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Multiple sclerosis (MS) is an autoimmune neurodegenerative disease that affects the central nervous system (CNS) and is characterized by motor, sensory, and cognitive deficits. Current therapies for MS come mostly in the form of immunomodulatory drugs which indirectly slow disease progression. Our lab has shown that the estrogen receptor β (ERβ) specific ligand diarylpropionitrile (DPN) has a direct, neuroprotective effect in mouse models of MS. DPN is a moderately selective ligand, and there are more selective ERβ ligands available for study that could provide greater efficacy and safety. For example, WAY200070 and WAY200041 have a 200-fold selectivity for ERβ over ERα, compared to the 70-fold selectivity of DPN. Our aim was to investigate the potential neuroprotective effects
of prophylactic and therapeutic treatment with WAY200070 and WAY200041 in a chronic mouse model of MS:
experimental autoimmune encephalomyelitis (EAE). Treatment with the WAY compounds both prior to and after disease onset improved EAE clinical scores. Immunohistochemistry of brain and spinal cord sections from WAYtreated mice showed improved myelin density and increased mature oligodendrocyte and axon numbers compared to vehicle-treated mice. WAY200070 and WAY200041 treatment had no effect on the peripheral immune response or CNS inflammation. Together, these findings strongly support a direct, neuroprotective effect of WAY200070 and WAY200041 treatment in a chronic mouse model of MS. Therefore, these compounds should be investigated further as a potential treatment option for MS.
SEIZURE FREQUENCY AND SUSCEPTIBILITY IN SLEEP-DEPRIVED MICEWilmarie Hernández, Eli Wallace.
University of Wisconsin-Madison, Madison, WI.
Sleep and health have always been linked. Although there are many unknowns concerning the physiological purposes of sleep, it is clear that sleep is essential, and sleep deprivation causes major damage, including death.
However, there is evidence that sleep deprivation is closely related to one of the many triggers of seizures in epilepsy. Therefore, this research’s main focus is the relationship between sleep deprivation and seizure threshold and frequency. We hypothesized that the increase of seizure frequency in epileptic mice and seizure susceptibility in seizure-naïve mice will be directly proportional to the intensity and duration of the sleep deprivation protocol.
The seizure-naïve mice will be exposed to the volatile convulsant Flutothyl to induce seizures, quantifying latency to seizure. The epileptic mice will be used for EEG recording to monitor brain activity (seizure frequency) during and after sleep deprivation. Animals from both groups will be euthanized and brain slices prepared to record electrophysiological activity to determine specific cerebral changes. It is expected that, with sleep disruption, the naïve mouse susceptibility to Flurothyl-induced seizures and epileptic seizure frequency will increase indicating hyperexcitability in sleep-deprived mice. Because the main purpose of this research is to discover how sleep deprivation affects the frequency of and susceptibility to seizures in mice, the findings of this study carry great translational value in neurology, aiding in the diagnosis and treatment of this debilitating disease.
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Biological Sciences FRI-584
PROTEIN AGGREGATION ANHIBITORS DECREASE NEURAL CELL DEATH IN THE SPINAL CORD OF
DIETHYLMALEATE-TREATED MICEItzy Erin Morales Pantoja, Oscar Bizzozero, Anushka Dasgupta, Jianzheng Zheng.
University of New Mexico Health Sciences Center, University of New Mexico, Albuquerque, NM.
Reduced levels of the antioxidant glutathione and increased protein oxidation are observed in several neuroinflammatory and neurodegenerative disorders. Protein oxidation triggers the formation of large, proteaseresistant aggregates that are believed to be cytotoxic. Indeed, we have previously shown that the protein aggregation inhibitors congo red (CR) and 2-hydroxypropyl b-cyclodextrin (HPCD) significantly reduce cell death in glutathionedepleted, neuron-like PC12 cells. In this study, we investigate whether CR and HPCD also prevent neural cell death in vivo. Ten, week-old C57BL/6 mice were given an intraperitoneal (ip) injection of diethylmaleate (DEM) (6.0 mmol/kg), a treatment that reduces glutathione levels in the spinal cord by 70 to 80%. Some DEM-treated animals also received an ip injection of either CR (40 nmol/kg) or HPCD (20 nmol/kg). After 12 h, mice were euthanized and spinal cords were rapidly removed and processed for immunohistochemical analysis. Apoptotic cell death in the lumbar spinal cord was determined by TUNEL staining, and neurons, oligodendrocytes, and astrocytes were identified using antibodies against NeuN, CAII, and GFAP, respectively. We found that DEM treatment increases the number of apoptotic cells by 10-fold and that both protein aggregation inhibitors decrease cell death by 50%. TUNEL-positive cells in glutathione-depleted mice were identified as neurons (51%), oligodendrocytes (9%), and astrocytes (20%), and both CR and HPCD reduced apoptosis of all these cell types. Our results not only demonstrate the cytotoxic role of protein aggregation in vivo but also validate the therapeutic potential of these agents. (Supported by NIH grants NS057755 and NS084042, and by the IMSD program) SAT-596
ATTEMPT TO ATTENUATE AGE-RELATED HEARING LOSS CAUSED BY OXIDATIVE-STRESS BYPRODUCTS
USING AN ACROLEIN SCAVENGERJulie Luna1, Charneka Hopkins2, Aravindakshan Parthasarathy3, Edward Bartlett3.
University of Puerto Rico-Aguadilla, Aguadilla, PR, 2Rust College, Chicago, IL, 3Purdue University, West Lafayette, 1 IN.
Age related hearing loss is caused by degeneration of the peripheral auditory system, including the cochlea and the hair cells, or by changes in neurons of the central auditory pathway. Peripheral changes are seen mainly as an increase in the hearing threshold, while changes in processing complex sounds are thought to reflect central pathway damage. Theories speculate that damage to mitochondria caused by reactive oxygen species (ROS) is one of the causes of aging. Byproducts like acrolein affect cell membrane and myelin in axons, resulting in decreased responses of neurons in the central pathway. Our study aims to assess age related hearing loss using an acrolein scavenger called hydralazine to recover neuron damage in a rodent model of aging. Hydralazine was administered to aged Fischer-344 rats using intra peritoneal injections during a period of weeks, and the controls were treated with saline.
To test the auditory function, we used auditory-evoked potentials including auditory brainstem responses (ABR), middle latency responses (MLR), and frequency following responses (FFR) using subdermal-needle scalp electrodes.
Responses were recorded during the presentation of different auditory stimuli in a presession. We expect to see an increase in amplitude and a decrease in latency shifts in the ABR and MLR results. Positive results using this technique could lead to new therapeutic approaches to prevent, treat,or lessen the oxidative stress effects that cause age-related hearing loss.
VASCULAR COGNITIVE IMPAIRMENT IN AGED, SPONTANEOUSLY HYPERTENSIVE STROKE-PRONE RATSPatricia Perez Bonilla1, Anne Dorrance2.
University of Puerto Rico, Rio Piedras Campus, Rio Piedras, PR, 2Michigan State University, East Lansing, MI.
1 Carotid arteries are the major blood supply to the brain; about 600 to 700 ml of blood flows through the carotid arteries every minute. Impaired dilation in these arteries could affect the regulation of cerebral blood flow. The spontaneously hypertensive stroke-prone rat (SHRSP) was analyzed in this study because recent investigations using the SHR strain have demonstrated that hypertension combined with age significantly alters cerebrovascular resistance and impairs cerebrovascular activity. The purpose of this experiment is to study the thromboxane U46619-induced contraction and the acetylcholine (ACh)-induced dilation in the carotid arteries from the SHRSP at different ages. We will also test the role played by cyclooxygenase (COX) metabolites in controlling vascular function by inhibiting COX with
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indomethacin. This study will also assess the cognitive impairment in SHRSP using the elevated cross maze and the novel object test. Control normotensive Wistar Kyoto (WKY) rats will be used for comparison. Two hypotheses are proposed: the SHRSP strain will show an increase in cognitive impairment with increasing age, and COX activity will increase with age causing indomethacin to have a greater effect in arteries in aged SHRSP.
BASAL GANGLIA VOLUME RELATES TO THE SEVERITY OF SYMPTOMS OBSERVED IN AUTISM SPECTRUMDISORDER Raymond Alvarez, Andrea Stocco, Natalia Kleinhans, Chantel Pratt.
University of Washington, Seattle, WA.
Autism spectrum disorder (ASD) is a class of neurodevelopmental disorders characterized by broad social and cognitive impairments and the presence of repetitive behaviors. This research examined the hypothesis that a mechanism for routing signals to the frontal lobes through the basal ganglia (BG) is impaired in ASD. Functional implications of structural abnormalities in the BG have been limited to motor impairments. Our research correlates BG volume with indices of cognitive and social functioning in ASD. Anatomical tracings of the caudate and putamen of the BG were defined on high-resolution MPRAGE structural images by two trained tracers (inter-rater cross correlations =.86 -.90), for 31 individuals: 14 with ASD and 17 controls. BG nuclei volume was correlated with full intelligence (Weschler Adult Intelligence Scale) and scores from the subscales of the autism diagnostic interview (ADI) and the autism diagnostic observation scale (ADOS). No significance was found between groups t-tests in total BG volume between groups. Correlations with BG structure and behavioral measures indicated that size of the BG was positively correlated with IQ in controls r(17) =.50, but was negatively correlated with IQ in individuals with ASD r(14) = -.53.
BG size was correlated with measures of repetitive behaviors on the autism diagnostic interview r(14) =.59 and with a measure of social distress r(14) =.55. The results showed that larger BG are associated with better functioning in controls and poorer functioning in ASD.
THE BILINGUAL ADVANTAGEChristopher Hwozdek, Angélique Michelle Blackburn, Nicole Wicha.
University of Texas at San Antonio, San Antonio, TX.
Bilinguals demonstrate better cognitive control and later onset symptoms of Alzheimer’s than monolinguals. The specific aspect of bilingualism responsible for this advantage is still highly debated. Our goal is to determine whether experience in a code-switching environment affects language control, measured as the speed and accuracy of switching between languages. Code-switching is when an individual switches between two or more languages within a conversation. For the study we compared Spanish-English bilingual switchers: people who spend time in a codeswitching environment; non-switchers: people who speak only one language per conversation; and monolinguals.
Data was previously collected on a picture-naming paradigm in which bilinguals were cued to switch between naming pictures in Spanish and English. In some trials they stayed in the same language as the previous trial (nonswitch trials) and in some trials they were cued to switch languages (switch trials). We categorized errors and calculated both naming accuracy and reaction times for each participant. Switch cost is calculated as the average response time, switch minus nonswitch. We hypothesized that people who code switch frequently will have a smaller switch cost and higher accuracy than those who do not. This would indicate that code-switching experience improves the ability to switch between languages. This study is part of a larger goal of determining why bilinguals show a cognitive advantage over monolinguals in tasks that involve executive control, so we may better understand in what way it can delay cognitive decline.
CAN SCHEDULED EATING IMPROVE SLEEPING HABITS AND MOTOR FUNCTIONS IN BACHD MICERichard Flores, Danny Troung, Dawn Loh, Analyne Schroeder, Christopher Colwell.
University of California, Los Angeles, Los Angeles, CA.
Many suffering from neurodegenerative diseases such as Huntington’s disease (HD) experience a wide variety of ailments in addition to the loss of motor coordination that characterizes these diseases. Prior to the appearance of motor dysfunction in HD patients is the prevalence of poor sleep, suggesting a problem with the circadian clock.
BACHD mice, a mouse model of HD, exhibit poor motor skills and disrupted circadian rhythms in activity and heart rate. These daily rhythms in activity and physiology are regulated by the master pacemaker in the brain, the
THE CONTROL OF NEUROGENESIS BY FRAGILE X PROTEINSTyler Wishard1, Regina Faulkner2, Hollis Cline2.
University of California, San Diego, La Jolla, CA, 2The Scripps Research Institute, La Jolla, CA.