Progress 01/01/02 to 12/31/11
Outputs
OUTPUTS: Lab of Barbara Strupp (PI, Cornell University): During the past year we have (a) finished coding the videotapes and analyzing the data from our prior study which demonstrated lasting beneficial cognitive effects of perinatal choline supplementation in Ts65Dn and control mice; (b) constructed the radial arm water maze (RAWM) that we plan to use as the index of hippocampal function in our subsequent studies concerning the neural mechanisms underlying the beneficial cognitive effects of early choline supplementation in Ts65Dn and control mice, (c) established an experimental protocol for the RAWM that will provide us with an index of hippocampal dysfunction independent of the influence of frontal cortical dysfunction (needed for our planned studies on neural mechanisms); (d) conducted a series of pilot studies to perfect the RAWM testing protocol and gain information about the decay of memory across varying delays; (e) constructed 8 automated testing chambers for the attention testing in our planned studies; and (f) initiated the process at Jackson Labs to produce the 40 breeder pairs needed for the "burst mating" for our planned studies on neural mechanisms; this process was initiated in August and will be completed in the spring of 2009. Lab of Elliott Mufson (Collaborator: Rush University Medical Center): While awaiting behaviorally characterized choline and unsupplemented Ts65Dn and 2N controls from the Strupp Lab, we have been testing various procedures to ensure that the best type of fixation is used in the proposed studies concerning perinatal choline supplementation in the Ts65Dn mouse model of Down syndrome (DS) and Alzheimer's disease (AD). Lab of Stephen D. Ginsberg (Collaborator: Nathan Kline Institute): While awaiting behaviorally characterized choline and unsupplemented Ts65Dn and 2N controls from the Strupp Lab, our lab has engaged in several lines of research on Ts65Dn mice that will assist the quantitative and morphometric assessment of the behaviorally characterized cohort. Specific progress includes assessing amyloid precursor protein (APP) mRNA and holoprotein levels within young (4 months) and aged (>12 months) Ts65Dn mice compared to 2N controls. In addition, a combined imaging and morphologic study was performed to assess neurodegeneration in DS mouse models. Specifically, in vivo quantitative magnetic resonance imaging (MRI) was employed to detect brain pathology and map its distribution in Ts65Dn and Ts1Cje trisomy mice with features of human Down syndrome (DS) and disomic controls (2N). PARTICIPANTS: Barbara J. Strupp, Ph.D., Professor and PI of the proposed research, has primary responsibility for coordinating all aspects of this project. Ms. Strawderman (the biostatistician), Ms. Ash (the Research Support Specialist), and The Postdoctoral Associate (currently unnamed) are under her supervision and meet with her several times each week. The PI coordinates the research conducted at the three performance sites. David Levitsky, Ph.D., Professor, designed and oversaw the construction of the new automated testing units. In addition, he is responsible on a daily basis for apparatus and computer maintenance, repair, and programming. Myla Strawderman, M.S., is a biostatistician. Her role in the project is to coordinate the transfer of data from the collaborator's labs to Cornell, create a master database for the grant, write the programs that are needed for the in-depth analyses of the data, participate directly in the analysis of the data, and help the Postdoctoral Research Associate with programming and analyzing the data. Jessica Ash, B.S. (Research Support Specialist): Over the past year, Ms. Ash has been in charge of developing the protocol for the radial arm water maze and has conducted the testing of the pilot studies. She has also been the primary person in charge of supervising the undergraduates which have participated in the water maze testing. During subsequent years of the project, Ms. Ash's responsibilities will also include breeding the mice and maintaining the colony, playing a major role in the brain removal/dissection, code and de-code the treatments, monitor the health of the animals daily; check the automated units daily to ensure proper functioning; order supplies; prepare the data for statistical analyses. Stephen D. Ginsberg, Ph.D., is the Project director for the work done at the Center for Dementia Research, Nathan Kline Institute (NKI). He will oversee all aspects of the immunohistochemical processing of the tissues and immunoblot analysis for neurotrophins/neurotrophin receptors, including data analysis and manuscript writing of these data. In future years of the project, Dr. Ginsberg will be responsible for brain tissue accrual (perfusions as well as frozen tissue accession) from Dr. Strupp's laboratory. Melissa J. Alldred, Ph.D., Assistant Research Scientist, is responsible for assisting Dr. Ginsberg with tissue acquisition, isolating mRNAs and proteins from tissue samples and performing qPCR and immunoblot analysis, respectively. Dr. Alldred will also perform immunohistochemical analysis and subsequent morphometric analysis, and will assist with data analysis and manuscript preparation. Elliott Mufson, Ph.D. is the Project Director of the research conducted at Rush University Medical Center. He will oversee all aspects of the stereology project, data analysis and manuscript writing involving the data generated from these studies. Cassia Overk, Ph.D., Postdoctoral fellow, will perform all immunohistochemical experiments and the stereology counts in Dr. Mufson's lab. TARGET AUDIENCES: Not relevant to this project. PROJECT MODIFICATIONS: Not relevant to this project.
Impacts
Lab of Barbara Strupp (PI, Cornell University): We have finished coding the videotapes of performance during several of the tasks that comprised the large study on perinatal choline supplementation in Ts65Dn mice that formed the basis of the studies in this funded application. We have recently submitted the manuscript for publication (see Publications, below). One striking new finding from these additional analyses is that perinatal choline administration not only improved attentional function in the adult Ts65Dn mice but also normalized some aspects of the heightened emotionality seen the trisomic mice. The unsupplemented trisomic mice were significantly more active than controls specifically on trials that followed an error in the attention task with periodic reward omission. This error-induced hyperactivity was normalized by perinatal choline supplementation. However, the stereotypic jumping also induced by an error was not normalized by the early choline supplementation (data not shown). The planned studies should shed more light on the neural bases of these effects. Lab of Elliott Mufson (Collaborator, Rush University Medical Center) During the past funding period we have been testing various procedures to ensure that the best type of fixation is used in the proposed Down's mouse studies of Alzheimer's disease (AD). Since the animals needed for the current grant are still being bred by Jackson labs, we employed two other AD transgenic mouse models of AD: APPswe/PS1∆E9 mice and the triple transgenic (3xTg-AD) mouse harboring the APPswe, PS1M146V and Tau P301L human gene mutations. Both mutants display various aspects of the classic AD pathology, plaque and plaque and tangle-like structures, respectively. One study revealed that immunolabeling of select tau epitopes are fixation dependent in young but not old 3xTg-AD mice (Oh et al., 2008). Fixation method is crucial for the detection of select phosphorylated tau epitopes, AT8 and PHF-1, in young mutant mice, while Aβ, Alz50, and AT180 immunoreactivity is independent of fixation method and age in 3xTg-AD mice. Lab of Stephen D. Ginsberg (Collaborator: Nathan Kline Institute): Specific progress includes assessing amyloid precursor protein (APP) mRNA and holoprotein levels within young (4 months) and aged (>12 months) Ts65Dn mice compared to 2N controls. In spite of the additional App gene copy in Ts65Dn mice, we found APP holoprotein levels in the brains of 4-month-old trisomic mice to be similar to the levels seen in 2N littermates. In contrast, up regulation of App mRNA and APP holoprotein levels were observed in 12 month old Ts65Dn mice. While increased expression of APP is consistent with the additional App gene copy in Ts65Dn mice, the age-dependence of the APP holoprotein increase and the differential increases in APP holoprotein and its metabolites suggest that APP metabolism is altered in older Ts65Dn mice. Understanding APP metabolism in this model is likely to give insight into the mechanism by which AD neuropathology develops in DS individuals and may suggest an interrelationship between APP metabolism and neurodegeneration in Ts65Dn mice.
Publications
- Chen, Y., Dyakin, V.V., Branch, C.A., Ardekani, B., Yang, D., Guilfoyle, D.N., Peterson, J., Peterhoff, C., Ginsberg, S.D., Cataldo, A.M., and Nixon, R.A.: In vivo MRI identifies cholinergic circuitry deficits in a Down syndrome model. Neurobiol. Aging, 2008 Jan 2; [Epub ahead of print]. PMID: 18180075.
- Choi, J.H.K., Diaz, N.S., Mazzella, M.J., Ginsberg, S.D., Levy, E., Nixon, R.A., and Mathews, P.M.: Dysregulation of amyloid precursor protein levels, but not Abeta levels in Ts65Dn mouse brain. Alzheimer's and Dementia, 4: T208-T209, 2008.
- Moon J., Ginsberg SD, Chen M, Gandhy S., Maclean K, Levitsky DA, Mufson EJ, Strupp BJ. Perinatal choline supplementation ameliorates attentional dysfunction in the Ts65Dn mouse: a mouse model of Down syndrome and Alzheimer's disease. Soc. Neurosci. Abs. 2007.
- Oh, K.-J., Perez, S.E., Overk, C. R., Mufson, E. J.: Select intraneuronal tau immunoreactivity is fixation dependent in young 3xTg-AD mice, Soc. Neurosci. Abstr. 2008.
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Progress 10/01/06 to 09/30/07
Outputs
Over their life span nearly all individuals with Down syndrome (DS) develop neuropathologic abnormalities and clinical dementia similar to that observed in Alzheimer's Disease (AD) including a reduction in cortical-projecting cholinergic basal forebrain neurons. The Ts65Dn mouse model of DS exhibits similar neuropathology, including pronounced degeneration of cholinergic basal forebrain neurons by 6 months of age. Prior studies with normal rats have demonstrated that perinatal choline supplementation ameliorates aging-related cognitive decline, protects against various neurotoxic insults, and increases the size and/or number of basal forebrain cholinergic neurons. These findings suggest that perinatal choline treatment may ameliorate the cognitive decline seen at mid-life in both DS individuals and Ts65Dn mice. We conducted a study to test this hypothesis, using four groups of mice: (1) Ts65Dn mice supplemented with excess choline (approximately 4X normal choline
intake) during gestation and lactation (n=10), (2) Ts65Dn mice not supplemented with choline (i.e., maternal diet of normal lab chow) (n=11), (3) wild-type (2N) littermate controls supplemented with choline perinatally (n=16), and (4) 2N mice not supplemented with choline (n= 9). From 7-12 months of age, the mice were tested on a series of 5-choice visual attention tasks in which the location, onset time, and duration of a brief visual cue varied unpredictably across trials. The unsupplemented Ts65Dn mice exhibited marked attentional dysfunction. In addition their performance revealed heightened arousal and/or emotion in response ot committing an error or omission of an expected reward. All of these behavioral abnormalities in the Ts65Dn mice were significantly improved by the perinatal choline supplementation. Preliminary analysis from a different cohort of identically-treated mice revealed that perinatal choline supplementation produced a lasting increase in frontal cortical choline
acetyltransferase activity (assessed at 12-16 months of age) in both Ts65Dn and 2N mice relative to their respective unsupplemented controls.
Impacts
In 1998, the Institute of Medicine (IOM) established its first choline recommendations, based on the estimated level of choline intake required to prevent liver damage (Inst. Med.,Natl. Acad. Sci. USA. 1998). However, optimum health may require more choline. Our findings have implications for possibly revising such recommendations for pregnancy, lactation and early development, with the goal of producing optimal proficiency in learning, attention, and memory function for all individuals throughout their lifespan, as well as substantially ameliorating the cognitive dysfunction seen in individuals with DS. The implications of this type of intervention could be quite substantial as DS occurs in approximately 800 to 1,000 births, and currently afflicts approximately 350,000 individuals in this country. Based on our findings, a pregnant woman carrying a fetus diagnosed with DS might be able to substantially reduce the cognitive impairment of her child by increasing her
choline intake during pregnancy and lactation, and perhaps also the choline intake of her child during early development. This research (our findings to date, and our planned future studies) are designed to help inform such recommendations and to aid in elucidating the underlying molecular and cellular mechanisms. Furthermore, an understanding of the lasting beneficial effects of perinatal choline supplementation in the Ts65Dn mouse may also help inform choline recommendations as a means of minimizing the CBF dysfunction seen in AD, a disorder that is estimated to currently afflict 4.5 million Americans (100), with a projected increase to 11-16 million by 2050 unless effective treatments are identified. Our preliminary studies suggest that increased choline intake early in life might hold potential in this regard as well as for DS.
Publications
- No publications reported this period
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Progress 01/01/06 to 12/31/06
Outputs
During the past year, we completed testing of the second cohort of mice that will comprise the study. This study was designed to test the hypothesis that perinatal supplementation with choline will ameliorate the attentional dysfunction seen in the Ts65Dn mouse model of Down syndrome and Alzheimer's Disease. This study was a 2 X 2 factorial design, with two genotypes (Ts65Dn and 2N littermate controls) and two levels of maternal choline intake during gestation and lactation (sufficient or 4.5X normal intake). With the two cohorts combined, there will be a final sample size of approximately 20 mice in each of the 4 groups. Data preparation and analysis are currently underway. In addition, videotapes of the mice performing the attention tasks are currently being coded to ascertain whether the perinatal choline supplementation normalized the heightened reaction to errors seen in Ts65Dn mice in a prior study in this lab. In this prior study, the trisomic mice exhibited
stereotypic jumping, specifically on trials that followed an error. Preliminary analysis of the data from the first cohort of mice indicated a dramatic benefit of the choline supplementation for the trisomic mice. The performance of the trisomic mice supplementted with choline early in life equalled that of the disomic controls on several attention tasks. If confirmed with this second cohort, these data would indicate that increasing maternal choline intake may provide a means of improving cognitive function in individuals with DS and Alzheimer's disease, and reducing age-related cognitive decline in the population at large.
Impacts
Preliminary analysis of the data from the first cohort of mice indicated a dramatic benefit of the choline supplementation for the trisomic mice. If confirmed with this second cohort, these data would indicate that providing excess choline during early development might significantly reduce the cognitive dysfunction seen in Down syndrome and reduce the risk of AD and age-related cognitive decline in the population at large. The information provided by this study is needed to inform potential changes in the recommendated dietary intake of choline during pregnancy, lactation and early postnatal development, which may in turn, lead to lifelong improvements in cognitive functioning for individuals with DS and the population at large.
Publications
- Moon J, Chen M, Crnic L, Maclean KN, Strupp B. 2006. Perinatal choline supplementation ameliorates attentional dysfunction in the Ts65Dn mouse: a mouse model of Down syndrome and Alzheimer's disease. Washington, DC: Society for Neuroscience. Online, 2006.
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Progress 01/01/05 to 12/31/05
Outputs
We are currently conducting a study to test the efficacy of perinatal choline supplementation in ameliorating the attentional dysfunction in Ts65Dn mice, a mouse model of Down syndrome and Alzheimer's disease. The possible utility of this treatment is suggested by three converging lines of evidence: (1) the effects of perinatal choline supplementation on cognition, cholinergic neurons, and protection against various types of brain damage [e.g., 27, 6]; (2) the role of nerve growth factor (NGF) in dementia and the effects of cholinergic activity on NGF; and (3) the effects of cholinergic activity on neurogenesis (coupled with the putative role of neurogenesis in protecting against neurodegeneration). This final line of evidence also suggests that early choline supplementation may protect against neurodegeneration and cognitive decline in the normal elderly. This is a 2 X 2 factorial design involving trisomic and WT mice, and perinatal treatment with choline or the
vehicle solution. The assessment of attentional functioning, conducted in the Strupp lab at Cornell, is proceeding smoothly. The first of the two cohorts of mice comprising the study were sent to Cornell in late summer; this cohort included approximately 10 mice in each of the 4 treatment conditions, defined by genotype (trisomic or normosomic) and perinatal treatment (choline or vehicle). After adaptation of the mice to the Cornell lab, testing began in early September for the oldest animals, who had reached 6 months of age, the age at which cholinergic degeneration is apparent, and attentional dysfunction is predicted for the untreated trisomic mice. Because the age of these animals spans approximately 2-3 months, some animals will not reach 6 months of age until November. The testing of this cohort will take 4-6 months. Another cohort of equal size (10 mice per group) will be sent to Cornell in March, providing a sample size of 20 animals per cell, which is needed to have
sufficient power to detect partial amelioration of the choline treatment (as it is possible that only partial amelioration may be found). The oldest animals in this second cohort of animals will reach 6 months of age in May 2006, the age at which testing can begin. These animals will be tested for 4-6 months. If this cohort also spans a 2-month age period, the testing of this second cohort should be completed by December 2006. At this time, the data from the automated attention tasks will be analyzed. In addition, videotapes of the animals performing the sustained attention task will be coded and analyzed to assess the efficacy of the choline treatment in ameliorating the error-induced stereotypic jumping seen in our previous study with these mice (Driscoll et al., 2004).
Impacts
This study will provide information about the possibility utility of early choline supplementation as a potential treatment for the aging related decline in Down syndrome (with the onset of Alzheimer's disease) as well as the potential of early choline supplementation to improve attention in normal individuals.
Publications
- Driscoll L.L., Carroll, J.C., Moon, J., Crnic, L.S. and Strupp, B.J. 2005. Sustained attention deficits and error-induced stereotypy in aged Ts65Dn mice: a mouse model of Down syndrome and Alzheimer disease. Neurotox Teratol 27(3), 375.
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Progress 01/01/04 to 12/31/04
Outputs
We completed a study in which we administered a battery of visual discrimination and attention tasks to Ts65Dn and control mice. We analyzed the data from the automated attention task and coded and analyzed videotapes of the animals performing the task. This study revealed that the trisomic mice, a model of Down syndrome, exhibited significant impairments in sustained attention and exhibited stereotypic jumping in response to committing an error, indicative of impaired arousal regulation. This is the first demonstration of attentional impairments and stress-induced stereotypy in a mouse model of Down syndrome. These findings provide important support for this validity of this model, and provide an important model system for studying the mechanism by which the brain is damaged in DS, and for testing possible interventions. This is also the first demonstration of naturally occurring stereotypy in a mouse model of mental retardation. Stress-induced sterotypic behavior is
viewed as a significant problem in humans with mental retardation and there has not previously been a model system with which treatments could be tested. We are currently starting a study involving perinatal choline supplemenetation of these mice and will test whether the cognitive deficits are ameliorated.
Impacts
These results provide important new support for the validity of the Ts65Dn mouse model for studying both Down syndrome and Alzheimers disease. Attentional dysfunction is an important phenotypic feature of both disorders and this has never before been assessed in this mouse model. These findings therefore lay the ground work for future studies designed to elucidate the pathogenic mechanism in these two disorders and test potential therapies. In addition, the demonstration of error-induced stereotypic behavior represents the first clear demonstration of naturally occurring stereotypic behavior in an animal model of a mental retardation syndrome. This provides the first model system for studying the neurochemical bases of this type of behavior which is critical for developing improved therapies.
Publications
- Driscoll LL; Carroll JC; Moon J-S; Crnic LS, Levitsky DA; Strupp BJ. 2004. Impaired Sustained attention and error-induced stereotypy in the aged Ts65Dn mouse, a mouse model of Down syndrome and Alzheimer disease. Behavioral Neuroscience, 2004, 118 (6): 1196-1205.
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Progress 01/01/03 to 12/31/03
Outputs
Individuals with Down Syndrome (DS) exhibit deficits in sustained attention which become more pronounced in mid-life, due to the degenerative changes associated with Alzheimer disease (AD), which occurs in all DS individuals between the ages of 20 and 30. During the past year we completed a study in which we assessed sustained and selective attention and reactivity to errors in the Ts65Dn mouse model of DS, to further assess the validity of this mouse model for studying DS and AD. Control (n=18) and Ts65Dn (n=16) male mice, aged 15-17 months, were administered two attention tasks: (1) a 5-choice visual sustained attention task in which the location, onset time, and duration of brief visual cues varied between trials, and (2) a similar task in which olfactory distracters were randomly presented on one third of the trials. In both tasks, the Ts65Dn mice missed the cues more frequently than controls and made more inaccurate responses, particularly on trials with the
briefest cues, implicating attentional dysfunction. Videotape data revealed that (a) the Ts65Dn mice attended less than controls to the response ports in the period prior to cue presentation; and (b) the majority of Ts65Dn mice engaged in repetitive vertical jumping bouts immediately after making an error, behavior rarely seen in controls. Although distractibility was comparable in the two groups during the first few sessions on the task, the controls were more proficient than the DS mice in overcoming the disruption produced by the distracters. The present findings support the validity of this mouse model for studying DS and AD, and provide the first animal model for studying the stress-induced stereotypy commonly observed in mental retardation syndromes.
Impacts
These results provide important new support for the validity of the Ts65Dn mouse model for studying both Down syndrome and Alzheimers disease. Attentional dysfunction is an important phenotypic feature of both disorders and this has never before been assessed in this mouse model. These findings therefore lay the ground work for future studies designed to elucidate the pathogenic mechanism in these two disorders and test potential therapies. In addition, the demonstration of error-induced stereotypic behavior represents the first clear demonstration of naturally occurring stereotypic behavior in an animal model of a mental retardation syndrome. This provides the first model system for studying the neurochemical bases of this type of behavior which is critical for developing improved therapies.
Publications
- Driscoll LL, Carroll, J.C., Moon, J., Crnic, L.S., & Strupp, B.J. 2003. Sustained attention deficits and error-induced stereotypy in aged Ts65Dn mice: a mouse model of Down syndrome and Alzheimer disease. Program No. 646.14. 2003 Abstract Viewer/Itinerary Planner. Washington, DC: Society for Neuroscience. Online
- Moon J., Driscoll, L.L., Crnic, L.S., & Strupp, B.J. 2003. Assessment of selective attention and error reactivity in aged Ts65Dn mice: a mouse model of Down syndrome (DS) and Alzheimer disease (AD). Program No. 114.21. 2003 Abstract Viewer/Itinerary Planner. Washington, DC: Society for Neuroscience. Online.
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