Differential disruptions in population coding along the dorsal-ventral axis of CA1 in the APP/PS1 mouse model of Aß pathology.

Alzheimer's Disease (AD) is characterized by a range of behavioral alterations, including memory loss and psychiatric symptoms. While there is evidence that molecular pathologies, such as amyloid beta (Aß), contribute to AD, it remains unclear how this histopathology gives rise to such disparate behavioral deficits. One hypothesis is that Aß exerts differential effects on neuronal circuits across brain regions, depending on the neurophysiology and connectivity of different areas. To test this, we recorded from large neuronal populations in dorsal CA1 (dCA1) and ventral CA1 (vCA1), two hippocampal areas known to be structurally and functionally diverse, in the APP/PS1 mouse model of amyloidosis. Despite similar levels of Aß pathology, dCA1 and vCA1 showed distinct disruptions in neuronal population activity as animals navigated a virtual reality environment. In dCA1, pairwise correlations and entropy, a measure of the diversity of activity patterns, were decreased in APP/PS1 mice relative to age-matched C57BL/6 controls. However, in vCA1, APP/PS1 mice had increased pair-wise correlations and entropy as compared to age matched controls. Finally, using maximum entropy models, we connected the microscopic features of population activity (correlations) to the macroscopic features of the population code (entropy). We found that the models' performance increased in predicting dCA1 activity, but decreased in predicting vCA1 activity, in APP/PS1 mice relative to the controls. Taken together, we found that Aß exerts distinct effects across different hippocampal regions, suggesting that the various behavioral deficits of AD may reflect underlying heterogeneities in neuronal circuits and the different disruptions that Aß pathology causes in those circuits.

Preoperative recovery sleep ameliorates postoperative cognitive dysfunction aggravated by sleep fragmentation in aged mice by enhancing EEG delta-wave activity and LFP theta oscillation in hippocampal CA1.

Sleep fragmentation (SF) is a common sleep problem experienced during the perioperative period by older adults, and is associated with postoperative cognitive dysfunction (POCD). Increasing evidence indicates that delta-wave activity during non-rapid eye movement (NREM) sleep is involved in sleep-dependent memory consolidation and that hippocampal theta oscillations are related to spatial exploratory memory. Recovery sleep (RS), a self-regulated state of sleep homeostasis, enhances delta-wave power and memory performance in sleep-deprived older mice. However, it remains unclear whether RS therapy has a positive effect on cognitive changes following SF in older mouse models. Therefore, this study aimed to explore whether preoperative RS can alleviate cognitive deficits in aged mice with SF. A model of preoperative 24-h SF combined with exploratory laparotomy-induced POCD was established in 18-month-old mice. Aged mice were treated with preoperative 6-h RS following SF and postoperative 6-h RS following surgery, respectively. The changes in hippocampus-dependent cognitive function were investigated using behavioral tests, electroencephalography (EEG), local field potential (LFP), magnetic resonance imaging, and neuromorphology. Mice that underwent 24-h SF combined with surgery exhibited severe spatial memory impairment; impaired cognitive performance could be alleviated by preoperative RS treatment. In addition, preoperative RS increased NREM sleep; enhanced EEG delta-wave activity and LFP theta oscillation in the hippocampal CA1; and improved hippocampal perfusion, microstructural integrity, and neuronal damage. Taken together, these results provide evidence that preoperative RS may ameliorate the severity of POCD aggravated by SF by enhancing delta slow-wave activity and hippocampal theta oscillation, and by ameliorating the reduction in regional cerebral blood flow and white matter microstructure integrity in the hippocampus.

Modulating adult neurogenesis affects synaptic plasticity and cognitive functions in mouse models of Alzheimer's disease.

New neurons are abnormal in the adult hippocampus of Alzheimer's disease (AD) mouse models. The effects of modulating adult neurogenesis on AD pathogenesis differ from study to study. We reported recently that ablation of adult neural stem cells (aNSCs) was associated with improved memory in AD models. Here, we found that long-term potentiation (LTP) was improved in the hippocampus of APP/PS1 mice after ablation of aNSCs. This effect was confirmed in hAPP-J20 mice, a second AD mouse model. On the other hand, we found that exposure to enriched environment (EE) dramatically increased the number of DCX+ neurons, promoted dendritic growth, and affected the location of newborn neurons in the dentate gyrus of APP/PS1 mice, and EE exposure significantly ameliorated memory deficits in APP/PS1 mice. Together, our data suggest that both inhibiting abnormal adult neurogenesis and enhancing healthy adult neurogenesis could be beneficial for AD, and they are not mutually exclusive.

Effects and Mechanisms of Synaptotagmin-7 in the Hippocampus on Cognitive Impairment in Aging Mice.

Aging is an irreversible biological process that involves oxidative stress, neuroinflammation, and apoptosis, and eventually leads to cognitive dysfunction. However, the underlying mechanisms are not fully understood. In this study, we investigated the role and potential mechanisms of Synaptotagmin-7, a calcium membrane transporter in cognitive impairment in aging mice. Our results indicated that Synaptotagmin-7 expression significantly decreased in the hippocampus of D-galactose-induced or naturally aging mice when compared with healthy controls, as detected by western blot and quantitative reverse transcriptase-polymerase chain reaction analysis. Synaptotagmin-7 overexpression in the dorsal CA1 of the hippocampus reversed long-term potentiation and improved hippocampus-dependent spatial learning in D-galactose-induced aging mice. Synaptotagmin-7 overexpression also led to fully preserved learning and memory in 6-month-old mice. Mechanistically, we demonstrated that Synaptotagmin-7 improved learning and memory by elevating the level of fEPSP and downregulating the expression of aging-related genes such as p53 and p16. The results of our study provide new insights into the role of Synaptotagmin-7 in improving neuronal function and overcoming memory impairment caused by aging, suggesting that Synaptotagmin-7 overexpression may be an innovative therapeutic strategy for treating cognitive impairment.

Global cerebral ischemia in adolescent male Long Evans rats: Effects of vanillic acid supplementation on stress response, emotionality, and visuospatial memory.

The developmental period is critical in delineating plastic response to internal and external events. However, neurobehavioural effects of global cerebral ischemia (GCI) in the maturing brain remain largely unknown. This study characterised the effects of GCI experienced at puberty on adulthood (1) hippocampus CA1 neuronal damage, (2) cognitive and emotional impairments, and (3) glucocorticoid receptor (GR) expression. Effects of adolescent exposure to the phenol vanillic acid (VA) on post-ischemic outcomes were also determined. Male Long Evans rats (n = 35) were supplemented for 21 consecutive days (postnatal days 33-53) with VA (91 mg/kg) or nut paste vehicle (control) prior to a 10-min GCI or sham surgery. As adults, rats were tested in the Open Field Test (OFT), Elevated-Plus Maze (EPM), and Barnes Maze (BM). GR expression was determined in the basolateral amygdala (BLA), CA1, and paraventricular nucleus (PVN), and brain injury assessed via CA1 neuronal density. Adolescent GCI exposure induced extensive hippocampal CA1 injury, which was not prevented by VA supplementation. Behaviourally, GCI increased EPM exploration while having no impact on spatial memory. VA intake increased OFT peripheral exploration. Notably, while no delayed changes in CA1 and PVN GR immunoreactivity were noted, both treatments separately increased BLA GR expression when compared with sham-nut paste rats. Age at GCI occurrence plays a critical role on post-ischemic impairments. The observation of minimal functional impairments despite important CA1 neuronal damage supports use of compensatory mechanisms. Our findings also show daily VA supplementation during adolescence to have no protective effects on post-ischemic outcomes, contrasting adult intake.

Downregulation of lncRNA GAS5 Alleviates Hippocampal Neuronal Damage in Mice with Depression-Like Behaviors Via Modulation of MicroRNA-26a/EGR1 Axis.

BACKGROUND: Accumulating evidences have demonstrated the roles of several long non-coding RNAs (lncRNAs) in depression. We aim to examine the capabilities of lncRNA growth arrest-specific transcript 5 (GAS5) on mice with depression-like behaviors and the mechanism of action. METHODS: Fifty-six healthy mice were selected for model establishment. Morris water maze test and trapeze test were performed for evaluating learning and memory ability. The binding relationship between lncRNA GAS5 and microRNA-26a (miR-26a) and the target relationship between miR-26a and EGR1 were verified by dual-luciferase reporter gene assay. The apoptosis of neurons in the hippocampal CA1 region of mice was detected by TUNEL staining. The expression of inflammatory factors, lncRNA GAS5, miR-26a, early growth response gene 1 (EGR1), phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) pathway- and apoptosis-related factors in hippocampal tissues was tested by RT-qPCR and western blot analysis. RESULTS: miR-26a expression was down-regulated while EGR1 and lncRNA GAS5 expression were up-regulated in hippocampal tissues of mice with depression-like behaviors. LncRNA GAS5 specifically bound to miR-26a and miR-26a targeted EGR1. Silencing of lncRNA GAS5 curtailed the release of inflammatory factors and the apoptosis of hippocampal neuron of mice with depression-like behaviors. EGR1 suppressed PI3K/AKT pathway activation to promote the release of inflammatory factors and the apoptosis of hippocampal neurons in mice with depression-like behaviors. CONCLUSION: Our study provides evidence that silencing of lncRNA GAS5 could activate PI3K/AKT pathway to protect hippocampal neurons against damage in mice with depression-like behaviors by regulating the miR-26a/EGR1 axis.

Unexpected Role of Physiological Estrogen in Acute Stress-Induced Memory Deficits.

Stress may promote emotional and cognitive disturbances, which differ by sex. Adverse outcomes, including memory disturbances, are typically observed following chronic stress, but are now being recognized also after short events, including mass shootings, assault, or natural disasters, events that consist of concurrent multiple acute stresses (MAS). Prior work has established profound and enduring effects of MAS on memory in males. Here we examined the effects of MAS on female mice and probed the role of hormonal fluctuations during the estrous cycle on MAS-induced memory problems and the underlying brain network and cellular mechanisms. Female mice were impacted by MAS in an estrous cycle-dependent manner: MAS impaired hippocampus-dependent spatial memory in early-proestrous mice, characterized by high levels of estradiol, whereas memory of mice stressed during estrus (low estradiol) was spared. As spatial memory requires an intact dorsal hippocampal CA1, we examined synaptic integrity in mice stressed at different cycle phases and found a congruence of dendritic spine density and spatial memory deficits, with reduced spine density only in mice stressed during high estradiol cycle phases. Assessing MAS-induced activation of brain networks interconnected with hippocampus, we identified differential estrous cycle-dependent activation of memory- and stress-related regions, including the amygdala. Network analyses of the cross-correlation of fos expression among these regions uncovered functional connectivity that differentiated impaired mice from those not impaired by MAS. In conclusion, the estrous cycle modulates the impact of MAS on spatial memory, and fluctuating physiological levels of sex hormones may contribute to this effect.SIGNIFICANCE STATEMENT: Effects of stress on brain functions, including memory, are profound and sex-dependent. Acute stressors occurring simultaneously result in spatial memory impairments in males, but effects on females are unknown. Here we identified estrous cycle-dependent effects of such stresses on memory in females. Surprisingly, females with higher physiological estradiol experienced stress-induced memory impairment and a loss of underlying synapses. Memory- and stress-responsive brain regions interconnected with hippocampus were differentially activated across high and low estradiol mice, and predicted memory impairment. Thus, at functional, network, and cellular levels, physiological estradiol influences the effects of stress on memory in females, providing insight into mechanisms of prominent sex differences in stress-related memory disorders, such as post-traumatic stress disorder.

Axonal Conduction Velocity in CA1 Area of Hippocampus is Reduced in Mouse Models of Alzheimer's Disease.

The timing of action potentials arrival at synaptic terminals partially determines integration of synaptic inputs and is important for information processing in the CNS. Therefore, axonal conduction velocity (VC) is a salient parameter, influencing the timing of synaptic inputs. Even small changes in VC may disrupt information coding in networks requiring accurate timing. We recorded compound action potentials in hippocampal slices to measure VC in three mouse models of Alzheimer's disease. We report an age-dependent reduction in VC in area CA1 in two amyloid-ß precursor protein transgenic mouse models, line 41 and APP/PS1, and in a tauopathy model, rTg4510.

PKA and Ube3a regulate SK2 channel trafficking to promote synaptic plasticity in hippocampus: Implications for Angelman Syndrome.

The ubiquitin ligase, Ube3a, plays important roles in brain development and functions, since its deficiency results in Angelman Syndrome (AS) while its over-expression increases the risk for autism. We previously showed that the lack of Ube3a-mediated ubiquitination of the Ca2+-activated small conductance potassium channel, SK2, contributes to impairment of synaptic plasticity and learning in AS mice. Synaptic SK2 levels are also regulated by protein kinase A (PKA), which phosphorylates SK2 in its C-terminal domain, facilitating its endocytosis. Here, we report that PKA activation restores theta burst stimulation (TBS)-induced long-term potentiation (LTP) in hippocampal slices from AS mice by enhancing SK2 internalization. While TBS-induced SK2 endocytosis is facilitated by PKA activation, SK2 recycling to synaptic membranes after TBS is inhibited by Ube3a. Molecular and cellular studies confirmed that phosphorylation of SK2 in the C-terminal domain increases its ubiquitination and endocytosis. Finally, PKA activation increases SK2 phosphorylation and ubiquitination in Ube3a-overexpressing mice. Our results indicate that, although both Ube3a-mediated ubiquitination and PKA-induced phosphorylation reduce synaptic SK2 levels, phosphorylation is mainly involved in TBS-induced endocytosis, while ubiquitination predominantly inhibits SK2 recycling. Understanding the complex interactions between PKA and Ube3a in the regulation of SK2 synaptic levels might provide new platforms for developing treatments for AS and various forms of autism.

A new mouse line with reduced GluA2 Q/R site RNA editing exhibits loss of dendritic spines, hippocampal CA1-neuron loss, learning and memory impairments and NMDA receptor-independent seizure vulnerability.

Calcium (Ca2+)-permeable AMPA receptors may, in certain circumstances, contribute to normal synaptic plasticity or to neurodegeneration. AMPA receptors are Ca2+-permeable if they lack the GluA2 subunit or if GluA2 is unedited at a single nucleic acid, known as the Q/R site. In this study, we examined mice engineered with a point mutation in the intronic editing complementary sequence (ECS) of the GluA2 gene, Gria2. Mice heterozygous for the ECS mutation (named GluA2+/ECS(G)) had a ~ 20% reduction in GluA2 RNA editing at the Q/R site. We conducted an initial phenotypic analysis of these mice, finding altered current-voltage relations (confirming expression of Ca2+-permeable AMPA receptors at the synapse). Anatomically, we observed a loss of hippocampal CA1 neurons, altered dendritic morphology and reductions in CA1 pyramidal cell spine density. Behaviourally, GluA2+/ECS(G) mice exhibited reduced motor coordination, and learning and memory impairments. Notably, the mice also exhibited both NMDA receptor-independent long-term potentiation (LTP) and vulnerability to NMDA receptor-independent seizures. These NMDA receptor-independent seizures were rescued by the Ca2+-permeable AMPA receptor antagonist IEM-1460. In summary, unedited GluA2(Q) may have the potential to drive NMDA receptor-independent processes in brain function and disease. Our study provides an initial characterisation of a new mouse model for studying the role of unedited GluA2(Q) in synaptic and dendritic spine plasticity in disorders where unedited GluA2(Q), synapse loss, neurodegeneration, behavioural impairments and/or seizures are observed, such as ischemia, seizures and epilepsy, Huntington's disease, amyotrophic lateral sclerosis, astrocytoma, cocaine seeking behaviour and Alzheimer's disease.

Tumor Necrosis Factor-α-Mediated Metaplastic Inhibition of LTP Is Constitutively Engaged in an Alzheimer's Disease Model.

LTP, a fundamental mechanism of learning and memory, is a highly regulated process. One form of regulation is metaplasticity (i.e., the activity-dependent and long-lasting changes in neuronal state that orchestrate the direction, magnitude, and persistence of future synaptic plasticity). We have previously described a heterodendritic metaplasticity effect, whereby strong high-frequency priming stimulation in stratum oriens inhibits subsequent LTP in the stratum radiatum of hippocampal area CA1, potentially by engagement of the enmeshed astrocytic network. This effect may occur due to neuron-glia interactions in response to priming stimulation that leads to the release of gliotransmitters. Here we found in male rats that TNFα and associated signal transduction enzymes, but not interleukin-1ß (IL-1ß), were responsible for mediating the metaplasticity effect. Replacing priming stimulation with TNFα incubation reproduced these effects. As TNFα levels are elevated in Alzheimer's disease, we examined whether heterodendritic metaplasticity is dysregulated in a transgenic mouse model of the disease, either before or after amyloid plaque formation. We showed that TNFα and IL-1ß levels were significantly increased in aged but not young transgenic mice. Although control LTP was impaired in the young transgenic mice, it was not TNFα-dependent. In the older transgenic mice, however, LTP was impaired in a way that occluded further reduction by heterosynaptic metaplasticity, whereas LTP was entirely rescued by incubation with a TNFα antibody, but not an IL-1ß antibody. Thus, TNFα mediates a heterodendritic metaplasticity in healthy rodents that becomes constitutively and selectively engaged in a mouse model of Alzheimer's disease.SIGNIFICANCE STATEMENT The proinflammatory cytokine TNFα is known to be capable of inhibiting LTP and is upregulated several-fold in brain tissue, serum, and CSF of Alzheimer's disease (AD) patients. However, the mechanistic roles played by TNFα in plasticity and AD remain poorly understood. Here we show that TNFα and its downstream signaling molecules p38 MAPK, ERK, and JNK contribute fundamentally to a long-range metaplastic inhibition of LTP in rats. Moreover, the impaired LTP in aged APP/PS1 mice is rescued by incubation with a TNFα antibody. Thus, there is an endogenous engagement of the metaplasticity mechanism in this mouse model of AD, supporting the idea that blocking TNFα might be of therapeutic benefit in the disease.

Synaptic plasticity in hippocampal CA1 neurons and learning behavior in acute kidney injury, and estradiol replacement in ovariectomized rats.

BACKGROUND: Neurological complications may occur in patients with acute or chronic renal failure; however, in cases of acute renal failure, the signs and symptoms are usually more pronounced, and progressed rapidly. Oxidative stress and nitric oxide in the hippocampus, following kidney injury may be involved in cognitive impairment in patients with uremia. Although many women continue taking hormone therapy for menopausal symptom relief, but there are also some controversies about the efficacy of exogenous sex hormones, especially estrogen therapy alone, in postmenopausal women with kidney injury. Herein, to the best of our knowledge for the first time, spatial memory and synaptic plasticity at the CA1 synapse of a uremic ovariectomized rat model of menopause was characterized by estradiol replacement alone. RESULTS: While estradiol replacement in ovariectomized rats without uremia, promotes synaptic plasticity, it has an impairing effect on spatial memory through hippocampal oxidative stress under uremic conditions, with no change on synaptic plasticity. It seems that exogenous estradiol potentiated the deleterious effect of acute kidney injury (AKI) with increasing hippocampal oxidative stress. CONCLUSIONS: Although, estrogen may have some positive effects on cognitive function in healthy subjects, but its efficacy in menopause subjects under uremic states such as renal transplantation, needs to be further investigated in terms of dosage and duration.

A vicious cycle of ß amyloid-dependent neuronal hyperactivation.

ß-amyloid (Aß)-dependent neuronal hyperactivity is believed to contribute to the circuit dysfunction that characterizes the early stages of Alzheimer's disease (AD). Although experimental evidence in support of this hypothesis continues to accrue, the underlying pathological mechanisms are not well understood. In this experiment, we used mouse models of Aß-amyloidosis to show that hyperactivation is initiated by the suppression of glutamate reuptake. Hyperactivity occurred in neurons with preexisting baseline activity, whereas inactive neurons were generally resistant to Aß-mediated hyperactivation. Aß-containing AD brain extracts and purified Aß dimers were able to sustain this vicious cycle. Our findings suggest a cellular mechanism of Aß-dependent neuronal dysfunction that can be active before plaque formation.

Electroconvulsive Shock Enhances Responsive Motility and Purinergic Currents in Microglia in the Mouse Hippocampus.

Microglia are in a privileged position to both affect and be affected by neuroinflammation, neuronal activity and injury, which are all hallmarks of seizures and the epilepsies. Hippocampal microglia become activated after prolonged, damaging seizures known as status epilepticus (SE). However, since SE causes both hyperactivity and injury of neurons, the mechanisms triggering this activation remain unclear, as does the relevance of the microglial activation to the ensuing epileptogenic processes. In this study, we use electroconvulsive shock (ECS) to study the effect of neuronal hyperactivity without neuronal degeneration on mouse hippocampal microglia. Unlike SE, ECS did not alter hippocampal CA1 microglial density, morphology, or baseline motility. In contrast, both ECS and SE produced a similar increase in ATP-directed microglial process motility in acute slices, and similarly upregulated expression of the chemokine C-C motif chemokine ligand 2 (CCL2). Whole-cell patch-clamp recordings of hippocampal CA1sr microglia showed that ECS enhanced purinergic currents mediated by P2X7 receptors in the absence of changes in passive properties or voltage-gated currents, or changes in receptor expression. This differs from previously described alterations in intrinsic characteristics which coincided with enhanced purinergic currents following SE. These ECS-induced effects point to a "seizure signature" in hippocampal microglia characterized by altered purinergic signaling. These data demonstrate that ictal activity per se can drive alterations in microglial physiology without neuronal injury. These physiological changes, which up until now have been associated with prolonged and damaging seizures, are of added interest as they may be relevant to electroconvulsive therapy (ECT), which remains a gold-standard treatment for depression.

The susceptibility to chronic social defeat stress is related to low hippocampal extrasynaptic NMDA receptor function.

N-methyl-D-aspartate receptors (NMDARs) have been highly implicated in the pathogenesis and treatment of depression. While NMDARs can be found inside and outside glutamate synapses, it remains unclear if NMDARs at synaptic (sNMDAR) and extrasynaptic locations (exNMDAR) play different roles in the formation of depression-related behaviors. Using chronic social defeat stress (CSDS), an animal model for anxiety- and depression-related behaviors, we found that mice susceptible to CSDS exhibited low hippocampal exNMDAR function. Raising exNMDAR function by enhancing the release of glutamate from astrocytic cystine-glutamate antiporters or targeting extrasynaptic receptors with agonist-coated gold nanoparticles that cannot enter the synaptic cleft prevented social avoidance behavior in stressed mice. Interestingly, ketamine, which is a fast-acting antidepressant, exhibited stronger blockade to sNMDARs than to exNMDARs. These findings suggest that the susceptibility and resilience of mice toward CSDS is related to low and high exNMDAR function in the hippocampus, respectively. Enhancing exNMDAR function could be a novel treatment approach for mood and anxiety disorders.

Electroacupuncture Regulates Hippocampal Synaptic Plasticity via Inhibiting Janus-Activated Kinase 2/Signal Transducer and Activator of Transcription 3 Signaling in Cerebral Ischemic Rats.

OBJECTIVE: To determine the mechanism(s) involved in electroacupuncture (EA)-mediated improvements in synaptic plasticity in a rat model of middle cerebral artery occlusion and reperfusion (MCAO/R)-induced cognitive deficits. METHODS: Focal cerebral ischemic stroke was induced by (MCAO/R) surgery. Rats were randomly split into 4 groups: control group (sham operation control), MCAO group, Baihui (GV 20) and Shenting (GV 24) acupoint EA group (verum acupuncture, MCAO + VA), and nonacupoint EA group (control acupuncture, MCAO + CA). EA treatment was administered for 14 consecutive days in MCAO + VA and MCAO + CA groups. Neurological assessment, behavioral performance testing, and molecular biology assays were used to evaluate the MCAO/R model, EA therapeutic effect and potential therapeutic mechanism(s) of EA. RESULTS: Significant amelioration of neurological deficits was found in MCAO + VA rats compared with MCAO rats (P < .01). Moreover, learning and memory significantly improved in EA-treated rats compared with MCAO or MCAO + CA rats (P < .05) together with an increase in the number of PSD-95+ and SYN+ cells and synapses in the hippocampal CA1 region (P < .05). MCAO + VA rats also showed amelioration of pathological synaptic ultrastructural changes compared with MCAO or MCAO + CA groups (P < .001). In contrast, EA decreased the levels and phosphorylation of JAK2 (Janus-activated kinase 2) and STAT3 (signal transducer and activator of transcription 3) in the hippocampal CA1 region compared with MCAO or MCAO + CA group (P < .01). CONCLUSION: EA at GV 20 and GV 24 acupoints improved cognitive deficits in cerebral ischemic rats via the JAK2/STAT3 signaling pathway and mediated synaptic plasticity in the peri-infarct hippocampal CA1 region of rats following ischemic stroke.

Neuroprotective effects of pinocembrin on ischemia/reperfusion-induced brain injury by inhibiting autophagy.

BACKGROUND: Cerebral ischemia/reperfusion (I/R) injury is a common pathological process after cardiac arrest, shock and acute cerebral infarction recanalization, which causes serious injury in brain function. Pinocembrin (Pino), a natural flavonoid at the highest concentration in propolis, exhibited a variety of biological effects, including antitumor, antimicrobial and anti-inflammatory activities. However, the effects of Pino on brain injured after I/R and the mechanisms of its neuroprotective effects remain elusive. METHODS: In the present study, we used I/R model rats underwent transient cerebral ischemia inducing by four-vessel occlusion and reperfusion. Pino alone or in combination with autophagy inducer rapamycin (RAPA) was administered to I/R rats. The behavior and cognitive function were evaluated by open field test and Morris water maze test. HE staining was used to determine the survival of hippocampus CA1 pyramidal cells. Three key proteins of autophagy, LC3, Beclin1 and p62, were detected by Western blot. RESULTS: Our results showed that Pino could significantly reduce the damage of hippocampus CA1 pyramidal neurons and alleviate the impairments of behavior and cognitive function in I/R rats. Pino also decreased the expression of LC3II and Beclin1 and increased the level of p62 in hippocampus CA1 of I/R rats. In addition, Pino also decreased RAPA-induced neuronal damage and excessive activation of autophagy in I/R rats. CONCLUSIONS: Taken together, these results suggested that Pino could protect the brain injury induced by I/R and the potential mechanisms might attribute to inhibition of autophagy activity.

Synaptic transmission and excitability during hypoxia with inflammation and reoxygenation in hippocampal CA1 neurons.

Although a number of experimental and clinical studies have shown that hypoxia typically accompanies acute inflammatory responses, the combinatorial effect of the two insults on basic neural function has not been thoroughly investigated. Previous studies have predominantly suggested that hypoxia reduces network activity; however, several studies suggest the opposite effect. Of note, inflammation is known to increase neural activity. In the current study, we examined the effects of limited oxygen in combination with an inflammatory stimulus, as well as the effects of reoxygenation, on synaptic transmission and excitability. We observed a significant reduction of both synaptic transmission and excitability when hypoxia and inflammation occurred in combination, whereas reoxygenation caused hyperexcitability of neurons. Further, we found that the observed reduction in synaptic transmission was due to compromised presynaptic release efficiency based on an adenosine-receptor-dependent increase in synaptic facilitation. Excitability changes in both directions were attributable to dynamic regulation of the hyperpolarization-activated cation current (Ih) and to changes in the input resistance and the voltage difference between resting membrane potential and action potential threshold. We found that zatebradine, an Ih current inhibitor, reduced the fluctuation in excitability, suggesting that it may have potential as a drug to ameliorate reperfusion brain injury.

After Treatment with Methylene Blue is Effective against Delayed Encephalopathy after Acute Carbon Monoxide Poisoning.

Delayed encephalopathy after acute carbon monoxide (CO) poisoning (DEACMP) is the most severe and clinically intractable complication that occurs following acute CO poisoning. Unfortunately, the mechanism of DEACMP is still vague. Growing evidence indicates that delayed cerebral damage after CO poisoning is related to oxidative stress, abnormal neuro-inflammation, apoptosis and immune-mediated injury. Our recent report indicated that methylene blue (MB) may be a promising therapeutic agent in the prevention of neuronal cell death and cognitive deficits after transient global cerebral ischaemia (GCI). In this study, we aimed to investigate the potential of MB therapy to ameliorate the signs and symptoms of DEACMP. Rats were exposed to 1000 ppm CO for 40 min. in the first step; CO was then increased to 3000 ppm, which was maintained for another 20 min. The rats were implanted with 7-day release Alzet osmotic mini-pumps subcutaneously under the back skin, which provided MB at a dose of 0.5 mg/kg/day 1 hr after CO exposure. The results showed that MB significantly suppressed oxidative damage and expression of pro-inflammatory factors, including tumour necrosis factor-α and interleukin (IL)-1ß. MB treatment also suitably modulated mitochondrial fission and fusion, which is helpful in the preservation of mitochondrial function. Furthermore, MB dramatically attenuated apoptosis and neuronal death. Lastly, behavioural studies revealed that MB treatment preserved spatial learning and memory in the Barnes maze test. Our findings indicated that MB may have protective effects against DEACMP.

Effects of estrogen on learning-memory and expression of calbindin-D28K in hippocampus in vascular dementia rats.

Vascular dementia (VD) models were made first by repeating cerebral ischemia-reperfusion and followed by treating with estrogen. Learning-memory ability was measured by Morris water maze. Concentration of Ca2+ in hippocampus was determined by Fura-2/AM fluorescence probe and the expression of Calbindin-D28K (CB) in hippocampal CA1 was tested by immunohistochemistry. Learning-memory ability was improved in E group rats; Concentration of Ca2+ in hippocampus was decreased in E group rats. The expression of CB was less in E group rats. It implies that estrogen could improve learning-memory ability in VD rats, which may be associated with suppressing intracellular Ca2+ overload and increasing the expression of CB in hippocampus.