Assessment of the Effects of Perinatal Choline Treatment on Attention and Reactivity to Reward Omission in a Mouse Model of Down syndrome

Down syndrome (DS) is a genetic disorder caused by the trisomy of chromosome 21 in humans. Almost all individuals with DS also experience an early onset of Alzheimer's disease (AD) and show similar cognitive and learning deficits. There are currently no treatments for these deficits in DS. However, choline availability during the perinatal period has shown to have long-term benefits on memory and attentional function. This study utilized a series of attentional tests that evaluated the benefits of perinatal choline treatment in Ts65Dn mice, an animal model of Down syndrome. Specifically, we used the "Surprising Reward Omission" (SRO) Task in which an expected reward is omitted on 20% of the correct responses, to test attentional dysfunction and heightened error reactivity in these mice. Since previous SRO studies with Ts65Dn mice have shown an increase in locomotor activity and stereotypic behaviors such as jumping and grooming following reward omission, we supplemented our findings on overall performance with an analysis of video data We hypothesized that the Ts65Dn mice will exhibit an exaggerated response to the omission of an expected reward relative to controls, which will be reflected by their poor performance on the SRO task, and that choline treatment will alleviate these dysfunctions. Our results indicated that the unsupplemented Ts65Dn mice had significant attentional dysfunction and reacted to incorrect responses with increased activity level. These abnormalities in Ts65Dn mice were normalized by perinatal choline supplementation. The reward omission did not significantly affect the performance of any of the mice (in terms of correct responses). Yet the elevated alcove latencies and omission errors in unsupplemented Ts65Dn mice provided some indication of increased reaction to reward omission. We expect the behavioral video analysis (in progress) to elucidate the exact nature of these reactions and the effect of choline treatment on arousal regulation and subsequent behaviors in Ts65Dn mice. 2 Assessment of the Effects of Perinatal Choline Treatment INTRODUCnONANDBACKGROUND Down Syndrome Down syndrome (DS) is a genetic disorder caused by the trisomy of chromosome 21 in humans. It is the most common form of mental retardation with a known genetic basis. Individuals with DS have neuropathological abnormalities such as reduction in neuronal density, dendritic spine development, and synaptic function (Sea et al., 2005). Almost all individuals with DS also experience an early onset of Alzheimer's Disease (AD). The pattern of cognitive decline and neuropathology seen in both disorders are very similar. They include cognitive and learning deficits, attention deficits, and pathology such as neuritic plaques and neurofibrillary tangles (Salehi et al., 2006) A prominent neuropathological feature in both DS and AD is atrophy of basal forebrain cholinergic neurons (BFCNs), which provide the cholinergic innervation to the hippocampus and the cortex (Villar et aI., 2005; Hunter et aI., 2003). The frontal cortex is thought to be responsible for working memory and executive functions and the BFCNs playa key role in regulating these cognitive and attentional processes in both animals and humans (Kasa et al 1997). Similarly, in both humans and animals, the hippocampus subserves declarative or explicit memory function. Therefore, the impairments in memory and attentional function seen in DS is believed to be due to the atrophy of the BFCN that project, respectively, to the hippocampus and frontal cortex (Driscoll et aI., 2004; Hyde et aI., 2001).