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    Cadmium exposure during lactation causes learning and memory-impairment in F1 generation mice: amelioration by quercetin. Halder Sumita,Kar Rajarshi,Galav Vikas,Mehta Ashish K,Bhattacharya Swapan K,Mediratta Pramod K,Banerjee Basu D Drug and chemical toxicology Cadmium (Cd) is a known pollutant present in the environment at low levels and is reported to affect reproduction in many ways. The present study was undertaken to explore the effect of Cd in F1 generation mice on cognitive parameters, and to further investigate whether quercetin could modulate these effects. In this study, female lactating mice were exposed to cadmium for seven days just after delivery. The new born pups in their adulthood were tested for learning and memory parameters by passive avoidance task and Morris water maze (MWM) test. It was observed that pups exposed to Cd showed significant impairment of memory in step down latency test, which was reversed by quercetin (100 mg/kg). In MWM test for spatial memory, animals exposed to Cd exhibited increased escape latency, which was reversed by quercetin (50 mg/kg) significantly. Quercetin alone (50 and 100 mg/kg) also demonstrated improved spatial memory, and showed improved retention memory in the passive avoidance paradigm at dose 50 mg/kg. On testing oxidative stress parameters, we observed significantly increased malondialdehyde (MDA) levels in brain tissue of Cd-treated mice. Moreover, co-treatment with quercetin (50 mg/kg) and Cd significantly reduced these MDA levels. The other doses (25 and 100 mg/kg) also showed reduction in MDA levels as compared to the group exposed to Cd alone, though the difference was not statistically significant. Hence, this study highlights the possibility of cognitive impairment in adulthood if there is Cd exposure during lactation and oxidative stress could possibly attribute to this effect. 10.3109/01480545.2015.1092042
    Beneficial effects of garlic on learning and memory deficits and brain tissue damages induced by lead exposure during juvenile rat growth is comparable to the effect of ascorbic acid. Ghasemi Simagol,Hosseini Mahmoud,Feizpour Azadeh,Alipour Fatemeh,Sadeghi Akram,Vafaee Farzaneh,Mohammadpour Toktam,Soukhtanloo Mohammad,Ebrahimzadeh Bideskan Alireza,Beheshti Farimah Drug and chemical toxicology OBJECTIVE:The neuroprotective effects of both garlic and ascorbic acid (AA) have been documented. In this study the effects of garlic and ascorbic acid on memory deficits and brain tissue oxidative damages induced by lead exposure was investigated. METHODS:The juvenile rats were divided and treated: (1) Control, (2) Lead (lead acetate in drinking water, 8 weeks), (3) Lead - Ascorbic Acid (Lead-AA), (4)  Lead - Garlic (100 mg/kg, daily, gavage) (Lead-Gar). RESULTS:In Morris water maze (MWM), the escape latency and traveled path in the Lead group were significantly higher while, the time spent in the target quadrant (Q1) was lower than Control. Both Lead-Gar and Lead-AA groups spent more times in Q1than to lead group. There were no significant differences in swimming speed between the groups. In passive avoidance (PA) test, the time latency for entering the dark compartment by Lead group was lower than Control. Treatment of the animals by AA and garlic significantly increased the time latency. In Lead group, the total thiol concentration in brain tissues was significantly lower while, MDA was higher than Control. Treatment by both garlic and AA increased total thiol concentrations and decreased MDA. Both garlic and AA decreased the lead content of brain tissues. CONCLUSION:It is suggested that treatment with garlic attenuates the learning and memory impairments due to lead exposure during juvenile rat growth which is comparable to AA. The possible mechanism may be due to its protective effects against brain tissues oxidative damage as well the lowering effects of brain lead content. 10.1080/01480545.2016.1197238
    Enhancing GABA Signaling during Middle Adulthood Prevents Age-Dependent GABAergic Interneuron Decline and Learning and Memory Deficits in ApoE4 Mice. Tong Leslie M,Yoon Seo Yeon,Andrews-Zwilling Yaisa,Yang Alyssa,Lin Victoria,Lei Hanci,Huang Yadong The Journal of neuroscience : the official journal of the Society for Neuroscience UNLABELLED:Apolipoprotein E4 (apoE4) is the major genetic risk factor for Alzheimer's disease (AD). However, the underlying mechanisms are still poorly understood. We previously reported that female apoE4 knock-in (KI) mice had an age-dependent decline in hilar GABAergic interneurons that correlated with the extent of learning and memory deficits, as determined by Morris water maze (MWM), in aged mice. Enhancing GABA signaling by treating aged apoE4-KI mice with the GABAA receptor potentiator pentobarbital (PB) for 4 weeks before and during MWM rescued the learning and memory deficits. Here, we report that withdrawal of PB treatment for 2 weeks before MWM abolished the rescue in aged apoE4-KI mice, suggesting the importance of continuously enhancing GABA signaling in the rescue. However, treating apoE4-KI mice during middle adulthood (9-11 months of age) with PB for 6 weeks prevented age-dependent hilar GABAergic interneuron decline and learning and memory deficits, when examined at 16 month of age. These data imply that increasing inhibitory tone after substantial GABAergic interneuron loss may be an effective symptomatic, but not a disease-modifying, treatment for AD related to apoE4, whereas a similar intervention before substantial interneuron loss could be a disease-modifying therapeutic. SIGNIFICANCE STATEMENT:We previously reported that female apoE4-KI mice had an age-dependent decline in hilar GABAergic interneurons that correlated with the extent of cognitive deficits in aged mice. The current study demonstrates that enhancing GABA signaling by treating aged apoE4-KI mice with a GABAA receptor potentiator pentobarbital (PB) before and during behavioral tests rescued the cognitive deficits; but withdrawal of PB treatment for 2 weeks before the tests abolished the rescue, suggesting the importance of continuously enhancing GABA signaling. However, treating apoE4-KI mice during middle adulthood with PB for a short period of time prevented age-dependent hilar GABAergic interneuron decline and cognitive deficits late in life, suggesting early intervention by enhancing GABA signaling as a potential strategy to prevent AD related to apoE4. 10.1523/JNEUROSCI.3815-15.2016
    Diacylglycerol Lipase-Alpha Regulates Hippocampal-Dependent Learning and Memory Processes in Mice. Schurman Lesley D,Carper Moriah C,Moncayo Lauren V,Ogasawara Daisuke,Richardson Karen,Yu Laikang,Liu Xiaojie,Poklis Justin L,Liu Qing-Song,Cravatt Benjamin F,Lichtman Aron H The Journal of neuroscience : the official journal of the Society for Neuroscience Diacylglycerol lipase-α (DAGL-α), the principal biosynthetic enzyme of the endogenous cannabinoid 2-arachidonylglycerol (2-AG) on neurons, plays a key role in CB receptor-mediated synaptic plasticity and hippocampal neurogenesis, but its contribution to global hippocampal-mediated processes remains unknown. Thus, the present study examines the role that DAGL-α plays on LTP in hippocampus, as well as in hippocampal-dependent spatial learning and memory tasks, and on the production of endocannabinoid and related lipids through the use of complementary pharmacologic and genetic approaches to disrupt this enzyme in male mice. Here we show that DAGL-α gene deletion or pharmacological inhibition disrupts LTP in CA1 of the hippocampus but elicits varying magnitudes of behavioral learning and memory deficits in mice. In particular, -α mice display profound impairments in the Object Location assay and Morris Water Maze (MWM) acquisition engaging in nonspatial search strategies. In contrast, WT mice administered the DAGL-α inhibitor DO34 show delays in MWM acquisition and reversal learning, but no deficits in expression, extinction, forgetting, or perseveration processes in this task, as well as no impairment in Object Location. The deficits in synaptic plasticity and MWM performance occur in concert with decreased 2-AG and its major lipid metabolite (arachidonic acid), but increases of a 2-AG diacylglycerol precursor in hippocampus, PFC, striatum, and cerebellum. These novel behavioral and electrophysiological results implicate a direct and perhaps selective role of DAGL-α in the integration of new spatial information. Here we show that genetic deletion or pharmacologic inhibition of diacylglycerol lipase-α (DAGL-α) impairs hippocampal CA1 LTP, differentially disrupts spatial learning and memory performance in Morris water maze (MWM) and Object Location tasks, and alters brain levels of endocannabinoids and related lipids. Whereas -α mice exhibit profound phenotypic spatial memory deficits, a DAGL inhibitor selectively impairs the integration of new information in MWM acquisition and reversal tasks, but not memory processes of expression, extinction, forgetting, or perseveration, and does not affect performance in the Objection Location task. The findings that constitutive or short-term DAGL-α disruption impairs learning and memory at electrophysiological and selective levels implicate this enzyme as playing a key role in the integration of new spatial information. 10.1523/JNEUROSCI.1353-18.2019
    Lactate Mediates the Effects of Exercise on Learning and Memory through SIRT1-Dependent Activation of Hippocampal Brain-Derived Neurotrophic Factor (BDNF). El Hayek Lauretta,Khalifeh Mohamad,Zibara Victor,Abi Assaad Rawad,Emmanuel Nancy,Karnib Nabil,El-Ghandour Rim,Nasrallah Patrick,Bilen Maria,Ibrahim Pascale,Younes Joe,Abou Haidar Edwina,Barmo Nour,Jabre Vanessa,Stephan Joseph S,Sleiman Sama F The Journal of neuroscience : the official journal of the Society for Neuroscience Exercise promotes learning and memory formation. These effects depend on increases in hippocampal BDNF, a growth factor associated with cognitive improvement and the alleviation of depression symptoms. Identifying molecules that are produced during exercise and that mediate hippocampal expression will allow us to harness the therapeutic potential of exercise. Here, we report that an endogenous molecule produced during exercise in male mice induces the gene and promotes learning and memory formation. The metabolite lactate, which is released during exercise by the muscles, crosses the blood-brain barrier and induces expression and TRKB signaling in the hippocampus. Indeed, we find that lactate-dependent increases in BDNF are associated with improved spatial learning and memory retention. The action of lactate is dependent on the activation of the Sirtuin1 deacetylase. SIRT1 increases the levels of the transcriptional coactivator PGC1a and the secreted molecule FNDC5, known to mediate expression. These results reveal an endogenous mechanism to explain how physical exercise leads to the induction of BDNF, and identify lactate as a potential endogenous molecule that may have therapeutic value for CNS diseases in which BDNF signaling is disrupted. It is established that exercise promotes learning and memory formation and alleviates the symptoms of depression. These effects are mediated through inducing expression and signaling in the hippocampus. Understanding how exercise induces and identifying the molecules that mediate this induction will allow us to design therapeutic strategies that can mimic the effects of exercise on the brain, especially for patients with CNS disorders characterized by a decrease in expression and who cannot exercise because of their conditions. We identify lactate as an endogenous metabolite that is produced during exercise, crosses the blood-brain barrier and promotes hippocampal dependent learning and memory in a BDNF-dependent manner. Our work identifies lactate as a component of the "exercise pill." 10.1523/JNEUROSCI.1661-18.2019