Biology subjects

Matheos, D. P.

Publications and source records attributed to Matheos, D. P..

5 recordsLinked to original sources

bioRxiv2021

Systematic phenotyping and characterization of the 3xTg-AD mouse model of Alzheimer's Disease

Animal models of disease are valuable resources for investigating pathogenic mechanisms and potential therapeutic interventions. However, for complex disorders such as Alzheimers disease (AD), the generation and availability of innumerous distinct animal models present unique challenges to AD researchers and hinder the success of useful therapies. Here, we conducted an in-depth analysis of the 3xTg-AD mouse model of AD across its lifespan to better inform the field of the various pathologies that appear at specific ages, and comment on drift that has occurred in the development of pathology in this line since its development 20 years ago. This modern characterization of the 3xTg-AD model includes an assessment of impairments in behavior, cognition, and long-term potentiation followed by quantification of amyloid beta (A{beta}) plaque burden and neurofibrillary tau tangles, biochemical levels of A{beta} and tau protein, and neuropathological markers such as gliosis and accumulation of dystrophic neurites. We also present a novel comparison of the 3xTg-AD model with the 5xFAD model using the same deep-phenotyping characterization pipeline. The results from these analyses are freely available via the AD Knowledge Portal (https://admodelexplorer.synapse.org). Our work demonstrates the utility of a characterization pipeline that generates robust and standardized information relevant to investigating and comparing disease etiologies of current and future models of AD. Contribution to the Field StatementAlzheimers Disease (AD) is an age-related neurodegenerative disorder characterized by progressive memory impairments and affects more than 30 million individuals worldwide. Using animal models of AD, researchers have elucidated disease progression and hallmark pathologies that may underpin the memory impairments seen in patients. However, therapeutic targets have failed to translate successfully from animal studies to human clinical trials, prompting a reassessment of the development, use, and interpretation of data acquired using the innumerous AD animal models available to researchers. To address these shortcomings, we have developed a robust and reproducible modern characterization of pathologies within current and future animal models of AD to better assess distinct pathologies that arise at specific brain regions and ages of different models. Using the popular 3xTg-AD mouse, we demonstrate the utility of these deep-phenotyping analyses and highlight the drift that affected development of pathologies in this line over the past two decades. Utilizing this same systematic characterization, we also perform a direct comparison with 5xFAD mice, another popular animal model of AD. The robust and standardized data generated from these systematic deep-phenotyping analyses are available for broad use by the AD research community to assess, compare, and determine appropriate animal models of AD.

neuroscience↗

bioRxiv2021

Systematic Phenotyping and Characterization of the 5xFAD mouse model of Alzheimer's Disease

Mouse models of human diseases are invaluable tools for studying pathogenic mechanisms and testing interventions and therapeutics. For disorders such as Alzheimers disease in which numerous models are being generated, a challenging first step is to identify the most appropriate model and age to effectively evaluate new therapeutic approaches. Here we conducted a detailed phenotypic characterization of the 5xFAD model on a congenic C57BL/6J strain background, across its lifespan - including a seldomly analyzed 18-month old time point to provide temporally correlated phenotyping of this model and a template for characterization of new models of LOAD as they are generated. This comprehensive analysis included quantification of plaque burden, A{beta} biochemical levels, and neuropathology, neurophysiological measurements and behavioral and cognitive assessments, and evaluation of microglia, astrocytes, and neurons. Analysis of transcriptional changes was conducted using bulk-tissue generated RNA-seq data from microdissected cortices and hippocampi as a function of aging, which can be explored at the UCI Mouse Explorer and AD Knowledge Portal. This deep-phenotyping pipeline identified novel aspects of age-related pathology in the 5xFAD model.

neuroscience↗

bioRxiv2018

PP4-dependent HDAC3 dephosphorylation discriminates between axonal regeneration and regenerative failure

The molecular mechanisms discriminating between regenerative failure and success remain elusive. While a regeneration-competent peripheral nerve injury mounts a regenerative gene expression response in bipolar dorsal root ganglia (DRG) sensory neurons, a regeneration-incompetent central spinal cord injury does not. This dichotomic response offers a unique opportunity to investigate the fundamental biological mechanisms underpinning regenerative ability. Following a pharmacological screen with small molecule inhibitors targeting key epigenetic enzymes in DRG neurons we identified HDAC3 signalling as a novel candidate brake to axonal regenerative growth. In vivo, we determined that only a regenerative peripheral but not a central spinal injury induces an increase in calcium, which activates protein phosphatase 4 that in turn dephosphorylates HDAC3 thus impairing its activity and enhancing histone acetylation. Bioinformatics analysis of ex vivo H3K9ac ChIPseq and RNAseq from DRG followed by promoter acetylation and protein expression studies implicated HDAC3 in the regulation of multiple regenerative pathways. Finally, genetic or pharmacological HDAC3 inhibition overcame regenerative failure of sensory axons following spinal cord injury. Together, these data indicate that PP4-dependent HDAC3 dephosphorylation discriminates between axonal regeneration and regenerative failure.\n\n\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=122 SRC=\"FIGDIR/small/446963_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (40K):\norg.highwire.dtl.DTLVardef@1bd577corg.highwire.dtl.DTLVardef@1ba990aorg.highwire.dtl.DTLVardef@195813corg.highwire.dtl.DTLVardef@57abc7_HPS_FORMAT_FIGEXP M_FIG Graphical AbstractFollowing central nervous system (CNS) spinal injury, protein phosphatase 4/2 activity is not induced since calcium levels remain unchanged compared to uninjured conditions. HDAC3 remains phosphorylated and occupies deacetylated chromatin contributing to its compaction inhibiting gene expression. Following peripheral nervous system (PNS) sciatic injury, protein phosphatase 4/2 activity is induced by calcium. HDAC3 is dephosphorylated leading to its inhibition and release from chromatin sites contributing to increase in histone acetylation and in the expression of regeneration associated genes (RAGs).\n\nC_FIG

neuroscience↗

bioRxiv2018

Epigenetic regulation of the circadian gene Per1 in the hippocampus mediates age-related changes in memory and synaptic plasticity

Aging is accompanied by impairments in both circadian rhythmicity and long-term memory. Although it is clear that memory performance is affected by circadian cycling, it is unknown whether age-related disruption of the circadian clock causes impaired hippocampal memory. Here, we show that the repressive histone deacetylase HDAC3 restricts long-term memory, synaptic plasticity, and learning-induced expression of the circadian gene Per1 in the aging hippocampus without affecting rhythmic circadian activity patterns. We also demonstrate that hippocampal Per1 is critical for long-term memory formation. Together, our data challenge the traditional idea that alterations in the core circadian clock drive circadian-related changes in memory formation and instead argue for a more autonomous role for circadian clock gene function in hippocampal cells to gate the likelihood of long-term memory formation.

neuroscience↗

bioRxiv2017

Habits are negatively regulated by HDAC3 in the dorsal striatum

Optimal behavior results from a balance of control between two strategies, one cognitive/goal-directed and one habitual, which rely on the anatomically distinct dorsomedial (DMS) and dorsolateral (DLS) striatum, respectively. The transcriptional regulatory mechanisms required to learn and transition between these strategies are unknown. Here we identified a critical negative regulator of habit learning. Histone deacetylase (HDAC) inhibition following instrumental conditioning accelerated habitual control of behavior. HDAC3, a transcriptional repressor, was removed from the promoters of learning-related genes in the dorsal striatum as habits formed with overtraining and with post-training HDAC inhibition. Decreasing HDAC3 function in the DLS accelerated habit formation, while DLS HDAC3 overexpression prevented habit. HDAC3 activity in the DMS was also found to constrain habit formation. These results challenge the strict dissociation between DMS and DLS function in goal-directed v. habitual behavioral control and identify dorsal striatal HDAC3 as a critical molecular substrate of the transition to habit.

neuroscience↗