Thirty years of olfactory learning and memory research in Drosophila melanogaster

The last 30 years have witnessed tremendous progress in elucidating the basic mechanisms underlying a simple form of olfactory learning and memory in Drosophila. The application of the mutagenic approach to the study of olfactory learning and memory in Drosophila has yielded insights into the participation of a large number of genes in both the development of critical brain regions as well as in the physiology underlying the acquisition, storage, and retrieval of memory. Newer sophisticated molecular-genetic tools have further allowed for the specification and functional dissection of the neuronal circuitry involved in these processes at a systems level. With these advances in our understanding of the genes, neurons, and circuits involved in learning and memory, the field of Drosophila memory research is nearing a state of integration of the bottom up and top down approaches to understanding this form of behavioral plasticity.     

Hippocampus and olfactory discrimination learning: effects of entorhinal cortex lesions on olfactory learning and memory in a successive-cue, go-no-go task

Three experiments assessed the effect of entorhinal cortex lesions on olfactory learning and memory using a successive-cue olfactory discrimination paradigm. In contrast to the results of other studies that used a simultaneous-cue paradigm, lesions of the entorhinal cortex facilitated rats' acquisition of individual odor discrimination problems, with no impairment in memory for the individual odors across both short (24-hr) and long (65-day) retention intervals and despite limited training. When considered together with previous observations of facilitation or impairment in learning after damage to the hippocampal system, the present data suggest that the hippocampus is preferentially involved in encoding relations among multiple stimuli. By this account, facilitation of performance is due to an interaction between hippocampal system dysfunction and task conditions that hinder direct comparisons among cues.     

Progesterone modulates cadmium-induced oxidative stress and inflammation in hepatic tissues of Wistar rats

In recent times, there has been an increased risk of human exposure to cadmium especially in developing countries. We studied the role of progesterone as an anti-inflammatory and antioxidant agent in cadmium induced toxicity. Cadmium toxicity was induced with cadmium chloride (30 mg/kg) per oral while the control group was given distilled water. The Cd group was given CdCl₂ only, P₄ group; progesterone only (10 mg/kg intraperitoneally) and Cd+P₄ group; CdCl₂ and progesterone. All treatments lasted for 21 days. Following sacrifice, liver function tests and antioxidant status were assessed using standard kits; TNFα was immunolocalized across the study groups and the staining intensity measured using Image J software. Cadmium administration induced oxidative stress by a significant elevation in MDA and GC6P levels and a significant reduction in SOD, CAT, and GSH. These were attenuated by progesterone administration. While cadmium exposure caused an increase in serum ALT, AST, and ALP activities, progesterone significantly alleviated these effects. Inflammation shown by significant immunoreactivity in the TNFα positive cells in the liver in the cadmium group was reversed by progesterone. We conclude that cadmium toxicity induces oxidative stress that was attenuated by progesterone.     

丹酚酸B对APP/PS1小鼠学习记忆及氧化应激的作用及可能机制

目的 探讨丹酚酸B对APP/PS1转基因小鼠学习记忆能力、氧化应激水平及Nrf-2/HO-l信号通路的影响.方法 将7月龄的APP/PS1小鼠随机分为模型组、丹酚酸B低剂量组(30mg/kg)及丹酚酸B高剂量组(60 mg/kg),并取同龄C57BL/6小鼠作为对照组,每组10只,连续灌胃给药8周.Morris水迷宫观...     

Melatonin attenuates radiation-induced learning deficit and brain oxidative stress in mice

Oxidative stress has been implicated in cognitive impairment in both experimental animals and humans. This implication has led to the notion that antioxidant defence mechanisms in the brain are not sufficient to prevent oxidative damage, and that dietary intake of a variety of antioxidants might be beneficial for preserving brain function. The present study, therefore, aimed to investigate the protective effect of melatonin against radiation-induced impairment in the learning ability of mice. Twenty days oral administration of melatonin (0.1 mg/kg b.w.), followed by an acute exposure to T-radiation (6 Gy), inhibited the radiation-induced decline in learning ability. Biochemical estimation of brain protein carbonyls, malondialdehide (MDA) and reduced glutathione (GSH) in these mice indicated that radiation-induced augmentation of protein oxidation and lipid peroxidation had been significantly ameliorated in melatonin treated, irradiated mice. Radiation-induced deficit of glutathione was also normalized by melatonin administration, as there was no statistical difference from normal at P < 0.001. Results indicate the antioxidative as well as neuroprotective properties ofmelatonin against the radiation. These findings support results showing melatonin as a free radical scavenger.     

Estrogen modulates learning in female rats by acting directly at distinct memory systems

Physiologically high levels of circulating estradiol enhance the use of place learning and impair the use of response learning to find food on a land maze. These two types of learning are impaired by lesions of distinct neuronal structures, i.e. the hippocampus and striatum, respectively. Moreover, it has been shown in male rats that compromising hippocampal function can promote the use of response learning, while compromising striatal function can promote place learning. These findings suggest an ongoing competition between the hippocampus and striatum during cognition, such that intact functioning of one structure somehow obstructs the relative participation of the other. The goal of this study was to determine if estrogen's opposing effects on place and response learning in female rats are due to direct actions, either independent or interacting, at the hippocampus and striatum. We infused 0.5 microM 17beta-estradiol 3-sulfate sodium or vehicle bilaterally into the dorsal hippocampus or dorsolateral striatum of ovariectomized young adult female rats, 48, 24 and 2 h before training. Rats were tested on one of three appetitive tasks in a Y-maze: place learning, response learning, or response learning with reduced visual cues (cue-poor condition). Intrahippocampal estradiol infusions enhanced place learning, reversing a cannula-induced impairment, whereas intrastriatal infusions had no effects on place learning. Estradiol infusions into neither structure significantly affected response learning when extramaze cues were visible. However, in the response task, cue-poor condition, intrastriatal but not intrahippocampal infusions impaired learning. These data demonstrate that estrogen modulates place and response learning at the hippocampus and striatum respectively, most likely through independent actions at these two structures.     

Chronic oxidative stress in the RVLM modulates sympathetic control of circulation in pigs

Oxidative stress is a key event in the pathogenesis of several cardiovascular diseases and may be similarly induced by long-term treatment with organic nitrates. We examined the effects of inhibiting extracellular oxidative stress in the rostral ventrolateral medulla (RVLM), the brain stem area which primarily controls sympathetic tone. Superoxide dismutase (SOD, 10 U/microl) was microinjected into the RVLM of anesthetized pigs that were either untreated (control, n=10), treated for 4 weeks with the organic nitrate isosorbidedinitrate (ISDN, 4 mg kg(-1) day(-1), n=6) or ISDN-treated followed by a 2-week recovery period (recovery, n=4). In control animals SOD produced moderate inhibitory effects on baseline sympathetic activity, indicated by decreases in renal sympathetic nerve activity (RSNA), mean arterial blood pressure (MAP), and heart rate (HR) without causing changes in femoral vascular conductance (FC). These effects of SOD were greatly enhanced in ISDN-treated pigs. Following the recovery period, SOD again produced smaller effects in the RVLM but they were, however, still significantly greater than in untreated animals. In contrast, the transmission of sympathoexcitatory reflexes by the RVLM, as evoked by sciatic nerve stimulation, was not affected by SOD injections in either experimental group. Furthermore, the number of NO-synthase-positive neurons in the RVLM region was significantly reduced both in ISDN-treated and the recovery pigs, suggesting that oxidative stress caused sustained changes in NOS activity within the brain stem. These data suggest that excitatory actions of oxidative stress contribute significantly to the generation of baseline sympathetic tone in the RVLM during long-term treatment with organic nitrates. Similar mechanisms could promote sympathetic tone in cardiovascular diseases that are associated with endogenous oxidative stress for longer periods.     

APP17肽对快速老化小鼠SAMP10学习、记忆功能和海马神经 细胞线粒体氧化应激水平的影响

目的：观察APP17肽(β-Amyloid precursop protein,APP,319-335肽段)对快速老化小鼠SAMP10（senescence accelerated mouse/pr one 10）学习、记忆功能及海马神经细胞线粒体氧化应激的影响。方法:4月龄的SAMP10小鼠随机分为模型组和APP17肽治疗组，正常对照组采用抗快速老化小鼠SAM R1(senescence accelerated mouse/resistance 1)。APP17肽治疗组给予皮下注射APP17肽 ，每只每次0.34 μg，每周3次；模型组和正常对照给予等量的生理盐水；28周后成模。应 用水迷宫试验观察小鼠学习、记忆功能的变化，应用羟胺法和硫代巴比妥酸（TBA）比色法 分析海马神经细胞线粒体氧化应激反应水平。结果:(1)水迷宫结果显示 ，模型组小鼠存在明显的学习和记忆功能障碍，其游完全程的时间和错误反应次数均较正常 对照组增多（P<0.05）;APP17肽治疗组小鼠的行为学障碍明显轻于模型组，其上述 的水迷宫检测结果与正常对照组比较无显著差异。(2)模型组小鼠海马神经细胞线粒体SOD活 性明显低于正常对照组（P<0.01），MDA含量显著高于正常对照组（P<0.01）；A PP17肽治疗组检测结果与正常对照组接近，SOD活性高于模型组（P<0.05），而MDA含 量低于模型组（P<0.01）。结论:快速老化小鼠SAMP10存在学习和 记忆功能障碍；而且其海马神经细胞线粒体氧化应激反应明显加剧。APP17肽具有清除自由 基和抑制氧化应激反应的作用，从而提高脑组织的抗氧化能力，保护学习、记忆功能。     

Modulation of memory consolidation for olfactory learning by reversible inactivation of the basolateral amygdala

The role of the basolateral amygdala (BLA) in the consolidation of an association between an olfactory stimulus and footshock was investigated with a reversible lesion technique of post-training intra-BLA infusions of tetrodotoxin. Rats receiving tetrodotoxin infusions following paired odor-shock presentations spent more time near the odor, and reacted differently on contact with the odor when tested 24 hr after training, than did rats receiving paired presentations and saline infusions, but they did not differ from rats receiving unpaired presentations and saline infusions. The results indicate that the BLA plays a similar role in influencing consolidation of olfactory-based memory as it does for memory based on other modalities. Thus, these findings strengthen the view that the BLA plays a general role in modulation of memory storage for emotionally arousing events.     

辛夷挥发油经嗅觉通路改善自闭症模型昆明鼠学习记忆能力及其神经递质含量

目的:研究辛夷挥发油对自闭症模型昆明鼠学习记忆行为的影响,探讨其活性成分经嗅觉通路对自闭症模型昆明鼠学习记忆能力的干预作用及可能机制。方法:昆明鼠孕鼠12.5 d腹腔注射丙戊酸钠所产雄性子代为自闭症模型鼠,随机挑选24只,分为模型组和吸嗅组,每组12只,正常昆明鼠雄性子代随机挑选12只为空白组。吸嗅组6周龄时连续吸嗅2周辛夷挥发油,模型组和对照组吸嗅洁净空气。Morris水迷宫观察各组昆明鼠学习记忆能力,免疫组化检测昆明鼠海马、杏仁核和下丘脑5-色胺(5-HT)和多巴胺(DA)蛋白的表达。结果:与模型组相比,吸嗅组昆明鼠逃避潜伏期较短,穿平台次数增加,学习记忆能力明显增强(P0.05)。免疫组化结果显示,模型组海马、杏仁核和下丘脑内5-HT和DA含量明显低于正常组和吸嗅组。结论:辛夷挥发油可增强自闭症模型昆明鼠的学习记忆能力,可能与其维持相关脑区5-HT和DA含量稳定有关。     

Influence of isolation stress and inhibited protein biosynthesis on learning and memory in goldfish

Goldfish, Carassius auratus auratus L. (Pisces, Cyprinidae), were trained by different kinds of training procedures under the influence of cycloheximide or puromycin, two inhibitors of the protein biosynthesis. After active avoidance training in a shuttle box an apparent amnesia was found only when the fish were exposed to a one day lasting isolation stress prior to training. If the animals were accustomed to isolation over a period of 20 days the inhibitors did not affect memory formation. After learning by positive reinforcement (food rewarded color discrimination) in groups under stress-free conditions, neither learning nor memory formation were impaired in spite of the presence of cycloheximide. It is suggested that the amnestic effect of the inhibitors is caused by isolation treatment. Lack of the additional stress, however, leads to memory formation.     

Air movement evokes electro-olfactogram oscillations in the olfactory epithelium and modulates olfactory processing in a slug

In many animals, neurons in the olfactory system have been shown to respond not only to odorants but also to air movements. However, the manner in which the mechanical dynamics of odor stimulation affect olfactory processing remains poorly understood. Using a series of flow rates and odor concentrations from clean air to high-concentration vapors, we systematically analyzed the effects of air movement and odor concentration on olfactory processing. We extracellularly recorded local field potentials and spike units from the olfactory epithelium (OE) and tentacular nerve (TN), which connects the first and second relay centers of olfactory information, in the terrestrial slug Limax marginatus. We found that clean air puffs at a flow rate of 0.18 ml/s (gentle wind), but not high-concentration odor puffs at lower flow rates, induced electro-olfactogram (EOG) oscillations in the OE with a constant frequency (2.5 Hz), regardless of the odor. Surgically isolated OE preparations also showed these EOG oscillations, indicating that the oscillations arose from the OE independently of the downstream circuits. The EOG oscillations entrained the slower spontaneous TN oscillations (1-2 Hz) to the fixed rhythm (2.5 Hz). Spontaneous and odor-evoked units were phase-locked to the TN oscillation peaks. This TN oscillation entrainment by the EOG oscillations caused stronger phase-locking, specifically TN oscillation peaks and EOG oscillation troughs. Taken together, these results suggest that when odors are carried by a gentle wind, the air movement induces EOG oscillations and modulates rhythmic spike patterning of olfactory outputs to the second olfactory relay center in Limax.     

热应激预适应对小鼠学习记忆的影响

目的观察热应激对脑缺血处理的小鼠空间学习记忆能力、海马CA1区神经元CREB的影响。方法采用Morris水迷宫筛选空间学习记忆能力正常的昆明小鼠60只,体重(40±5)g,雌雄不限。将实验动物分为4组:正常对照组(Normal)、热应激预处理后缺血再灌注组(HS/IR)、缺血再灌注组(IR)、单纯热应激组(HS);处理后存活时间分别为3h、24h、72h,每个时间点6只,动物处死前再作水迷宫检测。用免疫组织化学方法检测CREB的表达。常规尼氏染色法镜下计数海马CA1区存活神经元。结果水迷宫检测IR组小鼠潜伏期增加,其搜索策略以边缘式和限制式为主,与其它3组比较有显著的统计学意义(P<0.01)。尼氏染色证实IR组锥体细胞神经元减少;24h的HS/IR组的CREB的表达高于IR组。结论热应激预处理可以改善动物因脑缺血引起的学习记忆功能下降。其机制可能涉及到热应激对CREB表达的上调。     

Holoturia arenicola extract modulates bile duct ligation-induced oxidative stress in rat kidney

Background: Acute Renal Failure (ARF) in patients with cirrhosis is one of the most frequently encountered complications of obstructive jaundice. Marine organisms from the Mediterranean Coast of Egypt are considered potential sources of bioactive molecules. The present study was undertaken to explore the curative effects of Holothuria arenicola extract (HaE) against renal injury induced by bile duct ligation in male albino rats. Methods: Fifty four male Wistar albino rats were assigned into two main groups, the Sham-operated control (received distilled water only for 28 days) and bile duct ligated (BDL) group, which divided into 2 subgroups, animals of these subgroups treated for 28 consecutive days as follow: Subgroup I (BDL), rats of this subgroup administered distilled water orally. Subgroup II, animals of this subgroup treated orally with HaE (200 mg/kg body weight). Results: BDL induced marked alteration on renal functions as manifested by a significant increase in the kidney function markers, serum creatinine, urea and uric acid. In addition, BDL caused significant increase in MDA level and significant decrease in GSH level as well as antioxidant enzymes activities (GST, SOD and CAT). However, administration of HaE for consecutive 28 days significantly reversed these changes, suggesting that the renal curative effect of HaE against oxidative stress- induced injury might be involved in decreasing lipid peroxide generation and stimulating antioxidant status. Conclusion: The present study revealed that HaE had a profound effect against BDL-induced oxidative stress in the kidney tissues which is the common feature of choestasis in the liver.     

The effects of aging and oxidative stress on learning behavior in C. elegans

Oxidative stress is associated with age-related declines of biological functions. However, the nervous system is preserved during aging in Caenorhabditis elegans and, thus, it is not well explored whether aging and oxidative stress affect nervous functions. Here we report that age-related decline can be observed in a type of associative-learning behavior, referred to as isothermal tracking. We also report the effects of mutants with altered sensitivity to oxidative stress on learning behavior and motor activity in young adults. The isp-1 and clk-1 mutants are members of the Clk class of mutants and have deficits in the function of the mitochondrial respiratory chain, leading to reduced levels of oxidative stress, increased longevity, delayed rhythmic behaviors and other phenotypes. Both the Clk mutations and pretreatment with a metabolic antioxidant, alpha-lipoic acid (LA), increased the ability to show isothermal tracking and modestly reduced motor activity. Mutants with increased oxidative stress showed severely impaired learning behavior and modestly reduced motor activity. Therefore, physiological levels of oxidative stress may be too high for learning behavior but, perhaps, not for motor activity. We discuss the relevance of oxidative stress to the aging and evolution of behaviors.     

Sparse odor representation and olfactory learning

Sensory systems create neural representations of environmental stimuli and these representations can be associated with other stimuli through learning. Are spike patterns the neural representations that get directly associated with reinforcement during conditioning? In the moth Manduca sexta, we found that odor presentations that support associative conditioning elicited only one or two spikes on the odor's onset (and sometimes offset) in each of a small fraction of Kenyon cells. Using associative conditioning procedures that effectively induced learning and varying the timing of reinforcement relative to spiking in Kenyon cells, we found that odor-elicited spiking in these cells ended well before the reinforcement was delivered. Furthermore, increasing the temporal overlap between spiking in Kenyon cells and reinforcement presentation actually reduced the efficacy of learning. Thus, spikes in Kenyon cells do not constitute the odor representation that coincides with reinforcement, and Hebbian spike timing-dependent plasticity in Kenyon cells alone cannot underlie this learning.     

Evidence for sex-specific shifting of neural processes underlying learning and memory following stress

Recent human research has been focused upon determining whether there is evidence that stress responses cause qualitative changes in neural activity such that people change their learning strategies from a spatial/contextual memory process through the hippocampus to a procedural stimulus-response process through the caudate nucleus. Moreover, interest has shifted to determining whether males and females exhibit the same type of stress-induced change in neural processing of associations. Presented is a select review of 2 different animal models that have examined how acute or chronic stressors change learning in a sex-specific manner. This is followed by a brief review of recent human studies documenting how learning and memory functions change following stressor exposure. In both cases, it is clear that ovarian hormones have a significant influence on how stress affects learning processes in females. We then examine the evidence for a role of acetylcholine, dopamine, norepinephrine, or serotonin in modulating this shifting of processing and how that may differ across sex. Conclusions drawn suggest that there may be evidence for sex-specific changes in amygdala and hippocampus neuromodulation; however, the behavioral data are still not conclusive as to whether this represents a common or sex-specific shift in how males and females process associations after stressor exposure.