Mice expressing P301S mutant human tau have deficits in interval timing

Larson, Travis; Khandelwal, Vaibhav; Weber, Matthew A.; Leidinger, Mariah; Meyerholz, David K.; Narayanan, Nandakumar S.; Zhang, Qiang

doi:10.1016/j.bbr.2022.113967

Cited by 15 publications

(17 citation statements)

References 39 publications

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“…We trained 35 mice starting at ~14-16 weeks of age to perform an interval timing task in which mice switched from one nosepoke to another based on internal timing cues to get a food reward (Fig. 1a) [14][15][16] . In these animals, we injected vehicle (0.03% ascorbic acid) as a surgical control or 6-OHDA to deplete dopamine in the VTA, which we have previously shown impairs interval timing 9,11,13 .…”

Section: Results Vta 6-ohda Increases Interval Timing Variabilitymentioning

confidence: 99%

“…Increased interval timing variability models some aspects of cognitive dysfunction in PD and Alzheimer's disease patients 8,9,11,16,17 . Importantly, the VTA is involved in PD and degenerates through the course of the disease 18 .…”

Section: Discussionmentioning

confidence: 99%

“…The interval timing switch task is designed to capture an animal's internal representation of time [14][15][16]23 , as in other interval timing tasks 13,24 . Mice are trained to switch from a short to a long nosepoke after approximately 6 s. This switch is an explicit timebased decision that requires working memory for temporal rules and attention to the passage of time, and models cognitive deficits in neurodegenerative disease 8,9,16,17 .…”

Section: Interval Timing Switch Taskmentioning

confidence: 99%

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Glycolysis-enhancing α1-adrenergic antagonists modify cognitive symptoms related to Parkinson’s disease

Weber

Sivakumar²,

Tabakovic³

et al. 2023

npj Parkinsons Dis.

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Terazosin is an α1-adrenergic receptor antagonist that enhances glycolysis and increases cellular ATP by binding to the enzyme phosphoglycerate kinase 1 (PGK1). Recent work has shown that terazosin is protective against motor dysfunction in rodent models of Parkinson’s disease (PD) and is associated with slowed motor symptom progression in PD patients. However, PD is also characterized by profound cognitive symptoms. We tested the hypothesis that terazosin protects against cognitive symptoms associated with PD. We report two main results. First, in rodents with ventral tegmental area (VTA) dopamine depletion modeling aspects of PD-related cognitive dysfunction, we found that terazosin preserved cognitive function. Second, we found that after matching for demographics, comorbidities, and disease duration, PD patients newly started on terazosin, alfuzosin, or doxazosin had a lower hazard of being diagnosed with dementia compared to tamsulosin, an α1-adrenergic receptor antagonist that does not enhance glycolysis. Together, these findings suggest that in addition to slowing motor symptom progression, glycolysis-enhancing drugs protect against cognitive symptoms of PD.

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Section: Results Vta 6-ohda Increases Interval Timing Variabilitymentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Interval Timing Switch Taskmentioning

confidence: 99%

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Glycolysis-enhancing α1-adrenergic antagonists modify cognitive symptoms related to Parkinson’s disease

Weber

Sivakumar²,

Tabakovic³

et al. 2023

npj Parkinsons Dis.

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“…We adapted an interval timing switch task used previously in rodents and humans (Balci et al, 2009; Larson et al, 2022; Weber et al, 2023). This task required participants to estimate when a short interval (2 s) had elapsed by switching response keys before the end of a longer interval (3 s; Figure 1A).…”

Section: Methodsmentioning

confidence: 99%

Sex similarities and dopaminergic differences in interval timing.

Stutt,

Weber,

Cole

et al. 2024

Behavioral Neuroscience

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“…All mice were trained to perform an interval timing switch task described in detail previously (Balci et al, 2008; Bruce et al, 2021; Larson et al, 2022; Weber et al, 2022). Interval timing behavior was assessed on two occasions: 1) 12 mpi; 2) 20 mpi.…”

Section: Methodsmentioning

confidence: 99%

Alpha-synuclein pre-formed fibrils injected into prefrontal cortex primarily spread to cortical and subcortical structures and lead to isolated behavioral symptoms

Weber

Choisy

Thangavel

et al. 2023

Preprint

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Parkinson's disease dementia (PDD) and Lewy Body dementia (LBD) are characterized by diffuse spread of alpha-synuclein (α-syn) throughout the brain. These patients have a neuropsychological pattern of deficits that include executive dysfunction, including abnormalities in planning, timing, working memory, and behavioral flexibility. The prefrontal cortex (PFC) plays a major role in normal executive function and often develops α-syn aggregates in LBD and PDD. To investigate the consequences of α-syn pathology in the cortex, we injected human α-syn pre-formed fibrils into the PFC of wildtype mice. We report that PFC PFFs: 1) induced α-syn deposition in multiple cortical and subcortical regions with sparse aggregation in midbrain and brainstem nuclei; 2) did not affect interval timing or working memory but did mildly alter behavioral flexibility as measured by reversal learning; 3) increased open field exploration; and 4) did not affect susceptibility to an inflammatory challenge. This model of cortical-dominant pathology adds to our understanding of the etiology of varied symptoms in PDD and LBD.

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Mice expressing P301S mutant human tau have deficits in interval timing

Cited by 15 publications

References 39 publications

Glycolysis-enhancing α1-adrenergic antagonists modify cognitive symptoms related to Parkinson’s disease

Glycolysis-enhancing α1-adrenergic antagonists modify cognitive symptoms related to Parkinson’s disease

Sex similarities and dopaminergic differences in interval timing.

Alpha-synuclein pre-formed fibrils injected into prefrontal cortex primarily spread to cortical and subcortical structures and lead to isolated behavioral symptoms

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