Department of Psychology Works

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Browsing Department of Psychology Works by Author "Abeysekera, Irushi"

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    Can Epigallocatechin gallate (EGCG) Treatment Rescue Hippocampal-Dependent Cognitive Function in a Down Syndrome Mouse Model?
    (Office of the Vice Chancellor for Research, 2016-04-08) East, Audrey; Stringer, Megan; Abeysekera, Irushi; Goodlett, Charles R.; Roper, Randall J.
    Down Syndrome (DS) is caused by the trisomy of human chromosome 21 (Hsa21). Trisomy 21 can cause various behavioral, cognitive, learning and memory deficits. Deficits in hippocampal structure and function have been identified in mouse models of DS and are implicated in cognitive and learning impairments. Mouse models have suggested that deficits in cognitive function are associated with overexpression of Dyrk1a, a gene on Hsa21 found in three copies of individuals with DS. Dyrk1a is a gene that is involved in brain development and function. Ts65Dn DS model mice exhibit trisomy for approximately half of the genes on Hsa21 including Dyrk1a and exhibit cognitive and learning impairments. We are using Ts65Dn mice to test the effects of Epigallocatechin gallate (EGCG), a Dyrk1a inhibitor, on Dyrk1a activity and cognitive function. We hypothesize that EGCG will reduce Dyrk1a activity in the hippocampus and improve hippocampal-dependent spatial learning and memory in the Morris water maze place learning task in Ts65Dn mice. The mice were given daily EGCG treatment (200 mg/kg per day) by means of oral gavage beginning on postnatal day 54 and continuing throughout water maze testing (postnatal days 67-74). Measures of spatial learning included latency and path length to find a submerged platform during acquisition trials (postnatal days 67-73). Memory for the previously learned location of the platform was assessed on a probe trial (postnatal day 74) in which the platform was removed and the amount of time spent swimming in the area of the tank previously containing the platform was measured. These measures allowed us to analyze the mice’s ability to learn and remember the position of the platform and to spatially orient themselves. Preliminary data indicates that EGCG treatment may not be an effective treatment for the spatial learning and memory deficits evident in this mouse model of DS.
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    Correction of cerebellar movement related deficits by normalizing Dyrk1a copy number in the Ts65Dn mouse model for Down syndrome
    (Office of the Vice Chancellor for Research, 2016-04-08) Patel, Roshni; Stringer, Megan; Abeysekera, Irushi; Roper, Randall J.; Goodlett, Charles R.
    Elucidation of the underlying mechanisms involved in brain related deficits of Down syndrome (DS) would be useful for consideration of therapeutic interventions. Several DSspecific phenotypes have been hypothesized to be linked to altered expression or function of specific trisomic genes. One such gene of interest is D YRK1A , which has been implicated in behavioral functions of the hippocampus and cerebellum. The Ts65Dn mouse model for DS includes a triplication of D yrk1a in addition to a triplication of >100 other human chromosome 21 mouse orthologs. To evaluate the role of D yrk1a in cerebellar function, we have genetically normalized the D yrk1a copy number in otherwise trisomicTs65Dn mice and reduced D yrk1a copy number in otherwise euploid mice (2N) for a total of 3 alternative genetic doses of D yrk1a: EuploidDyrk1a +/+ , EuploidDyrk1a +/, Ts65DnDyrk1a +/+/+ , and Ts65DnDyrk1a +/+/. Cerebellar movementrelated function in these knockdown models is being assessed through a novel behavioral balance beam task. Additionally, levels of D yrk1a activity in the cerebellum for all genotypes were analyzed by HPLC. We have previously demonstrated that Ts65DnDyrk1a +/+/+ mice perform worse in the balance beam task in comparison to EuploidDyrk1a +/+ mice. Preliminary results of the current study do not indicate such a difference among Ts65DnDyrk1a +/+/+ mice in comparison to EuploidDyrk1a +/+ mice. We hypothesize that the lack of replication of the previous findings may be due to differences in postweaning housing environments. Mice in the previous study were singlehoused, whereas mice in the present study were grouphoused, which may help mitigate motor deficits in the trisomic mice. Additionally, current trends display a deficit in balance beam performance of both the EuploidDyrk1a +/and the Ts65DnDyrk1a +/+/groups, which suggests that reducing the copy number of D yrk1a by one may have detrimental effects on motor coordination. Concomitant analysis of the balance beam performances and Dyrk1a activity levels may indicate the sensitivity of the balance beam task to assess the role Dyrk1a activity in cerebellar function.
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    The Effect of 200mg/kg EGCG Oral Gavage Treatment on the Cerebellar-Dependent Behavior in a Down Syndrome Mouse Model
    (Office of the Vice Chancellor for Research, 2016-04-08) Dalman, Noriel; Stringer, Megan; Abeysekera, Irushi; East, Audrey; Patel, Roshni; Roper, Randall J.; Goodlett, Charles R.
    Trisomy 21 (Ts21) causes deficits in motor and cognitive ability that are hallmark phenotypes in Down syndrome (DS). The Ts65Dn mouse model of DS has about 50% of the orthologous genes that are triplicated from human chromosome 21, including the Dual specificity tyrosinephosphorylation-regulated kinase 1A (Dyrk1A) gene. Three copies of Dyrk1A have been implicated in the motor and cognitive deficits and altered cerebellar structure and function may contribute these impairments in Ts65Dn mice. Epigallocatechin 3-gallate (EGCG) is a catechin found in green tea and an inhibitor of Dyrk1A activity. We hypothesize that a 200mg/kg EGCG treatment given by oral gavage will inhibit Dyrk1A activity in the cerebellum of Ts65Dn mice and rescue deficits in motor coordination while performing the balance beam task. Evidence of improvement in this task would be observed as a reduction of paw slips as the animal traverses across beams of varying widths. In previous studies, EGCG treatment was placed in the animal’s water to be consumed but EGCG rapidly degrades in solution and it is difficult to control treatment doses via treatment in drinking water, due to each animal’s consumption behavior. This study utilized a daily oral gavage treatment of EGCG to control the dose and limits loss due to degradation. Results to date indicate that the Ts65Dn mice show deficits on the balance beam task relative to the euploid mice, particularly at the narrowest beam width used. The EGCG treatment does not appear to improve the performance of the Ts65Dn mice, though the lack of observed effects of EGCG may be due to the relatively low numbers of Ts65Dn-EGCG treated mice that have completed testing so far. One notable trend is that we will continue to test additional mice to gain sufficient power to determine conclusively whether EGCG improves motor coordination performance in Ts65Dn mice.
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    Effects of EGCG treatment on deficits in a radial-arm maze spatial pattern separation task in a Down syndrome mouse model
    (Office of the Vice Chancellor for Research, 2015-04-17) Stringer, Megan; Stancombe, Kailey; Gainey, Sean; Sheikh, Zahir; Abeysekera, Irushi; Goodlett, Charles R.; Roper, Randall J.
    Down syndrome (DS) is caused by three copies of human chromosome 21 (Hsa 21) and results in a constellation of phenotypes that include intellectual disability. Ts65Dn mice, the most extensively studied model of DS, have three copies of approximately half the genes on Hsa 21 and display many of the phenotypes associated with DS, including cognitive deficits. DYRK1A is found in three copies in humans with Trisomy 21 and has increased expression in a number of tissues. Dyrk1a is also found in three copies in Ts65Dn mice, and has been shown to be involved in a number of critical pathways including CNS development and osteoclastogenesis. Epigallocatechin-3-gallate (EGCG), the main polyphenol found in green tea, is an inhibitor of Dyrk1a activity. We have previously shown that a three week treatment with EGCG normalizes skeletal abnormalities in Ts65Dn mice. Previous work has found that Ts65Dn mice are significantly impaired in several hippocampal-dependent tasks, including the Morris water maze and novel object recognition. Another hippocampal-dependent process, pattern separation, is the ability to differentiate between similar memories acquired during learning. Distinctive encoding of these similar memories in hippocampal formation is thought to be necessary to distinguish between them. Experimental reductions in adult neurogenesis have produced impairments in pattern separation performance. Given that recent studies in Ts65Dn mice have reported significant reductions in adult hippocampal neurogenesis, we hypothesize that Ts65Dn mice will be impaired in the pattern separation task. Furthermore, we hypothesize that treating Ts65Dn mice with EGCG throughout task learning would improve performance to control levels. A radial arm maze-delayed non-matching-toplace pattern separation task with three different degrees of spatial separation is used. Preliminary data suggests that, in contrast to control mice, Ts65Dn mice do not improve their performance over training.
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    Effects of Epigallcatechin-3-gallate in Novel Object Recognition of Ts65Dn Down Syndrome Mice
    (Office of the Vice Chancellor for Research, 2015-04-17) Minhas, Saniya; Abeysekera, Irushi; Delgado, Fatima; Dhillon, Hardeep; Goodlett, Charles R.; Roper, Randall J.
    Down syndrome (DS) is one of the most common genetic disorders and has an incidence of 1/700 births; which can lead to many impairments, both physically and mentally. All individuals with DS have cognitive impairments which results in learning and memory deficits. To study these deficits, we use the Ts65Dn mouse model that carries trisomy of approximately 50% of the genes found on human chromosome 21. DYRK1A, a gene found in three copies in both humans with DS and Ts65Dn mice has been shown to have increased expression in the brains of humans with DS. DYRK1A protein is involved in a number of critical pathways including CNS development. Epigallcatechin-3-gallate (EGCG), the main polyphenolic compound found in green tea, inhibits DYRK1A. We hypothesize that EGCG treatment help improve cognitive deficits in trisomic mice. After treatment, the mice were subjected to behavioral tasks, including the Novel Object Recognition (NOR) test. Our results indicate that there was a significant difference that existed due to trisomy in Ts65Dn mice; but there was no significant effect of a low dose EGCG treatment. Further studies are examining the effects of the NOR task after a higher dose EGCG treatment.
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    Effects of Increased Dosage EGCG Treatment on Cognitive Deficits in the Ts65Dn Down Syndrome Mouse Model
    (Office of the Vice Chancellor for Research, 2015-04-17) Dhillon, Hardeep; Abeysekera, Irushi; Stringer, Megan; Goodlett, Charles R.; Roper, Randall J.
    Down syndrome (DS), caused by trisomy of human chromosome 21 (Hsa21), is the leading genetic cause of cognitive impairment and results in a constellation of phenotypes. Although symptomatic and therapeutic treatments exist for some DS phenotypes, treatments generally do not address the genetic etiology. The Ts65Dn mouse model, which contains a triplication of approximately half the gene orthologs of Hsa21, exhibits hippocampal learning and memory deficits as well as cerebellar motor and spatial deficits similar to those present in individuals with DS. DYRK1A, one of the genes overexpressed in DS, has been identified as a potential cause of cognitive impairment; therefore normalization of DYRK1A activity may be a valid form of treatment. We have shown that Epigallocatechin-3-gallate (EGCG), a major polyphenol of green tea, can rescue skeletal deficits found in the Ts65Dn mouse model at a low dosage. When this same low dosage was used to rescue behavioral deficits, however, it was ineffective. We hypothesize that high dose EGCG treatment lasting throughout the behavioral testing period will rescue the cognitive deficits observed in Ts65Dn mice. Trisomic mice and euploid littermates were given EGCG or water (control) for 7 weeks while being tested sequentially on novel object recognition (NOR) and Morris water maze (MWM). Our current data set shows that Ts65Dn mice exhibit deficits in learning and memory; further data will be collected in order to identify the effect of EGCG. Data showing pure EGCG as being ineffective will suggest the importance adding a supplemental compound, while data showing pure EGCG as an effective form of treatment will strongly support use of EGCG in translational studies in individuals with Down syndrome.
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    Epigallocatechin-3-gallate (EGCG) consumption in the Ts65Dn model of Down syndrome fails to improve behavioral deficits and is detrimental to skeletal phenotypes
    (Elsevier, 2017-08-01) Stringer, Megan; Abeysekera, Irushi; Thomas, Jared; LaCombe, Jonathan; Stancombe, Kailey; Stewart, Robert J.; Dria, Karl J.; Wallace, Joseph M.; Goodlett, Charles R.; Roper, Randall J.; Psychology, School of Science
    Down syndrome (DS) is caused by three copies of human chromosome 21 (Hsa21) and results in phenotypes including intellectual disability and skeletal deficits. Ts65Dn mice have three copies of ~50% of the genes homologous to Hsa21 and display phenotypes associated with DS, including cognitive deficits and skeletal abnormalities. DYRK1A is found in three copies in humans with Trisomy 21 and in Ts65Dn mice, and is involved in a number of critical pathways including neurological development and osteoclastogenesis. Epigallocatechin-3-gallate (EGCG), the main polyphenol in green tea, inhibits Dyrk1a activity. We have previously shown that EGCG treatment (~10mg/kg/day) improves skeletal abnormalities in Ts65Dn mice, yet the same dose, as well as ~20mg/kg/day did not rescue deficits in the Morris water maze spatial learning task (MWM), novel object recognition (NOR) or balance beam task (BB). In contrast, a recent study reported that an EGCG-containing supplement with a dose of 2-3mg per day (~40-60mg/kg/day) improved hippocampal-dependent task deficits in Ts65Dn mice. The current study investigated if an EGCG dosage similar to that study would yield similar improvements in either cognitive or skeletal deficits. Ts65Dn mice and euploid littermates were given EGCG [0.4mg/mL] or a water control, with treatments yielding average daily intakes of ~50mg/kg/day EGCG, and tested on the multivariate concentric square field (MCSF)-which assesses activity, exploratory behavior, risk assessment, risk taking, and shelter seeking-and NOR, BB, and MWM. EGCG treatment failed to improve cognitive deficits; EGCG also produced several detrimental effects on skeleton in both genotypes. In a refined HPLC-based assay, its first application in Ts65Dn mice, EGCG treatment significantly reduced kinase activity in femora but not in the cerebral cortex, cerebellum, or hippocampus. Counter to expectation, 9-week-old Ts65Dn mice exhibited a decrease in Dyrk1a protein levels in Western blot analysis in the cerebellum. The lack of beneficial therapeutic behavioral effects and potentially detrimental skeletal effects of EGCG found in Ts65Dn mice emphasize the importance of identifying dosages of EGCG that reliably improve DS phenotypes and linking those effects to actions of EGCG (or EGCG-containing supplements) in specific targets in brain and bone.
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    Low dose EGCG treatment beginning in adolescence does not improve cognitive impairment in a Down syndrome mouse model
    (Elsevier, 2015-11) Stringer, Megan; Abeysekera, Irushi; Dria, Karl J.; Roper, Randall J.; Goodlett, Charles R.; Biology, School of Science
    Down syndrome (DS) or Trisomy 21 causes intellectual disabilities in humans and the Ts65Dn DS mouse model is deficient in learning and memory tasks. DYRK1A is triplicated in DS and Ts65Dn mice. Ts65Dn mice were given up to ~ 20 mg/kg/day epigallocatechin-3-gallate (EGCG), a Dyrk1a inhibitor, or water beginning on postnatal day 24 and continuing for three or seven weeks, and were tested on a series of behavioral and learning tasks, including a novel balance beam test. Ts65Dn as compared to control mice exhibited higher locomotor activity, impaired novel object recognition, impaired balance beam and decreased spatial learning and memory. Neither EGCG treatment improved performance of the Ts65Dn mice on these tasks. Ts65Dn mice had a non-significant increase in Dyrk1a activity in the hippocampus and cerebellum. Given the translational value of the Ts65Dn mouse model, further studies will be needed to identify the EGCG doses (and mechanisms) that may improve cognitive function.