Effect of the King Oyster Culinary-Medicinal Mushroom Pleurotus eryngii (Agaricomycetes) Basidiocarps Powder to Ameliorate Memory and Learning Deficit in Ability in Aß-Induced Alzheimer's Disease C57BL/6J Mice Model.

One of the major causes of Alzheimer's disease (AD) is oxidative stress, which accelerates ß-amyloid peptide (AP) plaque and neurofibrillary tangle accumulation in the brain. Pleurotus eryngii is known to be rich in antioxidants, including ergothioneine, adenosine, and polyphenol, which can reduce oxidative stress-related aging. The aim of this study was to investigate the proximate and functional composition of P. eryngii, and evaluate the cognitive effects of low (LPE), medium (MPE), and high (HPE) P. eryngii dosages in an Aß-induced Alzheimer's disease C57BL/6J mouse model. Mice fed P. eryngii for six weeks showed no adverse effects on body weight gain, food intake efficiency, serum biochemical parameters, and liver and kidney histopathological features. The relative brain weight was significantly lower in Aß-injected mice (p < 0.05). Further, P. eryngii was shown to delay brain atrophy. Reference memory behavioral tasks showed that LPE, MPE, and HPE significantly decreased escape latency (49-85%) and distance (53-69%, p < 0.05). Probe and T-maze tasks showed that P. eryngii potently ameliorated memory deficit in mice. An AD pathology index analysis showed that P. eryngii significantly decreased levels of brain phosphorylated τ-protein, Aß plaque deposition, malondialdehyde, and protein carbonyl (p < 0.05). P. eryngii may therefore promote memory and learning capacity in an Aß-induced AD mouse model.

Shank3B mutant mice display pitch discrimination enhancements and learning deficits.

Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterized by a core set of atypical behaviors in social-communicative and repetitive-motor domains. Individual profiles are widely heterogeneous and include language skills ranging from nonverbal to hyperlexic. The causal mechanisms underlying ASD remain poorly understood but appear to include a complex combination of polygenic and environmental risk factors. SHANK3 (SH3 and multiple ankyrin repeat domains 3) is one of a subset of well-replicated ASD-risk genes (i.e., genes demonstrating ASD associations in multiple studies), with haploinsufficiency of SHANK3 following deletion or de novo mutation seen in about 1% of non-syndromic ASD. SHANK3 is a synaptic scaffolding protein enriched in the postsynaptic density of excitatory synapses. In order to more closely evaluate the contribution of SHANK3 to neurodevelopmental expression of ASD, a knockout mouse model with a mutation in the PDZ domain was developed. Initial research showed compulsive/repetitive behaviors and impaired social interactions in these mice, replicating two core ASD features. The current study was designed to further examine Shank3B heterozygous and homozygous knockout mice for behaviors that might map onto atypical language in ASD (e.g., auditory processing, and learning/memory). We report findings of repetitive and atypical aggressive social behaviors (replicating prior reports), novel evidence that Shank3B KO mice have atypical auditory processing (low-level enhancements that might have a direct relationship with heightened pitch discrimination seen in ASD), as well as robust learning impairments.

Fear extinction learning ability predicts neuropathic pain behaviors and amygdala activity in male rats.

Background The amygdala plays a key role in fear learning and extinction and has emerged as an important node of emotional-affective aspects of pain and pain modulation. Impaired fear extinction learning, which involves prefrontal cortical control of amygdala processing, has been linked to neuropsychiatric disorders. Here, we tested the hypothesis that fear extinction learning ability can predict the magnitude of neuropathic pain. Results We correlated fear extinction learning in naive adult male rats with sensory and affective behavioral outcome measures (mechanical thresholds, vocalizations, and anxiety- and depression-like behaviors) before and after the induction of the spinal nerve ligation model of neuropathic pain compared to sham controls. Auditory fear conditioning, extinction learning, and extinction retention tests were conducted after baseline testing. All rats showed increased freezing responses after fear conditioning. During extinction training, the majority (75%) of rats showed a decline in freezing level to 50% in 5 min (fear extinction+), whereas 25% of the rats maintained a high freezing level (>50%, fear extinction-). Fear extinction- rats showed decreased open-arm preference in the elevated plus maze, reflecting anxiety-like behavior, but there were no significant differences in sensory thresholds, vocalizations, or depression-like behavior (forced swim test) between fear extinction+ and fear extinction- types. In the neuropathic pain model (four weeks after spinal nerve ligation), fear extinction- rats showed a greater increase in vocalizations and anxiety-like behavior than fear extinction+ rats. Fear extinction- rats, but not fear extinction+ rats, also developed depression-like behavior. Extracellular single unit recordings of amygdala (central nucleus) neurons in behaviorally tested rats (anesthetized with isoflurane) found greater increases in background activity, bursting, and evoked activity in fear extinction- rats than fear extinction+ rats in the spinal nerve ligation model compared to sham controls. Conclusion The data may suggest that fear extinction learning ability predicts the magnitude of neuropathic pain-related affective rather than sensory behaviors, which correlates with differences in amygdala activity changes.

EGCG ameliorates high-fat- and high-fructose-induced cognitive defects by regulating the IRS/AKT and ERK/CREB/BDNF signaling pathways in the CNS.

Obesity, which is caused by an energy imbalance between calorie intake and consumption, has become a major international health burden. Obesity increases the risk of insulin resistance and age-related cognitive decline, accompanied by peripheral inflammation. (-)-Epigallocatechin-3-gallate (EGCG), the major polyphenol in green tea, possesses antioxidant, anti-inflammatory, and cardioprotective activities; however, few reports have focused on its potential effect on cognitive disorders. In this study, our goal was to investigate the protective effects of EGCG treatment on insulin resistance and memory impairment induced by a high-fat and high-fructose diet (HFFD). We randomly assigned 3-mo-old C57BL/6J mice to 3 groups with different diets: control group, HFFD group, and HFFD plus EGCG group. Memory loss was assessed by using the Morris water maze test, during which EGCG was observed to prevent HFFD-elicited memory impairment and neuronal loss. Consistent with these results, EGCG attenuated HFFD-induced neuronal damage. Of note, EGCG significantly ameliorated insulin resistance and cognitive disorder by up-regulating the insulin receptor substrate-1 (IRS-1)/AKT and ERK/cAMP response element binding protein (CREB)/brain-derived neurotrophic factor (BDNF) signaling pathways. Long-term HFFD-triggered neuroinflammation was restored by EGCG supplementation by inhibiting the MAPK and NF-κB pathways, as well as the expression of inflammatory mediators, such as TNF-α. EGCG also reversed high glucose and glucosamine-induced insulin resistance in SH-SY5Y neuronal cells by improving the oxidized cellular status and mitochondrial function. To our knowledge, this study is the first to provide compelling evidence that the nutritional compound EGCG has the potential to ameliorate HFFD-triggered learning and memory loss.-Mi, Y., Qi, G., Fan, R., Qiao, Q., Sun, Y., Gao, Y., Liu, X. EGCG ameliorates high-fat- and high-fructose-induced cognitive defects by regulating the IRS/AKT and ERK/CREB/BDNF signaling pathways in the CNS.

Marginal vitamin A deficiency facilitates Alzheimer's pathogenesis.

Deposition of amyloid ß protein (Aß) to form neuritic plaques in the brain is the unique pathological hallmark of Alzheimer's disease (AD). Aß is derived from amyloid ß precursor protein (APP) by ß- and γ-secretase cleavages and turned over by glia in the central nervous system (CNS). Vitamin A deficiency (VAD) has been shown to affect cognitive functions. Marginal vitamin A deficiency (MVAD) is a serious and widespread public health problem among pregnant women and children in developing countries. However, the role of MVAD in the pathogenesis of AD remains elusive. Our study showed that MVAD is approximately twofold more prevalent than VAD in the elderly, and increased cognitive decline is positively correlated with lower VA levels. We found that MVAD, mostly prenatal MVAD, promotes beta-site APP cleaving enzyme 1 (BACE1)-mediated Aß production and neuritic plaque formation, and significantly exacerbates memory deficits in AD model mice. Supplementing a therapeutic dose of VA rescued the MVAD-induced memory deficits. Taken together, our study demonstrates that MVAD facilitates AD pathogenesis and VA supplementation improves cognitive deficits. These results suggest that VA supplementation might be a potential approach for AD prevention and treatment.

Maternal DHA supplementation protects rat offspring against impairment of learning and memory following prenatal exposure to valproic acid.

Docosahexaenoic acid (22:6n-3; DHA) is known to play a critical role in postnatal brain development. However, there have been no studies investigating the preventive effect of DHA on prenatal valproic acid (VPA)-induced behavioral and molecular alterations in offspring. The present study was to evaluate the neuroprotective effects in offspring using maternal feeding of DHA to rats exposed to VPA in pregnancy. In the present study, rats were exposed to VPA on day 12.5 of pregnancy; DHA was administered at the dosages of 100, 300 and 500 mg/kg/day for 3 weeks from day 1 to 21 of pregnancy. The results showed that maternal feeding of DHA to the prenatal exposed to VPA (1) prevented VPA-induced learning and memory impairment but did not change social-related behavior, (2) increased total DHA content in offspring plasma and hippocampus, (3) rescued VPA-induced neuronal loss and apoptosis of pyramidal cells in hippocampal CA1, (4) influenced the content of malondialdehyde and glutathione and the activities of superoxide dismutase and glutathione in the hippocampus, (5) altered levels of apoptosis-related proteins (Bcl-2, Bax and caspase-3) and inhibited the activity of caspase-3 in offspring hippocampus and (6) enhanced relative levels of p-CaMKII and p-CREB proteins in the hippocampus. These findings suggest that maternal feeding with DHA may prevent prenatal VPA-induced impairment of learning and memory, normalize several different molecules associated with oxidative stress and apoptosis in the hippocampus of offspring, and exert preventive effects on prenatal VPA-induced brain dysfunction.

Prenatal choline supplementation attenuates spatial learning deficits of offspring rats exposed to low-protein diet during fetal period.

Prenatal intake of choline has been reported to lead to enhanced cognitive function in offspring, but little is known about the effects on spatial learning deficits. The present study examined the effects of prenatal choline supplementation on developmental low-protein exposure and its potential mechanisms. Pregnant female rats were fed either a normal or low-protein diet containing sufficient choline (1.1g/kg choline chloride) or supplemented choline (5.0g/kg choline chloride) until delivery. The Barnes maze test was performed at postnatal days 31-37. Choline and its metabolites, the synaptic structural parameters of the CA1 region in the brain of the newborn rat, were measured. The Barnes maze test demonstrated that prenatal low-protein pups had significantly greater error scale values, hole deviation scores, strategy scores and spatial search strategy and had lesser random search strategy values than normal protein pups (all P<.05). These alterations were significantly reversed by choline supplementation. Choline supplementation increased the brain levels of choline, betaine, phosphatidylethanolamine and phosphatidylcholine of newborns by 51.35% (P<.05), 33.33% (P<.001), 28.68% (P<.01) and 23.58% (P<.05), respectively, compared with the LPD group. Prenatal choline supplementation reversed the increased width of the synaptic cleft (P<.05) and decreased the curvature of the synaptic interface (P<.05) induced by a low-protein diet. Prenatal choline supplementation could attenuate the spatial learning deficits caused by prenatal protein malnutrition by increasing brain choline, betaine and phospholipids and by influencing the hippocampus structure.

Neuroprotective effects of docosahexaenoic acid on hippocampal cell death and learning and memory impairments in a valproic acid-induced rat autism model.

Prenatal exposure to valproic acid (VPA) in rat offspring is capable of inducing experimental autism with neurobehavioral aberrations. This study investigated the effect of docosahexaenoic acid (DHA) on hippocampal cell death, learning and memory alteration in an experimental rat autism model. We found that DHA supplementation (75, 150 or 300 mg/kg/day, 21 days) rescued the VPA (600 mg/kg) induced DHA reduction in plasma and hippocampus in a dose-dependent manner, increased the levels of hippocampal p-CaMKII and p-CREB without affecting total protein level, and altered BDNF-AKT-Bcl-2 signaling pathway, as well as inhibited the activity of caspase-3. DHA also influenced the content of malondialdehyde (MDA) and the activities of antioxidant enzymes in the VPA-treated offspring. Consistent with the previous results, we also observed that 300 mg/kg DHA supplementation markedly increased the cell survival, decreased the cell apoptosis, and increased mature neuronal cell in the hippocampus in VPA-treated offspring. Utilizing the Morris water maze test, we found that DHA prevented cognitive impairment in offspring of VPA-treated rats. The data suggested that DHA may play a neuroprotective role in hippocampal neuronal cell and ameliorates dysfunctions in learning and memory in this rat autism model. Thus, DHA could be used as treatment intervention for mitigating behavioral dysfunctions in autism spectrum disorder (ASD).

Selective Brain-Targeted Antagonism of p38 MAPKα Reduces Hippocampal IL-1ß Levels and Improves Morris Water Maze Performance in Aged Rats.

BACKGROUND: P38 mitogen activated protein kinase (MAPK) α modulates microglia-mediated inflammatory responses and a number of neuronal physiological processes. OBJECTIVE: To evaluate pre-clinically the pharmacological effects in the brain of p38 MAPKα inhibition with a brain-penetrant specific chemical antagonist. METHODS: VX-745, a blood-brain barrier penetrant, highly selective p38 MAPKα inhibitor, and clinical stage investigational drug, was utilized. Initially, a pilot study in 26-month-old Tg2576 mice was conducted. Subsequently, a definitive dose-response study was conducted in aged (20-22 months) rats with identified cognitive deficits; n = 15 per group: vehicle, 0.5, 1.5, and 4.5 mg/kg VX-745 by oral gavage twice daily for 3 weeks. Assessments in aged rats included IL-1ß, PSD-95, TNFα protein levels in hippocampus; and Morris water maze (MWM) test for cognitive performance. RESULTS: Drug effect could not be assessed in Tg2576 mice, as little inflammation was evident. In cognitively-impaired aged rats, VX-745 led to significantly improved performance in the MWM and significant reduction in hippocampal IL-1ß protein levels, though the effects were dissociated as the MWM effect was evident at a lower dose level than that required to lower IL-1ß. Drug concentration-effect relationships and predicted human doses were determined. CONCLUSIONS: Selective inhibition of p38 MAPKα with VX-745 in aged rats reduces hippocampal IL-1ß levels and improves performance in the MWM. As the two effects occur at different dose levels, the behavioral effect appears to be via a mechanism that is independent of reducing cytokine production. The predicted human doses should minimize risks of systemic toxicity.

Compound IMM-H004, a novel coumarin derivative, protects against CA1 cell loss and spatial learning impairments resulting from transient global ischemia.

AIMS: Compound IMM-H004 (7-hydroxy-5-methoxy-4-methyl-3-[4-methylpiperazin-1-yl]-2H-chromen-2-one) is a new synthetic derivative of coumarin, and previous studies showed that it exhibited antioxidant and neuroprotective roles in focal cerebral ischemia. However, we know little about the compound's function in transient global ischemia. This study is to investigate whether compound IMM-H004 can protect against transient global ischemic injury. METHODS: Four-vessel occlusion (4VO) rat model was induced for a 20-min occlusion and different times of reperfusion to mimic transient global cerebral ischemia. IMM-H004 (3, 6, 9 mg/kg) or Edaravone (6 mg/kg) was administered after 30 min of reperfusion. Morris water maze tests were used to estimate the ability of spatial learning and memory. Nissl staining, TUNEL assay and Immunoblot for Bax/Bcl-2 and activated caspase-3 were used to detect hippocampal neuron injury. Immunoblot for PSD-95 and synapsin 1, and electron microscopy were used to observe synaptic function. RESULTS: Compared with vehicle group, IMM-H004 significantly improved the spatial learning performance and exhibited less CA1 neurons loss. The expressions of Bax/Bcl-2 and activated caspase-3 were decreased. IMM-H004 also ameliorated synaptic structure, decreased PSD-95 and increased synapsin 1 expression. CONCLUSION: These findings suggested that IMM-H004 exerted neuroprotective role in global ischemia by reducing apoptosis and maintaining the integrity of synaptic structure.

Effect of Convolvulus pluricaulis Choisy and Asparagus racemosus Willd on learning and memory in young and old mice: a comparative evaluation.

A dose dependent enhancement of memory was observed with A. racemosus and C. pluricaulis treatment as compared to control group when tested on second day. A. racemosus and C. pluricaulis at the dose of 200 mg/kg, po showed significantly higher percent retentions, than piracetam. Multiple treatment with A. racemosus and C. pluricaulis for three days also demonstrated significant dose dependent increase in percent retentions as compared to control group. The effect was more prominent with C. pluricaulis as compared with piracetam and A. racemosus. A significantly lower percent retention in aged mice was observed as compared to young mice. Aged mice (18-20 months) showed higher transfer latency (TL) values on first and second day (after 24 h) as compared to young mice, indicating impairment in learning and memory. Pretreatment with A. racemosus and C. pluricaulis for 7 days enhanced memory in aged mice, as significant increase in percent retention was observed. Significantly higher retention was observed with C. pluricaulis (200 mg/kg; po) as compared with piracetam (10 mg/kg/; po). Post-trial administration of C. pluricaulis and A. racemosus extract demonstrated significant decrease in latency time during retention trials. Hippocampal regions associated with the learning and memory functions showed dose dependent increase in AChE activity in CA 1 with A. reacemosus and CA3 area with C. pluracaulis treatment. The underlying mechanism of these actions of A. racemosus and C. pluricaulis may be attributed to their antioxidant, neuroprotective and cholinergic properties.

Neurotoxic lesions of the medial prefrontal cortex or medial striatum impair multiple-location place learning in the water task: evidence for neural structures with complementary roles in behavioural flexibility.

This series of experiments assessed the effects of neurotoxic damage to either the medial prefrontal cortex or the medial striatum on the acquisition of multiple-location place learning in the water task. During training, normal subjects learn to search for a new hidden platform location at the beginning of each training session and to continue to swim to that location until the end of training during that session. By the end of training, normal subjects show one-trail place learning in which they find the new location on the first trial and swim directly to that location on the second swim. Rats with damage to either the medial prefrontal cortex or dorso-medial striatum showed deficits in learning to swim to the new location each day. These deficits were interpreted as impairments in behavioural flexibility. The lesion-induced impairment was not caused by perseverative errors but was manifested in an inability to rapidly acquire a new spatial position in conflict with the previous position. Interestingly, the subjects from both lesion groups were able to show normal place learning and memory after repeated training within a session. The results were interpreted as suggestive of a complementary role of these neural structures in behavioural flexibility.

Hippocampal gray matter reduction associates with memory deficits in adolescents with history of prematurity.

Using optimized voxel-based morphometry (VBM), we compared the relationship between hippocampal and thalamic gray matter loss and memory impairment in 22 adolescents with history of prematurity (HP) and 22 normal controls. We observed significant differences between groups in verbal learning and verbal recognition, but not in visual memory. VBM analysis showed significant left hippocampal and bilateral thalamic reductions in HP subjects. Using stereological methods, we also observed a reduction in hippocampal volume, with left posterior predominance. We found correlations between left hippocampal gray matter reductions (assessed by VBM) and verbal memory (learning and percentage of memory loss) in the premature group. The stereological analysis showed a correlation between verbal learning and the left posterior hippocampus. Our results suggest that left hippocampal tissue loss may be responsible for memory impairment and is probably related to the learning disabilities that HP subjects present during schooling.

Posttraining but not pretraining lesions of the hippocampus interfere with feature-negative discrimination of fear-potentiated startle.

Previous studies have suggested that the hippocampus may play an important role in some forms of inhibitory learning. The goal of the present study was to assess whether the hippocampus is also important for inhibition of fear acquired after serial feature-negative discrimination training. Rats were given aspiration lesions of the hippocampus either before or after training in which a target light was paired with shock when presented alone, but not paired with shock when presented in serial compound with a noise feature (light+/noise-->light-). Conditioned fear to the target stimulus and feature-target compound were measured with fear-potentiated startle. Pre-training lesion of the hippocampus did not disrupt feature-negative discrimination performance relative to sham-operated and cortical lesioned controls. In contrast, hippocampal lesions performed after training severely disrupted performance. Specifically, rats with hippocampal lesions failed to inhibit fear when the noise feature was presented in compound with the target. However, these rats could reacquire the feature-negative discrimination. These observations suggest that the hippocampus may normally be involved in retention or retrieval of serial feature-negative discrimination; however, in its absence feature-negative discrimination can still be acquired.

Production of generalized learning deficit and permanent growth stunting by bilateral brain stem lesions.

Bilateral lesions of the globus pallidus, ventrolateral thalamus, substantia nigra, or the median raphe produce a generalized learning deficit in rats. Bilateral lesions of the dorsomedial hypothalamic nuclei stunt growth in rats without significantly disturbing endocrine functions and without producing a generalized learning deficit. Globus pallidus, ventrolateral thalamus, substantia nigra, median raphe, and dorsomedial hypothalamic nuclei lesions were produced in weanling Sprague-Dawley rats to compare their effect on physical growth. At approximately 72 d of age, all lesions had resulted in reduced body wt, tail length, and tibial length. The differences lacked significance only in body wt after median raphe lesions and tail length after ventrolateral thalamus lesions. In rats with the generalized learning deficit, body size was most stunted after substantia nigra lesions. Tibial epiphyseal width was modestly increased in rats with the generalized learning deficit. Food intake/average body wt ratio in substantia nigra and dorsomedial hypothalamic nuclei rats did not differ significantly from control values. Decreases in brain, heart, liver, kidney, and testes tended to occur after all the lesions, but brain and testis organ wt/body wt ratios were either increased or unchanged. We conclude that brain lesions producing a generalized learning deficit in rats result in impaired physical growth. The results indicated that the stunted animals maintain adequate food intake and have normal growth hormone function. The anatomical substrate for generalized learning impairment may overlap with that of a set point for body size.

Behavioral correlates of soman-induced neuropathology: deficits in DRL acquisition.

Rats (N = 45) pretrained to lever press for milk reinforcement on a continuous reinforcement (CRF) schedule were injected with 100-110 micrograms/kg of the anticholinesterase soman (N = 24) or saline (N = 21) SC. Subjects exposed to soman experienced moderate to severe acute symptoms of anticholinesterase intoxication. After a 3 week recovery period, all surviving subjects were retrained on CRF, then given 45 training sessions on a differential reinforcement of low rates (DRL) 20 sec schedule, followed by 10 sessions of extinction. Brains of all subjects were then examined for evidence of neuropathology. Subjects exposed to soman showed no improvement over sessions in the number of reinforcements earned on the DRL schedule due to an inefficient patterning of responses. There were no differences between groups in the number of total DRL responses or terminal extinction responses. Neuropathology was most evident in dorsal thalamic areas, primary olfactory/piriform cortex and amygdala of subjects exposed to soman. There were significant correlations between the severity of acute intoxication scores, degree of neuropathology, and deficits in DRL performance. The results demonstrate that exposure to high doses of this anticholinesterase agent can result in neural damage and persistent decrements in performance of certain operant tasks.

A contribution to the anatomical basis of thalamic amnesia.

Damage to diencephalic structures is stated to give rise to memory dysfunction. Amnesia is likely to occur following vascular lesions in the ventral portion of the thalamus. The CT findings of 6 of our own cases and 5 patients reported in the literature, all with selective vascular lesions of the thalamus, were studied to determine the critical structures involved in human memory processes more closely. Thalamic amnesia probably depends on intrathalamic white matter lesions more than on nuclear lesions. The mamillothalamic tract and the ventral portion of the lamina medullaris interna are the most likely candidates in the mediation of memory processes and a combined lesion of these structures may be responsible for thalamic amnesia in man. Two patients without significant memory dysfunction had lesions in the ventrobasal portion of the mediodorsal nucleus sparing the mamillothalamic tract and the ventral part of the lamina medullaris interna. Our findings correspond well with the understanding of amnesia as a 'disconnection syndrome' stressed recently by Warrington and Weiskrantz (1982) and with Mishkin's (1982) model of the memory system in monkeys.