pb and HFD further increased blood Pb levels, caused body weight loss and dyslipidemia. The results from Morris water maze (MWM) test and Nissl staining disclosed that Pb and HFD each contributed to cognitive deficits and neuronal damage and combined exposure enhanced this toxic injury. Pb and HFD decreased the levels of synapsin-1, GAP-43 and PSD-95 protein related to synaptic properties and SIRT1, NMDARs, phosphorylated CREB and BDNF related to synaptic plasticity regulatory, and these decreases was greater when combined exposure. Additionally, we revealed that Pb and HFD promoted IRS-1 phosphorylation and subsequently reduced downstream PI3K-Akt kinases phosphorylation in hippocampus and cortex of rats, and this process was aggravated when co-exposure. Collectively, our data suggested that combined exposure of Pb and HFD enhanced cognitive deficits, pointing to additive effects in rats than the individual stress effects related to multiple signaling pathways with CREB-BDNF signaling as the hub. This study emphasizes the need to evaluate the effects of mixed exposures on brain function in realistic environment and to better inform prevention of neurological disorders via modulating central pathway, such as CREB/BDNF signaling.

Melatonin alleviates hippocampal GR inhibition and depression-like behavior induced by constant light exposure in mice

Light pollution has become a potential health risk factor worldwide. Chronic exposure to constant light (CCL) leads to depressive-like behavior, yet the mechanism remains unclear. In this study, mice exposed to CCL for 3 weeks exhibited depression-like behaviors, with decreased melatonin in plasma and increased oxidative stress in hippocampus. Meanwhile, CCL-exposed mice showed elevated plasma corticosterone (CORT) levels and diminished glucocorticoid receptor (GR) phosphorylation in hippocampus. Concurrently, glycogen synthase kinase 3 beta (GSK3β) was inactivated with increased phosphorylation at Ser9. The interrelationship of GSK3β and GR was clarified in mouse hippocampal neuron (HT-22) cells. GSK3β inhibitor CHIR-99021 induced GR inhibition with diminished phosphorylation, while GR inhibitor RU486 did not affect GSK3β expression or phosphorylation. Furthermore, GSK3β-mediated GR inhibition was reproduced in vitro in HT-22 cells treated with melatonin receptor antagonist luzindole and H2O2 in combination. Finally, melatonin reversed GSK3β-mediated GR inhibition in hippocampus and improved CCL-induced depression-like behavior in mice. These results indicate that CCL induces melatonin deficiency and oxidative stress in hippocampus, which in turn leads to GSK3β-mediated GR inhibition and depression-like behavior in mice.

Melatonin ameliorated CUMS-induced depression-like behavior via restoring endoplasmic reticulum stress in rat hippocampus.

Melatonin is a hormone synthesized and secreted by the pineal gland with the effect of regulating sleep rhythm. Circadian and sleep disturbances may be central for understanding the pathophysiology and treatment of depression. Recently, the melatonergic system has been implicated in the pathophysiology and treatment of depression. In this study, we observed the effects of melatonin on depression-like behavior induced by chronic unpredictable mild stress (CUMS) in rats, and its molecular mechanism was explored. Adult male Sprague-Dawley rats were exposed to CUMS for 4 weeks. Melatonin or saline was injected intraperitoneally. Behavioral changes of Sprague-Dawley rats were detected by the open field test, sugar preference test, elevated O maze test and forced swimming test. In addition, the plasma corticosterone level and the expression of endoplasmic reticulum stress-related protein in the hippocampus of rats were measured. Compared with the control group, the CUMS-exposed Sprague-Dawley rats showed depression-like behavior, which was significantly improved by melatonin treatment. Moreover, CUMS induced endoplasmic reticulum stress and JNK phosphorylation in the hippocampus. Melatonin treatment could significantly reverse the endoplasmic reticulum stress and JNK phosphorylation induced by CUMS. These results suggest that melatonin improves depression-like behavior by inhibiting endoplasmic reticulum stress induced by CUMS. This study demonstrates that melatonin can improve depression-like behavior induced by CUMS, which may be related to the inhibition of endoplasmic reticulum stress and JNK phosphorylation in rat hippocampus.

Curcumin ameliorates scopolamine-induced mice memory retrieval deficit and restores hippocampal p-Akt and p-GSK-3β

The loss of cholinergic neurons has been a major issue in researches on Alzheimer's disease (AD) for about 40 years. Therefore, the scopolamine model of amnesia has been widely used in AD researches. Recently, it was reported that the early stage amnesia of AD is related to memory retrieval deficit. Curcumin, as the main ingredient of turmeric, has been suggested to decrease the prevalence of AD in human population. This study was conducted to assess if curcumin prevents retrieval deficit induced by scopolamine in passive avoidance task. Moreover, according to the proposed link between cholinergic system and Akt/GSK-3β (Glycogen synthase kinase 3 beta) signaling, the hippocampal contents of these proteins were determined. Male NMRI mice (20–25 g body weight) were treated with 50 or 100 mg/kg/po curcumin or its vehicle for 10 days. On day 10, the animals were trained in passive avoidance apparatus. The retention trial was performed 24 h later. Scopolamine (1 mg/kg/i.p.) or its vehicle was administered 30 min before retention test. At the completion of behavioral studies, the hippocampi were removed and western blot analysis was performed to determine hippocampal phosphorylated and total Akt and GSK-3β and beta actin contents. The results showed that curcumin treatment at 50 and 100 mg/kg doses prevented scopolamine-induced memory retrieval deficit and restored Akt and GSK dephosphorylation caused by scopolamine. Overall, these findings showed that pre-test scopolamine administration disrupts memory retrieval along with the diminished Akt and GSK-3β phosphorylation in hippocampus while curcumin administration prevented those changes.

Puerarin Up-regulates Methyl-CpG Binding Protein 2 Phosphorylation in Hippocampus of Vascular Dementia Rats.

To observe the effect of puerarin on methyl-CpG binding protein 2 (MeCP2) phosphorylation (pMeCP2) in the hippocampus of a rat model of vascular dementia (VD). Thirty-six healthy Sprague-Dawley rats were randomly assigned to the sham-operated group, dementia group and puerarintreated group using a random number table (n=12 per group). The modifified permanent bilateral common carotid artery occlusion method was used to establish the VD model. The sham-operated and dementia groups were given 2 mL/d of saline, while the puerarin-treated group was given 100 mg/(kg•d) of puerarin for 17 days. The learning and memory abilities were evaluated by the Morris water maze test. Hematoxylin-eosin staining, immunohistochemical (IHC) staining and Western blot analysis were carried out to observe changes in neuron morphology and in level of pMeCP2 in the hippocampus, respectively. The morphologies of rat hippocampal neurons in the puerarintreated group were markedly improved compared with the dementia group. The escape latency of the dementia group was significantly longer than the sham-operated group (P<0.05), while the puerarin-treated group was obviously shorter than the dementia group (P<0.05). Cross-platform times of the dementia group were signifificantly decreased compared with the sham-operated group (P<0.05), while the puerarin-treated group was obviously increased compared with the dementia group (P<0.05). IHC staining showed no significant difference in the number of MeCP2 positive cells among 3 groups (P>0.05). The number of pMeCP2 positive cells in the CA1 region of hippocampus in the dementia group was signifificantly increased compared with the sham-operated group, and the puerarin-treated group was signifificantly increased compared with the dementia group (both P<0.05). Western blot analysis showed no signifificant difference of MeCP2 expression among 3 groups (P>0.05). The expression of pMeCP2 in the dementia group was signifificantly increased compared with the sham-operated group, while it in the puerarin-treated group was signifificantly increased compared with the dementia group (P<0.05). Puerarin could play a role in the protection of nerve cells through up-regulating pMeCP2 in the hippocampus, improving neuron morphologies, and enhancing learning and memory ablities in a rat model of VD.

Resveratrol ameliorates spatial learning memory impairment induced by Aβ1–42 in rats

β-amyloid (Aβ) deposition is considered partially responsible for cognitive dysfunction in Alzheimer’s disease (AD). Recently, resveratrol has been reported to play a potential role as a neuroprotective biofactor by modulating Aβ pathomechanisms, including through anti-neuronal apoptotic, anti-oxidative stress, and anti-neuroinflammatory effects. In addition, SIRT1 has been demonstrated to modulate learning and memory function by regulating the expression of cAMP response binding protein (CREB), which involves in modulating the expression of SIRT1. However, whether resveratrol can alleviate Aβ-induced cognitive dysfunction, whether SIRT1 expression and CREB phosphorylation in the hippocampus are affected by Aβ, and whether resveratrol influences these effects remain unknown. In the present study, we used a hippocampal injection model in rats to investigate the effects of resveratrol on Aβ1–42-induced impairment of spatial learning, memory and synaptic plasticity as well as on alterations of SIRT1 expression and CREB phosphorylation. We found that resveratrol significantly reversed the water maze behavioral impairment and the attenuation of long-term potentiation (LTP) in area CA1 that were induced by hippocampal injection of Aβ1–42. Interestingly, resveratrol also prevented the Aβ1–42-induced reductions in SIRT1 expression and CREB phosphorylation in rat hippocampus. In conclusion, in rats, resveratrol protects neurons against Aβ1–42-induced disruption of spatial learning, memory and hippocampal LTP. The mechanisms underlying the neuroprotective effects may involve rescue of SIRT1 expression and CREB phosphorylation.

Olfactory deprivation hastens Alzheimer-like pathologies in a human tau overexpressed mouse model via activation of cdk5

Olfactory dysfunction is a recognized risk factor for the pathogenesis of Alzheimer’s disease (AD), while the mechanisms are still not clear. Here, we applied bilateral olfactory bulbectomy (OBX), an olfactory deprivation surgery to cause permanent anosmia, in human tau-overexpressed mice (htau mice) to investigate changes of AD-like pathologies including aggregation of abnormally phosphorylated tau and cholinergic neuron loss. We found that tau phosphorylation in hippocampus was increased at Thr-205, Ser-214, Thr-231, and Ser-396 after OBX. OBX also increased the level of sarkosyl-insoluble Tau at those epitopes and accelerated accumulation of somatodendritic tau. Moreover, OBX resulted in the elevation of calpain activity accompanied by an increased expression of the cyclin-dependent kinase 5 (cdk5) neuronal activators, p35 and p25, in hippocampus. Furthermore, OBX induces the loss of the cholinergic neurons in medial septal. Administration of cdk5 pharmacological inhibitor roscovitine into lateral ventricles suppressed tau hyperphosphorylation and mislocalization and restored the cholinergic neuron loss. These findings suggest that olfactory deprivation by OBX hastens tau pathology and cholinergic system impairment in htau mice possibly via activation of cdk5.

Sex differences in fear extinction and involvements of extracellular signal-regulated kinase (ERK)

Stress-related disorders, such as post-traumatic stress disorder (PTSD) and panic disorders, are disproportionately prevalent in females. However, the biological mechanism underlying these sex differences in the prevalence rate remains unclear. In the present study, we examined sex differences in fear memory, fear extinction, and spontaneous recovery of fear. We investigated the presence of sex differences in recent and remote fear memory in mice using contextual fear conditioning, as well as sex differences in spontaneous recovery of fear memory using a consecutive fear extinction paradigm. We examined the number of fear extinction days required to prevent spontaneous recovery of fear in either sex. We investigated whether ovariectomy affected fear extinction and spontaneous recovery. We also measured the activation of extracellular signal-regulated kinase (ERK) 1 and 2 in the dorsal hippocampus and the medial prefrontal cortex following fear extinction sessions. In our results, we found no sex difference in recent or remote fear memory. However, females required more fear extinction sessions compared to males to prevent spontaneous recovery. Within-extinction freezing also differed between males and females. Moreover, females required more extinction sessions than males to increase ERK2 phosphorylation in the dorsal hippocampus. Our data suggest that contextual fear extinction was unstable in females compared to males and that such sex differences may be related to the ERK2 phosphorylation in the hippocampus.

Simvastatin prevents β-amyloid25–35-impaired neurogenesis in hippocampal dentate gyrus through α7nAChR-dependent cascading PI3K-Akt and increasing BDNF via reduction of farnesyl pyrophosphate

Simvastatin (SV) is reported to improve cognition and slow progression of Alzheimer's disease (AD), however underlying mechanism still remains unclear. In hippocampal dentate gyrus (DG), β-amyloid (Aβ) selectively impairs survival and neurite growth of newborn neurons in the 2nd week after birth. The aim of this study was to examine the effects of SV on the impairment of neurogenesis and the spatial cognitive deficits in Aβ25–35 (3 nmol)-injected (i.c.v.) mice (Aβ25–35-mice). Herein, we reported that the SV-treatment (20 mg/kg) on days 2–14 after BrdU-injection could dose-dependently protect the survival and neurite growth of newborn neurons, which was blocked by the α7nAChR antagonist MLA or the farnesol (FOH) that can convert to farnesyl pyrophosphate (FPP), but not the α4β2nAChR antagonist DHβE. The SV-treatment in Aβ25–35-mice rescued the decline of Akt phosphorylation and increased the ERK1/2 phosphorylation in hippocampus, which was sensitive to MLA and FOH. The PI3K inhibitor LY294002 could abolish the SV-protected neurogenesis in Aβ25–35-mice, but the MEK inhibitor U0126 had no effects. The SV-treatment could correct the decline of hippocampal BDNF concentration in Aβ25–35-mice, which was blocked by MLA and FOH. Using Morris water maze and Y-maze tasks, we further observed that the SV-treatment in Aβ25–35-mice could improve their spatial cognitive deficits, which was sensitive to the application of FOH. The results indicate that the SV-treatment in Aβ25–35-mice via reduction of FPP can protect neurogenesis through α7nAChR-cascading PI3K-Akt and increasing BDNF, which may improve spatial cognitive function.

Possible Involvement of µ Opioid Receptor in the Antidepressant-Like Effect of Shuyu Formula in Restraint Stress-Induced Depression-Like Rats.

Recently μ opioid receptor (MOR) has been shown to be closely associated with depression. Here we investigated the action of Shuyu, a Chinese herbal prescription, on repeated restraint stress induced depression-like rats, with specific attention to the role of MOR and the related signal cascade. Our results showed that repeated restraint stress caused significant depressive-like behaviors, as evidenced by reduced body weight gain, prolonged duration of immobility in forced swimming test, and decreased number of square-crossings and rearings in open field test. The stress-induced depression-like behaviors were relieved by Shuyu, which was accompanied by decreased expression of MOR in hippocampus. Furthermore, Shuyu upregulated BDNF protein expression, restored the activity of CREB, and stimulated MEK and ERK phosphorylation in hippocampus of stressed rats. More importantly, MOR is involved in the effects of Shuyu on these depression-related signals, as they can be strengthened by MOR antagonist CTAP. Collectively, these data indicated that the antidepressant-like properties of Shuyu are associated with MOR and the corresponding CREB, BDNF, MEK, and ERK signal pathway. Our study supports clinical use of Shuyu as an effective treatment of depression and also suggests that MOR might be a target for treatment of depression and developing novel antidepressants.

Olfactory Deprivation Hastens Alzheimer-Like Pathologies in a Human Tau-Overexpressed Mouse Model via Activation of cdk5.

Olfactory dysfunction is a recognized risk factor for the pathogenesis of Alzheimer's disease (AD), while the mechanisms are still not clear. Here, we applied bilateral olfactory bulbectomy (OBX), an olfactory deprivation surgery to cause permanent anosmia, in human tau-overexpressed mice (htau mice) to investigate changes of AD-like pathologies including aggregation of abnormally phosphorylated tau and cholinergic neuron loss. We found that tau phosphorylation in hippocampus was increased at Thr-205, Ser-214, Thr-231, and Ser-396 after OBX. OBX also increased the level of sarkosyl-insoluble Tau at those epitopes and accelerated accumulation of somatodendritic tau. Moreover, OBX resulted in the elevation of calpain activity accompanied by an increased expression of the cyclin-dependent kinase 5 (cdk5) neuronal activators, p35 and p25, in hippocampus. Furthermore, OBX induces the loss of the cholinergic neurons in medial septal. Administration of cdk5 pharmacological inhibitor roscovitine into lateral ventricles suppressed tau hyperphosphorylation and mislocalization and restored the cholinergic neuron loss. These findings suggest that olfactory deprivation by OBX hastens tau pathology and cholinergic system impairment in htau mice possibly via activation of cdk5.

Sevoflurane induces tau phosphorylation and glycogen synthase kinase 3β activation in young mice.

Children with multiple exposures to anesthesia and surgery may have an increased risk of developing cognitive impairment. Sevoflurane is a commonly used anesthetic in children. Tau phosphorylation contributes to cognitive dysfunction. The authors therefore assessed the effects of sevoflurane on Tau phosphorylation and the underlying mechanisms in young mice. Six-day-old wild-type and Tau knockout mice were exposed to sevoflurane. The authors determined the effects of sevoflurane anesthesia on Tau phosphorylation, levels of the kinases and phosphatase related to Tau phosphorylation, interleukin-6 and postsynaptic density protein-95 in hippocampus, and cognitive function in both young wild-type and Tau knockout mice. Anesthesia with 3% sevoflurane 2 h daily for 3 days induced Tau phosphorylation (257 vs. 100%, P = 0.0025, n = 6) and enhanced activation of glycogen synthase kinase 3β, which is the kinase related to Tau phosphorylation in the hippocampus of postnatal day-8 wild-type mice. The sevoflurane anesthesia decreased hippocampus postsynaptic density protein-95 levels and induced cognitive impairment in the postnatal day-31 mice. Glycogen synthase kinase 3β inhibitor lithium inhibited the sevoflurane-induced glycogen synthase kinase 3β activation, Tau phosphorylation, increased levels of interleukin-6, and cognitive impairment in the wild-type young mice. Finally, the sevoflurane anesthesia did not induce an increase in interleukin-6 levels, reduction in postsynaptic density protein-95 levels in hippocampus, or cognitive impairment in Tau knockout young mice. These data suggested that sevoflurane induced Tau phosphorylation, glycogen synthase kinase 3β activation, increase in interleukin-6 and reduction in postsynaptic density protein-95 levels in hippocampus of young mice, and cognitive impairment in the mice. Future studies will dissect the cascade relation of these effects.

The role of hippocampal tau protein phosphorylation in isoflurane-induced cognitive dysfunction in transgenic APP695 mice.

Previous studies have shown that exposure to inhaled anesthetics can cause cognitive dysfunction, suggesting that general anesthesia might be a risk factor for the development of Alzheimer disease. However, the underlying mechanisms remain to be elucidated. In the present study, we tested our hypothesis that enhanced tau protein phosphorylation in hippocampus contributes to isoflurane-induced cognitive dysfunction in a mouse model of Alzheimer disease. Fifty-four male wild-type (WT) mice (12 months old) and 54 male amyloid precursor protein 695 (APP695) mice (12 months old) were either anesthetized for 4 hours with 1.0 minimum alveolar concentration isoflurane or sham-anesthetized (control). Learning and memory behaviors were measured using the Morris Water Maze test for mice. Phosphorylation of hippocampal tau protein at Ser262 site was analyzed with quantitative Western blotting. In the Morris Water Maze test, both WT and transgenic APP695 mice showed decreased latency times during a 4-day training period. Isoflurane exposure significantly increased the latency times on days 2 and 3 in WT mice as well as on days 3 and 4 in APP695 mice (WT: P = 0.005 for day 2 and P = 0.002 for day 3; APP695: P = 0.001 for day 3 and P < 0.0001 for day 4) and reduced platform quadrant times (WT: P < 0.0001; APP695: P < 0.0001) in both types of mice. Compared with WT mice, transgenic APP695 mice displayed worse learning and memory behaviors after isoflurane exposure (P = 0.0005 for escape latency testing on day 4 training; P = 0.009 for platform probe testing). Western blot analysis showed that the levels of phosphorylation of hippocampal tau protein at Ser262 site (tau[pS262]) in the transgenic APP695 mice were higher than those in WT mice (P < 0.0001) and that isoflurane exposure time dependently enhanced the hippocampal tau[pS262] levels in both types of mice, but this effect was much more significant in the transgenic APP695 mice (P < 0.0001). Our data also showed that isoflurane exposure had no effect on the expression of total tau protein in the hippocampi of all mice (P ≥ 0.54). Isoflurane may induce cognitive dysfunction by enhancing phosphorylation of hippocampal tau protein at Ser262 site, and this effect is more significant in transgenic APP695 mice.

Pro-neurogenesis and anti-dementia properties of tetradecyl 2,3-dihydroxybenzoate through TrkA receptor-mediated signalling pathways.

Tetradecyl 2,3-dihydroxybenzoate, termed ABG001, has been reported to enhance neurite outgrowth of PC12 cells. Herein, we report that oral administration of ABG001 for five days to adult male mice could dose-dependently enhance survival and neurite growth of newborn cells in hippocampal dentate gyrus (DG) without changes in cell proliferation and differentiation of progenitor cells. The ABG001 administration (0.5mg/kg) enhanced the phosphorylation of tyrosine kinase A (TrkA) receptor, which induced increases in the levels of ERK, Akt and mTOR phosphorylation in hippocampus. The pro-neurogenesis of ABG001 was blocked by the TrkA receptor inhibitor K252a. By contrast, the ERK inhibitor U0126 attenuated only the ABG001-increased number of newborn cells, while the PI3K inhibitor LY294002 prevented mainly the ABG001-enhanced neurite growth. In comparison with control mice, the mice treated with ABG001 showed a more preferential spatial cognitive function as assessed by Morris water maze and Y maze tests, which was sensitive to the blockade of TrkA receptor. In addition, a single injection (i.c.v.) of 'aggregated' Aβ 25-35 in adult male mice (Aβ 25-35-mice) impaired spatial memory, survival and neurite growth of newborn cells in the DG with reduced phosphorylation of Akt and mTOR. The treatment of Aβ 25-35-mice with ABG001 could protect the survival and neurite growth of newborn cells through increasing TrkA receptor-induced phosphorylation of Akt and mTOR, which was accompanied by the improvement of spatial cognitive performance.

Modafinil improves methamphetamine-induced object recognition deficits and restores prefrontal cortex ERK signaling in mice

Chronic use of methamphetamine (METH) leads to long-lasting cognitive dysfunction in humans and in animal models. Modafinil is a wake-promoting compound approved for the treatment of sleeping disorders. It is also prescribed off label to treat METH dependence. In the present study, we investigated whether modafinil could improve cognitive deficits induced by sub-chronic METH treatment in mice by measuring visual retention in a Novel Object Recognition (NOR) task. After sub-chronic METH treatment (1 mg/kg, once a day for 7 days), mice performed the NOR task, which consisted of habituation to the object recognition arena (5 min a day, 3 consecutive days), training session (2 equal objects, 10 min, day 4), and a retention session (1 novel object, 5 min, day 5). One hour before the training session, mice were given a single dose of modafinil (30 or 90 mg/kg). METH-treated mice showed impairments in visual memory retention, evidenced by equal preference of familiar and novel objects during the retention session. The lower dose of modafinil (30 mg/kg) had no effect on visual retention scores in METH-treated mice, while the higher dose (90 mg/kg) rescued visual memory retention to control values. We also measured extracellular signal-regulated kinase (ERK) phosphorylation in medial prefrontal cortex (mPFC), hippocampus, and nucleus accumbens (NAc) of METH- and vehicle-treated mice that received modafinil 1 h before exposure to novel objects in the training session, compared to mice placed in the arena without objects. Elevated ERK phosphorylation was found in the mPFC of vehicle-treated mice, but not in METH-treated mice, exposed to objects. The lower dose of modafinil had no effect on ERK phosphorylation in METH-treated mice, while 90 mg/kg modafinil treatment restored the ERK phosphorylation induced by novelty in METH-treated mice to values comparable to controls. We found neither a novelty nor treatment effect on ERK phosphorylation in hippocampus or NAc of vehicle- and METH-treated mice receiving acute 90 mg/kg modafinil treatment. Our results showed a palliative role of modafinil against METH-induced visual cognitive impairments, possibly by normalizing ERK signaling pathways in mPFC. Modafinil may be a valuable pharmacological tool for the treatment of cognitive deficits observed in human METH abusers as well as in other neuropsychiatric conditions.This article is part of the Special Issue entitled ‘CNS Stimulants’.

Effect of Chronic Noise Exposure on Expression of N-Methyl-D-Aspartic Acid Receptor 2B and Tau Phosphorylation in Hippocampus of Rats

ObjectiveTo study the effect of chronic noise exposure on expression of N-methyl-D-aspartic acid receptor 2B (NR2B) and tau phosphorylation in hippocampus of rats. MethodsTwenty-four male SD rats were divided in control group and chronic noise exposure group. NR2B expression and tau phosphorylation in hippocampus of rats were detected after chronic noise exposure (100 dB SPL white noise, 4 h/d×30d) and their mechanisms underlying neuronal apoptosis in hippocampus of rats with TUNEL staining. ResultsThe NR2B expression decreased significantly after chronic noise exposure which resulted in tau hyperphosphorylation and neural apoptosis in hippocampus of rats. Immunohistochemistry showed that the tau hyperphosphorylation was most prominent in dentate gyrus (DG) and CA1 region of rat hippocampus. ConclusionThe abnormality of neurotransmitter system, especially Glu and NR2B containing NMDA receptor, and tau hyperphosphorylation in hippocampus of rats, may play a role in chronic noise-induced neural apoptosis and cognition impairment.

Differential nuclear factor-kappa B phosphorylation induced by lipopolysaccharide in the hippocampus of P2X7 receptor knockout mouse

Objective: Lipopolysaccharide (LPS) stimulates the innate immune response in the brain through nuclear factor-kappaB (NF-kappaB) signaling. Since purinergic signals activate NF-kappaB through the P2X7 receptor (P2X7R), we investigated the roles of P2X7R in neuronal NF-kappaB phosphorylation in the mouse hippocampus under basal conditions and P2X7R deletion following LPS treatment in vivo.Methods: We performed immunohistochemical studies for neuronal NF-kappaB phosphorylation in the hippocampi of wild type (WT) and P2X7R knockout (KO) mice under basal conditions and LPS treatment.Results: LPS treatment did not induce neuronal damages in both WT and P2X7−/− KO mice. In WT animals, LPS treatment increased p65-Ser276 and p65-Ser311 NF-kappaB phosphorylations in hippocampal neurons. However, p52-Ser865, p52-Ser869, p65-Ser468, p65-Ser529, and p65-Ser536 NF-kappaB phosphorylations were unaffected by LPS treatment. In P2X7−/− KO mice, neuronal p65-Ser311 NF-kappaB phosphorylation in vehicle-treated animals was higher than that in WT animals. In addition, both p65-Ser276 and p65-Ser311 NF-kappaB phosphorylations were unaffected by LPS treatment in P2X7−/− KO mice.Discussion: These findings indicate that P2X7R may be involved in LPS-induced inflammatory response in neurons, and that p65-Ser311 NF-kappaB phosphorylation may compensate for the loss function of P2X7R by as yet unknown factors.