Biology subjects

Whittaker, H. T.

Publications and source records attributed to Whittaker, H. T..

3 recordsLinked to original sources

bioRxiv2024

Information-based rhythmic transcranial magnetic stimulation accelerates learning during auditory working memory training.

Rhythmic transcranial magnetic stimulation (rhTMS) has been shown to enhance auditory working memory manipulation, specifically by boosting theta oscillatory power in the dorsal auditory pathway during task performance. It remains unclear whether these enhancements i) persist beyond the period of stimulation, ii) if they can accelerate learning and iii) if they would accumulate over several days of stimulation. In the present study, we investigated the lasting behavioural and electrophysiological effects of applying rhTMS over the left intraparietal sulcus (IPS) throughout the course of seven sessions of cognitive training on an auditory working memory task. Fourteen neurologically healthy participants took part in the training protocol with an auditory working memory task while being stimulated with either theta (5Hz) rhTMS or sham TMS. Electroencephalography (EEG) was recorded before, throughout five training sessions and after the end of training to assess to effects of rhTMS on behavioural performance and on oscillatory entrainment of the dorsal auditory network. We show that this combined approach enhances theta oscillatory activity within the fronto-parietal network and causes improvements in auditory working memory performance. We show that compared to individuals who received sham stimulation, cognitive training can be accelerated when combined with optimized rhTMS, and that task performance benefits can outlast the training period by up to 3 days. Furthermore, we show that there is increased theta oscillatory power within the recruited dorsal auditory network during training, and that sustained EEG changes can be observed up to 3 days following stimulation. The present study improves our understanding of the causal dynamic interactions supporting auditory working memory. Our results constitute an important proof of concept for the potential translational impact of non-invasive brain stimulation protocols and provide preliminary data for developing optimized rhTMS and training protocols that could be implemented in clinical populations.

neuroscience↗

bioRxiv2020

The effects of CSTB duplication on APP/amyloid-β pathology and cathepsin activity in a mouse model

People with Down syndrome (DS), caused by trisomy of chromosome 21 have a greatly increased risk of developing Alzheimers disease (AD). This is in part because of triplication of a chromosome 21 gene, APP. This gene encodes amyloid precursor protein, which is cleaved to form amyloid-{beta} that accumulates in the brains of people who have AD. Recent experimental results demonstrate that a gene or genes on chromosome 21, other than APP, when triplicated significantly accelerate amyloid pathology in a transgenic mouse model of amyloid-{beta} deposition. Multiple lines of evidence indicate that cysteine cathepsin activity influences APP cleavage and amyloid-{beta} accumulation. Located on human chromosome 21 (Hsa21) is an endogenous inhibitor of cathepsin proteases, CYSTATIN B (CSTB) which is proposed to regulate cysteine cathepsin activity in vivo. Here we determined if three copies of the mouse gene Cstb is sufficient to modulate beta amyloid (A{beta}) accumulation and cathepsin activity in a transgenic APP mouse model. Duplication of Cstb resulted in an increase in transcriptional and translational levels of Cstb in the mouse cortex but had no effect on the deposition of insoluble A{beta} plaques or the levels of soluble or insoluble A{beta}42, A{beta}40, or A{beta}38 in 6-month old mice. In addition, the increased CSTB did not alter the activity of cathepsin B enzyme in the cortex of 3-month old mice. These results indicate that the single-gene duplication of Cstb is insufficient to elicit a disease-modifying phenotype in the dupCstb x tgAPP mice, underscoring the complexity of the genetic basis of AD-DS and the importance of multiple gene interactions in disease.

neuroscience↗

bioRxiv2020

Genetic dissection of Down syndrome-associated alterations in APP/amyloid-β biology using mouse models

Individuals who have Down syndrome (caused by trisomy of chromosome 21), have a greatly elevated risk of early-onset Alzheimers disease, in which amyloid-{beta} accumulates in the brain. Amyloid-{beta} is a product of the chromosome 21 gene APP (amyloid precursor protein) and the extra copy or dose of APP is thought to be the cause of this early-onset Alzheimers disease. However, other chromosome 21 genes likely modulate disease when in three-copies in people with Down syndrome. Here we show that an extra copy of chromosome 21 genes, other than APP, influences APP/A{beta} biology. We crossed Down syndrome mouse models with partial trisomies, to an APP transgenic model and found that extra copies of subgroups of chromosome 21 gene(s) modulate amyloid-{beta} aggregation and APP transgene-associated mortality, independently of changing amyloid precursor protein abundance. Thus, genes on chromosome 21, other than APP, likely modulate Alzheimers disease in people who have Down syndrome.

neuroscience↗