TThe aging brain can undergo a range of changes varying from subtle structural and physiological changes causing only minor functional decline under healthy normal aging conditions, to severe cognitive or neurological impairment associated with extensive loss of neurons and circuits due to age-associated neurodegenerative disease conditions. Understanding how biological aging processes affect the brain and how they contribute to the onset and progress of age-associated neurodegenerative diseases is a core research goal in contemporary neuroscience. This review focuses on the idea that changes in intrinsic neuronal electrical excitability associated with (per)oxidation of membrane lipids and activation of phospholipase A2 (PLA2) enzymes are an important mechanism of learning and memory failure under normal aging conditions. Specifically, in the context of this special issue on the Biology of cognitive aging we (1) portray the opportunities offered by the identifiable neurons and behaviorally characterized neural circuits of the freshwater snail Lymnaea stagnalis in neuronal aging research and (2) recapitulate recent insights indicating a key role of lipid peroxidation-induced PLA2 as instruments of aging, oxidative stress and inflammation in age-associated neuronal and memory impairment in this model system. The findings are discussed in view of accumulating evidence suggesting involvement of analogous mechanisms in the etiology of age-associated dysfunction and disease of the human and mammalian brain.
Abstract Background Cognitive impairment associated with subtle changes in neuron and neuronal network function rather than widespread neuron death is a feature of the normal aging process in humans and animals. Despite its broad evolutionary conservation, the etiology of this aging process is not well understood. However, recent evidence suggests the existence of a link between oxidative stress in the form of progressive membrane lipid peroxidation, declining neuronal electrical excitability and functional decline of the normal aging brain. The current study applies a combination of behavioural and electrophysiological techniques and pharmacological interventions to explore this hypothesis in a gastropod model ( Lymnaea stagnalis feeding system) that allows pinpointing the molecular and neurobiological foundations of age-associated long-term memory (LTM) failure at the level of individual identified neurons and synapses. Results Classical appetitive reward-conditioning induced robust LTM in mature animals in the first quartile of their lifespan but failed to do so in animals in the last quartile of their lifespan. LTM failure correlated with reduced electrical excitability of two identified serotonergic modulatory interneurons (CGCs) critical in chemosensory integration by the neural network controlling feeding behaviour. Moreover, while behavioural conditioning induced delayed-onset persistent depolarization of the CGCs known to underlie appetitive LTM formation in this model in the younger animals, it failed to do so in LTM-deficient senescent animals. Dietary supplementation of the lipophilic anti-oxidant α-tocopherol reversed the effect of age on CGCs electrophysiological characteristics but failed to restore appetitive LTM function. Treatment with the SSRI fluoxetine reversed both the neurophysiological and behavioural effects of age in senior animals. Conclusions The results identify the CGCs as cellular loci of age-associated appetitive learning and memory impairment in Lymnaea and buttress the hypothesis that lipid peroxidation-dependent depression of intrinsic excitability is a hallmark of normal neuronal aging. The data implicate both lipid peroxidation-dependent non-synaptic as well as apparently lipid peroxidation-independent synaptic mechanisms in the age-dependent decline in behavioural plasticity in this model system.
Reactive oxygen species (ROS) are essential for normal physiological functioning of the brain. However, uncompensated increase in ROS levels may results in oxidative stress. Phospholipase A2 (PLA2) is one of the key players activated by elevated ROS levels resulting in the hydrolysis of various products from the plasmamembrane such as peroxidized fatty acids. Free fatty acids (FFAs) and fatty acid metabolites are often implicated to the genesis of cognitive impairment. Previously we have shown that age-, and experimentally induced oxidative stress causes PLA2-dependent long-term memory (LTM) failure in an aversive operant conditioning model in Lymnaea stagnalis. In the present study, we investigate the effects of experimentally induced oxidative stress and the role of elevated levels of circulating FFAs on LTM function using a non-aversive appetitive classical conditioning paradigm.We show that intracoelomic injection of exogenous PLA2 or pro-oxidant induced PLA2 activation negatively affects LTM performance in our learning paradigm. In addition, we show that experimental induction of oxidative stress causes significant temporal changes in circulating FFA levels. Importantly, the time of training coincides with the peak of this change in lipid metabolism. However, intracoelomic injection with exogenous arachidonic acid, one of the main FFAs released by PLA2, does not affect LTM function. Moreover, sequestrating circulating FFAs with the aid of bovine serum albumin does not rescue pro-oxidant induced appetitive LTM failure.Our data substantiates previous evidence linking lipid peroxidation and PLA2 activation to age- and oxidative stress-related cognitive impairment, neuronal dysfunction and disease. In addition however, our data indicate that lipid peroxidation induced increased levels of circulating (per)oxidized FFAs are not a factor in oxidative stress induced LTM impairment.
I once had pretensions to writing tragedy instead of writing about it, and I carried those pretensions so far as to select, for possible poeticizing, The Most Tragic Story I'd Ever Heard. As my taste prefers Betrayed Innocence to Bloody Experience, I settled on a perfectly ghastly tale my schoolteacher mother brought home from her ghetto-bound, Welfare-ridden, delinquent-filled third grade class in remedial reading. One of her students was a particularly ragged, unfed, unwashed and ignored boy whose mother was perpetually with child and whose father was perpetually in jail. The boy appeared at school one morning with a fresh and only slightly-frayed shirt; his classmates, ill-at-ease with such airs taken on by such a person, wrestled him to the floor during lavatory break and took turns urinating on him. Complacently enough, and cleaned up as well as he might be, he returned to class and sat through the afternoon. Only when the bell had rung and the rest of the class had left school and the teacher was waiting to turn out the lights and lock the door and go home did he begin to cry, explaining that he was that afternoon to have been allowed to see his incarcerated dad, whom he had not seen in months and whom he would not see now at all, in order to spare him the shame of seeing his son befouled. I never wrote the story; two pages into it, I'd find myself enraged or in tears, I'd swear to find the bullies and thrash them, to bail out the father, to adopt the child and teach him Russian novels, to bomb City Hall, to castrate the rich and privileged (what did they have to do with it?), to reorganize the world, to pray for the millennium. To fictionalize such a horror seemed too pallid a response. Moreover, when I thought of the tragic fictions that had been held up to me as models of sobering experience, I realized that my response to
The present pilot study tested the use of a virtual game system (VGS) for exercise training in patients with moderate to very severe chronic obstructive pulmonary disease undergoing pulmonary rehabilitation (PR). Safety, feasibility, enjoyment and adherence were assessed.VGS (Wii [2006], Nintendo, USA) games were prescreened and categorized into lower- and upper-body workouts. Patients admitted for a three- to four-week inpatient PR program exercised daily. They were provided an opportunity to individually engage in VGS sessions three times weekly, varying with length of stay. Dyspnea, oxygen saturation and heart rate were measured before, during and after game sessions. Patients were considered to be adherent if they attended at least 50% of VGS sessions. Adverse events and enjoyment were evaluated.Thirty-two patients with a mean (± SD) age of 66±9 years and a mean forced expiratory volume in 1 s of 0.72±0.40 L participated. Among the 25 patients completing the program, adherence was 76%, with a mean attendance rate of 64±35%. Mean dyspnea score was 1.5±1.1 before and 3.2±1.2 after exercise. Mean oxygen saturation changed from 94±3% to 91±5% (P<0.001), while heart rate increased from 88±15 beats⁄min to 102±18 beats⁄min (P<0.001). One patient reported chest pain requiring nitroglycerin spray and five experienced transient desaturation below 85% with play. Patients enjoyed the program (visual analogue score 8±2.6⁄10) and most would highly recommend it to others.Moderate exercise using a VGS was safe, feasible and enjoyed as an adjunct to inpatient PR. This modality may encourage patients to maintain physical activity after PR.
Author(s): Watson, Shawn | Advisor(s): Monkkonen, Paavo | Abstract: This thesis analyzes the portrayals of the federal government’s role in public and private housing of the Los Angeles Times from 1940 to 1945. Further, it examines how these portrayals influenced the perceptions of the Times readers. The context of Los Angeles during World War is crucial because it was one of the few places in the country where home building, and the debates over it, continued during the war. Because of the city’s status as a critical defense area, both public and private housing were seen as viable options for addressing the city’s housing shortage. I examine four salient narratives from the discourse that provide insight into the paradoxical relationship between the private housing industry and the federal government. First, the Times provided descriptive examples of the city’s public housing program that were relatively neutral in tone although this was a relatively small subset of all the articles examined. Second, the paper attempted to limit the perceived scope of public housing by focusing on a narrative about competition between public and private housing. Although the Times portrays varying arguments as to whether the two were actually competitors, it does reveal how the private housing industry requested or demanded government assistance to put them at a competitive advantage. Third, the Times portrayed the role of government in ways that both obscured it, especially agencies that benefitted private industry, and were critical of it, which included arguments from the private industry for decentralizing government control of housing. Last, the newspaper portrayed an extensive argument during the war years about whether private or public housing would fill the postwar landscape. Ultimately, I argue these portrayals worked to limit readers’ perceptions about government involvement in the private housing industry while simultaneously presenting a case for the elimination of public housing.
