44f30ad56db3767746e615a17a307727 brainsci_a2021v11n4p426.pdf b07a424b0d4b00ece607174c4661c507d0d6d745 brainsci_a2021v11n4p426.pdf 17ef31da449fa61399e28fcdc5f010a22ce16290c228249b03f8e7da606332d4 brainsci_a2021v11n4p426.pdf Title: Clock/Sleep-Dependent Learning and Memory in Male 3xTg-AD Mice at Advanced Disease Stages and Extrinsic Effects of Huprine X and the Novel Multitarget Agent AVCRI104P3 Subject: A new hypothesis highlights sleep-dependent learning/memory consolidation and regards the sleep-wake cycle as a modulator of -amyloid and tau Alzheimer’s disease (AD) pathologies. Sundowning behavior is a common neuropsychiatric symptom (NPS) associated with dementia. Sleep fragmentation resulting from disturbances in sleep and circadian rhythms in AD may have important consequences on memory processes and exacerbate the other AD-NPS. The present work studied the effect of training time schedules on 12-month-old male 3xTg-AD mice modeling advanced disease stages. Their performance in two paradigms of the Morris water maze for spatial-reference and visual-perceptual learning and memory were found impaired at midday, after 4 h of non-active phase. In contrast, early-morning trained littermates, slowing down from their active phase, exhibited better performance and used goal-directed strategies and non-search navigation described for normal aging. The novel multitarget anticholinesterasic compound AVCRI104P3 (0.6 molkg-1, 21 days i.p.) exerted stronger cognitive benefits than its in vitro equipotent dose of AChEI huprine X (0.12 molkg-1, 21 days i.p.). Both compounds showed streamlined drug effectiveness, independently of the schedule. Their effects on anxiety-like behaviors were moderate. The results open a question of how time schedules modulate the capacity to respond to task demands and to assess/elucidate new drug effectiveness. Keywords: sleep; circadian activity; protocols; behavior; drug assessment; aging; Alzheimer’s disease; BPSD; AChEI; multitarget compounds; disease-modifying mechanisms Author: Lydia Giménez-Llort, Mikel Santana-Santana, Míriam Ratia, Belén Pérez, Pelayo Camps, Diego Muñoz-Torrero, Albert Badia and Maria Victòria Clos Creator: LaTeX with hyperref Producer: pdfTeX-1.40.21 CreationDate: Sat Mar 27 10:55:34 2021 CET ModDate: Fri Apr 9 05:01:16 2021 CEST Custom Metadata: no Metadata Stream: no Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 12 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 790960 bytes Optimized: no PDF version: 1.7 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- MWHIBA+VnURWPalladioL Type 1 Custom yes yes no 10 0 VVSYYB+EURM10 Type 1 Builtin yes yes no 15 0 UFLZJY+URWPalladioL-Ital Type 1 Custom yes yes no 19 0 PNHESM+URWPalladioL-Bold Type 1 Custom yes yes no 24 0 VTMOCI+URWPalladioL-Roma Type 1 Custom yes yes no 28 0 OJYQXC+CMSY10 Type 1 Builtin yes yes no 32 0 BFQLJI+VnURWPalladioL-Bold Type 1 Custom yes yes no 36 0 SLUQMQ+TimesNewRomanPS-BoldItalicMT Type 1C WinAnsi yes yes no 44 0 MCBCCI+SourceSansRoman-Regular Type 1C Custom yes yes no 66 0 MCBCCM+SourceSansRoman.613wght Type 1C Custom yes yes no 70 0 MCBCCO+SourceSansRoman-Bold Type 1C Custom yes yes no 74 0 XIRVNA+EURB10 Type 1 Builtin yes yes no 95 0 URYLRZ+URWPalladioL-BoldItal Type 1 Custom yes yes no 99 0 BOSUAG+PalatinoLinotype-Italic TrueType WinAnsi yes yes yes 114 0 SVIXEY+PalatinoLinotype-Bold TrueType WinAnsi yes yes yes 118 0 GLHDSW+PalatinoLinotype-Roman TrueType WinAnsi yes yes yes 122 0 BOSUAG+PalatinoLinotype-Italic TrueType WinAnsi yes yes yes 133 0 SVIXEY+PalatinoLinotype-Bold TrueType WinAnsi yes yes yes 137 0 GLHDSW+PalatinoLinotype-Roman TrueType WinAnsi yes yes yes 141 0 Jhove (Rel. 1.28.0, 2023-05-18) Date: 2024-10-02 03:51:42 CEST RepresentationInformation: brainsci_a2021v11n4p426.pdf ReportingModule: PDF-hul, Rel. 1.12.4 (2023-03-16) LastModified: 2023-03-31 11:50:52 CEST Size: 790960 Format: PDF Version: 1.7 Status: Well-Formed and valid SignatureMatches: PDF-hul MIMEtype: application/pdf PDFMetadata: Objects: 333 FreeObjects: 1 IncrementalUpdates: 0 DocumentCatalog: PageLayout: SinglePage PageMode: UseNone Outlines: Item: Title: Introduction Destination: section.1 Item: Title: Materials and Methods Destination: section.2 Children: Item: Title: Drug Treatment Destination: subsection.2.1 Item: Title: Side Effects and NPS-Like Behaviors Destination: subsection.2.2 Item: Title: Behavioral Assessment Destination: subsection.2.3 Children: Item: Title: Exploratory Activity and Anxiety-Like Behaviors Destination: subsubsection.2.3.1 Item: Title: Morris Water Maze (MWM) Destination: subsubsection.2.3.2 Item: Title: Statistics Destination: subsection.2.4 Item: Title: Results Destination: section.3 Children: Item: Title: Presence of AD-Phenotype before Treatments Destination: subsection.3.1 Item: Title: Absence of Side Effects of AVCRIP104P3 and Huprine X Destination: subsection.3.2 Item: Title: Training Schedule Affected Learning and Memory Destination: subsection.3.3 Item: Title: Training Schedule Affected Memory Retrieval Destination: subsection.3.4 Item: Title: Discussion Destination: section.4 Item: Title: References Destination: section.4 Info: Title: Clock/Sleep-Dependent Learning and Memory in Male 3xTg-AD Mice at Advanced Disease Stages and Extrinsic Effects of Huprine X and the Novel Multitarget Agent AVCRI104P3 Author: Lydia Giménez-Llort, Mikel Santana-Santana, Míriam Ratia, Belén Pérez, Pelayo Camps, Diego Muñoz-Torrero, Albert Badia and Maria Victòria Clos Subject: A new hypothesis highlights sleep-dependent learning/memory consolidation and regards the sleep-wake cycle as a modulator of -amyloid and tau Alzheimer’s disease (AD) pathologies. Sundowning behavior is a common neuropsychiatric symptom (NPS) associated with dementia. Sleep fragmentation resulting from disturbances in sleep and circadian rhythms in AD may have important consequences on memory processes and exacerbate the other AD-NPS. The present work studied the effect of training time schedules on 12-month-old male 3xTg-AD mice modeling advanced disease stages. Their performance in two paradigms of the Morris water maze for spatial-reference and visual-perceptual learning and memory were found impaired at midday, after 4 h of non-active phase. In contrast, early-morning trained littermates, slowing down from their active phase, exhibited better performance and used goal-directed strategies and non-search navigation described for normal aging. The novel multitarget anticholinesterasic compound AVCRI104P3 (0.6 molkg-1, 21 days i.p.) exerted stronger cognitive benefits than its in vitro equipotent dose of AChEI huprine X (0.12 molkg-1, 21 days i.p.). Both compounds showed streamlined drug effectiveness, independently of the schedule. Their effects on anxiety-like behaviors were moderate. The results open a question of how time schedules modulate the capacity to respond to task demands and to assess/elucidate new drug effectiveness. 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