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Weber, M. A.

Publications and source records attributed to Weber, M. A..

2 recordsLinked to original sources

Mice expressing P301S mutant human tau have deficits in interval timing

Interval timing is a key executive process that involves estimating the duration of an interval over several seconds or minutes. Patients with Alzheimers disease (AD) have deficits in interval timing. Since temporal control of action is highly conserved across mammalian species, studying interval timing tasks in animal AD models may be relevant to human disease. Amyloid plaques and tau neurofibrillary tangles are hallmark features of AD. While rodent models of amyloid pathology are known to have interval timing impairments, to our knowledge, interval timing has not been studied in models of tauopathy. Here, we evaluate interval timing performance of P301S transgenic mice, a widely studied model of tauopathy that overexpresses human tau with the P301S mutation. We employed the switch interval timing task, and found that P301S mice consistently underestimated temporal intervals compared to wild-type controls, responding early in anticipation of the target interval. Our study indicating timing deficits in a mouse tauopathy model could have relevance to human tauopathies such as AD. HIGHLIGHTSO_LIWe examined interval timing behavior in mice expressing P301S mutant tau C_LIO_LIP301S mice responded earler than littermate controls C_LIO_LIThese data provide insight into animal models of tauopathy C_LI

neuroscience↗

Quantifying the inverted U: A meta-analysis of prefrontal dopamine, D1-receptors, and working memory

Dopamine in the prefrontal cortex can be disrupted in human disorders that affect cognitive function such as Parkinsons disease (PD), attention-deficit hyperactivity disorder (ADHD), and schizophrenia. Dopamine has a powerful effect on prefrontal circuits via the D1-type dopamine receptor (D1DR). It has been proposed that prefrontal dopamine has "inverted U-shaped" dynamics, with optimal dopamine and D1DR signaling required for optimal cognitive function. However, the quantitative relationship between prefrontal dopamine and cognitive function is not clear. Here, we conducted a meta-analysis of published manipulations of prefrontal dopamine and the effects on working memory, a high-level executive function in humans, primates, and rodents that involves maintaining and manipulating information over seconds to minutes. We reviewed 646 papers and found that 75 studies met criteria for inclusion. Our quantification of effect sizes for dopamine, D1DRs, and behavior revealed a negative quadratic slope. This is consistent with the proposed inverted U-shape of prefrontal dopamine and D1DRs and working memory performance, explaining 10% of the variance. Of note, the inverted quadratic fit was much stronger for prefrontal D1DRs alone, explaining 26% of the variance, compared to prefrontal dopamine alone, explaining 10% of the variance. Taken together, these data, derived from a variety of manipulations and systems, demonstrate that optimal prefrontal dopamine signalling is linked with higher cognitive function. Our results provide insight into the fundamental dynamics of prefrontal dopamine, which could be useful for pharmacological interventions targeting prefrontal dopaminergic circuits, and into the pathophysiology of human brain disease.

neuroscience↗