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Clock/Sleep-Dependent Learning and Memory in Male 3Xtg-AD Mice At brain sciences Article 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 Lydia Giménez-Llort 1,* , Mikel Santana-Santana 1,Míriam Ratia 2, Belén Pérez 2 , Pelayo Camps 3 , Diego Muñoz-Torrero 3 , Albert Badia 2 and Maria Victòria Clos 2 1 Department of Psychiatry and Forensic Medicine & Institut de Neurociències, Universitat Autònoma de Barcelona, E-08193 Barcelona, Spain; [email protected] 2 Department of Pharmacology, Therapeutics and Toxicology & Institut de Neurociències, Universitat Autònoma de Barcelona, E-08193 Barcelona, Spain; [email protected] (M.R.); [email protected] (B.P.); [email protected] (A.B.); [email protected] (M.V.C.) 3 CSIC Associated Unit, Laboratory of Medicinal Chemistry, Faculty of Pharmacy and Food Sciences, Institute of Biomedicine (IBUB), University of Barcelona, E-08028 Barcelona, Spain; [email protected] (P.C.); [email protected] (D.M.-T.) * Correspondence: [email protected]; Tel.: +34-93-5812378 Abstract: A new hypothesis highlights sleep-dependent learning/memory consolidation and regards the sleep-wake cycle as a modulator of β-amyloid and tau Alzheimer’s disease (AD) pathologies. Citation: Giménez-Llort, L.; Sundowning behavior is a common neuropsychiatric symptom (NPS) associated with dementia. Santana-Santana, M.; Ratia, M.; Pérez, Sleep fragmentation resulting from disturbances in sleep and circadian rhythms in AD may have B.; Camps, P.; Muñoz-Torrero, D.; important consequences on memory processes and exacerbate the other AD-NPS. The present Badia, A.; Clos, M.V. work studied the effect of training time schedules on 12-month-old male 3xTg-AD mice modeling Clock/Sleep-Dependent Learning advanced disease stages. Their performance in two paradigms of the Morris water maze for spatial- and Memory in Male 3xTg-AD Mice reference and visual-perceptual learning and memory were found impaired at midday, after 4 h of at Advanced Disease Stages and Extrinsic Effects of Huprine X and the non-active phase. In contrast, early-morning trained littermates, slowing down from their active Novel Multitarget Agent phase, exhibited better performance and used goal-directed strategies and non-search navigation AVCRI104P3. Brain Sci. 2021, 11, 426. described for normal aging. The novel multitarget anticholinesterasic compound AVCRI104P3 −1 https://doi.org/10.3390/brainsci (0.6 µmol·kg , 21 days i.p.) exerted stronger cognitive benefits than its in vitro equipotent dose 11040426 of AChEI huprine X (0.12 µmol·kg−1, 21 days i.p.). Both compounds showed streamlined drug effectiveness, independently of the schedule. Their effects on anxiety-like behaviors were moderate. Academic Editor: Luigi De Gennaro The results open a question of how time schedules modulate the capacity to respond to task demands and to assess/elucidate new drug effectiveness. Received: 29 January 2021 Accepted: 23 March 2021 Keywords: sleep; circadian activity; protocols; behavior; drug assessment; aging; Alzheimer’s Published: 26 March 2021 disease; BPSD; AChEI; multitarget compounds; disease-modifying mechanisms Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- 1. Introduction iations. The new hypothesis on the physiological function of sleep highlights sleep-depending learning and memory consolidation [1] and associated plasticity, as well as their strong implications on skill performance involved in many daily life activities [2]. Similarly, visual discrimination learning requires sleep after training [3], and early sleep triggers memory Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. for early visual discrimination skills [4]. Through the life cycle, whereas adequate sleep This article is an open access article in childhood and beyond is important for development [5,6], new evidence supports the distributed under the terms and relevance of the sleep-wake cycle in aging but also since early pre-symptomatic stages of conditions of the Creative Commons Alzheimer’s disease (AD) [7–10]. At the pathological level, the sleep-awake cycle controls Attribution (CC BY) license (https:// Aβ levels [11], to the extent that it is regarded as a modulator of AD pathogenesis, while creativecommons.org/licenses/by/ sleep disturbances are proposed as a predictor of dementia and Aβ pathology [12]. The 4.0/). most recent of these outstanding works show that the interstitial fluid and cerebrospinal Brain Sci. 2021, 11, 426. https://doi.org/10.3390/brainsci11040426 https://www.mdpi.com/journal/brainsci Brain Sci. 2021, 11, 426 2 of 12 levels of tau are also regulated by the sleep-wake cycle. Indeed, sleep deprivation increases the levels of tau and the spread of tau pathology [13]. These frequent sleep disturbances, with awakenings during the night and increased proclivity to sleep during daytime [14–16], are referred to as sundowning behavior, one of the most common co-morbid clinical manifestations associated with AD. Sleep fragmentation as a result of disturbances in sleep and circadian rhythms in AD may have not only important consequences on memory processes [5,17], but it may also exacerbate the other neuropsychiatric symptoms (NPS) associated with dementia [18], since the impact of sleep in mood disorders, such as anxiety and depression, is also well known and vice versa. At the translational level, among the different animal models for AD, homozygous 3xTg-AD mice created by LaFerla [19] show a noticeable NPS-like profile, also mimicking diurnal rhythm disturbances [20–25]. These animals are sensitive to sleep restriction [26] and display a severe impairment of the functioning of the clock gene pathway [27,28], with males exhibiting worse circadian rhythm disruptions than females [28]. We have recently shown that they have altered slow and fast neocortical oscillations [29]. Therefore, this animal model is useful to investigate whether the alterations of their circadian activity may modify their cognitive performance and the sensitivity of behavioral tests aimed to assess the therapeutic efficacy of new drugs. Except for those studies of circadian activity, research in the rodents’ natural active dark cycle or using inverted cycle has scarcely been addressed, mostly due to practical reasons. To avoid influences of the time of the day, most behavioral research is usually done during the morning, their non-active circadian period [20]. However, on several occasions, we noticed that cognitive performance of 3xTg-AD mice, but not that of WT mice [30], was sensitive to the time schedules used for training and testing. We hypothesized that early morning was not optimal to observe their impaired cognitive profile in the Morris water maze. On the other hand, the complexity of AD has led to drug development of multitar- get compounds concurrently interfering with different mechanisms, aiming to provide symptomatic relief and exerting disease-modifying benefits [31,32]. In this sense, our multidisciplinary research consortium has synthesized and evaluated the pharmacolog- ical profile of new AChEIs, tacrine-huperzine A hybrids, and their derivatives of po- tential interest for the treatment of AD [33]. Among these, huprines and derivatives have been successfully characterized. Huprine X (HX), a reversible AChE inhibitor hybrid of tacrine and huperzine A, affects the amyloidogenic process in vitro and the AD-related neuropathology in vivo in mice models of AD [34–42]. More recently, we have shown that a new family of donepezil-huprine heterodimers that display a dual site binding within AChE has been synthesized, and these compounds have shown inhibitory a highly potent and selective inhibitory action on AChE and BChE. More- over, they inhibit AChE-induced and self-induced β-amyloid (Aβ) aggregation and β- secretase (BACE-1), and these new drugs are able to cross the blood-brain barrier. Among them, AVCRI104P3 ((±)-3-chloro-12-[(3-{4-[(5,6-dimethoxyindan-2-yl)methyl]piperidin-1- yl}propyl)amino]-6,7,10,11-tetrahydro-9-methyl-7,11-methanocycloocta[b]quinoline) has shown an interesting pharmacological profile. It is a potent in vitro inhibitor of human AChE and moderately potent inhibitor of human BChE, AChE-induced, and self-induced Aβ aggregation, and BACE-1 [30]. Therefore, in the present work, we investigated the impact of early morning and mid- day training schedules on the cognitive performance of male 3xTg-AD mice at 12 months of age, modeling neuropathological advanced disease stages [43]. Since 3xTg-AD mice exhibit circadian rhythm disturbances with sex preference, males were used for the present work purposes [28]. The hypothesis also considered the effect of chronic treatment with anti- Alzheimer compounds [44,45]. AVCRI104P3 is a novel multitarget compound endowed with potent in vitro inhibitory activity of human AChE and moderately potent inhibitory activity of human butyrylcholinesterase (BChE), AChE-induced and self-induced Aβ aggre- gation, and BACE-1, which has shown behavioral [30,46] and neuroprotective effects [47] Brain Sci. 2021, 11, 426 3 of 12 in middle-aged mice. For the sake of comparison, we used HX, a potent reversible AChE in- hibitor that affects the amyloidogenic process in vitro, and the AD-related neuropathology and behavior in mice models of AD [47]. 2. Materials and Methods Forty-two 12-month-old homozygous male mice from the Spanish colony of 3xTg-AD mice genetically engineered at the University
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